WorldWideScience

Sample records for m2 mtdna lineage

  1. The earliest settlers' antiquity and evolutionary history of Indian populations: evidence from M2 mtDNA lineage

    Kotal M

    2008-08-01

    Full Text Available Abstract Background The "out of Africa" model postulating single "southern route" dispersal posits arrival of "Anatomically Modern Human" to Indian subcontinent around 66–70 thousand years before present (kyBP. However the contributions and legacy of these earliest settlers in contemporary Indian populations, owing to the complex past population dynamics and later migrations has been an issue of controversy. The high frequency of mitochondrial lineage "M2" consistent with its greater age and distribution suggests that it may represent the phylogenetic signature of earliest settlers. Accordingly, we attempted to re-evaluate the impact and contribution of earliest settlers in shaping the genetic diversity and structure of contemporary Indian populations; using our newly sequenced 72 and 4 published complete mitochondrial genomes of this lineage. Results The M2 lineage, harbouring two deep rooting subclades M2a and M2b encompasses approximately one tenth of the mtDNA pool of studied tribes. The phylogeographic spread and diversity indices of M2 and its subclades among the tribes of different geographic regions and linguistic phyla were investigated in detail. Further the reconstructed demographic history of M2 lineage as a surrogate of earliest settlers' component revealed that the demographic events with pronounced regional variations had played pivotal role in shaping the complex net of populations phylogenetic relationship in Indian subcontinent. Conclusion Our results suggest that tribes of southern and eastern region along with Dravidian and Austro-Asiatic speakers of central India are the modern representatives of earliest settlers of subcontinent. The Last Glacial Maximum aridity and post LGM population growth mechanised some sort of homogeneity and redistribution of earliest settlers' component in India. The demic diffusion of agriculture and associated technologies around 3 kyBP, which might have marginalized hunter-gatherer, is

  2. mtDNA variation in the Yanomami: evidence for additional New World founding lineages.

    Easton, R D; Merriwether, D A; Crews, D E; Ferrell, R E

    1996-07-01

    Native Americans have been classified into four founding haplogroups with as many as seven founding lineages based on mtDNA RFLPs and DNA sequence data. mtDNA analysis was completed for 83 Yanomami from eight villages in the Surucucu and Catrimani Plateau regions of Roraima in northwestern Brazil. Samples were typed for 15 polymorphic mtDNA sites (14 RFLP sites and 1 deletion site), and a subset was sequenced for both hypervariable regions of the mitochondrial D-loop. Substantial mitochondrial diversity was detected among the Yanomami, five of seven accepted founding haplotypes and three others were observed. Of the 83 samples, 4 (4.8%) were lineage B1, 1 (1.2%) was lineage B2, 31 (37.4%) were lineage C1, 29 (34.9%) were lineage C2, 2 (2.4%) were lineage D1, 6 (7.2%) were lineage D2, 7 (8.4%) were a haplotype we designated "X6," and 3 (3.6%) were a haplotype we designated "X7." Sequence analysis found 43 haplotypes in 50 samples. B2, X6, and X7 are previously unrecognized mitochondrial founding lineage types of Native Americans. The widespread distribution of these haplotypes in the New World and Asia provides support for declaring these lineages to be New World founding types.

  3. Three reciprocally monophyletic mtDNA lineages elucidate the taxonomic status of Grant's gazelles

    Lorenzen, Eline Deidre; Arctander, Peter; Siegismund, Hans Redlef

    2008-01-01

    are discussed in reference to the four currently recognised subspecies. We suggest Grant's gazelles be raised to the superspecies Nanger (granti) comprising three taxonomic units corresponding to the three mtDNA lineages. There was no evidence of gene flow between the notata and granti lineages, despite...... their geographic proximity, suggesting reproductive isolation. These constitute evolutionary significant units within the adaptive evolutionary framework. Due to its restricted geographic distribution and genetic and morphological distinctiveness, we suggest the petersii lineage be raised to the species Nanger...

  4. Forensic and phylogeographic characterisation of mtDNA lineages from Somalia

    Mikkelsen, Martin; Fendt, Liane; Röck, Alexander W.

    2012-01-01

    Somali individuals to enrich the severely underrepresented African mtDNA pool. The majority (60.5 %) of the haplotypes were of sub-Saharan origin with L0a1d, L2a1h and L3f being the most frequently observed haplogroups. This is in sharp contrast to previous data reported from the Y-chromosome, where only...... about 5 % of the observed haplogroups were of sub-Saharan provenance. We compared the genetic distances based on population pairwise F (st) values between 11 published East, Central and North African as well as western Asian populations and the Somali sequences and displayed them in a multi...

  5. Forensic and phylogeographic characterisation of mtDNA lineages from Somalia.

    Mikkelsen, Martin; Fendt, Liane; Röck, Alexander W; Zimmermann, Bettina; Rockenbauer, Eszter; Hansen, Anders J; Parson, Walther; Morling, Niels

    2012-07-01

    The African mitochondrial (mt) phylogeny is coarsely resolved but the majority of population data generated so far is limited to the analysis of the first hypervariable segment (HVS-1) of the control region (CR). Therefore, this study aimed on the investigation of the entire CR of 190 unrelated Somali individuals to enrich the severely underrepresented African mtDNA pool. The majority (60.5 %) of the haplotypes were of sub-Saharan origin with L0a1d, L2a1h and L3f being the most frequently observed haplogroups. This is in sharp contrast to previous data reported from the Y-chromosome, where only about 5 % of the observed haplogroups were of sub-Saharan provenance. We compared the genetic distances based on population pairwise F (st) values between 11 published East, Central and North African as well as western Asian populations and the Somali sequences and displayed them in a multi-dimensional scaling plot. Genetic proximity evidenced by clustering roughly reflected the relative geographic location of the populations. The sequences will be included in the EMPOP database ( www.empop.org ) under accession number EMP00397 upon publication (Parson and Dür Forensic Sci Int Genet 1:88-92, 2007).

  6. MtDNA diversity and genetic lineages of four cattle breeds in Malaysia

    Somarny, W.W.M.Z.

    2015-06-01

    Full Text Available There is lack of comprehensive studies on the genetic diversity or phylogenetic analysis of beef cattle breeds in Malaysia. In this study, the partial sequence of mitochondrial DNA cytochrome b gene (cyt b was analysed from blood samples obtained from 25 Chinese Yellow Cattle (CY, 33 Kedah-Kelantan (KK, 32 Brakmas (BM and 30 Bali cattle (BC. Based on these 120 individuals, 19 mtDNA haplotypes (GenBank Accession No. GU67340 - GU67358 were identified by polymorphisms at 31 sites. Hap19 was predominant in BM (78%, KK (82% and CY (100% indicating similar origin or gene flow between breeds whilst Hap11 was exclusively for BC. However, there were only two nucleotide differences between these two major haplotypes. These results can be interpreted that these representative cattle in these haplotypes are admixtures of B. indicus or B. javanicus through maternal ancestry. Conversely, the CY cattle investigated are highly inbred where no variation could be observed in the short segment investigated.

  7. Clustering of Caucasian Leber hereditary optic neuropathy patients containing the 11778 or 14484 mutations on an mtDNA lineage

    Brown, M.D.; Sun, F.; Wallace, D.C. [Emory Univ. School of Medicine, Atlanta, GA (United States)

    1997-02-01

    Leber hereditary optic neuropathy (LHON) is a type of blindness caused by mtDNA mutations. Three LHON mtDNA mutations at nucleotide positions 3460, 11778, and 14484 are specific for LHON and account for 90% of worldwide cases and are thus designated as {open_quotes}primary{close_quotes} LHON mutations. Fifteen other {open_quotes}secondary{close_quotes} LHON mtDNA mutations have been identified, but their pathogenicity is unclear. mtDNA haplotype and phylogenetic analysis of the primary LHON mutations in North American Caucasian patients and controls has shown that, unlike the 3460 and 11778 mutations, which are distributed throughout the European-derived (Caucasian) mtDNA phylogeny, patients containing the 14484 mutation tended to be associated with European mtDNA haplotype J. To investigate this apparent clustering, we performed {chi}{sup 2}-based statistical analyses to compare the distribution of LHON patients on the Caucasian phylogenetic tree. Our results indicate that, unlike the 3460 and 11778 mutations, the 14484 mutation was not distributed on the phylogeny in proportion to the frequencies of the major Caucasian mtDNA haplogroups found in North America. The 14484 mutation was next shown to occur on the haplogroup J background more frequently that expected, consistent with the observation that {approximately}75% of worldwide 14484-positive LHON patients occur in association with haplogroup J. The 11778 mutation also exhibited a moderate clustering on haplogroup J. These observations were supported by statistical analysis using all available mutation frequencies reported in the literature. This paper thus illustrates the potential importance of genetic background in certain mtDNA-based diseases, speculates on a pathogenic role for a subset of LHON secondary mutations and their interaction with primary mutations, and provides support for a polygenic model for LHON expression in some cases. 18 refs., 3 tabs.

  8. West Eurasian mtDNA lineages in India: an insight into the spread of the Dravidian language and the origins of the caste system.

    Palanichamy, Malliya Gounder; Mitra, Bikash; Zhang, Cai-Ling; Debnath, Monojit; Li, Gui-Mei; Wang, Hua-Wei; Agrawal, Suraksha; Chaudhuri, Tapas Kumar; Zhang, Ya-Ping

    2015-06-01

    There is no indication from the previous mtDNA studies that west Eurasian-specific subclades have evolved within India and played a role in the spread of languages and the origins of the caste system. To address these issues, we have screened 14,198 individuals (4208 from this study) and analyzed 112 mitogenomes (41 new sequences) to trace west Eurasian maternal ancestry. This has led to the identification of two autochthonous subhaplogroups--HV14a1 and U1a1a4, which are likely to have originated in the Dravidian-speaking populations approximately 10.5-17.9 thousand years ago (kya). The carriers of these maternal lineages might have settled in South India during the time of the spread of the Dravidian language. In addition to this, we have identified several subsets of autochthonous U7 lineages, including U7a1, U7a2b, U7a3, U7a6, U7a7, and U7c, which seem to have originated particularly in the higher-ranked caste populations in relatively recent times (2.6-8.0 kya with an average of 5.7 kya). These lineages have provided crucial clues to the differentiation of the caste system that has occurred during the recent past and possibly, this might have been influenced by the Indo-Aryan migration. The remaining west Eurasian lineages observed in the higher-ranked caste groups, like the Brahmins, were found to cluster with populations who possibly arrived from west Asia during more recent times.

  9. Complete mtDNA genomes of Filipino ethnolinguistic groups: a melting pot of recent and ancient lineages in the Asia-Pacific region

    Delfin, Frederick; Min-Shan Ko, Albert; Li, Mingkun; Gunnarsdóttir, Ellen D; Tabbada, Kristina A; Salvador, Jazelyn M; Calacal, Gayvelline C; Sagum, Minerva S; Datar, Francisco A; Padilla, Sabino G; De Ungria, Maria Corazon A; Stoneking, Mark

    2014-01-01

    The Philippines is a strategic point in the Asia-Pacific region for the study of human diversity, history and origins, as it is a cross-road for human migrations and consequently exhibits enormous ethnolinguistic diversity. Following on a previous in-depth study of Y-chromosome variation, here we provide new insights into the maternal genetic history of Filipino ethnolinguistic groups by surveying complete mitochondrial DNA (mtDNA) genomes from a total of 14 groups (11 groups in this study and 3 groups previously published) including previously published mtDNA hypervariable segment (HVS) data from Filipino regional center groups. Comparison of HVS data indicate genetic differences between ethnolinguistic and regional center groups. The complete mtDNA genomes of 14 ethnolinguistic groups reveal genetic aspects consistent with the Y-chromosome, namely: diversity and heterogeneity of groups, no support for a simple dichotomy between Negrito and non-Negrito groups, and different genetic affinities with Asia-Pacific groups that are both ancient and recent. Although some mtDNA haplogroups can be associated with the Austronesian expansion, there are others that associate with South Asia, Near Oceania and Australia that are consistent with a southern migration route for ethnolinguistic group ancestors into the Asia-Pacific, with a timeline that overlaps with the initial colonization of the Asia-Pacific region, the initial colonization of the Philippines and a possible separate post-colonization migration into the Philippine archipelago. PMID:23756438

  10. Regional Differences in the Distribution of the Sub-Saharan, West Eurasian, and South Asian mtDNA Lineages in Yemen

    Černý, Viktor; Mulligan, C. J.; Rídl, J.; Žaloudková, M.; Edens, C. M.; Hájek, Martin; Pereira, L.

    2008-01-01

    Roč. 136, č. 2 (2008), s. 128-137 ISSN 0002-9483 R&D Projects: GA MŠk ME 917 Institutional research plan: CEZ:AV0Z80020508 Keywords : mtDNA diversity * regional sampling * population distances * phylogeography Subject RIV: AC - Archeology, Anthropology, Ethnology Impact factor: 2.353, year: 2008 http://www3.interscience.wiley.com/journal/117899911/abstract

  11. Two distinct mtDNA lineages of the blue crab reveal large-scale population structure in its native Atlantic distribution

    Alaniz Rodrigues, Marcos; Dumont, Luiz Felipe Cestari; dos Santos, Cléverson Rannieri Meira; D'Incao, Fernando; Weiss, Steven; Froufe, Elsa

    2017-10-01

    For the first time, a molecular approach was used to evaluate the phylogenetic structure of the disjunct native American distribution of the blue crab Callinectes sapidus. Population structure was investigated by sequencing 648bp of the Cytochrome oxidase subunit 1 (COI), in a total of 138 sequences stemming from individual samples from both the northern and southern hemispheres of the Western Atlantic distribution of the species. A Bayesian approach was used to construct a phylogenetic tree for all samples, and a 95% confidence parsimony network was created to depict the relationship among haplotypes. Results revealed two highly distinct lineages, one containing all samples from the United States and some from Brazil (lineage 1) and the second restricted to Brazil (lineage 2). In addition, gene flow (at least for females) was detected among estuaries at local scales and there is evidence for shared haplotypes in the south. Furthermore, the findings of this investigation support the contemporary introduction of haplotypes that have apparently spread from the south to the north Atlantic.

  12. Evidence of at least two evolutionary lineages in Melipona subnitida (Apidae, Meliponini) suggested by mtDNA variability and geometric morphometrics of forewings

    Bonatti, Vanessa; Simões, Zilá Luz Paulino; Franco, Fernando Faria; Francoy, Tiago Mauricio

    2014-01-01

    Melipona subnitida, a tropical stingless bee, is an endemic species of the Brazilian northeast and exhibits great potential for honey and pollen production in addition to its role as one of the main pollinators of the Caatinga biome. To understand the genetic structure and better assist in the conservation of this species, we characterized the population variability of M. subnitida using geometric morphometrics of the forewing and cytochrome c oxidase I gene fragment sequencing. We collected workers from six localities in the northernmost distribution. Both methodologies indicated that the variability among the sampled populations is related both to the environment in which samples were collected and the geographical distance between the sampling sites, indicating that differentiation among the populations is due to the existence of at least evolutionary lineages. Molecular clock data suggest that this differentiation may have begun in the middle Pleistocene, approximately 396 kya. The conservation of all evolutionary lineages is important since they can present differential resistance to environmental changes, as resistance to drought and diseases.

  13. The M2 Channel

    Santner, Paul

    Drug resistance of Influenza A against antivirals is an increasing problem. No effective Influenza A drugs targeting the crucial viral protein, the proton transporter M2 are available anymore due to widespread resistance. Thanks to research efforts elucidating M2 protein structure, function and i...... resistance escape routes from drug inhibition. We thereby were hopefully able to provide a platform for the large-scale evaluation of M2 channel activity, inhibitors and resistance....

  14. Founding Amerindian mitochondrial DNA lineages in ancient Maya from Xcaret, Quintana Roo.

    González-Oliver, A; Márquez-Morfín, L; Jiménez, J C; Torre-Blanco, A

    2001-11-01

    Ancient DNA from the bone remains of 25 out of 28 pre-Columbian individuals from the Late Classic-Postclassic Maya site of Xcaret, Quintana Roo, was recovered, and mitochondrial DNA (mtDNA) was amplified by using the polymerase chain reaction. The presence of the four founding Amerindian mtDNA lineages was investigated by restriction analysis and by direct sequencing in selected individuals. The mtDNA lineages A, B, and C were found in this population. Eighty-four percent of the individuals were lineage A, whereas lineages B and C were present at low frequencies, 4% and 8%, respectively. Lineage D was absent from our sample. One individual did not possess any of the four lineages. Six skeletons out of 7 dated from the Late Classic period were haplotype A, whereas 11 skeletons out of 16 dated from the Postclassic period were also haplotype A. The distribution of mtDNA lineages in the Xcaret population contrasts sharply with that found in ancient Maya from Copán, which lack lineages A and B. On the other hand, our results resemble more closely the frequencies of mtDNA lineages found in contemporary Maya from the Yucatán Peninsula and in other Native American contemporary populations of Mesoamerican origin. Copyright 2001 Wiley-Liss, Inc.

  15. Heterotic M2-branes

    Neil Lambert

    2015-10-01

    Full Text Available We construct the action for N M2-branes on S1/Z2. The resulting theory has a gauge anomaly but this can be cancelled if the two fixed point planes each support 8 chiral Fermions in the fundamental of U(N. Taking the low energy limit leads to the worldsheet theory of N free heterotic strings whose quantization induces an E8 spacetime gauge symmetry on each fixed point plane. Thus this paper presents a non-abelian worldvolume analogue of the classic Hořava–Witten analysis.

  16. Reduced Mtdna Diversity in the Ngobe Amerinds of Panama

    Kolman, C. J.; Bermingham, E.; Cooke, R.; Ward, R. H.; Arias, T. D.; Guionneau-Sinclair, F.

    1995-01-01

    Mitochondrial DNA (mtDNA) haplotype diversity was determined for 46 Ngobe Amerinds sampled widely across their geographic range in western Panama. The Ngobe data were compared with mtDNA control region I sequences from two additional Amerind groups located at the northern and southern extremes of Amerind distribution, the Nuu-Chah-Nulth of the Pacific Northwest and the Chilean Mapuche and from one Na-Dene group, the Haida of the Pacific Northwest. The Ngobe exhibit the lowest mtDNA control region sequence diversity yet reported for an Amerind group. Moreover, they carry only two of the four Amerind founding lineages first described by Wallace and coworkers. We posit that the Ngobe passed through a population bottleneck caused by ethnogenesis from a small founding population and/or European conquest and colonization. Dating of the Ngobe population expansion using the HARPENDING et al. approach to the analysis of pairwise genetic differences indicates a Ngobe expansion at roughly 6800 years before present (range: 1850-14,000 years before present), a date more consistent with a bottleneck at Chibcha ethnogenesis than a conquest-based event. PMID:7635293

  17. Homogeneous M2 duals

    Figueroa-O’Farrill, José; Ungureanu, Mara

    2016-01-01

    Motivated by the search for new gravity duals to M2 branes with N>4 supersymmetry — equivalently, M-theory backgrounds with Killing superalgebra osp(N|4) for N>4 — we classify (except for a small gap) homogeneous M-theory backgrounds with symmetry Lie algebra so(n)⊕so(3,2) for n=5,6,7. We find that there are no new backgrounds with n=6,7 but we do find a number of new (to us) backgrounds with n=5. All backgrounds are metrically products of the form AdS 4 ×P 7 , with P riemannian and homogeneous under the action of SO(5), or S 4 ×Q 7 with Q lorentzian and homogeneous under the action of SO(3,2). At least one of the new backgrounds is supersymmetric (albeit with only N=2) and we show that it can be constructed from a supersymmetric Freund-Rubin background via a Wick rotation. Two of the new backgrounds have only been approximated numerically.

  18. Homogeneous M2 duals

    Figueroa-O’Farrill, José [School of Mathematics and Maxwell Institute for Mathematical Sciences,The University of Edinburgh,James Clerk Maxwell Building, The King’s Buildings, Peter Guthrie Tait Road,Edinburgh EH9 3FD, Scotland (United Kingdom); Ungureanu, Mara [Humboldt-Universität zu Berlin, Institut für Mathematik,Unter den Linden 6, 10099 Berlin (Germany)

    2016-01-25

    Motivated by the search for new gravity duals to M2 branes with N>4 supersymmetry — equivalently, M-theory backgrounds with Killing superalgebra osp(N|4) for N>4 — we classify (except for a small gap) homogeneous M-theory backgrounds with symmetry Lie algebra so(n)⊕so(3,2) for n=5,6,7. We find that there are no new backgrounds with n=6,7 but we do find a number of new (to us) backgrounds with n=5. All backgrounds are metrically products of the form AdS{sub 4}×P{sup 7}, with P riemannian and homogeneous under the action of SO(5), or S{sup 4}×Q{sup 7} with Q lorentzian and homogeneous under the action of SO(3,2). At least one of the new backgrounds is supersymmetric (albeit with only N=2) and we show that it can be constructed from a supersymmetric Freund-Rubin background via a Wick rotation. Two of the new backgrounds have only been approximated numerically.

  19. Melanesian mtDNA complexity.

    Jonathan S Friedlaender

    Full Text Available Melanesian populations are known for their diversity, but it has been hard to grasp the pattern of the variation or its underlying dynamic. Using 1,223 mitochondrial DNA (mtDNA sequences from hypervariable regions 1 and 2 (HVR1 and HVR2 from 32 populations, we found the among-group variation is structured by island, island size, and also by language affiliation. The more isolated inland Papuan-speaking groups on the largest islands have the greatest distinctions, while shore dwelling populations are considerably less diverse (at the same time, within-group haplotype diversity is less in the most isolated groups. Persistent differences between shore and inland groups in effective population sizes and marital migration rates probably cause these differences. We also add 16 whole sequences to the Melanesian mtDNA phylogenies. We identify the likely origins of a number of the haplogroups and ancient branches in specific islands, point to some ancient mtDNA connections between Near Oceania and Australia, and show additional Holocene connections between Island Southeast Asia/Taiwan and Island Melanesia with branches of haplogroup E. Coalescence estimates based on synonymous transitions in the coding region suggest an initial settlement and expansion in the region at approximately 30-50,000 years before present (YBP, and a second important expansion from Island Southeast Asia/Taiwan during the interval approximately 3,500-8,000 YBP. However, there are some important variance components in molecular dating that have been overlooked, and the specific nature of ancestral (maternal Austronesian influence in this region remains unresolved.

  20. Mito-nuclear discord in six congeneric lineages of Holarctic ducks (genus Anas).

    Peters, Jeffrey L; Winker, Kevin; Millam, Kendra C; Lavretsky, Philip; Kulikova, Irina; Wilson, Robert E; Zhuravlev, Yuri N; McCracken, Kevin G

    2014-06-01

    Many species have Holarctic distributions that extend across Europe, Asia and North America. Most genetics research on these species has examined only mitochondrial (mt) DNA, which has revealed wide variance in divergence between Old World (OW) and New World (NW) populations, ranging from shallow, unstructured genealogies to deeply divergent lineages. In this study, we sequenced 20 nuclear introns to test for concordant patterns of OW-NW differentiation between mtDNA and nuclear (nu) DNA for six lineages of Holarctic ducks (genus Anas). Genetic differentiation for both marker types varied widely among these lineages (idiosyncratic population histories), but mtDNA and nuDNA divergence within lineages was not significantly correlated. Moreover, compared with the association between mtDNA and nuDNA divergence observed among different species, OW-NW nuDNA differentiation was generally lower than mtDNA divergence, at least for lineages with deeply divergent mtDNA. Furthermore, coalescent estimates indicated significantly higher rates of gene flow for nuDNA than mtDNA for four of the six lineages. Thus, Holarctic ducks show prominent mito-nuclear discord between OW and NW populations, and we reject differences in sorting rates as the sole cause of the within-species discord. Male-mediated intercontinental gene flow is likely a leading contributor to this discord, although selection could also cause increased mtDNA divergence relative to weak nuDNA differentiation. The population genetics of these ducks contribute to growing evidence that mtDNA can be an unreliable indicator of stage of speciation and that more holistic approaches are needed for species delimitation. © 2014 John Wiley & Sons Ltd.

  1. Genetic characterization of uniparental lineages in populations from Southwest Iberia with past malaria endemicity

    Pereira, Vania; Gomes, Verónica; Amorim, António

    2010-01-01

    then compared with data from other Portuguese and non-Portuguese populations. In Coruche, the genetic profile was similar to the profile usually found in Portugal. In Alcacer do Sal, the frequency of sub-Saharan mtDNA L lineages was the highest ever reported (22%) in Europe. In Pias, mtDNA diversity revealed...... influence might be traced to ancient contacts with Greeks, Phoenicians, and Carthaginians, who established important trading networks in southern Iberia....

  2. Phenotypic and mtDNA variation in Philippine Kappaphycus cottonii (Gigartinales, Rhodophyta).

    Dumilag, Richard V; Gallardo, William George M; Garcia, Christian Philip C; You, YeaEun; Chaves, Alyssa Keren G; Agahan, Lance

    2017-11-09

    Members of the carrageenan-producing seaweeds of the genus Kappapphycus have a complicated taxonomic history particularly with regard to species identification. Many taxonomic challenges in this group have been currently addressed with the use of mtDNA sequences. The phylogenetic status and genetic diversity of one of the lesser known species, Kappaphycus cottonii, have repeatedly come into question. This study explored the genetic variation in Philippine K. cottonii using the mtDNA COI-5P gene and cox2-3 spacer sequences. The six phenotypic forms in K. cottonii did not correspond to the observed genetic variability; hinting at the greater involvement of environmental factors in determining changes to the morphology of this alga. Our results revealed that the Philippine K. cottonii has the richest number of haplotypes that have been detected, so far, for any Kappaphycus species. Our inferred phylogenetic trees suggested two lineages: a lineage, which exclusively includes K. cottonii and another lineage comprising the four known Kappaphycus species: K. alvarezii, K. inermis, K. malesianus, and K. striatus. The dichotomy supports the apparent synamorphy for each of these lineages (the strictly terete thalli, lack of protuberances, and the presence of a hyphal central core in the latter group, while the opposite of these morphologies in K. cottonii). These findings shed new light on understanding the evolutionary history of the genus. Assessing the breadth of the phenotypic and genetic variation in K. cottonii has implications for the conservation and management of the overall Kappaphycus genetic resources, especially in the Philippines.

  3. Major Population Expansion of East Asians Began before Neolithic Time: Evidence of mtDNA Genomes

    Qin, Zhen-Dong; Wang, Yi; Tan, Jing-Ze; Li, Hui; Jin, Li

    2011-01-01

    It is a major question in archaeology and anthropology whether human populations started to grow primarily after the advent of agriculture, i.e., the Neolithic time, especially in East Asia, which was one of the centers of ancient agricultural civilization. To answer this question requires an accurate estimation of the time of lineage expansion as well as that of population expansion in a population sample without ascertainment bias. In this study, we analyzed all available mtDNA genomes of East Asians ascertained by random sampling, a total of 367 complete mtDNA sequences generated by the 1000 Genome Project, including 249 Chinese (CHB, CHD, and CHS) and 118 Japanese (JPT). We found that major mtDNA lineages underwent expansions, all of which, except for two JPT-specific lineages, including D4, D4b2b, D4a, D4j, D5a2a, A, N9a, F1a1'4, F2, B4, B4a, G2a1 and M7b1'2'4, occurred before 10 kya, i.e., before the Neolithic time (symbolized by Dadiwan Culture at 7.9 kya) in East Asia. Consistent to this observation, the further analysis showed that the population expansion in East Asia started at 13 kya and lasted until 4 kya. The results suggest that the population growth in East Asia constituted a need for the introduction of agriculture and might be one of the driving forces that led to the further development of agriculture. PMID:21998705

  4. M2 to D2

    Mukhi, Sunil; Papageorgakis, Constantinos

    2008-01-01

    We examine the recently proposed ''3-algebra'' field theory for multiple M2-branes and show that when a scalar field valued in the 3-algebra develops a vacuum expectation value, the resulting Higgs mechanism has the novel effect of promoting topological (Chern-Simons) to dynamical (Yang-Mills) gauge fields. This leads to a precise derivation of the maximally supersymmetric Yang-Mills theory on multiple D2-branes and thereby provides a relationship between 3-algebras and Yang-Mills theories. We discuss the physical interpretation of this result.

  5. Ancient mtDNA genetic variants modulate mtDNA transcription and replication.

    Sarit Suissa

    2009-05-01

    Full Text Available Although the functional consequences of mitochondrial DNA (mtDNA genetic backgrounds (haplotypes, haplogroups have been demonstrated by both disease association studies and cell culture experiments, it is not clear which of the mutations within the haplogroup carry functional implications and which are "evolutionary silent hitchhikers". We set forth to study the functionality of haplogroup-defining mutations within the mtDNA transcription/replication regulatory region by in vitro transcription, hypothesizing that haplogroup-defining mutations occurring within regulatory motifs of mtDNA could affect these processes. We thus screened >2500 complete human mtDNAs representing all major populations worldwide for natural variation in experimentally established protein binding sites and regulatory regions comprising a total of 241 bp in each mtDNA. Our screen revealed 77/241 sites showing point mutations that could be divided into non-fixed (57/77, 74% and haplogroup/sub-haplogroup-defining changes (i.e., population fixed changes, 20/77, 26%. The variant defining Caucasian haplogroup J (C295T increased the binding of TFAM (Electro Mobility Shift Assay and the capacity of in vitro L-strand transcription, especially of a shorter transcript that maps immediately upstream of conserved sequence block 1 (CSB1, a region associated with RNA priming of mtDNA replication. Consistent with this finding, cybrids (i.e., cells sharing the same nuclear genetic background but differing in their mtDNA backgrounds harboring haplogroup J mtDNA had a >2 fold increase in mtDNA copy number, as compared to cybrids containing haplogroup H, with no apparent differences in steady state levels of mtDNA-encoded transcripts. Hence, a haplogroup J regulatory region mutation affects mtDNA replication or stability, which may partially account for the phenotypic impact of this haplogroup. Our analysis thus demonstrates, for the first time, the functional impact of particular mtDNA

  6. The mitochondrial lineage U8a reveals a Paleolithic settlement in the Basque country

    Larruga José M

    2006-05-01

    Full Text Available Abstract Background It is customary, in population genetics studies, to consider Basques as the direct descendants of the Paleolithic Europeans. However, until now there has been no irrefutable genetic proof to support this supposition. Even studies based on mitochondrial DNA (mtDNA, an ideal molecule for constructing datable maternal genealogies, have failed to achieve this. It could be that incoming gene flow has replaced the Basque ancient lineages but it could also be that these lineages have not been detected due to a lack of resolution of the Basque mtDNA genealogies. To assess this possibility we analyzed here the mtDNA of a large sample of autochthonous Basques using mtDNA genomic sequencing for those lineages that could not be unequivocally classified by diagnostic RFLP analysis and control region (HVSI and HVSII sequencing. Results We show that Basques have the most ancestral phylogeny in Europe for the rare mitochondrial subhaplogroup U8a. Divergence times situate the Basque origin of this lineage in the Upper Palaeolithic. Most probably, their primitive founders came from West Asia. The lack of U8a lineages in Africa points to an European and not a North African route of entrance. Phylogeographic analysis suggest that U8a had two expansion periods in Europe, the first, from a south-western area including the Iberian peninsula and Mediterranean France before 30,000 years ago, and the second, from Central Europe around 15,000–10,000 years ago. Conclusion It has been demonstrated, for the first time, that Basques show the oldest lineages in Europe for subhaplogroup U8a. Coalescence times for these lineages suggest their presence in the Basque country since the Upper Paleolithic. The European U8 phylogeography is congruent with the supposition that Basques could have participated in demographic re-expansions to repopulate central Europe in the last interglacial periods.

  7. The mitochondrial DNA makeup of Romanians: A forensic mtDNA control region database and phylogenetic characterization.

    Turchi, Chiara; Stanciu, Florin; Paselli, Giorgia; Buscemi, Loredana; Parson, Walther; Tagliabracci, Adriano

    2016-09-01

    To evaluate the pattern of Romanian population from a mitochondrial perspective and to establish an appropriate mtDNA forensic database, we generated a high-quality mtDNA control region dataset from 407 Romanian subjects belonging to four major historical regions: Moldavia, Transylvania, Wallachia and Dobruja. The entire control region (CR) was analyzed by Sanger-type sequencing assays and the resulting 306 different haplotypes were classified into haplogroups according to the most updated mtDNA phylogeny. The Romanian gene pool is mainly composed of West Eurasian lineages H (31.7%), U (12.8%), J (10.8%), R (10.1%), T (9.1%), N (8.1%), HV (5.4%),K (3.7%), HV0 (4.2%), with exceptions of East Asian haplogroup M (3.4%) and African haplogroup L (0.7%). The pattern of mtDNA variation observed in this study indicates that the mitochondrial DNA pool is geographically homogeneous across Romania and that the haplogroup composition reveals signals of admixture of populations of different origin. The PCA scatterplot supported this scenario, with Romania located in southeastern Europe area, close to Bulgaria and Hungary, and as a borderland with respect to east Mediterranean and other eastern European countries. High haplotype diversity (0.993) and nucleotide diversity indices (0.00838±0.00426), together with low random match probability (0.0087) suggest the usefulness of this control region dataset as a forensic database in routine forensic mtDNA analysis and in the investigation of maternal genetic lineages in the Romanian population. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  8. mtDNA variation predicts population size in humans and reveals a major Southern Asian chapter in human prehistory.

    Atkinson, Quentin D; Gray, Russell D; Drummond, Alexei J

    2008-02-01

    The relative timing and size of regional human population growth following our expansion from Africa remain unknown. Human mitochondrial DNA (mtDNA) diversity carries a legacy of our population history. Given a set of sequences, we can use coalescent theory to estimate past population size through time and draw inferences about human population history. However, recent work has challenged the validity of using mtDNA diversity to infer species population sizes. Here we use Bayesian coalescent inference methods, together with a global data set of 357 human mtDNA coding-region sequences, to infer human population sizes through time across 8 major geographic regions. Our estimates of relative population sizes show remarkable concordance with the contemporary regional distribution of humans across Africa, Eurasia, and the Americas, indicating that mtDNA diversity is a good predictor of population size in humans. Plots of population size through time show slow growth in sub-Saharan Africa beginning 143-193 kya, followed by a rapid expansion into Eurasia after the emergence of the first non-African mtDNA lineages 50-70 kya. Outside Africa, the earliest and fastest growth is inferred in Southern Asia approximately 52 kya, followed by a succession of growth phases in Northern and Central Asia (approximately 49 kya), Australia (approximately 48 kya), Europe (approximately 42 kya), the Middle East and North Africa (approximately 40 kya), New Guinea (approximately 39 kya), the Americas (approximately 18 kya), and a second expansion in Europe (approximately 10-15 kya). Comparisons of relative regional population sizes through time suggest that between approximately 45 and 20 kya most of humanity lived in Southern Asia. These findings not only support the use of mtDNA data for estimating human population size but also provide a unique picture of human prehistory and demonstrate the importance of Southern Asia to our recent evolutionary past.

  9. Defining mtDNA origins and population stratification in Rio de Janeiro.

    Simão, Filipa; Ferreira, Ana Paula; de Carvalho, Elizeu Fagundes; Parson, Walther; Gusmão, Leonor

    2018-05-01

    The genetic composition of the Brazilian population was shaped by interethnic admixture between autochthonous Native Americans, Europeans settlers and African slaves. This structure, characteristic of most American populations, implies the need for large population forensic databases to capture the high diversity that is usually associated with admixed populations. In the present work, we sequenced the control region of mitochondrial DNA from 205 non-related individuals living in the Rio de Janeiro metropolitan region. Overall high haplotype diversity (0.9994 ± 0.0006) was observed, and pairwise comparisons showed a high proportion of haplotype pairs with more than one-point differences. When ignoring homopolymeric tracts, pairwise comparisons showed no differences 0.18% of the time, and differences in a single position were found with a frequency of 0.32%. A high percentage of African mtDNA was found (42%), with lineages showing a major South West origin. For the West Eurasian and Native American haplogroups (representing 32% and 26%, respectively) it was not possible to evaluate a clear geographic or linguistic affiliation. When grouping the mtDNA lineages according to their continental origin (Native American, European and African), differences were observed for the ancestry proportions estimated with autosomal ancestry-informative markers, suggesting some level of genetic substructure. The results from this study are in accordance with historical data where admixture processes are confirmed with a strong maternal contribution of African maternal ancestry and a relevant contribution of Native American maternal ancestry. Moreover, the evidence for some degree of association between mtDNA and autosomal information should be considered when combining these types of markers in forensic analysis. Copyright © 2018 Elsevier B.V. All rights reserved.

  10. A trans-Amazonian screening of mtDNA reveals deep intraspecific divergence in forest birds and suggests a vast underestimation of species diversity.

    Borja Milá

    Full Text Available The Amazonian avifauna remains severely understudied relative to that of the temperate zone, and its species richness is thought to be underestimated by current taxonomy. Recent molecular systematic studies using mtDNA sequence reveal that traditionally accepted species-level taxa often conceal genetically divergent subspecific lineages found to represent new species upon close taxonomic scrutiny, suggesting that intraspecific mtDNA variation could be useful in species discovery. Surveys of mtDNA variation in Holarctic species have revealed patterns of variation that are largely congruent with species boundaries. However, little information exists on intraspecific divergence in most Amazonian species. Here we screen intraspecific mtDNA genetic variation in 41 Amazonian forest understory species belonging to 36 genera and 17 families in 6 orders, using 758 individual samples from Ecuador and French Guiana. For 13 of these species, we also analyzed trans-Andean populations from the Ecuadorian Chocó. A consistent pattern of deep intraspecific divergence among trans-Amazonian haplogroups was found for 33 of the 41 taxa, and genetic differentiation and genetic diversity among them was highly variable, suggesting a complex range of evolutionary histories. Mean sequence divergence within families was the same as that found in North American birds (13%, yet mean intraspecific divergence in Neotropical species was an order of magnitude larger (2.13% vs. 0.23%, with mean distance between intraspecific lineages reaching 3.56%. We found no clear relationship between genetic distances and differentiation in plumage color. Our results identify numerous genetically and phenotypically divergent lineages which may result in new species-level designations upon closer taxonomic scrutiny and thorough sampling, although lineages in the tropical region could be older than those in the temperate zone without necessarily representing separate species. In

  11. Keeping mtDNA in shape between generations.

    James B Stewart

    2014-10-01

    Full Text Available Since the unexpected discovery that mitochondria contain their own distinct DNA molecules, studies of the mitochondrial DNA (mtDNA have yielded many surprises. In animals, transmission of the mtDNA genome is explicitly non-Mendelian, with a very high number of genome copies being inherited from the mother after a drastic bottleneck. Recent work has begun to uncover the molecular details of this unusual mode of transmission. Many surprising variations in animal mitochondrial biology are known; however, a series of recent studies have identified a core of evolutionarily conserved mechanisms relating to mtDNA inheritance, e.g., mtDNA bottlenecks during germ cell development, selection against specific mtDNA mutation types during maternal transmission, and targeted destruction of sperm mitochondria. In this review, we outline recent literature on the transmission of mtDNA in animals and highlight the implications for human health and ageing.

  12. MtDNA diversity among four Portuguese autochthonous dog breeds: a fine-scale characterisation

    Santa-Rita Pedro

    2005-06-01

    Full Text Available Abstract Background The picture of dog mtDNA diversity, as obtained from geographically wide samplings but from a small number of individuals per region or breed, has revealed weak geographic correlation and high degree of haplotype sharing between very distant breeds. We aimed at a more detailed picture through extensive sampling (n = 143 of four Portuguese autochthonous breeds – Castro Laboreiro Dog, Serra da Estrela Mountain Dog, Portuguese Sheepdog and Azores Cattle Dog-and comparatively reanalysing published worldwide data. Results Fifteen haplotypes belonging to four major haplogroups were found in these breeds, of which five are newly reported. The Castro Laboreiro Dog presented a 95% frequency of a new A haplotype, while all other breeds contained a diverse pool of existing lineages. The Serra da Estrela Mountain Dog, the most heterogeneous of the four Portuguese breeds, shared haplotypes with the other mainland breeds, while Azores Cattle Dog shared no haplotypes with the other Portuguese breeds. A review of mtDNA haplotypes in dogs across the world revealed that: (a breeds tend to display haplotypes belonging to different haplogroups; (b haplogroup A is present in all breeds, and even uncommon haplogroups are highly dispersed among breeds and continental areas; (c haplotype sharing between breeds of the same region is lower than between breeds of different regions and (d genetic distances between breeds do not correlate with geography. Conclusion MtDNA haplotype sharing occurred between Serra da Estrela Mountain dogs (with putative origin in the centre of Portugal and two breeds in the north and south of the country-with the Castro Laboreiro Dog (which behaves, at the mtDNA level, as a sub-sample of the Serra da Estrela Mountain Dog and the southern Portuguese Sheepdog. In contrast, the Azores Cattle Dog did not share any haplotypes with the other Portuguese breeds, but with dogs sampled in Northern Europe. This suggested that the

  13. Multiplexed SNP Typing of Ancient DNA Clarifies the Origin of Andaman mtDNA Haplogroups amongst South Asian Tribal Populations

    Endicott, Phillip; Metspalu, Mait; Stringer, Chris; Macaulay, Vincent; Cooper, Alan; Sanchez, Juan J.

    2006-01-01

    The issue of errors in genetic data sets is of growing concern, particularly in population genetics where whole genome mtDNA sequence data is coming under increased scrutiny. Multiplexed PCR reactions, combined with SNP typing, are currently under-exploited in this context, but have the potential to genotype whole populations rapidly and accurately, significantly reducing the amount of errors appearing in published data sets. To show the sensitivity of this technique for screening mtDNA genomic sequence data, 20 historic samples of the enigmatic Andaman Islanders and 12 modern samples from three Indian tribal populations (Chenchu, Lambadi and Lodha) were genotyped for 20 coding region sites after provisional haplogroup assignment with control region sequences. The genotype data from the historic samples significantly revise the topologies for the Andaman M31 and M32 mtDNA lineages by rectifying conflicts in published data sets. The new Indian data extend the distribution of the M31a lineage to South Asia, challenging previous interpretations of mtDNA phylogeography. This genetic connection between the ancestors of the Andamanese and South Asian tribal groups ∼30 kya has important implications for the debate concerning migration routes and settlement patterns of humans leaving Africa during the late Pleistocene, and indicates the need for more detailed genotyping strategies. The methodology serves as a low-cost, high-throughput model for the production and authentication of data from modern or ancient DNA, and demonstrates the value of museum collections as important records of human genetic diversity. PMID:17218991

  14. Lineage divergence and historical gene flow in the Chinese horseshoe bat (Rhinolophus sinicus.

    Xiuguang Mao

    Full Text Available Closely related taxa living in sympatry provide good opportunities to investigate the origin of barriers to gene flow as well as the extent of reproductive isolation. The only two recognized subspecies of the Chinese rufous horseshoe bat Rhinolophus sinicus are characterized by unusual relative distributions in which R. s. septentrionalis is restricted to a small area within the much wider range of its sister taxon R. s. sinicus. To determine the history of lineage divergence and gene flow between these taxa, we applied phylogenetic, demographic and coalescent analyses to multi-locus datasets. MtDNA gene genealogies and microsatellite-based clustering together revealed three divergent lineages of sinicus, corresponding to Central China, East China and the offshore Hainan Island. However, the central lineage of sinicus showed a closer relationship with septentrionalis than with other lineages of R. s. sinicus, in contrary to morphological data. Paraphyly of sinicus could result from either past asymmetric mtDNA introgression between these two taxa, or could suggest septentrionalis evolved in situ from its more widespread sister subspecies. To test between these hypotheses, we applied coalescent-based phylogenetic reconstruction and Approximate Bayesian Computation (ABC. We found that septentrionalis is likely to be the ancestral taxon and therefore a recent origin of this subspecies can be ruled out. On the other hand, we found a clear signature of asymmetric mtDNA gene flow from septentrionalis into central populations of sinicus yet no nuclear gene flow, thus strongly pointing to historical mtDNA introgression. We suggest that the observed deeply divergent lineages within R. sinicus probably evolved in isolation in separate Pleistocene refugia, although their close phylogeographic correspondence with distinct eco-environmental zones suggests that divergent selection might also have promoted broad patterns of population genetic structure.

  15. Recovering mitochondrial DNA lineages of extinct Amerindian nations in extant homopatric Brazilian populations.

    Gonçalves, Vanessa F; Parra, Flavia C; Gonçalves-Dornelas, Higgor; Rodrigues-Carvalho, Claudia; Silva, Hilton P; Pena, Sergio Dj

    2010-12-01

    Brazilian Amerindians have experienced a drastic population decrease in the past 500 years. Indeed, many native groups from eastern Brazil have vanished. However, their mitochondrial mtDNA haplotypes, still persist in Brazilians, at least 50 million of whom carry Amerindian mitochondrial lineages. Our objective was to test whether, by analyzing extant rural populations from regions anciently occupied by specific Amerindian groups, we could identify potentially authentic mitochondrial lineages, a strategy we have named 'homopatric targeting'. We studied 173 individuals from Queixadinha, a small village located in a territory previously occupied by the now extinct Botocudo Amerindian nation. Pedigree analysis revealed 74 unrelated matrilineages, which were screened for Amerindian mtDNA lineages by restriction fragment length polymorphism. A cosmopolitan control group was composed of 100 individuals from surrounding cities. All Amerindian lineages identified had their hypervariable segment HVSI sequenced, yielding 13 Amerindian haplotypes in Queixadinha, nine of which were not present in available databanks or in the literature. Among these haplotypes, there was a significant excess of haplogroup C (70%) and absence of haplogroup A lineages, which were the most common in the control group. The novelty of the haplotypes and the excess of the C haplogroup suggested that we might indeed have identified Botocudo lineages. To validate our strategy, we studied teeth extracted from 14 ancient skulls of Botocudo Amerindians from the collection of the National Museum of Rio de Janeiro. We recovered mtDNA sequences from all the teeth, identifying only six different haplotypes (a low haplotypic diversity of 0.8352 ± 0.0617), one of which was present among the lineages observed in the extant individuals studied. These findings validate the technique of homopatric targeting as a useful new strategy to study the peopling and colonization of the New World, especially when direct

  16. Most of the extant mtDNA boundaries in South and Southwest Asia were likely shaped during the initial settlement of Eurasia by anatomically modern humans

    Mastana Sarabjit

    2004-08-01

    Full Text Available Abstract Background Recent advances in the understanding of the maternal and paternal heritage of south and southwest Asian populations have highlighted their role in the colonization of Eurasia by anatomically modern humans. Further understanding requires a deeper insight into the topology of the branches of the Indian mtDNA phylogenetic tree, which should be contextualized within the phylogeography of the neighboring regional mtDNA variation. Accordingly, we have analyzed mtDNA control and coding region variation in 796 Indian (including both tribal and caste populations from different parts of India and 436 Iranian mtDNAs. The results were integrated and analyzed together with published data from South, Southeast Asia and West Eurasia. Results Four new Indian-specific haplogroup M sub-clades were defined. These, in combination with two previously described haplogroups, encompass approximately one third of the haplogroup M mtDNAs in India. Their phylogeography and spread among different linguistic phyla and social strata was investigated in detail. Furthermore, the analysis of the Iranian mtDNA pool revealed patterns of limited reciprocal gene flow between Iran and the Indian sub-continent and allowed the identification of different assemblies of shared mtDNA sub-clades. Conclusions Since the initial peopling of South and West Asia by anatomically modern humans, when this region may well have provided the initial settlers who colonized much of the rest of Eurasia, the gene flow in and out of India of the maternally transmitted mtDNA has been surprisingly limited. Specifically, our analysis of the mtDNA haplogroups, which are shared between Indian and Iranian populations and exhibit coalescence ages corresponding to around the early Upper Paleolithic, indicates that they are present in India largely as Indian-specific sub-lineages. In contrast, other ancient Indian-specific variants of M and R are very rare outside the sub-continent.

  17. Abundant mtDNA diversity and ancestral admixture in Colombian criollo cattle (Bos taurus).

    Carvajal-Carmona, Luis G; Bermudez, Nelson; Olivera-Angel, Martha; Estrada, Luzardo; Ossa, Jorge; Bedoya, Gabriel; Ruiz-Linares, Andrés

    2003-11-01

    Various cattle populations in the Americas (known as criollo breeds) have an origin in some of the first livestock introduced to the continent early in the colonial period (16th and 17th centuries). These cattle constitute a potentially important genetic reserve as they are well adapted to local environments and show considerable variation in phenotype. To examine the genetic ancestry and diversity of Colombian criollo we obtained mitochondrial DNA control region sequence information for 110 individuals from seven breeds. Old World haplogroup T3 is the most commonly observed CR lineage in criollo (0.65), in agreement with a mostly European ancestry for these cattle. However, criollo also shows considerable frequencies of haplogroups T2 (0.9) and T1 (0.26), with T1 lineages in criollo being more diverse than those reported for West Africa. The distribution and diversity of Old World lineages suggest some North African ancestry for criollo, probably as a result of the Arab occupation of Iberia prior to the European migration to the New World. The mtDNA diversity of criollo is higher than that reported for European and African cattle and is consistent with a differentiated ancestry for some criollo breeds.

  18. Traces of archaic mitochondrial lineages persist in Austronesian-speaking Formosan populations.

    Jean A Trejaut

    2005-08-01

    Full Text Available Genetic affinities between aboriginal Taiwanese and populations from Oceania and Southeast Asia have previously been explored through analyses of mitochondrial DNA (mtDNA, Y chromosomal DNA, and human leukocyte antigen loci. Recent genetic studies have supported the "slow boat" and "entangled bank" models according to which the Polynesian migration can be seen as an expansion from Melanesia without any major direct genetic thread leading back to its initiation from Taiwan. We assessed mtDNA variation in 640 individuals from nine tribes of the central mountain ranges and east coast regions of Taiwan. In contrast to the Han populations, the tribes showed a low frequency of haplogroups D4 and G, and an absence of haplogroups A, C, Z, M9, and M10. Also, more than 85% of the maternal lineages were nested within haplogroups B4, B5a, F1a, F3b, E, and M7. Although indicating a common origin of the populations of insular Southeast Asia and Oceania, most mtDNA lineages in Taiwanese aboriginal populations are grouped separately from those found in China and the Taiwan general (Han population, suggesting a prevalence in the Taiwanese aboriginal gene pool of its initial late Pleistocene settlers. Interestingly, from complete mtDNA sequencing information, most B4a lineages were associated with three coding region substitutions, defining a new subclade, B4a1a, that endorses the origin of Polynesian migration from Taiwan. Coalescence times of B4a1a were 13.2 +/- 3.8 thousand years (or 9.3 +/- 2.5 thousand years in Papuans and Polynesians. Considering the lack of a common specific Y chromosomal element shared by the Taiwanese aboriginals and Polynesians, the mtDNA evidence provided here is also consistent with the suggestion that the proto-Oceanic societies would have been mainly matrilocal.

  19. Traces of archaic mitochondrial lineages persist in Austronesian-speaking Formosan populations.

    Trejaut, Jean A; Kivisild, Toomas; Loo, Jun Hun; Lee, Chien Liang; He, Chun Lin; Hsu, Chia Jung; Lee, Zheng Yan; Li, Zheng Yuan; Lin, Marie

    2005-08-01

    Genetic affinities between aboriginal Taiwanese and populations from Oceania and Southeast Asia have previously been explored through analyses of mitochondrial DNA (mtDNA), Y chromosomal DNA, and human leukocyte antigen loci. Recent genetic studies have supported the "slow boat" and "entangled bank" models according to which the Polynesian migration can be seen as an expansion from Melanesia without any major direct genetic thread leading back to its initiation from Taiwan. We assessed mtDNA variation in 640 individuals from nine tribes of the central mountain ranges and east coast regions of Taiwan. In contrast to the Han populations, the tribes showed a low frequency of haplogroups D4 and G, and an absence of haplogroups A, C, Z, M9, and M10. Also, more than 85% of the maternal lineages were nested within haplogroups B4, B5a, F1a, F3b, E, and M7. Although indicating a common origin of the populations of insular Southeast Asia and Oceania, most mtDNA lineages in Taiwanese aboriginal populations are grouped separately from those found in China and the Taiwan general (Han) population, suggesting a prevalence in the Taiwanese aboriginal gene pool of its initial late Pleistocene settlers. Interestingly, from complete mtDNA sequencing information, most B4a lineages were associated with three coding region substitutions, defining a new subclade, B4a1a, that endorses the origin of Polynesian migration from Taiwan. Coalescence times of B4a1a were 13.2 +/- 3.8 thousand years (or 9.3 +/- 2.5 thousand years in Papuans and Polynesians). Considering the lack of a common specific Y chromosomal element shared by the Taiwanese aboriginals and Polynesians, the mtDNA evidence provided here is also consistent with the suggestion that the proto-Oceanic societies would have been mainly matrilocal.

  20. Human mtDNA hypervariable regions, HVR I and II, hint at deep common maternal founder and subsequent maternal gene flow in Indian population groups.

    Sharma, Swarkar; Saha, Anjana; Rai, Ekta; Bhat, Audesh; Bamezai, Ramesh

    2005-01-01

    We have analysed the hypervariable regions (HVR I and II) of human mitochondrial DNA (mtDNA) in individuals from Uttar Pradesh (UP), Bihar (BI) and Punjab (PUNJ), belonging to the Indo-European linguistic group, and from South India (SI), that have their linguistic roots in Dravidian language. Our analysis revealed the presence of known and novel mutations in both hypervariable regions in the studied population groups. Median joining network analyses based on mtDNA showed extensive overlap in mtDNA lineages despite the extensive cultural and linguistic diversity. MDS plot analysis based on Fst distances suggested increased maternal genetic proximity for the studied population groups compared with other world populations. Mismatch distribution curves, respective neighbour joining trees and other statistical analyses showed that there were significant expansions. The study revealed an ancient common ancestry for the studied population groups, most probably through common founder female lineage(s), and also indicated that human migrations occurred (maybe across and within the Indian subcontinent) even after the initial phase of female migration to India.

  1. Data from complete mtDNA sequencing of Tunisian centenarians: testing haplogroup association and the "golden mean" to longevity.

    Costa, Marta D; Cherni, Lotfi; Fernandes, Verónica; Freitas, Fernando; Ammar El Gaaied, Amel Ben; Pereira, Luísa

    2009-04-01

    Since the mitochondrial theory of ageing was proposed, mitochondrial DNA (mtDNA) diversity has been largely studied in old people, however complete genomes are still rare, being limited to Japanese and UK/US samples. In this work, we evaluated possible longevity associated polymorphisms/haplogroups in an African population, from Tunisia, by performing complete mtDNA sequencing. This population has a mixed Eurasian/sub-Saharan mtDNA gene pool, which could potentially facilitate the evaluation of association for sub-Saharan lineages. Sub-Saharan haplogroups were shown to be significantly less represented in centenarians (9.5%) than in controls (54.5%), but it is not possible to rule out an influence of population structure, which is high in these populations. No recurrent polymorphism were more frequent in centenarians than in controls, and although the Tunisian centenarians presented less synonymous and replacement polymorphisms than controls, this difference was not statistically significant. So far, it does not seem that centenarians have significantly less mildly deleterious substitutions, not only in Tunisia but also in Japanese and UK/US samples, as tested here, not favouring a "golden mean" to longevity.

  2. MtDNA variation in the Altai-Kizhi population of southern Siberia: a synthesis of genetic variation.

    Phillips-Krawczak, Christine; Devor, Eric; Zlojutro, Mark; Moffat-Wilson, Kristin; Crawford, Michael H

    2006-08-01

    The native peoples of Gorno Altai in southern Siberia represent a genetically diverse population and have been of great interest to anthropological genetics. In particular, the southern Altaian population is argued to be the best candidate for the New World ancestral population. In this study we sampled Altai-Kizhi from the southern Altaian village of Mendur-Sokkon, analyzed mtDNA RFLP markers and HVS-I sequences, and compared the results to other published mtDNA data from Derenko et al. (2003) and Shields et al. (1993) encompassing the same region. Because each independent study uses different sampling techniques in characterizing gene pools, in this paper we explore the accuracy and reliability of evolutionary studies on human populations. All the major Native American haplogroups (A, B, C, and D) were identified in the Mendur-Sokkon sample, including a single individual belonging to haplogroup X. The most common mtDNA lineages are C (35.7%) and D (13.3%), which is consistent with the haplogroup profiles of neighboring Siberian groups. The Mendur-Sokkon sample exhibits depressed HVS-I diversity values and neutrality test scores, which starkly differs from the Derenko et al. (2003) data set and more closely resembles the results for neighboring south Siberian groups. Furthermore, the multidimensional scaling plot of DA genetic distances does not cluster the Altai samples, showing different genetic affinities with various Asian groups. The findings underscore the importance of sampling strategy in the reconstruction of evolutionary history at the population level.

  3. Evolutionary analyses of entire genomes do not support the association of mtDNA mutations with Ras/MAPK pathway syndromes.

    Alberto Gómez-Carballa

    Full Text Available BACKGROUND: There are several known autosomal genes responsible for Ras/MAPK pathway syndromes, including Noonan syndrome (NS and related disorders (such as LEOPARD, neurofibromatosis type 1, although mutations of these genes do not explain all cases. Due to the important role played by the mitochondrion in the energetic metabolism of cardiac muscle, it was recently proposed that variation in the mitochondrial DNA (mtDNA genome could be a risk factor in the Noonan phenotype and in hypertrophic cardiomyopathy (HCM, which is a common clinical feature in Ras/MAPK pathway syndromes. In order to test these hypotheses, we sequenced entire mtDNA genomes in the largest series of patients suffering from Ras/MAPK pathway syndromes analyzed to date (n = 45, most of them classified as NS patients (n = 42. METHODS/PRINCIPAL FINDINGS: The results indicate that the observed mtDNA lineages were mostly of European ancestry, reproducing in a nutshell the expected haplogroup (hg patterns of a typical Iberian dataset (including hgs H, T, J, and U. Three new branches of the mtDNA phylogeny (H1j1, U5b1e, and L2a5 are described for the first time, but none of these are likely to be related to NS or Ras/MAPK pathway syndromes when observed under an evolutionary perspective. Patterns of variation in tRNA and protein genes, as well as redundant, private and heteroplasmic variants, in the mtDNA genomes of patients were as expected when compared with the patterns inferred from a worldwide mtDNA phylogeny based on more than 8700 entire genomes. Moreover, most of the mtDNA variants found in patients had already been reported in healthy individuals and constitute common polymorphisms in human population groups. CONCLUSIONS/SIGNIFICANCE: As a whole, the observed mtDNA genome variation in the NS patients was difficult to reconcile with previous findings that indicated a pathogenic role of mtDNA variants in NS.

  4. Evolutionary Analyses of Entire Genomes Do Not Support the Association of mtDNA Mutations with Ras/MAPK Pathway Syndromes

    Cerezo, María; Balboa, Emilia; Heredia, Claudia; Castro-Feijóo, Lidia; Rica, Itxaso; Barreiro, Jesús; Eirís, Jesús; Cabanas, Paloma; Martínez-Soto, Isabel; Fernández-Toral, Joaquín; Castro-Gago, Manuel; Pombo, Manuel; Carracedo, Ángel; Barros, Francisco

    2011-01-01

    Background There are several known autosomal genes responsible for Ras/MAPK pathway syndromes, including Noonan syndrome (NS) and related disorders (such as LEOPARD, neurofibromatosis type 1), although mutations of these genes do not explain all cases. Due to the important role played by the mitochondrion in the energetic metabolism of cardiac muscle, it was recently proposed that variation in the mitochondrial DNA (mtDNA) genome could be a risk factor in the Noonan phenotype and in hypertrophic cardiomyopathy (HCM), which is a common clinical feature in Ras/MAPK pathway syndromes. In order to test these hypotheses, we sequenced entire mtDNA genomes in the largest series of patients suffering from Ras/MAPK pathway syndromes analyzed to date (n = 45), most of them classified as NS patients (n = 42). Methods/Principal Findings The results indicate that the observed mtDNA lineages were mostly of European ancestry, reproducing in a nutshell the expected haplogroup (hg) patterns of a typical Iberian dataset (including hgs H, T, J, and U). Three new branches of the mtDNA phylogeny (H1j1, U5b1e, and L2a5) are described for the first time, but none of these are likely to be related to NS or Ras/MAPK pathway syndromes when observed under an evolutionary perspective. Patterns of variation in tRNA and protein genes, as well as redundant, private and heteroplasmic variants, in the mtDNA genomes of patients were as expected when compared with the patterns inferred from a worldwide mtDNA phylogeny based on more than 8700 entire genomes. Moreover, most of the mtDNA variants found in patients had already been reported in healthy individuals and constitute common polymorphisms in human population groups. Conclusions/Significance As a whole, the observed mtDNA genome variation in the NS patients was difficult to reconcile with previous findings that indicated a pathogenic role of mtDNA variants in NS. PMID:21526175

  5. Phylogeographical analysis of mtDNA data indicates postglacial expansion from multiple glacial refugia in woodland caribou (Rangifer tarandus caribou.

    Cornelya F C Klütsch

    Full Text Available Glacial refugia considerably shaped the phylogeographical structure of species and may influence intra-specific morphological, genetic, and adaptive differentiation. However, the impact of the Quaternary ice ages on the phylogeographical structure of North American temperate mammalian species is not well-studied. Here, we surveyed ~1600 individuals of the widely distributed woodland caribou (Rangifer tarandus caribou using mtDNA control region sequences to investigate if glacial refugia contributed to the phylogeographical structure in this subspecies. Phylogenetic tree reconstruction, a median-joining network, and mismatch distributions supported postglacial expansions of woodland caribou from three glacial refugia dating back to 13544-22005 years. These three lineages consisted almost exclusively of woodland caribou mtDNA haplotypes, indicating that phylogeographical structure was mainly shaped by postglacial expansions. The putative centres of these lineages are geographically separated; indicating disconnected glacial refugia in the Rocky Mountains, east of the Mississippi, and the Appalachian Mountains. This is in congruence with the fossil record that caribou were distributed in these areas during the Pleistocene. Our results suggest that the last glacial maximum substantially shaped the phylogeographical structure of this large mammalian North American species that will be affected by climatic change. Therefore, the presented results will be essential for future conservation planning in woodland caribou.

  6. Detailed mtDNA genotypes permit a reassessment of the settlement and population structure of the Andaman Islands.

    Barik, S S; Sahani, R; Prasad, B V R; Endicott, P; Metspalu, M; Sarkar, B N; Bhattacharya, S; Annapoorna, P C H; Sreenath, J; Sun, D; Sanchez, J J; Ho, S Y W; Chandrasekar, A; Rao, V R

    2008-05-01

    The population genetics of the Indian subcontinent is central to understanding early human prehistory due to its strategic location on the proposed corridor of human movement from Africa to Australia during the late Pleistocene. Previous genetic research using mtDNA has emphasized the relative isolation of the late Pleistocene colonizers, and the physically isolated Andaman Island populations of Island South-East Asia remain the source of claims supporting an early split between the populations that formed the patchy settlement pattern along the coast of the Indian Ocean. Using whole-genome sequencing, combined with multiplexed SNP typing, this study investigates the deep structure of mtDNA haplogroups M31 and M32 in India and the Andaman Islands. The identification of a so far unnoticed rare polymorphism shared between these two lineages suggests that they are actually sister groups within a single haplogroup, M31'32. The enhanced resolution of M31 allows for the inference of a more recent colonization of the Andaman Islands than previously suggested, but cannot reject the very early peopling scenario. We further demonstrate a widespread overlap of mtDNA and cultural markers between the two major language groups of the Andaman archipelago. Given the "completeness" of the genealogy based on whole genome sequences, and the multiple scenarios for the peopling of the Andaman Islands sustained by this inferred genealogy, our study hints that further mtDNA based phylogeographic studies are unlikely to unequivocally support any one of these possibilities. (c) 2008 Wiley-Liss, Inc.

  7. A proposal for M2-brane-anti-M2-brane action

    Garousi, Mohammad R.

    2010-01-01

    We propose a manifestly SO(8) invariant BF type Lagrangian for describing the dynamics of M2-brane-anti-M2-brane system in flat spacetime. When one of the scalars which satisfies a free-scalar equation takes a large expectation value, the M2-brane-anti-M2-brane action reduces to the tachyon DBI action of D2-brane-anti-D2-brane system in flat spacetime.

  8. Cryptic lineage diversity, body size divergence, and sympatry in a species complex of Australian lizards (Gehyra).

    Moritz, Craig C; Pratt, Renae C; Bank, Sarah; Bourke, Gayleen; Bragg, Jason G; Doughty, Paul; Keogh, J Scott; Laver, Rebecca J; Potter, Sally; Teasdale, Luisa C; Tedeschi, Leonardo G; Oliver, Paul M

    2018-01-01

    Understanding the joint evolutionary and ecological underpinnings of sympatry among close relatives remains a key challenge in biology. This problem can be addressed through joint phylogenomic and phenotypic analysis of complexes of closely related lineages within, and across, species and hence representing the speciation continuum. For a complex of tropical geckos from northern Australia-Gehyra nana and close relatives-we combine mtDNA phylogeography, exon-capture sequencing, and morphological data to resolve independently evolving lineages and infer their divergence history and patterns of morphological evolution. Gehyra nana is found to include nine divergent lineages and is paraphyletic with four other species from the Kimberley region of north-west Australia. Across these 13 taxa, 12 of which are restricted to rocky habitats, several lineages overlap geographically, including on the diverse Kimberley islands. Morphological evolution is dominated by body size shifts, and both body size and shape have evolved gradually across the group. However, larger body size shifts are observed among overlapping taxa than among closely related parapatric lineages of G. nana, and sympatric lineages are more divergent than expected at random. Whether elevated body size differences among sympatric lineages are due to ecological sorting or character displacement remains to be determined. © 2017 The Author(s). Evolution © 2017 The Society for the Study of Evolution.

  9. Alterations in mtDNA, gastric carcinogenesis and early diagnosis.

    Rodrigues-Antunes, S; Borges, B N

    2018-05-26

    Gastric cancer remains one of the most prevalent cancers in the world. Due to this, efforts are being made to improve the diagnosis of this neoplasm and the search for molecular markers that may be involved in its genesis. Within this perspective, the mitochondrial DNA is considered as a potential candidate, since it has several well documented changes and is readily accessible. However, numerous alterations have been reported in mtDNA, not facilitating the visualization of which alterations and molecular markers are truly involved with gastric carcinogenesis. This review presents a compilation of the main known changes relating mtDNA to gastric cancer and their clinical significance.

  10. Anti-influenza M2e antibody

    Bradbury, Andrew M [Santa Fe, NM

    2011-12-20

    Humanized recombinant and monoclonal antibodies specific for the ectodomain of the influenza virus M2 ion channel protein are disclosed. The antibodies of the invention have anti-viral activity and may be useful as anti-viral therapeutics and/or prophylactic/vaccine agents for inhibiting influenza virus replication and for treating individuals infected with influenza.

  11. On the edge of Bantu expansions: mtDNA, Y chromosome and lactase persistence genetic variation in southwestern Angola

    Beleza Sandra

    2009-04-01

    Full Text Available Abstract Background Current information about the expansion of Bantu-speaking peoples is hampered by the scarcity of genetic data from well identified populations from southern Africa. Here, we fill an important gap in the analysis of the western edge of the Bantu migrations by studying for the first time the patterns of Y-chromosome, mtDNA and lactase persistence genetic variation in four representative groups living around the Namib Desert in southwestern Angola (Ovimbundu, Ganguela, Nyaneka-Nkumbi and Kuvale. We assessed the differentiation between these populations and their levels of admixture with Khoe-San groups, and examined their relationship with other sub-Saharan populations. We further combined our dataset with previously published data on Y-chromosome and mtDNA variation to explore a general isolation with migration model and infer the demographic parameters underlying current genetic diversity in Bantu populations. Results Correspondence analysis, lineage sharing patterns and admixture estimates indicate that the gene pool from southwestern Angola is predominantly derived from West-Central Africa. The pastoralist Herero-speaking Kuvale people were additionally characterized by relatively high frequencies of Y-chromosome (12% and mtDNA (22% Khoe-San lineages, as well as by the presence of the -14010C lactase persistence mutation (6%, which likely originated in non-Bantu pastoralists from East Africa. Inferred demographic parameters show that both male and female populations underwent significant size growth after the split between the western and eastern branches of Bantu expansions occurring 4000 years ago. However, males had lower population sizes and migration rates than females throughout the Bantu dispersals. Conclusion Genetic variation in southwestern Angola essentially results from the encounter of an offshoot of West-Central Africa with autochthonous Khoisan-speaking peoples from the south. Interactions between the Bantus

  12. MtDNA T4216C variation in multiple sclerosis

    Andalib, Sasan; Emamhadi, Mohammadreza; Yousefzadeh-Chabok, Shahrokh

    2016-01-01

    MtDNA T4216C variation has frequently been investigated in Multiple Sclerosis (MS) patients; nonetheless, controversy has existed about the evidence of association of this variation with susceptibility to MS. The present systematic review and meta-analysis converge the results of the preceding pu...

  13. Human mitochondrial DNA (mtDNA) types in Malaysia

    Lian, L.H.; Koh, C.L.; Lim, M.E.

    2000-01-01

    Each human cell contains hundreds of mitochondria and thousands of double-stranded circular mtDNA. The delineation of human mtDNA variation and genetics over the past decade has provided unique and often startling insights into human evolution, degenerative diseases, and aging. Each mtDNA of 16,569 base pairs, encodes 13 polypeptides essential to the enzymes of the mitochondrial energy generating pathway, plus the necessary tRNAs and rRNAs. The highly polymorphic noncoding D-(displacement) loop region, also called the control region, is approximately 1.2 kb long. It contains two well-characterized hypervariable (HV-) regions, HV1 and HV2. MtDNA identification is usually based on these sequence differences. According to the TWTGDAM (Technical Working Group for DNA Analysis Methods), the minimum requirement for a mtDNA database for HV1 is from positions 16024 to 16365 and for HV2, from positions 00073 to 00340. The targeted Malaysian population subgroups for this study were mainly the Malays, Chinese, Indians, and indigenous Ibans, Bidayuhs, Kadazan-Dusuns, and Bajaus. Research methodologies undertaken included DNA extraction of samples from unrelated individuals, amplification of the specific regions via the polymerase chain reaction (PCR), and preparation of template DNA for sequencing by using an automated DNA sequencer. Sufficient nucleotide sequence data were generated from the mtDNA analysis. When the sequences were analyzed, sequence variations were found to be caused by nucleotide substitutions, insertions, and deletions. Of the three causes of the sequence variations, nucleotide substitutions (86.1%) accounted for the vast majority of polymorphism. It is noted that transitions (83.5%) were predominant when compared to the significantly lower frequencies of transversions (2.6%). Insertions (0.9%) and deletions (13.0%) were rather rare and found only in HV2. The data generated will also form the basis of a Malaysian DNA sequence database of mtDNA D

  14. Evolutionary history of the European whitefish Coregonus lavaretus (L.) species complex as inferred from mtDNA phylogeography and gill-raker numbers.

    Østbye, K; Bernatchez, L; Naesje, T F; Himberg, K-J M; Hindar, K

    2005-12-01

    We compared mitochondrial DNA and gill-raker number variation in populations of the European whitefish Coregonus lavaretus (L.) species complex to illuminate their evolutionary history, and discuss mechanisms behind diversification. Using single-strand conformation polymorphism (SSCP) and sequencing 528 bp of combined parts of the cytochrome oxidase b (cyt b) and NADH dehydrogenase subunit 3 (ND3) mithochondrial DNA (mtDNA) regions, we documented phylogeographic relationships among populations and phylogeny of mtDNA haplotypes. Demographic events behind geographical distribution of haplotypes were inferred using nested clade analysis (NCA) and mismatch distribution. Concordance between operational taxonomical groups, based on gill-raker numbers, and mtDNA patterns was tested. Three major mtDNA clades were resolved in Europe: a North European clade from northwest Russia to Denmark, a Siberian clade from the Arctic Sea to southwest Norway, and a South European clade from Denmark to the European Alps, reflecting occupation in different glacial refugia. Demographic events inferred from NCA were isolation by distance, range expansion, and fragmentation. Mismatch analysis suggested that clades which colonized Fennoscandia and the Alps expanded in population size 24 500-5800 years before present, with minute female effective population sizes, implying small founder populations during colonization. Gill-raker counts did not commensurate with hierarchical mtDNA clades, and poorly with haplotypes, suggesting recent origin of gill-raker variation. Whitefish designations based on gill-raker numbers were not associated with ancient clades. Lack of congruence in morphology and evolutionary lineages implies that the taxonomy of this species complex should be reconsidered.

  15. Ecological and genetic divergence between two lineages of Middle American túngara frogs Physalaemus (= Engystomops pustulosus

    Ron Santiago R

    2010-05-01

    Full Text Available Abstract Background Uncovering how populations of a species differ genetically and ecologically is important for understanding evolutionary processes. Here we combine population genetic methods (microsatellites with phylogenetic information (mtDNA to define genetic population clusters of the wide-spread Neotropical túngara frog (Physalaemus pustulosus. We measure gene flow and migration within and between population clusters and compare genetic diversity between population clusters. By applying ecological niche modeling we determine whether the two most divergent genetic groups of the túngara frog (1 inhabit different habitats, and (2 are separated geographically by unsuitable habitat across a gap in the distribution. Results Most population structure is captured by dividing all sample localities into two allopatric genetic lineages. The Northern genetic lineage (NW Costa Rica is genetically homogenous while the Southern lineage (SW Costa Rica and Panama is sub-divided into three population clusters by both microsatellite and mtDNA analyses. Gene flow is higher within the Northern lineage than within the Southern lineage, perhaps due to increased landscape heterogeneity in the South. Niche modeling reveals differences in suitable habitat between the Northern and Southern lineages: the Northern lineage inhabits dry/pine-oak forests, while the Southern lineage is confined to tropical moist forests. Both lineages seem to have had little movement across the distribution gap, which persisted during the last glacial maximum. The lack of movement was more pronounced for the Southern lineage than for the Northern lineage. Conclusions This study confirms the finding of previous studies that túngara frogs diverged into two allopatric genetic lineages north and south of the gap in the distribution in central Costa Rica several million years ago. The allopatric distribution is attributed to unsuitable habitat and probably other unknown ecological factors

  16. Global mtDNA genetic structure and hypothesized invasion history of a major pest of citrus, Diaphorina citri (Hemiptera: Liviidae).

    Luo, Yufa; Agnarsson, Ingi

    2018-01-01

    The Asian citrus psyllid Diaphorina citri Kuwayama is a key pest of citrus as the vector of the bacterium causing the "huanglongbing" disease (HLB). To assess the global mtDNA population genetic structure, and possible dispersal history of the pest, we investigated genetic variation at the COI gene collating newly collected samples with all previously published data. Our dataset consists of 356 colonies from 106 geographic sites worldwide. High haplotype diversity (H-mean = 0.702 ± 0.017), low nucleotide diversity (π-mean = 0.003), and significant positive selection (Ka/Ks = 32.92) were observed. Forty-four haplotypes (Hap) were identified, clustered into two matrilines: Both occur in southeastern and southern Asia, North and South America, and Africa; lineages A and B also occur in eastern and western Asia, respectively. The most abundant haplotypes were Hap4 in lineage A (35.67%), and Hap9 in lineage B (41.29%). The haplotype network identified them as the ancestral haplotypes within their respective lineages. Analysis of molecular variance showed significant genetic structure ( F ST  = 0.62, p  analysis suggests geographic structuring. We hypothesize a southern and/or southeastern Asia origin, three dispersal routes, and parallel expansions of two lineages. The hypothesized first route involved the expansion of lineage B from southern Asia into North America via West Asia. The second, the expansion of some lineage A individuals from Southeast Asia into East Asia, and the third involved both lineages from Southeast Asia spreading westward into Africa and subsequently into South America. To test these hypotheses and gain a deeper understanding of the global history of D. citri , more data-rich approaches will be necessary from the ample toolkit of next-generation sequencing (NGS). However, this study may serve to guide such sampling and in the development of biological control programs against the global pest D. citri .

  17. Association of low race performance with mtDNA haplogroup L3b of Australian thoroughbred horses.

    Lin, Xiang; Zheng, Hong-Xiang; Davie, Allan; Zhou, Shi; Wen, Li; Meng, Jun; Zhang, Yong; Aladaer, Qimude; Liu, Bin; Liu, Wu-Jun; Yao, Xin-Kui

    2018-03-01

    Mitochondrial DNA (mtDNA) encodes the genes for respiratory chain sub-units that determine the efficiency of oxidative phosphorylation in mitochondria. The aim of this study was to determine if there were any haplogroups and variants in mtDNA that could be associated with athletic performance of Thoroughbred horses. The whole mitochondrial genomes of 53 maternally unrelated Australian Thoroughbred horses were sequenced and an association study was performed with the competition histories of 1123 horses within their maternal lineages. A horse mtDNA phylogenetic tree was constructed based on a total of 195 sequences (including 142 from previous reports). The association analysis showed that the sample groups with poor racing performance history were enriched in haplogroup L3b (p = .0003) and its sub-haplogroup L3b1a (p = .0007), while those that had elite performance appeared to be not significantly associated with haplogroups G2 and L3a1a1a (p > .05). Haplogroup L3b and L3b1a bear two and five specific variants of which variant T1458C (site 345 in 16s rRNA) is the only potential functional variant. Furthermore, secondary reconstruction of 16s RNA showed considerable differences between two types of 16s RNA molecules (with and without T1458C), indicating a potential functional effect. The results suggested that haplogroup L3b, could have a negative association with elite performance. The T1458C mutation harboured in haplogroup L3b could have a functional effect that is related to poor athletic performance.

  18. Minding the gap: Frequency of indels in mtDNA control region sequence data and influence on population genetic analyses

    Pearce, J.M.

