Age at Death of Creutzfeldt-Jakob disease in subsequent family generation carrying the E200K mutation of the prion protein gene.

Directory of Open Access Journals (Sweden)

Maurizio Pocchiari

Full Text Available The E200K mutation of the prion protein gene (PRNP is the most frequent amino acid substitution in genetic Creutzfeldt-Jakob disease and is the only one responsible for the appearance of clustered cases in the world. In the Israel and Slovakian clusters, age of disease onset was reduced in successive generations but the absence of a clear molecular basis raised the possibility that this event was an observational bias. The aim of the present study was to investigate possible selection biases or confounding factors related to anticipation in E200K CJD patients belonging to a cluster in Southern Italy.Clinical and demographical data of 41 parent-offspring pairs from 19 pedigrees of the Italian cluster of E200K patients were collected. Age at death of parents was compared with age at death of E200K CJD offspring. Subgroup analyses were performed for controlling possible selection biases, confounding factors, or both.The mean age at death/last follow-up of the parent generation was 71.4 years while that of CJD offspring was 59.3 years with an estimated anticipation of 12.1 years. When the same analysis was performed including only parents with CJD or carrying the E200K mutation (n = 26, the difference between offspring and parents increased to 14.8 years.These results show that early age at death occurs in offspring of families carrying the E200K PRNP mutation and that this event is not linked to observational biases. Although molecular or environmental bases for this occurrence remain unsettled, this information is important for improving the accuracy of information to give to mutated carriers.

Programming and Playing with RoboSapien on line

Directory of Open Access Journals (Sweden)

Vladimir M Cvjetkovic

2011-07-01

Full Text Available RoboSapien is famous human like robot toy intended for playing with, of interested in, of all ages, and learning through the game, of some basic characteristics of robots and robotic control. The programming of RoboSapien as described in user’s manual is limited with the internal memory, battery life, and not very convenient input of actions through the multipurpose buttons of the RoboSapien IR remote control device. In order to offer better conditions for experimenting and using of RoboSapien, the web user interface was developed, that provides interactive user control, programming of command sequences of arbitrary length, observing of RoboSapien actions using the web cam that shows the movements and actions on web page. Access and control of RoboSapien by remote user through the web page user interface, is controlled by access levels depending on whether the user is logged in or not. The whole system is implemented in C# as ASP.NET project with NI USB 6501 digital I/O driving the CMOS 4066 analog switches for controlling the RoboSapien IR remote control device.

The Robo4 cytoplasmic domain is dispensable for vascular permeability and neovascularization.

Science.gov (United States)

Zhang, Feng; Prahst, Claudia; Mathivet, Thomas; Pibouin-Fragner, Laurence; Zhang, Jiasheng; Genet, Gael; Tong, Raymond; Dubrac, Alexandre; Eichmann, Anne

2016-11-24

Vascular permeability and neovascularization are implicated in many diseases including retinopathies and diabetic wound healing. Robo4 is an endothelial-specific transmembrane receptor that stabilizes the vasculature, as shown in Robo4 -/- mice that develop hyperpermeability, but how Robo4 signals remained unclear. Here we show that Robo4 deletion enhances permeability and revascularization in oxygen-induced retinopathy (OIR) and accelerates cutaneous wound healing. To determine Robo4 signalling pathways, we generated transgenic mice expressing a truncated Robo4 lacking the cytoplasmic domain (Robo4ΔCD). Robo4ΔCD expression is sufficient to prevent permeability, and inhibits OIR revascularization and wound healing in Robo4 -/- mice. Mechanistically, Robo4 does not affect Slit2 signalling, but Robo4 and Robo4ΔCD counteract Vegfr2-Y949 (Y951 in human VEGFR2) phosphorylation by signalling through the endothelial UNC5B receptor. We conclude that Robo4 inhibits angiogenesis and vessel permeability independently of its cytoplasmic domain, while activating VEGFR2-Y951 via ROBO4 inhibition might accelerate tissue revascularization in retinopathy of prematurity and in diabetic patients.

A protein-targeting strategy used to develop a selective inhibitor of the E17K point mutation in the PH domain of Akt1

Science.gov (United States)

Deyle, Kaycie M.; Farrow, Blake; Qiao Hee, Ying; Work, Jeremy; Wong, Michelle; Lai, Bert; Umeda, Aiko; Millward, Steven W.; Nag, Arundhati; Das, Samir; Heath, James R.

2015-05-01

Ligands that can bind selectively to proteins with single amino-acid point mutations offer the potential to detect or treat an abnormal protein in the presence of the wild type (WT). However, it is difficult to develop a selective ligand if the point mutation is not associated with an addressable location, such as a binding pocket. Here we report an all-chemical synthetic epitope-targeting strategy that we used to discover a 5-mer peptide with selectivity for the E17K-transforming point mutation in the pleckstrin homology domain of the Akt1 oncoprotein. A fragment of Akt1 that contained the E17K mutation and an I19[propargylglycine] substitution was synthesized to form an addressable synthetic epitope. Azide-presenting peptides that clicked covalently onto this alkyne-presenting epitope were selected from a library using in situ screening. One peptide exhibits a 10:1 in vitro selectivity for the oncoprotein relative to the WT, with a similar selectivity in cells. This 5-mer peptide was expanded into a larger ligand that selectively blocks the E17K Akt1 interaction with its PIP3 (phosphatidylinositol (3,4,5)-trisphosphate) substrate.

Neurological disease mutations of α3 Na+,K+-ATPase: Structural and functional perspectives and rescue of compromised function.

Science.gov (United States)

Holm, Rikke; Toustrup-Jensen, Mads S; Einholm, Anja P; Schack, Vivien R; Andersen, Jens P; Vilsen, Bente

2016-11-01

Na + ,K + -ATPase creates transmembrane ion gradients crucial to the function of the central nervous system. The α-subunit of Na + ,K + -ATPase exists as four isoforms (α1-α4). Several neurological phenotypes derive from α3 mutations. The effects of some of these mutations on Na + ,K + -ATPase function have been studied in vitro. Here we discuss the α3 disease mutations as well as information derived from studies of corresponding mutations of α1 in the light of the high-resolution crystal structures of the Na + ,K + -ATPase. A high proportion of the α3 disease mutations occur in the transmembrane sector and nearby regions essential to Na + and K + binding. In several cases the compromised function can be traced to disturbance of the Na + specific binding site III. Recently, a secondary mutation was found to rescue the defective Na + binding caused by a disease mutation. A perspective is that it may be possible to develop an efficient pharmaceutical mimicking the rescuing effect. Copyright © 2016 Elsevier B.V. All rights reserved.

A HRM assay for identification of low level BRAF V600E and V600K mutations using the CADMA principle in FFPE specimens.