    2006-01-01

    Insertions and deletions (indels) result in sequences of various lengths when homologous gene regions are compared among individuals or species. Although indels are typically phylogenetically informative, occurrence and incorporation of these characters as gaps in intraspecific population genetic data sets are rarely discussed. Moreover, the impact of gaps on estimates of fixation indices, such as FST, has not been reviewed. Here, I summarize the occurrence and population genetic signal of indels among 60 published studies that involved alignments of multiple sequences from the mitochondrial DNA (mtDNA) control region of vertebrate taxa. Among 30 studies observing indels, an average of 12% of both variable and parsimony-informative sites were composed of these sites. There was no consistent trend between levels of population differentiation and the number of gap characters in a data block. Across all studies, the average influence on estimates of ??ST was small, explaining only an additional 1.8% of among population variance (range 0.0-8.0%). Studies most likely to observe an increase in ??ST with the inclusion of gap characters were those with control region DNA appears small, dependent upon total number of variable sites in the data block, and related to species-specific characteristics and the spatial distribution of mtDNA lineages that contain indels. ?? 2006 Blackwell Publishing Ltd.

  19. M2 qualify laser beam propagation

    Abdelhalim, Bencheikh; Mohamed, Bouafia

    2010-01-01

    One of the most important properties of a laser resonator is the highly collimated or spatially coherent nature of the laser output beam. Laser beam diameter and quality factor M 2 are significant parameters in a wide range of laser applications. This is because the spatial beam quality determines how closely the beam can be focused or how well the beam propagates over long distances without significant dispersion. In the present paper we have used three different methods to qualify the spatial structure of a laser beam propagating in free space, the results are obtained and discussed, and we have found that the Wigner distribution function is a powerful tool which allows a global characterization of any kind of beam

  20. Malware Lineage in the Wild

    Haq, Irfan Ul; Chica, Sergio; Caballero, Juan; Jha, Somesh

    2017-01-01

    Malware lineage studies the evolutionary relationships among malware and has important applications for malware analysis. A persistent limitation of prior malware lineage approaches is to consider every input sample a separate malware version. This is problematic since a majority of malware are packed and the packing process produces many polymorphic variants (i.e., executables with different file hash) of the same malware version. Thus, many samples correspond to the same malware version and...

  1. Understanding influences of culture and history on mtDNA variation and population structure in three populations from Assam, Northeast India.

    Rej, Peter H; Deka, Ranjan; Norton, Heather L

    2017-05-06

    Positioned at the nexus of India, China, and Southeast Asia, Northeast India is presumed to have served as a channel for land-based human migration since the Upper Pleistocene. Assam is the largest state in the Northeast. We characterized the genetic background of three populations and examined the ways in which their population histories and cultural practices have influenced levels of intrasample and intersample variation. We examined sequence data from the mtDNA hypervariable control region and selected diagnostic mutations from the coding region in 128 individuals from three ethnic groups currently living in Assam: two Scheduled tribes (Sonowal Kachari and Rabha), and the non-Scheduled Tai Ahom. The populations of Assam sampled here express mtDNA lineages indicative of South Asian, Southeast Asian, and East Asian ancestry. We discovered two completely novel haplogroups in Assam that accounted for 6.2% of the lineages in our sample. We also identified a new subhaplogroup of M9a that is prevalent in the Sonowal Kachari of Assam (19.1%), but not present in neighboring Arunachal Pradesh, indicating substantial regional population structuring. Employing a large comparative dataset into a series of multidimensional scaling (MDS) analyses, we saw the Rabha cluster with populations sampled from Yunnan Province, indicating that the historical matrilineality of the Rabha has maintained lineages from Southern China. Assam has undergone multiple colonization events in the time since the initial peopling event, with populations from Southern China and Southeast Asia having the greatest influence on maternal lineages in the region. © 2017 Wiley Periodicals, Inc.

  2. Ancient and recent Middle Eastern maternal genetic contribution to North Africa as viewed by mtDNA diversity in Tunisian Arab populations.

    Elkamel, Sarra; Boussetta, Sami; Khodjet-El-Khil, Houssein; Benammar Elgaaied, Amel; Cherni, Lotfi

    2018-05-01

    Through previous mitochondrial DNA studies, the Middle Eastern maternal genetic contribution to Tunisian populations appears limited. In fact, most of the studied communities were cosmopolitan, or of Berber or Andalusian origin. To provide genetic evidence for the actual contribution of Middle Eastern mtDNA lineages to Tunisia, we focused on two Arab speaking populations from Kairouan and Wesletia known to belong to an Arab genealogical lineage. A total of 114 samples were sequenced for the mtDNA HVS-I and HVS-II regions. Using these data, we evaluated the distribution of Middle Eastern haplogroups in the study populations, constructed interpolation maps, and established phylogenetic networks allowing estimation of the coalescence time for three specific Middle Eastern subclades (R0a, J1b, and T1). Both studied populations displayed North African genetic structure and Middle Eastern lineages with a frequency of 12% and 28.12% in Kairouan and Wesletia, respectively. TMRCA estimates for haplogroups T1a, R0a, and J1b in Tunisian Arabian samples were around 15 000 YBP, 9000 to 5000 YBP, and 960 to 600 YBP, respectively. The Middle Eastern maternal genetic contribution to Tunisian populations, as to other North African populations, occurred mostly in deep prehistory. They were brought in different migration waves during the Upper Paleolithic, probably with the expansion of Iberomaurusian culture, and during Epipaleolithic and Early Neolithic periods, which are concomitant with the Capsian civilization. Middle Eastern lineages also came to Tunisia during the recent Islamic expansion of the 7th CE and the subsequent massive Bedouin migration during the 11th CE. © 2018 Wiley Periodicals, Inc.

  3. Phylogeography of mtDNA haplogroup R7 in the Indian peninsula

    Shukla Parul

    2008-08-01

    Full Text Available Abstract Background Human genetic diversity observed in Indian subcontinent is second only to that of Africa. This implies an early settlement and demographic growth soon after the first 'Out-of-Africa' dispersal of anatomically modern humans in Late Pleistocene. In contrast to this perspective, linguistic diversity in India has been thought to derive from more recent population movements and episodes of contact. With the exception of Dravidian, which origin and relatedness to other language phyla is obscure, all the language families in India can be linked to language families spoken in different regions of Eurasia. Mitochondrial DNA and Y chromosome evidence has supported largely local evolution of the genetic lineages of the majority of Dravidian and Indo-European speaking populations, but there is no consensus yet on the question of whether the Munda (Austro-Asiatic speaking populations originated in India or derive from a relatively recent migration from further East. Results Here, we report the analysis of 35 novel complete mtDNA sequences from India which refine the structure of Indian-specific varieties of haplogroup R. Detailed analysis of haplogroup R7, coupled with a survey of ~12,000 mtDNAs from caste and tribal groups over the entire Indian subcontinent, reveals that one of its more recently derived branches (R7a1, is particularly frequent among Munda-speaking tribal groups. This branch is nested within diverse R7 lineages found among Dravidian and Indo-European speakers of India. We have inferred from this that a subset of Munda-speaking groups have acquired R7 relatively recently. Furthermore, we find that the distribution of R7a1 within the Munda-speakers is largely restricted to one of the sub-branches (Kherwari of northern Munda languages. This evidence does not support the hypothesis that the Austro-Asiatic speakers are the primary source of the R7 variation. Statistical analyses suggest a significant correlation between

  4. A Molecular Assessment of Phylogenetic Relationships and LineageDiversification Within the Family Salamandridae (Amphibia, Caudata)

    Weisrock, David W.; Papenfuss, Theodore J.; Macey, J. Robert; Litvinchuk, Spartak N.; Polymeni, Rosa; Ugurtas, Ismail H.; Zhao, Ermi; Larson, Allan

    2005-08-08

    Phylogenetic relationships among species of the salamanderfamily Salamandridae are investigated using nearly 3000 nucleotide basesof newly reported mitochondrial DNA sequence data from the mtDNA genicregion spanning the genes tRNALeu-COI. This study uses nearlycomprehensive species-level sampling to provide the first completephylogeny for the Salamandridae. Deep phylogenetic relationships amongthe three most divergent lineages in the family Salamandrina terdigitata,a clade comprising the "True" salamanders, and a clade comprising allnewts except S. terdigitata are difficult to resolve. However, mostrelationships within the latter two lineages are resolved with robustlevels of branch support. The genera Euproctus and Triturus arestatistically shown to be nonmonophyletic, instead each contains adiverse set of lineages positioned within the large newt clade. The genusParamesotriton is also resolve as a nonmonophyletic group, with the newlydescribed species P. laoensis constituting a divergent lineage placed ina sister position to clade containing all Pachytriton species and allremaining Paramesotriton species. Sequence divergences between P.laoensis and other Paramesotriton species are as great as those comparingP. laoensis and species of the genera Cynops and Pachytriton. Analyses oflineage diversification across the Salamandridae indicate that, despiteits exceptional diversity, lineage accumulation appears to have beenconstant across time, indicating that it does not represent a truespecies radiation.

  5. Myopathic mtDNA Depletion Syndrome Due to Mutation in TK2 Gene.

    Martín-Hernández, Elena; García-Silva, María Teresa; Quijada-Fraile, Pilar; Rodríguez-García, María Elena; Rivera, Henry; Hernández-Laín, Aurelio; Coca-Robinot, David; Fernández-Toral, Joaquín; Arenas, Joaquín; Martín, Miguel A; Martínez-Azorín, Francisco

    2017-01-01

    Whole-exome sequencing was used to identify the disease gene(s) in a Spanish girl with failure to thrive, muscle weakness, mild facial weakness, elevated creatine kinase, deficiency of mitochondrial complex III and depletion of mtDNA. With whole-exome sequencing data, it was possible to get the whole mtDNA sequencing and discard any pathogenic variant in this genome. The analysis of whole exome uncovered a homozygous pathogenic mutation in thymidine kinase 2 gene ( TK2; NM_004614.4:c.323 C>T, p.T108M). TK2 mutations have been identified mainly in patients with the myopathic form of mtDNA depletion syndromes. This patient presents an atypical TK2-related myopathic form of mtDNA depletion syndromes, because despite having a very low content of mtDNA (TK2 gene in mtDNA depletion syndromes and expanded the phenotypic spectrum.

  6. M2M Optimizations in Public Mobile Networks

    Norp, A.H.J.; Landais, B.

    2012-01-01

    Many M2M applications use public telecommunications networks to transfer data from M2M devices to an M2M server. These telecommunications networks will have to be adapted to cope with the traffic generated by the projected growth of M2M applications. In the near future, many more devices will be

  7. Genetic diversity of the Chinese goat in the littoral zone of the Yangtze River as assessed by microsatellite and mtDNA.

    E, Guang-Xin; Zhao, Yong-Ju; Chen, Li-Peng; Ma, Yue-Hui; Chu, Ming-Xing; Li, Xiang-Long; Hong, Qiong-Hua; Li, Lan-Hui; Guo, Ji-Jun; Zhu, Lan; Han, Yan-Guo; Gao, Hui-Jiang; Zhang, Jia-Hua; Jiang, Huai-Zhi; Jiang, Cao-De; Wang, Gao-Fu; Ren, Hang-Xing; Jin, Mei-Lan; Sun, Yuan-Zhi; Zhou, Peng; Huang, Yong-Fu

    2018-05-01

    The objective of this study was to assess the genetic diversity and population structure of goats in the Yangtze River region using microsatellite and mtDNA to better understand the current status of those goat genetic diversity and the effects of natural landscape in fashion of domestic animal genetic diversity. The genetic variability of 16 goat populations in the littoral zone of the Yangtze River was estimated using 21 autosomal microsatellites, which revealed high diversity and genetic population clustering with a dispersed geographical distribution. A phylogenetic analysis of the mitochondrial D-loop region (482 bp) was conducted in 494 goats from the Yangtze River region. In total, 117 SNPs were reconstructed, and 173 haplotypes were identified, 94.5% of which belonged to lineages A and B. Lineages C, D, and G had lower frequencies (5.2%), and lineage F haplotypes were undetected. Several high-frequency haplotypes were shared by different ecogeographically distributed populations, and the close phylogenetic relationships among certain low-frequency haplotypes indicated the historical exchange of genetic material among these populations. In particular, the lineage G haplotype suggests that some west Asian goat genetic material may have been transferred to China via Muslim migration.

  8. Decreased Circulating mtDNA Levels in Professional Male Volleyball Players.

    Nasi, Milena; Cristani, Alessandro; Pinti, Marcello; Lamberti, Igor; Gibellini, Lara; De Biasi, Sara; Guazzaloca, Alessandro; Trenti, Tommaso; Cossarizza, Andrea

    2016-01-01

    Exercise exerts various effects on the immune system, and evidence is emerging on its anti-inflammatory effects; the mechanisms on the basis of these modifications are poorly understood. Mitochondrial DNA (mtDNA) released from damaged cells acts as a molecule containing the so-called damage-associated molecular patterns and can trigger sterile inflammation. Indeed, high plasma levels of mtDNA are associated to several inflammatory conditions and physiological aging and longevity. The authors evaluated plasma mtDNA in professional male volleyball players during seasonal training and the possible correlation between mtDNA levels and clinical parameters, body composition, and physical performance. Plasma mtDNA was quantified by real-time PCR every 2 mo in 12 professional volleyball players (PVPs) during 2 consecutive seasons. As comparison, 20 healthy nonathlete male volunteers (NAs) were analyzed. The authors found lower levels of mtDNA in plasma of PVPs than in NAs. However, PVPs showed a decrease of circulating mtDNA only in the first season, while no appreciable variations were observed during the second season. No correlation was observed among mtDNA, hematochemical, and anthropometric parameters. Regular physical activity appeared associated with lower levels of circulating mtDNA, further confirming the protective, anti-inflammatory effect of exercise.

  9. Brown and polar bear Y chromosomes reveal extensive male-biased gene flow within brother lineages.

    Bidon, Tobias; Janke, Axel; Fain, Steven R; Eiken, Hans Geir; Hagen, Snorre B; Saarma, Urmas; Hallström, Björn M; Lecomte, Nicolas; Hailer, Frank

    2014-06-01

    Brown and polar bears have become prominent examples in phylogeography, but previous phylogeographic studies relied largely on maternally inherited mitochondrial DNA (mtDNA) or were geographically restricted. The male-specific Y chromosome, a natural counterpart to mtDNA, has remained underexplored. Although this paternally inherited chromosome is indispensable for comprehensive analyses of phylogeographic patterns, technical difficulties and low variability have hampered its application in most mammals. We developed 13 novel Y-chromosomal sequence and microsatellite markers from the polar bear genome and screened these in a broad geographic sample of 130 brown and polar bears. We also analyzed a 390-kb-long Y-chromosomal scaffold using sequencing data from published male ursine genomes. Y chromosome evidence support the emerging understanding that brown and polar bears started to diverge no later than the Middle Pleistocene. Contrary to mtDNA patterns, we found 1) brown and polar bears to be reciprocally monophyletic sister (or rather brother) lineages, without signals of introgression, 2) male-biased gene flow across continents and on phylogeographic time scales, and 3) male dispersal that links the Alaskan ABC islands population to mainland brown bears. Due to female philopatry, mtDNA provides a highly structured estimate of population differentiation, while male-biased gene flow is a homogenizing force for nuclear genetic variation. Our findings highlight the importance of analyzing both maternally and paternally inherited loci for a comprehensive view of phylogeographic history, and that mtDNA-based phylogeographic studies of many mammals should be reevaluated. Recent advances in sequencing technology render the analysis of Y-chromosomal variation feasible, even in nonmodel organisms. © The Author 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e

  10. Phylogeny and patterns of diversity of goat mtDNA haplogroup A revealed by resequencing complete mitogenomes.

    Maria Grazia Doro

    Full Text Available We sequenced to near completion the entire mtDNA of 28 Sardinian goats, selected to represent the widest possible diversity of the most widespread mitochondrial evolutionary lineage, haplogroup (Hg A. These specimens were reporters of the diversity in the island but also elsewhere, as inferred from their affiliation to each of 11 clades defined by D-loop variation. Two reference sequences completed the dataset. Overall, 206 variations were found in the full set of 30 sequences, of which 23 were protein-coding non-synonymous single nucleotide substitutions. Many polymorphic sites within Hg A were informative for the reconstruction of its internal phylogeny. Bayesian and network clustering revealed a general similarity over the entire molecule of sequences previously assigned to the same D-loop clade, indicating evolutionarily meaningful lineages. Two major sister groupings emerged within Hg A, which parallel distinct geographical distributions of D-loop clades in extant stocks. The pattern of variation in protein-coding genes revealed an overwhelming role of purifying selection, with the quota of surviving variants approaching neutrality. However, a simple model of relaxation of selection for the bulk of variants here reported should be rejected. Non-synonymous diversity of Hg's A, B and C denoted that a proportion of variants not greater than that allowed in the wild was given the opportunity to spread into domesticated stocks. Our results also confirmed that a remarkable proportion of pre-existing Hg A diversity became incorporated into domestic stocks. Our results confirm clade A11 as a well differentiated and ancient lineage peculiar of Sardinia.

  11. Metabolic rescue in pluripotent cells from patients with mtDNA disease.

    Ma, Hong; Folmes, Clifford D L; Wu, Jun; Morey, Robert; Mora-Castilla, Sergio; Ocampo, Alejandro; Ma, Li; Poulton, Joanna; Wang, Xinjian; Ahmed, Riffat; Kang, Eunju; Lee, Yeonmi; Hayama, Tomonari; Li, Ying; Van Dyken, Crystal; Gutierrez, Nuria Marti; Tippner-Hedges, Rebecca; Koski, Amy; Mitalipov, Nargiz; Amato, Paula; Wolf, Don P; Huang, Taosheng; Terzic, Andre; Laurent, Louise C; Izpisua Belmonte, Juan Carlos; Mitalipov, Shoukhrat

    2015-08-13

    Mitochondria have a major role in energy production via oxidative phosphorylation, which is dependent on the expression of critical genes encoded by mitochondrial (mt)DNA. Mutations in mtDNA can cause fatal or severely debilitating disorders with limited treatment options. Clinical manifestations vary based on mutation type and heteroplasmy (that is, the relative levels of mutant and wild-type mtDNA within each cell). Here we generated genetically corrected pluripotent stem cells (PSCs) from patients with mtDNA disease. Multiple induced pluripotent stem (iPS) cell lines were derived from patients with common heteroplasmic mutations including 3243A>G, causing mitochondrial encephalomyopathy and stroke-like episodes (MELAS), and 8993T>G and 13513G>A, implicated in Leigh syndrome. Isogenic MELAS and Leigh syndrome iPS cell lines were generated containing exclusively wild-type or mutant mtDNA through spontaneous segregation of heteroplasmic mtDNA in proliferating fibroblasts. Furthermore, somatic cell nuclear transfer (SCNT) enabled replacement of mutant mtDNA from homoplasmic 8993T>G fibroblasts to generate corrected Leigh-NT1 PSCs. Although Leigh-NT1 PSCs contained donor oocyte wild-type mtDNA (human haplotype D4a) that differed from Leigh syndrome patient haplotype (F1a) at a total of 47 nucleotide sites, Leigh-NT1 cells displayed transcriptomic profiles similar to those in embryo-derived PSCs carrying wild-type mtDNA, indicative of normal nuclear-to-mitochondrial interactions. Moreover, genetically rescued patient PSCs displayed normal metabolic function compared to impaired oxygen consumption and ATP production observed in mutant cells. We conclude that both reprogramming approaches offer complementary strategies for derivation of PSCs containing exclusively wild-type mtDNA, through spontaneous segregation of heteroplasmic mtDNA in individual iPS cell lines or mitochondrial replacement by SCNT in homoplasmic mtDNA-based disease.

  12. Acute leukemias of ambiguous lineage.

    Béné, Marie C; Porwit, Anna

    2012-02-01

    The 2008 edition of the WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues recognizes a special category called "leukemias of ambiguous lineage." The vast majority of these rare leukemias are classified as mixed phenotype acute leukemia (MPAL), although acute undifferentiated leukemias and natural killer lymphoblastic leukemias are also included. The major immunophenotypic markers used by the WHO 2008 to determine the lineage for these proliferations are myeloperoxidase, CD19, and cytoplasmic CD3. However, extensive immunophenotyping is necessary to confirm that the cells indeed belong to 2 different lineages or coexpress differentiation antigens of more than 1 lineage. Specific subsets of MPAL are defined by chromosomal anomalies such as the t(9;22) Philadelphia chromosome BCR-ABL1 or involvement of the MLL gene on chromosome 11q23. Other MPAL are divided into B/myeloid NOS, T/myeloid NOS, B/T NOS, and B/T/myeloid NOS. MPAL are usually of dire prognosis, respond variably to chemotherapy of acute lymphoblastic or acute myeloblastic type, and benefit most from rapid allogeneic hematopoietic stem cell transplantation.

  13. Autosomal and mtDNA Markers Affirm the Distinctiveness of Lions in West and Central Africa

    Bertola, Laura D.; Tensen, Laura; van Hooft, Pim; White, Paula A.; Driscoll, Carlos A.; Henschel, Philipp; Caragiulo, Anthony; Dias-Freedman, Isabela; Sogbohossou, Etotépé A.; Tumenta, Pricelia N.; Jirmo, Tuqa H.; de Snoo, Geert R.

    2015-01-01

    The evolutionary history of a species is key for understanding the taxonomy and for the design of effective management strategies for species conservation. The knowledge about the phylogenetic position of the lion (Panthera leo) in West/Central Africa is largely based on mitochondrial markers. Previous studies using mtDNA only have shown this region to hold a distinct evolutionary lineage. In addition, anthropogenic factors have led to a strong decline in West/Central African lion numbers, thus, the conservation value of these populations is particularly high. Here, we investigate whether autosomal markers are concordant with previously described phylogeographic patterns, and confirm the unique position of the West/Central African lion. Analysis of 20 microsatellites and 1,454 bp of the mitochondrial DNA in 16 lion populations representing the entire geographic range of the species found congruence in both types of markers, identifying four clusters: 1) West/Central Africa, 2) East Africa, 3) Southern Africa and 4) India. This is not in line with the current taxonomy, as defined by the IUCN, which only recognizes an African and an Asiatic subspecies. There are no indications that genetic diversity in West/Central Africa lions is lower than in either East or Southern Africa, however, given this genetic distinction and the recent declines of lion numbers in this region, we strongly recommend prioritization of conservation projects in West/Central Africa. As the current taxonomic nomenclature does not reflect the evolutionary history of the lion, we suggest that a taxonomic revision of the lion is warranted. PMID:26466139

  14. Autosomal and mtDNA Markers Affirm the Distinctiveness of Lions in West and Central Africa.

    Bertola, Laura D; Tensen, Laura; van Hooft, Pim; White, Paula A; Driscoll, Carlos A; Henschel, Philipp; Caragiulo, Anthony; Dias-Freedman, Isabela; Sogbohossou, Etotépé A; Tumenta, Pricelia N; Jirmo, Tuqa H; de Snoo, Geert R; de Iongh, Hans H; Vrieling, Klaas

    2015-01-01

    The evolutionary history of a species is key for understanding the taxonomy and for the design of effective management strategies for species conservation. The knowledge about the phylogenetic position of the lion (Panthera leo) in West/Central Africa is largely based on mitochondrial markers. Previous studies using mtDNA only have shown this region to hold a distinct evolutionary lineage. In addition, anthropogenic factors have led to a strong decline in West/Central African lion numbers, thus, the conservation value of these populations is particularly high. Here, we investigate whether autosomal markers are concordant with previously described phylogeographic patterns, and confirm the unique position of the West/Central African lion. Analysis of 20 microsatellites and 1,454 bp of the mitochondrial DNA in 16 lion populations representing the entire geographic range of the species found congruence in both types of markers, identifying four clusters: 1) West/Central Africa, 2) East Africa, 3) Southern Africa and 4) India. This is not in line with the current taxonomy, as defined by the IUCN, which only recognizes an African and an Asiatic subspecies. There are no indications that genetic diversity in West/Central Africa lions is lower than in either East or Southern Africa, however, given this genetic distinction and the recent declines of lion numbers in this region, we strongly recommend prioritization of conservation projects in West/Central Africa. As the current taxonomic nomenclature does not reflect the evolutionary history of the lion, we suggest that a taxonomic revision of the lion is warranted.

  15. Autosomal and mtDNA Markers Affirm the Distinctiveness of Lions in West and Central Africa.

    Laura D Bertola

    Full Text Available The evolutionary history of a species is key for understanding the taxonomy and for the design of effective management strategies for species conservation. The knowledge about the phylogenetic position of the lion (Panthera leo in West/Central Africa is largely based on mitochondrial markers. Previous studies using mtDNA only have shown this region to hold a distinct evolutionary lineage. In addition, anthropogenic factors have led to a strong decline in West/Central African lion numbers, thus, the conservation value of these populations is particularly high. Here, we investigate whether autosomal markers are concordant with previously described phylogeographic patterns, and confirm the unique position of the West/Central African lion. Analysis of 20 microsatellites and 1,454 bp of the mitochondrial DNA in 16 lion populations representing the entire geographic range of the species found congruence in both types of markers, identifying four clusters: 1 West/Central Africa, 2 East Africa, 3 Southern Africa and 4 India. This is not in line with the current taxonomy, as defined by the IUCN, which only recognizes an African and an Asiatic subspecies. There are no indications that genetic diversity in West/Central Africa lions is lower than in either East or Southern Africa, however, given this genetic distinction and the recent declines of lion numbers in this region, we strongly recommend prioritization of conservation projects in West/Central Africa. As the current taxonomic nomenclature does not reflect the evolutionary history of the lion, we suggest that a taxonomic revision of the lion is warranted.

  16. Optimized mtDNA Control Region Primer Extension Capture Analysis for Forensically Relevant Samples and Highly Compromised mtDNA of Different Age and Origin

    Mayra Eduardoff

    2017-09-01

    Full Text Available The analysis of mitochondrial DNA (mtDNA has proven useful in forensic genetics and ancient DNA (aDNA studies, where specimens are often highly compromised and DNA quality and quantity are low. In forensic genetics, the mtDNA control region (CR is commonly sequenced using established Sanger-type Sequencing (STS protocols involving fragment sizes down to approximately 150 base pairs (bp. Recent developments include Massively Parallel Sequencing (MPS of (multiplex PCR-generated libraries using the same amplicon sizes. Molecular genetic studies on archaeological remains that harbor more degraded aDNA have pioneered alternative approaches to target mtDNA, such as capture hybridization and primer extension capture (PEC methods followed by MPS. These assays target smaller mtDNA fragment sizes (down to 50 bp or less, and have proven to be substantially more successful in obtaining useful mtDNA sequences from these samples compared to electrophoretic methods. Here, we present the modification and optimization of a PEC method, earlier developed for sequencing the Neanderthal mitochondrial genome, with forensic applications in mind. Our approach was designed for a more sensitive enrichment of the mtDNA CR in a single tube assay and short laboratory turnaround times, thus complying with forensic practices. We characterized the method using sheared, high quantity mtDNA (six samples, and tested challenging forensic samples (n = 2 as well as compromised solid tissue samples (n = 15 up to 8 kyrs of age. The PEC MPS method produced reliable and plausible mtDNA haplotypes that were useful in the forensic context. It yielded plausible data in samples that did not provide results with STS and other MPS techniques. We addressed the issue of contamination by including four generations of negative controls, and discuss the results in the forensic context. We finally offer perspectives for future research to enable the validation and accreditation of the PEC MPS

  17. Hypervariable region polymorphism of mtDNA of recurrent oral ulceration in Chinese.

    Mao Sun

    Full Text Available BACKGROUND: MtDNA haplogroups could have important implication for understanding of the relationship between the mutations of the mitochondrial genome and diseases. Distribution of a variety of diseases among these haplogroups showed that some of the mitochondrial haplogroups are predisposed to disease. To examine the susceptibility of mtDNA haplogroups to ROU, we sequenced the mtDNA HV1, HV2 and HV3 in Chinese ROU. METHODOLOGY/PRINCIPAL FINDINGS: MtDNA haplogroups were analyzed in the 249 cases of ROU patients and the 237 cases of healthy controls respectively by means of primer extension analysis and DNA sequencing. Haplogroups G1 and H were found significantly more abundant in ROU patients than in healthy persons, while haplogroups D5 and R showed a trend toward a higher frequency in control as compared to those in patients. The distribution of C-stretch sequences polymorphism in mtDNA HV1, HV2 and HV3 regions was found in diversity. CONCLUSIONS/SIGNIFICANCE: For the first time, the relationship of mtDNA haplogroups and ROU in Chinese was investigated. Our results indicated that mtDNA haplogroups G1 and H might constitute a risk factor for ROU, which possibly increasing the susceptibility of ROU. Meanwhile, haplogroups D5 and R were indicated as protective factors for ROU. The polymorphisms of C-stretch sequences might being unstable and influence the mtDNA replication fidelity.

  18. Infantile presentation of the mtDNA A3243G tRNA(Leu (UUR)) mutation.

    Okhuijsen-Kroes, E.J.; Trijbels, J.M.F.; Sengers, R.C.A.; Mariman, E.C.M.; Heuvel, L.P.W.J. van den; Wendel, U.A.H.; Koch, G.; Smeitink, J.A.M.

    2001-01-01

    Mitochondrial DNA (mtDNA) disorders are clinically very heterogeneous, ranging from single organ involvement to severe multisystem disease. One of the most frequently observed mtDNA mutations is the A-to-G transition at position 3243 of the tRNA(Leu (UUR)) gene. This mutation is often related to

  19. Nuclear DNA but not mtDNA controls tumor phenotypes in mouse cells

    Akimoto, Miho; Niikura, Mamoru; Ichikawa, Masami; Yonekawa, Hiromichi; Nakada, Kazuto; Honma, Yoshio; Hayashi, Jun-Ichi

    2005-01-01

    Recent studies showed high frequencies of homoplasmic mtDNA mutations in various human tumor types, suggesting that the mutated mtDNA haplotypes somehow contribute to expression of tumor phenotypes. We directly addressed this issue by isolating mouse mtDNA-less (ρ 0 ) cells for complete mtDNA replacement between normal cells and their carcinogen-induced transformants, and examined the effect of the mtDNA replacement on expression of tumorigenicity, a phenotype forming tumors in nude mice. The results showed that genome chimera cells carrying nuclear DNA from tumor cells and mtDNA from normal cells expressed tumorigenicity, whereas those carrying nuclear DNA from normal cells and mtDNA from tumor cells did not. These observations provided direct evidence that nuclear DNA, but not mtDNA, is responsible for carcinogen-induced malignant transformation, although it remains possible that mtDNA mutations and resultant respiration defects may influence the degree of malignancy, such as invasive or metastatic properties

  20. Oxidants and not alkylating agents induce rapid mtDNA loss and mitochondrial dysfunction

    Furda, Amy M.; Marrangoni, Adele M.; Lokshin, Anna; Van Houten, Bennett

    2013-01-01

    Mitochondrial DNA (mtDNA) is essential for proper mitochondrial function and encodes 22 tRNAs, 2 rRNAs and 13 polypeptides that make up subunits of complex I, III, IV, in the electron transport chain and complex V, the ATP synthase. Although mitochondrial dysfunction has been implicated in processes such as premature aging, neurodegeneration, and cancer, it has not been shown whether persistent mtDNA damage causes a loss of oxidative phosphorylation. We addressed this question by treating mouse embryonic fibroblasts with either hydrogen peroxide (H2O2) or the alkylating agent methyl methanesulfonate (MMS) and measuring several endpoints, including mtDNA damage and repair rates using QPCR, levels of mitochondrial- and nuclear-encoded proteins using antibody analysis, and a pharmacologic profile of mitochondria using the Seahorse Extracellular Flux Analyzer. We show that a 60 min treatment with H2O2 causes persistent mtDNA lesions, mtDNA loss, decreased levels of a nuclear-encoded mitochondrial subunit, a loss of ATP-linked oxidative phosphorylation and a loss of total reserve capacity. Conversely, a 60 min treatment with 2 mM MMS causes persistent mtDNA lesions but no mtDNA loss, no decrease in levels of a nuclear-encoded mitochondrial subunit, and no mitochondrial dysfunction. These results suggest that persistent mtDNA damage is not sufficient to cause mitochondrial dysfunction. PMID:22766155

  1. Adoptive transfer of M2 macrophages reduces neuropathic pain via opioid peptides.

    Pannell, Maria; Labuz, Dominika; Celik, Melih Ö; Keye, Jacqueline; Batra, Arvind; Siegmund, Britta; Machelska, Halina

    2016-10-07

    During the inflammation which occurs following nerve damage, macrophages are recruited to the site of injury. Phenotypic diversity is a hallmark of the macrophage lineage and includes pro-inflammatory M1 and anti-inflammatory M2 populations. Our aim in this study was to investigate the ability of polarized M0, M1, and M2 macrophages to secrete opioid peptides and to examine their relative contribution to the modulation of neuropathic pain. Mouse bone marrow-derived cells were cultured as unstimulated M0 macrophages or were stimulated into an M1 phenotype using lipopolysaccharide and interferon-γ or into an M2 phenotype using interleukin-4. The macrophage phenotypes were verified using flow cytometry for surface marker analysis and cytokine bead array for cytokine profile assessment. Opioid peptide levels were measured by radioimmunoassay and enzyme immunoassay. As a model of neuropathic pain, a chronic constriction injury (CCI) of the sciatic nerve was employed. Polarized M0, M1, and M2 macrophages (5 × 10 5 cells) were injected perineurally twice, on days 14 and 15 following CCI or sham surgery. Mechanical and heat sensitivity were measured using the von Frey and Hargreaves tests, respectively. To track the injected macrophages, we also transferred fluorescently stained polarized cells and analyzed the surface marker profile of endogenous and injected cells in the nerves ex vivo. Compared to M0 and M1 cells, M2 macrophages contained and released higher amounts of opioid peptides, including Met-enkephalin, dynorphin A (1-17), and β-endorphin. M2 cells transferred perineurally at the nerve injury site reduced mechanical, but not heat hypersensitivity following the second injection. The analgesic effect was reversed by the perineurally applied opioid receptor antagonist naloxone methiodide. M2 cells did not affect sensitivity following sham surgery. Neither M0 nor M1 cells altered mechanical and heat sensitivity in CCI or sham-operated animals. Tracing the

  2. Migration and interaction in a contact zone: mtDNA variation among Bantu-speakers in Southern Africa.

    Chiara Barbieri

    Full Text Available Bantu speech communities expanded over large parts of sub-Saharan Africa within the last 4000-5000 years, reaching different parts of southern Africa 1200-2000 years ago. The Bantu languages subdivide in several major branches, with languages belonging to the Eastern and Western Bantu branches spreading over large parts of Central, Eastern, and Southern Africa. There is still debate whether this linguistic divide is correlated with a genetic distinction between Eastern and Western Bantu speakers. During their expansion, Bantu speakers would have come into contact with diverse local populations, such as the Khoisan hunter-gatherers and pastoralists of southern Africa, with whom they may have intermarried. In this study, we analyze complete mtDNA genome sequences from over 900 Bantu-speaking individuals from Angola, Zambia, Namibia, and Botswana to investigate the demographic processes at play during the last stages of the Bantu expansion. Our results show that most of these Bantu-speaking populations are genetically very homogenous, with no genetic division between speakers of Eastern and Western Bantu languages. Most of the mtDNA diversity in our dataset is due to different degrees of admixture with autochthonous populations. Only the pastoralist Himba and Herero stand out due to high frequencies of particular L3f and L3d lineages; the latter are also found in the neighboring Damara, who speak a Khoisan language and were foragers and small-stock herders. In contrast, the close cultural and linguistic relatives of the Herero and Himba, the Kuvale, are genetically similar to other Bantu-speakers. Nevertheless, as demonstrated by resampling tests, the genetic divergence of Herero, Himba, and Kuvale is compatible with a common shared ancestry with high levels of drift, while the similarity of the Herero, Himba, and Damara probably reflects admixture, as also suggested by linguistic analyses.

  3. The congruence between matrilineal genetic (mtDNA) and geographic diversity of Iranians and the territorial populations

    Bahmanimehr, Ardeshir; Eskandari, Ghafar; Nikmanesh, Fatemeh

    2015-01-01

    Objective(s): From the ancient era, emergence of Agriculture in the connecting region of Mesopotamia and the Iranian plateau at the foothills of the Zagros Mountains, made Iranian gene pool as an important source of populating the region. It has differentiated the population spread and different language groups. In order to trace the maternal genetic affinity between Iranians and other populations of the area and to establish the place of Iranians in a broad framework of ethnically and linguistically diverse groups of Middle Eastern and South Asian populations, a comparative study of territorial groups was designed and used in the population statistical analysis. Materials and Methods: Mix of 616 samples was sequenced for complete mtDNA or hyper variable regions in this study. A published dataset of neighboring populations was used as a comparison in the Iranian matrilineal lineage study based on mtDNA haplogroups. Results: Statistical analyses data, demonstrate a close genetic structure of all Iranian populations, thus suggesting their origin from a common maternal ancestral gene pool and show that the diverse maternal genetic structure does not reflect population differentiation in the region in their language. Conclusion: In the aggregate of the eastward spreads of proto-Elamo-Dravidian language from the Southwest region of Iran, the Elam province, a reasonable degree of homogeneity has been observed among Iranians in this study. The approach will facilitate our perception of the more detailed relationship of the ethnic groups living in Iran with the other ancient peoples of the area, testing linguistic hypothesis and population movements. PMID:25810873

  4. mtDNA, Metastasis, and the Mitochondrial Unfolded Protein Response (UPRmt).

    Kenny, Timothy C; Germain, Doris

    2017-01-01

    While several studies have confirmed a link between mitochondrial DNA (mtDNA) mutations and cancer cell metastasis, much debate remains regarding the nature of the alternations in mtDNA leading to this effect. Meanwhile, the mitochondrial unfolded protein response (UPR mt ) has gained much attention in recent years, with most studies of this pathway focusing on its role in aging. However, the UPR mt has also been studied in the context of cancer. More recent work suggests that rather than a single mutation or alternation, specific combinatorial mtDNA landscapes able to activate the UPR mt may be those that are selected by metastatic cells, while mtDNA landscapes unable to activate the UPR mt do not. This review aims at offering an overview of the confusing literature on mtDNA mutations and metastasis and the more recent work on the UPR mt in this setting.

  5. Lake Tanganyika--a 'melting pot' of ancient and young cichlid lineages (Teleostei: Cichlidae?

    Juliane D Weiss

    Full Text Available A long history of research focused on the East Africa cichlid radiations (EAR revealed discrepancies between mtDNA and nuclear phylogenies, suggesting that interspecific hybridisation may have been significant during the radiation of these fishes. The approximately 250 cichlid species of Lake Tanganyika have their roots in a monophyletic African cichlid assemblage, but controversies remain about the precise phylogenetic origin and placement of different lineages and consequently about L. Tanganyika colonization scenarios. 3312 AFLP loci and the mitochondrial ND2 gene were genotyped for 91 species representing almost all major lacustrine and riverine haplotilapiine east African cichlid lineages with a focus on L. Tanganyika endemics. Explicitly testing for the possibility of ancient hybridisation events, a comprehensive phylogenetic network hypothesis is proposed for the origin and diversification of L. Tanganyika cichlids. Inference of discordant phylogenetic signal strongly suggests that the genomes of two endemic L. Tanganyika tribes, Eretmodini and Tropheini, are composed of an ancient mixture of riverine and lacustrine lineages. For the first time a strong monophyly signal of all non-haplochromine mouthbrooding species endemic to L. Tanganyika ("ancient mouthbrooders" was detected. Further, in the genomes of early diverging L. Tanganyika endemics Trematocarini, Bathybatini, Hemibatini and Boulengerochromis genetic components of other lineages belonging to the East African Radiation appear to be present. In combination with recent palaeo-geological results showing that tectonic activity in the L. Tanganyika region resulted in highly dynamic and heterogeneous landscape evolution over the Neogene and Pleistocene, the novel phylogenetic data render a single lacustrine basin as the geographical cradle of the endemic L. Tanganyika cichlid lineages unlikely. Instead a scenario of a pre-rift origin of several independent L. Tanganyika precursor

  6. No variation and low synonymous substitution rates in coral mtDNA despite high nuclear variation

    Hellberg Michael E

    2006-03-01

    Full Text Available Abstract Background The mitochondrial DNA (mtDNA of most animals evolves more rapidly than nuclear DNA, and often shows higher levels of intraspecific polymorphism and population subdivision. The mtDNA of anthozoans (corals, sea fans, and their kin, by contrast, appears to evolve slowly. Slow mtDNA evolution has been reported for several anthozoans, however this slow pace has been difficult to put in phylogenetic context without parallel surveys of nuclear variation or calibrated rates of synonymous substitution that could permit quantitative rate comparisons across taxa. Here, I survey variation in the coding region of a mitochondrial gene from a coral species (Balanophyllia elegans known to possess high levels of nuclear gene variation, and estimate synonymous rates of mtDNA substitution by comparison to another coral (Tubastrea coccinea. Results The mtDNA surveyed (630 bp of cytochrome oxidase subunit I was invariant among individuals sampled from 18 populations spanning 3000 km of the range of B. elegans, despite high levels of variation and population subdivision for allozymes over these same populations. The synonymous substitution rate between B. elegans and T. coccinea (0.05%/site/106 years is similar to that in most plants, but 50–100 times lower than rates typical for most animals. In addition, while substitutions to mtDNA in most animals exhibit a strong bias toward transitions, mtDNA from these corals does not. Conclusion Slow rates of mitochondrial nucleotide substitution result in low levels of intraspecific mtDNA variation in corals, even when nuclear loci vary. Slow mtDNA evolution appears to be the basal condition among eukaryotes. mtDNA substitution rates switch from slow to fast abruptly and unidirectionally. This switch may stem from the loss of just one or a few mitochondrion-specific DNA repair or replication genes.

  7. Demography or selection on linked cultural traits or genes? Investigating the driver of low mtDNA diversity in the sperm whale using complementary mitochondrial and nuclear genome analyses.

    Morin, Phillip A; Foote, Andrew D; Baker, C Scott; Hancock-Hanser, Brittany L; Kaschner, Kristin; Mate, Bruce R; Mesnick, Sarah L; Pease, Victoria L; Rosel, Patricia E; Alexander, Alana

    2018-04-19

    Mitochondrial DNA has been heavily utilized in phylogeography studies for several decades. However, underlying patterns of demography and phylogeography may be misrepresented due to coalescence stochasticity, selection, variation in mutation rates, and cultural hitchhiking (linkage of genetic variation to culturally transmitted traits affecting fitness). Cultural hitchhiking has been suggested as an explanation for low genetic diversity in species with strong social structures, counteracting even high mobility, abundance and limited barriers to dispersal. One such species is the sperm whale, which shows very limited phylogeographic structure and low mtDNA diversity despite a worldwide distribution and large population. Here, we use analyses of 175 globally distributed mitogenomes and three nuclear genomes to evaluate hypotheses of a population bottleneck/expansion versus a selective sweep due to cultural-hitchhiking or selection on mtDNA as the mechanism contributing to low worldwide mitochondrial diversity in sperm whales. In contrast to mtDNA control region (CR) data, mitogenome haplotypes are largely ocean-specific, with only one of 80 shared between the Atlantic and Pacific. Demographic analyses of nuclear genomes suggest low mtDNA diversity is consistent with a global reduction in population size that ended approximately 125,000 years ago, correlated with the Eemian interglacial. Phylogeographic analysis suggests that extant sperm whales descend from maternal lineages endemic to the Pacific during the period of reduced abundance, and have subsequently colonized the Atlantic several times. Results highlight the apparent impact of past climate change, and suggest selection and hitchhiking are not the sole processes responsible for low mtDNA diversity in this highly social species. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  8. Estimates of Continental Ancestry Vary Widely among Individuals with the Same mtDNA Haplogroup

    Emery, Leslie S.; Magnaye, Kevin M.; Bigham, Abigail W.; Akey, Joshua M.; Bamshad, Michael J.

    2015-01-01

    The association between a geographical region and an mtDNA haplogroup(s) has provided the basis for using mtDNA haplogroups to infer an individual’s place of origin and genetic ancestry. Although it is well known that ancestry inferences using mtDNA haplogroups and those using genome-wide markers are frequently discrepant, little empirical information exists on the magnitude and scope of such discrepancies between multiple mtDNA haplogroups and worldwide populations. We compared genetic-ancestry inferences made by mtDNA-haplogroup membership to those made by autosomal SNPs in ∼940 samples of the Human Genome Diversity Panel and recently admixed populations from the 1000 Genomes Project. Continental-ancestry proportions often varied widely among individuals sharing the same mtDNA haplogroup. For only half of mtDNA haplogroups did the highest average continental-ancestry proportion match the highest continental-ancestry proportion of a majority of individuals with that haplogroup. Prediction of an individual’s mtDNA haplogroup from his or her continental-ancestry proportions was often incorrect. Collectively, these results indicate that for most individuals in the worldwide populations sampled, mtDNA-haplogroup membership provides limited information about either continental ancestry or continental region of origin. PMID:25620206

  9. The mitochondrial outer membrane protein MDI promotes local protein synthesis and mtDNA replication.

    Zhang, Yi; Chen, Yong; Gucek, Marjan; Xu, Hong

    2016-05-17

    Early embryonic development features rapid nuclear DNA replication cycles, but lacks mtDNA replication. To meet the high-energy demands of embryogenesis, mature oocytes are furnished with vast amounts of mitochondria and mtDNA However, the cellular machinery driving massive mtDNA replication in ovaries remains unknown. Here, we describe a Drosophila AKAP protein, MDI that recruits a translation stimulator, La-related protein (Larp), to the mitochondrial outer membrane in ovaries. The MDI-Larp complex promotes the synthesis of a subset of nuclear-encoded mitochondrial proteins by cytosolic ribosomes on the mitochondrial surface. MDI-Larp's targets include mtDNA replication factors, mitochondrial ribosomal proteins, and electron-transport chain subunits. Lack of MDI abolishes mtDNA replication in ovaries, which leads to mtDNA deficiency in mature eggs. Targeting Larp to the mitochondrial outer membrane independently of MDI restores local protein synthesis and rescues the phenotypes of mdi mutant flies. Our work suggests that a selective translational boost by the MDI-Larp complex on the outer mitochondrial membrane might be essential for mtDNA replication and mitochondrial biogenesis during oogenesis. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

  10. [Whole Genome Sequencing of Human mtDNA Based on Ion Torrent PGM™ Platform].

    Cao, Y; Zou, K N; Huang, J P; Ma, K; Ping, Y

    2017-08-01

    To analyze and detect the whole genome sequence of human mitochondrial DNA (mtDNA) by Ion Torrent PGM™ platform and to study the differences of mtDNA sequence in different tissues. Samples were collected from 6 unrelated individuals by forensic postmortem examination, including chest blood, hair, costicartilage, nail, skeletal muscle and oral epithelium. Amplification of whole genome sequence of mtDNA was performed by 4 pairs of primer. Libraries were constructed with Ion Shear™ Plus Reagents kit and Ion Plus Fragment Library kit. Whole genome sequencing of mtDNA was performed using Ion Torrent PGM™ platform. Sanger sequencing was used to determine the heteroplasmy positions and the mutation positions on HVⅠ region. The whole genome sequence of mtDNA from all samples were amplified successfully. Six unrelated individuals belonged to 6 different haplotypes. Different tissues in one individual had heteroplasmy difference. The heteroplasmy positions and the mutation positions on HVⅠ region were verified by Sanger sequencing. After a consistency check by the Kappa method, it was found that the results of mtDNA sequence had a high consistency in different tissues. The testing method used in present study for sequencing the whole genome sequence of human mtDNA can detect the heteroplasmy difference in different tissues, which have good consistency. The results provide guidance for the further applications of mtDNA in forensic science. Copyright© by the Editorial Department of Journal of Forensic Medicine

  11. 26 CFR 1.401(m)-2 - ACP test.

    2010-04-01

    ... 26 Internal Revenue 5 2010-04-01 2010-04-01 false ACP test. 1.401(m)-2 Section 1.401(m)-2 Internal... TAXES Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.401(m)-2 ACP test. (a) Actual contribution percentage (ACP) test—(1) In general—(i) ACP test formula. A plan satisfies the ACP test for a plan year only...

  12. Mitochondrial DNA copy number threshold in mtDNA depletion myopathy.

    Durham, S E; Bonilla, E; Samuels, D C; DiMauro, S; Chinnery, P F

    2005-08-09

    The authors measured the absolute amount of mitochondrial DNA (mtDNA) within single muscle fibers from two patients with thymidine kinase 2 (TK2) deficiency and two healthy controls. TK2 deficient fibers containing more than 0.01 mtDNA/microm3 had residual cytochrome c oxidase (COX) activity. This defines the minimum amount of wild-type mtDNA molecules required to maintain COX activity in skeletal muscle and provides an explanation for the mosaic histochemical pattern seen in patients with mtDNA depletion syndrome.

  13. Towards Horizontal Architecture for Autonomic M2M Service Networks

    Juhani Latvakoski

    2014-05-01

    Full Text Available Today, increasing number of industrial application cases rely on the Machine to Machine (M2M services exposed from physical devices. Such M2M services enable interaction of physical world with the core processes of company information systems. However, there are grand challenges related to complexity and “vertical silos” limiting the M2M market scale and interoperability. It is here expected that horizontal approach for the system architecture is required for solving these challenges. Therefore, a set of architectural principles and key enablers for the horizontal architecture have been specified in this work. A selected set of key enablers called as autonomic M2M manager, M2M service capabilities, M2M messaging system, M2M gateways towards energy constrained M2M asset devices and creation of trust to enable end-to-end security for M2M applications have been developed. The developed key enablers have been evaluated separately in different scenarios dealing with smart metering, car sharing and electric bike experiments. The evaluation results shows that the provided architectural principles, and developed key enablers establish a solid ground for future research and seem to enable communication between objects and applications, which are not initially been designed to communicate together. The aim as the next step in this research is to create a combined experimental system to evaluate the system interoperability and performance in a more detailed manner.

  14. Genetic origin, admixture, and asymmetry in maternal and paternal human lineages in Cuba

    Martínez-Fuentes Antonio

    2008-07-01

    Full Text Available Abstract Background Before the arrival of Europeans to Cuba, the island was inhabited by two Native American groups, the Tainos and the Ciboneys. Most of the present archaeological, linguistic and ancient DNA evidence indicates a South American origin for these populations. In colonial times, Cuban Native American people were replaced by European settlers and slaves from Africa. It is still unknown however, to what extent their genetic pool intermingled with and was 'diluted' by the arrival of newcomers. In order to investigate the demographic processes that gave rise to the current Cuban population, we analyzed the hypervariable region I (HVS-I and five single nucleotide polymorphisms (SNPs in the mitochondrial DNA (mtDNA coding region in 245 individuals, and 40 Y-chromosome SNPs in 132 male individuals. Results The Native American contribution to present-day Cubans accounted for 33% of the maternal lineages, whereas Africa and Eurasia contributed 45% and 22% of the lineages, respectively. This Native American substrate in Cuba cannot be traced back to a single origin within the American continent, as previously suggested by ancient DNA analyses. Strikingly, no Native American lineages were found for the Y-chromosome, for which the Eurasian and African contributions were around 80% and 20%, respectively. Conclusion While the ancestral Native American substrate is still appreciable in the maternal lineages, the extensive process of population admixture in Cuba has left no trace of the paternal Native American lineages, mirroring the strong sexual bias in the admixture processes taking place during colonial times.

  15. A Survey on M2M Service Networks

    Juhani Latvakoski

    2014-11-01

    Full Text Available The number of industrial applications relying on the Machine to Machine (M2M services exposed from physical world has been increasing in recent years. Such M2M services enable communication of devices with the core processes of companies. However, there is a big challenge related to complexity and to application-specific M2M systems called “vertical silos”. This paper focuses on reviewing the technologies of M2M service networks and discussing approaches from the perspectives of M2M information and services, M2M communication and M2M security. Finally, a discussion on technologies and approaches potentially enabling future autonomic M2M service networks are provided. According to our conclusions, it is seen that clear definition of the architectural principles is needed to solve the “vertical silo” problem and then, proceeding towards enabling autonomic capabilities for solving complexity problem appears feasible. Several areas of future research have been identified, e.g., autonomic information based services, optimization of communications with limited capability devices, real-time messaging, creation of trust and end to end security, adaptability, reliability, performance, interoperability, and maintenance.

  16. mtDNA point and length heteroplasmy in high- and low radiation areas of Kerala

    Forster, L.; Forster, P.; Gurney, S.M.; Spencer, M.; Huang, C.; Röhl, A.; Brinkmann, B.

    2010-01-01

    A coastal peninsula in Kerala (India) contains the world's highest level of natural radioactivity in a densely populated area, offering an opportunity to characterize radiation-associated DNA mutations. Here, we focus on mitochondrial DNA (mtDNA) mutations, which are passed exclusively from the mother to her children. To analyse point mutations, we sampled 248 pedigrees (988 individuals) in the high-radiation peninsula and in nearby low-radiation islands as a control population. Then, in an extended sample of 1,172 mtDNA sequences (containing some non-Indians for comparison), we also analysed length mutations, which in mtDNA can lead to the phenomenon of length heteroplasmy, i.e. the existence of different DNA types in the same cell. We wished to find out how fast mtDNA mutates between generations, and whether the mutation rate is increased in radioactive conditions compared to the low-irradiation sample

  17. Mitochondrial DNA (mtDNA haplogroups in 1526 unrelated individuals from 11 Departments of Colombia

    Juan J. Yunis

    2013-01-01

    Full Text Available The frequencies of four mitochondrial Native American DNA haplogroups were determined in 1526 unrelated individuals from 11 Departments of Colombia and compared to the frequencies previously obtained for Amerindian and Afro-Colombian populations. Amerindian mtDNA haplogroups ranged from 74% to 97%. The lowest frequencies were found in Departments on the Caribbean coast and in the Pacific region, where the frequency of Afro-Colombians is higher, while the highest mtDNA Amerindian haplogroup frequencies were found in Departments that historically have a strong Amerindian heritage. Interestingly, all four mtDNA haplogroups were found in all Departments, in contrast to the complete absence of haplogroup D and high frequencies of haplogroup A in Amerindian populations in the Caribbean region of Colombia. Our results indicate that all four Native American mtDNA haplogroups were widely distributed in Colombia at the time of the Spanish conquest.

  18. M2 polarization enhances silica nanoparticle uptake by macrophages

    Jessica eHoppstädter

    2015-03-01

    Full Text Available While silica nanoparticles have enabled numerous industrial and medical applications, their toxicological safety requires further evaluation. Macrophages are the major cell population responsible for nanoparticle clearance in vivo. The prevailing macrophage phenotype largely depends on the local immune status of the host. Whereas M1-polarized macrophages are considered as pro-inflammatory macrophages involved in host defense, M2 macrophages exhibit anti-inflammatory and wound-healing properties, but also promote tumor growth.We employed different models of M1 and M2 polarization: GM-CSF/LPS/IFN-gamma was used to generate primary human M1 cells and M-CSF/IL-10 to differentiate M2 monocyte-derived macrophages. PMA-differentiated THP-1 cells were polarized towards an M1 type by LPS/IFN-gamma and towards M2 by IL-10. Uptake of fluorescent silica nanoparticles (Ø 26 and 41 nm and microparticles (Ø 1.75 µm was quantified. At the concentration used (50 µg/ml, silica nanoparticles did not influence cell viability as assessed by MTT assay. Nanoparticle uptake was enhanced in M2-polarized primary human monocyte-derived macrophages compared with M1 cells, as shown by flow cytometric and microscopic approaches. In contrast, the uptake of microparticles did not differ between M1 and M2 phenotypes. M2 polarization was also associated with increased nanoparticle uptake in the macrophage-like THP-1 cell line. In accordance, in vivo polarized M2-like primary human tumor-associated macrophages (TAM obtained from lung tumors took up more nanoparticles than M1-like alveolar macrophages isolated from the surrounding lung tissue.In summary, our data indicate that the M2 polarization of macrophages promotes nanoparticle internalization. Therefore, the phenotypical differences between macrophage subsets should be taken into consideration in future investigations on nanosafety, but might also open up therapeutic perspectives allowing to specifically target M2

  19. Mitochondrial depolarization in yeast zygotes inhibits clonal expansion of selfish mtDNA.

    Karavaeva, Iuliia E; Golyshev, Sergey A; Smirnova, Ekaterina A; Sokolov, Svyatoslav S; Severin, Fedor F; Knorre, Dmitry A

    2017-04-01

    Non-identical copies of mitochondrial DNA (mtDNA) compete with each other within a cell and the ultimate variant of mtDNA present depends on their relative replication rates. Using yeast Saccharomyces cerevisiae cells as a model, we studied the effects of mitochondrial inhibitors on the competition between wild-type mtDNA and mutant selfish mtDNA in heteroplasmic zygotes. We found that decreasing mitochondrial transmembrane potential by adding uncouplers or valinomycin changes the competition outcomes in favor of the wild-type mtDNA. This effect was significantly lower in cells with disrupted mitochondria fission or repression of the autophagy-related genes ATG8 , ATG32 or ATG33 , implying that heteroplasmic zygotes activate mitochondrial degradation in response to the depolarization. Moreover, the rate of mitochondrially targeted GFP turnover was higher in zygotes treated with uncoupler than in haploid cells or untreated zygotes. Finally, we showed that vacuoles of zygotes with uncoupler-activated autophagy contained DNA. Taken together, our data demonstrate that mitochondrial depolarization inhibits clonal expansion of selfish mtDNA and this effect depends on mitochondrial fission and autophagy. These observations suggest an activation of mitochondria quality control mechanisms in heteroplasmic yeast zygotes. © 2017. Published by The Company of Biologists Ltd.

  20. Random mtDNA mutations modulate proliferation capacity in mouse embryonic fibroblasts

    Kukat, Alexandra; Edgar, Daniel; Bratic, Ivana; Maiti, Priyanka; Trifunovic, Aleksandra

    2011-01-01

    Highlights: → Increased mtDNA mutations in MEFs lead to high level of spontaneous immortalization. → This process is independent of endogenous ROS production. → Aerobic glycolysis significantly contributes to spontaneous immortalization of MEFs. -- Abstract: An increase in mtDNA mutation load leads to a loss of critical cells in different tissues thereby contributing to the physiological process of organismal ageing. Additionally, the accumulation of senescent cells that display changes in metabolic function might act in an active way to further disrupt the normal tissue function. We believe that this could be the important link missing in our understanding of the molecular mechanisms of premature ageing in the mtDNA mutator mice. We tested proliferation capacity of mtDNA mutator cells in vitro. When cultured in physiological levels of oxygen (3%) their proliferation capacity is somewhat lower than wild-type cells. Surprisingly, in conditions of increased oxidative stress (20% O 2 ) mtDNA mutator mouse embryonic fibroblasts exhibit continuous proliferation due to spontaneous immortalization, whereas the same conditions promote senescence in wild-type cells. We believe that an increase in aerobic glycolysis observed in mtDNA mutator mice is a major mechanism behind this process. We propose that glycolysis promotes proliferation and allows a fast turnover of metabolites, but also leads to energy crisis due to lower ATP production rate. This could lead to compromised replication and/or repair and therefore, in rare cases, might lead to mutations in tumor suppressor genes and spontaneous immortalization.

  1. The amount and integrity of mtDNA in maize decline with development.

    Oldenburg, Delene J; Kumar, Rachana A; Bendich, Arnold J

    2013-02-01

    In maize and other grasses there is a developmental gradient from the meristematic cells at the base of the stalk to the differentiated cells at the leaf tip. This gradient presents an opportunity to investigate changes in mitochondrial DNA (mtDNA) that accompany growth under light and dark conditions, as done previously for plastid DNA. Maize mtDNA was analyzed by DAPI-DNA staining of individual mitochondria, gel electrophoresis/blot hybridization, and real-time qPCR. Both the amount and integrity of the mtDNA were found to decline with development. There was a 20-fold decline in mtDNA copy number per cell from the embryo to the light-grown leaf blade. The amount of DNA per mitochondrial particle was greater in dark-grown leaf blade (24 copies, on average) than in the light (2 copies), with some mitochondria lacking any detectable DNA. Three factors that influence the demise of mtDNA during development are considered: (1) the decision to either repair or degrade mtDNA molecules that are damaged by the reactive oxygen species produced as byproducts of respiration; (2) the generation of ATP by photophosphorylation in chloroplasts, reducing the need for respiratory-competent mitochondria; and (3) the shift in mitochondrial function from energy-generating respiration to photorespiration during the transition from non-green to green tissue.

  2. Strong and stable geographic differentiation of swamp buffalo maternal and paternal lineages indicates domestication in the China/Indochina border region.

    Zhang, Yi; Lu, Yongfang; Yindee, Marnoch; Li, Kuan-Yi; Kuo, Hsiao-Yun; Ju, Yu-Ten; Ye, Shaohui; Faruque, Md Omar; Li, Qiang; Wang, Yachun; Cuong, Vu Chi; Pham, Lan Doan; Bouahom, Bounthong; Yang, Bingzhuang; Liang, Xianwei; Cai, Zhihua; Vankan, Dianne; Manatchaiworakul, Wallaya; Kowlim, Nonglid; Duangchantrasiri, Somphot; Wajjwalku, Worawidh; Colenbrander, Ben; Zhang, Yuan; Beerli, Peter; Lenstra, Johannes A; Barker, J Stuart F

    2016-04-01

    The swamp type of the Asian water buffalo is assumed to have been domesticated by about 4000 years BP, following the introduction of rice cultivation. Previous localizations of the domestication site were based on mitochondrial DNA (mtDNA) variation within China, accounting only for the maternal lineage. We carried out a comprehensive sampling of China, Taiwan, Vietnam, Laos, Thailand, Nepal and Bangladesh and sequenced the mtDNA Cytochrome b gene and control region and the Y-chromosomal ZFY, SRY and DBY sequences. Swamp buffalo has a higher diversity of both maternal and paternal lineages than river buffalo, with also a remarkable contrast between a weak phylogeographic structure of river buffalo and a strong geographic differentiation of swamp buffalo. The highest diversity of the swamp buffalo maternal lineages was found in south China and north Indochina on both banks of the Mekong River, while the highest diversity in paternal lineages was in the China/Indochina border region. We propose that domestication in this region was later followed by introgressive capture of wild cows west of the Mekong. Migration to the north followed the Yangtze valley as well as a more eastern route, but also involved translocations of both cows and bulls over large distances with a minor influence of river buffaloes in recent decades. Bayesian analyses of various migration models also supported domestication in the China/Indochina border region. Coalescence analysis yielded consistent estimates for the expansion of the major swamp buffalo haplogroups with a credibility interval of 900 to 3900 years BP. The spatial differentiation of mtDNA and Y-chromosomal haplotype distributions indicates a lack of gene flow between established populations that is unprecedented in livestock. © 2015 John Wiley & Sons Ltd.

  3. Traces of sub-Saharan and Middle Eastern lineages in Indian Muslim populations

    Eaaswarkhanth, Muthukrishnan; Haque, Ikramul; Ravesh, Zeinab; Romero, Irene Gallego; Meganathan, Poorlin Ramakodi; Dubey, Bhawna; Khan, Faizan Ahmed; Chaubey, Gyaneshwer; Kivisild, Toomas; Tyler-Smith, Chris; Singh, Lalji; Thangaraj, Kumarasamy

    2010-01-01

    Islam is the second most practiced religion in India, next to Hinduism. It is still unclear whether the spread of Islam in India has been only a cultural transformation or is associated with detectable levels of gene flow. To estimate the contribution of West Asian and Arabian admixture to Indian Muslims, we assessed genetic variation in mtDNA, Y-chromosomal and LCT/MCM6 markers in 472, 431 and 476 samples, respectively, representing six Muslim communities from different geographical regions of India. We found that most of the Indian Muslim populations received their major genetic input from geographically close non-Muslim populations. However, low levels of likely sub-Saharan African, Arabian and West Asian admixture were also observed among Indian Muslims in the form of L0a2a2 mtDNA and E1b1b1a and J*(xJ2) Y-chromosomal lineages. The distinction between Iranian and Arabian sources was difficult to make with mtDNA and the Y chromosome, as the estimates were highly correlated because of similar gene pool compositions in the sources. In contrast, the LCT/MCM6 locus, which shows a clear distinction between the two sources, enabled us to rule out significant gene flow from Arabia. Overall, our results support a model according to which the spread of Islam in India was predominantly cultural conversion associated with minor but still detectable levels of gene flow from outside, primarily from Iran and Central Asia, rather than directly from the Arabian Peninsula. PMID:19809480

  4. TNF Counterbalances the Emergence of M2 Tumor Macrophages

    Franz Kratochvill

    2015-09-01

    Full Text Available Cancer can involve non-resolving, persistent inflammation where varying numbers of tumor-associated macrophages (TAMs infiltrate and adopt different activation states between anti-tumor M1 and pro-tumor M2 phenotypes. Here, we resolve a cascade causing differential macrophage phenotypes in the tumor microenvironment. Reduction in TNF mRNA production or loss of type I TNF receptor signaling resulted in a striking pattern of enhanced M2 mRNA expression. M2 gene expression was driven in part by IL-13 from eosinophils co-recruited with inflammatory monocytes, a pathway that was suppressed by TNF. Our data define regulatory nodes within the tumor microenvironment that balance M1 and M2 populations. Our results show macrophage polarization in cancer is dynamic and dependent on the balance between TNF and IL-13, thus providing a strategy for manipulating TAMs.

  5. Theoretical Assessment of 178m2Hf De-Excitation

    Hartouni, E P; Chen, M; Descalle, M A; Escher, J E; Loshak, A; Navratil, P; Ormand, W E; Pruet, J; Thompson, I J; Wang, T F

    2008-10-06

    This document contains a comprehensive literature review in support of the theoretical assessment of the {sup 178m2}Hf de-excitation, as well as a rigorous description of controlled energy release from an isomeric nuclear state.

  6. Between the Balkans and the Baltic: Phylogeography of a Common Vole Mitochondrial DNA Lineage Limited to Central Europe.

    Stojak, Joanna; McDevitt, Allan D; Herman, Jeremy S; Kryštufek, Boris; Uhlíková, Jitka; Purger, Jenő J; Lavrenchenko, Leonid A; Searle, Jeremy B; Wójcik, Jan M

    2016-01-01

    The common vole (Microtus arvalis) has been a model species of small mammal for studying end-glacial colonization history. In the present study we expanded the sampling from central and eastern Europe, analyzing contemporary genetic structure to identify the role of a potential 'northern glacial refugium', i.e. a refugium at a higher latitude than the traditional Mediterranean refugia. Altogether we analyzed 786 cytochrome b (cytb) sequences (representing mitochondrial DNA; mtDNA) from the whole of Europe, adding 177 new sequences from central and eastern Europe, and we conducted analyses on eight microsatellite loci for 499 individuals (representing nuclear DNA) from central and eastern Europe, adding data on 311 new specimens. Our new data fill gaps in the vicinity of the Carpathian Mountains, the potential northern refugium, such that there is now dense sampling from the Balkans to the Baltic Sea. Here we present evidence that the Eastern mtDNA lineage of the common vole was present in the vicinity of this Carpathian refugium during the Last Glacial Maximum and the Younger Dryas. The Eastern lineage expanded from this refugium to the Baltic and shows low cytb nucleotide diversity in those most northerly parts of the distribution. Analyses of microsatellites revealed a similar pattern but also showed little differentiation between all of the populations sampled in central and eastern Europe.

  7. A distributed approach for secure M2M communications

    BEN SAIED , Yosra; OLIVEREAU , Alexis; LAURENT , Maryline

    2012-01-01

    International audience; A key establishment solution for heterogeneous Machine to Machine (M2M) communications is proposed. Decentralization in M2M environment leads to situations where highly resource-constrained nodes have to establish end-to-end secured contexts with powerful remote servers, which would normally be impossible because of the technological gap between these classes of devices. This paper proposes a novel collaborative session key exchange method, wherein a highly resource-co...

  8. LEU WWR-M2 fuel assemblies burnable test

    Kirsanov, G.A.; Konoplev, K.A.; Pikulik, R.G.; Sajkov, Yu. P.; Tchmshkyan, D.V.; Tedoradze, L.V.; Zakharov, A.S.

    2000-01-01

    The results of in-pile irradiation tests of LEU WWR-M2 fuel assemblies with reduced enrichment of fuel are submitted in the report. The tests are made according to the Russian Program on Reduced Enrichment for Research and Test Reactors (RERTR). United States Department of Energy and the Ministry of Atomic Energy of Russian Federation jointly fund this Program. The irradiation tests of 5 WWR-M2 experimental assemblies are carried out at WWR-M reactor of the Petersburg Nuclear Physics Institute (PNPI). The information on assembly design and technique of irradiation tests is presented. In the irradiation tests the integrity of fuel assemblies is periodically measured. The report presents the data for the integrity maintained during the burnup of 5 fuel assemblies up to 45%. These results demonstrate the high reliability of the experimental fuel assemblies within the guaranteed burnup limits specified by the manufacturer. The tests are still in progress; it is planned to test and analyze the change in integrity for burnup of up to 70% - 75% or more. LEU WWR-M2 fuel assemblies are to be offered for export by their Novosibirsk manufacturer. Currently, HEU WWR-M2 fuel assemblies are used in Hungary, Ukraine and Vietnam. LEU WWR-M2 fuel assemblies were designed as a possible replacement for the HEU WWR-M2 fuel assemblies in those countries, but their use can be extended to other research reactors. (author)

  9. Acetylcholine Attenuates Hypoxia/ Reoxygenation-Induced Mitochondrial and Cytosolic ROS Formation in H9c2 Cells via M2 Acetylcholine Receptor

    Yi Miao

    2013-02-01

    Full Text Available Background: The anti-infammatory and cardioprotective effect of acetylcholine (ACh has been reported; nevertheless, whether and how ACh exhibits an antioxidant property against ischemia/reperfusion (I/R-induced oxidative stress remains obscure. Methods: In the present study, H9c2 rat cardiomyocytes were exposed to hypoxia/reoxygenation (H/R to mimic I/R injury. We estimated intracellular different sources of reactive oxygen species (ROS by measuring mitochondrial ROS (mtROS, mitochondrial DNA (mtDNA copy number, xanthine oxidase (XO and NADPH oxidase (NOX activity and expression of rac 1. Cell injury was determined by lactate dehydrogenase (LDH release and cleaved caspase-3 expression. The siRNA transfection was performed to knockdown of M2 acetylcholine receptor (M2 AChR expression. Results: 12-h hypoxia followed by 2-h reoxygenation resulted in an abrupt burst of ROS in H9c2 cells. Administration of ACh reduced the levels of ROS in a concentration-dependent manner. Compared to the H/R group, ACh decreased mtROS, recovered mtDNA copy number, diminished XO and NOX activity, rac 1 expression as well as cell injury. Co- treatment with atropine rather than hexamethonium abolished the antioxidant and cardioprotective effect of ACh. Moreover, knockdown of M2 AChR by siRNA showed the similar trends as atropine co-treatment group. Conclusions: ACh inhibits mitochondria-, XO- and NOX-derived ROS production thus protecting H9c2 cells against H/R-induced oxidative stress, and these benefcial effects are mainly mediated by M2 AChR. Our findings suggested that increasing ACh release could be a potential therapeutic strategy for treatment and prevention of I/R injury.

  10. Divorcing the Late Upper Palaeolithic demographic histories of mtDNA haplogroups M1 and U6 in Africa

    Pennarun Erwan

    2012-12-01

    Full Text Available Abstract Background A Southwest Asian origin and dispersal to North Africa in the Early Upper Palaeolithic era has been inferred in previous studies for mtDNA haplogroups M1 and U6. Both haplogroups have been proposed to show similar geographic patterns and shared demographic histories. Results We report here 24 M1 and 33 U6 new complete mtDNA sequences that allow us to refine the existing phylogeny of these haplogroups. The resulting phylogenetic information was used to genotype a further 131 M1 and 91 U6 samples to determine the geographic spread of their sub-clades. No southwest Asian specific clades for M1 or U6 were discovered. U6 and M1 frequencies in North Africa, the Middle East and Europe do not follow similar patterns, and their sub-clade divisions do not appear to be compatible with their shared history reaching back to the Early Upper Palaeolithic. The Bayesian Skyline Plots testify to non-overlapping phases of expansion, and the haplogroups’ phylogenies suggest that there are U6 sub-clades that expanded earlier than those in M1. Some M1 and U6 sub-clades could be linked with certain events. For example, U6a1 and M1b, with their coalescent ages of ~20,000–22,000 years ago and earliest inferred expansion in northwest Africa, could coincide with the flourishing of the Iberomaurusian industry, whilst U6b and M1b1 appeared at the time of the Capsian culture. Conclusions Our high-resolution phylogenetic dissection of both haplogroups and coalescent time assessments suggest that the extant main branching pattern of both haplogroups arose and diversified in the mid-later Upper Palaeolithic, with some sub-clades concomitantly with the expansion of the Iberomaurusian industry. Carriers of these maternal lineages have been later absorbed into and diversified further during the spread of Afro-Asiatic languages in North and East Africa.

  11. Y-chromosome lineages from Portugal, Madeira and Açores record elements of Sephardim and Berber ancestry.

    Gonçalves, Rita; Freitas, Ana; Branco, Marta; Rosa, Alexandra; Fernandes, Ana T; Zhivotovsky, Lev A; Underhill, Peter A; Kivisild, Toomas; Brehm, António

    2005-07-01

    A total of 553 Y-chromosomes were analyzed from mainland Portugal and the North Atlantic Archipelagos of Açores and Madeira, in order to characterize the genetic composition of their male gene pool. A large majority (78-83% of each population) of the male lineages could be classified as belonging to three basic Y chromosomal haplogroups, R1b, J, and E3b. While R1b, accounting for more than half of the lineages in any of the Portuguese sub-populations, is a characteristic marker of many different West European populations, haplogroups J and E3b consist of lineages that are typical of the circum-Mediterranean region or even East Africa. The highly diverse haplogroup E3b in Portuguese likely combines sub-clades of distinct origins. The present composition of the Y chromosomes in Portugal in this haplogroup likely reflects a pre-Arab component shared with North African populations or testifies, at least in part, to the influence of Sephardic Jews. In contrast to the marginally low sub-Saharan African Y chromosome component in Portuguese, such lineages have been detected at a moderately high frequency in our previous survey of mtDNA from the same samples, indicating the presence of sex-related gene flow, most likely mediated by the Atlantic slave trade.

  12. Mitochondrial lineage M1 traces an early human backflow to Africa.

    González, Ana M; Larruga, José M; Abu-Amero, Khaled K; Shi, Yufei; Pestano, José; Cabrera, Vicente M

    2007-07-09

    The out of Africa hypothesis has gained generalized consensus. However, many specific questions remain unsettled. To know whether the two M and N macrohaplogroups that colonized Eurasia were already present in Africa before the exit is puzzling. It has been proposed that the east African clade M1 supports a single origin of haplogroup M in Africa. To test the validity of that hypothesis, the phylogeographic analysis of 13 complete mitochondrial DNA (mtDNA) sequences and 261 partial sequences belonging to haplogroup M1 was carried out. The coalescence age of the African haplogroup M1 is younger than those for other M Asiatic clades. In contradiction to the hypothesis of an eastern Africa origin for modern human expansions out of Africa, the most ancestral M1 lineages have been found in Northwest Africa and in the Near East, instead of in East Africa. The M1 geographic distribution and the relative ages of its different subclades clearly correlate with those of haplogroup U6, for which an Eurasian ancestor has been demonstrated. This study provides evidence that M1, or its ancestor, had an Asiatic origin. The earliest M1 expansion into Africa occurred in northwestern instead of eastern areas; this early spread reached the Iberian Peninsula even affecting the Basques. The majority of the M1a lineages found outside and inside Africa had a more recent eastern Africa origin. Both western and eastern M1 lineages participated in the Neolithic colonization of the Sahara. The striking parallelism between subclade ages and geographic distribution of M1 and its North African U6 counterpart strongly reinforces this scenario. Finally, a relevant fraction of M1a lineages present today in the European Continent and nearby islands possibly had a Jewish instead of the commonly proposed Arab/Berber maternal ascendance.

  13. Mitochondrial lineage M1 traces an early human backflow to Africa

    Pestano José

    2007-07-01

    Full Text Available Abstract Background The out of Africa hypothesis has gained generalized consensus. However, many specific questions remain unsettled. To know whether the two M and N macrohaplogroups that colonized Eurasia were already present in Africa before the exit is puzzling. It has been proposed that the east African clade M1 supports a single origin of haplogroup M in Africa. To test the validity of that hypothesis, the phylogeographic analysis of 13 complete mitochondrial DNA (mtDNA sequences and 261 partial sequences belonging to haplogroup M1 was carried out. Results The coalescence age of the African haplogroup M1 is younger than those for other M Asiatic clades. In contradiction to the hypothesis of an eastern Africa origin for modern human expansions out of Africa, the most ancestral M1 lineages have been found in Northwest Africa and in the Near East, instead of in East Africa. The M1 geographic distribution and the relative ages of its different subclades clearly correlate with those of haplogroup U6, for which an Eurasian ancestor has been demonstrated. Conclusion This study provides evidence that M1, or its ancestor, had an Asiatic origin. The earliest M1 expansion into Africa occurred in northwestern instead of eastern areas; this early spread reached the Iberian Peninsula even affecting the Basques. The majority of the M1a lineages found outside and inside Africa had a more recent eastern Africa origin. Both western and eastern M1 lineages participated in the Neolithic colonization of the Sahara. The striking parallelism between subclade ages and geographic distribution of M1 and its North African U6 counterpart strongly reinforces this scenario. Finally, a relevant fraction of M1a lineages present today in the European Continent and nearby islands possibly had a Jewish instead of the commonly proposed Arab/Berber maternal ascendance.