Science.gov (United States)

Huebner, Claudia; Weber, Remeny; Lloydd, Richard

2017-12-01

Melanoma patients with BRAF V600E and V600K mutations show complete or partial response to vemurafenib. Detection assays often scan for the common V600E mutation rather than the rare V600K variant, although this mutation can be found in a high proportion of melanoma patients in the South Pacific. Herein, we describe a BRAF high resolution melting (HRM) assay that can differentiate low level of V600E and V600K mutations using formalin fixed, paraffin embedded (FFPE) reference standards for assay validation. The assay is based on the competitive amplification of differentially melting amplicons (CADMA principle) and has a limit of detection of 0.8% mutant allele for V600K and 1.4% mutant allele for V600E. A differentiation between the two mutations based on the melting profile is possible even at low mutation level. Sixty FFPE specimens were scanned and mutations could be scored correctly as confirmed by castPCR. In summary, the developed HRM assay is suitable for detection of V600K and V600E mutations and proved to be reliable and cost effective in a diagnostic environment. Copyright © 2017 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.

Diffuse high-grade gliomas with H3 K27M mutations carry a dismal prognosis independent of tumor location.

Science.gov (United States)

Karremann, Michael; Gielen, Gerrit H; Hoffmann, Marion; Wiese, Maria; Colditz, Niclas; Warmuth-Metz, Monika; Bison, Brigitte; Claviez, Alexander; van Vuurden, Dannis G; von Bueren, André O; Gessi, Marco; Kühnle, Ingrid; Hans, Volkmar H; Benesch, Martin; Sturm, Dominik; Kortmann, Rolf-Dieter; Waha, Andreas; Pietsch, Torsten; Kramm, Christof M

2018-01-10

The novel entity of "diffuse midline glioma, H3 K27M-mutant" has been defined in the 2016 revision of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS). Tumors of this entity arise in CNS midline structures of predominantly pediatric patients and are associated with an overall dismal prognosis. They are defined by K27M mutations in H3F3A or HIST1H3B/C, encoding for histone 3 variants H3.3 and H3.1, respectively, which are considered hallmark events driving gliomagenesis. Here, we characterized 85 centrally reviewed diffuse gliomas on midline locations enrolled in the nationwide pediatric German HIT-HGG registry regarding tumor site, histone 3 mutational status, WHO grade, age, sex, and extent of tumor resection. We found 56 H3.3 K27M-mutant tumors (66%), 6 H3.1 K27M-mutant tumors (7%), and 23 H3-wildtype tumors (27%). H3 K27M-mutant gliomas shared an aggressive clinical course independent of their anatomic location. Multivariate regression analysis confirmed the significant impact of the H3 K27M mutation as the only independent parameter predictive of overall survival (P = 0.009). In H3 K27M-mutant tumors, neither anatomic midline location nor histopathological grading nor extent of tumor resection had an influence on survival. These results substantiate the clinical significance of considering diffuse midline glioma, H3 K27M-mutant, as a distinct entity corresponding to WHO grade IV, carrying a universally fatal prognosis. © The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Darier disease mutation E917K/E918K of SERCA causes accumulation of the E2 form

DEFF Research Database (Denmark)

Mikkelsen, Stine; Holdensen, Anne Nyholm; Vilsen, Bente

2011-01-01

. SERCA2b E917K as well as SERCA1a E918K reduces the apparent Ca2+ affinity 2- to 3-fold, compared with the respective wild type. The resulting disturbance of Ca2+ homeostasis is probably the reason for the abnormalities of epidermal cells in the Darier disease patients. The reduction of apparent Ca2...

MicroRNA-218 inhibits cell invasion and migration of pancreatic cancer via regulating ROBO1.

Science.gov (United States)

He, Hang; Hao, Si-Jie; Yao, Lie; Yang, Feng; Di, Yang; Li, Ji; Jiang, Yong-Jian; Jin, Chen; Fu, De-Liang

2014-10-01

miRNA-218 is a highlighted tumor suppressor and its underlying role in tumor progression is still unknown. Here, we restored the expression of miRNA-218 in pancreatic cancer to clarify the function and potent downstream pathway of miRNA-218. The expressions of both miRNA-218 and its potent target gene ROBO1 were revealed by RT-PCR and western blotting analysis. Transfection of miRNA-218 precursor mimics and luciferase assay were performed to elucidate the regulation mechanism between miRNA-218 and ROBO1. Cells, stably expressing miRNA-218 followed by forced expression of mutant ROBO1, were established through co-transfections of both lentivirus vector and plasmid vector. The cell migration and invasion abilities were evaluated by migration assay and invasion assay respectively. An increased expression of ROBO1 was revealed in cell BxPC-3-LN compared with cell BxPC-3. Elevated expression of miRNA-218 would suppress the expression of ROBO1 via complementary binding to a specific region within 3'UTR of ROBO1 mRNA (sites 971-978) in pancreatic cancer cells. Stably restoring the expression of miRNA-218 in pancreatic cancer significantly downregulated the expression of ROBO1 and effectively inhibited cell migration and invasion. Forced expression of mutant ROBO1 could reverse the repression effects of miRNA-218 on cell migration and invasion. Consequently, miRNA-218 acted as a tumor suppressor in pancreatic cancer by inhibiting cell invasion and migration. ROBO1 was a functional target of miRNA-218's downstream pathway involving in cell invasion and migration of pancreatic cancer.

Robo-Sensei's NLP-Based Error Detection and Feedback Generation

Science.gov (United States)

Nagata, Noriko

2009-01-01

This paper presents a new version of Robo-Sensei's NLP (Natural Language Processing) system which updates the version currently available as the software package "ROBO-SENSEI: Personal Japanese Tutor" (Nagata, 2004). Robo-Sensei's NLP system includes a lexicon, a morphological generator, a word segmentor, a morphological parser, a syntactic…

Desentendimiento moral y dinámicas del robo escolar

Directory of Open Access Journals (Sweden)

Claudia Bolívar

2010-06-01

Full Text Available En una investigación reciente sobre violencia escolar en Bogotá, Colombia, el 56% de los estudiantes reportaron haber sido robados en el colegio durante el último año. El presente estudio cualitativo, de corte deductivo, pretendió profundizar en este fenómeno, buscando comprender las dinámicas de robos, así como los mecanismos de desentendimiento moral que podrían estar facilitando que los vinculados sientan menos culpa. El estudio fue realizado en un colegio público de nivel socioeconómico bajo y con altos niveles de criminalidad en su contexto comunitario. Inicialmente, 227 alumnos de sexto y octavo grados respondieron una encuesta de actitudes frente al robo. Con base en sus respuestas, 20 estudiantes con niveles altos de favorabilidad fueron entrevistados, y 40 que tenían niveles bajos o promedio de favorabilidad participaron en grupos focales. Los resultados indicaron que el robo en este colegio presenta un nivel elevado de organización, e involucra con frecuencia planeación, división de labores y amenazas. Además, según los participantes, el robo está muy relacionado con la presencia de pandillas en el colegio y con la falta de respuesta institucional clara y consistente. También se encontró que los involucrados recurren a varios mecanismos de desentendimiento moral, como las comparaciones ventajosas, el desplazamiento o la difusión de la responsabilidad, y la atribución de la culpa, como estrategias para justificar sus acciones. El estudio indica que es urgente implementar y evaluar intervenciones que busquen prevenir tanto el robo como la vinculación a trayectorias delictivas tempranas.

Robo-AO KP: A new era in robotic adaptive optics

Science.gov (United States)

Riddle, Reed L.; Baranec, Christoph; Law, Nicholas M.; Kulkarni, Shrinivas R.; Duev, Dmitry; Ziegler, Carl; Jensen-Clem, Rebecca M.; Atkinson, Dani Eleanor; Tanner, Angelle M.; Zhang, Celia; Ray, Amy

2016-01-01

Robo-AO is the first and only fully automated adaptive optics laser guide star AO instrument. It was developed as an instrument for 1-3m robotic telescopes, in order to take advantage of their availability to pursue large survey programs and target of opportunity observations that aren't possible with other AO systems. Robo-AO is currently the most efficient AO system in existence, and it can achieve an observation rate of 20+ science targets per hour. In more than three years of operations at Palomar Observatory, it has been quite successful, producing technology that is being adapted by other AO systems and robotic telescope projects, as well as several high impact scientific publications. Now, Robo-AO has been selected to take over operation of the Kitt Peak National Observatory 2.1m telescope. This will give Robo-AO KP the opportunity to pursue multiple science programs consisting of several thousand targets each during the three years it will be on the telescope. One-sixth of the observing time will be allocated to the US community through the NOAO TAC process. This presentation will discuss the process adapting Robo-AO to the KPNO 2.1m telescope, the plans for integration and initial operations, and the science operations and programs to be pursued.

Regulating Robo Advice across the Financial Services Industry

OpenAIRE

Baker, Tom; Dellaert, Benedict

2017-01-01

textabstractAutomated financial product advisors – “robo advisors” – are emerging across the financial services industry, helping consumers choose investments, banking products, and insurance policies. Robo advisors have the potential to lower the cost and increase the quality and transparency of financial advice for consumers. But they also pose significant new challenges for regulators who are accustomed to assessing human intermediaries. A well-designed robo advisor will be honest and comp...

Robo-AO M Dwarf Multiplicity Survey

Science.gov (United States)

Lamman, Claire; Baranec, Christoph; Berta-Thompson, Zachory K.; Law, Nicholas M.; Ziegler, Carl; Schonhut-Stasik, Jessica

2018-06-01

We analyzed close to 7,000 observations from Robo-AO’s field M dwarf survey taken on the 2.1m Kitt Peak telescope. Results will help determine the total multiplicity fraction and multiplicity functions of M dwarfs, which are crucial steps towards understanding their evolution and formation mechanics. Through its robotic, laser-guided, and automated system, the Robo-AO instrument has yielded the largest adaptive-optics M dwarf survey to date. I developed a graphical user interface to quickly analyze this data. Initial data analysis included assessing data quality, checking the result from Robo-AO’s automatic reduction pipeline, and determining existence as well as the relative position of companions through a visual inspection. This program can be applied to other datasets and was successfully tested by re-analyzing observations from a separate Robo-AO survey. After a conservative initial cut for quality, over 350 companions were found within 4” of a primary star out of 2,746 high quality Robo-AO M dwarf observations, including four triple systems. Further observations were done with the Keck II telescope by using its NIRC2 imager to follow up on ten select targets for the existence and physical association of companions. Future research will yield insights into low-mass stellar formation and provide a database of nearby M dwarf multiples that will potentially assist ongoing and future surveys for planets around these stars, such as the NASA TESS mission.

The axon guidance receptor gene ROBO1 is a candidate gene for developmental dyslexia.

Directory of Open Access Journals (Sweden)

Katariina Hannula-Jouppi

2005-10-01

Full Text Available Dyslexia, or specific reading disability, is the most common learning disorder with a complex, partially genetic basis, but its biochemical mechanisms remain poorly understood. A locus on Chromosome 3, DYX5, has been linked to dyslexia in one large family and speech-sound disorder in a subset of small families. We found that the axon guidance receptor gene ROBO1, orthologous to the Drosophila roundabout gene, is disrupted by a chromosome translocation in a dyslexic individual. In a large pedigree with 21 dyslexic individuals genetically linked to a specific haplotype of ROBO1 (not found in any other chromosomes in our samples, the expression of ROBO1 from this haplotype was absent or attenuated in affected individuals. Sequencing of ROBO1 in apes revealed multiple coding differences, and the selection pressure was significantly different between the human, chimpanzee, and gorilla branch as compared to orangutan. We also identified novel exons and splice variants of ROBO1 that may explain the apparent phenotypic differences between human and mouse in heterozygous loss of ROBO1. We conclude that dyslexia may be caused by partial haplo-insufficiency for ROBO1 in rare families. Thus, our data suggest that a slight disturbance in neuronal axon crossing across the midline between brain hemispheres, dendrite guidance, or another function of ROBO1 may manifest as a specific reading disability in humans.

The Axon Guidance Receptor Gene ROBO1 Is a Candidate Gene for Developmental Dyslexia.

Directory of Open Access Journals (Sweden)

2005-10-01

Full Text Available Dyslexia, or specific reading disability, is the most common learning disorder with a complex, partially genetic basis, but its biochemical mechanisms remain poorly understood. A locus on Chromosome 3, DYX5, has been linked to dyslexia in one large family and speech-sound disorder in a subset of small families. We found that the axon guidance receptor gene ROBO1, orthologous to the Drosophila roundabout gene, is disrupted by a chromosome translocation in a dyslexic individual. In a large pedigree with 21 dyslexic individuals genetically linked to a specific haplotype of ROBO1 (not found in any other chromosomes in our samples, the expression of ROBO1 from this haplotype was absent or attenuated in affected individuals. Sequencing of ROBO1 in apes revealed multiple coding differences, and the selection pressure was significantly different between the human, chimpanzee, and gorilla branch as compared to orangutan. We also identified novel exons and splice variants of ROBO1 that may explain the apparent phenotypic differences between human and mouse in heterozygous loss of ROBO1. We conclude that dyslexia may be caused by partial haplo-insufficiency for ROBO1 in rare families. Thus, our data suggest that a slight disturbance in neuronal axon crossing across the midline between brain hemispheres, dendrite guidance, or another function of ROBO1 may manifest as a specific reading disability in humans.

Nutritional, physico-chemical and sensory properties of Robo (A ...

African Journals Online (AJOL)

The vitamins – thiamine, riboflavin and niacin in the melon robo were 2.87, 0.65 and 1.28 mg/100 g while sesame robo contained 2.13, 1.05 and 0.56 mg/100 g respectively. The phytate and oxalate concentrations were relatively low in all the samples. The sensory evaluation results revealed that melon robo was rated ...

STAT3 mutations correlated with hyper-IgE syndrome lead to ...