  14. Evidence of animal mtDNA recombination between divergent populations of the potato cyst nematode Globodera pallida.

    Hoolahan, Angelique H; Blok, Vivian C; Gibson, Tracey; Dowton, Mark

    2012-03-01

    Recombination is typically assumed to be absent in animal mitochondrial genomes (mtDNA). However, the maternal mode of inheritance means that recombinant products are indistinguishable from their progenitor molecules. The majority of studies of mtDNA recombination assess past recombination events, where patterns of recombination are inferred by comparing the mtDNA of different individuals. Few studies assess contemporary mtDNA recombination, where recombinant molecules are observed as direct mosaics of known progenitor molecules. Here we use the potato cyst nematode, Globodera pallida, to investigate past and contemporary recombination. Past recombination was assessed within and between populations of G. pallida, and contemporary recombination was assessed in the progeny of experimental crosses of these populations. Breeding of genetically divergent organisms may cause paternal mtDNA leakage, resulting in heteroplasmy and facilitating the detection of recombination. To assess contemporary recombination we looked for evidence of recombination between the mtDNA of the parental populations within the mtDNA of progeny. Past recombination was detected between a South American population and several UK populations of G. pallida, as well as between two South American populations. This suggests that these populations may have interbred, paternal mtDNA leakage occurred, and the mtDNA of these populations subsequently recombined. This evidence challenges two dogmas of animal mtDNA evolution; no recombination and maternal inheritance. No contemporary recombination between the parental populations was detected in the progeny of the experimental crosses. This supports current arguments that mtDNA recombination events are rare. More sensitive detection methods may be required to adequately assess contemporary mtDNA recombination in animals.

  15. Post-glacial recolonization of the Great Lakes region by the common gartersnake (Thamnophis sirtalis) inferred from mtDNA sequences.

    Placyk, John S; Burghardt, Gordon M; Small, Randall L; King, Richard B; Casper, Gary S; Robinson, Jace W

    2007-05-01

    Pleistocene events played an important role in the differentiation of North American vertebrate populations. Michigan, in particular, and the Great Lakes region, in general, were greatly influenced by the last glaciation. While several hypotheses regarding the recolonization of this region have been advanced, none have been strongly supported. We generated 148 complete ND2 mitochondrial DNA (mtDNA) sequences from common gartersnake (Thamnophis sirtalis) populations throughout the Great Lakes region to evaluate phylogeographic patterns and population structure and to determine whether the distribution of haplotypic variants is related to the post-Pleistocene retreat of the Wisconsinan glacier. The common gartersnake was utilized, as it is believed to have been one of the primary vertebrate invaders of the Great Lakes region following the most recent period of glacial retreat and because it has been a model species for a variety of evolutionary, ecological, behavioral, and physiological studies. Several genetically distinct evolutionary lineages were supported by both genealogical and molecular population genetic analyses, although to different degrees. The geographic distribution of the majority of these lineages is interpreted as reflecting post-glacial recolonization dynamics during the late Pleistocene. These findings generally support previous hypotheses of range expansion in this region.

  16. Do mtDNA Deletions Play a Role in the Development of Nasal Polyposis?

    Arzu Tatar

    2014-04-01

    Full Text Available Objective:Nasal polyposis (NP is an inflammatory disease of the nasal mucosa and paranasal sinuses. Mitochondria are the cellular organelles which produce cellular energy by Oxidative Phosphorylation (OXPHOS, and they have own inheritance material, mtDNA. mtDNA is affected by reactive oxygen samples (ROS which are produced by both OXPHOS and the inflammatory process. The aim of this study was to investigate the 4977 bp and 7400 bp deletions of mtDNA in nasal polyposis tissue, and to indicate the possible association of mtDNA deletions with NP. Methods:Thirty-three patients, aged 15 to 65 years, with nasal polyposis were selected to be assessed for mitochondrial DNA deletions. The patients with possible mtDNA mutations due to mitochondrial disease, being treated with radiotherapy, of advanced age, with a familiar history, aspirin hypersensitivity, or a history of asthma, were excluded. Polyp excision surgery was applied to the treatment of the NP, and after histopathological diagnosis 1x1 cm of polyp tissue samples were used to isolate mtDNA. The 4977 bp and 7400 bp deletion regions, and two control regions of mtDNA were assessed by using four pairs of primers. DNA extractions from the NP tissues and peripheral blood samples of the patients were made, and then Polymerase Chain Reactions (PCR were made. PCR products were separated in 2% agarose gel.Results:No patient had either the 4977 bp deletion or the 7400 bp deletion in their NP tissue, and neither were these deletions evident in their peripheral blood. Two control sequences, one of them from a non-deleted region, and the other from a possible deletion region, were detected in the NP tissues and peripheral blood of all the patients.Conclusions:We had anticipated that some mtDNA deletion might have occurred in NP tissue due to the increased ROS levels caused by chronic inflammation, but we did not detect any deletion. Probably, the duration of inflammation in NP is insufficient to form mtDNA

  17. Inspecting close maternal relatedness: Towards better mtDNA population samples in forensic databases.

    Bodner, Martin; Irwin, Jodi A; Coble, Michael D; Parson, Walther

    2011-03-01

    Reliable data are crucial for all research fields applying mitochondrial DNA (mtDNA) as a genetic marker. Quality control measures have been introduced to ensure the highest standards in sequence data generation, validation and a posteriori inspection. A phylogenetic alignment strategy has been widely accepted as a prerequisite for data comparability and database searches, for forensic applications, for reconstructions of human migrations and for correct interpretation of mtDNA mutations in medical genetics. There is continuing effort to enhance the number of worldwide population samples in order to contribute to a better understanding of human mtDNA variation. This has often lead to the analysis of convenience samples collected for other purposes, which might not meet the quality requirement of random sampling for mtDNA data sets. Here, we introduce an additional quality control means that deals with one aspect of this limitation: by combining autosomal short tandem repeat (STR) marker with mtDNA information, it helps to avoid the bias introduced by related individuals included in the same (small) sample. By STR analysis of individuals sharing their mitochondrial haplotype, pedigree construction and subsequent software-assisted calculation of likelihood ratios based on the allele frequencies found in the population, closely maternally related individuals can be identified and excluded. We also discuss scenarios that allow related individuals in the same set. An ideal population sample would be representative for its population: this new approach represents another contribution towards this goal. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  18. No evidence of Neandertal mtDNA contribution to early modern humans.

    David Serre

    2004-03-01

    Full Text Available The retrieval of mitochondrial DNA (mtDNA sequences from four Neandertal fossils from Germany, Russia, and Croatia has demonstrated that these individuals carried closely related mtDNAs that are not found among current humans. However, these results do not definitively resolve the question of a possible Neandertal contribution to the gene pool of modern humans since such a contribution might have been erased by genetic drift or by the continuous influx of modern human DNA into the Neandertal gene pool. A further concern is that if some Neandertals carried mtDNA sequences similar to contemporaneous humans, such sequences may be erroneously regarded as modern contaminations when retrieved from fossils. Here we address these issues by the analysis of 24 Neandertal and 40 early modern human remains. The biomolecular preservation of four Neandertals and of five early modern humans was good enough to suggest the preservation of DNA. All four Neandertals yielded mtDNA sequences similar to those previously determined from Neandertal individuals, whereas none of the five early modern humans contained such mtDNA sequences. In combination with current mtDNA data, this excludes any large genetic contribution by Neandertals to early modern humans, but does not rule out the possibility of a smaller contribution.

  19. Main: 1M2Q [RPSD[Archive

    Full Text Available 1M2Q トウモロコシ Corn Zea mays L. Casein Kinase Ii, Alpha Chain Name=Ack2; Zea Mays Mole...cule: Casein Kinase Ii, Alpha Chain; Chain: A; Fragment: Catlytic Subunit; Synonym: Ckii; Engineered: Yes Tr...ansferase 2.7.1.37 (Casein Kinase Ii, Alpha Chain) E.De Moliner, S.Sarno, S.Moro, G.Zagotto, G.Zanotti, L.A....=2-326.|PDB; 1M2Q; X-ray; A=2-328.|PDB; 1M2R; X-ray; A=2-328.|PDB; 1OM1; X-ray; A=1-332.|Mai

  20. Polarized M2 macrophages in dogs with visceral leishmaniasis.

    Moreira, Pamela Rodrigues Reina; Fernando, Filipe Santos; Montassier, Hélio José; André, Marcos Rogério; de Oliveira Vasconcelos, Rosemeri

    2016-08-15

    The objective of the present study was to analyze the skin (nasal surface and ear regions), lymph nodes (popliteal and pre-scapular), spleen and liver of dogs with visceral leishmaniasis (VL), in order to investigate the relationship between the parasite load measured as DNA copy number of Alpha gene of DNA polymerase of Leishmania infantum by quantitative PCR and the number of M2 macrophages by immunohistochemistry. A set of 29 naturally infected dogs from an endemic area for VL were sampled and another set of six dogs negative for VL and from a non-endemic area were analyzed as the control group (C). The spleen presented the highest number of Leishmania DNA copies, with significant differences between the groups G1 and G2 (with and without skin lesions, respectively). The M2 phenotype immunostaining predominated among the macrophages in granulomas and inflammatory infiltrates of samples from the skin, lymph nodes and spleens examined. The presence of M2 macrophages in dogs from infected group differed significantly from the control group, in all organs analyzed, excepted liver. The highest proportion of M2 macrophages coincided with the highest parasitism loads found in more susceptible organs of VL dogs, even in the skin, considered a more resistant organ, while the liver showed low parasitism load and low immunostaining for M2 macrophages with no significant differences between infected and negative groups. It was concluded that the predominance of M2 phenotype in VL dogs favored the multiplication of Leishmania infantum in organs of dogs that are more susceptible to Leishmania infection, as skin, lymph nodes and spleen. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Asymptotic distributions of coalescence times and ancestral lineage numbers for populations with temporally varying size.

    Chen, Hua; Chen, Kun

    2013-07-01

    The distributions of coalescence times and ancestral lineage numbers play an essential role in coalescent modeling and ancestral inference. Both exact distributions of coalescence times and ancestral lineage numbers are expressed as the sum of alternating series, and the terms in the series become numerically intractable for large samples. More computationally attractive are their asymptotic distributions, which were derived in Griffiths (1984) for populations with constant size. In this article, we derive the asymptotic distributions of coalescence times and ancestral lineage numbers for populations with temporally varying size. For a sample of size n, denote by Tm the mth coalescent time, when m + 1 lineages coalesce into m lineages, and An(t) the number of ancestral lineages at time t back from the current generation. Similar to the results in Griffiths (1984), the number of ancestral lineages, An(t), and the coalescence times, Tm, are asymptotically normal, with the mean and variance of these distributions depending on the population size function, N(t). At the very early stage of the coalescent, when t → 0, the number of coalesced lineages n - An(t) follows a Poisson distribution, and as m → n, $$n\\left(n-1\\right){T}_{m}/2N\\left(0\\right)$$ follows a gamma distribution. We demonstrate the accuracy of the asymptotic approximations by comparing to both exact distributions and coalescent simulations. Several applications of the theoretical results are also shown: deriving statistics related to the properties of gene genealogies, such as the time to the most recent common ancestor (TMRCA) and the total branch length (TBL) of the genealogy, and deriving the allele frequency spectrum for large genealogies. With the advent of genomic-level sequencing data for large samples, the asymptotic distributions are expected to have wide applications in theoretical and methodological development for population genetic inference.

  2. Characteristics and potential role of M2 macrophages in COPD

    He S

    2017-10-01

    Full Text Available Shengyang He, Lihua Xie, Junjuan Lu, Shenghua SunDepartment of Respiratory Medicine, The Third Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of China Background: COPD is a multi-pathogenesis disease mainly caused by smoking. A further understanding of the mechanism of smoking-related COPD might contribute to preventions and treatments of this disease in the early stages. This study was designed to identify the characteristics of M2 macrophages in COPD for a better understanding about their potential role.Materials and methods: COPD models were built in the C57BL/6 mouse by cigarette smoke (CS exposure combined with intraperitoneal injection of cigarette smoke extract (CSE. The modeling efficiency was evaluated by lung function and hematoxylin and eosin (H&E staining. The number of different macrophage phenotypes was detected by immunohistochemical staining (IHS of CD206, CD86 and CD68 on the lung tissue paraffin section. The RAW264.7 cells were polarized toward the M2 phenotype by interleukin IL-4 and confirmed by a flow cytometer. The gene expression levels of TGF-βRII, Smad2, Smad3 and Smad7 in CSE-treated M2 macrophages were detected by real-time reverse transcription polymerase chain reaction (RT-PCR. The expression levels of TGF-β/Smad pathway-related makers (TGF-βRII, p-Smad2, p-Smad3, Smad7 and TGF-β in alveolar M2 macrophages were detected by two consecutive paraffin section IHS.Results: The COPD model is well established, which is confirmed by the lung function test and lung H&E staining. The whole number of macrophages and the ratio of M2/M1 phenotype are both increased (p<0.05. The level of CD206+ cells in IL-4-stimulated RAW264.7 cells is up to 93.4%, which is confirmed by a flow cytometer. The gene expression of TGF-βRII, Smad2, Smad3 and Smad7 are all enhanced (p<0.05 in CES-treated M2 macrophages, which is detected by RT-PCR. The protein levels of TGF-β/Smad pathway-related markers are

  3. Land, language, and loci: mtDNA in Native Americans and the genetic history of Peru.

    Lewis, Cecil M; Tito, Raúl Y; Lizárraga, Beatriz; Stone, Anne C

    2005-07-01

    Despite a long history of complex societies and despite extensive present-day linguistic and ethnic diversity, relatively few populations in Peru have been sampled for population genetic investigations. In order to address questions about the relationships between South American populations and about the extent of correlation between genetic distance, language, and geography in the region, mitochondrial DNA (mtDNA) hypervariable region I sequences and mtDNA haplogroup markers were examined in 33 individuals from the state of Ancash, Peru. These sequences were compared to those from 19 American Indian populations using diversity estimates, AMOVA tests, mismatch distributions, a multidimensional scaling plot, and regressions. The results show correlations between genetics, linguistics, and geographical affinities, with stronger correlations between genetics and language. Additionally, the results suggest a pattern of differential gene flow and drift in western vs. eastern South America, supporting previous mtDNA and Y chromosome investigations. (c) 2004 Wiley-Liss, Inc

  4. A nonperturbative test of M2-brane theory

    Hosomichi, Kazuo; Lee, Ki-Myeong; Lee, Sungjay; Yi, Piljin; Lee, Sangmin; Park, Jaemo

    2008-01-01

    We discuss non-perturbative effects in the ABJM model due to monopole instantons. We begin by constructing the instanton solutions in the U(2) x U(2) model, explicitly, and computing the Euclidean action. The Wick-rotated Lagrangian is complex and its BPS monopole instantons are found to be a delicate version of the usual 't Hooft-Polyakov monopole solutions. They are generically 1/3 BPS but become 1/2 BPS at special locus in the moduli space of two M2-branes, yet each instanton carries eight fermionic zero modes, regardless of the vacuum choice. The low energy effective action induced by monopole instantons are quartic order in derivatives. The resulting vertices are nonperturbative in 1/k, as expected, but are rational functions of the vacuum moduli. We also analyze the system of two M2-branes in the supergravity framework and compute the higher order interactions via 11-dimensional supergraviton exchange. The comparison of the two shows that the instanton vertices are precisely reproduced by this M2-brane picture, supporting the proposal that the ABJM model describes multiple M2-branes.

  5. Dimeric Complexes of Tryptophan with M2+ Metal Ions

    Dunbar, R. C.; Steill, J. D.; Polfer, N. C.; Oomens, J.

    2009-01-01

    IRMPD spectroscopy using the FELIX free electron laser and a Fourier transform ICR mass spectrometer was used to characterize the structures of electrosprayed dimer complexes M(2+)Trp(2) of tryptophan with a series of eight doubly charged metal ions, including alkaline earths Ca, Sr, and Ba, and

  6. Multiple M2-branes and the embedding tensor

    Bergshoeff, Eric A.; de Roo, Mees; Hohm, Olaf

    2008-01-01

    We show that the Bagger-Lambert theory of multiple M2-branes fits into the general construction of maximally supersymmetric gauge theories using the embedding tensor technique. We apply the embedding tensor technique in order to systematically obtain the consistent gaugings of N = 8 superconformal

  7. An N=1 superfield action for M2 branes

    Mauri, Andrea; Petkou, Anastasios C.

    2008-01-01

    We present an octonionic N=1 superfield action that reproduces in components the action of Bagger and Lambert for M2 branes. By giving an expectation value to one of the scalars we obtain the maximally supersymmetric superfield action for D2 branes

  8. DNA methyltransferase 1 mutations and mitochondrial pathology: is mtDNA methylated?

    Alessandra eMaresca

    2015-03-01

    Full Text Available Autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN and Hereditary sensory neuropathy with dementia and hearing loss (HSN1E are two rare, overlapping neurodegenerative syndromes that have been recently linked to allelic dominant pathogenic mutations in the DNMT1 gene, coding for DNA (cytosine-5-methyltransferase 1. DNMT1 is the enzyme responsible for maintaining the nuclear genome methylation patterns during the DNA replication and repair, thus regulating gene expression. The mutations responsible for ADCA-DN and HSN1E affect the replication foci targeting sequence domain, which regulates DNMT1 binding to chromatin. DNMT1 dysfunction is anticipated to lead to a global alteration of the DNA methylation pattern with predictable downstream consequences on gene expression. Interestingly, ADCA-DN and HSN1E phenotypes share some clinical features typical of mitochondrial diseases, such as optic atrophy, peripheral neuropathy and deafness, and some biochemical evidence of mitochondrial dysfunction. The recent discovery of a mitochondrial isoform of DNMT1 and its proposed role in methylating mitochondrial DNA (mtDNA suggests that DNMT1 mutations may directly affect mtDNA and mitochondrial physiology. On the basis of this latter finding the link between DNMT1 abnormal activity and mitochondrial dysfunction in ADCA-DN and HSN1E appears intuitive, however mtDNA methylation remains highly debated. In the last years several groups demonstrated the presence of 5-methylcytosine in mtDNA by different approaches, but, on the other end, the opposite evidence that mtDNA is not methylated has also been published. Since over 1500 mitochondrial proteins are encoded by the nuclear genome, the altered methylation of these genes may well have a critical role in leading to the mitochondrial impairment observed in ADCA-DN and HSN1E. Thus, many open questions still remain unanswered, such as why mtDNA should be methylated, and how this process is

  9. mtDNA mutation C1494T, haplogroup A, and hearing loss in Chinese

    Wang Chengye; Kong Qingpeng; Yao Yonggang; Zhang Yaping

    2006-01-01

    Mutation C1494T in mitochondrial 12S rRNA gene was recently reported in two large Chinese families with aminoglycoside-induced and nonsyndromic hearing loss (AINHL) and was claimed to be pathogenic. This mutation, however, was first reported in a sample from central China in our previous study that was aimed to reconstruct East Asian mtDNA phylogeny. All these three mtDNAs formed a subclade defined by mutation C1494T in mtDNA haplogroup A. It thus seems that mutation C1494T is a haplogroup A-associated mutation and this matrilineal background may contribute a high risk for the penetrance of mutation C1494T in Chinese with AINHL. To test this hypothesis, we first genotyped mutation C1494T in 553 unrelated individuals from three regional Chinese populations and performed an extensive search for published complete or near-complete mtDNA data sets (>3000 mtDNAs), we then screened the C1494T mutation in 111 mtDNAs with haplogroup A status that were identified from 1823 subjects across China. The search for published mtDNA data sets revealed no other mtDNA besides the above-mentioned three carrying mutation C1494T. None of the 553 randomly selected individuals and the 111 haplogroup A mtDNAs was found to bear this mutation. Therefore, our results suggest that C1494T is a very rare event. The mtDNA haplogroup A background in general is unlikely to play an active role in the penetrance of mutation C1494T in AINHL

  10. A randomized comparison of daunorubicin 90 mg/m2 vs 60 mg/m2 in AML induction

    Burnett, A. K.; Russell, N. H.; Hills, R. K.

    2015-01-01

    Modifying induction therapy in acute myeloid leukemia (AML) may improve the remission rate and reduce the risk of relapse, thereby improving survival. Escalation of the daunorubicin dose to 90 mg/m(2) has shown benefit for some patient subgroups when compared with a dose of 45 mg/m(2), and has been...... = .15). In an exploratory subgroup analysis, there was no subgroup that showed significant benefit, although there was a significant interaction by FLT3 ITD mutation. This trial is registered at http://www.isrctn.com as #ISRCTN55675535....

  11. Radiation induced genetic variability studies in M2 and F2M2 generation in chilli (Capsicum annum L.)

    Rangaiah, S.; Manjunath, A.; Naik, Puttarama; Gangappa, E.

    2002-01-01

    Chilli (Capsicum annum L.) is an important commercial crop in India. Mutation breeding is one of the effective tool to create new variability. Since, yield and its component characters show polygenic inheritance, information on amount of heritable portion of variability created through mutation for these characters is needed to use the induced variability for crop improvement. To harness more variability mutation has been superimposed on hybridization in several crops. The present study is undertaken to estimate the genetic variability induced through gamma irradiation for the polygenically inherited productive traits of chilli in M 2 and F 2 M 2 generation

  12. The origin of widespread species in a poor dispersing lineage (diving beetle genus Deronectes

    David García-Vázquez

    2016-09-01

    Full Text Available In most lineages, most species have restricted geographic ranges, with only few reaching widespread distributions. How these widespread species reached their current ranges is an intriguing biogeographic and evolutionary question, especially in groups known to be poor dispersers. We reconstructed the biogeographic and temporal origin of the widespread species in a lineage with particularly poor dispersal capabilities, the diving beetle genus Deronectes (Dytiscidae. Most of the ca. 60 described species of Deronectes have narrow ranges in the Mediterranean area, with only four species with widespread European distributions. We sequenced four mitochondrial and two nuclear genes of 297 specimens of 109 different populations covering the entire distribution of the four lineages of Deronectes, including widespread species. Using Bayesian probabilities with an a priori evolutionary rate, we performed (1 a global phylogeny/phylogeography to estimate the relationships of the main lineages within each group and root them, and (2 demographic analyses of the best population coalescent model for each species group, including a reconstruction of the geographical history estimated from the distribution of the sampled localities. We also selected 56 specimens to test for the presence of Wolbachia, a maternally transmitted parasite that can alter the patterns of mtDNA variability. All species of the four studied groups originated in the southern Mediterranean peninsulas and were estimated to be of Pleistocene origin. In three of the four widespread species, the central and northern European populations were nested within those in the northern areas of the Anatolian, Balkan and Iberian peninsulas respectively, suggesting a range expansion at the edge of the southern refugia. In the Mediterranean peninsulas the widespread European species were replaced by vicariant taxa of recent origin. The fourth species (D. moestus was proven to be a composite of unrecognised

  13. Canis mtDNA HV1 database: a web-based tool for collecting and surveying Canis mtDNA HV1 haplotype in public database.

    Thai, Quan Ke; Chung, Dung Anh; Tran, Hoang-Dung

    2017-06-26

    Canine and wolf mitochondrial DNA haplotypes, which can be used for forensic or phylogenetic analyses, have been defined in various schemes depending on the region analyzed. In recent studies, the 582 bp fragment of the HV1 region is most commonly used. 317 different canine HV1 haplotypes have been reported in the rapidly growing public database GenBank. These reported haplotypes contain several inconsistencies in their haplotype information. To overcome this issue, we have developed a Canis mtDNA HV1 database. This database collects data on the HV1 582 bp region in dog mitochondrial DNA from the GenBank to screen and correct the inconsistencies. It also supports users in detection of new novel mutation profiles and assignment of new haplotypes. The Canis mtDNA HV1 database (CHD) contains 5567 nucleotide entries originating from 15 subspecies in the species Canis lupus. Of these entries, 3646 were haplotypes and grouped into 804 distinct sequences. 319 sequences were recognized as previously assigned haplotypes, while the remaining 485 sequences had new mutation profiles and were marked as new haplotype candidates awaiting further analysis for haplotype assignment. Of the 3646 nucleotide entries, only 414 were annotated with correct haplotype information, while 3232 had insufficient or lacked haplotype information and were corrected or modified before storing in the CHD. The CHD can be accessed at http://chd.vnbiology.com . It provides sequences, haplotype information, and a web-based tool for mtDNA HV1 haplotyping. The CHD is updated monthly and supplies all data for download. The Canis mtDNA HV1 database contains information about canine mitochondrial DNA HV1 sequences with reconciled annotation. It serves as a tool for detection of inconsistencies in GenBank and helps identifying new HV1 haplotypes. Thus, it supports the scientific community in naming new HV1 haplotypes and to reconcile existing annotation of HV1 582 bp sequences.

  14. New Lineage of Lassa Virus, Togo, 2016

    Whitmer, Shannon L.M.; Strecker, Thomas; Cadar, Daniel; Dienes, Hans-Peter; Faber, Kelly; Patel, Ketan; Brown, Shelley M.; Davis, William G.; Klena, John D.; Rollin, Pierre E.; Schmidt-Chanasit, Jonas; Fichet-Calvet, Elisabeth; Noack, Bernd; Emmerich, Petra; Rieger, Toni; Wolff, Svenja; Fehling, Sarah Katharina; Eickmann, Markus; Mengel, Jan Philipp; Schultze, Tilman; Hain, Torsten; Ampofo, William; Bonney, Kofi; Aryeequaye, Juliana Naa Dedei; Ribner, Bruce; Varkey, Jay B.; Mehta, Aneesh K.; Lyon, G. Marshall; Kann, Gerrit; De Leuw, Philipp; Schuettfort, Gundolf; Stephan, Christoph; Wieland, Ulrike; Fries, Jochen W.U.; Kochanek, Matthias; Kraft, Colleen S.; Wolf, Timo; Nichol, Stuart T.; Becker, Stephan; Ströher, Ute

    2018-01-01

    We describe a strain of Lassa virus representing a putative new lineage that was isolated from a cluster of human infections with an epidemiologic link to Togo. This finding extends the known range of Lassa virus to Togo. PMID:29460758

  15. Tyrosine 129 of the murine gammaherpesvirus M2 protein is critical for M2 function in vivo.

    Rangaswamy, Udaya S; O'Flaherty, Brigid M; Speck, Samuel H

    2014-01-01

    A common strategy shared by all known gammaherpesviruses is their ability to establish a latent infection in lymphocytes--predominantly in B cells. In immunocompromised patients, such as transplant recipients or AIDS patients, gammaherpesvirus infections can lead to the development of lymphoproliferative disease and lymphoid malignancies. The human gamma-herpesviruses, EBV and KSHV, encode proteins that are capable of modulating the host immune signaling machinery, thereby subverting host immune responses. Murine gamma-herpesvirus 68 (MHV68) infection of laboratory strains of mice has proven to be useful small-animal model that shares important pathogenic strategies with the human gamma-herpesviruses. The MHV68 M2 protein is known to manipulate B cell signaling and, dependent on route and dose of virus inoculation, plays a role in both the establishment of latency and virus reactivation. M2 contains two tyrosines that are targets for phosphorylation, and have been shown to interact with the B cell signaling machinery. Here we describe in vitro and in vivo studies of M2 mutants which reveals that while both tyrosines Y120 and Y129 are required for M2 induction of IL-10 expression from primary murine B cells in vitro, only Y129 is critical for reactivation from latency and plasma cell differentiation in vivo.

  16. Tyrosine 129 of the murine gammaherpesvirus M2 protein is critical for M2 function in vivo.

    Udaya S Rangaswamy

    Full Text Available A common strategy shared by all known gammaherpesviruses is their ability to establish a latent infection in lymphocytes--predominantly in B cells. In immunocompromised patients, such as transplant recipients or AIDS patients, gammaherpesvirus infections can lead to the development of lymphoproliferative disease and lymphoid malignancies. The human gamma-herpesviruses, EBV and KSHV, encode proteins that are capable of modulating the host immune signaling machinery, thereby subverting host immune responses. Murine gamma-herpesvirus 68 (MHV68 infection of laboratory strains of mice has proven to be useful small-animal model that shares important pathogenic strategies with the human gamma-herpesviruses. The MHV68 M2 protein is known to manipulate B cell signaling and, dependent on route and dose of virus inoculation, plays a role in both the establishment of latency and virus reactivation. M2 contains two tyrosines that are targets for phosphorylation, and have been shown to interact with the B cell signaling machinery. Here we describe in vitro and in vivo studies of M2 mutants which reveals that while both tyrosines Y120 and Y129 are required for M2 induction of IL-10 expression from primary murine B cells in vitro, only Y129 is critical for reactivation from latency and plasma cell differentiation in vivo.

  17. Lineage Selection and the Maintenance of Sex

    de Vienne, Damien M.; Giraud, Tatiana; Gouyon, Pierre-Henri

    2013-01-01

    Sex predominates in eukaryotes, despite its short-term disadvantage when compared to asexuality. Myriad models have suggested that short-term advantages of sex may be sufficient to counterbalance its twofold costs. However, despite decades of experimental work seeking such evidence, no evolutionary mechanism has yet achieved broad recognition as explanation for the maintenance of sex. We explore here, through lineage-selection models, the conditions favouring the maintenance of sex. In the first model, we allowed the rate of transition to asexuality to evolve, to determine whether lineage selection favoured species with the strongest constraints preventing the loss of sex. In the second model, we simulated more explicitly the mechanisms underlying the higher extinction rates of asexual lineages than of their sexual counterparts. We linked extinction rates to the ecological and/or genetic features of lineages, thereby providing a formalisation of the only figure included in Darwin's “The origin of species”. Our results reinforce the view that the long-term advantages of sex and lineage selection may provide the most satisfactory explanations for the maintenance of sex in eukaryotes, which is still poorly recognized, and provide figures and a simulation website for training and educational purposes. Short-term benefits may play a role, but it is also essential to take into account the selection of lineages for a thorough understanding of the maintenance of sex. PMID:23825582

  18. Mechanisms of mtDNA segregation and mitochondrial signalling in cells with the pathogenic A3243G mutation

    Jahangir Tafrechi, Roshan Sakineh

    2008-01-01

    Using newly developed single cell A3243G mutation load assays a novel mechanism of mtDNA segregation was identified in which the multi-copy mtDNA nucleoid takes a central position. Furthermore, likely due to low level changes in gene expression, no genes or gene sets could be identified with gene

  19. On relating multiple M2 and D2-branes

    Gran, U.; Nilsson, B.E.W; Petersson, C.

    2008-01-01

    Due to the difficulties of finding superconformal Lagrangian theories for multiple M2-branes, we will in this paper instead focus on the field equations. By relaxing the requirement of a Lagrangian formulation we can explore the possibility of having structure constants f ABC D satisfying the fundamental identity but which are not totally antisymmetric. We exemplify this discussion by making use of an explicit choice of a non-antisymmetric f ABC D constructed from the Lie algebra structure constants f ab c of an arbitrary gauge group. Although this choice of f ABC D does not admit an obvious Lagrangian description, it does reproduce the correct SYM theory for a stack of N D2-branes to leading order in g YM -1 upon reduction and, moreover, it sheds new light on the centre of mass coordinates for multiple M2-branes.

  20. Highly retarded M2 transition in 90Nb

    Sergeev, V.O.

    2006-01-01

    One studied properties of 2.3 keV transition between 124.67 (4 - ) and 122.37 keV (6 + ) in 90 Nb. The mentioned M2-transition is shown to be retarded by approximately 10 4 times and provided explanations of the mentioned extraordinary high factor of deceleration. One evaluated impurity of E3 possible multipolarity constituent in the mentioned transition (δ 2 [ru

  1. Solar thermal barometer. 12 million M2 installed in europe

    Anon.

    2002-01-01

    European thermal solar has once again reached its zenith. The difficult times of 1985-1995 are now a thing of the past. The best proof is the very good results of 2001 that show figures in significant progression with respect to those of the year 2000. 1480 320 m 2 . This is now the new record to beat in terms of the annual volume of thermal solar collector installation in the European Union. (author)

  2. State-of-the-art Model M-2 Maintenance System

    Herndon, J.N.; Martin, H.L.; Satterlee, P.E. Jr.; Jelatis, D.G.; Jennrich, C.E.

    1984-04-01

    The Model M-2 Maintenance System is part of an ongoing program within the Consolidated Fuel Reprocessing Program (CFRP) at Oak Ridge National Laboratory (ORNL) to improve remote manipulation technology for future nuclear fuel reprocessing and other remote applications. Techniques, equipment, and guidelines which can improve the efficiency of remote maintenance are being developed. The Model M-2 Maintenance System, installed in the Integrated Equipment Test (IET) Facility at ORNL, provides a complete, integrated remote maintenance system for the demonstration and development of remote maintenance techniques. The system comprises a pair of force-reflecting servomanipulator arms, television viewing, lighting, and auxiliary lifting capabilities, thereby allowing manlike maintenance operations to be executed remotely within the remote cell mockup area in the IET. The Model M-2 Maintenance System incorporates an upgraded version of the proven Central Research Laboratories' Model M servomanipulator. Included are state-of-the-art brushless dc servomotors for improved performance, remotely removable wrist assemblies, geared azimuth drive, and a distributed microprocessor-based digital control system. 5 references, 8 figures

  3. Penrose limits, pp waves, and deformed M2-branes

    Cvetic, M.; Lue, H.; Pope, C.N.

    2004-01-01

    Motivated by the recent discussions of the Penrose limit of AdS 5 xS 5 , we examine a more general class of supersymmetric pp-wave solutions of the type IIB theory, with a larger number of nonvanishing structures in the self-dual 5-form. One of the pp-wave solutions can be obtained as a Penrose limit of a D3-D3 intersection. In addition to 16 standard supersymmetries these backgrounds always allow for supernumerary supersymmetries. The latter are in one-to-one correspondence with the linearly realized world-sheet supersymmetries of the corresponding exactly solvable type IIB string action. The pp-waves provide new examples where supersymmetries will survive in a T-duality transformation on the x + coordinate. The T-dual solutions can be lifted to give supersymmetric deformed M2-branes in D=11. The deformed M2-brane is dual to a three-dimensional field theory whose renormalization group flow runs from the conformal fixed point in the infrared regime to a nonconformal theory as the energy increases. At a certain intermediate energy scale there is a phase transition associated with a naked singularity of the M2-brane. In the ultraviolet limit the theory is related by T duality to an exactly solvable massive type IIB string theory

  4. Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice

    Safdar, Adeel; Bourgeois, Jacqueline M.; Ogborn, Daniel I.; Little, Jonathan P.; Hettinga, Bart P.; Akhtar, Mahmood; Thompson, James E.; Melov, Simon; Mocellin, Nicholas J.; Kujoth, Gregory C.; Prolla, Tomas A.; Tarnopolsky, Mark A.

    2011-01-01

    A causal role for mitochondrial DNA (mtDNA) mutagenesis in mammalian aging is supported by recent studies demonstrating that the mtDNA mutator mouse, harboring a defect in the proofreading-exonuclease activity of mitochondrial polymerase gamma, exhibits accelerated aging phenotypes characteristic of human aging, systemic mitochondrial dysfunction, multisystem pathology, and reduced lifespan. Epidemiologic studies in humans have demonstrated that endurance training reduces the risk of chronic diseases and extends life expectancy. Whether endurance exercise can attenuate the cumulative systemic decline observed in aging remains elusive. Here we show that 5 mo of endurance exercise induced systemic mitochondrial biogenesis, prevented mtDNA depletion and mutations, increased mitochondrial oxidative capacity and respiratory chain assembly, restored mitochondrial morphology, and blunted pathological levels of apoptosis in multiple tissues of mtDNA mutator mice. These adaptations conferred complete phenotypic protection, reduced multisystem pathology, and prevented premature mortality in these mice. The systemic mitochondrial rejuvenation through endurance exercise promises to be an effective therapeutic approach to mitigating mitochondrial dysfunction in aging and related comorbidities. PMID:21368114

  5. Allozyme and mtDNA variation of white seabream Diplodus sargus ...

    These results can be explained by the chaotic genetic patchiness hypothesis. In contrast, the mtDNA data indicated genetic homogeneity among localities showing the absence of structure in white seabream populations across the Siculo-Tunisian Strait. Historical demography of this species suggests that it has undergone ...

  6. Characterization of mtDNA haplogroups in 14 Mexican indigenous populations.

    Peñaloza-Espinosa, Rosenda I; Arenas-Aranda, Diego; Cerda-Flores, Ricardo M; Buentello-Malo, Leonor; González-Valencia, Gerardo; Torres, Javier; Alvarez, Berenice; Mendoza, Irma; Flores, Mario; Sandoval, Lucila; Loeza, Francisco; Ramos, Irma; Muñoz, Leopoldo; Salamanca, Fabio

    2007-06-01

    In this descriptive study we investigated the genetic structure of 513 Mexican indigenous subjects grouped in 14 populations (Mixteca-Alta, Mixteca-Baja, Otomi, Purépecha, Tzeltal, Tarahumara, Huichol, Nahua-Atocpan, Nahua-Xochimilco, Nahua-Zitlala, Nahua-Chilacachapa, Nahua-Ixhuatlancillo, Nahua-Necoxtla, and Nahua-Coyolillo) based on mtDNA haplogroups. These communities are geographically and culturally isolated; parents and grandparents were born in the community. Our data show that 98.6% of the mtDNA was distributed in haplogroups A1, A2, B1, B2, C1, C2, D1, and D2. Haplotype X6 was present in the Tarahumara (1/53) and Huichol (3/15), and haplotype L was present in the Nahua-Coyolillo (3/38). The first two principal components accounted for 95.9% of the total variation in the sample. The mtDNA haplogroup frequencies in the Purépecha and Zitlala were intermediate to cluster 1 (Otomi, Nahua-Ixhuatlancillo, Nahua-Xochimilco, Mixteca-Baja, and Tzeltal) and cluster 2 (Nahua-Necoxtla, Nahua-Atocpan, and Nahua-Chilacachapa). The Huichol, Tarahumara, Mixteca-Alta, and Nahua-Coyolillo were separated from the rest of the populations. According to these findings, the distribution of mtDNA haplogroups found in Mexican indigenous groups is similar to other Amerindian haplogroups, except for the African haplogroup found in one population.

  7. Pleistocene-Holocene boundary in Southern Arabia from the perspective of human mtDNA variation

    Al-Abri, A.-R.; Podgorná, E.; Rose, J. I.; Pereira, L.; Mulligan, C. J.; Silva, N. M.; Bayoumi, R.; Soares, P.; Černý, Viktor

    2012-01-01

    Roč. 149, č. 2 (2012), s. 291-298 ISSN 0002-9483 R&D Projects: GA MŠk ME 917 Institutional research plan: CEZ:AV0Z80020508 Keywords : mtDNA variation * Arabian Peninsula * migrations Subject RIV: AC - Archeology, Anthropology, Ethnology Impact factor: 2.481, year: 2012

  8. Mutations of mtDNA polymerase-γ and hyperlactataemia in the HIV ...

    Mutations of mtDNA polymerase-γ and hyperlactataemia in the HIV-infected Zulu population of South Africa. ... D B A Ojwach, C Aldous, P Kocheleff, B Sartorius ... of their capacity to impede human mitochondrial DNA polymerase-γ (POLG), ...

  9. Comprehensive view of the population history of Arabia as inferred by mtDNA variation

    Černý, Viktor; Čížková, M.; Poloni, E. S.; Al-Meeri, A.; Mulligan, C. J.

    2016-01-01

    Roč. 159, č. 4 (2016), s. 607-616 ISSN 0002-9483 R&D Projects: GA ČR GA13-37998S Institutional support: RVO:67985912 Keywords : mtDNA variation * Arabian Peninsula * migrations Subject RIV: AC - Archeology, Anthropology, Ethnology Impact factor: 2.552, year: 2016

  10. The Expansion of mtDNA Haplogroup L3 within and out of Africa

    Soares, P.; Alshamali, F.; Pereira, J. B.; Fernandes, V.; Silva, N. M.; Afonso, C.; Costa, M. D.; Musilová, E.; Macaulay, V.; Richards, M. B.; Černý, Viktor; Pereira, L.

    2012-01-01

    Roč. 29, č. 3 (2012), s. 915-927 ISSN 0737-4038 R&D Projects: GA MŠk ME 917 Institutional research plan: CEZ:AV0Z80020508 Keywords : mtDNA * complete genomes * haplogroup L3 * out of Africa * modern human expansions Sub ject RIV: AC - Archeology, Anthropology, Ethnology Impact factor: 10.353, year: 2012

  11. mtDNA sequence diversity of Hazara ethnic group from Pakistan.

    Rakha, Allah; Fatima; Peng, Min-Sheng; Adan, Atif; Bi, Rui; Yasmin, Memona; Yao, Yong-Gang

    2017-09-01

    The present study was undertaken to investigate mitochondrial DNA (mtDNA) control region sequences of Hazaras from Pakistan, so as to generate mtDNA reference database for forensic casework in Pakistan and to analyze phylogenetic relationship of this particular ethnic group with geographically proximal populations. Complete mtDNA control region (nt 16024-576) sequences were generated through Sanger Sequencing for 319 Hazara individuals from Quetta, Baluchistan. The population sample set showed a total of 189 distinct haplotypes, belonging mainly to West Eurasian (51.72%), East & Southeast Asian (29.78%) and South Asian (18.50%) haplogroups. Compared with other populations from Pakistan, the Hazara population had a relatively high haplotype diversity (0.9945) and a lower random match probability (0.0085). The dataset has been incorporated into EMPOP database under accession number EMP00680. The data herein comprises the largest, and likely most thoroughly examined, control region mtDNA dataset from Hazaras of Pakistan. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. M2-Branes in N = 3 Harmonic Superspace

    E. Ivanov

    2010-01-01

    Full Text Available We give a brief account of the recently proposed N = 3 superfield formulation of the N = 6, 3D superconformal theory of Aharony et al (ABJM describing a low-energy limit of the system of multiple M2-branes on the AdS4×S7/Zk background. This formulation is given in harmonic N = 3 superspace and reveals a number of surprising new features. In particular, the sextic scalar potential of ABJM arises at the on-shell component level as the result of eliminating appropriate auxiliary fields, while there is no explicit superpotential at the off-shell superfield level.

  13. SLiM 2: Flexible, Interactive Forward Genetic Simulations.

    Haller, Benjamin C; Messer, Philipp W

    2017-01-01

    Modern population genomic datasets hold immense promise for revealing the evolutionary processes operating in natural populations, but a crucial prerequisite for this goal is the ability to model realistic evolutionary scenarios and predict their expected patterns in genomic data. To that end, we present SLiM 2: an evolutionary simulation framework that combines a powerful, fast engine for forward population genetic simulations with the capability of modeling a wide variety of complex evolutionary scenarios. SLiM achieves this flexibility through scriptability, which provides control over most aspects of the simulated evolutionary scenarios with a simple R-like scripting language called Eidos. An example SLiM simulation is presented to illustrate the power of this approach. SLiM 2 also includes a graphical user interface for simulation construction, interactive runtime control, and dynamic visualization of simulation output, facilitating easy and fast model development with quick prototyping and visual debugging. We conclude with a performance comparison between SLiM and two other popular forward genetic simulation packages. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  14. Determining Lineage Pathways from Cellular Barcoding Experiments

    Leïla Perié

    2014-02-01

    Full Text Available Cellular barcoding and other single-cell lineage-tracing strategies form experimental methodologies for analysis of in vivo cell fate that have been instrumental in several significant recent discoveries. Due to the highly nonlinear nature of proliferation and differentiation, interrogation of the resulting data for evaluation of potential lineage pathways requires a new quantitative framework complete with appropriate statistical tests. Here, we develop such a framework, illustrating its utility by analyzing data from barcoded multipotent cells of the blood system. This application demonstrates that the data require additional paths beyond those found in the classical model, which leads us to propose that hematopoietic differentiation follows a loss of potential mechanism and to suggest further experiments to test this deduction. Our quantitative framework can evaluate the compatibility of lineage trees with barcoded data from any proliferating and differentiating cell system.

  15. Parkinson's disease brain mitochondria have impaired respirasome assembly, age-related increases in distribution of oxidative damage to mtDNA and no differences in heteroplasmic mtDNA mutation abundance

    Keeney Paula M

    2009-09-01

    Full Text Available Abstract Background Sporadic Parkinson's disease (sPD is a nervous system-wide disease that presents with a bradykinetic movement disorder and is frequently complicated by depression and cognitive impairment. sPD likely has multiple interacting causes that include increased oxidative stress damage to mitochondrial components and reduced mitochondrial bioenergetic capacity. We analyzed mitochondria from postmortem sPD and CTL brains for evidence of oxidative damage to mitochondrial DNA (mtDNA, heteroplasmic mtDNA point mutations and levels of electron transport chain proteins. We sought to determine if sPD brains possess any mtDNA genotype-respiratory phenotype relationships. Results Treatment of sPD brain mtDNA with the mitochondrial base-excision repair enzyme 8-oxyguanosine glycosylase-1 (hOGG1 inhibited, in an age-dependent manner, qPCR amplification of overlapping ~2 kbase products; amplification of CTL brain mtDNA showed moderate sensitivity to hOGG1 not dependent on donor age. hOGG1 mRNA expression was not different between sPD and CTL brains. Heteroplasmy analysis of brain mtDNA using Surveyor nuclease® showed asymmetric distributions and levels of heteroplasmic mutations across mtDNA but no patterns that statistically distinguished sPD from CTL. sPD brain mitochondria displayed reductions of nine respirasome proteins (respiratory complexes I-V. Reduced levels of sPD brain mitochondrial complex II, III and V, but not complex I or IV proteins, correlated closely with rates of NADH-driven electron flow. mtDNA levels and PGC-1α expression did not differ between sPD and CTL brains. Conclusion PD brain mitochondria have reduced mitochondrial respiratory protein levels in complexes I-V, implying a generalized defect in respirasome assembly. These deficiencies do not appear to arise from altered point mutational burden in mtDNA or reduction of nuclear signaling for mitochondrial biogenesis, implying downstream etiologies. The origin of age

  16. Maternal DNA lineages at the gate of Europe in the 10th century AD

    Modi, Alessandra; Vai, Stefania; Pilli, Elena; Mircea, Cristina; Radu, Claudia; Urduzia, Claudia; Pinter, Zeno Karl; Bodolică, Vitalie; Dobrinescu, Cătălin; Hervella, Montserrat; Popescu, Octavian; Lari, Martina; Caramelli, David; Kelemen, Beatrice

    2018-01-01

    Given the paucity of archaeogenetic data available for medieval European populations in comparison to other historical periods, the genetic landscape of this age appears as a puzzle of dispersed, small, known pieces. In particular, Southeastern Europe has been scarcely investigated to date. In this paper, we report the study of mitochondrial DNA in 10th century AD human samples from Capidava necropolis, located in Dobruja (Southeastern Romania, Southeastern Europe). This geographical region is particularly interesting because of the extensive population flux following diverse migration routes, and the complex interactions between distinct population groups during the medieval period. We successfully amplified and typed the mitochondrial control region of 10 individuals. For five of them, we also reconstructed the complete mitochondrial genomes using hybridization-based DNA capture combined with Next Generation Sequencing. We have portrayed the genetic structure of the Capidava medieval population, represented by 10 individuals displaying 8 haplotypes (U5a1c2a, V1a, R0a2’3, H1, U3a, N9a9, H5e1a1, and H13a1a3). Remarkable for this site is the presence of both Central Asiatic (N9a) and common European mtDNA haplotypes, establishing Capidava as a point of convergence between East and West. The distribution of mtDNA lineages in the necropolis highlighted the existence of two groups of two individuals with close maternal relationships as they share the same haplotypes. We also sketch, using comparative statistical and population genetic analyses, the genetic relationships between the investigated dataset and other medieval and modern Eurasian populations. PMID:29538439

  17. Mitochondrial mosaics in the liver of 3 infants with mtDNA defects

    Scalais Emmanuel

    2009-06-01

    Full Text Available Abstract Background In muscle cytochrome oxidase (COX negative fibers (mitochondrial mosaics have often been visualized. Methods COX activity staining of liver for light and electron microscopy, muscle stains, blue native gel electrophoresis and activity assays of respiratory chain proteins, their immunolocalisation, mitochondrial and nuclear DNA analysis. Results Three unrelated infants showed a mitochondrial mosaic in the liver after staining for COX activity, i.e. hepatocytes with strongly reactive mitochondria were found adjacent to cells with many negative, or barely reactive, mitochondria. Deficiency was most severe in the patient diagnosed with Pearson syndrome. Ragged-red fibers were absent in muscle biopsies of all patients. Enzyme biochemistry was not diagnostic in muscle, fibroblasts and lymphocytes. Blue native gel electrophoresis of liver tissue, but not of muscle, demonstrated a decreased activity of complex IV; in both muscle and liver subcomplexes of complex V were seen. Immunocytochemistry of complex IV confirmed the mosaic pattern in two livers, but not in fibroblasts. MRI of the brain revealed severe white matter cavitation in the Pearson case, but only slight cortical atrophy in the Alpers-Huttenlocher patient, and a normal image in the 3rd. MtDNA in leucocytes showed a common deletion in 50% of the mtDNA molecules of the Pearson patient. In the patient diagnosed with Alpers-Huttenlocher syndrome, mtDNA was depleted for 60% in muscle. In the 3rd patient muscular and hepatic mtDNA was depleted for more than 70%. Mutations in the nuclear encoded gene of POLG were subsequently found in both the 2nd and 3rd patients. Conclusion Histoenzymatic COX staining of a liver biopsy is fast and yields crucial data about the pathogenesis; it indicates whether mtDNA should be assayed. Each time a mitochondrial disorder is suspected and muscle data are non-diagnostic, a liver biopsy should be recommended. Mosaics are probably more frequent

  18. Supersymmetric states in M5/M2 CFTs

    Bhattacharyya, Sayantani; Minwalla, Shiraz

    2007-01-01

    We propose an exact, finite N formula for the partition function over 1/4 th BPS states in the conformal field theory on the world volume of N coincident M5 branes, and 1/8 th BPS states in the theory of N conincident M2 branes. We obtain our partition function by performing the radial quantization of the Coulomb Branches of these theories and rederive the same formula from the quantization of supersymmetric giant and dual giant gravitons in AdS 7 x S 4 and AdS 4 x S 7 . Our partition function is qualitatively similar to the analogous quantity in N = 4 Yang Mills. It reduces to the sum over supersymmetric multi gravitons at low energies, but deviates from this supergravity formula at energies that scale like a positive power of N

  19. TREAT experiment M2 post-test examination

    Holland, J.W.; Teske, G.M.; Florek, J.C.

    1986-01-01

    Transient Reactor Test (TREAT) Facility experiment M2 was performed to evaluate the transient behavior of metal-alloy fuel under accident conditions to investigate the inherent safety features of the fuel in integral fast reactor (IFR) system designs. Objectives were to obtain early information on the key fuel behavior characteristics at transient overpower (TOP) conditions in metal-fueled fast reactors; namely, margin to cladding breach and extent of axial self-extrusion of fuel within intact cladding. The onset of cladding breaching depends on fuel/cladding eutectic formation, as well as cladding pressurization and melting. Driving forces for fuel extrusion are fission gas, liquid sodium, and volatile fission products trapped within the fuel matrix. The post-test examination provided data essential for correctly modeling fuel behavior in accident codes

  20. mtDNA copy number in oocytes of different sizes from individual pre- and post-pubertal pigs

    Pedersen, Hanne Skovsgaard; Løvendahl, Peter; Larsen, Knud Erik

    2014-01-01

    from ovaries of 10 pre- and 10 post-pubertal pigs. Cumulus cells were removed and the oocytes were measured (inside-ZP-diameter). Oocytes were transferred to DNAase-free tubes, snap-frozen, and stored at –80°C. The genes ND1 and COX1 were used to determine the mtDNA copy number. Plasmid preparations...... Reproduction 131, 233–245). However, the correlation between size and mtDNA copy number in single oocytes has not been determined. This study describes the relation between oocytes of defined diameters from individual pre- and postpubertal pigs and mtDNA copy number. Cumulus-oocyte complexes were aspirated...

  1. Targeted transgenic overexpression of mitochondrial thymidine kinase (TK2) alters mitochondrial DNA (mtDNA) and mitochondrial polypeptide abundance: transgenic TK2, mtDNA, and antiretrovirals.

    Hosseini, Seyed H; Kohler, James J; Haase, Chad P; Tioleco, Nina; Stuart, Tami; Keebaugh, Erin; Ludaway, Tomika; Russ, Rodney; Green, Elgin; Long, Robert; Wang, Liya; Eriksson, Staffan; Lewis, William

    2007-03-01

    Mitochondrial toxicity limits nucleoside reverse transcriptase inhibitors (NRTIs) for acquired immune deficiency syndrome. NRTI triphosphates, the active moieties, inhibit human immunodeficiency virus reverse transcriptase and eukaryotic mitochondrial DNA polymerase pol-gamma. NRTI phosphorylation seems to correlate with mitochondrial toxicity, but experimental evidence is lacking. Transgenic mice (TGs) with cardiac overexpression of thymidine kinase isoforms (mitochondrial TK2 and cytoplasmic TK1) were used to study NRTI mitochondrial toxicity. Echocardiography and nuclear magnetic resonance imaging defined cardiac performance and structure. TK gene copy and enzyme activity, mitochondrial (mt) DNA and polypeptide abundance, succinate dehydrogenase and cytochrome oxidase histochemistry, and electron microscopy correlated with transgenesis, mitochondrial structure, and biogenesis. Antiretroviral combinations simulated therapy. Untreated hTK1 or TK2 TGs exhibited normal left ventricle mass. In TK2 TGs, cardiac TK2 gene copy doubled, activity increased 300-fold, and mtDNA abundance doubled. Abundance of the 17-kd subunit of complex I, succinate dehydrogenase histochemical activity, and cristae density increased. NRTIs increased left ventricle mass 20% in TK2 TGs. TK activity increased 3 logs in hTK1 TGs, but no cardiac phenotype resulted. NRTIs abrogated functional effects of transgenically increased TK2 activity but had no effect on TK2 mtDNA abundance. Thus, NRTI mitochondrial phosphorylation by TK2 is integral to clinical NRTI mitochondrial toxicity.

  2. Stem Cell Lineages: Between Cell and Organism

    Melinda Bonnie Fagan

    2017-01-01

    Full Text Available Ontologies of living things are increasingly grounded on the concepts and practices of current life science. Biological development is a process, undergone by living things, which begins with a single cell and (in an important class of cases ends with formation of a multicellular organism. The process of development is thus prima facie central for ideas about biological individuality and organismality. However, recent accounts of these concepts do not engage developmental biology. This paper aims to fill the gap, proposing the lineage view of stem cells as an ontological framework for conceptualizing organismal development. This account is grounded on experimental practices of stem cell research, with emphasis on new techniques for generating biological organization in vitro. On the lineage view, a stem cell is the starting point of a cell lineage with a specific organismal source, time-interval of existence, and ‘tree topology’ of branch-points linking the stem to developmental termini. The concept of ‘enkapsis’ accommodates the cell-organism relation within the lineage view; this hierarchical notion is further explicated by considering the methods and results of stem cell experiments. Results of this examination include a (partial characterization of stem cells’ developmental versatility, and the context-dependence of developmental processes involving stem cells.

  3. Diversity rankings among bacterial lineages in soil.

    Youssef, Noha H; Elshahed, Mostafa S

    2009-03-01

    We used rarefaction curve analysis and diversity ordering-based approaches to rank the 11 most frequently encountered bacterial lineages in soil according to diversity in 5 previously reported 16S rRNA gene clone libraries derived from agricultural, undisturbed tall grass prairie and forest soils (n=26,140, 28 328, 31 818, 13 001 and 53 533). The Planctomycetes, Firmicutes and the delta-Proteobacteria were consistently ranked among the most diverse lineages in all data sets, whereas the Verrucomicrobia, Gemmatimonadetes and beta-Proteobacteria were consistently ranked among the least diverse. On the other hand, the rankings of alpha-Proteobacteria, Acidobacteria, Actinobacteria, Bacteroidetes and Chloroflexi varied widely in different soil clone libraries. In general, lineages exhibiting largest differences in diversity rankings also exhibited the largest difference in relative abundance in the data sets examined. Within these lineages, a positive correlation between relative abundance and diversity was observed within the Acidobacteria, Actinobacteria and Chloroflexi, and a negative diversity-abundance correlation was observed within the Bacteroidetes. The ecological and evolutionary implications of these results are discussed.

  4. The mtDNA haplogroup P of modern Asian cattle: A genetic legacy of Asian aurochs?

    Noda, Aoi; Yonesaka, Riku; Sasazaki, Shinji

    2018-01-01

    Background Aurochs (Bos primigenius) were distributed throughout large parts of Eurasia and Northern Africa during the late Pleistocene and the early Holocene, and all modern cattle are derived from the aurochs. Although the mtDNA haplogroups of most modern cattle belong to haplogroups T and I, several additional haplogroups (P, Q, R, C and E) have been identified in modern cattle and aurochs. Haplogroup P was the most common haplogroup in European aurochs, but so far, it has been identified in only three of >3,000 submitted haplotypes of modern Asian cattle. Methodology We sequenced the complete mtDNA D-loop region of 181 Japanese Shorthorn cattle and analyzed these together with representative bovine mtDNA sequences. The haplotype P of Japanese Shorthorn cattle was analyzed along with that of 36 previously published European aurochs and three modern Asian cattle sequences using the hypervariable 410 bp of the D-loop region. Conclusions We detected the mtDNA haplogroup P in Japanese Shorthorn cattle with an extremely high frequency (83/181). Phylogenetic networks revealed two main clusters, designated as Pa for haplogroup P in European aurochs and Pc in modern Asian cattle. We also report the genetic diversity of haplogroup P compared with the sequences of extinct aurochs. No shared haplotypes are observed between the European aurochs and the modern Asian cattle. This finding suggests the possibility of local and secondary introgression events of haplogroup P in northeast Asian cattle, and will contribute to a better understanding of its origin and genetic diversity. PMID:29304129

  5. The mtDNA haplogroup P of modern Asian cattle: A genetic legacy of Asian aurochs?

    Noda, Aoi; Yonesaka, Riku; Sasazaki, Shinji; Mannen, Hideyuki

    2018-01-01

    Aurochs (Bos primigenius) were distributed throughout large parts of Eurasia and Northern Africa during the late Pleistocene and the early Holocene, and all modern cattle are derived from the aurochs. Although the mtDNA haplogroups of most modern cattle belong to haplogroups T and I, several additional haplogroups (P, Q, R, C and E) have been identified in modern cattle and aurochs. Haplogroup P was the most common haplogroup in European aurochs, but so far, it has been identified in only three of >3,000 submitted haplotypes of modern Asian cattle. We sequenced the complete mtDNA D-loop region of 181 Japanese Shorthorn cattle and analyzed these together with representative bovine mtDNA sequences. The haplotype P of Japanese Shorthorn cattle was analyzed along with that of 36 previously published European aurochs and three modern Asian cattle sequences using the hypervariable 410 bp of the D-loop region. We detected the mtDNA haplogroup P in Japanese Shorthorn cattle with an extremely high frequency (83/181). Phylogenetic networks revealed two main clusters, designated as Pa for haplogroup P in European aurochs and Pc in modern Asian cattle. We also report the genetic diversity of haplogroup P compared with the sequences of extinct aurochs. No shared haplotypes are observed between the European aurochs and the modern Asian cattle. This finding suggests the possibility of local and secondary introgression events of haplogroup P in northeast Asian cattle, and will contribute to a better understanding of its origin and genetic diversity.

  6. mtDNA of Fulani Nomads and Their Genetic Relationships to Neighboring Sedentary Populations

    Černý, Viktor; Hájek, Martin; Bromová, Markéta; Čmejla, R.; Diallo, I.; Brdička, R.

    2006-01-01

    Roč. 78, č. 1 (2006), s. 9-27 ISSN 0018-7143 R&D Projects: GA ČR(CZ) GA404/03/0318 Institutional research plan: CEZ:AV0Z80020508 Keywords : mtDNA variation * HVS-I * Fulani nomads * sub-Saharan populations * Chad * Cameroon * Burkina Faso Subject RIV: AC - Archeology, Anthropology, Ethnology Impact factor: 1.132, year: 2006

  7. Does aerobic exercises induce mtDNA mutation in human blood ...

    The aim of this study was to determine the effect of eight weeks aerobic training on mitochondrial DNA (mtDNA) mutation in human blood leucocytes. Twenty untrained healthy students (training group: n =10, age = 20.7±1.5 yrs, weight = 67.7±10 kg, BF% = 17.5±7.35 & control group: n =10, age = 21±1.3 yrs, weight ...

  8. Pliocene-Pleistocene lineage diversifications in the Eastern Indigo Snake (Drymarchon couperi) in the Southeastern United States.

    Krysko, Kenneth L; Nuñez, Leroy P; Lippi, Catherine A; Smith, Daniel J; Granatosky, Michael C

    2016-05-01

    Indigo Snakes (Drymarchon; with five currently recognized species) occur from northern Argentina, northward to the United States in southern Texas and eastward in disjunct populations in Florida and Georgia. Based on this known allopatry and a difference in supralabial morphology the two United States taxa previously considered as subspecies within D. corais (Boie 1827), the Western Indigo Snake, D. melanurus erebennus (Cope 1860), and Eastern Indigo Snake, D. couperi (Holbrook 1842), are currently recognized as separate species. Drymarchon couperi is a Federally-designated Threatened species by the United States Fish and Wildlife Service under the Endangered Species Act, and currently being incorporated into a translocation program. This, combined with its disjunct distribution makes it a prime candidate for studying speciation and genetic divergence. In this study, we (1) test the hypothesis that D. m. erebennus and D. couperi are distinct lineages by analyzing 2411 base pairs (bp) of two mitochondrial (mtDNA) loci and one single copy nuclear (scnDNA) locus; (2) estimate the timing of speciation using a relaxed phylogenetics method to determine if Milankovitch cycles during the Pleistocene might have had an influence on lineage diversifications; (3) examine historical population demography to determine if identified lineages have undergone population declines, expansions, or remained stable during the most recent Milankovitch cycles; and (4) use this information to assist in an effective and scientifically sound translocation program. Our molecular data support the initial hypothesis that D. melanurus and D. couperi should be recognized as distinct species, but further illustrate that D. couperi is split into two distinct genetic lineages that correspond to historical biogeography and sea level changes in peninsular Florida. These two well-supported genetic lineages (herein termed Atlantic and Gulf lineages) illustrate a common biogeographic distributional break

  9. Human settlement history between Sunda and Sahul: a focus on East Timor (Timor-Leste) and the Pleistocenic mtDNA diversity.

    Gomes, Sibylle M; Bodner, Martin; Souto, Luis; Zimmermann, Bettina; Huber, Gabriela; Strobl, Christina; Röck, Alexander W; Achilli, Alessandro; Olivieri, Anna; Torroni, Antonio; Côrte-Real, Francisco; Parson, Walther

    2015-02-14

    Distinct, partly competing, "waves" have been proposed to explain human migration in(to) today's Island Southeast Asia and Australia based on genetic (and other) evidence. The paucity of high quality and high resolution data has impeded insights so far. In this study, one of the first in a forensic environment, we used the Ion Torrent Personal Genome Machine (PGM) for generating complete mitogenome sequences via stand-alone massively parallel sequencing and describe a standard data validation practice. In this first representative investigation on the mitochondrial DNA (mtDNA) variation of East Timor (Timor-Leste) population including >300 individuals, we put special emphasis on the reconstruction of the initial settlement, in particular on the previously poorly resolved haplogroup P1, an indigenous lineage of the Southwest Pacific region. Our results suggest a colonization of southern Sahul (Australia) >37 kya, limited subsequent exchange, and a parallel incubation of initial settlers in northern Sahul (New Guinea) followed by westward migrations <28 kya. The temporal proximity and possible coincidence of these latter dispersals, which encompassed autochthonous haplogroups, with the postulated "later" events of (South) East Asian origin pinpoints a highly dynamic migratory phase.

  10. Internucleotide correlations and nucleotide periodicity in Drosophila mtDNA: New evidence for panselective evolution

    Carlos Y Valenzuela

    2010-01-01

    Full Text Available Analysis for the homogeneity of the distribution of the second base of dinucleotides in relation to the first, whose bases are separated by 0, 1, 2,... 21 nucleotide sites, was performed with the VIH-1 genome (cDNA, the Drosophila mtDNA, the Drosophila Torso gene and the human p-globin gene. These four DNA segments showed highly significant heterogeneities of base distributions that cannot be accounted for by neutral or nearly neutral evolution or by the "neighbor influence" of nucleotides on mutation rates. High correlations are found in the bases of dinucleotides separated by 0, 1 and more number of sites. A periodicity of three consecutive significance values (measured by the x²9 was found only in Drosophila mtDNA. This periodicity may be due to an unknown structure or organization of mtDNA. This non-random distribution of the two bases of dinucleotides widespread throughout these DNA segments is rather compatible with panselective evolution and generalized internucleotide co-adaptation.

  11. Genetic diversity of mtDNA D-loop sequences in four native Chinese chicken breeds.

    Guo, H W; Li, C; Wang, X N; Li, Z J; Sun, G R; Li, G X; Liu, X J; Kang, X T; Han, R L

    2017-10-01

    1. To explore the genetic diversity of Chinese indigenous chicken breeds, a 585 bp fragment of the mitochondrial DNA (mtDNA) region was sequenced in 102 birds from the Xichuan black-bone chicken, Yunyang black-bone chicken and Lushi chicken. In addition, 30 mtDNA D-loop sequences of Silkie fowls were downloaded from NCBI. The mtDNA D-loop sequence polymorphism and maternal origin of 4 chicken breeds were analysed in this study. 2. The results showed that a total of 33 mutation sites and 28 haplotypes were detected in the 4 chicken breeds. The haplotype diversity and nucleotide diversity of these 4 native breeds were 0.916 ± 0.014 and 0.012 ± 0.002, respectively. Three clusters were formed in 4 Chinese native chickens and 12 reference breeds. Both the Xichuan black-bone chicken and Yunyang black-bone chicken were grouped into one cluster. Four haplogroups (A, B, C and E) emerged in the median-joining network in these breeds. 3. It was concluded that these 4 Chinese chicken breeds had high genetic diversity. The phylogenetic tree and median network profiles showed that Chinese native chickens and its neighbouring countries had at least two maternal origins, one from Yunnan, China and another from Southeast Asia or its surrounding area.

  12. Evolutionary relationships in the sand-dwelling cichlid lineage of lake tanganyika suggest multiple colonization of rocky habitats and convergent origin of biparental mouthbrooding.

    Koblmüller, Stephan; Salzburger, Walter; Sturmbauer, Christian

    2004-01-01

    The cichlid species flock of Lake Tanganyika is comprised of seven seeding lineages that evolved in step with changes of the lake environment. One seeding lineage diversified into at least six lineages within a short period of time. Our study focuses on the diversification of one of these lineages, the Ectodini, comprising highly specialized, sand- and rock-dwelling species. They display two distinct breeding styles: maternal and biparental mouthbrooding. By analyzing three mtDNA gene segments in 30 species representing all 13 described genera, we show that the Ectodini rapidly diversified into four clades at the onset of their radiation. The monotypic genus Grammatotria is likely to represent the most ancestral split, followed by the almost contemporary origin of three additional clades, the first comprising the benthic genus Callochromis, the second comprising the benthic genera Asprotilapia, Xenotilapia, Enantiopus, and Microdontochromis, and the third comprising the semi-pelagic genera Ophthalmotilapia, Cardiopharynx, Cyathopharynx, Ectodus, Aulonocranus, Lestradea, and Cunningtonia. Our study confirms the benthic and sand-dwelling life-style as ancestral. Rocky habitats were colonized independently in the Xenotilapia- and Ophthalmotilapia-clade. The Xenotilapia-clade comprises both maternal and biparental mouthbrooders. Their mode of breeding appears to be highly plastic: biparental mouthbrooding either evolved once in the common ancestor of the clade, to be reverted at least three times, or evolved at least five times independently from a maternally mouthbrooding ancestor. Furthermore, the genera Xenotilapia, Microdontochromis, Lestradea, and Ophthalmotilapia appeared paraphyletic in our analyses, suggesting the need of taxonomic revision.

  13. Admixture of Eastern and Western European Red Deer Lineages as a Result of Postglacial Recolonization of the Czech Republic (Central Europe).

    Krojerová-Prokešová, Jarmila; Barančeková, Miroslava; Koubek, Petr

    2015-01-01

    Due to a restriction of the distributional range of European red deer (Cervus elaphus L.) during the Quaternary and subsequent recolonization of Europe from different refugia, a clear phylogeographical pattern in genetic structure has been revealed using mitochondrial DNA markers. In Central Europe, 2 distinct, eastern and western, lineages of European red deer are present; however, admixture between them has not yet been studied in detail. We used mitochondrial DNA (control region and cytochrome b gene) sequences and 22 microsatellite loci from 522 individuals to investigate the genetic diversity of red deer in what might be expected to be an intermediate zone. We discovered a high number of unique mtDNA haplotypes belonging to each lineage and high levels of genetic diversity (cyt b H = 0.867, D-loop H = 0.914). The same structuring of red deer populations was also revealed by microsatellite analysis, with results from both analyses thus suggesting a suture zone between the 2 lineages. Despite the fact that postglacial recolonization of Central Europe by red deer occurred more than 10000 years ago, the degree of admixture between the 2 lineages is relatively small, with only 10.8% admixed individuals detected. Direct translocations of animals by humans have slightly blurred the pattern in this region; however, this blurring was more apparent when using maternally inherited markers than nuclear markers. © The American Genetic Association 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  14. Thymidine Kinase 2 Deficiency-Induced mtDNA Depletion in Mouse Liver Leads to Defect beta-Oxidation

    Zhou, Xiaoshan; Kannisto, Kristina; Curbo, Sophie; von Dobeln, Ulrika; Hultenby, Kjell; Isetun, Sindra; Gåfvels, Mats; Karlsson, Anna

    2013-01-01

    Thymidine kinase 2 (TK2) deficiency in humans causes mitochondrial DNA (mtDNA) depletion syndrome. To study the molecular mechanisms underlying the disease and search for treatment options, we previously generated and described a TK2 deficient mouse strain (TK2(-/-)) that progressively loses its mtDNA. The TK2(-/-) mouse model displays symptoms similar to humans harboring TK2 deficient infantile fatal encephalomyopathy. Here, we have studied the TK2(-/-) mouse model to clarify the pathologica...

  15. Mesenchymal progenitor cells for the osteogenic lineage.

    Ono, Noriaki; Kronenberg, Henry M

    2015-09-01

    Mesenchymal progenitors of the osteogenic lineage provide the flexibility for bone to grow, maintain its function and homeostasis. Traditionally, colony-forming-unit fibroblasts (CFU-Fs) have been regarded as surrogates for mesenchymal progenitors; however, this definition cannot address the function of these progenitors in their native setting. Transgenic murine models including lineage-tracing technologies based on the cre-lox system have proven to be useful in delineating mesenchymal progenitors in their native environment. Although heterogeneity of cell populations of interest marked by a promoter-based approach complicates overall interpretation, an emerging complexity of mesenchymal progenitors has been revealed. Current literatures suggest two distinct types of bone progenitor cells; growth-associated mesenchymal progenitors contribute to explosive growth of bone in early life, whereas bone marrow mesenchymal progenitors contribute to the much slower remodeling process and response to injury that occurs mainly in adulthood. More detailed relationships of these progenitors need to be studied through further experimentation.

  16. Comparative mtDNA phylogeography of neotropical freshwater fishes: testing shared history to infer the evolutionary landscape of lower Central America.

    Bermingham, E; Martin, A P

    1998-04-01

    Historical biogeography seeks to explain contemporary distributions of taxa in the context of intrinsic biological and extrinsic geological and climatic factors. To decipher the relative importance of biological characteristics vs. environmental conditions, it is necessary to ask whether groups of taxa with similar distributions share the same history of diversification. Because all of the taxa will have shared the same climatic and geological history, evidence of shared history across multiple species provides an estimate of the role of extrinsic factors in shaping contemporary biogeographic patterns. Similarly, differences in the records of evolutionary history across species will probably be signatures of biological differences. In this study, we focus on inferring the evolutionary history for geographical populations and closely related species representing three genera of primary freshwater fishes that are widely distributed in lower Central America (LCA) and northwestern Colombia. Analysis of mitochondrial gene trees provides the opportunity for robust tests of shared history across taxa. Moreover, because mtDNA permits inference of the temporal scale of diversification we can test hypotheses regarding the chronological development of the Isthmian corridor linking North and South America. We have focused attention on two issues. First, we show that many of the distinct populations of LCA fishes diverged in a relatively brief period of time thus limiting the phylogenetic signal available for tests of shared history. Second, our results provide reduced evidence of shared history when all drainages are included in the analysis because of inferred dispersion events that obscure the evolutionary history among drainage basins. When we restrict the analysis to areas that harbour endemic mitochondrial lineages, there is evidence of shared history across taxa. We hypothesize that there were two to three distinct waves of invasion into LCA from putative source

  17. Some maternal lineages of domestic horses may have origins in East Asia revealed with further evidence of mitochondrial genomes and HVR-1 sequences

    Hongying Ma

    2018-06-01

    Full Text Available Objectives There are large populations of indigenous horse (Equus caballus in China and some other parts of East Asia. However, their matrilineal genetic diversity and origin remained poorly understood. Using a combination of mitochondrial DNA (mtDNA and hypervariable region (HVR-1 sequences, we aim to investigate the origin of matrilineal inheritance in these domestic horses. Methods To investigate patterns of matrilineal inheritance in domestic horses, we conducted a phylogenetic study using 31 de novo mtDNA genomes together with 317 others from the GenBank. In terms of the updated phylogeny, a total of 5,180 horse mitochondrial HVR-1 sequences were analyzed. Results Eightteen haplogroups (Aw-Rw were uncovered from the analysis of the whole mitochondrial genomes. Most of which have a divergence time before the earliest domestication of wild horses (about 5,800 years ago and during the Upper Paleolithic (35–10 KYA. The distribution of some haplogroups shows geographic patterns. The Lw haplogroup contained a significantly higher proportion of European horses than the horses from other regions, while haplogroups Jw, Rw, and some maternal lineages of Cw, have a higher frequency in the horses from East Asia. The 5,180 sequences of horse mitochondrial HVR-1 form nine major haplogroups (A-I. We revealed a corresponding relationship between the haplotypes of HVR-1 and those of whole mitochondrial DNA sequences. The data of the HVR-1 sequences also suggests that Jw, Rw, and some haplotypes of Cw may have originated in East Asia while Lw probably formed in Europe. Conclusions Our study supports the hypothesis of the multiple origins of the maternal lineage of domestic horses and some maternal lineages of domestic horses may have originated from East Asia.

  18. Effects of a sex-ratio distorting endosymbiont on mtDNA variation in a global insect pest

    Cook James M

    2009-03-01

    Full Text Available Abstract Background Patterns of mtDNA variation within a species reflect long-term population structure, but may also be influenced by maternally inherited endosymbionts, such as Wolbachia. These bacteria often alter host reproductive biology and can drive particular mtDNA haplotypes through populations. We investigated the impacts of Wolbachia infection and geography on mtDNA variation in the diamondback moth, a major global pest whose geographic distribution reflects both natural processes and transport via human agricultural activities. Results The mtDNA phylogeny of 95 individuals sampled from 10 countries on four continents revealed two major clades. One contained only Wolbachia-infected individuals from Malaysia and Kenya, while the other contained only uninfected individuals, from all countries including Malaysia and Kenya. Within the uninfected group was a further clade containing all individuals from Australasia and displaying very limited sequence variation. In contrast, a biparental nuclear gene phylogeny did not have infected and uninfected clades, supporting the notion that maternally-inherited Wolbachia are responsible for the mtDNA pattern. Only about 5% (15/306 of our global sample of individuals was infected with the plutWB1 isolate and even within infected local populations, many insects were uninfected. Comparisons of infected and uninfected isofemale lines revealed that plutWB1 is associated with sex ratio distortion. Uninfected lines have a 1:1 sex ratio, while infected ones show a 2:1 female bias. Conclusion The main correlate of mtDNA variation in P. xylostella is presence or absence of the plutWB1 infection. This is associated with substantial sex ratio distortion and the underlying mechanisms deserve further study. In contrast, geographic origin is a poor predictor of moth mtDNA sequences, reflecting human activity in moving the insects around the globe. The exception is a clade of Australasian individuals, which may

  19. Thymidine kinase 2 deficiency-induced mtDNA depletion in mouse liver leads to defect β-oxidation.

    Xiaoshan Zhou

    Full Text Available Thymidine kinase 2 (TK2 deficiency in humans causes mitochondrial DNA (mtDNA depletion syndrome. To study the molecular mechanisms underlying the disease and search for treatment options, we previously generated and described a TK2 deficient mouse strain (TK2(-/- that progressively loses its mtDNA. The TK2(-/- mouse model displays symptoms similar to humans harboring TK2 deficient infantile fatal encephalomyopathy. Here, we have studied the TK2(-/- mouse model to clarify the pathological role of progressive mtDNA depletion in liver for the severe outcome of TK2 deficiency. We observed that a gradual depletion of mtDNA in the liver of the TK2(-/- mice was accompanied by increasingly hypertrophic mitochondria and accumulation of fat vesicles in the liver cells. The levels of cholesterol and nonesterified fatty acids were elevated and there was accumulation of long chain acylcarnitines in plasma of the TK2(-/- mice. In mice with hepatic mtDNA levels below 20%, the blood sugar and the ketone levels dropped. These mice also exhibited reduced mitochondrial β-oxidation due to decreased transport of long chain acylcarnitines into the mitochondria. The gradual loss of mtDNA in the liver of the TK2(-/- mice causes impaired mitochondrial function that leads to defect β-oxidation and, as a result, insufficient production of ketone bodies and glucose. This study provides insight into the mechanism of encephalomyopathy caused by TK2 deficiency-induced mtDNA depletion that may be used to explore novel therapeutic strategies.