Indian Academy of Sciences (India)

Of all the causes identified for the disease hyper-immunoglobulinemia E syndrome (HIES), a homozygous mutation in tyrosine kinase2 (TYK2) and heterozygous mutations in STAT3 are implicated the defects in Jak/STAT signalling pathway in the pathogenesis of HIES. Mutations of STAT3 have been frequently clinically ...

K-Ras and β-catenin mutations cooperate with Fgfr3 mutations in mice to promote tumorigenesis in the skin and lung, but not in the bladder

Directory of Open Access Journals (Sweden)

Imran Ahmad

2011-07-01

The human fibroblast growth factor receptor 3 (FGFR3 gene is frequently mutated in superficial urothelial cell carcinoma (UCC. To test the functional significance of FGFR3 activating mutations as a ‘driver’ of UCC, we targeted the expression of mutated Fgfr3 to the murine urothelium using Cre-loxP recombination driven by the uroplakin II promoter. The introduction of the Fgfr3 mutations resulted in no obvious effect on tumorigenesis up to 18 months of age. Furthermore, even when the Fgfr3 mutations were introduced together with K-Ras or β-catenin (Ctnnb1 activating mutations, no urothelial dysplasia or UCC was observed. Interestingly, however, owing to a sporadic ectopic Cre recombinase expression in the skin and lung of these mice, Fgfr3 mutation caused papilloma and promoted lung tumorigenesis in cooperation with K-Ras and β-catenin activation, respectively. These results indicate that activation of FGFR3 can cooperate with other mutations to drive tumorigenesis in a context-dependent manner, and support the hypothesis that activation of FGFR3 signaling contributes to human cancer.

ROBO-AO M DWARF MULTIPLICITY SURVEY

Science.gov (United States)

Lamman, Claire; Berta-Thompson, Zachory; Baranec, Christoph; Law, Nicholas; Schonhut, Jessica

2018-01-01

We analyzed over 7,000 observations from Robo-AO’s field M dwarf survey taken on the 2.1m Kitt Peak telescope. Results will help determine the multiplicity fraction of M dwarfs as a function of primary mass, which is a crucial step towards understanding their evolution and formation mechanics. Through its robotic, laser-guided, and automated system, the Robo-AO instrument has yielded the largest adaptive-optics M dwarf survey to date. I developed a graphical user interface to quickly analyze this data. Initial data analysis included assessing data quality, checking the result from Robo-AO’s automatic reduction pipeline, and determining existence as well as the relative position of companions through a visual inspection. This program can be applied to other datasets and was successfully tested by re-analyzing observations from a separate Robo-AO survey. Following the preliminary results from this data analysis tool, further observations were done with the Keck II telescope by using its NIRC2 imager to follow up on ten select targets for the existence and physical association of companions. After a conservative initial cut for quality, 356 companions were found within 4” of a primary star out of 2,746 high quality Robo-AO M dwarf observations, including four triple systems. We will present a preliminary estimate for the multiplicity rate of wide M dwarf companions after accounting for observation limitations and the completeness of our search. Future research will yield insights into low-mass stellar formation and provide a database of nearby M dwarf multiples that will potentially assist ongoing and future surveys for planets around these stars, such as the NASA TESS mission.

Automated Advice: A Portfolio Management Perspective on Robo-Advisors

OpenAIRE

Vukovic, Ana; Bjerknes, Line

2017-01-01

In this paper we investigate the predominant robo-advisor model, uncovering that however novel this solution might be, it also relies religiously on imperative contributions to modern portfolio theory that have been made in the past half a century. Despite conforming by and large to passive investment, we find that the slight variations in the methodologies used by robo-advisors introduce significant variability in risk-adjusted returns across the robo-advisor spectrum. Nonetheless, our perfo...

Design and Implementation of a General Decision-Making Model in RoboCup Simulation

Directory of Open Access Journals (Sweden)

Changda Wang

2004-09-01

Full Text Available The study of the collaboration, coordination and negotiation among different agents in a multi-agent system (MAS has always been the most challenging yet popular in the research of distributed artificial intelligence. In this paper, we will suggest for RoboCup simulation, a typical MAS, a general decision-making model, rather than define a different algorithm for each tactic (e.g. ball handling, pass, shoot and interception, etc. in soccer games as most RoboCup simulation teams did. The general decision-making model is based on two critical factors in soccer games: the vertical distance to the goal line and the visual angle for the goalpost. We have used these two parameters to formalize the defensive and offensive decisions in RoboCup simulation and the results mentioned above had been applied in NOVAURO®, original name is UJDB, a RoboCup simulation team of Jiangsu University, whose decision-making model, compared with that of Tsinghua University, the world champion team in 2001, is a universal model and easier to be implemented.

Regulating Robo Advice across the Financial Services Industry

NARCIS (Netherlands)

T. Baker (Tom); B.G.C. Dellaert (Benedict)

2017-01-01

textabstractAutomated financial product advisors – “robo advisors” – are emerging across the financial services industry, helping consumers choose investments, banking products, and insurance policies. Robo advisors have the potential to lower the cost and increase the quality and transparency of

Regulation of Drosophila Brain Wiring by Neuropil Interactions via a Slit-Robo-RPTP Signaling Complex.

Science.gov (United States)

Oliva, Carlos; Soldano, Alessia; Mora, Natalia; De Geest, Natalie; Claeys, Annelies; Erfurth, Maria-Luise; Sierralta, Jimena; Ramaekers, Ariane; Dascenco, Dan; Ejsmont, Radoslaw K; Schmucker, Dietmar; Sanchez-Soriano, Natalia; Hassan, Bassem A

2016-10-24

The axonal wiring molecule Slit and its Round-About (Robo) receptors are conserved regulators of nerve cord patterning. Robo receptors also contribute to wiring brain circuits. Whether molecular mechanisms regulating these signals are modified to fit more complex brain wiring processes is unclear. We investigated the role of Slit and Robo receptors in wiring Drosophila higher-order brain circuits and identified differences in the cellular and molecular mechanisms of Robo/Slit function. First, we find that signaling by Robo receptors in the brain is regulated by the Receptor Protein Tyrosine Phosphatase RPTP69d. RPTP69d increases membrane availability of Robo3 without affecting its phosphorylation state. Second, we detect no midline localization of Slit during brain development. Instead, Slit is enriched in the mushroom body, a neuronal structure covering large areas of the brain. Thus, a divergent molecular mechanism regulates neuronal circuit wiring in the Drosophila brain, partly in response to signals from the mushroom body. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Loss-of-function mutations in co-chaperone BAG3 destabilize small HSPs and cause cardiomyopathy.

Science.gov (United States)

Fang, Xi; Bogomolovas, Julius; Wu, Tongbin; Zhang, Wei; Liu, Canzhao; Veevers, Jennifer; Stroud, Matthew J; Zhang, Zhiyuan; Ma, Xiaolong; Mu, Yongxin; Lao, Dieu-Hung; Dalton, Nancy D; Gu, Yusu; Wang, Celine; Wang, Michael; Liang, Yan; Lange, Stephan; Ouyang, Kunfu; Peterson, Kirk L; Evans, Sylvia M; Chen, Ju

2017-08-01

Defective protein quality control (PQC) systems are implicated in multiple diseases. Molecular chaperones and co-chaperones play a central role in functioning PQC. Constant mechanical and metabolic stress in cardiomyocytes places great demand on the PQC system. Mutation and downregulation of the co-chaperone protein BCL-2-associated athanogene 3 (BAG3) are associated with cardiac myopathy and heart failure, and a BAG3 E455K mutation leads to dilated cardiomyopathy (DCM). However, the role of BAG3 in the heart and the mechanisms by which the E455K mutation leads to DCM remain obscure. Here, we found that cardiac-specific Bag3-KO and E455K-knockin mice developed DCM. Comparable phenotypes in the 2 mutants demonstrated that the E455K mutation resulted in loss of function. Further experiments revealed that the E455K mutation disrupted the interaction between BAG3 and HSP70. In both mutants, decreased levels of small heat shock proteins (sHSPs) were observed, and a subset of proteins required for cardiomyocyte function was enriched in the insoluble fraction. Together, these observations suggest that interaction between BAG3 and HSP70 is essential for BAG3 to stabilize sHSPs and maintain cardiomyocyte protein homeostasis. Our results provide insight into heart failure caused by defects in BAG3 pathways and suggest that increasing BAG3 protein levels may be of therapeutic benefit in heart failure.

Why it is harder to run RoboCup in South Africa

Directory of Open Access Journals (Sweden)

Alexander Ferrein

2016-10-01

Full Text Available Robots are widely used as a vehicle to spark interest in science and technology in learners. A number of initiatives focus on this issue, for instance, the Roberta Initiative, the FIRST Lego League, the World Robot Olympiad and RoboCup Junior. Robotic competitions are valuable not only for school learners but also for university students, as the RoboCup initiative shows. Besides technical skills, the students get some project exposure and experience what it means to finish their tasks on time. But qualifying students for future high-tech areas should not only be for students from developed countries. In this article, we present our experiences with research and education in robotics within the RoboCup initiative, in Germany and South Africa; we report on our experiences with trying to get the RoboCup initiative in South Africa going. RoboCup has a huge support base of academic institutions in Germany; this is not the case in South Africa. We present our ‘north–south’ collaboration initiatives in RoboCup between Germany and South Africa and discuss some of the reasons why we think it is harder to run RoboCup in South Africa.

A histone H3K9M mutation traps histone methyltransferase Clr4 to prevent heterochromatin spreading

Energy Technology Data Exchange (ETDEWEB)

Shan, Chun-Min; Wang, Jiyong; Xu, Ke; Chen, Huijie; Yue, Jia-Xing; Andrews, Stuart; Moresco, James J.; Yates, John R.; Nagy, Peter L.; Tong, Liang; Jia, Songtao

2016-09-20

Histone lysine-to-methionine (K-to-M) mutations are associated with multiple cancers, and they function in a dominant fashion to block the methylation of corresponding lysines on wild type histones. However, their mechanisms of function are controversial. Here we show that in fission yeast, introducing the K9M mutation into one of the three histone H3 genes dominantly blocks H3K9 methylation on wild type H3 across the genome. In addition, H3K9M enhances the interaction of histone H3 tail with the H3K9 methyltransferase Clr4 in a SAM (S-adenosyl-methionine)-dependent manner, and Clr4 is trapped at nucleation sites to prevent its spreading and the formation of large heterochromatin domains. We further determined the crystal structure of an H3K9M peptide in complex with human H3K9 methyltransferase G9a and SAM, which reveales that the methionine side chain had enhanced van der Waals interactions with G9a. Therefore, our results provide a detailed mechanism by which H3K9M regulates H3K9 methylation.

Robo4 maintains vessel integrity and inhibits angiogenesis by interacting with UNC5B.

Science.gov (United States)

Koch, Alexander W; Mathivet, Thomas; Larrivée, Bruno; Tong, Raymond K; Kowalski, Joe; Pibouin-Fragner, Laurence; Bouvrée, Karine; Stawicki, Scott; Nicholes, Katrina; Rathore, Nisha; Scales, Suzie J; Luis, Elizabeth; del Toro, Raquel; Freitas, Catarina; Bréant, Christiane; Michaud, Annie; Corvol, Pierre; Thomas, Jean-Léon; Wu, Yan; Peale, Franklin; Watts, Ryan J; Tessier-Lavigne, Marc; Bagri, Anil; Eichmann, Anne

2011-01-18

Robo4 is an endothelial cell-specific member of the Roundabout axon guidance receptor family. To identify Robo4 binding partners, we performed a protein-protein interaction screen with the Robo4 extracellular domain. We find that Robo4 specifically binds to UNC5B, a vascular Netrin receptor, revealing unexpected interactions between two endothelial guidance receptors. We show that Robo4 maintains vessel integrity by activating UNC5B, which inhibits signaling downstream of vascular endothelial growth factor (VEGF). Function-blocking monoclonal antibodies against Robo4 and UNC5B increase angiogenesis and disrupt vessel integrity. Soluble Robo4 protein inhibits VEGF-induced vessel permeability and rescues barrier defects in Robo4(-/-) mice, but not in mice treated with anti-UNC5B. Thus, Robo4-UNC5B signaling maintains vascular integrity by counteracting VEGF signaling in endothelial cells, identifying a novel function of guidance receptor interactions in the vasculature. Copyright © 2011 Elsevier Inc. All rights reserved.

ALDH2(E487K) mutation increases protein turnover and promotes murine hepatocarcinogenesis.

Science.gov (United States)

Jin, Shengfang; Chen, Jiang; Chen, Lizao; Histen, Gavin; Lin, Zhizhong; Gross, Stefan; Hixon, Jeffrey; Chen, Yue; Kung, Charles; Chen, Yiwei; Fu, Yufei; Lu, Yuxuan; Lin, Hui; Cai, Xiujun; Yang, Hua; Cairns, Rob A; Dorsch, Marion; Su, Shinsan M; Biller, Scott; Mak, Tak W; Cang, Yong

2015-07-21

Mitochondrial aldehyde dehydrogenase 2 (ALDH2) in the liver removes toxic aldehydes including acetaldehyde, an intermediate of ethanol metabolism. Nearly 40% of East Asians inherit an inactive ALDH2*2 variant, which has a lysine-for-glutamate substitution at position 487 (E487K), and show a characteristic alcohol flush reaction after drinking and a higher risk for gastrointestinal cancers. Here we report the characterization of knockin mice in which the ALDH2(E487K) mutation is inserted into the endogenous murine Aldh2 locus. These mutants recapitulate essentially all human phenotypes including impaired clearance of acetaldehyde, increased sensitivity to acute or chronic alcohol-induced toxicity, and reduced ALDH2 expression due to a dominant-negative effect of the mutation. When treated with a chemical carcinogen, these mutants exhibit increased DNA damage response in hepatocytes, pronounced liver injury, and accelerated development of hepatocellular carcinoma (HCC). Importantly, ALDH2 protein levels are also significantly lower in patient HCC than in peritumor or normal liver tissues. Our results reveal that ALDH2 functions as a tumor suppressor by maintaining genomic stability in the liver, and the common human ALDH2 variant would present a significant risk factor for hepatocarcinogenesis. Our study suggests that the ALDH2*2 allele-alcohol interaction may be an even greater human public health hazard than previously appreciated.