  20. Thymidine kinase 2 deficiency-induced mtDNA depletion in mouse liver leads to defect β-oxidation.

    Zhou, Xiaoshan; Kannisto, Kristina; Curbo, Sophie; von Döbeln, Ulrika; Hultenby, Kjell; Isetun, Sindra; Gåfvels, Mats; Karlsson, Anna

    2013-01-01

    Thymidine kinase 2 (TK2) deficiency in humans causes mitochondrial DNA (mtDNA) depletion syndrome. To study the molecular mechanisms underlying the disease and search for treatment options, we previously generated and described a TK2 deficient mouse strain (TK2(-/-)) that progressively loses its mtDNA. The TK2(-/-) mouse model displays symptoms similar to humans harboring TK2 deficient infantile fatal encephalomyopathy. Here, we have studied the TK2(-/-) mouse model to clarify the pathological role of progressive mtDNA depletion in liver for the severe outcome of TK2 deficiency. We observed that a gradual depletion of mtDNA in the liver of the TK2(-/-) mice was accompanied by increasingly hypertrophic mitochondria and accumulation of fat vesicles in the liver cells. The levels of cholesterol and nonesterified fatty acids were elevated and there was accumulation of long chain acylcarnitines in plasma of the TK2(-/-) mice. In mice with hepatic mtDNA levels below 20%, the blood sugar and the ketone levels dropped. These mice also exhibited reduced mitochondrial β-oxidation due to decreased transport of long chain acylcarnitines into the mitochondria. The gradual loss of mtDNA in the liver of the TK2(-/-) mice causes impaired mitochondrial function that leads to defect β-oxidation and, as a result, insufficient production of ketone bodies and glucose. This study provides insight into the mechanism of encephalomyopathy caused by TK2 deficiency-induced mtDNA depletion that may be used to explore novel therapeutic strategies.

  1. Therapeutic Targeting of the Mitochondria Initiates Excessive Superoxide Production and Mitochondrial Depolarization Causing Decreased mtDNA Integrity.

    Pokrzywinski, Kaytee L; Biel, Thomas G; Kryndushkin, Dmitry; Rao, V Ashutosh

    2016-01-01

    Mitochondrial dysregulation is closely associated with excessive reactive oxygen species (ROS) production. Altered redox homeostasis has been implicated in the onset of several diseases including cancer. Mitochondrial DNA (mtDNA) and proteins are particularly sensitive to ROS as they are in close proximity to the respiratory chain (RC). Mitoquinone (MitoQ), a mitochondria-targeted redox agent, selectively damages breast cancer cells possibly through damage induced via enhanced ROS production. However, the effects of MitoQ and other triphenylphosphonium (TPP+) conjugated agents on cancer mitochondrial homeostasis remain unknown. The primary objective of this study was to determine the impact of mitochondria-targeted agent [(MTAs) conjugated to TPP+: mitoTEMPOL, mitoquinone and mitochromanol-acetate] on mitochondrial physiology and mtDNA integrity in breast (MDA-MB-231) and lung (H23) cancer cells. The integrity of the mtDNA was assessed by quantifying the degree of mtDNA fragmentation and copy number, as well as by measuring mitochondrial proteins essential to mtDNA stability and maintenance (TFAM, SSBP1, TWINKLE, POLG and POLRMT). Mitochondrial status was evaluated by measuring superoxide production, mitochondrial membrane depolarization, oxygen consumption, extracellular acidification and mRNA or protein levels of the RC complexes along with TCA cycle activity. In this study, we demonstrated that all investigated MTAs impair mitochondrial health and decrease mtDNA integrity in MDA-MB-231 and H23 cells. However, differences in the degree of mitochondrial damage and mtDNA degradation suggest unique properties among each MTA that may be cell line, dose and time dependent. Collectively, our study indicates the potential for TPP+ conjugated molecules to impair breast and lung cancer cells by targeting mitochondrial homeostasis.

  2. Report ETSI M2M-14bis JTC March 2011 meeting

    Keesmaat, N.W.

    2011-01-01

    The ETSI Technical Committee (TC) M2M focuses on the development of a generic M2M architecture and underlying protocols suitable for a wide range of M2M environments. Whereas in the past effort has been put in the development of several use cases, the focus of this M2M 14bis meeting – held in Sophia

  3. In search of the genetic footprints of Sumerians: a survey of Y-chromosome and mtDNA variation in the Marsh Arabs of Iraq

    Olivieri Anna

    2011-10-01

    Full Text Available Abstract Background For millennia, the southern part of the Mesopotamia has been a wetland region generated by the Tigris and Euphrates rivers before flowing into the Gulf. This area has been occupied by human communities since ancient times and the present-day inhabitants, the Marsh Arabs, are considered the population with the strongest link to ancient Sumerians. Popular tradition, however, considers the Marsh Arabs as a foreign group, of unknown origin, which arrived in the marshlands when the rearing of water buffalo was introduced to the region. Results To shed some light on the paternal and maternal origin of this population, Y chromosome and mitochondrial DNA (mtDNA variation was surveyed in 143 Marsh Arabs and in a large sample of Iraqi controls. Analyses of the haplogroups and sub-haplogroups observed in the Marsh Arabs revealed a prevalent autochthonous Middle Eastern component for both male and female gene pools, with weak South-West Asian and African contributions, more evident in mtDNA. A higher male than female homogeneity is characteristic of the Marsh Arab gene pool, likely due to a strong male genetic drift determined by socio-cultural factors (patrilocality, polygamy, unequal male and female migration rates. Conclusions Evidence of genetic stratification ascribable to the Sumerian development was provided by the Y-chromosome data where the J1-Page08 branch reveals a local expansion, almost contemporary with the Sumerian City State period that characterized Southern Mesopotamia. On the other hand, a more ancient background shared with Northern Mesopotamia is revealed by the less represented Y-chromosome lineage J1-M267*. Overall our results indicate that the introduction of water buffalo breeding and rice farming, most likely from the Indian sub-continent, only marginally affected the gene pool of autochthonous people of the region. Furthermore, a prevalent Middle Eastern ancestry of the modern population of the marshes of

  4. mtDNA variation in caste populations of Andhra Pradesh, India.

    Bamshad, M; Fraley, A E; Crawford, M H; Cann, R L; Busi, B R; Naidu, J M; Jorde, L B

    1996-02-01

    Various anthropological analyses have documented extensive regional variation among populations on the subcontinent of India using morphological, protein, blood group, and nuclear DNA polymorphisms. These patterns are the product of complex population structure (genetic drift, gene flow) and a population history noted for numerous branching events. As a result, the interpretation of relationships among caste populations of South India and between Indians and continental populations remains controversial. The Hindu caste system is a general model of genetic differentiation among endogamous populations stratified by social forces (e.g., religion and occupation). The mitochondrial DNA (mtDNA) molecule has unique properties that facilitate the exploration of population structure. We analyzed 36 Hindu men born in Andhra Pradesh who were unrelated matrilineally through at least 3 generations and who represent 4 caste populations: Brahmin (9), Yadava (10), Kapu (7), and Relli (10). Individuals from Africa (36), Asia (36), and Europe (36) were sampled for comparison. A 200-base-pair segment of hypervariable segment 2 (HVS2) of the mtDNA control region was sequenced in all individuals. In the Indian castes 25 distinct haplotypes are identified. Aside from the Cambridge reference sequence, only two haplotypes are shared between caste populations. Middle castes form a highly supported cluster in a neighbor-joining network. Mean nucleotide diversity within each caste is 0.015, 0.012, 0.011, and 0.012 for the Brahmin, Yadava, Kapu, and Relli, respectively. mtDNA variation is highly structured between castes (GST = 0.17; p caste populations of Andhra Pradesh cluster more often with Africans than with Asians or Europeans. This is suggestive of admixture with African populations.

  5. Heterogeneous periodicity of drosophila mtDNA: new refutations of neutral and nearly neutral evolution

    Carlos Y Valenzuela

    2011-01-01

    Full Text Available We found a consistent 3-site periodicity of the X²9 values for the heterogeneity of the distribution of the second base in relation to the first base of dinucleotides separated by 0 (contiguous, 1, 2, 3 ... 17 (K nucleotide sites in Drosophila mtDNA. Triplets of X²9 values were found where the first was over 300 and the second and third ranged between 37 and 114 (previous studies. In this study, the periodicity was significant until separation of 2011K, and a structure of deviations from randomness among dinucleotides was found. The most deviant dinucleotides were G-G, G-C and C-G for the first, second and third element of the triplet, respectively. In these three cases there were more dinucleotides observed than expected. This inter-bases correlation and periodicity may be related to the tertiary structure of circular DNA, like that of prokaryotes and mitochondria, to protect and preserve it. The mtDNA with 19.517 bp was divided into four equal segments of 4.879 bp. The fourth sub-segment presented a very low proportion of G and C, the internucleotide interaction was weaker in this sub-segment and no periodicity was found. The maintenance of this mtDNA structure and organization for millions of generations, in spite of a high recurrent mutation rate, does not support the notion of neutralism or near neutralism. The high level of internucleotide interaction and periodicity indicate that every nucleotide is co-adapted with the residual genome.

  6. The Landscape of mtDNA Modifications in Cancer: A Tale of Two Cities.

    Hertweck, Kate L; Dasgupta, Santanu

    2017-01-01

    Mitochondria from normal and cancerous cells represent a tale of two cities, wherein both execute similar processes but with different cellular and molecular effects. Given the number of reviews currently available which describe the functional implications of mitochondrial mutations in cancer, this article focuses on documenting current knowledge in the abundance and distribution of somatic mitochondrial mutations, followed by elucidation of processes which affect the fate of mutations in cancer cells. The conclusion includes an overview of translational implications for mtDNA mutations, as well as recommendations for future research uniting mitochondrial variants and tumorigenesis.

  7. Mitochondrial nucleoid clusters protect newly synthesized mtDNA during Doxorubicin- and Ethidium Bromide-induced mitochondrial stress

    Alán, Lukáš, E-mail: lukas.alan@fgu.cas.cz; Špaček, Tomáš; Pajuelo Reguera, David; Jabůrek, Martin; Ježek, Petr

    2016-07-01

    Mitochondrial DNA (mtDNA) is compacted in ribonucleoprotein complexes called nucleoids, which can divide or move within the mitochondrial network. Mitochondrial nucleoids are able to aggregate into clusters upon reaction with intercalators such as the mtDNA depletion agent Ethidium Bromide (EB) or anticancer drug Doxorobicin (DXR). However, the exact mechanism of nucleoid clusters formation remains unknown. Resolving these processes may help to elucidate the mechanisms of DXR-induced cardiotoxicity. Therefore, we addressed the role of two key nucleoid proteins; mitochondrial transcription factor A (TFAM) and mitochondrial single-stranded binding protein (mtSSB); in the formation of mitochondrial nucleoid clusters during the action of intercalators. We found that both intercalators cause numerous aberrations due to perturbing their native status. By blocking mtDNA replication, both agents also prevented mtDNA association with TFAM, consequently causing nucleoid aggregation into large nucleoid clusters enriched with TFAM, co-existing with the normal nucleoid population. In the later stages of intercalation (> 48 h), TFAM levels were reduced to 25%. In contrast, mtSSB was released from mtDNA and freely distributed within the mitochondrial network. Nucleoid clusters mostly contained nucleoids with newly replicated mtDNA, however the nucleoid population which was not in replication mode remained outside the clusters. Moreover, the nucleoid clusters were enriched with p53, an anti-oncogenic gatekeeper. We suggest that mitochondrial nucleoid clustering is a mechanism for protecting nucleoids with newly replicated DNA against intercalators mediating genotoxic stress. These results provide new insight into the common mitochondrial response to mtDNA stress and can be implied also on DXR-induced mitochondrial cytotoxicity. - Highlights: • The mechanism for mitochondrial nucleoid clustering is proposed. • DNA intercalators (Doxorubicin or Ethidium Bromide) prevent TFAM

  8. Uncovering the mutation-fixation correlation in short lineages

    Vallender Eric J

    2007-09-01

    Full Text Available Abstract Background We recently reported a highly unexpected positive correlation between the fixation probability of nonsynonymous mutations (estimated by ω and neutral mutation rate (estimated by Ks in mammalian lineages. However, this positive correlation was observed for lineages with relatively long divergence time such as the human-mouse lineage, and was not found for very short lineages such as the human-chimpanzee lineage. It was previously unclear how to interpret this discrepancy. It may indicate that the positive correlation between ω and Ks in long lineages is a false finding. Alternatively, it may reflect a biologically meaningful difference between various lineages. Finally, the lack of positive correlation in short lineages may be the result of methodological artifacts. Results Here we show that a strong positive correlation can indeed be seen in short lineages when a method was introduced to correct for the inherently high levels of stochastic noise in the use of Ks as an estimator of neutral mutation rate. Thus, the previously noted lack of positive correlation between ω and Ks in short lineages is due to stochastic noise in Ks that makes it a far less reliable estimator of neutral mutation rate in short lineages as compared to long lineages. Conclusion A positive correlation between ω and Ks can be observed in all mammalian lineages for which large amounts of sequence data are available, including very short lineages. It confirms the authenticity of this highly unexpected correlation, and argues that the correction likely applies broadly across all mammals and perhaps even non-mammalian species.

  9. Lineage specific recombination rates and microevolution in Listeria monocytogenes

    Nightingale Kendra K

    2008-10-01

    Full Text Available Abstract Background The bacterium Listeria monocytogenes is a saprotroph as well as an opportunistic human foodborne pathogen, which has previously been shown to consist of at least two widespread lineages (termed lineages I and II and an uncommon lineage (lineage III. While some L. monocytogenes strains show evidence for considerable diversification by homologous recombination, our understanding of the contribution of recombination to L. monocytogenes evolution is still limited. We therefore used STRUCTURE and ClonalFrame, two programs that model the effect of recombination, to make inferences about the population structure and different aspects of the recombination process in L. monocytogenes. Analyses were performed using sequences for seven loci (including the house-keeping genes gap, prs, purM and ribC, the stress response gene sigB, and the virulence genes actA and inlA for 195 L. monocytogenes isolates. Results Sequence analyses with ClonalFrame and the Sawyer's test showed that recombination is more prevalent in lineage II than lineage I and is most frequent in two house-keeping genes (ribC and purM and the two virulence genes (actA and inlA. The relative occurrence of recombination versus point mutation is about six times higher in lineage II than in lineage I, which causes a higher genetic variability in lineage II. Unlike lineage I, lineage II represents a genetically heterogeneous population with a relatively high proportion (30% average of genetic material imported from external sources. Phylograms, constructed with correcting for recombination, as well as Tajima's D data suggest that both lineages I and II have suffered a population bottleneck. Conclusion Our study shows that evolutionary lineages within a single bacterial species can differ considerably in the relative contributions of recombination to genetic diversification. Accounting for recombination in phylogenetic studies is critical, and new evolutionary models that

  10. A defect in the thymidine kinase 2 gene causing isolated mitochondrial myopathy without mtDNA depletion.

    Leshinsky-Silver, E; Michelson, M; Cohen, S; Ginsberg, M; Sadeh, M; Barash, V; Lerman-Sagie, T; Lev, D

    2008-07-01

    Isolated mitochondrial myopathies (IMM) are either due to primary defects in mtDNA, in nuclear genes that control mtDNA abundance and structure such as thymidine kinase 2 (TK2), or due to CoQ deficiency. Defects in the TK2 gene have been found to be associated with mtDNA depletion attributed to a depleted mitochondrial dNTP pool in non-dividing cells. We report an unusual case of IMM, homozygous for the H90N mutation in the TK2 gene but unlike other cases with the same mutation, does not demonstrate mtDNA depletion. The patient's clinical course is relatively mild and a muscle biopsy showed ragged red muscle fibers with a mild decrease in complexes I and an increase in complexes IV and II activities. This report extends the phenotypic expression of TK2 defects and suggests that all patients who present with an IMM even with normal quantities of mtDNA should be screened for TK2 mutations.

  11. A Phenotype-Driven Approach to Generate Mouse Models with Pathogenic mtDNA Mutations Causing Mitochondrial Disease

    Johanna H.K. Kauppila

    2016-09-01

    Full Text Available Mutations of mtDNA are an important cause of human disease, but few animal models exist. Because mammalian mitochondria cannot be transfected, the development of mice with pathogenic mtDNA mutations has been challenging, and the main strategy has therefore been to introduce mutations found in cell lines into mouse embryos. Here, we describe a phenotype-driven strategy that is based on detecting clonal expansion of pathogenic mtDNA mutations in colonic crypts of founder mice derived from heterozygous mtDNA mutator mice. As proof of concept, we report the generation of a mouse line transmitting a heteroplasmic pathogenic mutation in the alanine tRNA gene of mtDNA displaying typical characteristics of classic mitochondrial disease. In summary, we describe a straightforward and technically simple strategy based on mouse breeding and histology to generate animal models of mtDNA-mutation disease, which will be of great importance for studies of disease pathophysiology and preclinical treatment trials.

  12. Identification of West Eurasian mitochondrial haplogroups by mtDNA SNP screening: results of the 2006-2007 EDNAP collaborative exercise

    Parson, Walther; Fendt, Liane; Ballard, David

    2008-01-01

    no previous experience with the technology and/or mtDNA analysis. The results of this collaborative exercise stimulate the expansion of screening methods in forensic laboratories to increase efficiency and performance of mtDNA typing, and thus demonstrates that mtDNA SNP typing is a powerful tool for forensic......The European DNA Profiling (EDNAP) Group performed a collaborative exercise on a mitochondrial (mt) DNA screening assay that targeted 16 nucleotide positions in the coding region and allowed for the discrimination of major west Eurasian mtDNA haplogroups. The purpose of the exercise was to evaluate...

  13. MtDNA barcode identification of fish larvae in the southern Great Barrier Reef – Australia

    Graham G. Pegg

    2006-10-01

    Full Text Available Planktonic larvae were captured above a shallow coral reef study site on the Great Barrier Reef (GBR around spring-summer new moon periods (October-February using light trap or net capture devices. Larvae were identified to the genus or species level by comparison with a phylogenetic tree of tropical marine fish species using mtDNA HVR1 sequence data. Further analysis showed that within-species HVR1 sequence variation was typically 1-3%, whereas between-species variation for the same genus ranged up to 50%, supporting the suitability of HVR1 for species identification. Given the current worldwide interest in DNA barcoding and species identification using an alternative mtDNA gene marker (cox1, we also explored the efficacy of different primer sets for amplification of cox1 in reef fish, and its suitability for species identification. Of those tested, the Fish-F1 and -R1 primer set recently reported by Ward et al. (2005 gave the best results.

  14. Molecular Characterization of Sudanese and Southern Sudanese Chicken Breeds Using mtDNA D-Loop

    Charles E. Wani

    2014-01-01

    Full Text Available The objective of this study was to assess the genetic relationships and diversity and to estimate the amount of gene flow among the five chicken populations from Sudan and South Sudan and commercial strain of egg line White Leghorn chickens. The chicken populations were genotyped using mtDNA D-loop as a molecular marker. PCR product of the mtDNA D-loop segment was 600 bp and 14 haplotypes were identified. The neighbor-joining phylogenetic tree indicated that the indigenous Sudanese chickens can be grouped into two clades, IV and IIIa only. Median joining networks analysis showed that haplotype LBB49 has the highest frequency. The hierarchal analysis of molecular variance (AMOVA showed that genetic variation within the population was 88.6% and the differentiation among the population was 11.4%. When the populations was redefined into two geographical zones, rich and poor Savanna, the results were fractioned into three genetic variations: between individuals within population 95.5%, between populations within the group 0.75%, and genetic variation between groups 3.75%. The pair wise Fst showed high genetic difference between Betwil populations and the rest with Fst ranging from 0.1492 to 0.2447. We found that there is large number of gene exchanges within the Sudanese indigenous chicken (Nm=4.622.

  15. Somatic mtDNA mutation spectra in the aging human putamen.

    Siôn L Williams

    Full Text Available The accumulation of heteroplasmic mitochondrial DNA (mtDNA deletions and single nucleotide variants (SNVs is a well-accepted facet of the biology of aging, yet comprehensive mutation spectra have not been described. To address this, we have used next generation sequencing of mtDNA-enriched libraries (Mito-Seq to investigate mtDNA mutation spectra of putamen from young and aged donors. Frequencies of the "common" deletion and other "major arc" deletions were significantly increased in the aged cohort with the fold increase in the frequency of the common deletion exceeding that of major arc deletions. SNVs also increased with age with the highest rate of accumulation in the non-coding control region which contains elements necessary for translation and replication. Examination of predicted amino acid changes revealed a skew towards pathogenic SNVs in the coding region driven by mutation bias. Levels of the pathogenic m.3243A>G tRNA mutation were also found to increase with age. Novel multimeric tandem duplications that resemble murine control region multimers and yeast ρ(- mtDNAs, were identified in both young and aged specimens. Clonal ∼50 bp deletions in the control region were found at high frequencies in aged specimens. Our results reveal the complex manner in which the mitochondrial genome alters with age and provides a foundation for studies of other tissues and disease states.

  16. A new view on dam lines in Polish Arabian horses based on mtDNA analysis

    Sell Jerzy

    2007-09-01

    Full Text Available Abstract Polish Arabian horses are one of the oldest and the most important Arab populations in the world. The Polish Arabian Stud Book and the Genealogical Charts by Skorkowski are the main sources of information on the ancestors of Polish Arabs. Both publications were viewed as credible sources of information until the 1990s when the data regarding one of the dam lines was questioned. The aim of the current study was to check the accuracy of the pedigree data of Polish dam lines using mtDNA analysis. The analyses of a 458 bp mtDNA D-loop fragment from representatives of 15 Polish Arabian dam lines revealed 14 distinct haplotypes. The results were inconsistent with pedigree data in the case of two lines. A detailed analysis of the historical sources was performed to explain these discrepancies. Our study revealed that representatives of different lines shared the same haplotypes. We also noted a genetic identity between some lines founded by Polish mares of unknown origin and lines established by desert-bred mares.

  17. Contrasting microsatellite diversity in the evolutionary lineages of Phytophthora lateralis.

    Vettraino, AnnaMaria; Brasier, Clive M; Webber, Joan F; Hansen, Everett M; Green, Sarah; Robin, Cecile; Tomassini, Alessia; Bruni, Natalia; Vannini, Andrea

    2017-02-01

    Following recent discovery of Phytophthora lateralis on native Chamaecyparis obtusa in Taiwan, four phenotypically distinct lineages were discriminated: the Taiwan J (TWJ) and Taiwan K (TWK) in Taiwan, the Pacific Northwest (PNW) in North America and Europe and the UK in west Scotland. Across the four lineages, we analysed 88 isolates from multiple sites for microsatellite diversity. Twenty-one multilocus genotypes (MLGs) were resolved with high levels of diversity of the TWK and PNW lineages. No alleles were shared between the PNW and the Taiwanese lineages. TWK was heterozygous at three loci, whereas TWJ isolates were homozygous apart from one isolate, which exhibited a unique allele also present in the TWK lineage. PNW lineage was heterozygous at three loci. The evidence suggests its origin may be a yet unknown Asian source. North American and European PNW isolates shared all their alleles and also a dominant MLG, consistent with a previous proposal that this lineage is a recent introduction into Europe from North America. The UK lineage was monomorphic and homozygous at all loci. It shared its alleles with the PNW and the TWJ and TWK lineages, hence a possible origin in a recent hybridisation event between a Taiwan lineage and PNW cannot be ruled out. Copyright © 2016 British Mycological Society. Published by Elsevier Ltd. All rights reserved.

  18. Cytomegalovirus immune evasion of myeloid lineage cells.

    Brinkmann, Melanie M; Dağ, Franziska; Hengel, Hartmut; Messerle, Martin; Kalinke, Ulrich; Čičin-Šain, Luka

    2015-06-01

    Cytomegalovirus (CMV) evades the immune system in many different ways, allowing the virus to grow and its progeny to spread in the face of an adverse environment. Mounting evidence about the antiviral role of myeloid immune cells has prompted the research of CMV immune evasion mechanisms targeting these cells. Several cells of the myeloid lineage, such as monocytes, dendritic cells and macrophages, play a role in viral control, but are also permissive for CMV and are naturally infected by it. Therefore, CMV evasion of myeloid cells involves mechanisms that qualitatively differ from the evasion of non-CMV-permissive immune cells of the lymphoid lineage. The evasion of myeloid cells includes effects in cis, where the virus modulates the immune signaling pathways within the infected myeloid cell, and those in trans, where the virus affects somatic cells targeted by cytokines released from myeloid cells. This review presents an overview of CMV strategies to modulate and evade the antiviral activity of myeloid cells in cis and in trans.

  19. Comparative mtDNA analyses of three sympatric macropodids from a conservation area on the Huon Peninsula, Papua New Guinea.

    McGreevy, Thomas J; Dabek, Lisa; Husband, Thomas P

    2016-07-01

    Matschie's tree kangaroo (Dendrolagus matschiei), New Guinea pademelon (Thylogale browni), and small dorcopsis (Dorcopsulus vanheurni) are sympatric macropodid taxa, of conservation concern, that inhabit the Yopno-Urawa-Som (YUS) Conservation Area on the Huon Peninsula, Papua New Guinea. We sequenced three partial mitochondrial DNA (mtDNA) genes from the three taxa to (i) investigate network structure; and (ii) identify conservation units within the YUS Conservation Area. All three taxa displayed a similar pattern in the spatial distribution of their mtDNA haplotypes and the Urawa and Som rivers on the Huon may have acted as a barrier to maternal gene flow. Matschie's tree kangaroo and New Guinea pademelon within the YUS Conservation Area should be managed as single conservation units because mtDNA nucleotides were not fixed for a given geographic area. However, two distinct conservation units were identified for small dorcopsis from the two different mountain ranges within the YUS Conservation Area.

  20. MELAS and Kearns–Sayre overlap syndrome due to the mtDNA m. A3243G mutation and large-scale mtDNA deletions

    Nian Yu

    2016-09-01

    Full Text Available This paper reported an unusual manifestation of a 19-year-old Chinese male patient presented with a complex phenotype of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS syndrome and Kearns–Sayre syndrome (KSS. He was admitted to our hospital with the chief complaint of “acute fever, headache and slow reaction for 21 days”. He was initially misdiagnosed as “viral encephalitis”. This Chinese man with significant past medical history of intolerating fatigue presented paroxysmal neurobehavioral attacks that started about 10 years ago. During this span, 3 or 4 attack clusters were described during which several attacks occurred over a few days. The further examination found that the hallmark signs of this patient included progressive myoclonus epilepsy, cerebellar ataxia, hearing loss, myopathic weakness, ophthalmoparesis, pigmentary retinopathy and bifascicular heart block (Wolff–Parkinson–White syndrome. By young age the disease progression is characterized by the addition of migraine, vomiting, and stroke-like episodes, symptoms of MELAS expression, which indicated completion of the MELAS/KSS overlap syndrome. The m. A3243G mitochondrial DNA mutation and single large-scale mtDNA deletions were found in this patient. This mutation has been reported with MELAS, KSS, myopathy, deafness and mental disorder with cognitive impairment. This is the first description with a MELAS/KSS syndrome in Chinese.

  1. mtDNA depletion myopathy: elucidation of the tissue specificity in the mitochondrial thymidine kinase (TK2) deficiency.

    Saada, Ann; Shaag, Avraham; Elpeleg, Orly

    2003-05-01

    Decreased mitochondrial thymidine kinase (TK2) activity is associated with mitochondrial DNA (mtDNA) depletion and respiratory chain dysfunction and is manifested by isolated, fatal skeletal myopathy. Other tissues such as liver, brain, heart, and skin remain unaffected throughout the patients' life. In order to elucidate the mechanism of tissue specificity in the disease we have investigated the expression of the mitochondrial deoxynucleotide carrier, the mtDNA content and the activity of TK2 in mitochondria of various tissues. Our results suggest that low basal TK2 activity combined with a high requirement for mitochondrial encoded proteins in muscle predispose this tissue to the devastating effect of TK2 deficiency.

  2. Deep sequencing shows that oocytes are not prone to accumulate mtDNA heteroplasmic mutations during ovarian ageing.

    Boucret, L; Bris, C; Seegers, V; Goudenège, D; Desquiret-Dumas, V; Domin-Bernhard, M; Ferré-L'Hotellier, V; Bouet, P E; Descamps, P; Reynier, P; Procaccio, V; May-Panloup, P

    2017-10-01

    Does ovarian ageing increase the number of heteroplasmic mitochondrial DNA (mtDNA) point mutations in oocytes? Our results suggest that oocytes are not subject to the accumulation of mtDNA point mutations during ovarian ageing. Ageing is associated with the alteration of mtDNA integrity in various tissues. Primary oocytes, present in the ovary since embryonic life, may accumulate mtDNA mutations during the process of ovarian ageing. This was an observational study of 53 immature oocyte-cumulus complexes retrieved from 35 women undergoing IVF at the University Hospital of Angers, France, from March 2013 to March 2014. The women were classified in two groups, one including 19 women showing signs of ovarian ageing objectified by a diminished ovarian reserve (DOR), and the other, including 16 women with a normal ovarian reserve (NOR), which served as a control group. mtDNA was extracted from isolated oocytes, and from their corresponding cumulus cells (CCs) considered as a somatic cell compartment. The average mtDNA content of each sample was assessed by using a quantitative real-time PCR technique. Deep sequencing was performed using the Ion Torrent Proton for Next-Generation Sequencing. Signal processing and base calling were done by the embedded pre-processing pipeline and the variants were analyzed using an in-house workflow. The distribution of the different variants between DOR and NOR patients, on one hand, and oocyte and CCs, on the other, was analyzed with the generalized mixed linear model to take into account the cluster of cells belonging to a given mother. There were no significant differences between the numbers of mtDNA variants between the DOR and the NOR patients, either in the oocytes (P = 0.867) or in the surrounding CCs (P = 0.154). There were also no differences in terms of variants with potential functional consequences. De-novo mtDNA variants were found in 28% of the oocytes and in 66% of the CCs with the mean number of variants being

  3. Yellow tails in the Red Sea: phylogeography of the Indo-Pacific goatfish Mulloidichthys flavolineatus reveals isolation in peripheral provinces and cryptic evolutionary lineages

    Fernandez-Silva, Iria; Randall, John E.; Coleman, Richard R.; DiBattista, Joseph; Rocha, Luiz A.; Reimer, James D.; Meyer, Carl G.; Bowen, Brian W.

    2015-01-01

    Aim: Broadly distributed reef fishes tend to have high gene flow mediated by a pelagic larval phase. Here, we survey a reef-associated fish distributed across half the tropical oceans, from the Red Sea to the central Pacific. Our goal is to determine whether genetic structure of the broadly distributed Yellowstripe Goatfish (Mulloidichthys flavolineatus) is defined by biogeographical barriers, or facilitated via larval dispersal. Location: Red Sea, Indian Ocean, Pacific Ocean Methods: Specimens were obtained at 19 locations from the Red Sea to Hawai'i. Genetic data include mtDNA cytochrome b (n = 217) and 12 microsatellite loci (n = 185). Analysis of molecular variance (AMOVA), structure, a parsimony network and coalescence analyses were used to resolve recent population history and connectivity. Results: Population structure was significant (mtDNA ϕST = 0.68, P < 0.001; microsatellite FST = 0.08, P < 0.001), but mostly driven by samples from the North-western (NW) Indian Ocean (including the Red Sea) and Hawai'i. There was little population structure across the Indian Ocean to the central Pacific. Hawai'i was distinguished as an isolated population (mtDNA ϕST = 0.03-0.08, P = n.s.; microsatellites FST = 0.05-0.10, P < 0.001). Specimens from the NW Indian Ocean clustered as a distinct phylogenetic lineage that diverged approximately 493 ka (d = 1.7%), which indicates that these fish persisted in isolation through several Pleistocene glacial cycles. Main conclusions: These data reinforce the emerging themes that: (1) phylogeographical breaks within species often coincide with biogeographical breaks based on species distributions, and (2) populations on the periphery of the range (NW Indian Ocean and Hawai'i) are isolated and may be evolutionary incubators producing new species. © 2015 John Wiley & Sons Ltd.

  4. Yellow tails in the Red Sea: phylogeography of the Indo-Pacific goatfish Mulloidichthys flavolineatus reveals isolation in peripheral provinces and cryptic evolutionary lineages

    Fernandez-Silva, Iria

    2015-10-20

    Aim: Broadly distributed reef fishes tend to have high gene flow mediated by a pelagic larval phase. Here, we survey a reef-associated fish distributed across half the tropical oceans, from the Red Sea to the central Pacific. Our goal is to determine whether genetic structure of the broadly distributed Yellowstripe Goatfish (Mulloidichthys flavolineatus) is defined by biogeographical barriers, or facilitated via larval dispersal. Location: Red Sea, Indian Ocean, Pacific Ocean Methods: Specimens were obtained at 19 locations from the Red Sea to Hawai\\'i. Genetic data include mtDNA cytochrome b (n = 217) and 12 microsatellite loci (n = 185). Analysis of molecular variance (AMOVA), structure, a parsimony network and coalescence analyses were used to resolve recent population history and connectivity. Results: Population structure was significant (mtDNA ϕST = 0.68, P < 0.001; microsatellite FST = 0.08, P < 0.001), but mostly driven by samples from the North-western (NW) Indian Ocean (including the Red Sea) and Hawai\\'i. There was little population structure across the Indian Ocean to the central Pacific. Hawai\\'i was distinguished as an isolated population (mtDNA ϕST = 0.03-0.08, P = n.s.; microsatellites FST = 0.05-0.10, P < 0.001). Specimens from the NW Indian Ocean clustered as a distinct phylogenetic lineage that diverged approximately 493 ka (d = 1.7%), which indicates that these fish persisted in isolation through several Pleistocene glacial cycles. Main conclusions: These data reinforce the emerging themes that: (1) phylogeographical breaks within species often coincide with biogeographical breaks based on species distributions, and (2) populations on the periphery of the range (NW Indian Ocean and Hawai\\'i) are isolated and may be evolutionary incubators producing new species. © 2015 John Wiley & Sons Ltd.

  5. Phylogeography of the common vampire bat (Desmodus rotundus: Marked population structure, Neotropical Pleistocene vicariance and incongruence between nuclear and mtDNA markers

    Morgante João S

    2009-12-01

    Full Text Available Abstract Background The common vampire bat Desmodus rotundus is an excellent model organism for studying ecological vicariance in the Neotropics due to its broad geographic range and its preference for forested areas as roosting sites. With the objective of testing for Pleistocene ecological vicariance, we sequenced a mitocondrial DNA (mtDNA marker and two nuclear markers (RAG2 and DRB to try to understand how Pleistocene glaciations affected the distribution of intraspecific lineages in this bat. Results Five reciprocally monophyletic clades were evident in the mitochondrial gene tree, and in most cases with high bootstrap support: Central America (CA, Amazon and Cerrado (AMC, Pantanal (PAN, Northern Atlantic Forest (NAF and Southern Atlantic Forest (SAF. The Atlantic forest clades formed a monophyletic clade with high bootstrap support, creating an east/west division for this species in South America. On the one hand, all coalescent and non-coalescent estimates point to a Pleistocene time of divergence between the clades. On the other hand, the nuclear markers showed extensive sharing of haplotypes between distant localities, a result compatible with male-biased gene flow. In order to test if the disparity between the mitochondrial and nuclear markers was due to the difference in mutation rate and effective size, we performed a coalescent simulation to examine the feasibility that, given the time of separation between the observed lineages, even with a gene flow rate close to zero, there would not be reciprocal monophyly for a neutral nuclear marker. We used the observed values of theta and an estimated mutation rate for the nuclear marker gene to perform 1000 iterations of the simulation. The results of this simulation were inconclusive: the number of iterations with and without reciprocal monophyly of one or more clades are similar. Conclusions We therefore conclude that the pattern exhibited by the common vampire bat, with marked

  6. Dual role of YM1+ M2 macrophages in allergic lung inflammation

    Draijer, Christina; Robbe, Patricia; Boorsma, Carian E; Hylkema, Machteld N; Melgert, Barbro N

    2018-01-01

    Alternatively activated (M2 or YM1+) macrophages have been associated with the development of asthma but their contribution to disease initiation and progression remains unclear. To assess the therapeutic potential of modulating these M2 macrophages, we have studied inhibition of M2 polarisation

  7. Machine-to-Machine networks: integration of M2M networks into companies' administrative networks

    Pointereau, Romain

    2013-01-01

    This analysis will address the technical, economic and regulatory aspects and will identify the position taken by the various market actors. Integration of M2M Networks into Companies' Administrative Networks. Integración de redes M2M en redes administrativas de las empresas. Integració de xarxes M2M en xarxes administratives de les empreses.

  8. Increased immunogenicity and protective efficacy of influenza M2e fused to a tetramerizing protein

    Andersson, Anne-Marie Carola; Håkansson, Kjell Ove; Jensen, Benjamin Anderschou Holbech

    2012-01-01

    by diverse influenza A viruses, a vaccine (M2e-NSP4) was constructed linking M2e (in its consensus sequence) to the rotavirus fragment NSP4(98-135); due to its coiled-coil region this fragment is known to form tetramers in aqueous solution and in this manner we hoped to mimick the natural configuration of M2...

  9. Feedback, Lineages and Self-Organizing Morphogenesis.

    Sameeran Kunche

    2016-03-01

    Full Text Available Feedback regulation of cell lineage progression plays an important role in tissue size homeostasis, but whether such feedback also plays an important role in tissue morphogenesis has yet to be explored. Here we use mathematical modeling to show that a particular feedback architecture in which both positive and negative diffusible signals act on stem and/or progenitor cells leads to the appearance of bistable or bi-modal growth behaviors, ultrasensitivity to external growth cues, local growth-driven budding, self-sustaining elongation, and the triggering of self-organization in the form of lamellar fingers. Such behaviors arise not through regulation of cell cycle speeds, but through the control of stem or progenitor self-renewal. Even though the spatial patterns that arise in this setting are the result of interactions between diffusible factors with antagonistic effects, morphogenesis is not the consequence of Turing-type instabilities.

  10. Feedback, Lineages and Self-Organizing Morphogenesis

    Calof, Anne L.; Lowengrub, John S.; Lander, Arthur D.

    2016-01-01

    Feedback regulation of cell lineage progression plays an important role in tissue size homeostasis, but whether such feedback also plays an important role in tissue morphogenesis has yet to be explored. Here we use mathematical modeling to show that a particular feedback architecture in which both positive and negative diffusible signals act on stem and/or progenitor cells leads to the appearance of bistable or bi-modal growth behaviors, ultrasensitivity to external growth cues, local growth-driven budding, self-sustaining elongation, and the triggering of self-organization in the form of lamellar fingers. Such behaviors arise not through regulation of cell cycle speeds, but through the control of stem or progenitor self-renewal. Even though the spatial patterns that arise in this setting are the result of interactions between diffusible factors with antagonistic effects, morphogenesis is not the consequence of Turing-type instabilities. PMID:26989903

  11. Somatic point mutations in mtDNA control region are influenced by genetic background and associated with healthy aging: a GEHA study

    Rose, Giuseppina; Romeo, Giuseppe; Dato, Serena

    2010-01-01

    and of mortality risk in the elderly. Our study provides new evidence on the relevance of mtDNA somatic mutations in aging and longevity and confirms that the occurrence of specific point mutations in the mtDNA control region may represent a strategy for the age-related remodelling of organismal functions....

  12. Recent introgressive hybridization revealed by exclusive mtDNA transfer from Oreochromis leucostictus (Trewavas, 1933) to Oreochromis niloticus (Linnaeus, 1758) in Lake Baringo, Kenya

    Nyingi, Dorothy W.; Agnèse, Jean-François

    2007-01-01

    Nuclear DNA and mtDNA polymorphisms were surveyed in various species of East African Oreochromis. In Lake Baringo, where only Oreochromis niloticus baringoensis is present, alien mtDNA haplotypes were observed, apparently the result of introgressive hybridization with Oreochromis leucostictus. This introgression is not accompanied by any substantial or recorded transfer of nuclear genes into O. n. baringoensis.

  13. Human maternal heritage in Andalusia (Spain): its composition reveals high internal complexity and distinctive influences of mtDNA haplogroups U6 and L in the western and eastern side of region.

    Hernández, Candela L; Reales, Guillermo; Dugoujon, Jean-Michel; Novelletto, Andrea; Rodríguez, Juan Nicolás; Cuesta, Pedro; Calderón, Rosario

    2014-01-24

    The archeology and history of the ancient Mediterranean have shown that this sea has been a permeable obstacle to human migration. Multiple cultural exchanges around the Mediterranean have taken place with presumably population admixtures. A gravitational territory of those migrations has been the Iberian Peninsula. Here we present a comprehensive analysis of the maternal gene pool, by means of control region sequencing and PCR-RFLP typing, of autochthonous Andalusians originating from the coastal provinces of Huelva and Granada, located respectively in the west and the east of the region. The mtDNA haplogroup composition of these two southern Spanish populations has revealed a wide spectrum of haplogroups from different geographical origins. The registered frequencies of Eurasian markers, together with the high incidence and diversification of African maternal lineages (15% of the total mitochondrial variability) among Huelva Andalusians when compared to its eastwards relatives of Granada and other Iberian populations, constitute relevant findings unknown up-to-date on the characteristics of mtDNA within Andalusia that testifies a female population substructure. Therefore, Andalusia must not be considered a single, unique population. The maternal legacy among Andalusians reflects distinctive local histories, pointing out the role of the westernmost territory of Peninsular Spain as a noticeable recipient of multiple and diverse human migrations. The obtained results underline the necessity of further research on genetic relationships in both sides of the western Mediterranean, using carefully collected samples from autochthonous individuals. Many studies have focused on recent North African gene flow towards Iberia, yet scientific attention should be now directed to thoroughly study the introduction of European genes in northwest Africa across the sea, in order to determine its magnitude, timescale and methods, and to compare them to those terrestrial movements

  14. Primary quantitative analysis of the mtDNA4977bp deletion induced by lonizing radiation in human peripheral blood u-sing real-time PCR

    Duan Zhikai; Liu Jiangong; Guo Wanlong; Zhang Shuxian

    2011-01-01

    Objective: To observe the influence of mtDNA4977bp deletion induced by different dose of γ ray in human peripheral blood in order to explore the feasibility of mtDNA4977bp deletion as biodosimeter. Methods: Human peripheral blood samples were collected from three healthy donors and irradiated by γ ray, MtDNA4977bp deletion was detected by real-time PCR. Results: It indicated that that from the range of 0 ∼ 8 Gy, the relationship between mtDNA4977bp deletion and irradiation dose represents certain curvilinear correlation (Y=1.2693+1.0660X+0.0198X 2 ). Conclusion: We find that γ ray has influence on the mtDNA4977bp deletion, so it may be an important biodosmeter in future. (authors)

  15. Cells Lacking mtDNA Display Increased dNTP Pools upon DNA Damage

    Skovgaard, Tine; Rasmussen, Lene Juel; Munch-Petersen, Birgitte

    Imbalanced dNTP pools are highly mutagenic due to a deleterious effect on DNA polymerase fidelity. Mitochondrial DNA defects, including mutations and deletions, are commonly found in a wide variety of different cancer types. In order to further study the interconnection between dNTP pools...... and mitochondrial function we have examined the effect of DNA damage on dNTP pools in cells deficient of mtDNA. We show that DNA damage induced by UV irradiation, in a dose corresponding to LD50, induces an S phase delay in different human osteosarcoma cell lines. The UV pulse also has a destabilizing effect...... shows that normal mitochondrial function is prerequisite for retaining stable dNTP pools upon DNA damage. Therefore it is likely that mitochondrial deficiency defects may cause an increase in DNA mutations by disrupting dNTP pool balance....

  16. M1 and M2 Monocytes in Rheumatoid Arthritis: A Contribution of Imbalance of M1/M2 Monocytes to Osteoclastogenesis

    Shoichi Fukui

    2018-01-01

    Full Text Available ObjectivesWe investigated the relationships among M1 monocytes, M2 monocytes, osteoclast (OC differentiation ability, and clinical characteristics in patients with rheumatoid arthritis (RA.MethodsPeripheral blood mononuclear cells (PBMCs were isolated from RA patients and healthy donors, and we then investigated the number of M1 monocytes or M2 monocytes by fluorescence-activated cell sorting. We also obtained and cultured CD14-positive cells from PBMCs from RA patients and healthy donors to investigate OC differentiation in vitro.ResultsForty RA patients and 20 healthy donors were included. Twenty-two patients (55% were anticitrullinated protein antibody (ACPA positive. The median M1/M2 ratio was 0.59 (0.31–1.11, interquartile range. There were no significant differences between the RA patients and healthy donors. There was a positive correlation between the M1/M2 ratio and the differentiated OC number in vitro in RA patients (ρ = 0.81, p < 0.001. The ACPA-positive patients had significantly higher M1/M2 ratios in vivo (p = 0.028 and significantly greater numbers of OCs in vitro (p = 0.005 than the ACPA-negative patients. Multivariable regression analysis revealed that the M1/M2 ratio was the sole significant contribution factor to in vitro osteoclastogenesis. RA patients with M1/M2 ratios >1 (having relatively more M1 monocytes had higher C-reactive protein and erythrocyte sedimentation rates than RA patients with M1/M2 ratios ≤1. M1-dominant monocytes in vitro produced higher concentrations of interleukin-6 upon stimulation with lipopolysaccharide than M2 monocytes.ConclusionM1/M2 monocytes imbalance strongly contributes to osteoclastogenesis of RA patients. Our findings cast M1 and M2 monocyte subsets in a new light as a new target of treatments for RA to prevent progression of osteoclastic bone destruction.

  17. Identification and Characterization of Mouse Otic Sensory Lineage Genes

    Byron H. Hartman

    2015-03-01

    Full Text Available Vertebrate embryogenesis gives rise to all cell types of an organism through the development of many unique lineages derived from the three primordial germ layers. The otic sensory lineage arises from the otic vesicle, a structure formed through invagination of placodal non-neural ectoderm. This developmental lineage possesses unique differentiation potential, giving rise to otic sensory cell populations including hair cells, supporting cells, and ganglion neurons of the auditory and vestibular organs. Here we present a systematic approach to identify transcriptional features that distinguish the otic sensory lineage (from early otic progenitors to otic sensory populations from other major lineages of vertebrate development. We used a microarray approach to analyze otic sensory lineage populations including microdissected otic vesicles (embryonic day 10.5 as well as isolated neonatal cochlear hair cells and supporting cells at postnatal day 3. Non-otic tissue samples including periotic tissues and whole embryos with otic regions removed were used as reference populations to evaluate otic specificity. Otic populations shared transcriptome-wide correlations in expression profiles that distinguish members of this lineage from non-otic populations. We further analyzed the microarray data using comparative and dimension reduction methods to identify individual genes that are specifically expressed in the otic sensory lineage. This analysis identified and ranked top otic sensory lineage-specific transcripts including Fbxo2, Col9a2, and Oc90, and additional novel otic lineage markers. To validate these results we performed expression analysis on select genes using immunohistochemistry and in situ hybridization. Fbxo2 showed the most striking pattern of specificity to the otic sensory lineage, including robust expression in the early otic vesicle and sustained expression in prosensory progenitors and auditory and vestibular hair cells and supporting

  18. Understanding the Mysterious M2 Macrophage through Activation Markers and Effector Mechanisms

    Rőszer, Tamás

    2015-01-01

    The alternatively activated or M2 macrophages are immune cells with high phenotypic heterogeneity and are governing functions at the interface of immunity, tissue homeostasis, metabolism, and endocrine signaling. Today the M2 macrophages are identified based on the expression pattern of a set of M2 markers. These markers are transmembrane glycoproteins, scavenger receptors, enzymes, growth factors, hormones, cytokines, and cytokine receptors with diverse and often yet unexplored functions. This review discusses whether these M2 markers can be reliably used to identify M2 macrophages and define their functional subdivisions. Also, it provides an update on the novel signals of the tissue environment and the neuroendocrine system which shape the M2 activation. The possible evolutionary roots of the M2 macrophage functions are also discussed. PMID:26089604

  19. Reexamination of M2,3 atomic level widths and L1M2,3 transition energies of elements 69≤Z≤95

    Fennane, K.; Berset, M.; Dousse, J.-Cl.; Hoszowska, J.; Raboud, P.-A.; Campbell, J. L.

    2013-11-01

    We report on high-resolution measurements of the photoinduced L1M2 and L1M3 x-ray emission lines of 69Tm, 70Yb, 71Lu, 73Ta, 74W, 75Re, 77Ir, 81Tl, 83Bi, and 95Am. From the linewidths of the measured transitions an accurate set of M2 and M3 level widths is determined assuming for the L1 level widths the values reported by Raboud [P.-A. Raboud et al., Phys. Rev. APLRAAN1050-294710.1103/PhysRevA.65.022512 65, 022512 (2002)]. Furthermore, the present experimental M2,3 data set is extended to 80Hg, 90Th, and 92U, using former L1M2,3 high-resolution x-ray emission spectroscopy measurements performed by our group. A detailed comparison of the M2 and M3 level widths determined in the present work with those recommended by Campbell and Papp [J. L. Campbell and T. Papp, At. Data Nucl. Data TablesADNDAT0092-640X10.1006/adnd.2000.0848 77, 1 (2001)] and other available experimental data as well as theoretical predictions is done. The observed abrupt changes of the M2,3 level widths versus atomic number Z can be explained satisfactorily by the cutoffs and onsets of the M2M4N1, respectively M3M4N3,4,5 and M3M5N2,3 Coster-Kronig transitions deduced from the semiempirical (Z+1) approximation. As a spin-off result of this study, precise L1M2 and L1M3 transition energies are obtained for the investigated elements. A very good agreement with transition energies calculated within the many-body perturbation theory is found.

  20. A Signal, from Human mtDNA, of Postglacial Recolonization in Europe

    Torroni, Antonio; Bandelt, Hans-Jürgen; Macaulay, Vincent; Richards, Martin; Cruciani, Fulvio; Rengo, Chiara; Martinez-Cabrera, Vicente; Villems, Richard; Kivisild, Toomas; Metspalu, Ene; Parik, Jüri; Tolk, Helle-Viivi; Tambets, Kristiina; Forster, Peter; Karger, Bernd; Francalacci, Paolo; Rudan, Pavao; Janicijevic, Branka; Rickards, Olga; Savontaus, Marja-Liisa; Huoponen, Kirsi; Laitinen, Virpi; Koivumäki, Satu; Sykes, Bryan; Hickey, Eileen; Novelletto, Andrea; Moral, Pedro; Sellitto, Daniele; Coppa, Alfredo; Al-Zaheri, Nadia; Santachiara-Benerecetti, A. Silvana; Semino, Ornella; Scozzari, Rosaria

    2001-01-01

    Mitochondrial HVS-I sequences from 10,365 subjects belonging to 56 populations/geographical regions of western Eurasia and northern Africa were first surveyed for the presence of the T→C transition at nucleotide position 16298, a mutation which has previously been shown to characterize haplogroup V mtDNAs. All mtDNAs with this mutation were then screened for a number of diagnostic RFLP sites, revealing two major subsets of mtDNAs. One is haplogroup V proper, and the other has been termed “pre*V,” since it predates V phylogenetically. The rather uncommon pre*V tends to be scattered throughout Europe (and northwestern Africa), whereas V attains two peaks of frequency: one situated in southwestern Europe and one in the Saami of northern Scandinavia. Geographical distributions and ages support the scenario that pre*V originated in Europe before the Last Glacial Maximum (LGM), whereas the more recently derived haplogroup V arose in a southwestern European refugium soon after the LGM. The arrival of V in eastern/central Europe, however, occurred much later, possibly with (post-)Neolithic contacts. The distribution of haplogroup V mtDNAs in modern European populations would thus, at least in part, reflect the pattern of postglacial human recolonization from that refugium, affecting even the Saami. Overall, the present study shows that the dissection of mtDNA variation into small and well-defined evolutionary units is an essential step in the identification of spatial frequency patterns. Mass screening of a few markers identified using complete mtDNA sequences promises to be an efficient strategy for inferring features of human prehistory. PMID:11517423

  1. Rare mtDNA haplogroups and genetic differences in rich and poor Danish Iron-Age villages

    Melchior, L; Gilbert, M T P; Kivisild, T

    2008-01-01

    The Roman Iron-Age (0-400 AD) in Southern Scandinavia was a formative period, where the society changed from archaic chiefdoms to a true state formation, and the population composition has likely changed in this period due to immigrants from Middle Scandinavia. We have analyzed mtDNA from 22 indi...

  2. An economical mtDNA SNP assay detecting different mitochondrial haplogroups in identical HVR 1 samples of Caucasian ancestry.

    Köhnemann, Stephan; Hohoff, Carsten; Pfeiffer, Heidi

    2009-09-01

    We had sequenced 329 Caucasian samples in Hypervariable Region 1 (HVR 1) and found that they belong to eleven different mitochondrial DNA (mtDNA) haplotypes. The sample set was further analysed by an mtDNA assay examining 32 single nucleotide polymorphisms (SNPs) for haplogroup discrimination. In a validation study on 160 samples of different origin it was shown that these SNPs were able to discriminate between the evolved superhaplogroups worldwide (L, M and N) and between the nine most common Caucasian haplogroups (H, I, J, K, T, U, V, W and X). The 32 mtDNA SNPs comprised 42 different SNP haplotypes instead of only eleven haplotypes after HVR 1 sequencing. The assay provided stable results in a range of 5ng genomic DNA down to virtually no genomic DNA per reaction. It was possible to detect samples of African, Asian and Eurasian ancestry, respectively. The 32 mtDNA SNP assay is a helpful adjunct to further distinguish between identical HVR 1 sequences of Caucasian origin. Our results suggest that haplogroup prediction using HVR 1 sequencing provides instable results. The use of coding region SNPs for haplogroup assignment is more suited than using HVR 1 haplotypes.

  3. Human aging and somatic point mutations in mtDNA: a comparative study of generational differences (grandparents and grandchildren

    Anderson Nonato do Rosário Marinho

    2011-01-01

    Full Text Available The accumulation of somatic mutations in mtDNA is correlated with aging. In this work, we sought to identify somatic mutations in the HVS-1 region (D-loop of mtDNA that might be associated with aging. For this, we compared 31 grandmothers (mean age: 63 ± 2.3 years and their 62 grandchildren (mean age: 15 ± 4.1 years, the offspring of their daughters. Direct DNA sequencing showed that mutations absent in the grandchildren were detected in a presumably homoplasmic state in three grandmothers and in a heteroplasmic state in an additional 13 grandmothers; no mutations were detected in the remaining 15 grandmothers. However, cloning followed by DNA sequencing in 12 grandmothers confirmed homoplasia in only one of the three mutations previously considered to be homoplasmic and did not confirm heteroplasmy in three out of nine grandmothers found to be heteroplasmic by direct sequencing. Thus, of 12 grandmothers in whom mtDNA was analyzed by cloning, eight were heteroplasmic for mutations not detected in their grandchildren. In this study, the use of genetically related subjects allowed us to demonstrate the occurrence of age-related (> 60 years old mutations (homoplasia and heteroplasmy. It is possible that both of these situations (homoplasia and heteroplasmy were a long-term consequence of mitochondrial oxidative phosphorylation that can lead to the accumulation of mtDNA mutations throughout life.

  4. Human iPSC-Derived Neural Progenitors Are an Effective Drug Discovery Model for Neurological mtDNA Disorders.

    Lorenz, Carmen; Lesimple, Pierre; Bukowiecki, Raul; Zink, Annika; Inak, Gizem; Mlody, Barbara; Singh, Manvendra; Semtner, Marcus; Mah, Nancy; Auré, Karine; Leong, Megan; Zabiegalov, Oleksandr; Lyras, Ekaterini-Maria; Pfiffer, Vanessa; Fauler, Beatrix; Eichhorst, Jenny; Wiesner, Burkhard; Huebner, Norbert; Priller, Josef; Mielke, Thorsten; Meierhofer, David; Izsvák, Zsuzsanna; Meier, Jochen C; Bouillaud, Frédéric; Adjaye, James; Schuelke, Markus; Wanker, Erich E; Lombès, Anne; Prigione, Alessandro

    2017-05-04

    Mitochondrial DNA (mtDNA) mutations frequently cause neurological diseases. Modeling of these defects has been difficult because of the challenges associated with engineering mtDNA. We show here that neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (iPSCs) retain the parental mtDNA profile and exhibit a metabolic switch toward oxidative phosphorylation. NPCs derived in this way from patients carrying a deleterious homoplasmic mutation in the mitochondrial gene MT-ATP6 (m.9185T>C) showed defective ATP production and abnormally high mitochondrial membrane potential (MMP), plus altered calcium homeostasis, which represents a potential cause of neural impairment. High-content screening of FDA-approved drugs using the MMP phenotype highlighted avanafil, which we found was able to partially rescue the calcium defect in patient NPCs and differentiated neurons. Overall, our results show that iPSC-derived NPCs provide an effective model for drug screening to target mtDNA disorders that affect the nervous system. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Genetic characterization of human T-cell lymphotropic virus type 1 in Mozambique: transcontinental lineages drive the HTLV-1 endemic.

    Ana Carolina P Vicente

    2011-04-01

    Full Text Available Human T-Cell Lymphotropic Virus Type 1 (HTLV-1 is the etiological agent of adult T-cell leukemia (ATL and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP. It has been estimated that 10-20 million people are infected worldwide, but no successful treatment is available. Recently, the epidemiology of this virus was addressed in blood donors from Maputo, showing rates from 0.9 to 1.2%. However, the origin and impact of HTLV endemic in this population is unknown.To assess the HTLV-1 molecular epidemiology in Mozambique and to investigate their relationship with HTLV-1 lineages circulating worldwide.Blood donors and HIV patients were screened for HTLV antibodies by using enzyme immunoassay, followed by Western Blot. PCR and sequencing of HTLV-1 LTR region were applied and genetic HTLV-1 subtypes were assigned by the neighbor-joining method. The mean genetic distance of Mozambican HTLV-1 lineages among the genetic clusters were determined. Human mitochondrial (mt DNA analysis was performed and individuals classified in mtDNA haplogroups.LTR HTLV-1 analysis demonstrated that all isolates belong to the Transcontinental subgroup of the Cosmopolitan subtype. Mozambican HTLV-1 sequences had a high inter-strain genetic distance, reflecting in three major clusters. One cluster is associated with the South Africa sequences, one is related with Middle East and India strains and the third is a specific Mozambican cluster. Interestingly, 83.3% of HIV/HTLV-1 co-infection was observed in the Mozambican cluster. The human mtDNA haplotypes revealed that all belong to the African macrohaplogroup L with frequencies representatives of the country.The Mozambican HTLV-1 genetic diversity detected in this study reveals that although the strains belong to the most prevalent and worldwide distributed Transcontinental subgroup of the Cosmopolitan subtype, there is a high HTLV diversity that could be correlated with at least 3 different HTLV-1 introductions

  6. [Differences on geographic distribution of rabies virus lineages in China].

    Wang, Q; Li, M L; Chen, Y; Wang, B; Tao, X Y; Zhu, W Y

    2018-04-10

    Objective: To study the lineages of rabies virus and the epidemic characteristics in different provincial populations of China, to provide information for the development of control and prevention measures in each respective provinces. Methods: Full length N and G genes and full-genome of epidemic strains of rabies virus collected in China were downloaded from GenBank and combined with newly sequenced strains by our lab. Each strain was classified under six lineages of China rabies by constructing phylogenetic trees based on the N or G sequences. Numbers of strains and lineages in each province were counted and compared. Results: Six lineages (China Ⅰ-Ⅵ) were prevalent in China, with 4 found in Yunnan and Hunan. In 6 provinces, including Henan and Fujian, 3 lineages were found. In 8 provinces, including Shanghai and Jiangxi, 2 lineages were found Only 1 lineage, were found in Beijing, Tianjin and other 12 provinces. the China Ⅰ, was the dominant one in 25 provinces. In recent years, China Ⅲ had been found in wild animals and spread over livestock in Inner Mongolia and Xinjiang areas. Qinghai and Tibet had been influenced by China Ⅳ, which also been found in wild animals of Inner Mongolia and Heilongjiang. Conclusion: There had been obvious differences in lineages and strain numbers of rabies virus identified in different provinces in China.

  7. Evidence of multiple divergent mitochondrial lineages within the ...

    On this basis, the mitochondrial cytochrome c oxidase subunit 1 (COI) was used to reconstruct the phylogeny of Bicoxidens and reveal divergent lineages within the genus. Maximum likelihood and Bayesian inference analyses recovered a paraphyletic Bicoxidens phylogram with divergent lineages present in three species ...

  8. Increased immunogenicity and protective efficacy of influenza M2e fused to a tetramerizing protein.

    Anne-Marie Carola Andersson

    Full Text Available The ectodomain of the matrix 2 protein (M2e of influenza A virus represents an attractive target for developing a universal influenza A vaccine, with its sequence being highly conserved amongst human variants of this virus. With the aim of targeting conformational epitopes presumably shared by diverse influenza A viruses, a vaccine (M2e-NSP4 was constructed linking M2e (in its consensus sequence to the rotavirus fragment NSP4(98-135; due to its coiled-coil region this fragment is known to form tetramers in aqueous solution and in this manner we hoped to mimick the natural configuration of M2e as presented in membranes. M2e-NSP4 was then evaluated side-by-side with synthetic M2e peptide for its immunogenicity and protective efficacy in a murine influenza challenge model. Here we demonstrate that M2e fused to the tetramerizing protein induces an accelerated, augmented and more broadly reactive antibody response than does M2e peptide as measured in two different assays. Most importantly, vaccination with M2e-NSP4 caused a significant decrease in lung virus load early after challenge with influenza A virus and maintained its efficacy against a lethal challenge even at very low vaccine doses. Based on the results presented in this study M2e-NSP4 merits further investigation as a candidate for or as a component of a universal influenza A vaccine.

  9. Luminal progenitors restrict their lineage potential during mammary gland development.

    Rodilla, Veronica; Dasti, Alessandro; Huyghe, Mathilde; Lafkas, Daniel; Laurent, Cécile; Reyal, Fabien; Fre, Silvia

    2015-02-01

    The hierarchical relationships between stem cells and progenitors that guide mammary gland morphogenesis are still poorly defined. While multipotent basal stem cells have been found within the myoepithelial compartment, the in vivo lineage potential of luminal progenitors is unclear. Here we used the expression of the Notch1 receptor, previously implicated in mammary gland development and tumorigenesis, to elucidate the hierarchical organization of mammary stem/progenitor cells by lineage tracing. We found that Notch1 expression identifies multipotent stem cells in the embryonic mammary bud, which progressively restrict their lineage potential during mammary ductal morphogenesis to exclusively generate an ERαneg luminal lineage postnatally. Importantly, our results show that Notch1-labelled cells represent the alveolar progenitors that expand during pregnancy and survive multiple successive involutions. This study reveals that postnatal luminal epithelial cells derive from distinct self-sustained lineages that may represent the cells of origin of different breast cancer subtypes.

  10. β-adrenergic-stimulated macrophages: Comprehensive localization in the M1–M2 spectrum

    Lamkin, Donald M.; Ho, Hsin-Yun; Ong, Tiffany H.; Kawanishi, Carly K.; Stoffers, Victoria L.; Ahlawat, Nivedita; Ma, Jeffrey C.Y.; Arevalo, Jesusa M. G.; Cole, Steve W.; Sloan, Erica K.

    2016-01-01

    β-adrenergic signaling can regulate macrophage involvement in several diseases and often produces anti-inflammatory properties in macrophages, which are similar to M2 properties in a dichotomous M1 vs. M2 macrophage taxonomy. However, it is not clear that β-adrenergic-stimulated macrophages may be classified strictly as M2. In this in vitro study, we utilized recently published criteria and transcriptome-wide bioinformatics methods to map the relative polarity of murine β-adrenergic-stimulated macrophages within a wider M1–M2 spectrum. Results show that β-adrenergic-stimulated macrophages did not fit entirely into any one predefined category of the M1–M2 spectrum but did express genes that are representative of some M2 side categories. Moreover, transcript origin analysis of genome-wide transcriptional profiles located β-adrenergic-stimulated macrophages firmly on the M2 side of the M1–M2 spectrum and found active suppression of M1 side gene transcripts. The signal transduction pathways involved were mapped through blocking experiments and bioinformatics analysis of transcription factor binding motifs. M2-promoting effects were mediated specifically through β2-adrenergic receptors and were associated with CREB, C/EBPβ, and ATF transcription factor pathways but not with established M1–M2 STAT pathways. Thus, β-adrenergic-signaling induces a macrophage transcriptome that locates on the M2 side of the M1–M2 spectrum but likely accomplishes this effect through a signaling pathway that is atypical for M2-spectrum macrophages. PMID:27485040

  11. Genetic analysis of maternal and paternal lineages in Kabardian horses by uniparental molecular markers

    Aliy-bek D. Khaudov

    2018-02-01

    Full Text Available Studies of mitochondrial DNA (mtDNA as well as the non-recombining part of the Y chromosome help to understand the origin and distribution of maternal and paternal lineages. The Kabardian horse from Northern Caucasia which is well-known for strength, stamina and endurance in distance riding has a large gap in its breeding documentation especially in the recent past. A 309 bp fragment of the mitochondrial D-loop (156 Kabardian horses and six mutations in Y chromosome (49 Kabardian stallions, respectively, were analyzed to get a better insight into breeding history, phylogenetic relationship to related breeds, maternal and paternal diversity and genetic structure. We found a high mitochondrial diversity represented by 64 D-loop haplotypes out of 14 haplogroups. The most frequent haplogroups were G (19.5%, L (12.3%, Q (11.7%, and B (11.0%. Although these four haplogroups are also frequently found in Asian riding horses (e.g. Buryat, Kirghiz, Mongolian, Transbaikalian, Tuvinian the percentage of the particular haplogroups varies sometimes remarkable. In contrast, the obtained haplogroup pattern from Kabardian horse was more similar to that of breeds reared in the Middle East. No specific haplotype cluster was observed in the phylogenetic tree for Kabardian horses. On Kabardian Y chromosome, two mutations were found leading to three haplotypes with a percentage of 36.7% (haplotype HT1, 38.8% (haplotype HT2 and 24.5% (haplotype HT3, respectively. The high mitochondrial and also remarkable paternal diversity of the Kabardian horse is caused by its long history with a widely spread maternal origin and the introduction of Arabian as well as Thoroughbred influenced stallions for improvement. This high genetic diversity provides a good situation for the ongoing breed development and performance selection as well as avoiding inbreeding.

  12. Ecotype diversification of an abundant Roseobacter lineage.

    Sun, Ying; Zhang, Yao; Hollibaugh, James T; Luo, Haiwei

    2017-04-01

    The Roseobacter DC5-80-3 cluster (also known as the RCA clade) is among the most abundant bacterial lineages in temperate and polar oceans. Previous studies revealed two phylotypes within this cluster that are distinctly distributed in the Antarctic and other ocean provinces. Here, we report a nearly complete genome co-assembly of three closely related single cells co-occurring in the Antarctic, and compare it to the available genomes of the other phylotype from ocean regions where iron is more accessible but phosphorus and nitrogen are less. The Antarctic phylotype exclusively contains an operon structure consisting of a dicitrate transporter fecBCDE and an upstream regulator likely for iron uptake, whereas the other phylotype consistently carry a high-affinity phosphate pst transporter and the phoB-phoR regulatory system, a high-affinity ammonium amtB transporter, urea and taurine utilization systems. Moreover, the Antarctic phylotype uses proteorhodopsin to acquire light, whereas the other uses bacteriochlorophyll-a and the sulfur-oxidizing sox cluster for energy acquisition. This is potentially an iron-saving strategy for the Antarctic phylotype because only the latter two pathways have iron-requiring cytochromes. Therefore, the two DC5-80-3 phylotypes, while diverging by only 1.1% in their 16S rRNA genes, have evolved systematic differences in metabolism to support their distinct ecologies. © 2017 Society for Applied Microbiology and John Wiley & Sons Ltd.

  13. Origin, lineage and function of cerebellar glia.

    Buffo, Annalisa; Rossi, Ferdinando

    2013-10-01

    The glial cells of the cerebellum, and particularly astrocytes and oligodendrocytes, are characterized by a remarkable phenotypic variety, in which highly peculiar morphological features are associated with specific functional features, unique among the glial cells of the entire CNS. Here, we provide a critical report about the present knowledge of the development of cerebellar glia, including lineage relationships between cerebellar neurons, astrocytes and oligodendrocytes, the origins and the genesis of the repertoire of glial types, and the processes underlying their acquisition of mature morphological and functional traits. In parallel, we describe and discuss some fundamental roles played by specific categories of glial cells during cerebellar development. In particular, we propose that Bergmann glia exerts a crucial scaffolding activity that, together with the organizing function of Purkinje cells, is necessary to achieve the normal pattern of foliation and layering of the cerebellar cortex. Moreover, we discuss some of the functional tasks of cerebellar astrocytes and oligodendrocytes that are distinctive of cerebellar glia throughout the CNS. Notably, we report about the regulation of synaptic signalling in the molecular and granular layer mediated by Bergmann glia and parenchymal astrocytes, and the functional interaction between oligodendrocyte precursor cells and neurons. On the whole, this review provides an extensive overview of the available literature and some novel insights about the origin and differentiation of the variety of cerebellar glial cells and their function in the developing and mature cerebellum. Copyright © 2013 Elsevier Ltd. All rights reserved.

  14. Distributed Energy-Efficient Topology Control Algorithm in Home M2M Networks

    Lee, Chao-Yang; Yang, Chu-Sing

    2012-01-01

    Because machine-to-machine (M2M) technology enables machines to communicate with each other without human intervention, it could play a big role in sensor network systems. Through wireless sensor network (WSN) gateways, various information can be collected by sensors for M2M systems. For home M2M networks, this study proposes a distributed energy-efficient topology control algorithm for both topology construction and topology maintenance. Topology control is an effective method of enhancing e...

  15. Reliable Reporting for Massive M2M Communications with Periodic Resource Pooling

    Madueño, Germán Corrales; Stefanovic, Cedomir; Popovski, Petar

    2014-01-01

    This letter considers a wireless M2M communication scenario with a massive number of M2M devices. Each device needs to send its reports within a given deadline and with certain reliability, e.g., 99.99%. A pool of resources available to all M2M devices is periodically available for transmission...... to guarantee the desired reliability of the report delivery within the deadline. The fact that the pool of resources is used by a massive number of devices allows to base the dimensioning on the central limit theorem. The results are interpreted in the context of LTE, but they are applicable to any M2M...

  16. Lineage fusion in Galápagos giant tortoises.

    Garrick, Ryan C; Benavides, Edgar; Russello, Michael A; Hyseni, Chaz; Edwards, Danielle L; Gibbs, James P; Tapia, Washington; Ciofi, Claudio; Caccone, Adalgisa

    2014-11-01

    Although many classic radiations on islands are thought to be the result of repeated lineage splitting, the role of past fusion is rarely known because during these events, purebreds are rapidly replaced by a swarm of admixed individuals. Here, we capture lineage fusion in action in a Galápagos giant tortoise species, Chelonoidis becki, from Wolf Volcano (Isabela Island). The long generation time of Galápagos tortoises and dense sampling (841 individuals) of genetic and demographic data were integral in detecting and characterizing this phenomenon. In C. becki, we identified two genetically distinct, morphologically cryptic lineages. Historical reconstructions show that they colonized Wolf Volcano from Santiago Island in two temporally separated events, the first estimated to have occurred ~199 000 years ago. Following arrival of the second wave of colonists, both lineages coexisted for approximately ~53 000 years. Within that time, they began fusing back together, as microsatellite data reveal widespread introgressive hybridization. Interestingly, greater mate selectivity seems to be exhibited by purebred females of one of the lineages. Forward-in-time simulations predict rapid extinction of the early arriving lineage. This study provides a rare example of reticulate evolution in action and underscores the power of population genetics for understanding the past, present and future consequences of evolutionary phenomena associated with lineage fusion. © 2014 John Wiley & Sons Ltd.

  17. Instruction of hematopoietic lineage choice by cytokine signaling

    Endele, Max; Etzrodt, Martin; Schroeder, Timm, E-mail: timm.schroeder@bsse.ethz.ch

    2014-12-10

    Hematopoiesis is the cumulative consequence of finely tuned signaling pathways activated through extrinsic factors, such as local niche signals and systemic hematopoietic cytokines. Whether extrinsic factors actively instruct the lineage choice of hematopoietic stem and progenitor cells or are only selectively allowing survival and proliferation of already intrinsically lineage-committed cells has been debated over decades. Recent results demonstrated that cytokines can instruct lineage choice. However, the precise function of individual cytokine-triggered signaling molecules in inducing cellular events like proliferation, lineage choice, and differentiation remains largely elusive. Signal transduction pathways activated by different cytokine receptors are highly overlapping, but support the production of distinct hematopoietic lineages. Cellular context, signaling dynamics, and the crosstalk of different signaling pathways determine the cellular response of a given extrinsic signal. New tools to manipulate and continuously quantify signaling events at the single cell level are therefore required to thoroughly interrogate how dynamic signaling networks yield a specific cellular response. - Highlights: • Recent studies provided definite proof for lineage-instructive action of cytokines. • Signaling pathways involved in hematopoietic lineage instruction remain elusive. • New tools are emerging to quantitatively study dynamic signaling networks over time.

  18. Cell lineage branching as a strategy for proliferative control.

    Buzi, Gentian; Lander, Arthur D; Khammash, Mustafa

    2015-02-19

    How tissue and organ sizes are specified is one of the great unsolved mysteries in biology. Experiments and mathematical modeling implicate feedback control of cell lineage progression, but a broad understanding of what lineage feedback accomplishes is lacking. By exploring the possible effects of various biologically relevant disturbances on the dynamic and steady state behaviors of stem cell lineages, we find that the simplest and most frequently studied form of lineage feedback - which we term renewal control - suffers from several serious drawbacks. These reflect fundamental performance limits dictated by universal conservation-type laws, and are independent of parameter choice. Here we show that introducing lineage branches can circumvent all such limitations, permitting effective attenuation of a wide range of perturbations. The type of feedback that achieves such performance - which we term fate control - involves promotion of lineage branching at the expense of both renewal and (primary) differentiation. We discuss the evidence that feedback of just this type occurs in vivo, and plays a role in tissue growth control. Regulated lineage branching is an effective strategy for dealing with disturbances in stem cell systems. The existence of this strategy provides a dynamics-based justification for feedback control of cell fate in vivo.

  19. [Identification of the Mycobacterium tuberculosis Beijing lineage in Ecuador].

    Jiménez, Patricia; Calvopiña, Karina; Herrera, Diana; Rojas, Carlos; Pérez-Lago, Laura; Grijalva, Marcelo; Guna, Remedios; García-de Viedma, Darío

    2017-06-01

    Mycobacterium tuberculosis Beijing lineage isolates are considered to be especially virulent, transmissible and prone to acquire resistances. Beijing strains have been reported worldwide, but studies in Latin America are still scarce. The only multinational study performed in the region indicated a heterogeneous distribution for this lineage, which was absent in Chile, Colombia and Ecuador, although further studies found the lineage in Chile and Colombia. To search for the presence of the Beijing lineage in Ecuador, the only country in the region where it remains unreported. We obtained a convenience sample (2006-2012) from two hospitals covering different populations. The isolates were genotyped using 24-MIRU-VNTR. Lineages were assigned by comparing their patterns to those in the MIRU-VNTRplus platform. Isolates belonging to the Beijing lineage were confirmed by allele-specific PCR. We identified the first Beijing isolate in Ecuador in an unexpected epidemiological scenario: A patient was infected in the Andean region, in a population with low mobility and far from the borders of the neighboring countries where Beijing strains had been previously reported. This is the first report of the presence of the Beijing lineage in Ecuador in an unusual epidemiological context that deserves special attention.

  20. Dynamic formation of asexual diploid and polyploid lineages: multilocus analysis of Cobitis reveals the mechanisms maintaining the diversity of clones.

    Karel Janko

    Full Text Available Given the hybrid genomic constitutions and increased ploidy of many asexual animals, the identification of processes governing the origin and maintenance of clonal diversity provides useful information about the evolutionary consequences of interspecific hybridization, asexuality and polyploidy. In order to understand the processes driving observed diversity of biotypes and clones in the Cobitis taenia hybrid complex, we performed fine-scale genetic analysis of Central European hybrid zone between two sexual species using microsatellite genotyping and mtDNA sequencing. We found that the hybrid zone is populated by an assemblage of clonally (gynogenetically reproducing di-, tri- and tetraploid hybrid lineages and that successful clones, which are able of spatial expansion, recruit from two ploidy levels, i.e. diploid and triploid. We further compared the distribution of observed estimates of clonal ages to theoretical distributions simulated under various assumptions and showed that new clones are most likely continuously recruited from ancestral populations. This suggests that the clonal diversity is maintained by dynamic equilibrium between origination and extinction of clonal lineages. On the other hand, an interclonal selection is implied by nonrandom spatial distribution of individual clones with respect to the coexisting sexual species. Importantly, there was no evidence for sexually reproducing hybrids or clonally reproducing non-hybrid forms. Together with previous successful laboratory synthesis of clonal Cobitis hybrids, our data thus provide the most compelling evidence that 1 the origin of asexuality is causally linked to interspecific hybridization; 2 successful establishment of clones is not restricted to one specific ploidy level and 3 the initiation of clonality and polyploidy may be dynamic and continuous in asexual complexes.