RoboCon: A general purpose telerobotic control center

Energy Technology Data Exchange (ETDEWEB)

Draper, J.V.; Noakes, M.W. [Oak Ridge National Lab., TN (United States). Robotics and Process Systems Div.; Schempf, H. [Carnegie Mellon Univ., Pittsburgh, PA (United States); Blair, L.M. [Human Machine Interfaces, Inc., Knoxville, TN (United States)

1997-02-01

This report describes human factors issues involved in the design of RoboCon, a multi-purpose control center for use in US Department of Energy remote handling applications. RoboCon is intended to be a flexible, modular control center capable of supporting a wide variety of robotic devices.

RoboCon: A general purpose telerobotic control center

International Nuclear Information System (INIS)

Draper, J.V.; Noakes, M.W.; Blair, L.M.

1997-01-01

This report describes human factors issues involved in the design of RoboCon, a multi-purpose control center for use in US Department of Energy remote handling applications. RoboCon is intended to be a flexible, modular control center capable of supporting a wide variety of robotic devices

Absence of mutations in the coding sequence of the potential tumor suppressor 3pK in metastatic melanoma

Directory of Open Access Journals (Sweden)

Houben Roland

2005-12-01

Full Text Available Abstract Background Activation of Ras or Raf contributes to tumorigenesis of melanoma. However, constitutive Raf activation is also a characteristic of the majority of benign melanocytic nevi and high intensity signaling of either Ras or Raf was found to induce growth inhibition and senescence rather than transformation. Since the chromosome 3p kinase (3pK is a target of the Ras/Raf/Mek/Erk signaling pathway which antagonizes the function of the oncogene and anti-differentiation factor Bmi-1, 3pK may function as a tumor suppressor in tumors with constitutive Ras/Raf activation. Consequently, we tested whether inactivating 3pK mutations are present in melanoma. Methods 30 metastatic melanoma samples, which were positive for activating mutations of either BRaf or NRas, were analyzed for possible mutations in the 3pk gene. The 10 coding exons and their flanking intron sequences were amplified by PCR and direct sequencing of the PCR products was performed. Results This analysis revealed that besides the presence of some single nucleotide polymorphisms in the 3pk gene, we could not detect any possible loss of function mutation in any of these 30 metastatic melanoma samples selected for the presence of activating mutations within the Ras/Raf/Mek/Erk signaling pathway. Conclusion Hence, in melanoma with constitutively active Ras/Raf inactivating mutations within the 3pk gene do not contribute to the oncogenic phenotype of this highly malignant tumor.

7 CFR 319.37-3 - Permits.

Science.gov (United States)

2010-01-01

...; (2) Articles subject to the postentry quarantine conditions of § 319.37-7; (3) Bulbs of Allium sativum (garlic), Crocosmia spp. (montebretia), Gladiolus spp. (gladiolus), and Watsonia spp. (bugle lily...

Utility of BRAF V600E mutation detection in cytologically indeterminate thyroid nodules

Directory of Open Access Journals (Sweden)

Rowe Leslie R

2006-04-01

Full Text Available Abstract Background Fine needle aspiration (FNA is widely utilized for evaluation of patients with thyroid nodules. However, approximately 30% are indeterminate for malignancy. Recently, a mutation in the BRAF gene has been reported to be the most common genetic event in papillary thyroid carcinoma (PTC. In this retrospective study, we assessed the utility of BRAF V600E mutation detection for refining indeterminate preoperative cytologic diagnoses in patients with PTC. Methods Archival indeterminate thyroid FNAs and corresponding formalin-fixed, paraffin-embedded (FFPE surgical samples with PTC were identified in our patient files. DNA extracted from slide scape lysates and 5 μm FFPE sections were evaluated for the BRAF V600E mutation using LightCycler PCR and fluorescent melting curve analysis (LCPCR. Amplification products that showed deviation from the wild-type genomic DNA melting peak, discordant FNA and FFPE matched pairs, and all benign control samples, underwent direct DNA sequencing. Results A total of 19 indeterminate thyroid FNAs demonstrating PTC on FFPE surgical samples were included in the study. Using BRAF mutation analysis, the preoperative diagnosis of PTC was confirmed in 3/19 (15.8% FNA samples that could not be conclusively diagnosed on cytology alone. However, 9/19 (47.4% FFPE tissue samples were positive for the V600E mutation. Of the discordant pairs, 5/6 FNAs contained less than 50% tumor cells. Conclusion When used with indeterminate FNA samples, BRAF mutation analysis may be a useful adjunct technique for confirming the diagnosis of malignancy in an otherwise equivocal case. However, overall tumor cell content of some archival FNA smear slides is a limiting factor for mutation detection.

Slit/Robo1 signaling regulates neural tube development by balancing neuroepithelial cell proliferation and differentiation

Energy Technology Data Exchange (ETDEWEB)

Wang, Guang; Li, Yan; Wang, Xiao-yu [Key Laboratory for Regenerative Medicine of The Ministry of Education, Department of Histology and Embryology, School of Medicine, Jinan University, Guangzhou 510632 (China); Han, Zhe [Institute of Vascular Biological Sciences, Guangdong Pharmaceutical University, Guangzhou 510224 (China); Chuai, Manli [College of Life Sciences Biocentre, University of Dundee, Dundee DD1 5EH (United Kingdom); Wang, Li-jing [Institute of Vascular Biological Sciences, Guangdong Pharmaceutical University, Guangzhou 510224 (China); Ho Lee, Kenneth Ka [Stem Cell and Regeneration Thematic Research Programme, School of Biomedical Sciences, Chinese University of Hong Kong, Shatin (Hong Kong); Geng, Jian-guo, E-mail: jgeng@umich.edu [Institute of Vascular Biological Sciences, Guangdong Pharmaceutical University, Guangzhou 510224 (China); Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, MI 48109 (United States); Yang, Xuesong, E-mail: yang_xuesong@126.com [Key Laboratory for Regenerative Medicine of The Ministry of Education, Department of Histology and Embryology, School of Medicine, Jinan University, Guangzhou 510632 (China)

2013-05-01

Formation of the neural tube is the morphological hallmark for development of the embryonic central nervous system (CNS). Therefore, neural tube development is a crucial step in the neurulation process. Slit/Robo signaling was initially identified as a chemo-repellent that regulated axon growth cone elongation, but its role in controlling neural tube development is currently unknown. To address this issue, we investigated Slit/Robo1 signaling in the development of chick neCollege of Life Sciences Biocentre, University of Dundee, Dundee DD1 5EH, UKural tube and transgenic mice over-expressing Slit2. We disrupted Slit/Robo1 signaling by injecting R5 monoclonal antibodies into HH10 neural tubes to block the Robo1 receptor. This inhibited the normal development of the ventral body curvature and caused the spinal cord to curl up into a S-shape. Next, Slit/Robo1 signaling on one half-side of the chick embryo neural tube was disturbed by electroporation in ovo. We found that the morphology of the neural tube was dramatically abnormal after we interfered with Slit/Robo1 signaling. Furthermore, we established that silencing Robo1 inhibited cell proliferation while over-expressing Robo1 enhanced cell proliferation. We also investigated the effects of altering Slit/Robo1 expression on Sonic Hedgehog (Shh) and Pax7 expression in the developing neural tube. We demonstrated that over-expressing Robo1 down-regulated Shh expression in the ventral neural tube and resulted in the production of fewer HNK-1{sup +} migrating neural crest cells (NCCs). In addition, Robo1 over-expression enhanced Pax7 expression in the dorsal neural tube and increased the number of Slug{sup +} pre-migratory NCCs. Conversely, silencing Robo1 expression resulted in an enhanced Shh expression and more HNK-1{sup +} migrating NCCs but reduced Pax7 expression and fewer Slug{sup +} pre-migratory NCCs were observed. In conclusion, we propose that Slit/Robo1 signaling is involved in regulating neural tube

RoboMusic with modular playware

DEFF Research Database (Denmark)

Falkenberg, Kasper; Bærendsen, Niels Kristian; Nielsen, Jacob

2011-01-01

Based on the concepts of RoboMusic and modular playware, we developed a system composed of modular playware devices which allow any user to perform music in a simple, interactive manner. The key features exploited in the modular playware approach are modularity, fl exibility, construction......, immediate feedback to stimulate engagement, creative exploration of play activities, and in some cases activity design by end-users (e.g., DJs). We exemplify the approach with the development of 11 rock genres and 6 pop music pieces for modular I-BLOCKS, which are exhibited and in daily use at the Rock Me...

RoboMusic with Modular Playware

DEFF Research Database (Denmark)

Lund, Henrik Hautop; Bærendsen, Niels Kristian; Nielsen, Jacob

2010-01-01

Based on the concepts of RoboMusic and Modular Playware, we developed a system composed of modular playware devices, which allow any user to perform music in a simple, interactive manner. The key features exploited from the Modular Playware approach are modularity, flexibility, and construction......, immediate feedback to stimulate engagement, creative exploration of play activities, and in some cases activity design by end-users (e.g. DJ’s). We exemplify the approach with the development of 11 rock genres and 6 pop music pieces for modular I-BLOCKS, which are exhibited and in daily use at the Rock Me...

Characterization of a novel oncogenic K-ras mutation in colon cancer

International Nuclear Information System (INIS)

Akagi, Kiwamu; Uchibori, Ryosuke; Yamaguchi, Kensei; Kurosawa, Keiko; Tanaka, Yoichiro; Kozu, Tomoko

2007-01-01

Activating mutations of RAS are frequently observed in subsets of human cancers, indicating that RAS activation is involved in tumorigenesis. Here, we identified and characterized a novel G to T transversion mutation of the K-ras gene at the third position of codon 19 (TTG) which substituted phenylalanine for leucine in 3 primary colon carcinomas. Biological and biochemical activity was examined using transformed NIH3T3 cells expressing mutant or wild-type K-ras. Transformants harboring the K-ras mutation at codon 19 showed proliferative capacity under serum-starved conditions, less contact inhibition, anchorage-independent growth, tumorigenicity in nude mice and elevation of active Ras-GTP levels. These results indicated that this novel mutation possesses high oncogenic activity

Oligomerization of optineurin and its oxidative stress- or E50K mutation-driven covalent cross-linking: possible relationship with glaucoma pathology.

Directory of Open Access Journals (Sweden)

Jie Gao

Full Text Available The optineurin gene, OPTN, is one of the causative genes of primary open-angle glaucoma. Although oligomerization of optineurin in cultured cells was previously observed by gel filtration analysis and blue native gel electrophoresis (BNE, little is known about the characteristics of optineurin oligomers. Here, we aimed to analyze the oligomeric state of optineurin and factors affecting oligomerization, such as environmental stimuli or mutations in OPTN. Using BNE or immunoprecipitation followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE, we demonstrated that both endogenous and transfected optineurin exist as oligomers, rather than monomers, in NIH3T3 cells. We also applied an in situ proximity ligation assay to visualize the self-interaction of optineurin in fixed HeLaS3 cells and found that the optineurin oligomers were localized diffusely in the cytoplasm. Optineurin oligomers were usually detected as a single band of a size equal to that of the optineurin monomer upon SDS-PAGE, while an additional protein band of a larger size was observed when cells were treated with H2O2. We showed that larger protein complex is optineurin oligomers by immunoprecipitation and termed it covalent optineurin oligomers. In cells expressing OPTN bearing the most common glaucoma-associated mutation, E50K, covalent oligomers were formed even without H2O2 stimulation. Antioxidants inhibited the formation of E50K-induced covalent oligomers to various degrees. A series of truncated constructs of OPTN was used to reveal that covalent oligomers may be optineurin trimers and that the ubiquitin-binding domain is essential for formation of these trimers. Our results indicated that optineurin trimers may be the basic unit of these oligomers. The oligomeric state can be affected by many factors that induce covalent bonds, such as H2O2 or E50K, as demonstrated here; this provides novel insights into the pathogenicity of E50K. Furthermore

RoboDB: an application of Semantic Web Technologies to robotics

NARCIS (Netherlands)

Juarez, Alex; Hu, J.; Feijs, L.M.G.

2011-01-01

RoboDB is a knowledge acquisition system that gathers information about robots. RoboDB uses Semantic Web technologies and tools to help the user in creating semantic descriptions of robot embodiments and their capabilities, as well as in building an ontology of robotics projects, research

RoboCup European Championship: Report of the Amsterdam 2000 event

NARCIS (Netherlands)

Groen, F.; van der Hoek, W.; Jonker, P.; Krose, B.; Spoelder, H.J.W.; Stramigioli, S.