  1. Analysis of mtDNA sequence variants in colorectal adenomatous polyps

    Grizzle William

    2010-10-01

    Full Text Available Abstract Colorectal tumors mostly arise from sporadic adenomatous polyps. Polyps are defined as a mass of cells that protrudes into the lumen of the colon. Adenomatous polyps are benign neoplasms that, by definition display some characteristics of dysplasia. It has been shown that polyps were benign tumors which may undergo malignant transformation. Adenomatous polyps have been classified into three histologic types; tubular, tubulovillous, and villous with increasing malignant potential. The ability to differentially diagnose these colorectal adenomatous polyps is important for therapeutic intervention. To date, little efforts have been directed to identifying genetic changes involved in adenomatous polyps. This study was designed to examine the relevance of mitochondrial genome alterations in the three adenomatous polyps. Using high resolution restriction endonucleases and PCR-based sequencing, fifty-seven primary fresh frozen tissues of adenomatous polyps (37 tumors and 20 matched surrounding normal tissues obtained from the southern regional Cooperative Human Tissue Network (CHTN and Grady Memorial Hospital at Atlanta were screened with three mtDNA regional primer pairs that spanned 5.9 kbp. Results from our data analyses revealed the presence of forty-four variants in some of these mitochondrial genes that the primers spanned; COX I, II, III, ATP 6, 8, CYT b, ND 5, 6 and tRNAs. Based on the MITODAT database as a sequence reference, 25 of the 44 (57% variants observed were unreported. Notably, a heteroplasmic variant C8515G/T in the MT-ATP 8 gene and a germline variant 8327delA in the tRNAlys was observed in all the tissue samples of the three adenomatous polyps in comparison to the referenced database sequence. A germline variant G9055A in the MT-ATP 6 gene had a frequency of 100% (17/17 in tubular and 57% (13/23 in villous adenomas; no corresponding variant was in tubulovillous adenomas. Furthermore, A9006G variant at MT-ATP 6 gene was

  2. Fast and scalable inference of multi-sample cancer lineages.

    Popic, Victoria

    2015-05-06

    Somatic variants can be used as lineage markers for the phylogenetic reconstruction of cancer evolution. Since somatic phylogenetics is complicated by sample heterogeneity, novel specialized tree-building methods are required for cancer phylogeny reconstruction. We present LICHeE (Lineage Inference for Cancer Heterogeneity and Evolution), a novel method that automates the phylogenetic inference of cancer progression from multiple somatic samples. LICHeE uses variant allele frequencies of somatic single nucleotide variants obtained by deep sequencing to reconstruct multi-sample cell lineage trees and infer the subclonal composition of the samples. LICHeE is open source and available at http://viq854.github.io/lichee .

  3. Fast and scalable inference of multi-sample cancer lineages.

    Popic, Victoria; Salari, Raheleh; Hajirasouliha, Iman; Kashef-Haghighi, Dorna; West, Robert B; Batzoglou, Serafim

    2015-01-01

    Somatic variants can be used as lineage markers for the phylogenetic reconstruction of cancer evolution. Since somatic phylogenetics is complicated by sample heterogeneity, novel specialized tree-building methods are required for cancer phylogeny reconstruction. We present LICHeE (Lineage Inference for Cancer Heterogeneity and Evolution), a novel method that automates the phylogenetic inference of cancer progression from multiple somatic samples. LICHeE uses variant allele frequencies of somatic single nucleotide variants obtained by deep sequencing to reconstruct multi-sample cell lineage trees and infer the subclonal composition of the samples. LICHeE is open source and available at http://viq854.github.io/lichee .

  4. Properties of M1-M2-Si-Al-O-N glasses (M1 = La or Nd, M2 = Y or Er)

    Pomeroy, M.J.; Nestor, E.; Hampshire, S. [Limerick Univ. (Ireland). Materials and Surface Science Inst.; Ramesh, R. [Littelfuse Ireland, Dundalk, Co. Louth (Ireland)

    2002-07-01

    Mixed lanthanide cation oxynitride glasses have been prepared in the M1 - M2 - Si-Al-O-N systems where M1 = La or Nd and M2 = Y or Er. The densities ({rho}), Young's moduli (E), microhardnesses (H{sub v}), glass transition temperatures (T{sub g}), dilatometric softening temperatures (T{sub dil}) and coefficients of thermal expansion (CTE) of 13 glasses were determined. The molar volume values (MV) calculated from density data, E, H{sub v}, T{sub g}, T{sub dil} and CTE values were all found to vary linearly with the effective cation field strength arising from the M1 and M2 modifier cations. Least squares intercept and slope values are presented which correlate each property to effective cation field strength together with error values which arise from glass and specimen preparation and measurement inconsistencies. These linear correlations clearly indicate that the overall glass structure remains the same for each of the thirteen glasses with only the modifier cation(s) having any influence. This influence appears to be a cross-linking effect, the strength of which increases as the effective cation field strength of the M1, M2 modifiers increases. (orig.)

  5. Models for financial crisis detection in Indonesia based on M1, M2 per foreign exchange reverse, and M2 multiplier indicators

    Sugiyanto; Zukhronah, Etik; Pratiwi, Esteti Sophia

    2017-12-01

    Indonesia has been hit by financial crisis in the middle of 1997. The financial crisis that has occurred gives a severe impact to the economy of Indonesia resulting the needs for a detection system of financial crisis. Crisis can be detected based on several indicators such as M1, M2 per foreign exchange reserves, and M2 multiplier. These three indicators can affect the exchange rate stability and may further affect the financial stability so that it can be one of the causes of the financial crisis. This research aims to determine the appropriate model that can detect the financial crisis in Indonesia. Markov switching is an alternative model that can be approach and used often for detecting financial crisis. We can determine the combination of volatility and Markov switching model with AR and volatility model are determined first. The results of this research are that M1 can be modelled by SWARCH (3, 1) while M2 per foreign research exchange reserves and M2 multiplier can be modelled by SWARCH(3,2).

  6. 12 CFR Appendix M2 to Part 226 - Actual Repayment Disclosures

    2010-01-01

    ... 12 Banks and Banking 3 2010-01-01 2010-01-01 false Actual Repayment Disclosures M2 Appendix M2 to Part 226 Banks and Banking FEDERAL RESERVE SYSTEM (CONTINUED) BOARD OF GOVERNORS OF THE FEDERAL RESERVE... nearest whole year if the estimate contains a fractional year less than 0.5, and rounded up to the nearest...

  7. Establishing a Research Center: The Minority Male Community College Collaborative (M2C3)

    Wood, J. Luke; Urias, Marissa Vasquez; Harris, Frank, III

    2016-01-01

    This chapter describes the establishment of the Minority Male Community College Collaborative (M2C3), a research and practice center at San Diego State University. M2C3 partners with community colleges across the United States to enhance access, achievement, and success among men of color. This chapter begins with a description of the national…

  8. Lineage-Restricted Mammary Stem Cells Sustain the Development, Homeostasis, and Regeneration of the Estrogen Receptor Positive Lineage.

    Van Keymeulen, Alexandra; Fioramonti, Marco; Centonze, Alessia; Bouvencourt, Gaëlle; Achouri, Younes; Blanpain, Cédric

    2017-08-15

    The mammary gland (MG) is composed of different cell lineages, including the basal and the luminal cells (LCs) that are maintained by distinct stem cell (SC) populations. LCs can be subdivided into estrogen receptor (ER) + and ER - cells. LCs act as the cancer cell of origin in different types of mammary tumors. It remains unclear whether the heterogeneity found in luminal-derived mammary tumors arises from a pre-existing heterogeneity within LCs. To investigate LC heterogeneity, we used lineage tracing to assess whether the ER + lineage is maintained by multipotent SCs or by lineage-restricted SCs. To this end, we generated doxycycline-inducible ER-rtTA mice that allowed us to perform genetic lineage tracing of ER + LCs and study their fate and long-term maintenance. Our results show that ER + cells are maintained by lineage-restricted SCs that exclusively contribute to the expansion of the ER + lineage during puberty and their maintenance during adult life. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  9. M2- and M5-branes in E11 current algebra formulation of M-theory

    Shiba, Shotaro; Sugawara, Hirotaka

    2018-03-01

    Equations of motion for M2- and M5-branes are written down in the E11 current algebra formulation of M-theory. These branes correspond to currents of the second and the fifth rank antisymmetric tensors in the E11 representation, whereas the electric and magnetic fields (coupled to M2- and M5-branes) correspond to currents of the third and the sixth rank antisymmetric tensors, respectively. We show that these equations of motion have solutions in terms of the coordinates on M2- and M5-branes. We also discuss the geometric equations, and show that there are static solutions when M2- or M5-brane exists alone and also when M5-brane wraps around M2-brane. This situation is realized because our Einstein-like equation contains an extra term which can be interpreted as gravitational energy contributing to the curvature, thus avoiding the usual intersection rule.

  10. Reliable Radio Access for Massive Machine-to-Machine (M2M) Communication

    Madueño, Germán Corrales

    the service requirements can range from massive number of devices to ultra-reliable. This PhD thesis focuses on novel mechanisms to meet these requirements in a variety of wireless systems, from well-established technologies such as cellular networks, to emerging technologies like IEEE 802.11ah. Today...... an overwhelming 89% of the deployed M2M modules are GPRS-based. This motivates us to investigate the potential of GPRS as a dedicated M2M network. We show that by introducing minimal modifications to GPRS operation, a large number of devices can be reliably supported. Surprisingly, even though LTE is seen...... as the preferable solution for M2M, no mechanisms are in place to guarantee reliable M2M access. Contrary to mainstream solutions that focus on preventing overload, we introduce mechanisms to provide reliable M2M service. We also investigate what cellular networks can do about upcoming smart metering traffic...

  11. Evaluation of secure capability-based access control in the M2M local cloud platform

    Anggorojati, Bayu; Prasad, Neeli R.; Prasad, Ramjee

    2016-01-01

    delegation. Recently, the capability based access control has been considered as method to manage access in the Internet of Things (IoT) or M2M domain. In this paper, the implementation and evaluation of a proposed secure capability based access control in the M2M local cloud platform is presented......Managing access to and protecting resources is one of the important aspect in managing security, especially in a distributed computing system such as Machine-to-Machine (M2M). One such platform known as the M2M local cloud platform, referring to BETaaS architecture [1], which conceptually consists...... of multiple distributed M2M gateways, creating new challenges in the access control. Some existing access control systems lack in scalability and flexibility to manage access from users or entity that belong to different authorization domains, or fails to provide fine grained and flexible access right...

  12. Regional Variation in mtDNA of the Lesser Prairie-Chicken

    Hagen, Christian A.; Pitman, James C.; Sandercock, Brett K.; Wolfe, Don H.; Robel, Robel J.; Applegate, Roger D.; Oyler-McCance, Sara J.

    2010-01-01

    Cumulative loss of habitat and long-term decline in the populations of the Lesser Prairie-Chicken (Tympanuchus pallidicinctus) have led to concerns for the species' viability throughout its range in the southern Great Plains. For more efficient conservation past and present distributions of genetic variation need to be understood. We examined the distribution of mitochondrial DNA (mtDNA) variation in the Lesser Prairie-Chicken across Kansas, Colorado, Oklahoma, and New Mexico. Throughout the range we found little genetic differentiation except for the population in New Mexico, which was significantly different from most other publications. We did, however, find significant isolation by distance at the rangewide scale (r=0.698). We found no relationship between haplotype phylogeny and geography, and our analyses provide evidence for a post-glacial population expansion within the species that is consistent with the idea that speciation within Tympanuchus is recent. Conservation actions that increase the likelihood of genetically viable populations in the future should be evaluated for implementation.

  13. History of Lipizzan horse maternal lines as revealed by mtDNA analysis

    Dovč Peter

    2002-09-01

    Full Text Available Abstract Sequencing of the mtDNA control region (385 or 695 bp of 212 Lipizzans from eight studs revealed 37 haplotypes. Distribution of haplotypes among studs was biased, including many private haplotypes but only one haplotype was present in all the studs. According to historical data, numerous Lipizzan maternal lines originating from founder mares of different breeds have been established during the breed's history, so the broad genetic base of the Lipizzan maternal lines was expected. A comparison of Lipizzan sequences with 136 sequences of domestic- and wild-horses from GenBank showed a clustering of Lipizzan haplotypes in the majority of haplotype subgroups present in other domestic horses. We assume that haplotypes identical to haplotypes of early domesticated horses can be found in several Lipizzan maternal lines as well as in other breeds. Therefore, domestic horses could arise either from a single large population or from several populations provided there were strong migrations during the early phase after domestication. A comparison of Lipizzan haplotypes with 56 maternal lines (according to the pedigrees showed a disagreement of biological parentage with pedigree data for at least 11% of the Lipizzans. A distribution of haplotype-frequencies was unequal (0.2%–26%, mainly due to pedigree errors and haplotype sharing among founder mares.

  14. Sympatric speciation: perfume preferences of orchid bee lineages.

    Jackson, Duncan E

    2008-12-09

    Female attraction to an environmentally derived mating signal released by male orchid bees may be tightly linked to shared olfactory preferences of both sexes. A change in perfume preference may have led to divergence of two morphologically distinct lineages.

  15. Involvement of multiple cell lineages in atherogenesis | Ogeng'o ...

    Involvement of multiple cell lineages in atherogenesis. ... mast cells, dendritic cells, macrophages and immigrant cells usually found in blood, namely ... which influence inflammation, migration, proliferation and secretory activity of each other in ...

  16. Circumpolar diversity and geographic differentiation of mtDNA in the critically endangered Antarctic blue whale (Balaenoptera musculus intermedia.

    Angela L Sremba

    Full Text Available The Antarctic blue whale (Balaenoptera musculus intermedia was hunted to near extinction between 1904 and 1972, declining from an estimated initial abundance of more than 250,000 to fewer than 400. Here, we describe mtDNA control region diversity and geographic differentiation in the surviving population of the Antarctic blue whale, using 218 biopsy samples collected under the auspices of the International Whaling Commission (IWC during research cruises from 1990-2009. Microsatellite genotypes and mtDNA sequences identified 166 individuals among the 218 samples and documented movement of a small number of individuals, including a female that traveled at least 6,650 km or 131° longitude over four years. mtDNA sequences from the 166 individuals were aligned with published sequences from 17 additional individuals, resolving 52 unique haplotypes from a consensus length of 410 bp. From this minimum census, a rarefaction analysis predicted that only 72 haplotypes (95% CL, 64, 86 have survived in the contemporary population of Antarctic blue whales. However, haplotype diversity was relatively high (0.968±0.004, perhaps as a result of the longevity of blue whales and the relatively recent timing of the bottleneck. Despite the potential for circumpolar dispersal, we found significant differentiation in mtDNA diversity (F(ST = 0.032, p<0.005 and microsatellite alleles (F(ST = 0.005, p<0.05 among the six Antarctic Areas historically used by the IWC for management of blue whales.

  17. Species phylogeny and diversification process of Northeast Asian Pungitius revealed by AFLP and mtDNA markers

    Takahashi, Hiroshi; Møller, Peter Rask; Shedko, Sergei V.

    2016-01-01

    Pungitius is a highly diversified genus of sticklebacks (Gasterosteidae) occurring widely in northern parts of the Northern Hemisphere. Several ecologically and genetically divergent types that are largely isolated reproductively but occasionally hybridize in sympatry have been discovered...... of hybridization and mtDNA introgression among distinct species. Our results highlight that the marginal seas of Northeast Asia played a key role as barriers to or facilitators of gene flow in the evolution of species diversity of Pungitius concentrated in this region...

  18. Anthropology. Response to Comment on "Late Pleistocene human skeleton and mtDNA link Paleoamericans and modern Native Americans".

    Kemp, Brian M; Lindo, John; Bolnick, Deborah A; Malhi, Ripan S; Chatters, James C

    2015-02-20

    Prüfer and Meyer raise concerns over the mitochondrial DNA (mtDNA) results we reported for the Hoyo Negro individual, citing failure of a portion of these data to conform to their expectations of ancient DNA (aDNA). Because damage patterns in aDNA vary, outright rejection of our findings on this basis is unwarranted, especially in light of our other observations. Copyright © 2015, American Association for the Advancement of Science.

  19. MtDNA genomes reveal a relaxation of selective constraints in low-BMI individuals in a Uyghur population.

    Zheng, Hong-Xiang; Li, Lei; Jiang, Xiao-Yan; Yan, Shi; Qin, Zhendong; Wang, Xiaofeng; Jin, Li

    2017-10-01

    Considerable attention has been focused on the effect of deleterious mutations caused by the recent relaxation of selective constraints on human health, including the prevalence of obesity, which might represent an adaptive response of energy-conserving metabolism under the conditions of modern society. Mitochondrial DNA (mtDNA) encoding 13 core subunits of oxidative phosphorylation plays an important role in metabolism. Therefore, we hypothesized that a relaxation of selection constraints on mtDNA and an increase in the proportion of deleterious mutations have played a role in obesity prevalence. In this study, we collected and sequenced the mtDNA genomes of 722 Uyghurs, a typical population with a high prevalence of obesity. We identified the variants that occurred in the Uyghur population for each sample and found that the number of nonsynonymous mutations carried by Uyghur individuals declined with elevation of their BMI (P = 0.015). We further calculated the nonsynonymous and synonymous ratio (N/S) of the high-BMI and low-BMI haplogroups, and the results showed that a significantly higher N/S occurred in the whole mtDNA genomes of the low-BMI haplogroups (0.64) than in that of the high-BMI haplogroups (0.35, P = 0.030) and ancestor haplotypes (0.41, P = 0.032); these findings indicated that low-BMI individuals showed a recent relaxation of selective constraints. In addition, we investigated six clinical characteristics and found that fasting plasma glucose might be correlated with the N/S and selective pressures. We hypothesized that a higher proportion of deleterious mutations led to mild mitochondrial dysfunction, which helps to drive glucose consumption and thereby prevents obesity. Our results provide new insights into the relationship between obesity predisposition and mitochondrial genome evolution.

  20. Possible role of mtDNA depletion and respiratory chain defects in aristolochic acid I-induced acute nephrotoxicity

    Jiang, Zhenzhou, E-mail: jiangcpu@yahoo.com.cn; Bao, Qingli, E-mail: bao_ql@126.com; Sun, Lixin, E-mail: slxcpu@126.com; Huang, Xin, E-mail: huangxinhx66@sohu.com; Wang, Tao, E-mail: wangtao1331@126.com; Zhang, Shuang, E-mail: cat921@sina.com; Li, Han, E-mail: hapo1101@163.com; Zhang, Luyong, E-mail: lyzhang@cpu.edu.cn

    2013-01-15

    This report describes an investigation of the pathological mechanism of acute renal failure caused by toxic tubular necrosis after treatment with aristolochic acid I (AAI) in Sprague–Dawley (SD) rats. The rats were gavaged with AAI at 0, 5, 20, or 80 mg/kg/day for 7 days. The pathologic examination of the kidneys showed severe acute tubular degenerative changes primarily affecting the proximal tubules. Supporting these results, we detected significantly increased concentrations of blood urea nitrogen (BUN) and creatinine (Cr) in the rats treated with AAI, indicating damage to the kidneys. Ultrastructural examination showed that proximal tubular mitochondria were extremely enlarged and dysmorphic with loss and disorientation of their cristae. Mitochondrial function analysis revealed that the two indicators for mitochondrial energy metabolism, the respiratory control ratio (RCR) and ATP content, were reduced in a dose-dependent manner after AAI treatment. The RCR in the presence of substrates for complex I was reduced more significantly than in the presence of substrates for complex II. In additional experiments, the activity of respiratory complex I, which is partly encoded by mitochondrial DNA (mtDNA), was more significantly impaired than that of respiratory complex II, which is completely encoded by nuclear DNA (nDNA). A real-time PCR assay revealed a marked reduction of mtDNA in the kidneys treated with AAI. Taken together, these results suggested that mtDNA depletion and respiratory chain defects play critical roles in the pathogenesis of kidney injury induced by AAI, and that the same processes might contribute to aristolochic acid-induced nephrotoxicity in humans. -- Highlights: ► AAI-induced acute renal failure in rats and the proximal tubule was the target. ► Tubular mitochondria were morphologically aberrant in ultrastructural examination. ► AAI impair mitochondrial bioenergetic function and mtDNA replication.

  1. Two Hemocyte Lineages Exist in Silkworm Larval Hematopoietic Organ

    Nakahara, Yuichi; Kanamori, Yasushi; Kiuchi, Makoto; Kamimura, Manabu

    2010-01-01

    BACKGROUND: Insects have multiple hemocyte morphotypes with different functions as do vertebrates, however, their hematopoietic lineages are largely unexplored with the exception of Drosophila melanogaster. METHODOLOGY/PRINCIPAL FINDINGS: To study the hematopoietic lineage of the silkworm, Bombyx mori, we investigated in vivo and in vitro differentiation of hemocyte precursors in the hematopoietic organ (HPO) into the four mature hemocyte subsets, namely, plasmatocytes, granulocytes, oenocyto...

  2. Polycomb enables primitive endoderm lineage priming in embryonic stem cells

    Illingworth, Robert S; Hölzenspies, Jurriaan J; Roske, Fabian V

    2016-01-01

    Mouse embryonic stem cells (ESCs), like the blastocyst from which they are derived, contain precursors of the epiblast (Epi) and primitive endoderm (PrEn) lineages. While transient in vivo, these precursor populations readily interconvert in vitro. We show that altered transcription is the driver...... polycomb with dynamic changes in transcription and stalled lineage commitment, allowing cells to explore alternative choices prior to a definitive decision....

  3. Heterozygous SSBP1 start loss mutation co-segregates with hearing loss and the m.1555A>G mtDNA variant in a large multigenerational family.

    Kullar, Peter J; Gomez-Duran, Aurora; Gammage, Payam A; Garone, Caterina; Minczuk, Michal; Golder, Zoe; Wilson, Janet; Montoya, Julio; Häkli, Sanna; Kärppä, Mikko; Horvath, Rita; Majamaa, Kari; Chinnery, Patrick F

    2018-01-01

    The m.1555A>G mtDNA variant causes maternally inherited deafness, but the reasons for the highly variable clinical penetrance are not known. Exome sequencing identified a heterozygous start loss mutation in SSBP1, encoding the single stranded binding protein 1 (SSBP1), segregating with hearing loss in a multi-generational family transmitting m.1555A>G, associated with mtDNA depletion and multiple deletions in skeletal muscle. The SSBP1 mutation reduced steady state SSBP1 levels leading to a perturbation of mtDNA metabolism, likely compounding the intra-mitochondrial translation defect due to m.1555A>G in a tissue-specific manner. This family demonstrates the importance of rare trans-acting genetic nuclear modifiers in the clinical expression of mtDNA disease. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.

  4. The Mitochondrial DNA (mtDNA)-Associated Protein SWIB5 Influences mtDNA Architecture and Homologous Recombination

    Blomme, Jonas

    2017-04-19

    In addition to the nucleus, mitochondria and chloroplasts in plant cells also contain genomes. Efficient DNA repair pathways are crucial in these organelles to fix damage resulting from endogenous and exogenous factors. Plant organellar genomes are complex compared with their animal counterparts, and although several plant-specific mediators of organelle DNA repair have been reported, many regulators remain to be identified. Here, we show that a mitochondrial SWI/SNF (nucleosome remodeling) complex B protein, SWIB5, is capable of associating with mitochondrial DNA (mtDNA) in Arabidopsis thaliana. Gainand loss-of-function mutants provided evidence for a role of SWIB5 in influencing mtDNA architecture and homologous recombination at specific intermediate-sized repeats both under normal and genotoxic conditions. SWIB5 interacts with other mitochondrial SWIB proteins. Gene expression and mutant phenotypic analysis of SWIB5 and SWIB family members suggests a link between organellar genome maintenance and cell proliferation. Taken together, our work presents a protein family that influences mtDNA architecture and homologous recombination in plants and suggests a link between organelle functioning and plant development.

  5. Sex-specific influences of mtDNA mitotype and diet on mitochondrial functions and physiological traits in Drosophila melanogaster.

    Wen C Aw

    Full Text Available Here we determine the sex-specific influence of mtDNA type (mitotype and diet on mitochondrial functions and physiology in two Drosophila melanogaster lines. In many species, males and females differ in aspects of their energy production. These sex-specific influences may be caused by differences in evolutionary history and physiological functions. We predicted the influence of mtDNA mutations should be stronger in males than females as a result of the organelle's maternal mode of inheritance in the majority of metazoans. In contrast, we predicted the influence of diet would be greater in females due to higher metabolic flexibility. We included four diets that differed in their protein: carbohydrate (P:C ratios as they are the two-major energy-yielding macronutrients in the fly diet. We assayed four mitochondrial function traits (Complex I oxidative phosphorylation, reactive oxygen species production, superoxide dismutase activity, and mtDNA copy number and four physiological traits (fecundity, longevity, lipid content, and starvation resistance. Traits were assayed at 11 d and 25 d of age. Consistent with predictions we observe that the mitotype influenced males more than females supporting the hypothesis of a sex-specific selective sieve in the mitochondrial genome caused by the maternal inheritance of mitochondria. Also, consistent with predictions, we found that the diet influenced females more than males.

  6. [Sequence polymorphism of mtDNA HVR Iand HVR II of Oroqen ethnic group in Inner Mongolia].

    Yan, Chun-Xia; Chen, Feng; Dang, Yong-Hui; Li, Tao; Zheng, Hai-Bo; Chen, Teng; Li, Sheng-Bin

    2008-04-01

    Venous blood samples from 50 unrelated Oroqen individuals living in Inner Mongolia were collected and their mtDNA HVR I and HVR II sequences were detected by using ABI PRISM377 sequencers. The number of polymorphic loci, haplotype, haplotype frequence, average nucleotide variability and other polymorphic parameters were calculated. Based on Oroqen mtDNA sequence data obtained in our experiments and published data, genetic distance between Oroqen ethnic group and other populations were computered by Nei's measure. Phylogenetic tree was constructed by Neighbor Joining method. Comparing with Anderson sequence, 52 polymorphic loci in HVR I and 24 loci in HVR II were found in Oroqen mtDNA sequence, 38 and 27 haplotypes were defined herewith. Haplotype diversity and average nucleotide variability were 0.964+/-0.018 and 7.379 in HVR I, 0.929+/-0.019 and 2.408 in HVR II respectively. Fst and dA genetic distance between 12 populations were calculated based on HVR I sequence, and their relative coefficients were 0.993(P HVR I and HVR II in Oroqen ethnic group has some specificities compared with that of other populations. These data provide a useful tool in forensic identification, population genetic study and other research fields.

  7. Dysphagia is prevalent in patients with CPEO and single, large-scale deletions in mtDNA

    Pedersen, Gitte Hedermann; Løkken, Nicoline; Dahlqvist, Julia R.

    2017-01-01

    Background  The aim of this study was to assess the frequency of subjective and objective dysphagia in patients with chronic progressive external ophthalmoplegia (CPEO) due to single, large-scale deletions (LSDs) of mitochondrial DNA (mtDNA). Methods  Sixteen patients with CPEO and single LSDs...... and single LSDs of mtDNA had a prolonged cold-water test, including one with a PEG-tube, who was unable to perform the test, and nine patients reported subjective swallowing problems (56.3%). All mitochondrial myopathy patients in the control group had a normal duration of the cold-water test.  Conclusions......  The study shows that dysphagia is a common problem in patients with CPEO and LSDs of mtDNA. Dysphagia seems to be progressive with age as abnormal swallowing occurred preferentially in persons ≥ 45 years. The study shows that increased awareness of this symptom should be given to address appropriate...

  8. Two hemocyte lineages exist in silkworm larval hematopoietic organ.

    Yuichi Nakahara

    Full Text Available BACKGROUND: Insects have multiple hemocyte morphotypes with different functions as do vertebrates, however, their hematopoietic lineages are largely unexplored with the exception of Drosophila melanogaster. METHODOLOGY/PRINCIPAL FINDINGS: To study the hematopoietic lineage of the silkworm, Bombyx mori, we investigated in vivo and in vitro differentiation of hemocyte precursors in the hematopoietic organ (HPO into the four mature hemocyte subsets, namely, plasmatocytes, granulocytes, oenocytoids, and spherulocytes. Five days after implantation of enzymatically-dispersed HPO cells from a GFP-expressing transgenic line into the hemocoel of normal larvae, differentiation into plasmatocytes, granulocytes and oenocytoids, but not spherulocytes, was observed. When the HPO cells were cultured in vitro, plasmatocytes appeared rapidly, and oenocytoids possessing prophenol oxidase activity appeared several days later. HPO cells were also able to differentiate into a small number of granulocytes, but not into spherulocytes. When functionally mature plasmatocytes were cultured in vitro, oenocytoids were observed 10 days later. These results suggest that the hemocyte precursors in HPO first differentiate into plasmatocytes, which further change into oenocytoids. CONCLUSIONS/SIGNIFICANCE: From these results, we propose that B. mori hemocytes can be divided into two major lineages, a granulocyte lineage and a plasmatocyte-oenocytoid lineage. The origins of the spherulocytes could not be determined in this study. We construct a model for the hematopoietic lineages at the larval stage of B. mori.

  9. Two hemocyte lineages exist in silkworm larval hematopoietic organ.

    Nakahara, Yuichi; Kanamori, Yasushi; Kiuchi, Makoto; Kamimura, Manabu

    2010-07-28

    Insects have multiple hemocyte morphotypes with different functions as do vertebrates, however, their hematopoietic lineages are largely unexplored with the exception of Drosophila melanogaster. To study the hematopoietic lineage of the silkworm, Bombyx mori, we investigated in vivo and in vitro differentiation of hemocyte precursors in the hematopoietic organ (HPO) into the four mature hemocyte subsets, namely, plasmatocytes, granulocytes, oenocytoids, and spherulocytes. Five days after implantation of enzymatically-dispersed HPO cells from a GFP-expressing transgenic line into the hemocoel of normal larvae, differentiation into plasmatocytes, granulocytes and oenocytoids, but not spherulocytes, was observed. When the HPO cells were cultured in vitro, plasmatocytes appeared rapidly, and oenocytoids possessing prophenol oxidase activity appeared several days later. HPO cells were also able to differentiate into a small number of granulocytes, but not into spherulocytes. When functionally mature plasmatocytes were cultured in vitro, oenocytoids were observed 10 days later. These results suggest that the hemocyte precursors in HPO first differentiate into plasmatocytes, which further change into oenocytoids. From these results, we propose that B. mori hemocytes can be divided into two major lineages, a granulocyte lineage and a plasmatocyte-oenocytoid lineage. The origins of the spherulocytes could not be determined in this study. We construct a model for the hematopoietic lineages at the larval stage of B. mori.

  10. Respiratory syncytial virus M2-1 protein induces the activation of nuclear factor kappa B

    Reimers, Kerstin [Klinik fuer Plastische, Hand-und Wiederherstellungschirurgie, Podbielskistrasse 380, D-30659 Hannover (Germany); Buchholz, Katja [Institut fuer Medizinische Mikrobiologie, Otto-von-Guericke-Universitaet Magdeburg, Leipzigerstrasse 44, D-39120 Magdeburg (Germany); Werchau, Hermann [Institut fuer Medizinische Mikrobiologie, Otto-von-Guericke-Universitaet Magdeburg, Leipzigerstrasse 44, D-39120 Magdeburg (Germany)

    2005-01-20

    Respiratory syncytial virus (RSV) induces the production of a number of cytokines and chemokines by activation of nuclear factor kappa B (NF-{kappa}B). The activation of NF-{kappa}B has been shown to depend on viral replication in the infected cells. In this study, we demonstrate that expression of RSV M2-1 protein, a transcriptional processivity and anti-termination factor, is sufficient to activate NF-{kappa}B in A549 cells. Electromobility shift assays show increased NF-{kappa}B complexes in the nuclei of M2-1-expressing cells. M2-1 protein is found in nuclei of M2-1-expressing cells and in RSV-infected cells. Co-immunoprecipitations of nuclear extracts of M2-1-expressing cells and of RSV-infected cells revealed an association of M2-1 with Rel A protein. Furthermore, the activation of NF-{kappa}B depends on the C-terminus of the RSV M2-1 protein, as shown by NF-{kappa}B-induced gene expression of a reporter gene construct.

  11. A humanized anti-M2 scFv shows protective in vitro activity against influenza

    Bradbury, Andrew M [Los Alamos National Laboratory; Velappan, Nileena [Los Alamos National Laboratory; Schmidt, Jurgen G [Los Alamos National Laboratory

    2008-01-01

    M2 is one of the most conserved influenza proteins, and has been widely prospected as a potential universal vaccine target, with protection predominantly mediated by antibodies. In this paper we describe the creation of a humanized single chain Fv from 14C2, a potent monoclonal antibody against M2. We show that the humanized scFv demonstrates similar activity to the parental mAb: it is able to recognize M2 in its native context on cell surfaces and is able to show protective in vitro activity against influenza, and so represents a potential lead antibody candidate for universal prophylactic or therapeutic intervention in influenza.

  12. Phosphorylation of Human Metapneumovirus M2-1 Protein Upregulates Viral Replication and Pathogenesis.

    Cai, Hui; Zhang, Yu; Lu, Mijia; Liang, Xueya; Jennings, Ryan; Niewiesk, Stefan; Li, Jianrong

    2016-08-15

    Human metapneumovirus (hMPV) is a major causative agent of upper- and lower-respiratory-tract infections in infants, the elderly, and immunocompromised individuals worldwide. Like all pneumoviruses, hMPV encodes the zinc binding protein M2-1, which plays important regulatory roles in RNA synthesis. The M2-1 protein is phosphorylated, but the specific role(s) of the phosphorylation in viral replication and pathogenesis remains unknown. In this study, we found that hMPV M2-1 is phosphorylated at amino acid residues S57 and S60. Subsequent mutagenesis found that phosphorylation is not essential for zinc binding activity and oligomerization, whereas inhibition of zinc binding activity abolished the phosphorylation and oligomerization of the M2-1 protein. Using a reverse genetics system, recombinant hMPVs (rhMPVs) lacking either one or both phosphorylation sites in the M2-1 protein were recovered. These recombinant viruses had a significant decrease in both genomic RNA replication and mRNA transcription. In addition, these recombinant viruses were highly attenuated in cell culture and cotton rats. Importantly, rhMPVs lacking phosphorylation in the M2-1 protein triggered high levels of neutralizing antibody and provided complete protection against challenge with wild-type hMPV. Collectively, these data demonstrated that phosphorylation of the M2-1 protein upregulates hMPV RNA synthesis, replication, and pathogenesis in vivo The pneumoviruses include many important human and animal pathogens, such as human respiratory syncytial virus (hRSV), hMPV, bovine RSV, and avian metapneumovirus (aMPV). Among these viruses, hRSV and hMPV are the leading causes of acute respiratory tract infection in infants and children. Currently, there is no antiviral or vaccine to combat these diseases. All known pneumoviruses encode a zinc binding protein, M2-1, which is a transcriptional antitermination factor. In this work, we found that phosphorylation of M2-1 is essential for virus

  13. Beta3 adrenoceptors substitute the role of M(2) muscarinic receptor in coping with cold stress in the heart: evidence from M(2)KO mice.

    Benes, Jan; Novakova, Martina; Rotkova, Jana; Farar, Vladimir; Kvetnansky, Richard; Riljak, Vladimir; Myslivecek, Jaromir

    2012-07-01

    We investigated the role of beta3-adrenoceptors (AR) in cold stress (1 or 7 days in cold) in animals lacking main cardioinhibitive receptors-M2 muscarinic receptors (M(2)KO). There was no change in receptor number in the right ventricles. In the left ventricles, there was decrease in binding to all cardiostimulative receptors (beta1-, and beta2-AR) and increase in cardiodepressive receptors (beta3-AR) in unstressed KO in comparison to WT. The cold stress in WT animals resulted in decrease in binding to beta1- and beta2-AR (to 37%/35% after 1 day in cold and to 27%/28% after 7 days in cold) while beta3-AR were increased (to 216% of control) when 7 days cold was applied. MR were reduced to 46% and 58%, respectively. Gene expression of M2 MR in WT was not changed due to stress, while M3 was changed. The reaction of beta1- and beta2-AR (binding) to cold was similar in KO and WT animals, and beta3-AR in stressed KO animals did not change. Adenylyl cyclase activity was affected by beta3-agonist CL316243 in cold stressed WT animals but CL316243 had almost no effects on adenylyl cyclase activity in stressed KO. Nitric oxide activity (NOS) was not affected by BRL37344 (beta3-agonist) both in WT and KO animals. Similarly, the stress had no effects on NOS activity in WT animals and in KO animals. We conclude that the function of M2 MR is substituted by beta3-AR and that these effects are mediated via adenylyl cyclase rather than NOS.

  14. Comparison of 14 MeV isomer production of 178m2Hf and 179m2Hf using Feshbach-Kerman-Koonin and exciton preequilibrium models

    Chadwick, M.B.; Young, P.G.

    1993-01-01

    The 178m2 Hf(16+) isomeric state has a 31-yr half life and could pose serious radioactive problems in nuclear fusion reactors if its production in 14 MeV neutron-induced reactions is significant. We present statistical/preequilibrium model calculations for the production of this isomer in the 179 Hf(n, 2n) 178m2 Hf reaction, as well as the 25-days 12.5 - isomer in the 179 Hf(n,n') 179m2 Hf reaction, using two different preequilibrium models: the exciton model and the Feshbach-Kerman-Koonin (FKK) theory. Our calculations which use the exciton model agree well with measurements, but those with the FKK theory underestimate measurements. Our calculations axe the first to probe angular momentum transfer effects in the FKK theory and suggest that, as it is presently applied, high spin-transfer reactions are underestimated. We suggest modifications to the FKK statistical averaging procedure which may result in an improved agreement with experiment

  15. Ab initio study of M2AlN (M = Ti,V,Cr)

    Sun, Zhimei; Music, Denis; Ahuja, Rajeev; Schneider, Jochen M

    2005-01-01

    We have studied M 2 AlN phases, where M = Ti, V, and Cr, by means of ab initio total energy calculations. The bulk modulus of M 2 AlN increases as Ti is replaced with V and Cr by 19.0% and 26.5%, respectively, which can be understood on the basis of the increased number of valence electrons filling the p-d hybridized bonding states. The bulk modulus of M 2 AlN is generally higher than that of the corresponding M 2 AlC phase, which may be explained by an extra electron in the former phases contributing to stronger chemical bonding. This work is important for fundamental understanding of elastic properties of these ternary nitrides and may inspire future experimental research. (letter to the editor)

  16. HF183/BFDrev and HumM2 qPCR data

    U.S. Environmental Protection Agency — Concentration estimates for HF183/BFDrev and HumM2 qPCR genetic markers in raw sewage collected from 54 geographic locations across the United States. This dataset...

  17. An allostatic mechanism for M2 pyruvate kinase as an amino-acid sensor.

    Yuan, Meng; McNae, Iain W; Chen, Yiyuan; Blackburn, Elizabeth A; Wear, Martin A; Michels, Paul A M; Fothergill-Gilmore, Linda A; Hupp, Ted; Walkinshaw, Malcolm D

    2018-05-10

    We have tested the effect of all 20 proteinogenic amino acids on the activity of the M2 isoenzyme of pyruvate kinase (M2PYK) and show that within physiologically relevant concentrations, phenylalanine, alanine, tryptophan, methionine, valine, and proline act as inhibitors while histidine and serine act as activators. Size exclusion chromatography has been used to show that all amino acids, whether activators or inhibitors, stabilise the tetrameric form of M2PYK. In the absence of amino-acid ligands an apparent tetramer-monomer dissociation K d is estimated to be ~0.9 µM with a slow dissociation rate (t 1/2 ~ 15 min). X-ray structures of M2PYK complexes with alanine, phenylalanine, and tryptophan show the M2PYK locked in an inactive T-state conformation, while activators lock the M2PYK tetramer in the active R-state conformation. Amino-acid binding in the allosteric pocket triggers rigid body rotations (11°) stabilising either T or R-states. The opposing inhibitory and activating effects of the non-essential amino acids serine and alanine suggest that M2PYK could act as a rapid-response nutrient sensor to rebalance cellular metabolism. This competition at a single allosteric site between activators and inhibitors provides a novel regulatory mechanism by which M2PYK activity is finely tuned by the relative (but not absolute) concentrations of activator and inhibitor amino acids. Such 'allostatic' regulation may be important in metabolic reprogramming and influencing cell fate. ©2018 The Author(s).

  18. Organophosphorus pesticides decrease M2 muscarinic receptor function in guinea pig airway nerves via indirect mechanisms.

    Becky J Proskocil

    Full Text Available BACKGROUND: Epidemiological studies link organophosphorus pesticide (OP exposures to asthma, and we have shown that the OPs chlorpyrifos, diazinon and parathion cause airway hyperreactivity in guinea pigs 24 hr after a single subcutaneous injection. OP-induced airway hyperreactivity involves M2 muscarinic receptor dysfunction on airway nerves independent of acetylcholinesterase (AChE inhibition, but how OPs inhibit neuronal M2 receptors in airways is not known. In the central nervous system, OPs interact directly with neurons to alter muscarinic receptor function or expression; therefore, in this study we tested whether the OP parathion or its oxon metabolite, paraoxon, might decrease M2 receptor function on peripheral neurons via similar direct mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: Intravenous administration of paraoxon, but not parathion, caused acute frequency-dependent potentiation of vagally-induced bronchoconstriction and increased electrical field stimulation (EFS-induced contractions in isolated trachea independent of AChE inhibition. However, paraoxon had no effect on vagally-induced bradycardia in intact guinea pigs or EFS-induced contractions in isolated ileum, suggesting mechanisms other than pharmacologic antagonism of M2 receptors. Paraoxon did not alter M2 receptor expression in cultured cells at the mRNA or protein level as determined by quantitative RT-PCR and radio-ligand binding assays, respectively. Additionally, a biotin-labeled fluorophosphonate, which was used as a probe to identify molecular targets phosphorylated by OPs, did not phosphorylate proteins in guinea pig cardiac membranes that were recognized by M2 receptor antibodies. CONCLUSIONS/SIGNIFICANCE: These data indicate that neither direct pharmacologic antagonism nor downregulated expression of M2 receptors contributes to OP inhibition of M2 function in airway nerves, adding to the growing evidence of non-cholinergic mechanisms of OP neurotoxicity.

  19. 10D massive type IIA supergravities as the uplift of parabolic M2-brane torus bundles

    Garcia del Moral, Maria Pilar [Universidad de Antofagasta (Chile). Dept. de Fisica; Restuccia, Alvaro [Universidad de Antofagasta (Chile). Dept. de Fisica; Universidad Simon Bolivar, Caracas (Venezuela, Bolivarian Republic of). Dept. de Fisica

    2016-04-15

    We remark that the two 10D massive deformations of the N = 2 maximal type IIA supergravity (Romans and HLW supergravity) are associated to the low energy limit of the uplift to 10D of M2-brane torus bundles with parabolic monodromy linearly and non-linearly realized respectively. Romans supergravity corresponds to M2-brane compactified on a twice-punctured torus bundle. (copyright 2015 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim)

  20. Enhanced M1/M2 macrophage ratio promotes orthodontic root resorption.

    He, D; Kou, X; Luo, Q; Yang, R; Liu, D; Wang, X; Song, Y; Cao, H; Zeng, M; Gan, Y; Zhou, Y

    2015-01-01

    Mechanical force-induced orthodontic root resorption is a major clinical challenge in orthodontic treatment. Macrophages play an important role in orthodontic root resorption, but the underlying mechanism remains unclear. In this study, we examined the mechanism by which the ratio of M1 to M2 macrophage polarization affects root resorption during orthodontic tooth movement. Root resorption occurred when nickel-titanium coil springs were applied on the upper first molars of rats for 3 to 14 d. Positively stained odontoclasts or osteoclasts with tartrate-resistant acid phosphatase were found in resorption areas. Meanwhile, M1-like macrophages positive for CD68 and inducible nitric oxide synthase (iNOS) persistently accumulated on the compression side of periodontal tissues. In addition, the expressions of the M1 activator interferon-γ and the M1-associated pro-inflammatory cytokine tumor necrosis factor (TNF)-α were upregulated on the compression side of periodontal tissues. When the coil springs were removed at the 14th day after orthodontic force application, root resorption was partially rescued. The number of CD68(+)CD163(+) M2-like macrophages gradually increased on the compression side of periodontal tissues. The levels of M2 activator interleukin (IL)-4 and the M2-associated anti-inflammatory cytokine IL-10 also increased. Systemic injection of the TNF-α inhibitor etanercept or IL-4 attenuated the severity of root resorption and decreased the ratio of M1 to M2 macrophages. These data imply that the balance between M1 and M2 macrophages affects orthodontic root resorption. Root resorption was aggravated by an enhanced M1/M2 ratio but was partially rescued by a reduced M1/M2 ratio. © International & American Associations for Dental Research 2014.

  1. Presenting Influenza A M2e Antigen on Recombinant Spores of Bacillus subtilis.

    Tomasz Łęga

    Full Text Available Effective vaccination against influenza virus infection is a serious problem mainly due to antigenic variability of the virus. Among many of investigated antigens, the extracellular domain of the M2 protein (M2e features high homology in all strains of influenza A viruses and antibodies against M2e and is protective in animal models; this makes it a potential candidate for generation of a universal influenza vaccine. However, due to the low immunogenicity of the M2e, formulation of a vaccine based on this antigen requires some modification to induce effective immune responses. In this work we evaluated the possible use of Bacillus subtilis spores as a carrier of the Influenza A M2e antigen in mucosal vaccination. A tandem repeat of 4 consensus sequences coding for human-avian-swine-human M2e (M2eH-A-S-H peptide was fused to spore coat proteins and stably exposed on the spore surface, as demonstrated by the immunostaining of intact, recombinant spores. Oral immunization of mice with recombinant endospores carrying M2eH-A-S-H elicited specific antibody production without the addition of adjuvants. Bacillus subtilis endospores can serve as influenza antigen carriers. Recombinant spores constructed in this work showed low immunogenicity although were able to induce antibody production. The System of influenza antigen administration presented in this work is attractive mainly due to the omitting time-consuming and cost-intensive immunogen production and purification. Therefore modification should be made to increase the immunogenicity of the presented system.

  2. Cardiac macrophages adopt profibrotic/M2 phenotype in infarcted hearts: Role of urokinase plasminogen activator.

    Carlson, Signe; Helterline, Deri; Asbe, Laura; Dupras, Sarah; Minami, Elina; Farris, Stephen; Stempien-Otero, April

    2017-07-01

    Macrophages (mac) that over-express urokinase plasminogen activator (uPA) adopt a profibrotic M2 phenotype in the heart in association with cardiac fibrosis. We tested the hypothesis that cardiac macs are M2 polarized in infarcted mouse and human hearts and that polarization is dependent on mac-derived uPA. Studies were performed using uninjured (UI) or infarcted (MI) hearts of uPA overexpressing (SR-uPA), uPA null, or nontransgenic littermate (Ntg) mice. At 7days post-infarction, cardiac mac were isolated, RNA extracted and M2 markers Arg1, YM1, and Fizz1 measured with qrtPCR. Histologic analysis for cardiac fibrosis, mac and myofibroblasts was performed at the same time-point. Cardiac macs were also isolated from Ntg hearts and RNA collected after primary isolation or culture with vehicle, IL-4 or plasmin and M2 marker expression measured. Cardiac tissue and blood was collected from humans with ischemic heart disease. Expression of M2 marker CD206 and M1 marker TNFalpha was measured. Macs from WT mice had increased expression of Arg1 and Ym1 following MI (41.3±6.5 and 70.3±36, fold change vs UI, n=8, Padopt a M2 phenotype in association with fibrosis. Plasmin can induce an M2 phenotype in cardiac macs. However, M2 activation can occur in the heart in vivo in the absence of uPA indicating that alternative pathways to activate plasmin are present in the heart. Excess uPA promotes increased fibroblast density potentially via potentiating fibroblast migration or proliferation. Altering macrophage phenotype in the heart is a potential target to modify cardiac fibrosis. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. Detailed profile of m=2 islands with TVTS on JFT-2M

    Yamauchi, T.; Grek, B.; Hoshino, K.; Le Blanc, B.; Johnson, D.; Felt, J.; Shiina, T.; Kurita, G.; Ishige, Y.; Kozawa, H.

    1996-01-01

    The detailed electron temperature profile (spatial resolution: 0.86 cm) of a low density JFT-2M plasma is measured with the TV Thomson scattering system (TVTS). Flat profiles showing the electron temperature shapes of m=2/n=1 islands are presented, which are in contrast to that without islands. On the other hand, the m=2/n=1 islands are effectively suppressed with local ECRH heating. (orig.)

  4. Trophoblast lineage cells derived from human induced pluripotent stem cells

    Chen, Ying, E-mail: ying.chen@hc.msu.edu [Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University, 333 Bostwick NE, Grand Rapids, MI 49503 (United States); Wang, Kai; Chandramouli, Gadisetti V.R. [Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University, 333 Bostwick NE, Grand Rapids, MI 49503 (United States); Knott, Jason G. [Developmental Epigenetics Laboratory, Department of Animal Science, Michigan State University (United States); Leach, Richard, E-mail: Richard.leach@hc.msu.edu [Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University, 333 Bostwick NE, Grand Rapids, MI 49503 (United States); Department of Obstetrics, Gynecology and Women’s Health, Spectrum Health Medical Group (United States)

    2013-07-12

    Highlights: •Epithelial-like phenotype of trophoblast lineage cells derived from human iPS cells. •Trophoblast lineage cells derived from human iPS cells exhibit trophoblast function. •Trophoblasts from iPS cells provides a proof-of-concept in regenerative medicine. -- Abstract: Background: During implantation, the blastocyst trophectoderm attaches to the endometrial epithelium and continues to differentiate into all trophoblast subtypes, which are the major components of a placenta. Aberrant trophoblast proliferation and differentiation are associated with placental diseases. However, due to ethical and practical issues, there is almost no available cell or tissue source to study the molecular mechanism of human trophoblast differentiation, which further becomes a barrier to the study of the pathogenesis of trophoblast-associated diseases of pregnancy. In this study, our goal was to generate a proof-of-concept model for deriving trophoblast lineage cells from induced pluripotency stem (iPS) cells from human fibroblasts. In future studies the generation of trophoblast lineage cells from iPS cells established from patient’s placenta will be extremely useful for studying the pathogenesis of individual trophoblast-associated diseases and for drug testing. Methods and results: Combining iPS cell technology with BMP4 induction, we derived trophoblast lineage cells from human iPS cells. The gene expression profile of these trophoblast lineage cells was distinct from fibroblasts and iPS cells. These cells expressed markers of human trophoblasts. Furthermore, when these cells were differentiated they exhibited invasive capacity and placental hormone secretive capacity, suggesting extravillous trophoblasts and syncytiotrophoblasts. Conclusion: Trophoblast lineage cells can be successfully derived from human iPS cells, which provide a proof-of-concept tool to recapitulate pathogenesis of patient placental trophoblasts in vitro.

  5. Trophoblast lineage cells derived from human induced pluripotent stem cells

    Chen, Ying; Wang, Kai; Chandramouli, Gadisetti V.R.; Knott, Jason G.; Leach, Richard

    2013-01-01

    Highlights: •Epithelial-like phenotype of trophoblast lineage cells derived from human iPS cells. •Trophoblast lineage cells derived from human iPS cells exhibit trophoblast function. •Trophoblasts from iPS cells provides a proof-of-concept in regenerative medicine. -- Abstract: Background: During implantation, the blastocyst trophectoderm attaches to the endometrial epithelium and continues to differentiate into all trophoblast subtypes, which are the major components of a placenta. Aberrant trophoblast proliferation and differentiation are associated with placental diseases. However, due to ethical and practical issues, there is almost no available cell or tissue source to study the molecular mechanism of human trophoblast differentiation, which further becomes a barrier to the study of the pathogenesis of trophoblast-associated diseases of pregnancy. In this study, our goal was to generate a proof-of-concept model for deriving trophoblast lineage cells from induced pluripotency stem (iPS) cells from human fibroblasts. In future studies the generation of trophoblast lineage cells from iPS cells established from patient’s placenta will be extremely useful for studying the pathogenesis of individual trophoblast-associated diseases and for drug testing. Methods and results: Combining iPS cell technology with BMP4 induction, we derived trophoblast lineage cells from human iPS cells. The gene expression profile of these trophoblast lineage cells was distinct from fibroblasts and iPS cells. These cells expressed markers of human trophoblasts. Furthermore, when these cells were differentiated they exhibited invasive capacity and placental hormone secretive capacity, suggesting extravillous trophoblasts and syncytiotrophoblasts. Conclusion: Trophoblast lineage cells can be successfully derived from human iPS cells, which provide a proof-of-concept tool to recapitulate pathogenesis of patient placental trophoblasts in vitro

  6. MtDNA genetic diversity and structure of Eurasian Collared Dove (Streptopelia decaocto).

    Bagi, Zoltán; Dimopoulos, Evangelos Antonis; Loukovitis, Dimitrios; Eraud, Cyril; Kusza, Szilvia

    2018-01-01

    The Eurasian Collared Dove (Streptopelia decaocto) is one of the most successful biological invaders among terrestrial vertebrates. However, little information is available on the genetic diversity of the species. A total of 134 Eurasian Collared Doves from Europe, Asia and the Caribbean (n = 20) were studied by sequencing a 658-bp length of mitochondrial DNA (mtDNA) cytochrome oxidase I (COI). Fifty-two different haplotypes and relatively high haplotype and nucleotide diversities (Hd±SD = 0.843±0.037 and π±SD = 0.026±0.013) were detected. Haplotype Ht1 was particularly dominant: it included 44.03% of the studied individuals, and contained sequences from 75% of the studied countries. Various analyses (FST, AMOVA, STRUCTURE) distinguished 2 groups on the genetic level, designated 'A' and 'B'. Two groups were also separated in the median-joining network and the maximum likelihood tree. The results of the neutrality tests were negative (Fu FS = -25.914; Tajima D = -2.606) and significantly different from zero (P≤0.001) for group A, whereas both values for group B were positive (Fu FS = 1.811; Tajima D = 0.674) and not significant (P>0.05). Statistically significant positive autocorrelation was revealed among individuals located up to 2000 km apart (r = 0.124; P = 0.001). The present results provide the first information on the genetic diversity and structure of the Eurasian Collared Dove, and can thereby serve as a factual and comparative basis for similar studies in the future.

  7. Hyperglycemia induces mixed M1/M2 cytokine profile in primary human monocyte-derived macrophages.

    Moganti, Kondaiah; Li, Feng; Schmuttermaier, Christina; Riemann, Sarah; Klüter, Harald; Gratchev, Alexei; Harmsen, Martin C; Kzhyshkowska, Julia

    2017-10-01

    Hyperglycaemia is a key factor in diabetic pathology. Macrophages are essential regulators of inflammation which can be classified into two major vectors of polarisation: classically activated macrophages (M1) and alternatively activated macrophages (M2). Both types of macrophages play a role in diabetes, where M1 and M2-produced cytokines can have detrimental effects in development of diabetes-associated inflammation and diabetic vascular complications. However, the effect of hyperglycaemia on differentiation and programming of primary human macrophages was not systematically studied. We established a unique model to assess the influence of hyperglycaemia on M1 and M2 differentiation based on primary human monocyte-derived macrophages. The effects of hyperglycaemia on the gene expression and secretion of prototype M1 cytokines TNF-alpha and IL-1beta, and prototype M2 cytokines IL-1Ra and CCL18 were quantified by RT-PCR and ELISA. Hyperglycaemia stimulated production of TNF-alpha, IL-1beta and IL-1Ra during macrophage differentiation. The effect of hyperglycaemia on TNF-alpha was acute, while the stimulating effect on IL-1beta and IL-1Ra was constitutive. Expression of CCL18 was supressed in M2 macrophages by hyperglycaemia. However the secreted levels remained to be biologically significant. Our data indicate that hyperglycaemia itself, without additional metabolic factors induces mixed M1/M2 cytokine profile that can support of diabetes-associated inflammation and development of vascular complications. Copyright © 2016 Elsevier GmbH. All rights reserved.

  8. Cyclooxygenase-2 inhibition blocks M2 macrophage differentiation and suppresses metastasis in murine breast cancer model.

    Yi-Rang Na

    Full Text Available Tumor cells are often associated with abundant macrophages that resemble the alternatively activated M2 subset. Tumor-associated macrophages (TAMs inhibit anti-tumor immune responses and promote metastasis. Cyclooxygenase-2 (COX-2 inhibition is known to prevent breast cancer metastasis. This study hypothesized that COX-2 inhibition affects TAM characteristics potentially relevant to tumor cell metastasis. We found that the specific COX-2 inhibitor, etodolac, inhibited human M2 macrophage differentiation, as determined by decreased CD14 and CD163 expressions and increased TNFα production. Several key metastasis-related mediators, such as vascular endothelial growth factor-A, vascular endothelial growth factor-C, and matrix metalloproteinase-9, were inhibited in the presence of etodolac as compared to untreated M2 macrophages. Murine bone marrow derived M2 macrophages also showed enhanced surface MHCII IA/IE and CD80, CD86 expressions together with enhanced TNFα expressions with etodolac treatment during differentiation. Using a BALB/c breast cancer model, we found that etodolac significantly reduced lung metastasis, possibly due to macrophages expressing increased IA/IE and TNFα, but decreased M2 macrophage-related genes expressions (Ym1, TGFβ. In conclusion, COX-2 inhibition caused loss of the M2 macrophage characteristics of TAMs and may assist prevention of breast cancer metastasis.

  9. Biome specificity of distinct genetic lineages within the four-striped mouse Rhabdomys pumilio (Rodentia: Muridae) from southern Africa with implications for taxonomy.

    du Toit, Nina; van Vuuren, Bettine Jansen; Matthee, Sonja; Matthee, Conrad A

    2012-10-01

    Within southern Africa, a link between past climatic changes and faunal diversification has been hypothesized for a diversity of taxa. To test the hypothesis that evolutionary divergences may be correlated to vegetation changes (induced by changes in climate), we selected the widely distributed four-striped mouse, Rhabdomys, as a model. Two species are currently recognized, the mesic-adapted R. dilectus and arid-adapted R. pumilio. However, the morphology-based taxonomy and the distribution boundaries of previously described subspecies remain poorly defined. The current study, which spans seven biomes, focuses on the spatial genetic structure of the arid-adapted R. pumilio (521 specimens from 31 localities), but also includes limited sampling of the mesic-adapted R. dilectus (33 specimens from 10 localities) to act as a reference for interspecific variation within the genus. The mitochondrial COI gene and four nuclear introns (Eef1a1, MGF, SPTBN1, Bfib7) were used for the construction of gene trees. Mitochondrial DNA analyses indicate that Rhabdomys consists of four reciprocally monophyletic, geographically structured clades, with three distinct lineages present within the arid-adapted R. pumilio. These monophyletic lineages differ by at least 7.9% (±0.3) and these results are partly confirmed by a multilocus network of the combined nuclear intron dataset. Ecological niche modeling in MaxEnt supports a strong correlation between regional biomes and the distribution of distinct evolutionary lineages of Rhabdomys. A Bayesian relaxed molecular clock suggests that the geographic clades diverged between 3.09 and 4.30Ma, supporting the hypothesis that the radiation within the genus coincides with paleoclimatic changes (and the establishment of the biomes) characterizing the Miocene-Pliocene boundary. Marked genetic divergence at the mitochondrial DNA level, coupled with strong nuclear and mtDNA signals of non-monophyly of R. pumilio, support the notion that a taxonomic

  10. SG-ADVISER mtDNA: a web server for mitochondrial DNA annotation with data from 200 samples of a healthy aging cohort.

    Rueda, Manuel; Torkamani, Ali

    2017-08-18

    Whole genome and exome sequencing usually include reads containing mitochondrial DNA (mtDNA). Yet, state-of-the-art pipelines and services for human nuclear genome variant calling and annotation do not handle mitochondrial genome data appropriately. As a consequence, any researcher desiring to add mtDNA variant analysis to their investigations is forced to explore the literature for mtDNA pipelines, evaluate them, and implement their own instance of the desired tool. This task is far from trivial, and can be prohibitive for non-bioinformaticians. We have developed SG-ADVISER mtDNA, a web server to facilitate the analysis and interpretation of mtDNA genomic data coming from next generation sequencing (NGS) experiments. The server was built in the context of our SG-ADVISER framework and on top of the MtoolBox platform (Calabrese et al., Bioinformatics 30(21):3115-3117, 2014), and includes most of its functionalities (i.e., assembly of mitochondrial genomes, heteroplasmic fractions, haplogroup assignment, functional and prioritization analysis of mitochondrial variants) as well as a back-end and a front-end interface. The server has been tested with unpublished data from 200 individuals of a healthy aging cohort (Erikson et al., Cell 165(4):1002-1011, 2016) and their data is made publicly available here along with a preliminary analysis of the variants. We observed that individuals over ~90 years old carried low levels of heteroplasmic variants in their genomes. SG-ADVISER mtDNA is a fast and functional tool that allows for variant calling and annotation of human mtDNA data coming from NGS experiments. The server was built with simplicity in mind, and builds on our own experience in interpreting mtDNA variants in the context of sudden death and rare diseases. Our objective is to provide an interface for non-bioinformaticians aiming to acquire (or contrast) mtDNA annotations via MToolBox. SG-ADVISER web server is freely available to all users at https://genomics.scripps.edu/mtdna .

  11. The MHV68 M2 protein drives IL-10 dependent B cell proliferation and differentiation.

    Andrea M Siegel

    2008-04-01

    Full Text Available Murine gammaherpesvirus 68 (MHV68 establishes long-term latency in memory B cells similar to the human gammaherpesvirus Epstein Barr Virus (EBV. EBV encodes an interleukin-10 (IL-10 homolog and modulates cellular IL-10 expression; however, the role of IL-10 in the establishment and/or maintenance of chronic EBV infection remains unclear. Notably, MHV68 does not encode an IL-10 homolog, but virus infection has been shown to result in elevated serum IL-10 levels in wild-type mice, and IL-10 deficiency results in decreased establishment of virus latency. Here we show that a unique MHV68 latency-associated gene product, the M2 protein, is required for the elevated serum IL-10 levels observed at 2 weeks post-infection. Furthermore, M2 protein expression in primary murine B cells drives high level IL-10 expression along with increased secretion of IL-2, IL-6, and MIP-1alpha. M2 expression was also shown to significantly augment LPS driven survival and proliferation of primary murine B cells. The latter was dependent on IL-10 expression as demonstrated by the failure of IL10-/- B cells to proliferate in response to M2 protein expression and rescue of M2-associated proliferation by addition of recombinant murine IL-10. M2 protein expression in primary B cells also led to upregulated surface expression of the high affinity IL-2 receptor (CD25 and the activation marker GL7, along with down-regulated surface expression of B220, MHC II, and sIgD. The cells retained CD19 and sIgG expression, suggesting differentiation to a pre-plasma memory B cell phenotype. These observations are consistent with previous analyses of M2-null MHV68 mutants that have suggested a role for the M2 protein in expansion and differentiation of MHV68 latently infected B cells-perhaps facilitating the establishment of virus latency in memory B cells. Thus, while the M2 protein is unique to MHV68, analysis of M2 function has revealed an important role for IL-10 in MHV68 pathogenesis

  12. The MHV68 M2 protein drives IL-10 dependent B cell proliferation and differentiation.

    Siegel, Andrea M; Herskowitz, Jeremy H; Speck, Samuel H

    2008-04-04

    Murine gammaherpesvirus 68 (MHV68) establishes long-term latency in memory B cells similar to the human gammaherpesvirus Epstein Barr Virus (EBV). EBV encodes an interleukin-10 (IL-10) homolog and modulates cellular IL-10 expression; however, the role of IL-10 in the establishment and/or maintenance of chronic EBV infection remains unclear. Notably, MHV68 does not encode an IL-10 homolog, but virus infection has been shown to result in elevated serum IL-10 levels in wild-type mice, and IL-10 deficiency results in decreased establishment of virus latency. Here we show that a unique MHV68 latency-associated gene product, the M2 protein, is required for the elevated serum IL-10 levels observed at 2 weeks post-infection. Furthermore, M2 protein expression in primary murine B cells drives high level IL-10 expression along with increased secretion of IL-2, IL-6, and MIP-1alpha. M2 expression was also shown to significantly augment LPS driven survival and proliferation of primary murine B cells. The latter was dependent on IL-10 expression as demonstrated by the failure of IL10-/- B cells to proliferate in response to M2 protein expression and rescue of M2-associated proliferation by addition of recombinant murine IL-10. M2 protein expression in primary B cells also led to upregulated surface expression of the high affinity IL-2 receptor (CD25) and the activation marker GL7, along with down-regulated surface expression of B220, MHC II, and sIgD. The cells retained CD19 and sIgG expression, suggesting differentiation to a pre-plasma memory B cell phenotype. These observations are consistent with previous analyses of M2-null MHV68 mutants that have suggested a role for the M2 protein in expansion and differentiation of MHV68 latently infected B cells-perhaps facilitating the establishment of virus latency in memory B cells. Thus, while the M2 protein is unique to MHV68, analysis of M2 function has revealed an important role for IL-10 in MHV68 pathogenesis-identifying a

  13. Broad phylogenomic sampling and the sister lineage of land plants.

    Ruth E Timme

    Full Text Available The tremendous diversity of land plants all descended from a single charophyte green alga that colonized the land somewhere between 430 and 470 million years ago. Six orders of charophyte green algae, in addition to embryophytes, comprise the Streptophyta s.l. Previous studies have focused on reconstructing the phylogeny of organisms tied to this key colonization event, but wildly conflicting results have sparked a contentious debate over which lineage gave rise to land plants. The dominant view has been that 'stoneworts,' or Charales, are the sister lineage, but an alternative hypothesis supports the Zygnematales (often referred to as "pond scum" as the sister lineage. In this paper, we provide a well-supported, 160-nuclear-gene phylogenomic analysis supporting the Zygnematales as the closest living relative to land plants. Our study makes two key contributions to the field: 1 the use of an unbiased method to collect a large set of orthologs from deeply diverging species and 2 the use of these data in determining the sister lineage to land plants. We anticipate this updated phylogeny not only will hugely impact lesson plans in introductory biology courses, but also will provide a solid phylogenetic tree for future green-lineage research, whether it be related to plants or green algae.

  14. Cell lineages of the embryo of the nematode Caenorhabditis elegans.

    Deppe, U; Schierenberg, E; Cole, T; Krieg, C; Schmitt, D; Yoder, B; von Ehrenstein, G

    1978-01-01

    Embryogenesis of the free-living soil nematode Caenorhabditis elegans produces a juvenile having about 550 cells at hatching. We have determined the lineages of 182 cells by tracing the divisions of individual cells in living embryos. An invariant pattern of cleavage divisions of the egg generates a set of stem cells. These stem cells are the founders of six stem cell lineages. Each lineage has its own clock--i.e., an autonomous rhythm of synchronous cell divisions. The rhythms are maintained in spite of extensive cellular rearrangement. The rate and the orientation of the cell divisions of the cell lineages are essentially invariant among individuals. Thus, the destiny of cells seems to depend primarily on their lineage history. The anterior position of the site of origin of the stem cells in the egg relates to the rate of the cell cycle clock, suggesting intracellular preprogramming of the uncleaved egg. We used a technique that allows normal embryogenesis, from the fertilized egg to hatching, outside the parent under a cover glass. Embryogenesis was followed microscopically with Nomarski interference optics and high-resolution video recording.

  15. Highly variable rates of genome rearrangements between hemiascomycetous yeast lineages.

    2006-03-01

    Full Text Available Hemiascomycete yeasts cover an evolutionary span comparable to that of the entire phylum of chordates. Since this group currently contains the largest number of complete genome sequences it presents unique opportunities to understand the evolution of genome organization in eukaryotes. We inferred rates of genome instability on all branches of a phylogenetic tree for 11 species and calculated species-specific rates of genome rearrangements. We characterized all inversion events that occurred within synteny blocks between six representatives of the different lineages. We show that the rates of macro- and microrearrangements of gene order are correlated within individual lineages but are highly variable across different lineages. The most unstable genomes correspond to the pathogenic yeasts Candida albicans and Candida glabrata. Chromosomal maps have been intensively shuffled by numerous interchromosomal rearrangements, even between species that have retained a very high physical fraction of their genomes within small synteny blocks. Despite this intensive reshuffling of gene positions, essential genes, which cluster in low recombination regions in the genome of Saccharomyces cerevisiae, tend to remain syntenic during evolution. This work reveals that the high plasticity of eukaryotic genomes results from rearrangement rates that vary between lineages but also at different evolutionary times of a given lineage.

  16. Cell lineage analysis of the mammalian female germline.

    Yitzhak Reizel

    Full Text Available Fundamental aspects of embryonic and post-natal development, including maintenance of the mammalian female germline, are largely unknown. Here we employ a retrospective, phylogenetic-based method for reconstructing cell lineage trees utilizing somatic mutations accumulated in microsatellites, to study female germline dynamics in mice. Reconstructed cell lineage trees can be used to estimate lineage relationships between different cell types, as well as cell depth (number of cell divisions since the zygote. We show that, in the reconstructed mouse cell lineage trees, oocytes form clusters that are separate from hematopoietic and mesenchymal stem cells, both in young and old mice, indicating that these populations belong to distinct lineages. Furthermore, while cumulus cells sampled from different ovarian follicles are distinctly clustered on the reconstructed trees, oocytes from the left and right ovaries are not, suggesting a mixing of their progenitor pools. We also observed an increase in oocyte depth with mouse age, which can be explained either by depth-guided selection of oocytes for ovulation or by post-natal renewal. Overall, our study sheds light on substantial novel aspects of female germline preservation and development.

  17. Possible conservation units of the sun bear (Helarctos malayanus) in Sarawak based on variation of mtDNA control region.

    Onuma, Manabu; Suzuki, Masatsugu; Ohtaishi, Noriyuki

    2006-11-01

    The mitochondrial DNA control region of the sun bear (Helarctos malayanus) was sequenced using 21 DNA samples collected from confiscated sun bears to identify conservation units, such as evolutionarily significant units and management units, in Sarawak, Borneo Island. A total of 10 haplotypes were observed, indicating the presence of at least two lineages in the sun bear population in Sarawak. Presumably, these two lineages could represent evolutionarily significant units. However, the geographical distributions of the two lineages remained unknown due to the lack of information regarding the exact capture locations of the confiscated sun bears. It is essential to elucidate the geographical distributions of these lineages in order to create a proper conservation plan for the sun bears in Sarawak. Therefore, further studies examining the haplotype distributions using DNA samples from known localities are essential.

  18. ZMS regulation of M2 muscarinic receptor mRNA stability requires protein factor

    Zhang Yongfang; Xia Zongqin; Hu Ya'er

    2010-01-01

    Aim The aim of this work is to study the elevation mechanism of ZMS on muscarinic M2 receptor mRNA expression. Methods Actinomycin D was added to cultured CHOm2 cells to stop the de novo synthesis of M2 receptor mRNA and samples were taken at various times to determine the time course of mRNA of M2 receptor with real-time quantitative RT-PCR. Half-life of M2 receptor mRNA and the effect of ZMS on the half-life was obtained from the slope of the exponential curves. Cycloheximide was added at 4 h prior to and 24 h after the addition of ZMS to examine the effect of de novo protein synthesis on the action of ZMS. Results The half-life of m2 mRNA was prolonged by ZMS treatment without cycloheximide (4.75±0.54 h and 2.13 h±0.23 h for ZMS and vehicle treated groups, respectively, P<0.05). When cycloheximide was added to the culture medium 4h prior to the addition of ZMS, the effect of ZMS in prolonging the half-life of m2 mRNA disappeared (3.06 h±0.23 h and 3.00 h±l.20 h for cells with and without ZMS, respectively). However, when the ZMS was added to the medium 24h prior to the addition of cycloheximide, the action of ZMS was not abolished by cycloheximide (half-life was 5.43 h±1.13 h and 2.46 h±0.09 h for cells with and without ZMS, respectively). Conclusion These data suggest that de novo protein synthesis was required for the increase in M2 mRNA stability induced by ZMS. (authors)

  19. Rac2 controls tumor growth, metastasis and M1-M2 macrophage differentiation in vivo.

    Shweta Joshi

    Full Text Available Although it is well-established that the macrophage M1 to M2 transition plays a role in tumor progression, the molecular basis for this process remains incompletely understood. Herein, we demonstrate that the small GTPase, Rac2 controls macrophage M1 to M2 differentiation and the metastatic phenotype in vivo. Using a genetic approach, combined with syngeneic and orthotopic tumor models we demonstrate that Rac2-/- mice display a marked defect in tumor growth, angiogenesis and metastasis. Microarray, RT-PCR and metabolomic analysis on bone marrow derived macrophages isolated from the Rac2-/- mice identify an important role for Rac2 in M2 macrophage differentiation. Furthermore, we define a novel molecular mechanism by which signals transmitted from the extracellular matrix via the α4β1 integrin and MCSF receptor lead to the activation of Rac2 and potentially regulate macrophage M2 differentiation. Collectively, our findings demonstrate a macrophage autonomous process by which the Rac2 GTPase is activated downstream of the α4β1 integrin and the MCSF receptor to control tumor growth, metastasis and macrophage differentiation into the M2 phenotype. Finally, using gene expression and metabolomic data from our Rac2-/- model, and information related to M1-M2 macrophage differentiation curated from the literature we executed a systems biologic analysis of hierarchical protein-protein interaction networks in an effort to develop an iterative interactome map which will predict additional mechanisms by which Rac2 may coordinately control macrophage M1 to M2 differentiation and metastasis.

  20. Underestimation of species richness in neotropical frogs revealed by mtDNA analyses.

    Antoine Fouquet

    2007-10-01

    Full Text Available Amphibians are rapidly vanishing. At the same time, it is most likely that the number of amphibian species is highly underestimated. Recent DNA barcoding work has attempted to define a threshold between intra- and inter-specific genetic distances to help identify candidate species. In groups with high extinction rates and poorly known species boundaries, like amphibians, such tools may provide a way to rapidly evaluate species richness.Here we analyse published and new 16S rDNA sequences from 60 frog species of Amazonia-Guianas to obtain a minimum estimate of the number of undescribed species in this region. We combined isolation by distance, phylogenetic analyses, and comparison of molecular distances to evaluate threshold values for the identification of candidate species among these frogs.In most cases, geographically distant populations belong to genetically highly distinct lineages that could be considered as candidate new species. This was not universal among the taxa studied and thus widespread species of Neotropical frogs really do exist, contrary to previous assumptions. Moreover, the many instances of paraphyly and the wide overlap between distributions of inter- and intra-specific distances reinforce the hypothesis that many cryptic species remain to be described. In our data set, pairwise genetic distances below 0.02 are strongly correlated with geographical distances. This correlation remains statistically significant until genetic distance is 0.05, with no such relation thereafter. This suggests that for higher distances allopatric and sympatric cryptic species prevail. Based on our analyses, we propose a more inclusive pairwise genetic distance of 0.03 between taxa to target lineages that could correspond to candidate species.Using this approach, we identify 129 candidate species, two-fold greater than the 60 species included in the current study. This leads to estimates of around 170 to 460 frog taxa unrecognized in Amazonia

  1. A Corticocortical Circuit Directly Links Retrosplenial Cortex to M2 in the Mouse

    Radulovic, Jelena

    2016-01-01

    Retrosplenial cortex (RSC) is a dorsomedial parietal area involved in a range of cognitive functions, including episodic memory, navigation, and spatial memory. Anatomically, the RSC receives inputs from dorsal hippocampal networks and in turn projects to medial neocortical areas. A particularly prominent projection extends rostrally to the posterior secondary motor cortex (M2), suggesting a functional corticocortical link from the RSC to M2 and thus a bridge between hippocampal and neocortical networks involved in mnemonic and sensorimotor aspects of navigation. We investigated the cellular connectivity in this RSC→M2 projection in the mouse using optogenetic photostimulation, retrograde labeling, and electrophysiology. Axons from RSC formed monosynaptic excitatory connections onto M2 pyramidal neurons across layers and projection classes, including corticocortical/intratelencephalic neurons (reciprocally and callosally projecting) in layers 2–6, pyramidal tract neurons (corticocollicular, corticopontine) in layer 5B, and, to a lesser extent, corticothalamic neurons in layer 6. In addition to these direct connections, disynaptic connections were made via posterior parietal cortex (RSC→PPC→M2) and anteromedial thalamus (RSC→AM→M2). In the reverse direction, axons from M2 monosynaptically excited M2-projecting corticocortical neurons in the RSC, especially in the superficial layers of the dysgranular region. These findings establish an excitatory RSC→M2 corticocortical circuit that engages diverse types of excitatory projection neurons in the downstream area, suggesting a basis for direct communication from dorsal hippocampal networks involved in spatial memory and navigation to neocortical networks involved in diverse aspects of sensorimotor integration and motor control. SIGNIFICANCE STATEMENT Corticocortical pathways interconnect cortical areas extensively, but the cellular connectivity in these pathways remains largely uncharacterized. Here, we

  2. Y-chromosome and mtDNA genetics reveal significant contrasts in affinities of modern Middle Eastern populations with European and African populations.

    Badro, Danielle A; Douaihy, Bouchra; Haber, Marc; Youhanna, Sonia C; Salloum, Angélique; Ghassibe-Sabbagh, Michella; Johnsrud, Brian; Khazen, Georges; Matisoo-Smith, Elizabeth; Soria-Hernanz, David F; Wells, R Spencer; Tyler-Smith, Chris; Platt, Daniel E; Zalloua, Pierre A

    2013-01-01

    The Middle East was a funnel of human expansion out of Africa, a staging area for the Neolithic Agricultural Revolution, and the home to some of the earliest world empires. Post LGM expansions into the region and subsequent population movements created a striking genetic mosaic with distinct sex-based genetic differentiation. While prior studies have examined the mtDNA and Y-chromosome contrast in focal populations in the Middle East, none have undertaken a broad-spectrum survey including North and sub-Saharan Africa, Europe, and Middle Eastern populations. In this study 5,174 mtDNA and 4,658 Y-chromosome samples were investigated using PCA, MDS, mean-linkage clustering, AMOVA, and Fisher exact tests of F(ST)'s, R(ST)'s, and haplogroup frequencies. Geographic differentiation in affinities of Middle Eastern populations with Africa and Europe showed distinct contrasts between mtDNA and Y-chromosome data. Specifically, Lebanon's mtDNA shows a very strong association to Europe, while Yemen shows very strong affinity with Egypt and North and East Africa. Previous Y-chromosome results showed a Levantine coastal-inland contrast marked by J1 and J2, and a very strong North African component was evident throughout the Middle East. Neither of these patterns were observed in the mtDNA. While J2 has penetrated into Europe, the pattern of Y-chromosome diversity in Lebanon does not show the widespread affinities with Europe indicated by the mtDNA data. Lastly, while each population shows evidence of connections with expansions that now define the Middle East, Africa, and Europe, many of the populations in the Middle East show distinctive mtDNA and Y-haplogroup characteristics that indicate long standing settlement with relatively little impact from and movement into other populations.

  3. eCOMPAGT integrates mtDNA: import, validation and export of mitochondrial DNA profiles for population genetics, tumour dynamics and genotype-phenotype association studies

    Specht Günther

    2010-03-01

    Full Text Available Abstract Background Mitochondrial DNA (mtDNA is widely being used for population genetics, forensic DNA fingerprinting and clinical disease association studies. The recent past has uncovered severe problems with mtDNA genotyping, not only due to the genotyping method itself, but mainly to the post-lab transcription, storage and report of mtDNA genotypes. Description eCOMPAGT, a system to store, administer and connect phenotype data to all kinds of genotype data is now enhanced by the possibility of storing mtDNA profiles and allowing their validation, linking to phenotypes and export as numerous formats. mtDNA profiles can be imported from different sequence evaluation programs, compared between evaluations and their haplogroup affiliations stored. Furthermore, eCOMPAGT has been improved in its sophisticated transparency (support of MySQL and Oracle, security aspects (by using database technology and the option to import, manage and store genotypes derived from various genotyping methods (SNPlex, TaqMan, and STRs. It is a software solution designed for project management, laboratory work and the evaluation process all-in-one. Conclusions The extended mtDNA version of eCOMPAGT was designed to enable error-free post-laboratory data handling of human mtDNA profiles. This software is suited for small to medium-sized human genetic, forensic and clinical genetic laboratories. The direct support of MySQL and the improved database security options render eCOMPAGT a powerful tool to build an automated workflow architecture for several genotyping methods. eCOMPAGT is freely available at http://dbis-informatik.uibk.ac.at/ecompagt.

  4. eCOMPAGT integrates mtDNA: import, validation and export of mitochondrial DNA profiles for population genetics, tumour dynamics and genotype-phenotype association studies.

    Weissensteiner, Hansi; Schönherr, Sebastian; Specht, Günther; Kronenberg, Florian; Brandstätter, Anita

    2010-03-09

    Mitochondrial DNA (mtDNA) is widely being used for population genetics, forensic DNA fingerprinting and clinical disease association studies. The recent past has uncovered severe problems with mtDNA genotyping, not only due to the genotyping method itself, but mainly to the post-lab transcription, storage and report of mtDNA genotypes. eCOMPAGT, a system to store, administer and connect phenotype data to all kinds of genotype data is now enhanced by the possibility of storing mtDNA profiles and allowing their validation, linking to phenotypes and export as numerous formats. mtDNA profiles can be imported from different sequence evaluation programs, compared between evaluations and their haplogroup affiliations stored. Furthermore, eCOMPAGT has been improved in its sophisticated transparency (support of MySQL and Oracle), security aspects (by using database technology) and the option to import, manage and store genotypes derived from various genotyping methods (SNPlex, TaqMan, and STRs). It is a software solution designed for project management, laboratory work and the evaluation process all-in-one. The extended mtDNA version of eCOMPAGT was designed to enable error-free post-laboratory data handling of human mtDNA profiles. This software is suited for small to medium-sized human genetic, forensic and clinical genetic laboratories. The direct support of MySQL and the improved database security options render eCOMPAGT a powerful tool to build an automated workflow architecture for several genotyping methods. eCOMPAGT is freely available at http://dbis-informatik.uibk.ac.at/ecompagt.

  5. Lineage plasticity-mediated therapy resistance in prostate cancer.

    Blee, Alexandra M; Huang, Haojie

    2018-06-12

    Therapy resistance is a significant challenge for prostate cancer treatment in clinic. Although targeted therapies such as androgen deprivation and androgen receptor (AR) inhibition are effective initially, tumor cells eventually evade these strategies through multiple mechanisms. Lineage reprogramming in response to hormone therapy represents a key mechanism that is increasingly observed. The studies in this area have revealed specific combinations of alterations present in adenocarcinomas that provide cells with the ability to transdifferentiate and perpetuate AR-independent tumor growth after androgen-based therapies. Interestingly, several master regulators have been identified that drive plasticity, some of which also play key roles during development and differentiation of the cell lineages in the normal prostate. Thus, further study of each AR-independent tumor type and understanding underlying mechanisms are warranted to develop combinational therapies that combat lineage plasticity in prostate cancer.

  6. Little Divergence Among Mitochondrial Lineages of Prochilodus (Teleostei, Characiformes

    Bruno F. Melo

    2018-04-01

    Full Text Available Evidence that migration prevents population structure among Neotropical characiform fishes has been reported recently but the effects upon species diversification remain unclear. Migratory species of Prochilodus have complex species boundaries and intrincate taxonomy representing a good model to address such questions. Here, we analyzed 147 specimens through barcode sequences covering all species of Prochilodus across a broad geographic area of South America. Species delimitation and population genetic methods revealed very little genetic divergence among mitochondrial lineages suggesting that extensive gene flow resulted likely from the highly migratory behavior, natural hybridization or recent radiation prevent accumulation of genetic disparity among lineages. Our results clearly delimit eight genetic lineages in which four of them contain a single species and four contain more than one morphologically problematic taxon including a trans-Andean species pair and species of the P. nigricans group. Information about biogeographic distribution of haplotypes presented here might contribute to further research on the population genetics and taxonomy of Prochilodus.

  7. Reticulate evolution and incomplete lineage sorting among the ponderosa pines.

    Willyard, Ann; Cronn, Richard; Liston, Aaron

    2009-08-01

    Interspecific gene flow via hybridization may play a major role in evolution by creating reticulate rather than hierarchical lineages in plant species. Occasional diploid pine hybrids indicate the potential for introgression, but reticulation is hard to detect because ancestral polymorphism is still shared across many groups of pine species. Nucleotide sequences for 53 accessions from 17 species in subsection Ponderosae (Pinus) provide evidence for reticulate evolution. Two discordant patterns among independent low-copy nuclear gene trees and a chloroplast haplotype are better explained by introgression than incomplete lineage sorting or other causes of incongruence. Conflicting resolution of three monophyletic Pinus coulteri accessions is best explained by ancient introgression followed by a genetic bottleneck. More recent hybridization transferred a chloroplast from P. jeffreyi to a sympatric P. washoensis individual. We conclude that incomplete lineage sorting could account for other examples of non-monophyly, and caution against any analysis based on single-accession or single-locus sampling in Pinus.

  8. Imaging retinal progenitor lineages in developing zebrafish embryos.

    Jusuf, Patricia; Harris, William A; Poggi, Lucia

    2013-03-01

    In this protocol, we describe how to make and analyze four dimensional (4D) movies of retinal lineage in the zebrafish embryo in vivo. 4D consists of three spatial dimensions (3D) reconstructed from stacks of confocal planes plus one time dimension. Our imaging is performed on transgenic cells that express fluorescent proteins under the control of cell-specific promoters or on cells that transiently express such reporters in specific retinal cell progenitors. An important aspect of lineage tracing is the ability to follow individual cells as they undergo multiple cell divisions, final migration, and differentiation. This may mean many hours of 4D imaging, requiring that cells be kept healthy and maintained under conditions suitable for normal development. The longest movies we have made are ∼50 h. By analyzing these movies, we can see when a specific cell was born and who its sister was, allowing us to reconstruct its retinal lineages in vivo.

  9. Bacillus anthracis in China and its relationship to worldwide lineages

    Schupp James M

    2009-04-01

    Full Text Available Abstract Background The global pattern of distribution of 1033 B. anthracis isolates has previously been defined by a set of 12 conserved canonical single nucleotide polymorphisms (canSNP. These studies reinforced the presence of three major lineages and 12 sub-lineages and sub-groups of this anthrax-causing pathogen. Isolates that form the A lineage (unlike the B and C lineages have become widely dispersed throughout the world and form the basis for the geographical disposition of "modern" anthrax. An archival collection of 191 different B. anthracis isolates from China provides a glimpse into the possible role of Chinese trade and commerce in the spread of certain sub-lineages of this pathogen. Canonical single nucleotide polymorphism (canSNP and multiple locus VNTR analysis (MLVA typing has been used to examine this archival collection of isolates. Results The canSNP study indicates that there are 5 different sub-lineages/sub-groups in China out of 12 previously described world-wide canSNP genotypes. Three of these canSNP genotypes were only found in the western-most province of China, Xinjiang. These genotypes were A.Br.008/009, a sub-group that is spread across most of Europe and Asia; A.Br.Aust 94, a sub-lineage that is present in Europe and India, and A.Br.Vollum, a lineage that is also present in Europe. The remaining two canSNP genotypes are spread across the whole of China and belong to sub-group A.Br.001/002 and the A.Br.Ames sub-lineage, two closely related genotypes. MLVA typing adds resolution to the isolates in each canSNP genotype and diversity indices for the A.Br.008/009 and A.Br.001/002 sub-groups suggest that these represent older and established clades in China. Conclusion B. anthracis isolates were recovered from three canSNP sub-groups (A.Br.008/009, A.Br.Aust94, and A.Br.Vollum in the western most portion of the large Chinese province of Xinjiang. The city of Kashi in this province appears to have served as a crossroads

  10. Expanding the Entamoeba Universe: New Hosts Yield Novel Ribosomal Lineages.

    Jacob, Alison S; Busby, Eloise J; Levy, Abigail D; Komm, Natasha; Clark, C Graham

    2016-01-01

    Removing the requirement for cell culture has led to a substantial increase in the number of lineages of Entamoeba recognized as distinct. Surveying the range of potential host species for this parasite genus has barely been started and it is clear that additional sampling of the same host in different locations often identifies additional diversity. In this study, using small subunit ribosomal RNA gene sequencing, we identify four new lineages of Entamoeba, including the first report of Entamoeba from an elephant, and extend the host range of some previously described lineages. In addition, examination of microbiome data from a number of host animals suggests that substantial Entamoeba diversity remains to be uncovered. © 2015 The Author(s) Journal of Eukaryotic Microbiology © 2015 International Society of Protistologists.

  11. Identification of Aquifex aeolicus tRNA (m2(2G26) methyltransferase gene.

    Takeda, Hiroshi; Hori, Hiroyuki; Endo, Yaeta

    2002-01-01

    The modifications of N2,N2-dimethylguanine (m2(2)G) are found in tRNAs and rRNAs from eukarya and archaea. In tRNAs, modification at position G26 is generated by tRNA (m2(2)G26) methyltransferase, which is encoded by the corresponding gene, trm1. This enzyme catalyzes the methyl-transfer from S-adenosyl-L-methionine to the semi-conserved residue, G26, via the intermediate modified base, m2G26. Recent genome sequencing project has been reported that the putative trm1 is encoded in the genome of Aquifex aeolicus, a hyper-thermophilic eubacterium as only one exception among eubacteria. In order to confirm whether this bacterial trm1 gene product is a real tRNA (m2(2)G26) methyltransferase or not, we expressed this protein by wheat germ in vitro cell-free translation system. Our biochemical analysis clearly showed that this gene product possessed tRNA (m2(2)G26) methyltransferase activity.

  12. The challenges of M2M massive access in wireless cellular networks

    Andrea Biral

    2015-02-01

    Full Text Available The next generation of communication systems, which is commonly referred to as 5G, is expected to support, besides the traditional voice and data services, new communication paradigms, such as Internet of Things (IoT and Machine-to-Machine (M2M services, which involve communication between Machine-Type Devices (MTDs in a fully automated fashion, thus, without or with minimal human intervention. Although the general requirements of 5G systems are progressively taking shape, the technological issues raised by such a vision are still partially unclear. Nonetheless, general consensus has been reached upon some specific challenges, such as the need for 5G wireless access networks to support massive access by MTDs, as a consequence of the proliferation of M2M services. In this paper, we describe the main challenges raised by the M2M vision, focusing in particular on the problems related to the support of massive MTD access in current cellular communication systems. Then we analyze the most common approaches proposed in the literature to enable the coexistence of conventional and M2M services in the current and next generation of cellular wireless systems. We finally conclude by pointing out the research challenges that require further investigation in order to provide full support to the M2M paradigm.

  13. Unraveling a molecular determinant for clathrin-independent internalization of the M2 muscarinic acetylcholine receptor

    Wan, Min; Zhang, Wenhua; Tian, Yangli; Xu, Chanjuan; Xu, Tao; Liu, Jianfeng; Zhang, Rongying

    2015-01-01

    Endocytosis and postendocytic sorting of G-protein-coupled receptors (GPCRs) is important for the regulation of both their cell surface density and signaling profile. Unlike the mechanisms of clathrin-dependent endocytosis (CDE), the mechanisms underlying the control of GPCR signaling by clathrin-independent endocytosis (CIE) remain largely unknown. Among the muscarinic acetylcholine receptors (mAChRs), the M4 mAChR undergoes CDE and recycling, whereas the M2 mAChR is internalized through CIE and targeted to lysosomes. Here we investigated the endocytosis and postendocytic trafficking of M2 mAChR based on a comparative analysis of the third cytoplasmic domain in M2 and M4 mAChRs. For the first time, we identified that the sequence 374KKKPPPS380 servers as a sorting signal for the clathrin-independent internalization of M2 mAChR. Switching 374KKKPPPS380 to the i3 loop of the M4 mAChR shifted the receptor into lysosomes through the CIE pathway; and therefore away from CDE and recycling. We also found another previously unidentified sequence that guides CDE of the M2 mAChR, 361VARKIVKMTKQPA373, which is normally masked in the presence of the downstream sequence 374KKKPPPS380. Taken together, our data indicate that endocytosis and postendocytic sorting of GPCRs that undergo CIE could be sequence-dependent. PMID:26094760

  14. Occurrence of different Canine distemper virus lineages in Italian dogs.

    Balboni, Andrea; De Lorenzo Dandola, Giorgia; Scagliarini, Alessandra; Prosperi, Santino; Battilani, Mara

    2014-01-01

    This study describes the sequence analysis of the H gene of 7 Canine distemper virus (CDV) strains identified in dogs in Italy between years 2002-2012. The phylogenetic analysis showed that the CDV strains belonged to 2 clusters: 6 viruses were identified as Arctic-like lineage and 1 as Europe 1 lineage. These data show a considerable prevalence of Arctic-like-CDVs in the analysed dogs. The dogs and the 3 viruses more recently identified showed 4 distinctive amino acid mutations compared to all other Arctic CDVs.

  15. The phylogeny of the four pan-American MtDNA haplogroups: implications for evolutionary and disease studies.

    Alessandro Achilli

    Full Text Available Only a limited number of complete mitochondrial genome sequences belonging to Native American haplogroups were available until recently, which left America as the continent with the least amount of information about sequence variation of entire mitochondrial DNAs. In this study, a comprehensive overview of all available complete mitochondrial DNA (mtDNA genomes of the four pan-American haplogroups A2, B2, C1, and D1 is provided by revising the information scattered throughout GenBank and the literature, and adding 14 novel mtDNA sequences. The phylogenies of haplogroups A2, B2, C1, and D1 reveal a large number of sub-haplogroups but suggest that the ancestral Beringian population(s contributed only six (successful founder haplotypes to these haplogroups. The derived clades are overall starlike with coalescence times ranging from 18,000 to 21,000 years (with one exception using the conventional calibration. The average of about 19,000 years somewhat contrasts with the corresponding lower age of about 13,500 years that was recently proposed by employing a different calibration and estimation approach. Our estimate indicates a human entry and spread of the pan-American haplogroups into the Americas right after the peak of the Last Glacial Maximum and comfortably agrees with the undisputed ages of the earliest Paleoindians in South America. In addition, the phylogenetic approach also indicates that the pathogenic status proposed for various mtDNA mutations, which actually define branches of Native American haplogroups, was based on insufficient grounds.

  16. Aggregation and Trunking of M2M Traffic via D2D Connections

    Rigazzi, Giovanni; Kiilerich Pratas, Nuno; Popovski, Petar

    2015-01-01

    Machine-to-Machine (M2M) communications is one of the key enablers of the Internet of Things (IoT). Billions of devices are expected to be deployed in the near future for novel M2M applications demanding ubiquitous access and global connectivity. In order to cope with the massive number of machines......, there is a need for new techniques to coordinate the access and allocate the resources. Although the majority of the proposed solutions are focused on the adaptation of the traditional cellular networks to the M2M traffic patterns, novel approaches based on the direct communication among nearby devices may...... represent an effective way to avoid access congestion and cell overload. In this paper, we propose a new strategy inspired by the classical Trunked Radio Systems (TRS), exploiting the Device-to-Device (D2D) connectivity between cellular users and Machine-Type Devices (MTDs). The aggregation of the locally...

  17. M2-F1 in flight being towed by a C-47

    1964-01-01

    The M2-F1 Lifting Body is seen here being towed behind a C-47 at the Flight Research Center (later redesignated the Dryden Flight Research Center), Edwards, California. In this rear view, the M2-F1 is flying above and to one side of the C-47. This was done to avoid wake turbulence from the towplane. Lacking wings, the M2-F1 used an unusual configuration for its control surfaces. It had two rudders on the fins, two elevons (called 'elephant ears') mounted on the outsides of the fins, and two body flaps on the upper rear fuselage. The wingless, lifting body aircraft design was initially concieved as a means of landing an aircraft horizontally after atmospheric reentry. The absence of wings would make the extreme heat of re-entry less damaging to the vehicle. In 1962, Dryden management approved a program to build a lightweight, unpowered lifting body as a prototype to flight test the wingless concept. It would look like a 'flying bathtub,' and was designated the M2-F1, the 'M' referring to 'manned' and 'F' referring to 'flight' version. It featured a plywood shell placed over a tubular steel frame crafted at Dryden. Construction was completed in 1963. The first flight tests of the M2-F1 were over Rogers Dry Lake at the end of a tow rope attached to a hopped-up Pontiac convertible driven at speeds up to about 120 mph. These initial tests produced enough flight data about the M2-F1 to proceed with flights behind the C-47 tow plane at greater altitudes. The C-47 took the craft to an altitude of 12,000 where free flights back to Rogers Dry Lake began. Pilot for the first series of flights of the M2-F1 was NASA research pilot Milt Thompson. Typical glide flights with the M2-F1 lasted about two minutes and reached speeds of 110 to l20 mph. More than 400 ground tows and 77 aircraft tow flights were carried out with the M2-F1. The success of Dryden's M2-F1 program led to NASA's development and construction of two heavyweight lifting bodies based on studies at NASA's Ames and

  18. Holographic cosmology from a system of M2–M5 branes

    Sepehri, Alireza, E-mail: alireza.sepehri@uk.ac.ir [Faculty of Physics, Shahid Bahonar University, P.O. Box 76175, Kerman (Iran, Islamic Republic of); Research Institute for Astronomy and Astrophysics of Maragha (RIAAM), Maragha (Iran, Islamic Republic of); Faizal, Mir, E-mail: f2mir@uwaterloo.ca [Department of Physics and Astronomy, University of Waterloo, Waterloo, ON, N2L 3G1 (Canada); Setare, Mohammad Reza, E-mail: rezakord@ipm.ir [Department of Science, Campus of Bijar, University of Kurdistan, Bijar (Iran, Islamic Republic of); Ali, Ahmed Farag, E-mail: afali@fsu.edu [Department of Physics, Florida State University, Tallahassee, FL 32306 (United States); Department of Physics, Faculty of Science, Benha University, Benha 13518 (Egypt)

    2016-05-15

    In this paper, we analyze the holographic cosmology using a M2–M5 brane configuration. In this configuration, a M2-brane will be placed in between a M5-brane and an anti-M5-brane. The M2-brane will act as a channel for energy to flow from an anti-M5-brane to a M5-brane, and this will increase the degrees of freedom on the M5-brane causing inflation. The inflation will end when the M5-brane and anti-M5-brane get separated. However, at a later stage the distance between the M5-brane and the anti-M5-bran can reduce and this will cause the formation of tachyonic states. These tachyonic states will again open a bridge between the M5-branes and the anti-M5-branes, which will cause further acceleration of the universe.

  19. Holographic cosmology from a system of M2–M5 branes

    Sepehri, Alireza; Faizal, Mir; Setare, Mohammad Reza; Ali, Ahmed Farag

    2016-01-01

    In this paper, we analyze the holographic cosmology using a M2–M5 brane configuration. In this configuration, a M2-brane will be placed in between a M5-brane and an anti-M5-brane. The M2-brane will act as a channel for energy to flow from an anti-M5-brane to a M5-brane, and this will increase the degrees of freedom on the M5-brane causing inflation. The inflation will end when the M5-brane and anti-M5-brane get separated. However, at a later stage the distance between the M5-brane and the anti-M5-bran can reduce and this will cause the formation of tachyonic states. These tachyonic states will again open a bridge between the M5-branes and the anti-M5-branes, which will cause further acceleration of the universe.

  20. Comments on the Bagger-Lambert theory and multiple M2-branes

    Raamsdonk, Mark Van

    2008-01-01

    We study the SO(8) superconformal theory proposed recently by Bagger and Lambert as a possible worldvolume theory for multiple M2-branes. For their explicit example with gauge group SO(4), we rewrite the theory (originally formulated in terms of a three-algebra) as an ordinary SU(2) x SU(2) gauge theory with bifundamental matter. In this description, the parity invariance of the theory, required for a proper description of M2-branes, is clarified. We describe the subspace of scalar field configurations on which the potential vanishes, correcting an earlier claim. Finally, we point out, for general three-algebras, a difficulty in constructing the required set of superconformal primary operators which should be present in the correct theory describing multiple M2-branes.

  1. M2 FILTER FOR SPECKLE NOISE SUPPRESSION IN BREAST ULTRASOUND IMAGES

    E.S. Samundeeswari

    2016-11-01

    Full Text Available Breast cancer, commonly found in women is a serious life threatening disease due to its invasive nature. Ultrasound (US imaging method plays an effective role in screening early detection and diagnosis of Breast cancer. Speckle noise generally affects medical ultrasound images and also causes a number of difficulties in identifying the Region of Interest. Suppressing speckle noise is a challenging task as it destroys fine edge details. No specific filter is designed yet to get a noise free BUS image that is contaminated by speckle noise. In this paper M2 filter, a novel hybrid of linear and nonlinear filter is proposed and compared to other spatial filters with 3×3 kernel size. The performance of the proposed M2 filter is measured by statistical quantity parameters like MSE, PSNR and SSI. The experimental analysis clearly shows that the proposed M2 filter outperforms better than other spatial filters by 2% high PSNR values with regards to speckle suppression.

  2. Purinergic signaling during macrophage differentiation results in M2 alternative activated macrophages.

    Barberà-Cremades, Maria; Baroja-Mazo, Alberto; Pelegrín, Pablo

    2016-02-01

    Macrophages represent a highly heterogenic cell population of the innate immune system, with important roles in the initiation and resolution of the inflammatory response. Purinergic signaling regulates both M1 and M2 macrophage function at different levels by controlling the secretion of cytokines, phagocytosis, and the production of reactive oxygen species. We found that extracellular nucleotides arrest macrophage differentiation from bone marrow precursors via adenosine and P2 receptors. This results in a mature macrophage with increased expression of M2, but not M1, genes. Similar to adenosine and ATP, macrophage growth arrested with LPS treatment resulted in an increase of the M2-related marker Ym1. Recombinant Ym1 was able to affect macrophage proliferation and could, potentially, be involved in the arrest of macrophage growth during hematopoiesis. © Society for Leukocyte Biology.

  3. M2IRAGE: Management of measurements during radiological interventions geographically assisted in the environment

    Gerphagnon, O.; Roche, H.; Lelache, H.; Guelin, M.; Fauquant, J.M.; Kacenelen, Y.; Armand, Y.

    2010-01-01

    This report presents the M 2 IRAGE software, a data processing tool designed to share radioactivity measurements and to give a schematised view of a radiological situation and of its evolution, while respecting different legal frameworks, notably the obligation to produce a radiological measurement programme. After a simplified recall of the crisis management organisation, the authors describe the M 2 IRAGE software and hardware architecture, the functions of its main modules (presentation of radioprotection information during field intervention, field mission management, data browsing, and data transmission to field teams). While giving some display examples, the authors describe how an event is managed and processed by this tool: event creation, measurement acquisition, aid to decision, team management. They report and discuss the results of a national exercise which took place in September 2009 in Saclay with a prototype version of M 2 IRAGE

  4. Critical illness induces alternative activation of M2 macrophages in adipose tissue.

    Langouche, Lies; Marques, Mirna B; Ingels, Catherine; Gunst, Jan; Derde, Sarah; Vander Perre, Sarah; D'Hoore, André; Van den Berghe, Greet

    2011-01-01

    We recently reported macrophage accumulation in adipose tissue of critically ill patients. Classically activated macrophage accumulation in adipose tissue is a known feature of obesity, where it is linked with increasing insulin resistance. However, the characteristics of adipose tissue macrophage accumulation in critical illness remain unknown. We studied macrophage markers with immunostaining and gene expression in visceral and subcutaneous adipose tissue from healthy control subjects (n = 20) and non-surviving prolonged critically ill patients (n = 61). For comparison, also subcutaneous in vivo adipose tissue biopsies were studied from 15 prolonged critically ill patients. Subcutaneous and visceral adipose tissue biopsies from non-surviving prolonged critically ill patients displayed a large increase in macrophage staining. This staining corresponded with elevated gene expression of "alternatively activated" M2 macrophage markers arginase-1, IL-10 and CD163 and low levels of the "classically activated" M1 macrophage markers tumor necrosis factor (TNF)-α and inducible nitric-oxide synthase (iNOS). Immunostaining for CD163 confirmed positive M2 macrophage staining in both visceral and subcutaneous adipose tissue biopsies from critically ill patients. Surprisingly, circulating levels and tissue gene expression of the alternative M2 activators IL-4 and IL-13 were low and not different from controls. In contrast, adipose tissue protein levels of peroxisome proliferator-activated receptor-γ (PPARγ), a nuclear receptor required for M2 differentiation and acting downstream of IL-4, was markedly elevated in illness. In subcutaneous abdominal adipose tissue biopsies from surviving critically ill patients, we could confirm positive macrophage staining with CD68 and CD163. We also could confirm elevated arginase-1 gene expression and elevated PPARγ protein levels. Unlike obesity, critical illness evokes adipose tissue accumulation of alternatively activated M2

  5. Screening of respiration deficiency mutants of yeasts (Saccharomyces cerevisiae) induced by ion irradiation and the mtDNA restriction analysis

    Mao Shuhong; Chinese Academy of Sciences, Beijing; Jin Genming; Wei Zengquan; Xie Hongmei; Ma Qiufeng; Gu Ying

    2005-01-01

    Screening of the respiration deficiency mutants of Saccharomyces cerevisiae induced by 5.19 MeV/u 22 Ne 5+ ion irradiation is reported in this paper. Some respiration deficiency mutants of white colony phenotype, in a condition of selective culture of TTC medium, were obtained. A new and simplified method based on mtDNA restriction analysis is described. The authors found that there are many obvious differences in mtDNAs between wild yeasts and the respiration deficiency mutants. The mechanism of obtaining the respiration deficiency mutants induced by heavy ion irradiation is briefly discussed. (authors)

  6. Control software architecture and operating modes of the Model M-2 maintenance system

    Satterlee, P.E. Jr.; Martin, H.L.; Herndon, J.N.

    1984-04-01

    The Model M-2 maintenance system is the first completely digitally controlled servomanipulator. The M-2 system allows dexterous operations to be performed remotely using bilateral force-reflecting master/slave techniques, and its integrated operator interface takes advantage of touch-screen-driven menus to allow selection of all possible operating modes. The control system hardware for this system has been described previously. This paper describes the architecture of the overall control system. The system's various modes of operation are identified, the software implementation of each is described, system diagnostic routines are described, and highlights of the computer-augmented operator interface are discussed. 3 references, 5 figures.

  7. Modelling the enigmatic Late Pliocene Glacial Event - Marine Isotope Stage M2

    Dolan, Aisling M.; Haywood, Alan M.; Hunter, Stephen J.; Tindall, Julia C.; Dowsett, Harry J.; Hill, Daniel J.; Pickering, Steven J.

    2015-01-01

    The Pliocene Epoch (5.2 to 2.58 Ma) has often been targeted to investigate the nature of warm climates. However, climate records for the Pliocene exhibit significant variability and show intervals that apparently experienced a cooler than modern climate. Marine Isotope Stage (MIS) M2 (~ 3.3 Ma) is a globally recognisable cooling event that disturbs an otherwise relatively (compared to present-day) warm background climate state. It remains unclear whether this event corresponds to significant ice sheet build-up in the Northern and Southern Hemisphere. Estimates of sea level for this interval vary, and range from modern values to estimates of 65 m sea level fall with respect to present day. Here we implement plausible M2 ice sheet configurations into a coupled atmosphere–ocean climate model to test the hypothesis that larger-than-modern ice sheet configurations may have existed at M2. Climate model results are compared with proxy climate data available for M2 to assess the plausibility of each ice sheet configuration. Whilst the outcomes of our data/model comparisons are not in all cases straight forward to interpret, there is little indication that results from model simulations in which significant ice masses have been prescribed in the Northern Hemisphere are incompatible with proxy data from the North Atlantic, Northeast Arctic Russia, North Africa and the Southern Ocean. Therefore, our model results do not preclude the possibility of the existence of larger ice masses during M2 in the Northern or Southern Hemisphere. Specifically they are not able to discount the possibility of significant ice masses in the Northern Hemisphere during the M2 event, consistent with a global sea-level fall of between 40 m and 60 m. This study highlights the general need for more focused and coordinated data generation in the future to improve the coverage and consistency in proxy records for M2, which will allow these and future M2 sensitivity tests to be interrogated

  8. Complete Suppression of the m=2/n=1 NTM Using ECCD on DIII-D

    Petty, C.C.; La Haye, R.J.; Luce, T.C.; Humphreys, D.A.; Lohr, J.; Prater, R.; Austin, M.E.; Harvey, R.W.; Wade, M.R.

    2003-01-01

    Complete suppression of the m=2/n=1 neoclassical tearing mode (NTM) is reported for the first time using electron cyclotron current drive (ECCD) to noninductively generate current at the radius of the island O-point. Experiments on the DIII-D tokamak show that the maximum shrinkage of the m=2/n=1 island amplitude occurs when the ECCD location coincides with the q=2 surface. Estimates of the ECCD radial profile width from the island shrinkage are consistent with ray tracing calculations but may allow for a factor-of-1.5 broadening from electron radial transport

  9. Control software architecture and operating modes of the Model M-2 maintenance system

    Satterlee, P.E. Jr.; Martin, H.L.; Herndon, J.N.

    1984-04-01

    The Model M-2 maintenance system is the first completely digitally controlled servomanipulator. The M-2 system allows dexterous operations to be performed remotely using bilateral force-reflecting master/slave techniques, and its integrated operator interface takes advantage of touch-screen-driven menus to allow selection of all possible operating modes. The control system hardware for this system has been described previously. This paper describes the architecture of the overall control system. The system's various modes of operation are identified, the software implementation of each is described, system diagnostic routines are described, and highlights of the computer-augmented operator interface are discussed. 3 references, 5 figures

  10. MMS exposure promotes increased MtDNA mutagenesis in the presence of replication-defective disease-associated DNA polymerase γ variants.

    Stumpf, Jeffrey D; Copeland, William C

    2014-10-01

    Mitochondrial DNA (mtDNA) encodes proteins essential for ATP production. Mutant variants of the mtDNA polymerase cause mutagenesis that contributes to aging, genetic diseases, and sensitivity to environmental agents. We interrogated mtDNA replication in Saccharomyces cerevisiae strains with disease-associated mutations affecting conserved regions of the mtDNA polymerase, Mip1, in the presence of the wild type Mip1. Mutant frequency arising from mtDNA base substitutions that confer erythromycin resistance and deletions between 21-nucleotide direct repeats was determined. Previously, increased mutagenesis was observed in strains encoding mutant variants that were insufficient to maintain mtDNA and that were not expected to reduce polymerase fidelity or exonuclease proofreading. Increased mutagenesis could be explained by mutant variants stalling the replication fork, thereby predisposing the template DNA to irreparable damage that is bypassed with poor fidelity. This hypothesis suggests that the exogenous base-alkylating agent, methyl methanesulfonate (MMS), would further increase mtDNA mutagenesis. Mitochondrial mutagenesis associated with MMS exposure was increased up to 30-fold in mip1 mutants containing disease-associated alterations that affect polymerase activity. Disrupting exonuclease activity of mutant variants was not associated with increased spontaneous mutagenesis compared with exonuclease-proficient alleles, suggesting that most or all of the mtDNA was replicated by wild type Mip1. A novel subset of C to G transversions was responsible for about half of the mutants arising after MMS exposure implicating error-prone bypass of methylated cytosines as the predominant mutational mechanism. Exposure to MMS does not disrupt exonuclease activity that suppresses deletions between 21-nucleotide direct repeats, suggesting the MMS-induce mutagenesis is not explained by inactivated exonuclease activity. Further, trace amounts of CdCl2 inhibit mtDNA replication but

  11. Protection of horses from West Nile virus Lineage 2 challenge following immunization with a whole, inactivated WNV lineage 1 vaccine.

    Bowen, Richard A; Bosco-Lauth, Angela; Syvrud, Kevin; Thomas, Anne; Meinert, Todd R; Ludlow, Deborah R; Cook, Corey; Salt, Jeremy; Ons, Ellen

    2014-09-22

    Over the last years West Nile virus (WNV) lineage 2 has spread from the African to the European continent. This study was conducted to demonstrate efficacy of an inactivated, lineage 1-based, WNV vaccine (Equip WNV) against intrathecal challenge of horses with a recent isolate of lineage 2 WNV. Twenty horses, sero-negative for WNV, were enrolled and were randomly allocated to one of two treatment groups: an unvaccinated control group (T01, n=10) and a group administered with Equip WNV (T02, n=10). Horses were vaccinated at Day 0 and 21 and were challenged at day 42 with WNV lineage 2, Nea Santa/Greece/2010. Personnel performing clinical observations were blinded to treatment allocation. Sixty percent of the controls had to be euthanized after challenge compared to none of the vaccinates. A significantly lower percentage of the vaccinated animals showed clinical disease (two different clinical observations present on the same day) on six different days of study and the percentage of days with clinical disease was significantly lower in the vaccinated group. A total of 80% of the non-vaccinated horses showed viremia while only one vaccinated animal was positive by virus isolation on a single occasion. Vaccinated animals started to develop antibodies against WNV lineage 2 from day 14 (2 weeks after the first vaccination) and at day 42 (the time of onset of immunity) they had all developed a strong antibody response. Histopathology scores for all unvaccinated animals ranged from mild to very severe in each of the tissues examined (cervical spinal cord, medulla and pons), whereas in vaccinated horses 8 of 10 animals had no lesions and 2 had minimal lesions in one tissue. In conclusion, Equip WNV significantly reduced the number of viremic horses, the duration and severity of clinical signs of disease and mortality following challenge with lineage 2 WNV. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. M2-F1 in flight over lakebed on tow line

    1963-01-01

    After initial ground-tow flights of the M2-F1 using the Pontiac as a tow vehicle, the way was clear to make air tows behind a C-47. The first air tow took place on 16 August 1963. Pilot Milt Thompson found that the M2-F1 flew well, with good control. This first flight lasted less than two minutes from tow-line release to touchdown. The descent rate was 4,000 feet per minute. The wingless, lifting body aircraft design was initially concieved as a means of landing an aircraft horizontally after atmospheric reentry. The absence of wings would make the extreme heat of re-entry less damaging to the vehicle. In 1962, Dryden management approved a program to build a lightweight, unpowered lifting body as a prototype to flight test the wingless concept. It would look like a 'flying bathtub,' and was designated the M2-F1, the 'M' referring to 'manned' and 'F' referring to 'flight' version. It featured a plywood shell placed over a tubular steel frame crafted at Dryden. Construction was completed in 1963. The first flight tests of the M2-F1 were over Rogers Dry Lake at the end of a tow rope attached to a hopped-up Pontiac convertible driven at speeds up to about 120 mph. This vehicle needed to be able to tow the M2-F1 on the Rogers Dry Lakebed adjacent to NASA's Flight Research Center (FRC) at a minimum speed of 100 miles per hour. To do that, it had to handle the 400-pound pull of the M2-F1. Walter 'Whitey' Whiteside, who was a retired Air Force maintenance officer working in the FRC's Flight Operations Division, was a dirt-bike rider and hot-rodder. Together with Boyden 'Bud' Bearce in the Procurement and Supply Branch of the FRC, Whitey acquired a Pontiac Catalina convertible with the largest engine available. He took the car to Bill Straup's renowned hot-rod shop near Long Beach for modification. With a special gearbox and racing slicks, the Pontiac could tow the 1,000-pound M2-F1 110 miles per hour in 30 seconds. It proved adequate for the roughly 400 car tows that got

  13. Investigation into adamantane-based M2 inhibitors with FB-QSAR.

    Wei, Hang; Wang, Cheng-Hua; Du, Qi-Shi; Meng, Jianzong; Chou, Kuo-Chen

    2009-07-01

    Because of their high resistance rate to the existing drugs, influenza A viruses have become a threat to human beings. It is known that the replication of influenza A viruses needs a pH-gated proton channel, the so-called M2 channel. Therefore, to develop effective drugs against influenza A, the most logic strategy is to inhibit the M2 channel. Recently, the atomic structure of the M2 channel was determined by NMR spectroscopy (Schnell, J.R. and Chou, J.J., Nature, 2008, 451, 591-595). The high-resolution NMR structure has provided a solid basis for structure-based drug design approaches. In this study, a benchmark dataset has been constructed that contains 34 newly-developed adamantane-based M2 inhibitors and covers considerable structural diversities and wide range of bioactivities. Based on these compounds, an in-depth analysis was performed with the newly developed fragment-based quantitative structure-activity relationship (FB-QSAR) algorithm. The results thus obtained provide useful insights for dealing with the drug-resistant problem and designing effective adamantane-based antiflu drugs.

  14. Functional motifs responsible for human metapneumovirus M2-2-mediated innate immune evasion.

    Chen, Yu; Deng, Xiaoling; Deng, Junfang; Zhou, Jiehua; Ren, Yuping; Liu, Shengxuan; Prusak, Deborah J; Wood, Thomas G; Bao, Xiaoyong

    2016-12-01

    Human metapneumovirus (hMPV) is a major cause of lower respiratory infection in young children. Repeated infections occur throughout life, but its immune evasion mechanisms are largely unknown. We recently found that hMPV M2-2 protein elicits immune evasion by targeting mitochondrial antiviral-signaling protein (MAVS), an antiviral signaling molecule. However, the molecular mechanisms underlying such inhibition are not known. Our mutagenesis studies revealed that PDZ-binding motifs, 29-DEMI-32 and 39-KEALSDGI-46, located in an immune inhibitory region of M2-2, are responsible for M2-2-mediated immune evasion. We also found both motifs prevent TRAF5 and TRAF6, the MAVS downstream adaptors, to be recruited to MAVS, while the motif 39-KEALSDGI-46 also blocks TRAF3 migrating to MAVS. In parallel, these TRAFs are important in activating transcription factors NF-kB and/or IRF-3 by hMPV. Our findings collectively demonstrate that M2-2 uses its PDZ motifs to launch the hMPV immune evasion through blocking the interaction of MAVS and its downstream TRAFs. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Massive M2M Access with Reliability Guarantees in LTE Systems

    Madueño, Germán Corrales; Kiilerich Pratas, Nuno; Stefanovic, Cedomir

    2015-01-01

    Machine-to-Machine (M2M) communications are one of the major drivers of the cellular network evolution towards 5G systems. One of the key challenges is on how to provide reliability guarantees to each accessing device in a situation in which there is a massive number of almost-simultaneous arriva...

  16. Initial search for triggered gamma emission from Hf-178(m2) using the YSU miniball array

    Carroll, J. J.; Burnett, J.; Drummond, T.; Lepak, J.; Propri, R.; Smith, D.; Karamian, S. A.; Adam, Jindřich; Stedile, F.; Agee, FJ.

    2002-01-01

    Roč. 143, 1, 2, 3, 4 (2002), s. 37-54 ISSN 0304-3843 Institutional research plan: CEZ:AV0Z1048901 Keywords : triggered gamma emission * Hf-178(m2) * nuclear batteries Subject RIV: BG - Nuclear, Atomic and Molecular Physics, Colliders Impact factor: 0.533, year: 2002

  17. Almost optimal distributed M2M multicasting in wireless mesh networks

    Xin, Qin; Manne, Fredrik; Zhang, Yan

    2012-01-01

    Wireless Mesh Networking (WMN) is an emerging communication paradigm to enable resilient, cost-efficient and reliable services for the future-generation wireless networks. In this paper, we study the problem of multipoint-to- multipoint (M2M) multicasting in a WMN which aims to use the minimum nu...

  18. Neuropeptide FF increases M2 activation and self-renewal of adipose tissue macrophages

    Waqas, Syed F. Hassnain; Hoang, Anh Cuong; Ampem, Grace; Azegrouz, Hind; Balogh, Lajos; Thuróczy, Julianna; Gerling, Ivan C.; Nam, Sorim; Lim, Jong-Seok; Martinez-Ibañez, Juncal; Real, José T.; Paschke, Stephan; Quillet, Raphaëlle; Ayachi, Safia; Simonin, Frédéric; Schneider, E. Marion; Brinkman, Jacqueline A.; Seroogy, Christine M.

    2017-01-01

    The quantity and activation state of adipose tissue macrophages (ATMs) impact the development of obesity-induced metabolic diseases. Appetite-controlling hormones play key roles in obesity; however, our understanding of their effects on ATMs is limited. Here, we have shown that human and mouse ATMs express NPFFR2, a receptor for the appetite-reducing neuropeptide FF (NPFF), and that NPFFR2 expression is upregulated by IL-4, an M2-polarizing cytokine. Plasma levels of NPFF decreased in obese patients and high-fat diet–fed mice and increased following caloric restriction. NPFF promoted M2 activation and increased the proliferation of murine and human ATMs. Both M2 activation and increased ATM proliferation were abolished in NPFFR2-deficient ATMs. Mechanistically, the effects of NPFF involved the suppression of E3 ubiquitin ligase RNF128 expression, resulting in enhanced stability of phosphorylated STAT6 and increased transcription of the M2 macrophage–associated genes IL-4 receptor α (Il4ra), arginase 1 (Arg1), IL-10 (Il10), and alkylglycerol monooxygenase (Agmo). NPFF induced ATM proliferation concomitantly with the increase in N-Myc downstream-regulated gene 2 (Ndrg2) expression and suppressed the transcription of Ifi200 cell-cycle inhibitor family members and MAF bZIP transcription factor B (Mafb), a negative regulator of macrophage proliferation. NPFF thus plays an important role in supporting healthy adipose tissue via the maintenance of metabolically beneficial ATMs. PMID:28581443

  19. Formation of the high-spin Hf-179m2 isomer in reactor irradiations

    Karamian, S. A.; Carroll, J. J.; Adam, Jindřich; Kulagin, EN.; Shabalin, EP.

    2004-01-01

    Roč. 14, č. 4 (2004), s. 438-441 ISSN 1054-660X R&D Projects: GA MŠk(CZ) ME 134 Keywords : reactor irradiation * high-spin Hf-179m2 Subject RIV: BG - Nuclear, Atomic and Molecular Physics, Colliders Impact factor: 0.836, year: 2004

  20. Comparison of Plasma Tu-M2-PK and CA19-9 in Pancreatic Cancer

    Joergensen, Maiken Thyregod; Heegaard, Niels H H; Schaffalitzky de Muckadell, Ove B

    2009-01-01

    because of suspicion of pancreatic cancer. Of these, 51 patients had their conditions diagnosed as PDAC, whereas this diagnosis was ruled out in 52 after 12 months of follow-up. The performance of Tu-M2-PK was compared with that of CA19-9 using cutoff values 15 and 37 U/mL, respectively. RESULTS...

  1. M2-F1 mounted in NASA Ames Research Center 40x80 foot wind tunnel

    1962-01-01

    After the first attempted ground-tow tests of the M2-F1 in March 1963, the vehicle was taken to the Ames Research Center, Mountain View, CA, for wind-tunnel testing. During these tests, Milt Thompson and others were in the M2-F1 to position the control surfaces for each test. The wingless, lifting body aircraft design was initially conceived as a means of landing an aircraft horizontally after atmospheric reentry. The absence of wings would make the extreme heat of re-entry less damaging to the vehicle. In 1962, Dryden management approved a program to build a lightweight, unpowered lifting body as a prototype to flight test the wingless concept. It would look like a 'flying bathtub,' and was designated the M2-F1, the 'M' referring to 'manned' and 'F' referring to 'flight' version. It featured a plywood shell placed over a tubular steel frame crafted at Dryden. Construction was completed in 1963. The first flight tests of the M2-F1 were over Rogers Dry Lake at the end of a tow rope attached to a hopped-up Pontiac convertible driven at speeds up to about 120 mph. This vehicle needed to be able to tow the M2-F1 on the Rogers Dry Lakebed adjacent to NASA's Flight Research Center (FRC) at a minimum speed of 100 miles per hour. To do that, it had to handle the 400-pound pull of the M2-F1. Walter 'Whitey' Whiteside, who was a retired Air Force maintenance officer working in the FRC's Flight Operations Division, was a dirt-bike rider and hot-rodder. Together with Boyden 'Bud' Bearce in the Procurement and Supply Branch of the FRC, Whitey acquired a Pontiac Catalina convertible with the largest engine available. He took the car to Bill Straup's renowned hot-rod shop near Long Beach for modification. With a special gearbox and racing slicks, the Pontiac could tow the 1,000-pound M2-F1 110 miles per hour in 30 seconds. It proved adequate for the roughly 400 car tows that got the M2-F1 airborne to prove it could fly safely and to train pilots before they were towed behind a C

  2. A Survey on M2M Systems for mHealth: A Wireless Communications Perspective

    Elli Kartsakli

    2014-09-01

    Full Text Available In the new era of connectivity, marked by the explosive number of wireless electronic devices and the need for smart and pervasive applications, Machine-to-Machine (M2M communications are an emerging technology that enables the seamless device interconnection without the need of human interaction. The use of M2M technology can bring to life a wide range of mHealth applications, with considerable benefits for both patients and healthcare providers. Many technological challenges have to be met, however, to ensure the widespread adoption of mHealth solutions in the future. In this context, we aim to provide a comprehensive survey on M2M systems for mHealth applications from a wireless communication perspective. An end-to-end holistic approach is adopted, focusing on different communication aspects of the M2M architecture. Hence, we first provide a systematic review ofWireless Body Area Networks (WBANs, which constitute the enabling technology at the patient’s side, and then discuss end-to-end solutions that involve the design and implementation of practical mHealth applications. We close the survey by identifying challenges and open research issues, thus paving the way for future research opportunities.

  3. Growth and properties of M2-xCexCuO4+d single crystals

    Matacotta, F.C.; Morales de La Garza, L.; Nevriva, M.; Nardin, G.; Randaccio, L.; Zangrando, E.

    1989-10-01

    The M 2-x Ce x CuO 4+d crystals where M is a rare earth ion (like Nd, Pr etc.) were prepared by a modified flux method, their structure has been investigated by scanning electron microscopy and energy dispersive X-ray analysis and the electrical resistivity was measured on a number of crystals. 5 refs, 3 figs, 3 tabs

  4. Efficient LTE Access with Collision Resolution for Massive M2M Communications

    Madueño, Germán Corrales; Stefanovic, Cedomir; Popovski, Petar

    2014-01-01

    outage. In this work we propose a LTE RACH scheme tailored for delay-sensitive M2M services with synchronous traffic arrivals. The key idea is, upon detection of a RACH overload, to apply a collision resolution algorithm based on splitting trees. The solution is implemented on top of the existing LTE...

  5. Macrophages during the fibrotic process: M2 as friend and foe.

    Tarcio Teodoro Braga

    2015-11-01

    Full Text Available Macrophages play essential activities in homeostasis maintenance, tissue regeneration and wound healing. However, when the physiological process of wound healing is deregulated by persistent insults and chronic diseases, macrophages can participate actively in the development of fibrosis. In this regard, the exacerbation or resolution of fibrosis depends on the type of macrophages polarized and the severity and duration of the inflammatory insult. M1 macrophages use glycolytic metabolism to optimize oxygen consumption and activate myofibroblasts and fibrocytes. On the other hand, M2 macrophages, which use oxidative metabolism, have anti-inflammatory properties due to their capacity to produce and secrete IL-10, TGFβ and arginase that promotes tissue repair. However, when the primary insult is not controlled and there is a persistent M2 macrophage activity, these cells promote ECM deposition through the continuous production of TGFβ and growth factors. In this scenario, M2 macrophages act as a break point between normal wound healing and the pro-fibrotic process. Here, we review the aspects of tissue repair based on macrophage biology and we evidence scar formation is directly related to the degree of inflammation, but also with the appearance of M2 macrophages.

  6. Multiple promoters drive tissue-specific expression of the human M2 muscarinic acetylcholine receptor gene

    Krejčí, Alena; Bruce, A. W.; Doležal, Vladimír; Tuček, Stanislav; Buckley, N. J.

    2004-01-01

    Roč. 91, č. 1 (2004), s. 88-98 ISSN 0022-3042 R&D Projects: GA AV ČR IAA5011306 Institutional research plan: CEZ:AV0Z5011922 Keywords : M2 muscarinic receptor * neuron-restrictive silence factor * promoter Subject RIV: ED - Physiology Impact factor: 4.824, year: 2004

  7. Kinetics of proton transport into influenza virions by the viral M2 channel.

    Tijana Ivanovic

    Full Text Available M2 protein of influenza A viruses is a tetrameric transmembrane proton channel, which has essential functions both early and late in the virus infectious cycle. Previous studies of proton transport by M2 have been limited to measurements outside the context of the virus particle. We have developed an in vitro fluorescence-based assay to monitor internal acidification of individual virions triggered to undergo membrane fusion. We show that rimantadine, an inhibitor of M2 proton conductance, blocks the acidification-dependent dissipation of fluorescence from a pH-sensitive virus-content probe. Fusion-pore formation usually follows internal acidification but does not require it. The rate of internal virion acidification increases with external proton concentration and saturates with a pK(m of ∼4.7. The rate of proton transport through a single, fully protonated M2 channel is approximately 100 to 400 protons per second. The saturating proton-concentration dependence and the low rate of internal virion acidification derived from authentic virions support a transporter model for the mechanism of proton transfer.

  8. Thermoelectric Performance of the MXenes M2CO2 (M = Ti, Zr, or Hf)

    Gandi, Appala; Alshareef, Husam N.; Schwingenschlö gl, Udo

    2016-01-01

    MXenes, M2CO2, where M = Ti, Zr, or Hf, in order to evaluate the effect of the metal M on the thermoelectric performance. The lattice contribution to the thermal conductivity, obtained from the phonon life times, is found to be lowest in Ti2CO2

  9. Exploiting the Capture Effect to Enhance RACH Performance in Cellular-Based M2M Communications

    Jonghun Kim

    2017-09-01

    Full Text Available Cellular-based machine-to-machine (M2M communication is expected to facilitate services for the Internet of Things (IoT. However, because cellular networks are designed for human users, they have some limitations. Random access channel (RACH congestion caused by massive access from M2M devices is one of the biggest factors hindering cellular-based M2M services because the RACH congestion causes random access (RA throughput degradation and connection failures to the devices. In this paper, we show the possibility exploiting the capture effects, which have been known to have a positive impact on the wireless network system, on RA procedure for improving the RA performance of M2M devices. For this purpose, we analyze an RA procedure using a capture model. Through this analysis, we examine the effects of capture on RA performance and propose an Msg3 power-ramping (Msg3 PR scheme to increase the capture probability (thereby increasing the RA success probability even when severe RACH congestion problem occurs. The proposed analysis models are validated using simulations. The results show that the proposed scheme, with proper parameters, further improves the RA throughput and reduces the connection failure probability, by slightly increasing the energy consumption. Finally, we demonstrate the effects of coexistence with other RA-related schemes through simulation results.

  10. Pax7 lineage contributions to the mammalian neural crest.

    Barbara Murdoch

    Full Text Available Neural crest cells are vertebrate-specific multipotent cells that contribute to a variety of tissues including the peripheral nervous system, melanocytes, and craniofacial bones and cartilage. Abnormal development of the neural crest is associated with several human maladies including cleft/lip palate, aggressive cancers such as melanoma and neuroblastoma, and rare syndromes, like Waardenburg syndrome, a complex disorder involving hearing loss and pigment defects. We previously identified the transcription factor Pax7 as an early marker, and required component for neural crest development in chick embryos. In mammals, Pax7 is also thought to play a role in neural crest development, yet the precise contribution of Pax7 progenitors to the neural crest lineage has not been determined.Here we use Cre/loxP technology in double transgenic mice to fate map the Pax7 lineage in neural crest derivates. We find that Pax7 descendants contribute to multiple tissues including the cranial, cardiac and trunk neural crest, which in the cranial cartilage form a distinct regional pattern. The Pax7 lineage, like the Pax3 lineage, is additionally detected in some non-neural crest tissues, including a subset of the epithelial cells in specific organs.These results demonstrate a previously unappreciated widespread distribution of Pax7 descendants within and beyond the neural crest. They shed light regarding the regionally distinct phenotypes observed in Pax3 and Pax7 mutants, and provide a unique perspective into the potential roles of Pax7 during disease and development.

  11. Lineage fate of ductular reactions in liver injury and carcinogenesis.

    Jörs, Simone; Jeliazkova, Petia; Ringelhan, Marc; Thalhammer, Julian; Dürl, Stephanie; Ferrer, Jorge; Sander, Maike; Heikenwalder, Mathias; Schmid, Roland M; Siveke, Jens T; Geisler, Fabian

    2015-06-01

    Ductular reactions (DRs) are observed in virtually all forms of human liver disease; however, the histogenesis and function of DRs in liver injury are not entirely understood. It is widely believed that DRs contain bipotential liver progenitor cells (LPCs) that serve as an emergency cell pool to regenerate both cholangiocytes and hepatocytes and may eventually give rise to hepatocellular carcinoma (HCC). Here, we used a murine model that allows highly efficient and specific lineage labeling of the biliary compartment to analyze the histogenesis of DRs and their potential contribution to liver regeneration and carcinogenesis. In multiple experimental and genetic liver injury models, biliary cells were the predominant precursors of DRs but lacked substantial capacity to produce new hepatocytes, even when liver injuries were prolonged up to 12 months. Genetic modulation of NOTCH and/or WNT/β-catenin signaling within lineage-tagged DRs impaired DR expansion but failed to redirect DRs from biliary differentiation toward the hepatocyte lineage. Further, lineage-labeled DRs did not produce tumors in genetic and chemical HCC mouse models. In summary, we found no evidence in our system to support mouse biliary-derived DRs as an LPC pool to replenish hepatocytes in a quantitatively relevant way in injury or evidence that DRs give rise to HCCs.

  12. Putative Lineage of Novel African Usutu Virus, Central Europe

    2015-10-15

    Sarah Gregory reads an abridged version of "Putative Lineage of Novel African Usutu Virus, Central Europe.".  Created: 10/15/2015 by National Center for Emerging and Zoonotic Infectious Diseases (NCEZID).   Date Released: 10/15/2015.

  13. Cell fate determination in the Caenorhabditis elegans epidermal lineages

    Soete, G.A.J.

    2007-01-01

    The starting point for this work was to use the hypodermal seam of C. elegans as a model system to study cell fate determination. Even though the seam is a relatively simple developmental system, the mechanisms that control cell fate determination in the seam lineages are connected in a highly

  14. Even Cancers Want Commitment: Lineage Identity and Medulloblastoma Formation

    Eberhart, Charles G.

    2015-01-01

    In this issue of Cancer Cell, Yang et al. (2008) and Schüller et al. (2008) show that Hedgehog activation in either multipotent neural stem cells or developmentally restricted progenitors causes only medulloblastomas to form. These data suggest that some stem cell-derived tumors must commit to a specific lineage in order to grow. PMID:18691544

  15. Neisseria gonorrhoeae Modulates Immunity by Polarizing Human Macrophages to a M2 Profile.

    María Carolina Ortiz

    Full Text Available Current data suggest that Neisseria gonorrhoeae is able to suppress the protective immune response at different levels, such as B and T lymphocytes and antigen-presenting cells. The present report is focused on gonococcus evasion mechanism on macrophages (MФ and its impact in the subsequent immune response. In response to various signals MФ may undergo classical-M1 (M1-MФ or alternative-M2 (M2-MФ activation. Until now there are no reports of the gonococcus effects on human MФ polarization. We assessed the phagocytic ability of monocyte-derived MФ (MDM upon gonococcal infection by immunofluorescence and gentamicin protection experiments. Then, we evaluated cytokine profile and M1/M2 specific-surface markers on MФ challenged with N. gonorrhoeae and their proliferative effect on T cells. Our findings lead us to suggest N. gonorrhoeae stimulates a M2-MФ phenotype in which some of the M2b and none of the M1-MФ-associated markers are induced. Interestingly, N. gonorrhoeae exposure leads to upregulation of a Programmed Death Ligand 1 (PD-L1, widely known as an immunosuppressive molecule. Moreover, functional results showed that N. gonorrhoeae-treated MФ are unable to induce proliferation of human T-cells, suggesting a more likely regulatory phenotype. Taken together, our data show that N. gonorroheae interferes with MФ polarization. This study has important implications for understanding the mechanisms of clearance versus long-term persistence of N. gonorroheae infection and might be applicable for the development of new therapeutic strategies.

  16. Construction of Δm2--sin2 2θ plots

    Snyder, R.

    1991-01-01

    In the two-flavor approximation, the probability for a neutrino to oscillate from one flavor to the other is given by Ρ νa → νb = sin 2 2θ sin 2 (1.27 Δm 2 L/E ν ) where θ is the mixing angle, Δm 2 = |m νa 2 - m νb 2 | is measured in (eV/c 2 ) 2 , L, the distance from the source, is measured in km, and E, the beam energy, is measured in GeV. If either Δm 2 or sin 2 2Θ is zero, there is no oscillation. They might also have small, non-zero values, causing the oscillations to be so small as to be unobservable in a particular experiment. They may also have values which allow us to determine the probability of oscillation, but so far no compelling evidence for oscillation exists. The universal method of portraying what region of parameter space is explored by a neutrino oscillation experiment is to mark off an area on a Δm 2 vs. sin 2 2θ plot. Typically, a line is graphed, with the claim that if the experiment finds not evidence of oscillation, one can, for example, be 90% certain that Δm 2 and sin 2 2θ lie within the region below and to the left of the line. Since these plots are so widely used, it is useful to understand the process by which they are created

  17. M2-F1 in flight during low-speed car tow

    1963-01-01

    The M2-F1 shown in flight during a low-speed car tow runs across the lakebed. Such tests allowed about two minutes to test the vehicle's handling in flight. NASA Flight Research Center (later redesignated the Dryden Flight Research Center) personnel conducted as many as 8 to 14 ground-tow flights in a single day either to test the vehicle in preparation for air tows or to train pilots to fly the vehicle before they undertook air tows. The wingless, lifting body aircraft design was initially concieved as a means of landing an aircraft horizontally after atmospheric reentry. The absence of wings would make the extreme heat of re-entry less damaging to the vehicle. In 1962, Dryden management approved a program to build a lightweight, unpowered lifting body as a prototype to flight test the wingless concept. It would look like a 'flying bathtub,' and was designated the M2-F1, the 'M' referring to 'manned' and 'F' referring to 'flight' version. It featured a plywood shell placed over a tubular steel frame crafted at Dryden. Construction was completed in 1963. The first flight tests of the M2-F1 were over Rogers Dry Lake at the end of a tow rope attached to a hopped-up Pontiac convertible driven at speeds up to about 120 mph. This vehicle needed to be able to tow the M2-F1 on the Rogers Dry Lakebed adjacent to NASA's Flight Research Center (FRC) at a minimum speed of 100 miles per hour. To do that, it had to handle the 400-pound pull of the M2-F1. Walter 'Whitey' Whiteside, who was a retired Air Force maintenance officer working in the FRC's Flight Operations Division, was a dirt-bike rider and hot-rodder. Together with Boyden 'Bud' Bearce in the Procurement and Supply Branch of the FRC, Whitey acquired a Pontiac Catalina convertible with the largest engine available. He took the car to Bill Straup's renowned hot-rod shop near Long Beach for modification. With a special gearbox and racing slicks, the Pontiac could tow the 1,000-pound M2-F1 110 miles per hour in 30

  18. A 28,000 Years Old Cro-Magnon mtDNA Sequence Differs from All Potentially Contaminating Modern Sequences

    Caramelli, David; Milani, Lucio; Vai, Stefania; Modi, Alessandra; Pecchioli, Elena; Girardi, Matteo; Pilli, Elena; Lari, Martina; Lippi, Barbara; Ronchitelli, Annamaria; Mallegni, Francesco; Casoli, Antonella; Bertorelle, Giorgio; Barbujani, Guido

    2008-01-01

    Background DNA sequences from ancient speciments may in fact result from undetected contamination of the ancient specimens by modern DNA, and the problem is particularly challenging in studies of human fossils. Doubts on the authenticity of the available sequences have so far hampered genetic comparisons between anatomically archaic (Neandertal) and early modern (Cro-Magnoid) Europeans. Methodology/Principal Findings We typed the mitochondrial DNA (mtDNA) hypervariable region I in a 28,000 years old Cro-Magnoid individual from the Paglicci cave, in Italy (Paglicci 23) and in all the people who had contact with the sample since its discovery in 2003. The Paglicci 23 sequence, determined through the analysis of 152 clones, is the Cambridge reference sequence, and cannot possibly reflect contamination because it differs from all potentially contaminating modern sequences. Conclusions/Significance: The Paglicci 23 individual carried a mtDNA sequence that is still common in Europe, and which radically differs from those of the almost contemporary Neandertals, demonstrating a genealogical continuity across 28,000 years, from Cro-Magnoid to modern Europeans. Because all potential sources of modern DNA contamination are known, the Paglicci 23 sample will offer a unique opportunity to get insight for the first time into the nuclear genes of early modern Europeans. PMID:18628960

  19. Targeted Transgenic Overexpression of Mitochondrial Thymidine Kinase (TK2) Alters Mitochondrial DNA (mtDNA) and Mitochondrial Polypeptide Abundance

    Hosseini, Seyed H.; Kohler, James J.; Haase, Chad P.; Tioleco, Nina; Stuart, Tami; Keebaugh, Erin; Ludaway, Tomika; Russ, Rodney; Green, Elgin; Long, Robert; Wang, Liya; Eriksson, Staffan; Lewis, William

    2007-01-01

    Mitochondrial toxicity limits nucleoside reverse transcriptase inhibitors (NRTIs) for acquired immune deficiency syndrome. NRTI triphosphates, the active moieties, inhibit human immunodeficiency virus reverse transcriptase and eukaryotic mitochondrial DNA polymerase pol-γ. NRTI phosphorylation seems to correlate with mitochondrial toxicity, but experimental evidence is lacking. Transgenic mice (TGs) with cardiac overexpression of thymidine kinase isoforms (mitochondrial TK2 and cytoplasmic TK1) were used to study NRTI mitochondrial toxicity. Echocardiography and nuclear magnetic resonance imaging defined cardiac performance and structure. TK gene copy and enzyme activity, mitochondrial (mt) DNA and polypeptide abundance, succinate dehydrogenase and cytochrome oxidase histochemistry, and electron microscopy correlated with transgenesis, mitochondrial structure, and biogenesis. Antiretroviral combinations simulated therapy. Untreated hTK1 or TK2 TGs exhibited normal left ventricle mass. In TK2 TGs, cardiac TK2 gene copy doubled, activity increased 300-fold, and mtDNA abundance doubled. Abundance of the 17-kd subunit of complex I, succinate dehydrogenase histochemical activity, and cristae density increased. NRTIs increased left ventricle mass 20% in TK2 TGs. TK activity increased 3 logs in hTK1 TGs, but no cardiac phenotype resulted. NRTIs abrogated functional effects of transgenically increased TK2 activity but had no effect on TK2 mtDNA abundance. Thus, NRTI mitochondrial phosphorylation by TK2 is integral to clinical NRTI mitochondrial toxicity. PMID:17322372

  20. Tracing the phylogeography of human populations in Britain based on 4th-11th century mtDNA genotypes.

    Töpf, A L; Gilbert, M T P; Dumbacher, J P; Hoelzel, A R

    2006-01-01

    Some of the transitional periods of Britain during the first millennium A.D. are traditionally associated with the movement of people from continental Europe, composed largely of invading armies (e.g., the Roman, Saxon, and Viking invasions). However, the extent to which these were migrations (as opposed to cultural exchange) remains controversial. We investigated the history of migration by women by amplifying mitochondrial DNA (mtDNA) from ancient Britons who lived between approximately A.D. 300-1,000 and compared these with 3,549 modern mtDNA database genotypes from England, Europe, and the Middle East. The objective was to assess the dynamics of the historical population composition by comparing genotypes in a temporal context. Towards this objective we test and calibrate the use of rho statistics to identify relationships between founder and source populations. We find evidence for shared ancestry between the earliest sites (predating Viking invasions) with modern populations across the north of Europe from Norway to Estonia, possibly reflecting common ancestors dating back to the last glacial epoch. This is in contrast with a late Saxon site in Norwich, where the genetic signature is consistent with more recent immigrations from the south, possibly as part of the Saxon invasions.

  1. Feather barbs as a good source of mtDNA for bird species identification in forensic wildlife investigations.

    Speller, Camilla F; Nicholas, George P; Yang, Dongya Y

    2011-07-28

    The ability to accurately identify bird species is crucial for wildlife law enforcement and bird-strike investigations. However, such identifications may be challenging when only partial or damaged feathers are available for analysis. By applying vigorous contamination controls and sensitive PCR amplification protocols, we found that it was feasible to obtain accurate mitochondrial (mt)DNA-based species identification with as few as two feather barbs. This minimally destructive DNA approach was successfully used and tested on a variety of bird species, including North American wild turkey (Meleagris gallopavo), Canada goose (Branta canadensis), blue heron (Ardea herodias) and pygmy owl (Glaucidium californicum). The mtDNA was successfully obtained from 'fresh' feathers, historic museum specimens and archaeological samples, demonstrating the sensitivity and versatility of this technique. By applying appropriate contamination controls, sufficient quantities of mtDNA can be reliably recovered and analyzed from feather barbs. This previously overlooked substrate provides new opportunities for accurate DNA species identification when minimal feather samples are available for forensic analysis.

  2. Eurasian otters, Lutra lutra, have a dominant mtDNA haplotype from the Iberian Peninsula to Scandinavia.

    Ferrando, Ainhoa; Ponsà, Montserrat; Marmi, Josep; Domingo-Roura, Xavier

    2004-01-01

    The Eurasian otter, Lutra lutra, has a Palaearctic distribution and has suffered a severe decline throughout Europe during the last century. Previous studies in this and other mustelids have shown reduced levels of variability in mitochondrial DNA, although otter phylogeographic studies were restricted to central-western Europe. In this work we have sequenced 361 bp of the mtDNA control region in 73 individuals from eight countries and added our results to eight sequences available from GenBank and the literature. The range of distribution has been expanded in relation to previous works north towards Scandinavia, east to Russia and Belarus, and south to the Iberian Peninsula. We found a single dominant haplotype in 91.78% of the samples, and six more haplotypes deviating a maximum of two mutations from the dominant haplotype restricted to a single country. Variability was extremely low in western Europe but higher in eastern countries. This, together with the lack of phylogeographical structuring, supports the postglacial recolonization of Europe from a single refugium. The Eurasian otter mtDNA control region has a 220-bp variable minisatellite in Domain III that we sequenced in 29 otters. We found a total of 19 minisatellite haplotypes, but they showed no phylogenetic information.

  3. A 28,000 years old Cro-Magnon mtDNA sequence differs from all potentially contaminating modern sequences.

    David Caramelli

    Full Text Available BACKGROUND: DNA sequences from ancient specimens may in fact result from undetected contamination of the ancient specimens by modern DNA, and the problem is particularly challenging in studies of human fossils. Doubts on the authenticity of the available sequences have so far hampered genetic comparisons between anatomically archaic (Neandertal and early modern (Cro-Magnoid Europeans. METHODOLOGY/PRINCIPAL FINDINGS: We typed the mitochondrial DNA (mtDNA hypervariable region I in a 28,000 years old Cro-Magnoid individual from the Paglicci cave, in Italy (Paglicci 23 and in all the people who had contact with the sample since its discovery in 2003. The Paglicci 23 sequence, determined through the analysis of 152 clones, is the Cambridge reference sequence, and cannot possibly reflect contamination because it differs from all potentially contaminating modern sequences. CONCLUSIONS/SIGNIFICANCE: The Paglicci 23 individual carried a mtDNA sequence that is still common in Europe, and which radically differs from those of the almost contemporary Neandertals, demonstrating a genealogical continuity across 28,000 years, from Cro-Magnoid to modern Europeans. Because all potential sources of modern DNA contamination are known, the Paglicci 23 sample will offer a unique opportunity to get insight for the first time into the nuclear genes of early modern Europeans.

  4. Mutation of mtDNA ND1 Gene in 20 Type 2 Diabetes Mellitus Patients of Gorontalonese and Javanese Ethnicity

    AMIEN RAMADHAN ISHAK

    2014-12-01

    Full Text Available Mitochondrial gene mutation plays a role in the development of type two diabetes mellitus (T2DM. A point mutation in the mitochondrial gene Nicotinamide adenine dinucleotide dehydrogenase 1 (mtDNA ND1 gene mainly reported as the most common mutation related to T2DM. However, several studies have identified another SNP (single-nucleotide polymorphisms in the RNA region of mtDNA from patients from specific ethnic populations in Indonesia. Building on those findings, this study aimed to use PCR and DNA sequencing technology to identify nucleotides in RNA and ND1 fragment from 20 Gorontalonese and 20 Javanese T2DM patients, that may trigger T2DM expression. The results showed successful amplification of RNA along 294 bp for all samples. From these samples, we found two types of point mutation in Javanese patients in the G3316A and T3200C points of the rRNA and ND1 gene. In samples taken from Gorontalonese patients, no mutation were found in the RNA or ND1 region. We conclude that T2DM was triggered differently in our two populations. While genetic mutation is implicated for the 20 Javanese patients, T2DM pathogenesis in the Gorontalonese patients must be traced to other genetic, environmental, or behavioral factors.

  5. Mitochondrial DNA (mtDNA haplogroups and serum levels of anti-oxidant enzymes in patients with osteoarthritis

    Fernandez-Moreno Mercedes

    2011-11-01

    Full Text Available Abstract Background Oxidative stress play a main role in the initiation and progression of the OA disease and leads to the degeneration of mitochondria. To prevent this, the chondrocytes possess a well-coordinated enzymatic antioxidant system. Besides, the mitochondrial DNA (mtDNA haplogroups are associated with the OA disease. Thus, the main goal of this work is to assess the incidence of the mtDNA haplogroups on serum levels of two of the main antioxidant enzymes, Manganese Superoxide Dismutase (Mn-SOD or SOD2 and catalase, and to test the suitability of these two proteins for potential OA-related biomarkers. Methods We analyzed the serum levels of SOD2 and catalase in 73 OA patients and 77 healthy controls carrying the haplogroups J, U and H, by ELISA assay. Knee and hip radiographs were classified according to Kellgren and Lawrence (K/L scoring from Grade 0 to Grade IV. Appropriate statistical analyses were performed to test the effects of clinical variables, including gender, body mass index (BMI, age, smoking status, diagnosis, haplogroups and radiologic K/L grade on serum levels of these enzymes. Results Serum levels of SOD2 appeared statistically increased in OA patients when compared with healthy controls (p Conclusions The increased levels of SOD2 in OA patients indicate an increased oxidative stress OA-related, therefore this antioxidant enzyme could be a suitable candidate biomarker for diagnosis of OA. Mitochondrial haplogroups significantly correlates with serum levels of catalase

  6. Mitochondrial DNA (mtDNA) variants in the European haplogroups HV, JT, and U do not have a major role in schizophrenia.

    Torrell, Helena; Salas, Antonio; Abasolo, Nerea; Morén, Constanza; Garrabou, Glòria; Valero, Joaquín; Alonso, Yolanda; Vilella, Elisabet; Costas, Javier; Martorell, Lourdes

    2014-10-01

    It has been reported that certain genetic factors involved in schizophrenia could be located in the mitochondrial DNA (mtDNA). Therefore, we hypothesized that mtDNA mutations and/or variants would be present in schizophrenia patients and may be related to schizophrenia characteristics and mitochondrial function. This study was performed in three steps: (1) identification of pathogenic mutations and variants in 14 schizophrenia patients with an apparent maternal inheritance of the disease by sequencing the entire mtDNA; (2) case-control association study of 23 variants identified in step 1 (16 missense, 3 rRNA, and 4 tRNA variants) in 495 patients and 615 controls, and (3) analyses of the associated variants according to the clinical, psychopathological, and neuropsychological characteristics and according to the oxidative and enzymatic activities of the mitochondrial respiratory chain. We did not identify pathogenic mtDNA mutations in the 14 sequenced patients. Two known variants were nominally associated with schizophrenia and were further studied. The MT-RNR2 1811A > G variant likely does not play a major role in schizophrenia, as it was not associated with clinical, psychopathological, or neuropsychological variables, and the MT-ATP6 9110T > C p.Ile195Thr variant did not result in differences in the oxidative and enzymatic functions of the mitochondrial respiratory chain. The patients with apparent maternal inheritance of schizophrenia did not exhibit any mutations in their mtDNA. The variants nominally associated with schizophrenia in the present study were not related either to phenotypic characteristics or to mitochondrial function. We did not find evidence pointing to a role for mtDNA sequence variation in schizophrenia. © 2014 Wiley Periodicals, Inc.

  7. Macrophage polarisation: an immunohistochemical approach for identifying M1 and M2 macrophages.

    Mário Henrique M Barros

    Full Text Available Macrophage polarization is increasingly recognised as an important pathogenetic factor in inflammatory and neoplastic diseases. Proinflammatory M1 macrophages promote T helper (Th 1 responses and show tumoricidal activity. M2 macrophages contribute to tissue repair and promote Th2 responses. CD68 and CD163 are used to identify macrophages in tissue sections. However, characterisation of polarised macrophages in situ has remained difficult. Macrophage polarisation is regulated by transcription factors, pSTAT1 and RBP-J for M1, and CMAF for M2. We reasoned that double-labelling immunohistochemistry for the detection of macrophage markers together with transcription factors may be suitable to characterise macrophage polarisation in situ. To test this hypothesis, we have studied conditions associated with Th1- and Th2-predominant immune responses: infectious mononucleosis and Crohn's disease for Th1 and allergic nasal polyps, oxyuriasis, wound healing and foreign body granulomas for predominant Th2 response. In all situations, CD163+ cells usually outnumbered CD68+ cells. Moreover, CD163+ cells, usually considered as M2 macrophages, co-expressing pSTAT1 and RBP-J were found in all conditions examined. The numbers of putative M1 macrophages were higher in Th1- than in Th2-associated diseases, while more M2 macrophages were seen in Th2- than in Th1 related disorders. In most Th1-related diseases, the balance of M1 over M2 cells was shifted towards M1 cells, while the reverse was observed for Th2-related conditions. Hierarchical cluster analysis revealed two distinct clusters: cluster I included Th1 diseases together with cases with high numbers of CD163+pSTAT1+, CD68+pSTAT1+, CD163+RBP-J+ and CD68+RBP-J+ macrophages; cluster II comprised Th2 conditions together with cases displaying high numbers of CD163+CMAF+ and CD68+CMAF+ macrophages. These results suggest that the detection of pSTAT1, RBP-J, and CMAF in the context of CD68 or CD163 expression is a

  8. Endovascular thrombectomy for M2 occlusions: comparison between forced arterial suction thrombectomy and stent retriever thrombectomy.

    Kim, Yong-Won; Son, Seungnam; Kang, Dong-Hun; Hwang, Yang-Ha; Kim, Yong-Sun

    2017-07-01

    To date there has been no direct comparison of two frequently used endovascular thrombectomy (EVT) methods (forced arterial suction thrombectomy (FAST) and stent retriever thrombectomy) in M2 occlusions. We review our experiences with EVT performed using FAST and stent retriever thrombectomy in such cases. The subjects comprised 41 patients with an M2 occlusion who underwent EVT (25 with FAST, 16 with stent retriever thrombectomy). The patients' data were retrospectively analyzed to evaluate the technical characteristics and angiographic outcome of the two EVT techniques. Thrombolysis In Cerebral Infarction (TICI) grades 2b-3 using the first chosen technique did not differ significantly between the two techniques (FAST 64.0% vs stent retriever thrombectomy 81.2%, p=0.305). Time from groin puncture to reperfusion was significantly shorter for stent retriever thrombectomy (53.0 vs 38.5 min; p=0.045). Distal embolization occurred in three cases (12.0%) in the FAST group and in four (26.7%) in the stent retriever group (p=0.362). However, the two techniques did not differ significantly in the final TICI 2b-3 rate (72.0% vs 87.5%; p=0.441). A frequent angiographic finding regarding the failure of FAST was that the M2 occlusion was located immediately after severe acute angulation between M1 and M2. Stent retriever thrombectomy may provide faster reperfusion than FAST, while the FAST technique might be associated with lower distal embolization and a higher reperfusion rate for the first thrombectomy attempt, but without any significant difference in clinical outcome. When choosing the EVT method for M2 occlusions, consideration of the location of the occlusion and tortuosity between M1 and M2 might be helpful to achieve a better angiographic outcome. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  9. Macrophage polarisation: an immunohistochemical approach for identifying M1 and M2 macrophages.

    Barros, Mário Henrique M; Hauck, Franziska; Dreyer, Johannes H; Kempkes, Bettina; Niedobitek, Gerald

    2013-01-01

    Macrophage polarization is increasingly recognised as an important pathogenetic factor in inflammatory and neoplastic diseases. Proinflammatory M1 macrophages promote T helper (Th) 1 responses and show tumoricidal activity. M2 macrophages contribute to tissue repair and promote Th2 responses. CD68 and CD163 are used to identify macrophages in tissue sections. However, characterisation of polarised macrophages in situ has remained difficult. Macrophage polarisation is regulated by transcription factors, pSTAT1 and RBP-J for M1, and CMAF for M2. We reasoned that double-labelling immunohistochemistry for the detection of macrophage markers together with transcription factors may be suitable to characterise macrophage polarisation in situ. To test this hypothesis, we have studied conditions associated with Th1- and Th2-predominant immune responses: infectious mononucleosis and Crohn's disease for Th1 and allergic nasal polyps, oxyuriasis, wound healing and foreign body granulomas for predominant Th2 response. In all situations, CD163+ cells usually outnumbered CD68+ cells. Moreover, CD163+ cells, usually considered as M2 macrophages, co-expressing pSTAT1 and RBP-J were found in all conditions examined. The numbers of putative M1 macrophages were higher in Th1- than in Th2-associated diseases, while more M2 macrophages were seen in Th2- than in Th1 related disorders. In most Th1-related diseases, the balance of M1 over M2 cells was shifted towards M1 cells, while the reverse was observed for Th2-related conditions. Hierarchical cluster analysis revealed two distinct clusters: cluster I included Th1 diseases together with cases with high numbers of CD163+pSTAT1+, CD68+pSTAT1+, CD163+RBP-J+ and CD68+RBP-J+ macrophages; cluster II comprised Th2 conditions together with cases displaying high numbers of CD163+CMAF+ and CD68+CMAF+ macrophages. These results suggest that the detection of pSTAT1, RBP-J, and CMAF in the context of CD68 or CD163 expression is a suitable tool for

  10. The modulatory role of M2 muscarinic receptor on apomorphine-induced yawning and genital grooming.

    Gamberini, Maria Thereza; Bolognesi, Maria Laura; Nasello, Antonia Gladys

    2012-12-07

    The interaction between dopaminergic and cholinergic pathways in the induction of behavioral responses has been previously established. In the brain, M2 receptors are found predominantly in presynaptic cholinergic neurons as autoreceptors, and in dopaminergic neurons as heteroceptors, suggesting a control role of acetylcholine and dopamine release, respectively. Our aim was to investigate the role of M2 receptors on the yawning and genital grooming of rats induced by apomorphine, a dopaminergic receptor agonist, focusing on the interaction between cholinergic and dopaminergic pathways. Initially, the effect of atropine, a non-selective muscarinic antagonist, on yawning and genital grooming induced by apomorphine (100 μg/kg s.c.) was analyzed. Atropine doses of 0.5, 1 and 2 mg/kg i.p. were administered to Wistar rats 30 min before induction of the behavioral responses by apomorphine. Number of yawns and time spent genital grooming were quantified over a 60 min period. Apomorphine-induced yawning was increased by low dose (0.5 mg/kg i.p.) but not by high doses (1 and 2 mg/kg, i.p.) of atropine. Genital grooming was antagonized by 2 mg/kg i.p. of atropine and showed no changes at the other doses tested. Tripitramine, a selective M2 cholinergic antagonist, was used as a tool for distinguishing between M2 and all other muscarinic receptor subtypes in yawning and genital grooming. Tripitramine doses of 0.01, 0.02 and 0.04 μmol/kg i.p. were administered to Wistar rats 30 min before apomorphine (100 μg/kg s.c.). Number of yawns and time spent genital grooming were also quantified over a 60 min period. Tripitramine 0.01 μmol/kg increased all parameters. Higher doses, which possibly block all subtypes of muscarinic receptor, did not modify the response of apomorphine, suggesting a non-selective effect of tripitramine at these doses. Given that low doses of tripitramine increased the behavioral responses induced by apomorphine and that the main distribution of the M2

  11. Potent neutralization of influenza A virus by a single-domain antibody blocking M2 ion channel protein.

    Guowei Wei

    Full Text Available Influenza A virus poses serious health threat to humans. Neutralizing antibodies against the highly conserved M2 ion channel is thought to offer broad protection against influenza A viruses. Here, we screened synthetic Camel single-domain antibody (VHH libraries against native M2 ion channel protein. One of the isolated VHHs, M2-7A, specifically bound to M2-expressed cell membrane as well as influenza A virion, inhibited replication of both amantadine-sensitive and resistant influenza A viruses in vitro, and protected mice from a lethal influenza virus challenge. Moreover, M2-7A showed blocking activity for proton influx through M2 ion channel. These pieces of evidence collectively demonstrate for the first time that a neutralizing antibody against M2 with broad specificity is achievable, and M2-7A may have potential for cross protection against a number of variants and subtypes of influenza A viruses.

  12. How the Aridification of Australia Structured the Biogeography and Influenced the Diversification of a Large Lineage of Australian Cicadas.

    Owen, Christopher L; Marshall, David C; Hill, Kathy B R; Simon, Chris

    2017-07-01

    Over the last 30 million years, Australia's landscape has undergone dramatic cooling and drying due to the establishment of the Antarctic Circumpolar Current and change in global CO$_{2}$ levels. Studies have shown that many Australian organisms went extinct during these major cooling events, while others experienced adaptive radiations and increases in diversification rates as a result of exploiting new niches in the arid zone. Despite the many studies on diversification and biogeography in Australia, few have been continent-wide and none have focused on a group of organisms adapted to feeding on plants. We studied 162 species of cicadas in the Australian Pauropsalta complex, a large generic lineage within the tribe Cicadettini. We asked whether there were changes in the diversification rate of Pauropsalta over time and if so: 1) which clades were associated with the rate change? 2) did timing of rate shifts correspond to known periods of dramatic historical climate change, 3) did increases in diversification rate along select lineages correspond to adaptive radiations with movement into the arid zone? To address these questions, we estimated a molecular phylogeny of the Pauropsalta complex using ${\\sim}$5300 bp of nucleotide sequence data distributed among five loci (one mtDNA locus and four nDNA loci). We found that this large group of cicadas did not diversify at a constant rate as they spread through Australia; instead the signature of decreasing diversification rate changed roughly around the time of the expansion of the east Antarctic ice sheets ${\\sim}$16 Ma and the glaciation of the northern hemisphere ${\\sim}$3 Ma. Unlike other Australian taxa, the Pauropsalta complex did not explosively radiate in response to an early invasion of the arid zone. Instead multiple groups invaded the arid zone and experienced rates of diversification similar to mesic-distributed taxa. We found evidence for relictual groups, located in pre-Mesozoic habitat, that have not

  13. Novel 12S mtDNA findings in sloths (Pilosa, Folivora) and anteaters (Pilosa, Vermilingua) suggest a true case of long branch attraction

    Barros, Maria Claudene; Sampaio, Iracilda; Schneider, Horacio

    2008-01-01

    We sequenced 12S RNA mtDNA for the majority of the extant species of sloths and anteaters and compared our results with previous data obtained by our group using 16S RNA mtDNA in the same specimens and to GenBank sequences of the extinct giant sloth Mylodon. Our results suggest that pigmy-anteaters may be a case of the long-branch attraction phenomenon and also show the large genetic difference between the Amazonian and Atlantic forest three-toed sloths, contrasting with the small differences...

  14. Soft X-Ray Magneto-optical Faraday Effect around Ni M2,3 Edges

    Kai, Chen; Ming-Qi, Cui; Fen, Yan; Li-Juan, Sun; Lei, Zheng; Chen-Yan, Ma; Shi-Bo, Xi; Yi-Dong, Zhao; Jia, Zhao

    2008-01-01

    We present magneto-optical (MO) Faraday spectra measured around the M 2,3 edges (60–70eV) of Ni films at the Beijing Synchrotron Radiation Facility (BSRF). A polarization analysis of the final state of the transmitted radiation from the Ni film is employed to determine the Faraday rotation at the edges. The MO effect becomes resonantly enhanced at the M 2,3 edges, and accordingly large values for the rotation angle β of 1.85 ± 0.19° for this ferromagnetic Ni film with thickness of 31 nm are measured. Without the magnetic field, the azimuthal angles do not shift; with parallel and antiparallel magnetic field the rotation angles shift in the opposite way and they are symmetrical. The uncertainty of Faraday rotation angles mainly comes from the data fitting and the state change of the beamline when the angles are measured

  15. M2-brane surface operators and gauge theory dualities in Toda

    Gomis, Jaume; Floch, Bruno Le

    2016-01-01

    We give a microscopic two dimensional N=(2,2) gauge theory description of arbitrary M2-branes ending on N _f M5-branes wrapping a punctured Riemann surface. These realize surface operators in four dimensional N=2 field theories. We show that the expectation value of these surface operators on the sphere is captured by a Toda CFT correlation function in the presence of an additional degenerate vertex operator labelled by a representation R of SU(N _f), which also labels M2-branes ending on M5-branes. We prove that symmetries of Toda CFT correlators provide a geometric realization of dualities between two dimensional gauge theories, including N=(2,2) analogues of Seiberg and Kutasov-Schwimmer dualities. As a bonus, we find new explicit conformal blocks, braiding matrices, and fusion rules in Toda CFT.

  16. Wilson loops on three-manifolds and their M2-brane duals

    Farquet, Daniel; Sparks, James

    2014-01-01

    We compute the large N limit of Wilson loop expectation values for a broad class of N=2 supersymmetric gauge theories defined on a general class of background three-manifolds M_3, diffeomorphic to S"3. We find a simple closed formula which depends on the background geometry only through a certain supersymmetric Killing vector field. The supergravity dual of such a Wilson loop is an M2-brane wrapping the M-theory circle, together with a complex curve Σ_2 in a self-dual Einstein manifold M_4, whose conformal boundary is M_3. We show that the regularized action of this M2-brane also depends only on the supersymmetric Killing vector, precisely reproducing the large N field theory computation.

  17. EcoM2 web portal: Collecting empirical data and supporting companies' ecodesign implementation and management

    Pigosso, Daniela Cristina Antelmi; McAloone, Tim C.; Rozenfeld, Henrique

    2013-01-01

    to that a comprehensive framework has been developed, with the aim of ensuring systematic management, implementation and continuous improvement of the ecodesign process. The framework, called Ecodesign Maturity Model (EcoM2), enables the diagnosis of the company’s ecodesign maturity profile; the identification...... of strengths and limitations; and the establishment of strategic roadmaps for improved ecodesign implementation. This paper describes the development of the EcoM2 web portal, which will allow for the framework to be tested on greater numbers of companies and at the same time to provide a quick diagnosis......Despite the recognition of the potential benefits of ecodesign, a promising approach to integrate environmental concerns into the product development process, its application has failed to reach large numbers of companies and sectors worldwide due to managerial difficulties. In response...

  18. Alternatively activated macrophages (M2 macrophages) in the skin of patient with localized scleroderma.

    Higashi-Kuwata, Nobuyo; Makino, Takamitsu; Inoue, Yuji; Takeya, Motohiro; Ihn, Hironobu

    2009-08-01

    Localized scleroderma is a connective tissue disorder that is limited to the skin and subcutaneous tissue. Macrophages have been reported to be particularly activated in patients with skin disease including systemic sclerosis and are potentially important sources for fibrosis-inducing cytokines, such as transforming growth factor beta. To clarify the features of immunohistochemical characterization of the immune cell infiltrates in localized scleroderma focusing on macrophages, skin biopsy specimens were analysed by immunohistochemistry. The number of cells stained with monoclonal antibodies, CD68, CD163 and CD204, was calculated. An evident macrophage infiltrate and increased number of alternatively activated macrophages (M2 macrophages) in their fibrotic areas were observed along with their severity of inflammation. This study revealed that alternatively activated macrophages (M2 macrophages) may be a potential source of fibrosis-inducing cytokines in localized scleroderma, and may play a crucial role in the pathogenesis of localized scleroderma.

  19. Access Control in IoT/M2M - Cloud Platform

    Anggorojati, Bayu

    Billions of devices are connected to the Internet nowadays, and the number will continue to grow in the future thanks to the advances in the electronics and telecommunication technology developments. Its application in broad aspects of human’s life brings a lot of benefits by improving productivity...... and quality of life. This paradigm, which is often called Internet of Things (IoT) or Machine-to-Machine (M2M), will provide an unprecedented opportunity to create applications and services that go far beyond the mere purpose of each participant. Many studies on the both technical and social aspects of Io......T have shown that the concern about the security and privacy play a huge role for the mass adoption of the IoT/M2M as cloud services. Among the important topics within the security and privacy, the access control is an important mechanism, which essentially manages how the important assets or resource...

  20. The new VLT-DSM M2 unit: construction and electromechanical testing

    Gallieni, Daniele; Biasi, Roberto

    2013-12-01

    We present the design, construction and validation of the new M2 unit of the VLT Deformable Secondary Mirror. In the framework of the Adaptive Optics Facility program, ADS and Microgate designed a new secondary unit which replaces the current Dornier one. The M2 is composed by the mechanical structure, a new hexapod positioner and the Deformable Secondary Mirror unit.The DSM is based on the well proven contactless, voice coil motor technology that has been already successfully implemented in the MMT, LBT and Magellan adaptive secondaries, and is considered a promising technical choice for the E-ELT M4 and the GMT ASM. The VLT adaptive unit has been fully integrated and, before starting the optical calibration, has completed the electromechanical characterization, focused on the dynamic performance. With respect to the previous units we introduced several improvements, both in hardware and control architecture that allowed achieving a significant enhancement of the system dynamics and reduction of power consumption.

  1. Industry 4.0, M2m, Iot&S - All Equal?

    Dobrin, Carmen

    2014-11-01

    Similarity between Industry 4.0, M2M, IOT&S. Advantages and disadvantages obtained using this three important methods. Decreasing costs while components are getting smaller and smaller in a world with better networking. Influence of business management applications integrated in smart factory logistic. The most important impacts in merging virtual and real production world, with the improvement of best processes having the same goal: creating value by open innovation

  2. Giant graviton interactions and M2-branes ending on multiple M5-branes

    Hirano, Shinji; Sato, Yuki

    2018-05-01

    We study splitting and joining interactions of giant gravitons with angular momenta N 1/2 ≪ J ≪ N in the type IIB string theory on AdS 5 × S 5 by describing them as instantons in the tiny graviton matrix model introduced by Sheikh-Jabbari. At large J the instanton equation can be mapped to the four-dimensional Laplace equation and the Coulomb potential for m point charges in an n-sheeted Riemann space corresponds to the m-to- n interaction process of giant gravitons. These instantons provide the holographic dual of correlators of all semi-heavy operators and the instanton amplitudes exactly agree with the pp-wave limit of Schur polynomial correlators in N = 4 SYM computed by Corley, Jevicki and Ramgoolam. By making a slight change of variables the same instanton equation is mathematically transformed into the Basu-Harvey equation which describes the system of M2-branes ending on M5-branes. As it turns out, the solutions to the sourceless Laplace equation on an n-sheeted Riemann space correspond to n M5-branes connected by M2-branes and we find general solutions representing M2-branes ending on multiple M5-branes. Among other solutions, the n = 3 case describes an M2-branes junction ending on three M5-branes. The effective theory on the moduli space of our solutions might shed light on the low energy effective theory of multiple M5-branes.

  3. Genetic variability for different quantitative traits in M2 generations of opium poppy (Papaver somniferum L.)

    Chatterjee, A.; Shukla, S.; Singh, S.P.

    2004-01-01

    An experiment on induced mutation in two varieties of opium poppy was laid out to create new genetic variability for isolation of high yielding genotypes. Varieties NBRI-1 and NBRI-5 were subjected to irradiation for five doses of gamma rays and NBRI-5 was also treated with four doses of EMS and 20 mixed doses of EMS plus gamma rays. The data were recorded on 15 plants/treatment for 10 polygenic characters as pooled in M1 and M2 generations separately as well as in each dose-wise in M2 population. The results indicated that GCV, heritability and genetic advance were higher in M1 than M2 in both the varieties for all the traits except for opium and seed yield. The genetic advance was consistently high for opium yield, seed yield and capsule weight in all the doses for both the varieties with some exception. The dose level of kR10 and kR30 in NBRI-1 revealed high GCV, heritability and genetic advance for seed weight. These treatment levels also had high values of all these three genetic parameters for capsules per plant, capsule size and capsule weight. The values of these three parameters were also high for all the doses in M2 generations of both the varieties for opium yield, seed weight, capsule weight and capsule size in comparison to control. The GCV, heritability and genetic advance were consistently high for all the mixed doses in NBRI-5 for opium yield, seed weight and capsule weight, with some exception [it

  4. Human mesenchymal stromal cell-secreted lactate induces M2-macrophage differentiation by metabolic reprogramming

    Selleri, Silvia; Bifsha, Panojot; Civini, Sara; Pacelli, Consiglia; Dieng, Mame Massar; Lemieux, William; Jin, Ping; Bazin, Ren?e; Patey, Natacha; Marincola, Francesco M.; Moldovan, Florina; Zaouter, Charlotte; Trudeau, Louis-Eric; Benabdhalla, Basma; Louis, Isabelle

    2016-01-01

    Human mesenchymal stromal cells (MSC) have been shown to dampen immune response and promote tissue repair, but the underlying mechanisms are still under investigation. Herein, we demonstrate that umbilical cord-derived MSC (UC-MSC) alter the phenotype and function of monocyte-derived dendritic cells (DC) through lactate-mediated metabolic reprogramming. UC-MSC can secrete large quantities of lactate and, when present during monocyte-to-DC differentiation, induce instead the acquisition of M2-...

  5. Power Aware Mobility Management of M2M for IoT Communications

    Awais Ahmad

    2015-01-01

    Full Text Available Machine-to-Machine (M2M communications framework is evolving to sustain faster networks with the potential to connect millions of devices in the following years. M2M is one of the essential competences for implementing Internet of Things (IoT. Therefore, various organizations are now focusing on enhancing improvements into their standards to support M2M communications. Thus, Heterogeneous Mobile Ad Hoc Network (HetMANET can normally be considered appropriate for M2M challenges. These challenges incorporated when a mobile node (MN selects a target network in an energy efficient scanning for efficient handover. Therefore, to cope with these constraints, we proposed a vertical handover scheme for handover triggering and selection of an appropriate network. The proposed scheme is composed of two phases. Firstly, the MNs perform handover triggering based on the optimization of the Receive Signal Strength (RSS from an access point/base station (AP/BS. Secondly, the network selection process is performed by considering the cost and energy consumption of a particular application during handover. Moreover, if there are more networks available, then the MN selects the one provided with the highest quality of service (QoS. The decision regarding the selection of available networks is made on three metrics, that is, cost, energy, and data rate. Furthermore, the selection of an AP/BS of the selected network is made on five parameters: delay, jitter, Bit Error Rate (BER, communication cost, and response time. The numerical and experimental results are compared in the context of energy consumption by an MN, traffic management on an AP/BS, and QoS of the available networks. The proposed scheme efficiently optimizes the handoff related parameters, and it shows significant improvement in the existing models used for similar purpose.

  6. Carbides crystalline structure of AISI M2 high-speed steel

    Serna, M.M.; Galego, E.; Rossi, J.L.

    2005-01-01

    The aim of this study was to identify the crystallographic structure of the extracted carbides of AISI M2 steel spray formed The structure determination of these carbides. The structure determination of these carbides is a very hard work. Since these structures were formed by atom migration it is not possible to reproduce them by a controlled process with a determined chemical composition. The solution of this problem is to obtain the carbide by chemical extraction from the steel. (Author)

  7. Seasonal variability of the M2 tide in the seas adjacent to Korea

    Kang, Sok Kuh; Chung, Jong-yul; Lee, Sang-Ryong; Yum, Ki-Dat

    1995-08-01

    Seasonal variability of the M2 tidal harmonic constants is revealed through analyses of monthly tidal data at 12 representative tidal stations in the seas adjacent to the Korean peninsula. The variability remain systematic over the 9 years (1965-1973) of data analysis with a range comparable to that of the 18.6 year nodal modulation. Spatial inhomogeneity of the seasonal variability in the observed harmonic constants is found to exist. The largest seasonal variability in M2 appears in the stations located along the Korea Strait. This variability is not explained by the equilibrium theory of tides, and such a variability or irregularities in the harmonic constants are considered as either a noise as done by Cartwright and Amin (1986), Deutsch Hydrography Zeitschrift, 39, 235-253, or a manifestation of frictional interaction as done by Godin and Gutierrez (1986) Continental Shelf Research, 5, 379-402 for the Bay of Fundy. Considering the opposite relation between monthly mean sea level differences in Izuhara-Pusan section and tidal characteristics in the Korea Strait, it is hypothesized that the interaction between the predominant tidal currents and oceanic currents varying with the seasons might be the main cause of the observed temporal variability in the M2 tide. The nonlinear effect of the Kuroshio is investigated along the shelf break region through scale analyses, which show that the presence of a mean current increases the non-linear terms in the momentum balance by about one order of magnitude. The seasonally different damping effect of the Tsushima Current to the M2 tide is also discussed to explain the process of dominant seasonal variability along the Korea Strait based on the actual current data, but further thorough investigation, considering the advection effect of the mean current, is required to investigate the associated dynamics more completely.

  8. Study of the solidification of M2 high speed steel Laser Cladding coatings

    Candel, J. J.

    2013-10-01

    Full Text Available High speed steel laser cladding coatings are complex because cracks appear and the hardness is lower than expected. In this paper AISI M2 tool steel coatings on medium carbon AISI 1045 steel substrate have been manufactured and after Laser Cladding (LC processing it has been applied a tempering heat treatment to reduce the amount of retained austenite and to precipitate secondary carbides. The study of metallurgical transformations by Scanning Electron Microscopy (SEM and Electron Back Scattered Diffraction (EBSD shows that the microstructure is extremely fine and complex, with eutectic transformations and MC, M2C and M6C precipitation. Therefore, after the laser coating is necessary to use post-weld heat treatments.Los recubrimientos de acero rápido por Laser Cladding (LC son complejos porque aparecen fisuras y la dureza es menor a la esperada. En este trabajo se han fabricado recubrimientos de acero AISI M2 sobre acero al carbono AISI 1045 y tras el procesado por láser, se han revenido para reducir la cantidad de austenita retenida y precipitar carburos secundarios. El estudio de las transformaciones metalúrgicas con Microscopía Electrónica de Barrido (MEB y Difracción de Electrones Retrodispersados (EBSD muestra que la microestructura es extremadamente fina y compleja, presenta transformaciones eutécticas y precipitación de carburos MC, M2C y M6C. Por tanto, tras el recubrimiento por láser es necesario recurrir a tratamientos térmicos post-soldeo.

  9. M2-like macrophage polarization in high lactic acid-producing head and neck cancer.

    Ohashi, Toshimitsu; Aoki, Mitsuhiro; Tomita, Hiroyuki; Akazawa, Takashi; Sato, Katsuya; Kuze, Bunya; Mizuta, Keisuke; Hara, Akira; Nagaoka, Hitoshi; Inoue, Norimitsu; Ito, Yatsuji

    2017-06-01

    Reprogramming of glucose metabolism in tumor cells is referred to as the Warburg effect and results in increased lactic acid secretion into the tumor microenvironment. We have previously shown that lactic acid has important roles as a pro-inflammatory and immunosuppressive mediator and promotes tumor progression. In this study, we examined the relationship between the lactic acid concentration and expression of LDHA and GLUT1, which are related to the Warburg effect, in human head and neck squamous cell carcinoma (HNSCC). Tumors expressing lower levels of LDHA and GLUT1 had a higher concentration of lactic acid than those with higher LDHA and GLUT1 expression. Lactic acid also suppressed the expression of LDHA and GLUT1 in vitro. We previously reported that lactic acid enhances expression of an M2 macrophage marker, ARG1, in murine macrophages. Therefore, we investigated the relationship between the lactic acid concentration and polarization of M2 macrophages in HNSCC by measuring the expression of M2 macrophage markers, CSF1R and CD163, normalized using a pan-macrophage marker, CD68. Tumors with lower levels of CD68 showed a higher concentration of lactic acid, whereas those with higher levels of CSF1R showed a significantly higher concentration of lactic acid. A similar tendency was observed for CD163. These results suggest that tumor-secreted lactic acid is linked to the reduction of macrophages in tumors and promotes induction of M2-like macrophage polarization in human HNSCC. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  10. Regional outbreak of CTX-M-2 β-lactamase-producing Proteus mirabilis in Japan.

    Nakano, Ryuichi; Nakano, Akiyo; Abe, Michiko; Inoue, Matsuhisa; Okamoto, Ryoichi

    2012-12-01

    Proteus mirabilis is a common cause of urinary tract infection. Wild-type P. mirabilis strains are usually susceptible to penicillins and cephalosporins, but occurrences of P. mirabilis producing extended-spectrum β-lactamases (ESBLs) have been recently reported. Here, we surveyed the prevalence of cefotaxime resistance among P. mirabilis strains at seven different hospitals in Kanagawa Prefecture, Japan, and investigated their molecular epidemiology to explain the mechanism of their spread. The prevalence of cefotaxime resistance among P. mirabilis increased annually, from 10.1 % in 1998 to 23.1 % in 2003, and increased drastically in 2004, exceeding 40 %. We collected 105 consecutive and non-duplicate cefotaxime-resistant P. mirabilis isolates (MIC 16 to >256 µg ml(-1)) from these hospitals from June 2004 to May 2005 and characterized their profile. PCR and sequence analysis revealed that all resistant strains produced exclusively CTX-M-2 β-lactamase. PFGE analysis identified 47 banding patterns with 83 % or greater similarity. These results indicated that a regional outbreak of P. mirabilis producing CTX-M-2 β-lactamase has occurred in Japan and suggest that the epidemic spread occurred within and across hospitals and communities by extended clonal strains. Plasmid analysis revealed that 44.8 % of plasmids harboured by bla(CTX-M-2) isolates had common profiles, encoding ISEcp1, IS26 and Int1, and belonged to incompatibility group T. Spread of the resistant isolates in Japan resulted from dissemination of narrow-host-range plasmids of the IncT group encoding bla(CTX-M-2). These findings indicate the rapidly developing problem of treating the species to prevent dissemination of ESBL producers.

  11. Resolving combinatorial ambiguities in dilepton t t¯ event topologies with constrained M2 variables

    Debnath, Dipsikha; Kim, Doojin; Kim, Jeong Han; Kong, Kyoungchul; Matchev, Konstantin T.

    2017-10-01

    We advocate the use of on-shell constrained M2 variables in order to mitigate the combinatorial problem in supersymmetry-like events with two invisible particles at the LHC. We show that in comparison to other approaches in the literature, the constrained M2 variables provide superior ansätze for the unmeasured invisible momenta and therefore can be usefully applied to discriminate combinatorial ambiguities. We illustrate our procedure with the example of dilepton t t ¯ events. We critically review the existing methods based on the Cambridge MT 2 variable and MAOS reconstruction of invisible momenta, and show that their algorithm can be simplified without loss of sensitivity, due to a perfect correlation between events with complex solutions for the invisible momenta and events exhibiting a kinematic endpoint violation. Then we demonstrate that the efficiency for selecting the correct partition is further improved by utilizing the M2 variables instead. Finally, we also consider the general case when the underlying mass spectrum is unknown, and no kinematic endpoint information is available.

  12. RESTful M2M Gateway for Remote Wireless Monitoring for District Central Heating Networks

    Bo Cheng

    2014-11-01

    Full Text Available In recent years, the increased interest in energy conservation and environmental protection, combined with the development of modern communication and computer technology, has resulted in the replacement of distributed heating by central heating in urban areas. This paper proposes a Representational State Transfer (REST Machine-to-Machine (M2M gateway for wireless remote monitoring for a district central heating network. In particular, we focus on the resource-oriented RESTful M2M gateway architecture, and present an uniform devices abstraction approach based on Open Service Gateway Initiative (OSGi technology, and implement the resource mapping mechanism between resource address mapping mechanism between RESTful resources and the physical sensor devices, and present the buffer queue combined with polling method to implement the data scheduling and Quality of Service (QoS guarantee, and also give the RESTful M2M gateway open service Application Programming Interface (API set. The performance has been measured and analyzed. Finally, the conclusions and future work are presented.

  13. Moldeo por inyección del acero rápido M2

    Ruiz-Román, J. M.

    1996-12-01

    Full Text Available The purpose of this work is to study the feasibility of Powder Injection Molding in order to obtain M2 High Speed Steels with higher performances than those obtained by conventional P/M. With this object trials have been carried out in order to optimize all the process steps (mixing, injection, debinding and sintering, and to evaluate the mechanical properties (hardness and transverse tensile strengh of the manufactured M2 HSS sample.

    Se estudia la viabilidad de la tecnología de Moldeo por Inyección de Polvos (MIM en la fabricación con acero rápido M2 a fin de obtener componentes de este material de prestaciones superiores a las que se consiguen mediante métodos convencionales pulvimetalúrgicos. Los ensayos realizados se han dirigido a optimizar los parámetros de la eliminación del ligante y de la sinterización, con objeto de controlar el contenido de carbono y la densidad final de las piezas, así como evitar la aparición de los defectos típicos de esta tecnología.

  14. β-elemene inhibits tumor-promoting effect of M2 macrophages in lung cancer.

    Yu, Xiaomu; Xu, Maoyi; Li, Na; Li, Zongjuan; Li, Hongye; Shao, Shujuan; Zou, Kun; Zou, Lijuan

    2017-08-19

    Macrophages in tumor are mostly M2-polarized and have been reported to promote tumorigenesis, which are also defined as tumor-associated macrophages (TAMs). β-elemene has therapeutic effects against several cancers, however, it remains unknown whether β-elemene could inhibit cancer by targeting TAMs. Herein, we examined the effect of β-elemene on macrophages to elucidate a novel mechanism of β-elemene in tumor therapy. We showed that the conditioned medium of M2 macrophages promoted lung cancer cells to migration, invasion and epithelial mesenchymal transition, which could be inhibited by β-elemene. Moreover, β-elemene regulated the polarization of macrophages from M2 to M1. β-elemene also inhibited the proliferation, migration, invasion of lung cancer cells and enhanced its radiosensitivity. These results indicate β-elemene suppresses lung cancer by regulating both macrophages and lung cancer cells, it is a promising drug for combination with chemotherapy or radiotherapy. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Human mesenchymal stromal cell-secreted lactate induces M2-macrophage differentiation by metabolic reprogramming

    Civini, Sara; Pacelli, Consiglia; Dieng, Mame Massar; Lemieux, William; Jin, Ping; Bazin, Renée; Patey, Natacha; Marincola, Francesco M.; Moldovan, Florina; Zaouter, Charlotte; Trudeau, Louis-Eric; Benabdhalla, Basma; Louis, Isabelle; Beauséjour, Christian; Stroncek, David; Le Deist, Françoise; Haddad, Elie

    2016-01-01

    Human mesenchymal stromal cells (MSC) have been shown to dampen immune response and promote tissue repair, but the underlying mechanisms are still under investigation. Herein, we demonstrate that umbilical cord-derived MSC (UC-MSC) alter the phenotype and function of monocyte-derived dendritic cells (DC) through lactate-mediated metabolic reprogramming. UC-MSC can secrete large quantities of lactate and, when present during monocyte-to-DC differentiation, induce instead the acquisition of M2-macrophage features in terms of morphology, surface markers, migratory properties and antigen presentation capacity. Microarray expression profiling indicates that UC-MSC modify the expression of metabolic-related genes and induce a M2-macrophage expression signature. Importantly, monocyte-derived DC obtained in presence of UC-MSC, polarize naïve allogeneic CD4+ T-cells into Th2 cells. Treatment of UC-MSC with an inhibitor of lactate dehydrogenase strongly decreases lactate concentration in culture supernatant and abrogates the effect on monocyte-to-DC differentiation. Metabolic analysis further revealed that UC-MSC decrease oxidative phosphorylation in differentiating monocytes while strongly increasing the spare respiratory capacity proportional to the amount of secreted lactate. Because both MSC and monocytes are recruited in vivo at the site of tissue damage and inflammation, we propose the local increase of lactate concentration induced by UC-MSC and the consequent enrichment in M2-macrophage generation as a mechanism to achieve immunomodulation. PMID:27070086

  16. Seamless communication in supply chains based on M2M technology

    Walid Moneimne

    2016-12-01

    Full Text Available Background: Access to information is the key element in the successful and efficient organization of transport & logistic processes. The importance of real-time access to information is confirmed by a panel workshop carried out with support of design thinking methodology. There are two ways of gaining access to the right information - manual, where human agency is needed and fully automatic, where new M2M technology is implemented. Implementation of such technology improves seamless communication during transport execution and allows real-time access to needed information. The aim of the paper is to evaluate the influence of the effectiveness of using M2M technology and traditional way of communication as well as data gathering in order to ensure seamless communication in the supply chain. Methods: Survey, design thinking, desk research and real case study results were used in the paper. Results and conclusions: Seamless communication and implementation of M2M technology within the whole supply (including modes of transport and transport units chain is a backbone of the lean and reliable digital supply chain.

  17. Microglia M2A Polarization as Potential Link between Food Allergy and Autism Spectrum Disorders

    Hans O. Kalkman

    2017-12-01

    Full Text Available Atopic diseases are frequently co-morbid with autism spectrum disorders (ASD. Allergic responses are associated with an activation of mast cells, innate lymphoid cells, and Th2 cells. These cells produce type-2 cytokines (IL4 and IL13, which stimulate microglia and macrophages to adopt a phenotype referred to as ‘alternative activation’ or ‘M2A’. M2A-polarized macrophages and microglia play a physiological role in tissue repair by secreting growth factors such as brain-derived neurotrophic factor (BDNF and insulin-like growth factor-1. In ASD there is evidence for increased type-2 cytokines, microglia activation, M2A polarization, and increased levels of growth factors. In neurons, these growth factors drive a signal transduction pathway that leads to activation of the enzyme mammalian Target of Rapamycin (mTOR, and thereby to the inhibition of autophagy. Activation of mTOR is an effect that is also common to several of the genetic forms of autism. In the central nervous system, redundant synapses are removed via an autophagic process. Activation of mTOR would diminish the pruning of redundant synapses, which in the context of ASD is likely to be undesired. Based on this line of reasoning, atopic diseases like food allergy, eczema or asthma would represent risk factors for autism spectrum disorders.

  18. Dynamic RACH Partition for Massive Access of Differentiated M2M Services

    Qinghe Du

    2016-03-01

    Full Text Available In machine-to-machine (M2M networks, a key challenge is to overcome the overload problem caused by random access requests from massive machine-type communication (MTC devices. When differentiated services coexist, such as delay-sensitive and delay-tolerant services, the problem becomes more complicated and challenging. This is because delay-sensitive services often use more aggressive policies, and thus, delay-tolerant services get much fewer chances to access the network. To conquer the problem, we propose an efficient mechanism for massive access control over differentiated M2M services, including delay-sensitive and delay-tolerant services. Specifically, based on the traffic loads of the two types of services, the proposed scheme dynamically partitions and allocates the random access channel (RACH resource to each type of services. The RACH partition strategy is thoroughly optimized to increase the access performances of M2M networks. Analyses and simulation demonstrate the effectiveness of our design. The proposed scheme can outperform the baseline access class barring (ACB scheme, which ignores service types in access control, in terms of access success probability and the average access delay.

  19. M2-9 - a planetary nebula with an eruptive nucleus?

    Balick, B.

    1989-01-01

    M2-9 is a striking bipolar, or butterfly, planetary nebula (PN) whose nuclear spectrum is uncharacteristic of PN nuclei. Narrow lines ranging in ionization from O I, Fe II, forbidden Fe II, and Si II through forbidden O III are observed in the stellar spectrum. The H-alpha emission line has wings extending nearly 11,000 km/s at the base, and there is a deep self-absorption feature near the H-alpha line peak at the same velocity as nebular gas observed in one of the two bipolar lobes. The spectrum of M2-9's nucleus is more similar to the slow nova RR Tel, some symbiotic stars, and Seyfert (type 1.9) galactic nuclei than the central stars of most other PNs. Although its morphology, size, and nebular spectrum share many similarities with other PNs, M2-9 may not share a common evolutionary history with that class of objects. 31 references

  20. Toward a proof of Montonen-Olive duality via multiple M2-branes

    Hashimoto, Koji; Tai, Ta-Sheng; Terashima, Seiji

    2009-01-01

    We derive 4-dimensional N = 4 U(N) supersymmetric Yang-Mills theory from a 3-dimensional Chern-Simons-matter theory with product gauge group (U(N)) 2n . The latter describes M2-branes probing an orbifold where a torus emerges in a scaling limit. It is expected that the SL(2,Z) duality of the 4-dimensional Yang-Mills theory will be shown in M-theory point of view since it is trivially realized as modular transformations of the torus. Indeed, starting from one single Chern-Simons-matter theory, we find infinitely many equivalent 4-dimensional theories differing up to T-transformation of the SL(2,Z) redefinition of the gauge coupling τ = θ/2π + 4πi/g 2 and a parity transformation in 4 dimensions. Although S-transformation can not be shown in our work, it is important that a part of the SL(2,Z) transformation is realized via the M2-brane action. Thus we think our work can be a step toward a proof of Montonen-Olive duality via M2-branes.

  1. Toward a proof of Montonen-Olive duality via multiple M2-branes

    Hashimoto, Koji; Tai, Ta-Sheng; Terashima, Seiji

    2009-04-01

    We derive 4-dimensional Script N = 4 U(N) supersymmetric Yang-Mills theory from a 3-dimensional Chern-Simons-matter theory with product gauge group (U(N))2n. The latter describes M2-branes probing an orbifold where a torus emerges in a scaling limit. It is expected that the SL(2,Z) duality of the 4-dimensional Yang-Mills theory will be shown in M-theory point of view since it is trivially realized as modular transformations of the torus. Indeed, starting from one single Chern-Simons-matter theory, we find infinitely many equivalent 4-dimensional theories differing up to T-transformation of the SL(2,Z) redefinition of the gauge coupling τ = θ/2π + 4πi/g2 and a parity transformation in 4 dimensions. Although S-transformation can not be shown in our work, it is important that a part of the SL(2,Z) transformation is realized via the M2-brane action. Thus we think our work can be a step toward a proof of Montonen-Olive duality via M2-branes.

  2. TPL-2 Regulates Macrophage Lipid Metabolism and M2 Differentiation to Control TH2-Mediated Immunopathology

    Entwistle, Lewis J.; Khoury, Hania; Papoutsopoulou, Stamatia; Mahmood, Radma; Mansour, Nuha R.; Ching-Cheng Huang, Stanley; Pearce, Edward J.; Pedro S. de Carvalho, Luiz; Ley, Steven C.

    2016-01-01

    Persistent TH2 cytokine responses following chronic helminth infections can often lead to the development of tissue pathology and fibrotic scarring. Despite a good understanding of the cellular mechanisms involved in fibrogenesis, there are very few therapeutic options available, highlighting a significant medical need and gap in our understanding of the molecular mechanisms of TH2-mediated immunopathology. In this study, we found that the Map3 kinase, TPL-2 (Map3k8; Cot) regulated TH2-mediated intestinal, hepatic and pulmonary immunopathology following Schistosoma mansoni infection or S. mansoni egg injection. Elevated inflammation, TH2 cell responses and exacerbated fibrosis in Map3k8 –/–mice was observed in mice with myeloid cell-specific (LysM) deletion of Map3k8, but not CD4 cell-specific deletion of Map3k8, indicating that TPL-2 regulated myeloid cell function to limit TH2-mediated immunopathology. Transcriptional and metabolic assays of Map3k8 –/–M2 macrophages identified that TPL-2 was required for lipolysis, M2 macrophage activation and the expression of a variety of genes involved in immuno-regulatory and pro-fibrotic pathways. Taken together this study identified that TPL-2 regulated TH2-mediated inflammation by supporting lipolysis and M2 macrophage activation, preventing TH2 cell expansion and downstream immunopathology and fibrosis. PMID:27487182

  3. Non-Neuronal Functions of the M2 Muscarinic Acetylcholine Receptor

    Ritva Tikkanen

    2013-04-01

    Full Text Available Acetylcholine is an important neurotransmitter whose effects are mediated by two classes of receptors. The nicotinic acetylcholine receptors are ion channels, whereas the muscarinic receptors belong to the large family of G protein coupled seven transmembrane helix receptors. Beyond its function in neuronal systems, it has become evident that acetylcholine also plays an important role in non-neuronal cells such as epithelial and immune cells. Furthermore, many cell types in the periphery are capable of synthesizing acetylcholine and express at least some of the receptors. In this review, we summarize the non-neuronal functions of the muscarinic acetylcholine receptors, especially those of the M2 muscarinic receptor in epithelial cells. We will review the mechanisms of signaling by the M2 receptor but also the cellular trafficking and ARF6 mediated endocytosis of this receptor, which play an important role in the regulation of signaling events. In addition, we provide an overview of the M2 receptor in human pathological conditions such as autoimmune diseases and cancer.

  4. Measurement of M2-Curve for Asymmetric Beams by Self-Referencing Interferometer Wavefront Sensor

    Yongzhao Du

    2016-11-01

    Full Text Available For asymmetric laser beams, the values of beam quality factor M x 2 and M y 2 are inconsistent if one selects a different coordinate system or measures beam quality with different experimental conditionals, even when analyzing the same beam. To overcome this non-uniqueness, a new beam quality characterization method named as M2-curve is developed. The M2-curve not only contains the beam quality factor M x 2 and M y 2 in the x-direction and y-direction, respectively; but also introduces a curve of M x α 2 versus rotation angle α of coordinate axis. Moreover, we also present a real-time measurement method to demonstrate beam propagation factor M2-curve with a modified self-referencing Mach-Zehnder interferometer based-wavefront sensor (henceforth SRI-WFS. The feasibility of the proposed method is demonstrated with the theoretical analysis and experiment in multimode beams. The experimental results showed that the proposed measurement method is simple, fast, and a single-shot measurement procedure without movable parts.

  5. M2 macrophages coexist with a Th1-driven profile in periapical cysts.

    Ribeiro, C M; de Carli, M L; Nonogaki, S; Nogueira, D A; Pereira, A A C; Sperandio, F F; Hanemann, J A C

    2018-02-01

    To evaluate the participation of both Th1 and Th2 responses in periapical cysts by assessing the presence of M2 macrophages, as well as acute IL-1 β, TNF-α and IL-6 cytokines. Twenty-four cases of periapical cysts were selected. Immuno-expressions of IL-1 β, IL-6, TNF-α and CD163 were analysed in the cystic capsules in both superficial and deeper regions. Data were analysed with paired Wilcoxon test and Spearman correlation coefficient (P ≤ 0.05). There was a higher expression of IL-1β, IL-6, TNF-α and M2 macrophages in the superficial region (P periapical cysts and correlated with the expression of certain acute Th1-related cytokines. This illustrates the coexistence of an acute and chronic Th2-driven immune response in these lesions. Although M2 macrophages favour the healing process, their presence is not sufficient for periapical cyst regression, once an acute active response has occurred due to an infectious stimuli. © 2017 International Endodontic Journal. Published by John Wiley & Sons Ltd.

  6. Tumor cell-derived microparticles polarize M2 tumor-associated macrophages for tumor progression.

    Ma, Ruihua; Ji, Tiantian; Chen, Degao; Dong, Wenqian; Zhang, Huafeng; Yin, Xiaonan; Ma, Jingwei; Liang, Xiaoyu; Zhang, Yi; Shen, Guanxin; Qin, Xiaofeng; Huang, Bo

    2016-04-01

    Despite identification of macrophages in tumors (tumor-associated macrophages, TAM) as potential targets for cancer therapy, the origin and function of TAM in the context of malignancy remain poorly characterized. Here, we show that microparticles (MPs), as a by-product, released by tumor cells act as a general mechanism to mediate M2 polarization of TAM. Taking up tumor MPs by macrophages is a very efficient process, which in turn results in the polarization of macrophages into M2 type, not only leading to promoting tumor growth and metastasis but also facilitating cancer stem cell development. Moreover, we demonstrate that the underlying mechanism involves the activation of the cGAS/STING/TBK1/STAT6 pathway by tumor MPs. Finally, in addition to murine tumor MPs, we show that human counterparts also possess consistent effect on human M2 polarization. These findings provide new insights into a critical role of tumor MPs in remodeling of tumor microenvironment and better understanding of the communications between tumors and macrophages.

  7. The state-of-the-art Model M-2 Maintenance System

    Herndon, J.N.; Martin, H.L.; Satterlee, P.E. Jr.; Jelatis, D.G.; Jennrich, C.E.

    1984-01-01

    The Model M-2 Maintenance System is part of an ongoing program within the Consolidated Fuel Reprocessing Program (CFRP) at Oak Ridge National Laboratory (ORNL) to improve remote manipulation technology for future nuclear fuel reprocessing and other remote applications. Techniques, equipment, and guidelines which can improve the efficiency of remote maintenance are being developed. The Model M-2 Maintenance System, installed in the Integrated Equipment Test (IET) Facility at ORNL, provides a complete, integrated remote maintenance system for the demonstration and development of remote maintenance techniques. The system comprises a pair of force-reflecting servomanipulator arms, television viewing, lighting, and auxiliary lifting capabilities, thereby allowing manlike maintenance operations to be executed remotely within the remote cell mockup area in the IET. The Model M-2 Maintenance System incorporates an upgraded version of the proven Central Research Laboratories' Model M servomanipulator. Included are state-of-the-art brushless dc servomotors for improved performance, remotely removable wrist assemblies, geared azimuth drive, and a distributed microprocessor-based digital control system

  8. Thermal testing results of an electroformed nickel secondary (M2) mirror

    Smith, David R.; Gale, David M.; Cabrera Cuevas, Lizeth; Lucero Álvarez, Maribel; Castro Santos, David; Olmos Tapia, Arak

    2016-07-01

    To support higher-frequency operation, the Large Millimeter Telescope/Gran Telescopio Milimetrico (or LMT/GTM) is replacing its existing monolithic aluminum secondary mirror (M2). The new mirror is a segmented design based on the same electroformed nickel reflector panel technology that is already in use for the primary reflector segments. While the new M2 is lighter and has better surface accuracy than the original mirror, the electroformed panels are more sensitive to high temperatures. During the design phase, concerns were raised over the level of temperature increase that could occur at M2 during daytime observations. Although the panel surface is designed to scatter visible light, the LMT primary mirror is large enough to cause substantial solar heating, even at significant angular separation from the Sun. To address these concerns, the project conducted a series of field tests, within the constraint of having minimum impact on night time observations. The supplier sent two coupon samples of a reflector panel prepared identically to their proposed M2 surface. Temperature sensors were mounted on the samples and they were temporarily secured to the existing M2 mirror at different distances from the center. The goal was to obtain direct monitoring of the surface temperature under site thermal conditions and the concentration effects from the primary reflector. With the sensors installed, the telescope was then commanded to track the Sun with an elevation offset. Initially, elevation offsets from as far as 40 degrees to as close as 6 degrees were tested. The 6 degree separation test quickly passed the target maximum temperature and the telescope was returned to a safer separation. Based on these initial results, a second set of tests was performed using elevation separations from 30 degrees to 8 degrees. To account for the variability of site conditions, the temperature data were analyzed using multiple metrics. These metrics included maximum temperature, final

  9. Alternatively Activated (M2) Macrophage Phenotype Is Inducible by Endothelin-1 in Cultured Human Macrophages.

    Soldano, Stefano; Pizzorni, Carmen; Paolino, Sabrina; Trombetta, Amelia Chiara; Montagna, Paola; Brizzolara, Renata; Ruaro, Barbara; Sulli, Alberto; Cutolo, Maurizio

    2016-01-01

    Alternatively activated (M2) macrophages are phenotypically characterized by the expression of specific markers, mainly macrophage scavenger receptors (CD204 and CD163) and mannose receptor-1 (CD206), and participate in the fibrotic process by over-producing pro-fibrotic molecules, such as transforming growth factor-beta1 (TGFbeta1) and metalloproteinase (MMP)-9. Endothelin-1 (ET-1) is implicated in the fibrotic process, exerting its pro-fibrotic effects through the interaction with its receptors (ETA and ETB). The study investigated the possible role of ET-1 in inducing the transition from cultured human macrophages into M2 cells. Cultured human monocytes (THP-1 cell line) were activated into macrophages (M0 macrophages) with phorbol myristate acetate and subsequently maintained in growth medium (M0-controls) or treated with either ET-1 (100nM) or interleukin-4 (IL-4, 10ng/mL, M2 inducer) for 72 hours. Similarly, primary cultures of human peripheral blood monocyte (PBM)-derived macrophages obtained from healthy subjects, were maintained in growth medium (untreated cells) or treated with ET-1 or IL-4 for 6 days. Both M0 and PBM-derived macrophages were pre-treated with ET receptor antagonist (ETA/BRA, bosentan 10-5M) for 1 hour before ET-1 stimulation. Protein and gene expression of CD204, CD206, CD163, TGFbeta1 were analysed by immunocytochemistry, Western blotting and quantitative real time polymerase chain reaction (qRT-PCR). Gene expression of interleukin(IL)-10 and macrophage derived chemokine (CCL-22) was evaluated by qRT-PCR. MMP-9 production was investigated by gel zymography. ET-1 significantly increased the expression of M2 phenotype markers CD204, CD206, CD163, IL-10 and CCL-22, and the production of MMP-9 in both cultures of M0 and PBM-derived macrophages compared to M0-controls and untreated cells. In cultured PBM-derived macrophages, ET-1 increased TGFbeta1 protein and gene expression compared to untreated cells. The ET-1-mediated effects were

  10. SULFUR- AND SILICON-BEARING MOLECULES IN PLANETARY NEBULAE: THE CASE OF M2-48

    Edwards, J. L.; Ziurys, L. M., E-mail: lziurys@email.arizona.edu [Department of Chemistry, The University of Arizona, P.O. Box 210041, Tucson, AZ 85721 (United States)

    2014-10-20

    Molecular-line observations of the bipolar planetary nebula (PN) M2-48 have been conducted using the Sub-Millimeter Telescope and the 12 m antenna of the Arizona Radio Observatory at 1, 2, and 3 mm. M2-48 is estimated to be ∼4800 yr old, midway through the PN evolutionary track. SiO and SO{sub 2} were detected in this source—the first identification of either molecule in a PN. CN, HCN, HNC, CS, SO, HCO{sup +}, N{sub 2}H{sup +}, and several {sup 13}C isotopologues such as {sup 13}CN, H{sup 13}CN, and H{sup 13}CO{sup +} were also observed toward this object. A radiative transfer analysis of multiple SiO transitions indicates a gas kinetic temperature of T {sub K} ∼ 55 K and a density of n(H{sub 2}) ∼ 9 × 10{sup 5} cm{sup –3} in M2-48, in agreement with previous CS and CO modeling. After CO, CN, and SO were found to be the most prevalent molecules in this nebula, with fractional abundances, relative to H{sub 2}, of f ∼ 3.8 × 10{sup –7} and 2.4 × 10{sup –7}, respectively. SO{sub 2} and HCN are also abundant, with f ∼ 1.2 × 10{sup –7}, indicating an [SO]/[SO{sub 2}] ratio of ∼2. Relatively high ion abundances were measured in M2-48 as well, with f ∼ 10{sup –7} for both HCO{sup +} and N{sub 2}H{sup +}. An [HCN]/[HNC] ratio of ∼2 was determined, as typically observed in other PNe, independent of age. The high abundances of SO and SO{sub 2}, along with the presence of SiO with f ∼ 2.9 × 10{sup –8}, suggest O/C > 1 in this source; furthermore, the prevalence of CN and N{sub 2}H{sup +} indicates nitrogen enrichment. The {sup 12}C/{sup 13}C ratio of ∼3 in the nebula was also established. These factors indicate hot-bottom burning occurred in the progenitor star of M2-48, suggesting an initial mass > 4 M {sub ☉}.

  11. A Predominantly Neolithic Origin for European Paternal Lineages

    Balaresque, Patricia; Bowden, Georgina R.; Adams, Susan M.; Leung, Ho-Yee; King, Turi E.; Rosser, Zoë H.; Goodwin, Jane; Moisan, Jean-Paul; Richard, Christelle; Millward, Ann; Demaine, Andrew G.; Barbujani, Guido; Previderè, Carlo; Wilson, Ian J.; Tyler-Smith, Chris; Jobling, Mark A.

    2010-01-01

    The relative contributions to modern European populations of Paleolithic hunter-gatherers and Neolithic farmers from the Near East have been intensely debated. Haplogroup R1b1b2 (R-M269) is the commonest European Y-chromosomal lineage, increasing in frequency from east to west, and carried by 110 million European men. Previous studies suggested a Paleolithic origin, but here we show that the geographical distribution of its microsatellite diversity is best explained by spread from a single source in the Near East via Anatolia during the Neolithic. Taken with evidence on the origins of other haplogroups, this indicates that most European Y chromosomes originate in the Neolithic expansion. This reinterpretation makes Europe a prime example of how technological and cultural change is linked with the expansion of a Y-chromosomal lineage, and the contrast of this pattern with that shown by maternally inherited mitochondrial DNA suggests a unique role for males in the transition. PMID:20087410

  12. Functional Characterization of DNA Methylation in the Oligodendrocyte Lineage

    Sarah Moyon

    2016-04-01

    Full Text Available Oligodendrocytes derive from progenitors (OPCs through the interplay of epigenomic and transcriptional events. By integrating high-resolution methylomics, RNA-sequencing, and multiple transgenic lines, this study defines the role of DNMT1 in developmental myelination. We detected hypermethylation of genes related to cell cycle and neurogenesis during differentiation of OPCs, yet genetic ablation of Dnmt1 resulted in inefficient OPC expansion and severe hypomyelination associated with ataxia and tremors in mice. This phenotype was not caused by lineage switch or massive apoptosis but was characterized by a profound defect of differentiation associated with changes in exon-skipping and intron-retention splicing events and by the activation of an endoplasmic reticulum stress response. Therefore, loss of Dnmt1 in OPCs is not sufficient to induce a lineage switch but acts as an important determinant of the coordination between RNA splicing and protein synthesis necessary for myelin formation.

  13. Dale Reed with model in front of M2-F1

    1967-01-01

    Dale Reed with a model of the M2-F1 in front of the actual lifting body. Reed used the model to show the potential of the lifting bodies. He first flew it into tall grass to test stability and trim, then hand-launched it from buildings for longer flights. Finally, he towed the lifting-body model aloft using a powered model airplane known as the 'Mothership.' A timer released the model and it glided to a landing. Dale's wife Donna used a 9 mm. camera to film the flights of the model. Its stability as it glided--despite its lack of wings--convinced Milt Thompson and some Flight Research Center engineers including the center director, Paul Bikle, that a piloted lifting body was possible. The lifting body concept evolved in the mid-1950s as researchers considered alternatives to ballistic reentries of piloted space capsules. The designs for hypersonic, wingless vehicles were on the boards at NASA Ames and NASA Langley facilities, while the US Air Force was gearing up for its Dyna-Soar program, which defined the need for a spacecraft that would land like an airplane. Despite favorable research on lifting bodies, there was little support for a flight program. Dryden engineer R. Dale Reed was intrigued with the lifting body concept, and reasoned that some sort of flight demonstration was needed before wingless aircraft could be taken seriously. In February 1962, he built a model lifting body based upon the Ames M2 design, and air-launched it from a radio controlled 'mothership.' Home movies of these flights, plus the support of research pilot Milt Thompson, helped pursuade the facilities director, Paul Bikle, to give the go-ahead for the construction of a full-scale version, to be used as a wind-tunnel model and possibly flown as a glider. Comparing lifting bodies to space capsules, an unofficial motto of the project was, 'Don't be Rescued from Outer Space--Fly Back in Style.' The construction of the M2-F1 was a joint effort by Dryden and a local glider manufacturer, the

  14. Evolutionary change in physiological phenotypes along the human lineage.

    Vining, Alexander Q; Nunn, Charles L

    2016-01-01

    Research in evolutionary medicine provides many examples of how evolution has shaped human susceptibility to disease. Traits undergoing rapid evolutionary change may result in associated costs or reduce the energy available to other traits. We hypothesize that humans have experienced more such changes than other primates as a result of major evolutionary change along the human lineage. We investigated 41 physiological traits across 50 primate species to identify traits that have undergone marked evolutionary change along the human lineage. We analysed the data using two Bayesian phylogenetic comparative methods. One approach models trait covariation in non-human primates and predicts human phenotypes to identify whether humans are evolutionary outliers. The other approach models adaptive shifts under an Ornstein-Uhlenbeck model of evolution to assess whether inferred shifts are more common on the human branch than on other primate lineages. We identified four traits with strong evidence for an evolutionary increase on the human lineage (amylase, haematocrit, phosphorus and monocytes) and one trait with strong evidence for decrease (neutrophilic bands). Humans exhibited more cases of distinct evolutionary change than other primates. Human physiology has undergone increased evolutionary change compared to other primates. Long distance running may have contributed to increases in haematocrit and mean corpuscular haemoglobin concentration, while dietary changes are likely related to increases in amylase. In accordance with the pathogen load hypothesis, human monocyte levels were increased, but many other immune-related measures were not. Determining the mechanisms underlying conspicuous evolutionary change in these traits may provide new insights into human disease. The Author(s) 2016. Published by Oxford University Press on behalf of the Foundation for Evolution, Medicine, and Public Health.

  15. Quantifying Selective Pressures Driving Bacterial Evolution Using Lineage Analysis

    Lambert, Guillaume; Kussell, Edo

    2015-01-01

    Organisms use a variety of strategies to adapt to their environments and maximize long-term growth potential, but quantitative characterization of the benefits conferred by the use of such strategies, as well as their impact on the whole population's rate of growth, remains challenging. Here, we use a path-integral framework that describes how selection acts on lineages—i.e., the life histories of individuals and their ancestors—to demonstrate that lineage-based measurements can be used to quantify the selective pressures acting on a population. We apply this analysis to Escherichia coli bacteria exposed to cyclical treatments of carbenicillin, an antibiotic that interferes with cell-wall synthesis and affects cells in an age-dependent manner. While the extensive characterization of the life history of thousands of cells is necessary to accurately extract the age-dependent selective pressures caused by carbenicillin, the same measurement can be recapitulated using lineage-based statistics of a single surviving cell. Population-wide evolutionary pressures can be extracted from the properties of the surviving lineages within a population, providing an alternative and efficient procedure to quantify the evolutionary forces acting on a population. Importantly, this approach is not limited to age-dependent selection, and the framework can be generalized to detect signatures of other trait-specific selection using lineage-based measurements. Our results establish a powerful way to study the evolutionary dynamics of life under selection and may be broadly useful in elucidating selective pressures driving the emergence of antibiotic resistance and the evolution of survival strategies in biological systems.

  16. Spiralian phylogeny informs the evolution of microscopic lineages.

    Laumer, Christopher E; Bekkouche, Nicolas; Kerbl, Alexandra; Goetz, Freya; Neves, Ricardo C; Sørensen, Martin V; Kristensen, Reinhardt M; Hejnol, Andreas; Dunn, Casey W; Giribet, Gonzalo; Worsaae, Katrine

    2015-08-03

    Despite rapid advances in the study of metazoan evolutionary history [1], phylogenomic analyses have so far neglected a number of microscopic lineages that possess a unique combination of characters and are thus informative for our understanding of morphological evolution. Chief among these lineages are the recently described animal groups Micrognathozoa and Loricifera, as well as the two interstitial "Problematica" Diurodrilus and Lobatocerebrum [2]. These genera show a certain resemblance to Annelida in their cuticle and gut [3, 4]; however, both lack primary annelid characters such as segmentation and chaetae [5]. Moreover, they show unique features such as an inverted body-wall musculature or a novel pharyngeal organ. This and their ciliated epidermis have led some to propose relationships with other microscopic spiralians, namely Platyhelminthes, Gastrotricha, and in the case of Diurodrilus, with Micrognathozoa [6, 7]-lineages that are grouped by some analyses into "Platyzoa," a clade whose status remains uncertain [1, 8-11]. Here, we assess the interrelationships among the meiofaunal and macrofaunal members of Spiralia using 402 orthologs mined from genome and transcriptome assemblies of 90 taxa. Lobatocerebrum and Diurodrilus are found to be deeply nested members of Annelida, and unequivocal support is found for Micrognathozoa as the sister group of Rotifera. Analyses using site-heterogeneous substitution models further recover a lophophorate clade and position Loricifera + Priapulida as sister group to the remaining Ecdysozoa. Finally, with several meiofaunal lineages branching off early in the diversification of Spiralia, the emerging concept of a microscopic, acoelomate, direct-developing ancestor of Spiralia is reviewed. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Major genomic mitochondrial lineages delineate early human expansions

    Flores Carlos

    2001-08-01

    Full Text Available Abstract Background The phylogeographic distribution of human mitochondrial DNA variations allows a genetic approach to the study of modern Homo sapiens dispersals throughout the world from a female perspective. As a new contribution to this study we have phylogenetically analysed complete mitochondrial DNA(mtDNA sequences from 42 human lineages, representing major clades with known geographic assignation. Results We show the relative relationships among the 42 lineages and present more accurate temporal calibrations than have been previously possible to give new perspectives as how modern humans spread in the Old World. Conclusions The first detectable expansion occurred around 59,000–69,000 years ago from Africa, independently colonizing western Asia and India and, following this southern route, swiftly reaching east Asia. Within Africa, this expansion did not replace but mixed with older lineages detectable today only in Africa. Around 39,000–52,000 years ago, the western Asian branch spread radially, bringing Caucasians to North Africa and Europe, also reaching India, and expanding to north and east Asia. More recent migrations have entangled but not completely erased these primitive footprints of modern human expansions.

  18. Biodiversity and the Species Concept-Lineages are not Enough.

    Freudenstein, John V; Broe, Michael B; Folk, Ryan A; Sinn, Brandon T

    2017-07-01

    The nature and definition of species continue to be matters of debate. Current views of species often focus on their nature as lineages-maximal reproductive communities through time. Whereas many authors point to the Evolutionary Species Concept as optimal, in its original form it stressed the ecological role of species as well as their history as lineages, but most recent authors have ignored the role aspect of the concept, making it difficult to apply unambiguously in a time-extended way. This trend has been exacerbated by the application of methods and concepts emphasizing the notion of monophyly, originally applied only at higher levels, to the level of individuals, as well as by the current emphasis on molecular data. Hence, some current authors recognize units that are no more than probable exclusive lineages as species. We argue that biodiversity is inherently a phenotypic concept and that role, as manifested in the organismal extended phenotype, is a necessary component of the species concept. Viewing species as historically connected populations with unique role brings together the temporal and phenotypic natures of species, providing a clear way to view species both in a time-limited and time-extended way. Doing so alleviates perceived issues with "paraphyletic species" and returns the focus of species to units that are most relevant for biodiversity. © The Author(s) 2016. Published by Oxford University Press, on behalf of the Society of Systematic Biologists. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  19. Y-chromosome lineages in native South American population.

    Blanco-Verea, A; Jaime, J C; Brión, M; Carracedo, A

    2010-04-01

    The present work tries to investigate the population structure and variation of the Amerindian indigenous populations living in Argentina. A total of 134 individuals from three ethnic groups (Kolla, Mapuche and Diaguitas) living in four different regions were collected and analysed for 26 Y-SNPs and 11 Y-STRs. Intra-population variability was analysed, looking for population substructure and neighbour populations were considered for genetic comparative analysis, in order to estimate the contribution of the Amerindian and the European pool, to the current population. We observe a high frequency of R1b1 and Q1a3a* Y-chromosome haplogroups, in the ethnic groups Mapuche, Diaguita and Kolla, characteristic of European and Native American populations, respectively. When we compare our native Argentinean population with other from the South America we also observe that frequency values for Amerindian lineages are relatively lower in our population. These results show a clear Amerindian genetic component but we observe a predominant European influence too, suggesting that typically European male lineages have given rise to the displacement of genuinely Amerindian male lineages in our South American population. Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

  20. Circulation of influenza B lineages in northern Viet Nam, 2007-2014.

    Le, Thi Thanh; Pham, Thu Hang; Pham, Thi Hien; Nguyen, Le Khanh Hang; Nguyen, Co Thach; Hoang, Vu Mai Phuong; Tran, Thu Huong; Nguyen, Vu Son; Ngo, Huong Giang; Le, Quynh Mai

    2015-01-01

    Influenza B viruses circulate throughout Viet Nam, and their activities vary by region. There have been two antigenically distinct lineages of influenza B viruses co-circulating in the past 20 years; however, only one lineage is selected as a component of contemporary trivalent seasonal influenza vaccines. To improve the understanding of circulating influenza B lineages and influenza vaccine mismatches, we report the virus lineages circulating in northern Viet Nam over an eight-year period (2007-2014). Lineages of 331 influenza B viruses were characterized by haemagglutination inhibition assay against standard reference ferret (Yamagata) and sheep (Victoria) antisera. Sequence analysis of the haemagglutinin gene was performed in 64 selected influenza B isolates. The proportion of influenza B lineages changed by year. The Yamagata lineage predominated in 2007, 2008 and 2012; the Victoria lineage predominated in 2009-2014 except 2012. The two lineages showed continuous evolution over time. The Northern Hemisphere's influenza vaccine components were mismatched with the predominant circulating viruses in 2007, 2009 and 2014. The seasonality of influenza B activity is more variable in tropical and subtropical regions than in temperate zones. Our data showed a common co-circulation of both influenza B lineages in northern Viet Nam, and it was difficult to predict which one was the predominant lineage. Quadrivalent influenza vaccines containing both lineages may improve the effectiveness of influenza vaccine programmes in the future.

  1. Circulation of influenza B lineages in northern Viet Nam, 2007–2014

    Le, Thi Thanh; Pham, Thu Hang; Pham, Thi Hien; Nguyen, Le Khanh Hang; Hoang, Vu Mai Phuong; Tran, Thu Huong; Nguyen, Vu Son; Ngo, Huong Giang

    2015-01-01

    Introduction Influenza B viruses circulate throughout Viet Nam, and their activities vary by region. There have been two antigenically distinct lineages of influenza B viruses co-circulating in the past 20 years; however, only one lineage is selected as a component of contemporary trivalent seasonal influenza vaccines. To improve the understanding of circulating influenza B lineages and influenza vaccine mismatches, we report the virus lineages circulating in northern Viet Nam over an eight-year period (2007–2014). Methods Lineages of 331 influenza B viruses were characterized by haemagglutination inhibition assay against standard reference ferret (Yamagata) and sheep (Victoria) antisera. Sequence analysis of the haemagglutinin gene was performed in 64 selected influenza B isolates. Results The proportion of influenza B lineages changed by year. The Yamagata lineage predominated in 2007, 2008 and 2012; the Victoria lineage predominated in 2009–2014 except 2012. The two lineages showed continuous evolution over time. The Northern Hemisphere’s influenza vaccine components were mismatched with the predominant circulating viruses in 2007, 2009 and 2014. Discussion The seasonality of influenza B activity is more variable in tropical and subtropical regions than in temperate zones. Our data showed a common co-circulation of both influenza B lineages in northern Viet Nam, and it was difficult to predict which one was the predominant lineage. Quadrivalent influenza vaccines containing both lineages may improve the effectiveness of influenza vaccine programmes in the future. PMID:26798557

  2. Identification of a PVL-negative SCCmec-IVa sub-lineage of the methicillin-resistant Staphylococcus aureus CC80 lineage

    Edslev, Sofie Marie; Westh, Henrik Torkil; Andersen, Paal Skytt

    2018-01-01

    of the CC80 S. aureus lineage was conducted from whole-genome sequences of 217 isolates (23 MSSA and 194 MRSA) from 22 countries. All isolates were further genetically characterized in regard to resistance determinants and PVL carriage, and epidemiological data was obtained for selected isolates. RESULTS....... CONCLUSIONS: This study reports the emergence of a novel CC80 CA-MRSA sub-lineage, showing that the CC80 lineage is more diverse than previously assumed....

  3. Sequence-length variation of mtDNA HVS-I C-stretch in Chinese ethnic groups.

    Chen, Feng; Dang, Yong-hui; Yan, Chun-xia; Liu, Yan-ling; Deng, Ya-jun; Fulton, David J R; Chen, Teng

    2009-10-01

    The purpose of this study was to investigate mitochondrial DNA (mtDNA) hypervariable segment-I (HVS-I) C-stretch variations and explore the significance of these variations in forensic and population genetics studies. The C-stretch sequence variation was studied in 919 unrelated individuals from 8 Chinese ethnic groups using both direct and clone sequencing approaches. Thirty eight C-stretch haplotypes were identified, and some novel and population specific haplotypes were also detected. The C-stretch genetic diversity (GD) values were relatively high, and probability (P) values were low. Additionally, C-stretch length heteroplasmy was observed in approximately 9% of individuals studied. There was a significant correlation (r=-0.961, Ppopulations. The results from the Fst and dA genetic distance matrix, neighbor-joining tree, and principal component map also suggest that C-stretch could be used as a reliable genetic marker in population genetics.

  4. Pursuing the quest for better understanding the taxonomic distribution of the system of doubly uniparental inheritance of mtDNA

    Arthur Gusman

    2016-12-01

    Full Text Available There is only one exception to strict maternal inheritance of mitochondrial DNA (mtDNA in the animal kingdom: a system named doubly uniparental inheritance (DUI, which is found in several bivalve species. Why and how such a radically different system of mitochondrial transmission evolved in bivalve remains obscure. Obtaining a more complete taxonomic distribution of DUI in the Bivalvia may help to better understand its origin and function. In this study we provide evidence for the presence of sex-linked heteroplasmy (thus the possible presence of DUI in two bivalve species, i.e., the nuculanoid Yoldia hyperborea(Gould, 1841and the veneroid Scrobicularia plana(Da Costa,1778, increasing the number of families in which DUI has been found by two. An update on the taxonomic distribution of DUI in the Bivalvia is also presented.

  5. Molecular phylogeny of grey mullets (Teleostei: Mugilidae) in Greece: evidence from sequence analysis of mtDNA segments.

    Papasotiropoulos, Vasilis; Klossa-Kilia, Elena; Alahiotis, Stamatis N; Kilias, George

    2007-08-01

    Mitochondrial DNA sequence analysis has been used to explore genetic differentiation and phylogenetic relationships among five species of the Mugilidae family, Mugil cephalus, Chelon labrosus, Liza aurata, Liza ramada, and Liza saliens. DNA was isolated from samples originating from the Messolongi Lagoon in Greece. Three mtDNA segments (12s rRNA, 16s rRNA, and CO I) were PCR amplified and sequenced. Sequencing analysis revealed that the greatest genetic differentiation was observed between M. cephalus and all the other species studied, while C. labrosus and L. aurata were the closest taxa. Dendrograms obtained by the neighbor-joining method and Bayesian inference analysis exhibited the same topology. According to this topology, M. cephalus is the most distinct species and the remaining taxa are clustered together, with C. labrosus and L. aurata forming a single group. The latter result brings into question the monophyletic origin of the genus Liza.

  6. A molecular phylogeny of the Cephinae (Hymenoptera, Cephidae based on mtDNA COI gene: a test of traditional classification

    Mahir Budak

    2011-09-01

    Full Text Available Cephinae is traditionally divided into three tribes and about 24 genera based on morphology and host utilization. There has been no study testing the monophyly of taxa under a strict phylogenetic criterion. A molecular phylogeny of Cephinae based on a total of 68 sequences of mtDNA COI gene, representing seven genera of Cephinae, is reconstructed to test the traditional limits and relationships of taxa. Monophyly of the traditional tribes is not supported. Monophyly of the genera are largely supported except for Pachycephus. A few host shift events are suggested based on phylogenetic relationships among taxa. These results indicate that a more robust phylogeny is required for a more plausible conclusion. We also report two species of Cephus for the first time from Turkey.

  7. Improved analyses of human mtDNA sequences support a recent African origin for Homo sapiens.

    Penny, D; Steel, M; Waddell, P J; Hendy, M D

    1995-09-01

    New quantitative methods are applied to the 135 human mitochondrial sequences from the Vigilant et al. data set. General problems in analyzing large numbers of short sequences are discussed, and an improved strategy is suggested. A key feature is to focus not on individual trees but on the general "landscape" of trees. Over 1,000 searches were made from random starting trees with only one tree (a local optimum) being retained each time, thereby ensuring optima were found independently. A new tree comparison metric was developed that is unaffected by rearrangements of trees around many very short internal edges. Use of this metric showed that downweighting hypervariable sites revealed more evolutionary structure than studies that weighted all sites equally. Our results are consistent with convergence toward a global optimum. Crucial features are that the best optima show very strong regional differentiation, a common group of 49 African sequences is found in all the best optima, and the best optima contain the 16 !Kung sequences in a separate group of San people. The other 86 sequences form a heterogeneous mixture of Africans, Europeans, Australopapuans, and Asians. Thus all major human lineages occur in Africa, but only a subset occurs in the rest of the world. The existence of these African-only groups strongly contradicts multiregional theories for the origin of Homo sapiens that require widespread migration and interbreeding over the entire range of H. erectus. Only when the multiregional model is rejected is it appropriate to consider the root, based on a single locus, to be the center of origin of a population (otherwise different loci could give alternative geographic positions for the root). For this data, several methods locate the root within the group of 49 African sequences and are thus consistent with the recent African origin of H. sapiens. We demonstrate that the time of the last common ancestor cannot be the time of major expansion in human numbers

  8. Deciphering the link between doubly uniparental inheritance of mtDNA and sex determination in bivalves: Clues from comparative transcriptomics

    Capt, Charlotte; Renaut, Sébastien; Ghiselli, Fabrizio; Milani, Liliana; Johnson, Nathan A.; Sietman, Bernard E.; Stewart, Donald; Breton, Sophie

    2018-01-01

    Bivalves exhibit an astonishing diversity of sexual systems and sex-determining mechanisms. They can be gonochoric, hermaphroditic or androgenetic, with both genetic and environmental factors known to determine or influence sex. One unique sex-determining system involving the mitochondrial genome has also been hypothesized to exist in bivalves with doubly uniparental inheritance (DUI) of mtDNA. However, the link between DUI and sex determination remains obscure. In this study, we performed a comparative gonad transcriptomics analysis for two DUI-possessing freshwater mussel species to better understand the mechanisms underlying sex determination and DUI in these bivalves. We used a BLAST reciprocal analysis to identify orthologs between Venustaconcha ellipsiformis and Utterbackia peninsularis and compared our results with previously published sex-specific bivalve transcriptomes to identify conserved sex-determining genes. We also compared our data with other DUI species to identify candidate genes possibly involved in the regulation of DUI. A total of ∼12,000 orthologous relationships were found, with 2,583 genes differentially expressed in both species. Among these genes, key sex-determining factors previously reported in vertebrates and in bivalves (e.g., Sry, Dmrt1, Foxl2) were identified, suggesting that some steps of the sex-determination pathway may be deeply conserved in metazoans. Our results also support the hypothesis that a modified ubiquitination mechanism could be responsible for the retention of the paternal mtDNA in male bivalves, and revealed that DNA methylation could also be involved in the regulation of DUI. Globally, our results suggest that sets of genes associated with sex determination and DUI are similar in distantly-related DUI species.

  9. Integration of mtDNA pseudogenes into the nuclear genome coincides with speciation of the human genus. A hypothesis.

    Gunbin, Konstantin; Peshkin, Leonid; Popadin, Konstantin; Annis, Sofia; Ackermann, Rebecca R; Khrapko, Konstantin

    2017-05-01

    Fragments of mitochondrial DNA are known to get inserted into nuclear DNA to form NUMTs, i.e. nuclear pseudogenes of the mtDNA. The insertion of a NUMT is a rare event. Hundreds of pseudogenes have been cataloged in the human genome. NUMTs are, in essence, a special type of mutation with their own internal timer, which is synchronized with an established molecular clock, the mtDNA. Thus insertion of NUMTs can be timed with respect to evolution milestones such as the emergence of new species. We asked whether NUMTs were inserted uniformly over time or preferentially during certain periods of evolution, as implied by the "punctuated evolution" model. To our surprise, the NUMT insertion times do appear nonrandom with at least one cluster positioned at around 2.8 million years ago (Ma). Interestingly, 2.8Ma closely corresponds to the time of emergence of the genus Homo, and to a well-documented period of major climate change ca. 2.9-2.5Ma. It is tempting to hypothesize that the insertion of NUMTs is related to the speciation process. NUMTs could be either "riders", i.e., their insertion could be facilitated by the overall higher genome rearrangement activity during speciation, or "drivers", i.e. they may more readily get fixed in the population due to positive selection associated with speciation. If correct, the hypothesis would support the idea that evolution of our genus may have happened in a rapid, punctuated manner. Copyright © 2016 Elsevier B.V. and Mitochondria Research Society. All rights reserved.

  10. DsbA-L prevents obesity-induced inflammation and insulin resistance by suppressing the mtDNA release-activated cGAS-cGAMP-STING pathway

    Chronic inflammation in adipose tissue plays a key role in obesity-induced insulin resistance. However, the mechanisms underlying obesity-induced inflammation remain elusive. Here we show that obesity promotes mtDNA release into the cytosol, where it triggers inflammatory responses by activating the...

  11. Data on haplotype diversity in the hypervariable region I, II and III of mtDNA amongst the Brahmin population of Haryana

    Kapil Verma

    2018-04-01

    Full Text Available Human mitochondrial DNA (mtDNA is routinely analysed for pathogenic mutations, evolutionary studies, estimation of time of divergence within or between species, phylogenetic studies and identification of degraded remains. The data on various regions of human mtDNA has added enormously to the knowledge pool of population genetics as well as forensic genetics. The displacement-loop (D-loop in the control region of mtDNA is rated as the most rapidly evolving part, due to the presence of variations in this region. The control region consists of three hypervariable regions. These hypervariable regions (HVI, HVII and HVIII tend to mutate 5–10 times faster than nuclear DNA. The high mutation rate of these hypervariable regions is used in population genetic studies and human identity testing. In the present data, potentially informative hypervariable regions of mitochondrial DNA (mtDNA i.e. HVI (np 16024–16365, HVII (np 73–340 and HVIII (np 438–576 were estimated to understand the genetic diversity amongst Brahmin population of Haryana. Blood samples had been collected from maternally unrelated individuals from the different districts of Haryana. An array of parameters comprising of polymorphic sites, transitions, transversions, deletions, gene diversity, nucleotide diversity, pairwise differences, Tajima's D test, Fu's Fs test, mismatch observed variance and expected heterozygosity were estimated. The observed polymorphisms with their respective haplogroups in comparison to rCRS were assigned. Keywords: Mitochondrial DNA, D-loop, Hypervariable regions, Forensic genetics

  12. Variation and association to diabetes in 2000 full mtDNA sequences mined from an exome study in a Danish population

    Li, Shengting; Besenbacher, Soren; Li, Yingrui

    2014-01-01

    In this paper, we mine full mtDNA sequences from an exome capture data set of 2000 Danes, showing that it is possible to get high-quality full-genome sequences of the mitochondrion from this resource. The sample includes 1000 individuals with type 2 diabetes and 1000 controls. We characterise...

  13. The co-occurrence of mtDNA mutations on different oxidative phosphorylation subunits, not detected by haplogroup analysis, affects human longevity and is population specific

    Raule, Nicola; Sevini, Federica; Li, Shengting

    2014-01-01

    To re-examine the correlation between mtDNA variability and longevity, we examined mtDNAs from samples obtained from over 2200 ultranonagenarians (and an equal number of controls) collected within the framework of the GEHA EU project. The samples were categorized by high-resolution classification...

  14. LASIK flap characteristics using the Moria M2 microkeratome with the 90-microm single use head.

    Aslanides, Ioannis M; Tsiklis, Nikolaos S; Astyrakakis, Nikolaos I; Pallikaris, Ioannis G; Jankov, Mirko R

    2007-01-01

    To evaluate the accuracy and consistency of corneal flap thickness, horizontal diameter, and hinge size with the Moria M2 90-microm single use head. Fifty-two myopic patients (104 eyes), mean age 32.6 years, underwent bilateral LASIK with a superior hinged flap using the Moria M2 microkeratome (90-microm single use head). Prospective evaluation included flap thickness (subtraction method), diameter, hinge size, interface particles, intraoperative complications, and visual recovery. The mean preoperative spherical equivalent refraction was -5.72 +/- 2.59 diopters (D) (range: -2.88 to -10.75 D) and -5.84 +/- 2.73 D (range: -3.13 to -9.38 D) for right and left eyes, respectively. The mean preoperative central corneal thickness was 548 +/- 24 microm and 547 +/- 25 microm for right and left eyes, respectively. The mean preoperative steepest K was 44.12 +/- 1.28 D and 44.41 +/- 1.27 D for right and left eyes, respectively. Corneal diameter (white-to-white) was 12 +/- 0.4 mm and 11.9 +/- 0.4 mm for right and left eyes, respectively. The mean postoperative flap thickness was 109 +/- 18 microm (range: 67 to 152 microm) and 103 +/- 15 microm (range: 65 to 151 microm) for right and left eyes, respectively. The mean postoperative flap diameter was 9.4 +/- 0.3 mm (expected mean according to the nomogram given by the company was 9.5 mm). The mean postoperative hinge chord was 4.4 +/- 0.4 mm (expected mean 4.2 mm). No interface particles were detected on slit-lamp examination. The Moria M2 90-microm single use head is safe with reasonable predictability for LASIK flap creation.

  15. Towards Efficient Mobile M2M Communications: Survey and Open Challenges

    Carlos Pereira

    2014-10-01

    Full Text Available Machine-to-Machine (M2M communications enable networked devices and services to exchange information and perform actions seamlessly without the need for human intervention. They are viewed as a key enabler of the Internet of Things (IoT and ubiquitous applications, like mobile healthcare, telemetry, or intelligent transport systems. We survey existing work on mobile M2M communications, we identify open challenges that have a direct impact on performance and resource usage efficiency, especially the impact on energy efficiency, and we review techniques to improve communications. We review the ETSI standard and application protocols, and draw considerations on the impact of their use in constrained mobile devices. Nowadays, smartphones are equipped with a wide range of embedded sensors, with varied local and wide area connectivity capabilities, and thus they offer a unique opportunity to serve as mobile gateways for other more constrained devices with local connectivity. At the same time, they can gather context data about users and environment from the embedded sensors. These capabilities may be crucial for mobile M2M applications. Finally, in this paper, we consider a scenario where smartphones are used as gateways that collect and aggregate data from sensors in a cellular network. We conclude that, in order for their use to the feasible in terms of a normal depletion time of a smartphone’s battery, it is a good advice to maximize the collection of data necessary to be transmitted from nearby sensors, and maximize the intervals between transmissions. More research is required to devise energy efficient transmission methods that enable the use of smartphones as mobile gateways.

  16. Towards efficient mobile M2M communications: survey and open challenges.

    Pereira, Carlos; Aguiar, Ana

    2014-10-20

    Machine-to-Machine (M2M) communications enable networked devices and services to exchange information and perform actions seamlessly without the need for human intervention. They are viewed as a key enabler of the Internet of Things (IoT) and ubiquitous applications, like mobile healthcare, telemetry, or intelligent transport systems. We survey existing work on mobile M2M communications, we identify open challenges that have a direct impact on performance and resource usage efficiency, especially the impact on energy efficiency, and we review techniques to improve communications. We review the ETSI standard and application protocols, and draw considerations on the impact of their use in constrained mobile devices. Nowadays, smartphones are equipped with a wide range of embedded sensors, with varied local and wide area connectivity capabilities, and thus they offer a unique opportunity to serve as mobile gateways for other more constrained devices with local connectivity. At the same time, they can gather context data about users and environment from the embedded sensors. These capabilities may be crucial for mobile M2M applications. Finally, in this paper, we consider a scenario where smartphones are used as gateways that collect and aggregate data from sensors in a cellular network. We conclude that, in order for their use to the feasible in terms of a normal depletion time of a smartphone's battery, it is a good advice to maximize the collection of data necessary to be transmitted from nearby sensors, and maximize the intervals between transmissions. More research is required to devise energy efficient transmission methods that enable the use of smartphones as mobile gateways.

  17. A stringy origin of M2 brane Chern-Simons theories

    Aganagic, Mina

    2010-01-01

    We show that string duality relates M-theory on a local Calabi-Yau fourfold singularity X 4 to type IIA string theory on a Calabi-Yau threefold X 3 fibered over a real line, with RR 2-form fluxes turned on. The RR flux encodes how the M-theory circle is fibered over the IIA geometry. The theories on N D2 branes probing X 3 are the well-known quiver theories with N=2 supersymmetry in three dimensions. We show that turning on fluxes, and fibering the X 3 over a direction transverse to the branes, corresponds to turning on N=2 Chern-Simons couplings. String duality implies that, in the strong coupling limit, the N D2 branes on X 3 in this background become N M2 branes on X 4 . This provides a string theory derivation for the recently conjectured description of the M2 brane theories on Calabi-Yau fourfolds in terms of N=2 quiver Chern-Simons theories. We also provide a new N=2 Chern-Simons theory dual to AdS 4 xQ 1,1,1 . Type IIA/M-theory duality also relates IIA string theory on X 3 with only the RR fluxes turned on, to M-theory on a G 2 holonomy manifold. We show that this implies that the N M2 branes probing the G 2 manifold are described by the quiver Chern-Simons theory originating from the D2 branes probing X 3 , except that now Chern-Simons terms preserve only N=1 supersymmetry in three dimensions.

  18. Selection of mutants of Chenopodium quinoa Willd. in the generation M2, quantification of saponins on the Islunga and Barandales varieties adapted to the Toluca Valley

    Fernandez V, S.O.

    1996-01-01

    The saponins and total lipids was measured in the variants of Barandales and Isluga of Chenopodium quinoa Willd and the mutants of both variants in the M 2 lineage. These two variants were gamma radiated at different levels: 0, 50, 100, 150, 200, 250, 300, 350, 400 and 500 Gy in the M1 generation. At the same time the mutants with favorable agronomic characteristics were selected. The samples were growth on the field (cultivated) and the seeds were recovered (harvested), measuring the emergence agronomic variables, plant height, density and seed yield. Lipids totals and saponins were measured in the seeds. The samples of radiated seeds with gamma-ray at different levels, were dried and grinded until to obtain a powder. The lipids was extracted with diethyl-ether, and in this solution was measured the total lipid content. The saponins were extracted in a later step, concentrated and precipitated. After the precipitation step the sapogenins were hydrolized and extracted with methyl alcohol. The extracts were centifugated and the solid material was dried and weighted. Finally, the measurement of the oleanolic acid was carried out by high pressure liquid chromatography. One conversion factor permits to relate this acid with the total saponin content. (Author)

  19. An M/M/2 Queueing System with Heterogeneous Servers Including One with Working Vacation

    A. Krishnamoorthy

    2012-01-01

    Full Text Available This paper analyzes an M/M/2 queueing system with two heterogeneous servers, one of which is always available but the other goes on vacation in the absence of customers waiting for service. The vacationing server, however, returns to serve at a low rate as an arrival finds the other server busy. The system is analyzed in the steady state using matrix geometric method. Busy period of the system is analyzed and mean waiting time in the stationary regime computed. Conditional stochastic decomposition of stationary queue length is obtained. An illustrative example is also provided.

  20. Uptake of BSH in M2R melanoma cells monitored by NMR spectroscopy

    Koudinova, N.; Elhanati, G.; Salomon, Y.; Bendel, P.

    2000-01-01

    The accumulation ratio of BSH, relative to that of boric acid, in M2R mouse melanoma cells, was measured using 11 B NMR of the cell extracts. The cells were incubated in growth medium for up to 24 h, in the presence of 0.8 mM boric acid and 0.25-1.5 mM BSH. The aqueous phase of the cellular extracts was re-suspended for NMR spectroscopy. The relative accumulation ratio of BSH/boric acid determined from 9 separate experiments was 0.45±0.09. (author)

  1. M2 macrophages activate WNT signaling pathway in epithelial cells: relevance in ulcerative colitis.

    Jesús Cosín-Roger

    Full Text Available Macrophages, which exhibit great plasticity, are important components of the inflamed tissue and constitute an essential element of regenerative responses. Epithelial Wnt signalling is involved in mechanisms of proliferation and differentiation and expression of Wnt ligands by macrophages has been reported. We aim to determine whether the macrophage phenotype determines the expression of Wnt ligands, the influence of the macrophage phenotype in epithelial activation of Wnt signalling and the relevance of this pathway in ulcerative colitis. Human monocyte-derived macrophages and U937-derived macrophages were polarized towards M1 or M2 phenotypes and the expression of Wnt1 and Wnt3a was analyzed by qPCR. The effects of macrophages and the role of Wnt1 were analyzed on the expression of β-catenin, Tcf-4, c-Myc and markers of cell differentiation in a co-culture system with Caco-2 cells. Immunohistochemical staining of CD68, CD206, CD86, Wnt1, β-catenin and c-Myc were evaluated in the damaged and non-damaged mucosa of patients with UC. We also determined the mRNA expression of Lgr5 and c-Myc by qPCR and protein levels of β-catenin by western blot. Results show that M2, and no M1, activated the Wnt signaling pathway in co-culture epithelial cells through Wnt1 which impaired enterocyte differentiation. A significant increase in the number of CD206+ macrophages was observed in the damaged mucosa of chronic vs newly diagnosed patients. CD206 immunostaining co-localized with Wnt1 in the mucosa and these cells were associated with activation of canonical Wnt signalling pathway in epithelial cells and diminution of alkaline phosphatase activity. Our results show that M2 macrophages, and not M1, activate Wnt signalling pathways and decrease enterocyte differentiation in co-cultured epithelial cells. In the mucosa of UC patients, M2 macrophages increase with chronicity and are associated with activation of epithelial Wnt signalling and diminution in

  2. Study on surface modification of M2 steel induced by Cu ions and Al ions implantation

    Wang Chao; Liu Zhengmin

    2001-01-01

    Changes of surface hardness and wear resistances in M2 type steel implanted by Cu Al ions were reported. The dependence of surface strengthening on ion species and dose was studied by X-ray diffraction (XRD) and Rutherford Backscattering Spectroscopy (RBS) for microhardness and wear resistances measurement. It is shown that both hardness and wear resistance increases apparently after ion implantation. XRD analysis indicates that different phases formed after Al Cu ions implanted. It is also suggested that Cu, Al ions have different role in surface strengthening

  3. Anti-replicative recombinant 5S rRNA molecules can modulate the mtDNA heteroplasmy in a glucose-dependent manner.

    Loutre, Romuald; Heckel, Anne-Marie; Jeandard, Damien; Tarassov, Ivan; Entelis, Nina

    2018-01-01

    Mutations in mitochondrial DNA are an important source of severe and incurable human diseases. The vast majority of these mutations are heteroplasmic, meaning that mutant and wild-type genomes are present simultaneously in the same cell. Only a very high proportion of mutant mitochondrial DNA (heteroplasmy level) leads to pathological consequences. We previously demonstrated that mitochondrial targeting of small RNAs designed to anneal with mutant mtDNA can decrease the heteroplasmy level by specific inhibition of mutant mtDNA replication, thus representing a potential therapy. We have also shown that 5S ribosomal RNA, partially imported into human mitochondria, can be used as a vector to deliver anti-replicative oligoribonucleotides into human mitochondria. So far, the efficiency of cellular expression of recombinant 5S rRNA molecules bearing therapeutic insertions remained very low. In the present study, we designed new versions of anti-replicative recombinant 5S rRNA targeting a large deletion in mitochondrial DNA which causes the KSS syndrome, analyzed their specific annealing to KSS mitochondrial DNA and demonstrated their import into mitochondria of cultured human cells. To obtain an increased level of the recombinant 5S rRNA stable expression, we created transmitochondrial cybrid cell line bearing a site for Flp-recombinase and used this system for the recombinase-mediated integration of genes coding for the anti-replicative recombinant 5S rRNAs into nuclear genome. We demonstrated that stable expression of anti-replicative 5S rRNA versions in human transmitochondrial cybrid cells can induce a shift in heteroplasmy level of KSS mutation in mtDNA. This shift was directly dependent on the level of the recombinant 5S rRNA expression and the sequence of the anti-replicative insertion. Quantification of mtDNA copy number in transfected cells revealed the absence of a non-specific effect on wild type mtDNA replication, indicating that the decreased proportion

  4. Quantitation of heteroplasmy of mtDNA sequence variants identified in a population of AD patients and controls by array-based resequencing.

    Coon, Keith D; Valla, Jon; Szelinger, Szabolics; Schneider, Lonnie E; Niedzielko, Tracy L; Brown, Kevin M; Pearson, John V; Halperin, Rebecca; Dunckley, Travis; Papassotiropoulos, Andreas; Caselli, Richard J; Reiman, Eric M; Stephan, Dietrich A

    2006-08-01

    The role of mitochondrial dysfunction in the pathogenesis of Alzheimer's disease (AD) has been well documented. Though evidence for the role of mitochondria in AD seems incontrovertible, the impact of mitochondrial DNA (mtDNA) mutations in AD etiology remains controversial. Though mutations in mitochondrially encoded genes have repeatedly been implicated in the pathogenesis of AD, many of these studies have been plagued by lack of replication as well as potential contamination of nuclear-encoded mitochondrial pseudogenes. To assess the role of mtDNA mutations in the pathogenesis of AD, while avoiding the pitfalls of nuclear-encoded mitochondrial pseudogenes encountered in previous investigations and showcasing the benefits of a novel resequencing technology, we sequenced the entire coding region (15,452 bp) of mtDNA from 19 extremely well-characterized AD patients and 18 age-matched, unaffected controls utilizing a new, reliable, high-throughput array-based resequencing technique, the Human MitoChip. High-throughput, array-based DNA resequencing of the entire mtDNA coding region from platelets of 37 subjects revealed the presence of 208 loci displaying a total of 917 sequence variants. There were no statistically significant differences in overall mutational burden between cases and controls, however, 265 independent sites of statistically significant change between cases and controls were identified. Changed sites were found in genes associated with complexes I (30.2%), III (3.0%), IV (33.2%), and V (9.1%) as well as tRNA (10.6%) and rRNA (14.0%). Despite their statistical significance, the subtle nature of the observed changes makes it difficult to determine whether they represent true functional variants involved in AD etiology or merely naturally occurring dissimilarity. Regardless, this study demonstrates the tremendous value of this novel mtDNA resequencing platform, which avoids the pitfalls of erroneously amplifying nuclear-encoded mtDNA pseudogenes, and

  5. Distinct interneuron types express m2 muscarinic receptor immunoreactivity on their dendrites or axon terminals in the hippocampus.

    Hájos, N; Papp, E C; Acsády, L; Levey, A I; Freund, T F

    1998-01-01

    In previous studies m2 muscarinic acetylcholine receptor-immunoreactive interneurons and various types of m2-positive axon terminals have been described in the hippocampal formation. The aim of the present study was to identify the types of interneurons expressing m2 receptor and to examine whether the somadendritic and axonal m2 immunostaining labels the same or distinct cell populations. In the CA1 subfield, neurons immunoreactive for m2 have horizontal dendrites, they are located at the stratum oriens/alveus border and have an axon that project to the dendritic region of pyramidal cells. In the CA3 subfield and the hilus, m2-positive neurons are multipolar and are scattered in all layers except stratum lacunosum-moleculare. In stratum pyramidale of the CA1 and CA3 regions, striking axon terminal staining for m2 was observed, surrounding the somata and axon initial segments of pyramidal cells in a basket-like manner. The co-localization of m2 with neurochemical markers and GABA was studied using the "mirror" technique and fluorescent double-immunostaining at the light microscopic level and with double-labelling using colloidal gold-conjugated antisera and immunoperoxidase reaction (diaminobenzidine) at the electron microscopic level. GABA was shown to be present in the somata of most m2-immunoreactive interneurons, as well as in the majority of m2-positive terminals in all layers. The calcium-binding protein parvalbumin was absent from practically all m2-immunoreactive cell bodies and dendrites. In contrast, many of the terminals synapsing on pyramidal cell somata and axon initial segments co-localized parvalbumin and m2, suggesting a differential distribution of m2 receptor immunoreactivity on the axonal and somadendritic membrane of parvalbumin-containing basket and axo-axonic cells. The co-existence of m2 receptors with the calcium-binding protein calbindin and the neuropeptides cholecystokinin and vasoactive intestinal polypeptide was rare throughout the

  6. Limited phylogeographic signal in sex-linked and autosomal loci despite geographically, ecologically, and phenotypically concordant structure of mtDNA variation in the Holarctic avian genus Eremophila.

    Sergei V Drovetski

    Full Text Available Phylogeographic studies of Holarctic birds are challenging because they involve vast geographic scale, complex glacial history, extensive phenotypic variation, and heterogeneous taxonomic treatment across countries, all of which require large sample sizes. Knowledge about the quality of phylogeographic information provided by different loci is crucial for study design. We use sequences of one mtDNA gene, one sex-linked intron, and one autosomal intron to elucidate large scale phylogeographic patterns in the Holarctic lark genus Eremophila. The mtDNA ND2 gene identified six geographically, ecologically, and phenotypically concordant clades in the Palearctic that diverged in the Early-Middle Pleistocene and suggested paraphyly of the horned lark (E. alpestris with respect to the Temminck's lark (E. bilopha. In the Nearctic, ND2 identified five subclades which diverged in the Late Pleistocene. They overlapped geographically and were not concordant phenotypically or ecologically. Nuclear alleles provided little information on geographic structuring of genetic variation in horned larks beyond supporting the monophyly of Eremophila and paraphyly of the horned lark. Multilocus species trees based on two nuclear or all three loci provided poor support for haplogroups identified by mtDNA. The node ages calculated using mtDNA were consistent with the available paleontological data, whereas individual nuclear loci and multilocus species trees appeared to underestimate node ages. We argue that mtDNA is capable of discovering independent evolutionary units within avian taxa and can provide a reasonable phylogeographic hypothesis when geographic scale, geologic history, and phenotypic variation in the study system are too complex for proposing reasonable a priori hypotheses required for multilocus methods. Finally, we suggest splitting the currently recognized horned lark into five Palearctic and one Nearctic species.

  7. Neurotoxicity of cytarabine (Ara-C) in dorsal root ganglion neurons originates from impediment of mtDNA synthesis and compromise of mitochondrial function.

    Zhuo, Ming; Gorgun, Murat F; Englander, Ella W

    2018-06-01

    Peripheral Nervous System (PNS) neurotoxicity caused by cancer drugs hinders attainment of chemotherapy goals. Due to leakiness of the blood nerve barrier, circulating chemotherapeutic drugs reach PNS neurons and adversely affect their function. Chemotherapeutic drugs are designed to target dividing cancer cells and mechanisms underlying their toxicity in postmitotic neurons remain to be fully clarified. The objective of this work was to elucidate progression of events triggered by antimitotic drugs in postmitotic neurons. For proof of mechanism study, we chose cytarabine (ara-C), an antimetabolite used in treatment of hematological cancers. Ara-C is a cytosine analog that terminates DNA synthesis. To investigate how ara-C affects postmitotic neurons, which replicate mitochondrial but not genomic DNA, we adapted a model of Dorsal Root Ganglion (DRG) neurons. We showed that DNA polymerase γ, which is responsible for mtDNA synthesis, is inhibited by ara-C and that sublethal ara-C exposure of DRG neurons leads to reduction in mtDNA content, ROS generation, oxidative mtDNA damage formation, compromised mitochondrial respiration and diminution of NADPH and GSH stores, as well as, activation of the DNA damage response. Hence, it is plausible that in ara-C exposed DRG neurons, ROS amplified by the high mitochondrial content shifts from physiologic to pathologic levels signaling stress to the nucleus. Combined, the findings suggest that ara-C neurotoxicity in DRG neurons originates in mitochondria and that continuous mtDNA synthesis and reliance on oxidative phosphorylation for energy needs sensitize the highly metabolic neurons to injury by mtDNA synthesis terminating cancer drugs. Copyright © 2018 Elsevier Inc. All rights reserved.

  8. Mid-infrared imaging of the bipolar planetary nebula M2-9 from SOFIA

    Werner, M. W.; Sahai, R.; Davis, J.; Livingston, J. [Jet Propulsion Laboratory, California Institute of Technology, 4800 Oak Grove Drive, Pasadena, CA 91107 (United States); Lykou, F. [Institute for Astronomy, University of Vienna, Turkenschanzstrasse 17, A-1180, Vienna (Austria); DE Buizer, J. [USRA SOFIA Science Center, M/S 211-3, NASA Ames Research Center, Moffett Field, CA 94035 (United States); Morris, M. R. [Division of Astronomy, P.O. Box 951547, UCLA, Los Angeles, CA 90095 (United States); Keller, L. [Department of Physics, Ithaca College, Ithaca, NY 14850 (United States); Adams, J.; Gull, G.; Henderson, C.; Herter, T.; Schoenwald, J., E-mail: Michael.W.Werner@jpl.nasa.gov [Department of Astronomy, Cornell University, Ithaca, NY 14853 (United States)

    2014-01-10

    We have imaged the bipolar planetary nebula M2-9 using SOFIA's FORCAST instrument in six wavelength bands between 6.6 and 37.1 μm. A bright central point source, unresolved with SOFIA's ∼4''-5'' beam, is seen at each wavelength, and the extended bipolar lobes are clearly seen at 19.7 μm and beyond. The photometry between 10 and 25 μm is well fit by the emission predicted from a stratified disk seen at large inclination, as has been proposed for this source by Lykou et al. and by Smith and Gehrz. The principal new results in this paper relate to the distribution and properties of the dust that emits the infrared radiation. In particular, a considerable fraction of this material is spread uniformly through the lobes, although the dust density does increase at the sharp outer edge seen in higher resolution optical images of M2-9. The dust grain population in the lobes shows that small (<0.1 μm) and large (>1 μm) particles appear to be present in roughly equal amounts by mass. We suggest that collisional processing within the bipolar outflow plays an important role in establishing the particle size distribution.

  9. Mid-infrared imaging of the bipolar planetary nebula M2-9 from SOFIA

    Werner, M. W.; Sahai, R.; Davis, J.; Livingston, J.; Lykou, F.; DE Buizer, J.; Morris, M. R.; Keller, L.; Adams, J.; Gull, G.; Henderson, C.; Herter, T.; Schoenwald, J.

    2014-01-01

    We have imaged the bipolar planetary nebula M2-9 using SOFIA's FORCAST instrument in six wavelength bands between 6.6 and 37.1 μm. A bright central point source, unresolved with SOFIA's ∼4''-5'' beam, is seen at each wavelength, and the extended bipolar lobes are clearly seen at 19.7 μm and beyond. The photometry between 10 and 25 μm is well fit by the emission predicted from a stratified disk seen at large inclination, as has been proposed for this source by Lykou et al. and by Smith and Gehrz. The principal new results in this paper relate to the distribution and properties of the dust that emits the infrared radiation. In particular, a considerable fraction of this material is spread uniformly through the lobes, although the dust density does increase at the sharp outer edge seen in higher resolution optical images of M2-9. The dust grain population in the lobes shows that small (<0.1 μm) and large (>1 μm) particles appear to be present in roughly equal amounts by mass. We suggest that collisional processing within the bipolar outflow plays an important role in establishing the particle size distribution.

  10. An improved radiosynthesis of the muscarinic M2 radiopharmaceutical, [{sup 18}F]FP-TZTP

    Oosten, Erik M. van [Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, M5S 3H6 (Canada); PET Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, M5T 1R8 (Canada); Wilson, Alan A.; Stephenson, Karin A. [PET Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, M5T 1R8 (Canada); Department of Psychiatry, University of Toronto, 250 College Street, Toronto, Ontario, M5T 1R8 (Canada); Mamo, David C. [PET Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, M5T 1R8 (Canada); Department of Psychiatry, University of Toronto, 250 College Street, Toronto, Ontario, M5T 1R8 (Canada); Geriatric Mental Health Program, Centre for Addiction and Mental Health, 1001 Queen Street West, Toronto, Ontario, M6J 1H4 (Canada); Pollock, Bruce G.; Mulsant, Benoit H. [Department of Psychiatry, University of Toronto, 250 College Street, Toronto, Ontario, M5T 1R8 (Canada); Geriatric Mental Health Program, Centre for Addiction and Mental Health, 1001 Queen Street West, Toronto, Ontario, M6J 1H4 (Canada); Yudin, Andrei K. [Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, M5S 3H6 (Canada); Houle, Sylvain [PET Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, M5T 1R8 (Canada); Department of Psychiatry, University of Toronto, 250 College Street, Toronto, Ontario, M5T 1R8 (Canada); Vasdev, Neil [PET Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, M5T 1R8 (Canada); Department of Psychiatry, University of Toronto, 250 College Street, Toronto, Ontario, M5T 1R8 (Canada)], E-mail: neil.vasdev@camhpet.ca

    2009-04-15

    The radioligand 3-(4-(3-[{sup 18}F]fluoropropylthio)-1,2,5-thiadiazol-3-yl)-1-methyl-1,2,5, 6-tetrahydropyridine ([{sup 18}F]FP-TZTP) is an agonist with specificity towards subtype 2 of muscarinic acetylcholine (M2) receptors. It is currently the only radiotracer available for imaging M2 receptors in human subjects with positron emission tomography. The present study reports on an improved method for the synthesis of [{sup 18}F]FP-TZTP, automated using a GE TRACERlab{sup TM} FX{sub FN} radiosynthesis module. A key facet was the use of a new precursor, 3-(4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-3-ylthio) propyl 4-methylbenzenesulfonate. The precursor was fluorinated via nucleophilic displacement of the tosyloxy group by potassium cryptand [{sup 18}F]fluoride (K[{sup 18}F]/K{sub 222}) in CH{sub 3}CN at 80 deg. C for 5 min, and purified by HPLC. Formulated [{sup 18}F]FP-TZTP was prepared in an uncorrected radiochemical yield of 29{+-}4%, with a specific activity of 138{+-}41 GBq/{mu}mol (3732{+-}1109 mCi/{mu}mol) at the end of synthesis (35 min; n=3). This methodology offers higher yields, faster synthesis times, an optimized precursor, and simpler automation than previously reported.

  11. Development and evaluation of intelligent machine tools based on knowledge evolution in M2M environment

    Kim, Dong Hoon; Song, Jun Yeob; Lee, Jong Hyun; Cha, Suk Keun

    2009-01-01

    In the near future, the foreseen improvement in machine tools will be in the form of a knowledge evolution-based intelligent device. The goal of this study is to develop intelligent machine tools having knowledge-evolution capability in Machine to Machine (M2M) wired and wireless environment. The knowledge evolution-based intelligent machine tools are expected to be capable of gathering knowledge autonomously, producing knowledge, understanding knowledge, applying reasoning to knowledge, making new decisions, dialoguing with other machines, etc. The concept of the knowledge-evolution intelligent machine originated from the process of machine control operation by the sense, dialogue and decision of a human expert. The structure of knowledge evolution in M2M and the scheme for a dialogue agent among agent-based modules such as a sensory agent, a dialogue agent and an expert system (decision support agent) are presented in this paper, and work-offset compensation from thermal change and recommendation of cutting condition are performed on-line for knowledge-evolution verification

  12. 183-W, M2 = 2.4 Yb:YAG Q -switched laser

    Honea, E.C.; Beach, R.J.; Mitchell, S.C.; Avizonis, P.V.

    1999-01-01

    We have fabricated a diode-array end-pumped Yb:YAG rod laser with output powers greater than 200thinspthinspW cw and 195thinspthinspW Q -switched at 5thinspthinspkHz. At an output power of 183thinspthinspW and a repetition rate of 5thinspthinspkHz, the beam quality was measured to be M 2 =2.4 . The laser design incorporates a hollow lens duct to concentrate the diode pump light for delivery to the end of the laser rod while maintaining access to the laser beam. This configuration provides increased flexibility for the resonator design and permits the use of birefringence compensation in the cavity to yield polarized output with increased efficiency. Using the recently described birefringence compensation method of Clarkson et al.thinspthinsp[in Conference on Lasers and Electro-Optics (Optical Society of America, Washington, D.C., 1998), paper CTuI3], we obtained 112thinspthinspW of cw power with a polarized beam of M 2 =3.2 . copyright 1999 Optical Society of America

  13. Mini-magnetospheric plasma propulsion (M2P2): High speed propulsion sailing the solar wind

    Winglee, Robert; Slough, John; Ziemba, Tim; Goodson, Anthony

    2000-01-01

    Mini-Magnetospheric Plasma Propulsion (M2P2) seeks the creation of a magnetic wall or bubble (i.e. a magnetosphere) that will intercept the supersonic solar wind which is moving at 300-800 km/s. In so doing, a force of about 1 N will be exerted on the spacecraft by the spacecraft while only requiring a few mN of force to sustain the mini-magnetosphere. Equivalently, the incident solar wind power is about 1 MW while about 1 kW electrical power is required to sustain the system, with about 0.25-0.5 kg being expended per day. This nominal configuration utilizing only solar electric cells for power, the M2P2 will produce a magnetic barrier approximately 15-20 km in radius, which would accelerate a 70-140 kg payload to speeds of about 50-80 km/s. At this speed, missions to the heliopause and beyond can be achieved in under 10 yrs. Design characteristics for a prototype are also described

  14. Preliminary heat treatment of 4KhM2Fch die steel

    Leonidov, V.M.; Berezkin, Y.A.; Nikitenko, E.V.

    1986-01-01

    To improve the machinability and preparation of the structure for hardening, die steels are given a preliminary treatment which provides a reduction in hardness as a result of separation in the structure of the carbide and ferrite phases, coagulation of the carbides, and acquisition by them of a granular form and also the obtaining of fine grains and a uniform distribution of the structural constituents. The microstructure was evaluated after etching in 4% nital on an MIM-8M microscope. The 4KhM2Fch steel was given a preliminary heat treatment of normalize and anneal. It was concluded that for 4KhM2Fch steel a preliminary heat treatment of normalizing from 950 0 C with a hold of 1.5-2 h, annealing at 750-760 0 C with a hold of 2-3 h, cooling to the isothermal temperature of 670-680 0 C with a hold of 3-4 h, and further air cooling is recommended. The structure after such a heat is granular pearlite with a rating 1-2 and a hardness of 220-250 HB

  15. An improved radiosynthesis of the muscarinic M2 radiopharmaceutical, [18F]FP-TZTP

    Oosten, Erik M. van; Wilson, Alan A.; Stephenson, Karin A.; Mamo, David C.; Pollock, Bruce G.; Mulsant, Benoit H.; Yudin, Andrei K.; Houle, Sylvain; Vasdev, Neil

    2009-01-01

    The radioligand 3-(4-(3-[ 18 F]fluoropropylthio)-1,2,5-thiadiazol-3-yl)-1-methyl-1,2,5, 6-tetrahydropyridine ([ 18 F]FP-TZTP) is an agonist with specificity towards subtype 2 of muscarinic acetylcholine (M2) receptors. It is currently the only radiotracer available for imaging M2 receptors in human subjects with positron emission tomography. The present study reports on an improved method for the synthesis of [ 18 F]FP-TZTP, automated using a GE TRACERlab TM FX FN radiosynthesis module. A key facet was the use of a new precursor, 3-(4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-3-ylthio) propyl 4-methylbenzenesulfonate. The precursor was fluorinated via nucleophilic displacement of the tosyloxy group by potassium cryptand [ 18 F]fluoride (K[ 18 F]/K 222 ) in CH 3 CN at 80 deg. C for 5 min, and purified by HPLC. Formulated [ 18 F]FP-TZTP was prepared in an uncorrected radiochemical yield of 29±4%, with a specific activity of 138±41 GBq/μmol (3732±1109 mCi/μmol) at the end of synthesis (35 min; n=3). This methodology offers higher yields, faster synthesis times, an optimized precursor, and simpler automation than previously reported

  16. Numerical modelling of the M2 tide on the northern Patagonian Shelf

    Glorioso, P. D.; Simpson, J. H.

    1994-02-01

    The previously reported occurrence of tidal fronts on the Patagonian Shelf ( CARRETOet al., 1986 , Journal of Plankton Research, 8, 15-28; GLORIOSO, 1987 , Continental Shelf Research, 7, 27-34), motivated the application of a numerical model to solve the shallow-water equations with external forcing by the principal-lunar semidiurnal tide (M2) prescribed along the open boundary. The mean width of the Patagonian Shelf is comparable with a quarter wavelength of the semidiurnal tide, giving the conditions for standing wave resonance at that frequency ( WEBB, 1975 , Deep-Sea Research, 23, 1-15). The region is well recognized by its large tidal elevations and by the speed of the tidal wave changing phase very rapidly. Some of the results obtained from the modelling exercise include the mapping of the M2 tidal constants, the Simpson-Hunter stratification parameter, the mean sea surface elevation, and the distribution of tidal energy dissipation by bottom friction. These results agree qualitatively with the ship data available and with satellite infrared imagery.

  17. N = 6 superconformal Chern-Simons-matter theories, M2-branes and their gravity duals

    Aharony, Ofer; Bergman, Oren; Maldacena, Juan; Jafferis, Daniel Louis

    2008-01-01

    We construct three dimensional Chern-Simons-matter theories with gauge groups U(N) x U(N) and SU(N) x SU(N) which have explicit N = 6 superconformal symmetry. Using brane constructions we argue that the U(N) x U(N) theory at level k describes the low energy limit of N M2-branes probing a C 4 /Z k singularity. At large N the theory is then dual to M-theory on AdS 4 x S 7 /Z k . The theory also has a 't Hooft limit (of large N with a fixed ratio N/k) which is dual to type IIA string theory on AdS 4 x CP 3 . For k = 1 the theory is conjectured to describe N M2-branes in flat space, although our construction realizes explicitly only six of the eight supersymmetries. We give some evidence for this conjecture, which is similar to the evidence for mirror symmetry in d = 3 gauge theories. When the gauge group is SU(2) x SU(2) our theory has extra symmetries and becomes identical to the Bagger-Lambert theory.

  18. M2-like macrophages are responsible for collagen degradation through a mannose receptor–mediated pathway

    Madsen, Daniel H.; Leonard, Daniel; Masedunskas, Andrius; Moyer, Amanda; Jürgensen, Henrik Jessen; Peters, Diane E.; Amornphimoltham, Panomwat; Selvaraj, Arul; Yamada, Susan S.; Brenner, David A.; Burgdorf, Sven; Engelholm, Lars H.; Behrendt, Niels; Holmbeck, Kenn; Weigert, Roberto

    2013-01-01

    Tissue remodeling processes critically depend on the timely removal and remodeling of preexisting collagen scaffolds. Nevertheless, many aspects related to the turnover of this abundant extracellular matrix component in vivo are still incompletely understood. We therefore took advantage of recent advances in optical imaging to develop an assay to visualize collagen turnover in situ and identify cell types and molecules involved in this process. Collagen introduced into the dermis of mice underwent cellular endocytosis in a partially matrix metalloproteinase–dependent manner and was subsequently routed to lysosomes for complete degradation. Collagen uptake was predominantly executed by a quantitatively minor population of M2-like macrophages, whereas more abundant Col1a1-expressing fibroblasts and Cx3cr1-expressing macrophages internalized collagen at lower levels. Genetic ablation of the collagen receptors mannose receptor (Mrc1) and urokinase plasminogen activator receptor–associated protein (Endo180 and Mrc2) impaired this intracellular collagen degradation pathway. This study demonstrates the importance of receptor-mediated cellular uptake to collagen turnover in vivo and identifies a key role of M2-like macrophages in this process. PMID:24019537

  19. Posttranslational Modifications of Pyruvate Kinase M2: Tweaks that Benefit Cancer

    Gopinath Prakasam

    2018-02-01

    Full Text Available Cancer cells rewire metabolism to meet biosynthetic and energetic demands. The characteristic increase in glycolysis, i.e., Warburg effect, now considered as a hallmark, supports cancer in various ways. To attain such metabolic reshuffle, cancer cells preferentially re-express the M2 isoform of pyruvate kinase (PKM2, M2-PK and alter its quaternary structure to generate less-active PKM2 dimers. The relatively inactive dimers cause the accumulation of glycolytic intermediates that are redirected into anabolic pathways. In addition, dimeric PKM2 also benefits cancer cells through various non-glycolytic moonlight functions, such as gene transcription, protein kinase activity, and redox balance. A large body of data have shown that several distinct posttranslation modifications (PTMs regulate PKM2 in a way that benefits cancer growth, e.g., formation of PKM2 dimers. This review discusses the recent advancements in our understanding of various PTMs and the benefits they impart to the sustenance of cancer. Understanding the PTMs in PKM2 is crucial to assess their therapeutic potential and to design novel anticancer strategies.

  20. Anti-Inflammatory Strategy for M2 Microglial Polarization Using Retinoic Acid-Loaded Nanoparticles

    Marta Machado-Pereira

    2017-01-01

    Full Text Available Inflammatory mechanisms triggered by microglial cells are involved in the pathophysiology of several brain disorders, hindering repair. Herein, we propose the use of retinoic acid-loaded polymeric nanoparticles (RA-NP as a means to modulate microglia response towards an anti-inflammatory and neuroprotective phenotype (M2. RA-NP were first confirmed to be internalized by N9 microglial cells; nanoparticles did not affect cell survival at concentrations below 100 μg/mL. Then, immunocytochemical studies were performed to assess the expression of pro- and anti-inflammatory mediators. Our results show that RA-NP inhibited LPS-induced release of nitric oxide and the expression of inducible nitric oxide synthase and promoted arginase-1 and interleukin-4 production. Additionally, RA-NP induced a ramified microglia morphology (indicative of M2 state, promoting tissue viability, particularly neuronal survival, and restored the expression of postsynaptic protein-95 in organotypic hippocampal slice cultures exposed to an inflammatory challenge. RA-NP also proved to be more efficient than the free equivalent RA concentration. Altogether, our data indicate that RA-NP may be envisioned as a promising therapeutic agent for brain inflammatory diseases.

  1. ISOMP: An Instant Service-Orchestration Mobile M2M Platform

    Cholhong Im

    2016-01-01

    Full Text Available Smartphones have greater computing power than ever before, providing convenient applications to improve our lives. In general, people find it difficult to locate suitable applications and implementing new applications often requires professional skills. In this paper, we propose a new service platform that facilitates the implementation of new applications by composing prebuilt components that provide the context information of mobile devices such as location and contacts. Our platform introduces an innovative concept named context collaboration, in which smartphones exchange context information with each other, which in turn is used to deduct useful inferences. The concept is realized by instant orchestration, which assembles some components and implements a composite component. The interactive communication interface helps a mobile device to communicate with other devices using open APIs, such as SOAP and HTTP (REST. The platform also works in heterogeneous environments, for example, between Android and iOS operating systems. Throughout the platform, mobile devices can act as smart M2M machines with context awareness, enabling intelligent tasks on behalf of users. Our platform will open up a new and innovative pathway for both enhanced mobile context awareness and M2M, which is expected to be a fundamental feature of the next generation of mobile devices.

  2. Cytoplasmic transfer of heritable elements other than mtDNA from SAMP1 mice into mouse tumor cells suppresses their ability to form tumors in C57BL6 mice.

    Shimizu, Akinori; Tani, Haruna; Takibuchi, Gaku; Ishikawa, Kaori; Sakurazawa, Ryota; Inoue, Takafumi; Hashimoto, Tetsuo; Nakada, Kazuto; Takenaga, Keizo; Hayashi, Jun-Ichi

    2017-11-04

    In a previous study, we generated transmitochondrial P29mtSAMP1 cybrids, which had nuclear DNA from the C57BL6 (referred to as B6) mouse strain-derived P29 tumor cells and mitochondrial DNA (mtDNA) exogenously-transferred from the allogeneic strain SAMP1. Because P29mtSAMP1 cybrids did not form tumors in syngeneic B6 mice, we proposed that allogeneic SAMP1 mtDNA suppressed tumor formation of P29mtSAMP1 cybrids. To test this hypothesis, current study generated P29mt(sp)B6 cybrids carrying all genomes (nuclear DNA and mtDNA) from syngeneic B6 mice by eliminating SAMP1 mtDNA from P29mtSAMP1 cybrids and reintroducing B6 mtDNA. However, the P29mt(sp)B6 cybrids did not form tumors in B6 mice, even though they had no SAMP1 mtDNA, suggesting that SAMP1 mtDNA is not involved in tumor suppression. Then, we examined another possibility of whether SAMP1 mtDNA fragments potentially integrated into the nuclear DNA of P29mtSAMP1 cybrids are responsible for tumor suppression. We generated P29 H (sp)B6 cybrids by eliminating nuclear DNA from P29mt(sp)B6 cybrids and reintroducing nuclear DNA with no integrated SAMP1 mtDNA fragment from mtDNA-less P29 cells resistant to hygromycin in selection medium containing hygromycin. However, the P29 H (sp)B6 cybrids did not form tumors in B6 mice, even though they carried neither SAMP1 mtDNA nor nuclear DNA with integrated SAMP1 mtDNA fragments. Moreover, overproduction of reactive oxygen species (ROS) and bacterial infection were not involved in tumor suppression. These observations suggest that tumor suppression was caused not by mtDNA with polymorphic mutations or infection of cytozoic bacteria but by hypothetical heritable cytoplasmic elements other than mtDNA from SAMP1 mice. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  3. Ecological opportunity and the adaptive diversification of lineages.

    Wellborn, Gary A; Langerhans, R Brian

    2015-01-01

    The tenet that ecological opportunity drives adaptive diversification has been central to theories of speciation since Darwin, yet no widely accepted definition or mechanistic framework for the concept currently exists. We propose a definition for ecological opportunity that provides an explicit mechanism for its action. In our formulation, ecological opportunity refers to environmental conditions that both permit the persistence of a lineage within a community, as well as generate divergent natural selection within that lineage. Thus, ecological opportunity arises from two fundamental elements: (1) niche availability, the ability of a population with a phenotype previously absent from a community to persist within that community and (2) niche discordance, the diversifying selection generated by the adaptive mismatch between a population's niche-related traits and the newly encountered ecological conditions. Evolutionary response to ecological opportunity is primarily governed by (1) spatiotemporal structure of ecological opportunity, which influences dynamics of selection and development of reproductive isolation and (2) diversification potential, the biological properties of a lineage that determine its capacity to diversify. Diversification under ecological opportunity proceeds as an increase in niche breadth, development of intraspecific ecotypes, speciation, and additional cycles of diversification that may themselves be triggered by speciation. Extensive ecological opportunity may exist in depauperate communities, but it is unclear whether ecological opportunity abates in species-rich communities. Because ecological opportunity should generally increase during times of rapid and multifarious environmental change, human activities may currently be generating elevated ecological opportunity - but so far little work has directly addressed this topic. Our framework highlights the need for greater synthesis of community ecology and evolutionary biology, unifying

  4. Role of LRF/Pokemon in lineage fate decisions

    Lunardi, Andrea; Guarnerio, Jlenia; Wang, Guocan

    2013-01-01

    In the human genome, 43 different genes are found that encode proteins belonging to the family of the POK (poxvirus and zinc finger and Krüppel)/ZBTB (zinc finger and broad complex, tramtrack, and bric à brac) factors. Generally considered transcriptional repressors, several of these genes play fundamental roles in cell lineage fate decision in various tissues, programming specific tasks throughout the life of the organism. Here, we focus on functions of leukemia/lymphoma-related factor/POK erythroid myeloid ontogenic factor, which is probably one of the most exciting and yet enigmatic members of the POK/ZBTB family. PMID:23396304

  5. Developmental origin and lineage plasticity of endogenous cardiac stem cells

    Santini, Maria Paola; Forte, Elvira; Harvey, Richard P.; Kovacic, Jason C.

    2016-01-01

    Over the past two decades, several populations of cardiac stem cells have been described in the adult mammalian heart. For the most part, however, their lineage origins and in vivo functions remain largely unexplored. This Review summarizes what is known about different populations of embryonic and adult cardiac stem cells, including KIT+, PDGFRα+, ISL1+ and SCA1+ cells, side population cells, cardiospheres and epicardial cells. We discuss their developmental origins and defining characteristics, and consider their possible contribution to heart organogenesis and regeneration. We also summarize the origin and plasticity of cardiac fibroblasts and circulating endothelial progenitor cells, and consider what role these cells have in contributing to cardiac repair. PMID:27095490

  6. The Creation and Destruction of Hf-178m2 Isomer by Neutron Interaction

    Hsu, Hsiao-Hua [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); TechSource, Inc. Los Alamos, NM (United States); Talbert, Willard L. [TechSource, Inc. Los Alamos, NM (United States); Ward, Tom [TechSource, Inc. Los Alamos, NM (United States)

    2017-03-06

    The property of the isomer state in 178m2Hf was an interesting topic in nuclear structure studies during the time period 1970 to 1980. The state at 2.446 MeV with spin and parity Kπ = 16+, has a half-life of 31 years. The isomer is described as a four-quasi-particle state. The K forbidden deexcitatiion by gamma emission is the reason for long half-life. During 1980, the isomer became a troublesome issue for radiation safety workers, because this isomer can also be produced in the first wall of a fussion reactor containing tungsten and also in a tungsten beam stop of a high-energy accelerator.

  7. Thermoelectric Performance of the MXenes M2CO2 (M = Ti, Zr, or Hf)

    Gandi, Appala

    2016-02-21

    We present the first report in which the thermoelectric properties of two-dimensional MXenes are calculated by considering both the electron and phonon transport. Specifically, we solve the transport equations of the electrons and phonons for three MXenes, M2CO2, where M = Ti, Zr, or Hf, in order to evaluate the effect of the metal M on the thermoelectric performance. The lattice contribution to the thermal conductivity, obtained from the phonon life times, is found to be lowest in Ti2CO2 and highest in Hf2CO2 in the temperature range from 300 K to 700 K. The highest figure of merit is predicted for Ti2CO2 . The heavy mass of the electrons due to flat conduction bands results in a larger thermopower in the case of n-doping in these compounds.

  8. High-spin nuclear target of 178m2Hf: creation and nuclear reaction studies

    Oganessyan, Yu.Ts.; Karamyan, S.A.; Gangrskij, Yu.P.

    1993-01-01

    A long-lived (31 years) four-quasiparticle isomer 178m 2 Hf(I,K π =16,16 + ) was produced in microweight quantities using the nuclear reaction 176 Yb( 4 He, 2n). Methods of precision chemistry and mass-separation for the purification of the produced Hf material have been developed. Thin targets of isomeric hafnium-178 on carbon backings were prepared and used in experiments on a neutron, proton and deuteron beams. First results on nuclear reactions on a high-spin exotic target were obtained. Experiments on electromagnetic interactions of the isomeric hafnium using methods of the collinear laser spectroscopy as well as of the nuclear orientation of hafnium implanted into a crystalline media were started. 11 refs.; 11 figs.; 2 tabs

  9. The anomalous amplification of M2 tide in the Taiwan Strait

    Jan, Sen; Chern, Ching-Sheng; Wang, Joe; Chao, Shenn-Yu

    2004-04-01

    The complex tidal wave propagation pattern in the Taiwan Strait invites parochialism. Along the eastern (Taiwan) boundary of the strait, the anomalous amplification of M2 tide in the middle often led to the parochial view that two tidal waves coming from both ends of the strait collide in the middle, creating wave resonance. Along the western (China) boundary, one sees a southward progressive tidal wave and hence no wave collision. To reconcile, we examine a few solutions of a numerical tidal model below. Both realistic bottom bathymetry and idealized bottom topographies are used to identify dominant mechanism leading to the complex tidal wave propagation. Our process of elimination identifies the wave reflection of southward propagating tidal wave by the deep trench in the southern strait as the true cause responsible for the complex wave propagation pattern.

  10. M2-F1 lifting body and Paresev 1B on ramp

    1963-01-01

    In this photo of the M2-F1 lifting body and the Paresev 1B on the ramp, the viewer sees two vehicles representing different approaches to building a research craft to simulate a spacecraft able to land on the ground instead of splashing down in the ocean as the Mercury capsules did. The M2-F1 was a lifting body, a shape able to re-enter from orbit and land. The Paresev (Paraglider Research Vehicle) used a Rogallo wing that could be (but never was) used to replace a conventional parachute for landing a capsule-type spacecraft, allowing it to make a controlled landing on the ground. The wingless, lifting body aircraft design was initially conceived as a means of landing an aircraft horizontally after atmospheric reentry. The absence of wings would make the extreme heat of re-entry less damaging to the vehicle. In 1962, Dryden management approved a program to build a lightweight, unpowered lifting body as a prototype to flight test the wingless concept. It would look like a 'flying bathtub,' and was designated the M2-F1, the 'M' referring to 'manned' and 'F' referring to 'flight' version. It featured a plywood shell placed over a tubular steel frame crafted at Dryden. Construction was completed in 1963. The first flight tests of the M2-F1 were over Rogers Dry Lake at the end of a tow rope attached to a hopped-up Pontiac convertible driven at speeds up to about 120 mph. This vehicle needed to be able to tow the M2-F1 on the Rogers Dry Lakebed adjacent to NASA's Flight Research Center (FRC) at a minimum speed of 100 miles per hour. To do that, it had to handle the 400-pound pull of the M2-F1. Walter 'Whitey' Whiteside, who was a retired Air Force maintenance officer working in the FRC's Flight Operations Division, was a dirt-bike rider and hot-rodder. Together with Boyden 'Bud' Bearce in the Procurement and Supply Branch of the FRC, Whitey acquired a Pontiac Catalina convertible with the largest engine available. He took the car to Bill Straup's renowned hot-rod shop

  11. Radiative rates for E1, E2, M1 and M2 transitions in Fe X

    Aggarwal, K.M.; Keenan, F.P.

    2004-01-01

    Energies of the 54 levels belonging to the (1s 2 2s 2 2p 6 ) 3s 2 3p 5 , 3s3p 6 , 3s 2 3p 4 3d and 3s3p 5 3d configurations of Fe X have been calculated using the GRASP code of Dyall and colleagues (1989). Additionally, radiative rates, oscillator strengths, and line strengths are calculated for all electric dipole (E1), magnetic dipole (M1), electric quadrupole (E2), and magnetic quadrupole (M2) transitions among these levels. Comparisons are made with results available in the literature, and the accuracy of the data is assessed. Our energy levels are estimated to be accurate to better than 3%, whereas results for other parameters are probably accurate to better than 20% . Additionally, the agreement between measured and calculated lifetimes is better than 10%. (authors)

  12. M2, S2, K1 models of the global ocean tide

    Parke, M. E.; Hendershott, M. C.

    1979-01-01

    Ocean tidal signals appear in many geophysical measurements. Geophysicists need realistic tidal models to aid in interpretation of their data. Because of the closeness to resonance of dissipationless ocean tides, it is difficult for numerical models to correctly represent the actual open ocean tide. As an approximate solution to this problem, test functions derived by solving Laplace's Tidal Equations with ocean loading and self gravitation are used as a basis for least squares dynamic interpolation of coastal and island tidal data for the constituents M2, S2, and Kl. The resulting representations of the global tide are stable over at least a ?5% variation in the mean depth of the model basin, and they conserve mass. Maps of the geocentric tide, the induced free space potential, the induced vertical component of the solid earth tide, and the induced vertical component of the gravitational field for each contituent are presented.

  13. Primary structure of the human M2 mitochondrial autoantigen of primary biliary cirrhosis: Dihydrolipoamide acetyltransferase

    Coppel, R.L.; McNeilage, L.J.; Surh, C.D.; Van De Water, J.; Spithill, T.W.; Whittingham, S.; Gershwin, M.E.

    1988-01-01

    Primary biliary cirrhosis is a chronic, destructive autoimmune liver disease of humans. Patient sera are characterized by a high frequency of autoantibodies to a M r 70,000 mitochondrial antigen a component of the M2 antigen complex. The authors have identified a human cDNA clone encoding the complete amino acid sequence of this autoantigen. The predicted structure has significant similarity with the dihydrolipoamide acetyltransferase of the Escherichia coli pyruvate dehydrogenase multienzyme complex. The human sequence preserves the Glu-Thr-Asp-Lys-Ala motif of the lipoyl-binding site and has two potential binding sites. Expressed fragments of the cDNA react strongly with sera from patients with primary biliary cirrhosis but not with sera from patients with autoimmune chronic active hepatitis or sera from healthy subjects

  14. Solar thermal barometer. More than 2 million m2 installed in 2005

    Anon.

    2006-01-01

    With 22,8% growth, the european union solar thermal market (glazed, vacuum and unglazed collectors) has passed the 2 million m 2 benchmark corresponding to installed capacity of approximately 1450 MWth. This growth can be explained by the very good performance of the three leading EU solar thermal markets: Germany, Austria and Greece and the increase in importance of the French and Spanish markets. Statistical data are provided for the european union on the annually installed surfaces, breakdown by technologies of the solar thermal market, the solar thermal capacity in operation, the representative companies of the thermal solar sector and a comparison of current trend with the white book objectives. (A.L.B.)

  15. The mutual dependence of M1 fertility and M2 mutations in rice

    Gopinathan Nair, V.

    1982-01-01

    The mutual dependence of M 1 fertility and M 2 mutations in rice was studied after treatment with gamma rays and EMS. The frequency of chlorophyll mutations increased with decrease in seed fertility when M 1 ears were selected at random. However, at the lowest fertility class the mutation frequency was low. This reduction is attributed to the elimination of mutants in the high sterility class. The mutation yield can therefore be significantly enhanced by selecting M 1 ears of low fertility. The segregation ratio of mutants increased as fertility decreased. Mutation spectrum was however not influenced by M 1 fertility. This makes selection for fertility quite ineffective in altering the mutation spectrum. (author)

  16. Comparative Analysis of the $^{178m2}$Hf Yield at Reactions with Different Projectiles

    Karamian, S A

    2004-01-01

    The long-lived high-spin $^{178m2}$Hf $K$-isomer can be produced in nuclear reactions with different projectiles. The reaction yields and cross-sections have been measured in the series of experiments and the results are now overviewed. The systematics of isomer-to-ground state ratios are drawn and real production capabilities are estimated for the best reactions. Such a summary is relevant to the significance of the isomer studies both for the nuclear-science knowledge and for possible applications. Potential isomer applications have been earlier stressed in popular publications with probably overestimated expectations. The real possibilities are restricted in part by the production yield and by other shortcomings as well.

  17. Carrier Current Line Systems Technologies in M2M Architecture for Wireless Communication

    Hua-Ching Chen

    2016-01-01

    Full Text Available This paper investigates the Carrier Current Line Systems (CCLS technologies of Machine to Machine (M2M architecture which applied for mobile station coverage working with metro, high speed railway, and subway such as analysis for public transport of an indoor transition system. It is based on the theory and practical engineering principle which provide guidelines and formulas for link budget design to help designers fully control and analyze the single output power of uplink and downlink between Fiber Repeaters (FR and mobile station as well as base station. Finally, the results of this leakage cable system are successfully applied to indoor coverage design for metro rapid transit system which are easily installed cellular over fiber solutions for WCDMA/LTE access is becoming Ubiquitous Network to Internet of Thing (IOT real case hierarchy of telecommunication.

  18. Janus field theories from non-linear BF theories for multiple M2-branes

    Ryang, Shijong

    2009-01-01

    We integrate the nonpropagating B μ gauge field for the non-linear BF Lagrangian describing N M2-branes which includes terms with even number of the totally antisymmetric tensor M IJK in arXiv:0808.2473 and for the two-types of non-linear BF Lagrangians which include terms with odd number of M IJK as well in arXiv:0809:0985. For the former Lagrangian we derive directly the DBI-type Lagrangian expressed by the SU(N) dynamical A μ gauge field with a spacetime dependent coupling constant, while for the low-energy expansions of the latter Lagrangians the B μ integration is iteratively performed. The derived Janus field theory Lagrangians are compared.

  19. A novel quantitative assay of mitophagy: Combining high content fluorescence microscopy and mitochondrial DNA load to quantify mitophagy and identify novel pharmacological tools against pathogenic heteroplasmic mtDNA.

    Diot, Alan; Hinks-Roberts, Alex; Lodge, Tiffany; Liao, Chunyan; Dombi, Eszter; Morten, Karl; Brady, Stefen; Fratter, Carl; Carver, Janet; Muir, Rebecca; Davis, Ryan; Green, Charlotte J; Johnston, Iain; Hilton-Jones, David; Sue, Carolyn; Mortiboys, Heather; Poulton, Joanna

    2015-10-01

    Mitophagy is a cellular mechanism for the recycling of mitochondrial fragments. This process is able to improve mitochondrial DNA (mtDNA) quality in heteroplasmic mtDNA disease, in which mutant mtDNA co-exists with normal mtDNA. In disorders where the load of mutant mtDNA determines disease severity it is likely to be an important determinant of disease progression. Measuring mitophagy is technically demanding. We used pharmacological modulators of autophagy to validate two techniques for quantifying mitophagy. First we used the IN Cell 1000 analyzer to quantify mitochondrial co-localisation with LC3-II positive autophagosomes. Unlike conventional fluorescence and electron microscopy, this high-throughput system is sufficiently sensitive to detect transient low frequency autophagosomes. Secondly, because mitophagy preferentially removes pathogenic heteroplasmic mtDNA mutants, we developed a heteroplasmy assay based on loss of m.3243A>G mtDNA, during culture conditions requiring oxidative metabolism ("energetic stress"). The effects of the pharmacological modulators on these two measures were consistent, confirming that the high throughput imaging output (autophagosomes co-localising with mitochondria) reflects mitochondrial quality control. To further validate these methods, we performed a more detailed study using metformin, the most commonly prescribed antidiabetic drug that is still sometimes used in Maternally Inherited Diabetes and Deafness (MIDD). This confirmed our initial findings and revealed that metformin inhibits mitophagy at clinically relevant concentrations, suggesting that it may have novel therapeutic uses. Copyright © 2015. Published by Elsevier Ltd.

  20. Microwave and magnetic (M2 proteomics of a mouse model of mild traumatic brain injury

    Teresa M. Evans

    2014-06-01

    Full Text Available Short-term increases in oxidative stress and decreases in motor function, including debilitating effects on balance and motor control, can occur following primary mild traumatic brain injuries (mTBI. However, the long-term effects on motor unit impairment and integrity as well as the molecular mechanisms underlying secondary injuries are poorly understood. We hypothesized that changes in central nervous system-specific protein (CSP expression might correlate to these long-term effects. To test our hypothesis, we longitudinally assessed a closed-skull mTBI mouse model, vs. sham control, at 1, 7, 30, and 120 days post-injury. Motor impairment was determined by rotarod and grip strength performance measures, while motor unit integrity was determined using electromyography. Relative protein expression was determined by microwave and magnetic (M2 proteomics of ipsilateral brain tissue, as previously described. Isoprostane measurements were performed to confirm a primary oxidative stress response. Decoding the relative expression of 476 ± 56 top-ranked proteins for each specimen revealed statistically significant changes in the expression of two well-known CSPs at 1, 7 and 30 days post-injury: P < 0.001 for myelin basic protein (MBP and p < 0.05 for myelin associated glycoprotein (MAG. This was confirmed by Western blot. Moreover, MAG, αII-spectrin (SPNA2 and neurofilament light (NEFL expression at 30 days post-injury were directly related to grip strength (p < 0.05. While higher-powered studies of larger cohorts merit further investigation, this study supports the proof-of-concept that M2 proteomics is a rapid method to quantify putative protein biomarkers and therapeutic targets of mTBI and suggests the feasibility of CSP expression correlations to long-term effects on motor impairment.

  1. Imatinib and Nilotinib Off-Target Effects on Human NK Cells, Monocytes, and M2 Macrophages.

    Bellora, Francesca; Dondero, Alessandra; Corrias, Maria Valeria; Casu, Beatrice; Regis, Stefano; Caliendo, Fabio; Moretta, Alessandro; Cazzola, Mario; Elena, Chiara; Vinti, Luciana; Locatelli, Franco; Bottino, Cristina; Castriconi, Roberta

    2017-08-15

    Tyrosine kinase inhibitors (TKIs) are used in the clinical management of hematological neoplasms. Moreover, in solid tumors such as stage 4 neuroblastomas (NB), imatinib showed benefits that might depend on both on-target and immunological off-target effects. We investigated the effects of imatinib and nilotinib on human NK cells, monocytes, and macrophages. High numbers of monocytes died upon exposure to TKI concentrations similar to those achieved in patients. Conversely, NK cells were highly resistant to the TKI cytotoxic effect, were properly activated by immunostimulatory cytokines, and degranulated in the presence of NB cells. In NB, neither drug reduced the expression of ligands for activating NK receptors or upregulated that of HLA class I, B7-H3, PD-L1, and PD-L2, molecules that might limit NK cell function. Interestingly, TKIs modulated the chemokine receptor repertoire of immune cells. Acting at the transcriptional level, they increased the surface expression of CXCR4, an effect observed also in NK cells and monocytes of patients receiving imatinib for chronic myeloid leukemia. Moreover, TKIs reduced the expression of CXCR3 (in NK cells) and CCR1 (in monocytes). Monocytes also decreased the expression of M-CSFR, and low numbers of cells underwent differentiation toward macrophages. M0 and M2 macrophages were highly resistant to TKIs and maintained their phenotypic and functional characteristics. Importantly, also in the presence of TKIs, the M2 immunosuppressive polarization was reverted by TLR engagement, and M1-oriented macrophages fully activated autologous NK cells. Our results contribute to better interpreting the off-target efficacy of TKIs in tumors and to envisaging strategies aimed at facilitating antitumor immune responses. Copyright © 2017 by The American Association of Immunologists, Inc.

  2. Coupling of g proteins to reconstituted monomers and tetramers of the M2 muscarinic receptor.

    Redka, Dar'ya S; Morizumi, Takefumi; Elmslie, Gwendolynne; Paranthaman, Pranavan; Shivnaraine, Rabindra V; Ellis, John; Ernst, Oliver P; Wells, James W

    2014-08-29

    G protein-coupled receptors can be reconstituted as monomers in nanodiscs and as tetramers in liposomes. When reconstituted with G proteins, both forms enable an allosteric interaction between agonists and guanylyl nucleotides. Both forms, therefore, are candidates for the complex that controls signaling at the level of the receptor. To identify the biologically relevant form, reconstituted monomers and tetramers of the purified M2 muscarinic receptor were compared with muscarinic receptors in sarcolemmal membranes for the effect of guanosine 5'-[β,γ-imido]triphosphate (GMP-PNP) on the inhibition of N-[(3)H]methylscopolamine by the agonist oxotremorine-M. With monomers, a stepwise increase in the concentration of GMP-PNP effected a lateral, rightward shift in the semilogarithmic binding profile (i.e. a progressive decrease in the apparent affinity of oxotremorine-M). With tetramers and receptors in sarcolemmal membranes, GMP-PNP effected a vertical, upward shift (i.e. an apparent redistribution of sites from a state of high affinity to one of low affinity with no change in affinity per se). The data were analyzed in terms of a mechanistic scheme based on a ligand-regulated equilibrium between uncoupled and G protein-coupled receptors (the "ternary complex model"). The model predicts a rightward shift in the presence of GMP-PNP and could not account for the effects at tetramers in vesicles or receptors in sarcolemmal membranes. Monomers present a special case of the model in which agonists and guanylyl nucleotides interact within a complex that is both constitutive and stable. The results favor oligomers of the M2 receptor over monomers as the biologically relevant state for coupling to G proteins. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  3. Deletion of the M2-2 gene from avian metapneumovirus subgroup C impairs virus replication and immunogenicity in Turkeys.

    Yu, Qingzhong; Estevez, Carlos N; Roth, Jason P; Hu, Haixia; Zsak, Laszlo

    2011-06-01

    The second matrix (M2) gene of avian metapneumovirus subgroup C (aMPV-C) contains two overlapping open reading frames (ORFs), encoding two putative proteins, M2-1 and M2-2. Both proteins are believed to be involved in viral RNA transcription or replication. To further characterize the function of the M2-2 protein in virus replication, the non-overlapping region of the M2-2 ORF was deleted from an infectious cDNA clone of the aMPV-C strain, and a viable virus was rescued by using reverse genetics technology. The recombinant virus, raMPV-C ΔM2-2, was characterized in vitro and in vivo. In Vero cells, raMPV-C ΔM2-2 replicated slightly less efficiently than the parental virus, 10-fold reduction at 48-h post-infection. The raMPV-C ΔM2-2 virus induced typical cytopathic effects (CPE) that were indistinguishable from those seen with the parental virus infection. In specific-pathogen-free (SPF) turkeys, raMPV-C ΔM2-2 was attenuated and caused no clinical signs of disease. Less than 20% of the inoculated birds shed detectable virus in tracheal tissue during the first 5 days post-infection, and no virus shedding was detected afterward. Forty percent of infected birds produced a weak antibody response at 14 days post-infection. Upon challenge with a virulent aMPV-C strain, more than 80% of the raMPV-C ΔM2-2-inoculated birds showed typical disease signs and virus shedding in tracheal tissue. These results suggest that the M2-2 protein of aMPV-C virus is not essential for virus replication in vitro, but is required for sufficient virus replication to maintain pathogenicity and immunogenicity in the natural host.

  4. Deciphering the recent phylogenetic expansion of the originally deeply rooted Mycobacterium tuberculosis lineage 7.

    Yimer, Solomon A; Namouchi, Amine; Zegeye, Ephrem Debebe; Holm-Hansen, Carol; Norheim, Gunnstein; Abebe, Markos; Aseffa, Abraham; Tønjum, Tone

    2016-06-30

    A deeply rooted phylogenetic lineage of Mycobacterium tuberculosis (M. tuberculosis) termed lineage 7 was discovered in Ethiopia. Whole genome sequencing of 30 lineage 7 strains from patients in Ethiopia was performed. Intra-lineage genome variation was defined and unique characteristics identified with a focus on genes involved in DNA repair, recombination and replication (3R genes). More than 800 mutations specific to M. tuberculosis lineage 7 strains were identified. The proportion of non-synonymous single nucleotide polymorphisms (nsSNPs) in 3R genes was higher after the recent expansion of M. tuberculosis lineage 7 strain started. The proportion of nsSNPs in genes involved in inorganic ion transport and metabolism was significantly higher before the expansion began. A total of 22346 bp deletions were observed. Lineage 7 strains also exhibited a high number of mutations in genes involved in carbohydrate transport and metabolism, transcription, energy production and conversion. We have identified unique genomic signatures of the lineage 7 strains. The high frequency of nsSNP in 3R genes after the phylogenetic expansion may have contributed to recent variability and adaptation. The abundance of mutations in genes involved in inorganic ion transport and metabolism before the expansion period may indicate an adaptive response of lineage 7 strains to enable survival, potentially under environmental stress exposure. As lineage 7 strains originally were phylogenetically deeply rooted, this may indicate fundamental adaptive genomic pathways affecting the fitness of M. tuberculosis as a species.

  5. The transcriptional corepressor MTGR1 regulates intestinal secretory lineage allocation.

    Parang, Bobak; Rosenblatt, Daniel; Williams, Amanda D; Washington, Mary K; Revetta, Frank; Short, Sarah P; Reddy, Vishruth K; Hunt, Aubrey; Shroyer, Noah F; Engel, Michael E; Hiebert, Scott W; Williams, Christopher S

    2015-03-01

    Notch signaling largely determines intestinal epithelial cell fate. High Notch activity drives progenitors toward absorptive enterocytes by repressing secretory differentiation programs, whereas low Notch permits secretory cell assignment. Myeloid translocation gene-related 1 (MTGR1) is a transcriptional corepressor in the myeloid translocation gene/Eight-Twenty-One family. Given that Mtgr1(-/-) mice have a dramatic reduction of intestinal epithelial secretory cells, we hypothesized that MTGR1 is a key repressor of Notch signaling. In support of this, transcriptome analysis of laser capture microdissected Mtgr1(-/-) intestinal crypts revealed Notch activation, and secretory markers Mucin2, Chromogranin A, and Growth factor-independent 1 (Gfi1) were down-regulated in Mtgr1(-/-) whole intestines and Mtgr1(-/-) enteroids. We demonstrate that MTGR1 is in a complex with Suppressor of Hairless Homolog, a key Notch effector, and represses Notch-induced Hairy/Enhancer of Split 1 activity. Moreover, pharmacologic Notch inhibition using a γ-secretase inhibitor (GSI) rescued the hyperproliferative baseline phenotype in the Mtgr1(-/-) intestine and increased production of goblet and enteroendocrine lineages in Mtgr1(-/-) mice. GSI increased Paneth cell production in wild-type mice but failed to do so in Mtgr1(-/-) mice. We determined that MTGR1 can interact with GFI1, a transcriptional corepressor required for Paneth cell differentiation, and repress GFI1 targets. Overall, the data suggest that MTGR1, a transcriptional corepressor well characterized in hematopoiesis, plays a critical role in intestinal lineage allocation. © FASEB.

  6. Lineage tracing of lamellocytes demonstrates Drosophila macrophage plasticity.

    Martin Stofanko

    2010-11-01

    Full Text Available Leukocyte-like cells called hemocytes have key functions in Drosophila innate immunity. Three hemocyte types occur: plasmatocytes, crystal cells, and lamellocytes. In the absence of qimmune challenge, plasmatocytes are the predominant hemocyte type detected, while crystal cells and lamellocytes are rare. However, upon infestation by parasitic wasps, or in melanotic mutant strains, large numbers of lamellocytes differentiate and encapsulate material recognized as "non-self". Current models speculate that lamellocytes, plasmatocytes and crystal cells are distinct lineages that arise from a common prohemocyte progenitor. We show here that over-expression of the CoREST-interacting transcription factor Chn in plasmatocytes induces lamellocyte differentiation, both in circulation and in lymph glands. Lamellocyte increases are accompanied by the extinction of plasmatocyte markers suggesting that plasmatocytes are transformed into lamellocytes. Consistent with this, timed induction of Chn over-expression induces rapid lamellocyte differentiation within 18 hours. We detect double-positive intermediates between plasmatocytes and lamellocytes, and show that isolated plasmatocytes can be triggered to differentiate into lamellocytes in vitro, either in response to Chn over-expression, or following activation of the JAK/STAT pathway. Finally, we have marked plasmatocytes and show by lineage tracing that these differentiate into lamellocytes in response to the Drosophila parasite model Leptopilina boulardi. Taken together, our data suggest that lamellocytes arise from plasmatocytes and that plasmatocytes may be inherently plastic, possessing the ability to differentiate further into lamellocytes upon appropriate challenge.

  7. West Nile Virus lineage-2 in Culex specimens from Iran.

    Shahhosseini, Nariman; Chinikar, Sadegh; Moosa-Kazemi, Seyed Hassan; Sedaghat, Mohammad Mehdi; Kayedi, Mohammad Hassan; Lühken, Renke; Schmidt-Chanasit, Jonas

    2017-10-01

    Screening of mosquitoes for viruses is an important forecasting tool for emerging and re-emerging arboviruses. Iran has been known to harbour medically important arboviruses such as West Nile virus (WNV) and dengue virus (DENV) based on seroepidemiological data. However, there are no data about the potential mosquito vectors for arboviruses in Iran. This study was performed to provide mosquito and arbovirus data from Iran. A total of 32 317 mosquitos were collected at 16 sites in five provinces of Iran in 2015 and 2016. RT-PCR for detection of flaviviruses was performed. The PCR amplicons were sequenced, and 109 WNV sequences, including one obtained in this study, were used for phylogenetic analyses. The 32 317 mosquito specimens belonging to 25 species were morphologically distinguished and distributed into 1222 pools. Culex pipiens s.l. comprised 56.429%. One mosquito pool (0.08%), containing 46 unfed Cx. pipiens pipiens form pipiens (Cpp) captured in August 2015, was positive for flavivirus RNA. Subsequent sequencing and phylogenetic analyses revealed that the detected Iranian WNV strain belongs to lineage 2 and clusters with a strain recently detected in humans. No flaviviruses other than WNV were detected in the mosquito pools. Cpp could be a vector for WNV in Iran. Our findings indicate recent circulation of WNV lineage-2 strain in Iran and provide a solid base for more targeted arbovirus surveillance programs. © 2017 John Wiley & Sons Ltd.

  8. Recent reticulate evolution in the ecologically dominant lineage of coccolithophores

    El Mahdi eBendif

    2016-05-01

    Full Text Available The coccolithophore family Noëlaerhabdaceae contains a number of taxa that are very abundant in modern oceans, including the cosmopolitan bloom-forming Emiliania huxleyi. Introgressive hybridization has been suggested to account for incongruences between nuclear, mitochondrial and plastidial phylogenies of morphospecies within this lineage, but the number of species cultured to date remains rather limited. Here, we present the characterization of 5 new Noëlaerhabdaceae culture strains isolated from samples collected in the south-east Pacific Ocean. These were analyzed morphologically using scanning electron microscopy and phylogenetically by sequencing 5 marker genes (nuclear 18S and 28S rDNA, plastidial tufA, and mitochondrial cox1 and cox3 genes. Morphologically, one of these strains corresponded to Gephyrocapsa ericsonii and the four others to Reticulofenestra parvula. Ribosomal gene sequences were near identical between these new strains, but divergent from G. oceanica, G. muellerae and E. huxleyi. In contrast to the clear distinction in ribosomal phylogenies, sequences from other genomic compartments clustered with those of E. huxleyi strains with which they share an ecological range (i.e. warm temperate to tropical waters. These data provide strong support for the hypothesis of past (and potentially ongoing introgressive hybridization within this ecologically important lineage and for the transfer of R. parvula to Gephyrocapsa. These results have important implications for understanding the role of hybridization in speciation in vast ocean meta-populations of phytoplankton.

  9. Independent origins of Indian caste and tribal paternal lineages.

    Cordaux, Richard; Aunger, Robert; Bentley, Gillian; Nasidze, Ivane; Sirajuddin, S M; Stoneking, Mark

    2004-02-03

    The origins of the nearly one billion people inhabiting the Indian subcontinent and following the customs of the Hindu caste system are controversial: are they largely derived from Indian local populations (i.e. tribal groups) or from recent immigrants to India? Archaeological and linguistic evidence support the latter hypothesis, whereas recent genetic data seem to favor the former hypothesis. Here, we analyze the most extensive dataset of Indian caste and tribal Y chromosomes to date. We find that caste and tribal groups differ significantly in their haplogroup frequency distributions; caste groups are homogeneous for Y chromosome variation and more closely related to each other and to central Asian groups than to Indian tribal or any other Eurasian groups. We conclude that paternal lineages of Indian caste groups are primarily descended from Indo-European speakers who migrated from central Asia approximately 3,500 years ago. Conversely, paternal lineages of tribal groups are predominantly derived from the original Indian gene pool. We also provide evidence for bidirectional male gene flow between caste and tribal groups. In comparison, caste and tribal groups are homogeneous with respect to mitochondrial DNA variation, which may reflect the sociocultural characteristics of the Indian caste society.

  10. Widespread occurrence of secondary lipid biosynthesis potential in microbial lineages.

    Christine N Shulse

    Full Text Available Bacterial production of long-chain omega-3 polyunsaturated fatty acids (PUFAs, such as eicosapentaenoic acid (EPA, 20:5n-3 and docosahexaenoic acid (DHA, 22:6n-3, is constrained to a narrow subset of marine γ-proteobacteria. The genes responsible for de novo bacterial PUFA biosynthesis, designated pfaEABCD, encode large, multi-domain protein complexes akin to type I iterative fatty acid and polyketide synthases, herein referred to as "Pfa synthases". In addition to the archetypal Pfa synthase gene products from marine bacteria, we have identified homologous type I FAS/PKS gene clusters in diverse microbial lineages spanning 45 genera representing 10 phyla, presumed to be involved in long-chain fatty acid biosynthesis. In total, 20 distinct types of gene clusters were identified. Collectively, we propose the designation of "secondary lipids" to describe these biosynthetic pathways and products, a proposition consistent with the "secondary metabolite" vernacular. Phylogenomic analysis reveals a high degree of functional conservation within distinct biosynthetic path