2001-01-01

The local organizers of the RoboCup European Championship presents a brief, informal overview of this event with the aim to support organizers of future RoboCup events in the organization and coordination of such a rather complex tournament. The objective was to organize a low cost scientific event

The interactions in K{sub μ3} and K{sub e3} decay

Energy Technology Data Exchange (ETDEWEB)

McDowell, S. W. [Brazilian Centre of Research in Physics, Rio de Janeiro (Brazil)

1963-01-15

An attractive feature common to all present theories of weak interactions is the assumption that they result from the coupling (either direct or via intermediate bosons) of vector-axial vector currents. The V-A coupling of leptonic currents and baryonic currents conserving strangeness successfully explains the characteristic properties of μ-decay, π-decay and μ-decay. On the other hand, the leptonic decay modes of K-mesons provide the best source of information on the nature of the currents carrying strangeness. From K{sub μ2} one learns that there must exist an axial-vector current carrying strangeness; further, if the leptonic weak interaction is universal, one can explain the absence of the K{sub e2} mode by excluding a pseudo-scalar interaction. From K{sub μ3} and K{sub e3} decay one can obtain information on scalar, vector and tensor coupling of strangeness non-conserving currents with leptons. In recent experiments on K{sub e3} decay a good fitting of the pion spectrum was obtained with a constant vector form factor. Although regarding this result as strong evidence of pure vector coupling, one might still argue that other possibilities, such as a mixture of vector and tensor couplings with energy-dependent form factors, are not excluded. I shall discuss here, in the first place, some properties of the transition amplitudes which are independent of the structure of form factors. They provide a test of universality and a criterion for unambiguous determination of the nature of the weak interaction involved in these processes. Secondly, I shall discuss the structure of form factors, by means of dispersion relations and introducing explicitly the effect of the K*-resonance in the Kπ-interaction.

Aspects of radiative K+e3 decays

International Nuclear Information System (INIS)

Kubis, B.; Mueller, E.H.; Gasser, J.; Schmid, M.

2007-01-01

We re-investigate the radiative charged kaon decay K ± →π 0 e ± ν e γ [K e3γ ± ] in chiral perturbation theory, merging the chiral expansion with Low's theorem. We thoroughly analyze the precision of the predicted branching ratio relative to the non-radiative decay channel. Structure dependent terms and their impact on differential decay distributions are investigated in detail, and the possibility to see effects of the chiral anomaly in this decay channel is emphasized. (orig.)

PCP and SAX-3/Robo Pathways Cooperate to Regulate Convergent Extension-Based Nerve Cord Assembly in C. elegans.

Science.gov (United States)

Shah, Pavak K; Tanner, Matthew R; Kovacevic, Ismar; Rankin, Aysha; Marshall, Teagan E; Noblett, Nathaniel; Tran, Nhan Nguyen; Roenspies, Tony; Hung, Jeffrey; Chen, Zheqian; Slatculescu, Cristina; Perkins, Theodore J; Bao, Zhirong; Colavita, Antonio

2017-04-24

Formation and resolution of multicellular rosettes can drive convergent extension (CE) type cell rearrangements during tissue morphogenesis. Rosette dynamics are regulated by both planar cell polarity (PCP)-dependent and -independent pathways. Here we show that CE is involved in ventral nerve cord (VNC) assembly in Caenorhabditis elegans. We show that a VANG-1/Van Gogh and PRKL-1/Prickle containing PCP pathway and a Slit-independent SAX-3/Robo pathway cooperate to regulate, via rosette intermediaries, the intercalation of post-mitotic neuronal cell bodies during VNC formation. We show that VANG-1 and SAX-3 are localized to contracting edges and rosette foci and act to specify edge contraction during rosette formation and to mediate timely rosette resolution. Simultaneous loss of both pathways severely curtails CE resulting in a shortened, anteriorly displaced distribution of VNC neurons at hatching. Our results establish rosette-based CE as an evolutionarily conserved mechanism of nerve cord morphogenesis and reveal a role for SAX-3/Robo in this process. Copyright © 2017 Elsevier Inc. All rights reserved.

K-RAS and N-RAS mutations in testicular germ cell tumors

Directory of Open Access Journals (Sweden)

Bekir Muhammet Hacioglu

2017-05-01

Full Text Available Testicular cancer is a relatively rare tumor type, accounting for approximately 1% of all cancers in men. However, among men aged between 15 and 40 years, testicular cancer is the most commonly diagnosed malignancy. Testicular germ cell tumors (TGCTs are classified as seminoma and non-seminoma. The RAS oncogene controls several cellular functions, including cell proliferation, apoptosis, migration, and differentiation. Thus, RAS signaling is important for normal germ cell development. Mutations of the Kirsten RAS (K-RAS gene are present in over 20% of all cancers. RAS gene mutations have also been reported in TGCTs. We investigated K-RAS and N-RAS mutations in seminoma and non-seminoma TGCT patients. A total of 24 (55% pure seminoma cases and 19 (45% non-seminoma cases were included in the study. K-RAS and N-RAS analyses were performed in our molecular pathology laboratory, using K-RAS and N-RAS Pyro Kit 24 V1 (Qiagen. In total, a RAS mutation was present in 12 patients (27%: 7 seminoma (29% and 5 non-seminoma cases (26% [p = 0.55]. A K-RAS mutation was present in 4 pure seminoma tumors (16% and 3 non-seminoma tumors (15% [p = 0.63], and an N-RAS mutation was observed in 4 seminoma tumors (16% and 3 non-seminoma tumors (15% [p = 0.63]. Both, K-RAS and N-RAS mutations were present in two patients: one with seminoma tumor and the other with non-seminoma tumor. To date, no approved targeted therapy is available for the treatment of TGCTs. The analysis of K-RAS and N-RAS mutations in these tumors may provide more treatment options, especially in platinum-resistant tumors.

Overexpression of Robo2 causes defects in the recruitment of metanephric mesenchymal cells and ureteric bud branching morphogenesis

International Nuclear Information System (INIS)

Ji, Jiayao; Li, Qinggang; Xie, Yuansheng; Zhang, Xueguang; Cui, Shaoyuan; Shi, Suozhu; Chen, Xiangmei

2012-01-01

Highlights: ► Overexpression of Robo2 caused reduced UB branching and glomerular number. ► Fewer MM cells surrounding the UB after overexpression of Robo2 in vitro. ► No abnormal Epithelial Morphology of UB or apoptosis of mm cells in the kidney. ► Overexpression of Robo2 affected MM cells migration and caused UB deficit. ► The reduced glomerular number can also be caused by fewer MM cells. -- Abstract: Roundabout 2 (Robo2) is a member of the membrane protein receptor family. The chemorepulsive effect of Slit2–Robo2 signaling plays vital roles in nervous system development and neuron migration. Slit2–Robo2 signaling is also important for maintaining the normal morphogenesis of the kidney and urinary collecting system, especially for the branching of the ureteric bud (UB) at the proper site. Slit2 or Robo2 mouse mutants exhibit multilobular kidneys, multiple ureters, and dilatation of the ureter, renal pelvis, and collecting duct system, which lead to vesicoureteral reflux. To understand the effect of Robo2 on kidney development, we used microinjection and electroporation to overexpress GFP-Robo2 in an in vitro embryonic kidney model. Our results show reduced UB branching and decreased glomerular number after in vitro Robo2 overexpression in the embryonic kidneys. We found fewer metanephric mesenchymal (MM) cells surrounding the UB but no abnormal morphology in the branching epithelial UB. Meanwhile, no significant change in MM proliferation or apoptosis was observed. These findings indicate that Robo2 is involved in the development of embryonic kidneys and that the normal expression of Robo2 can help maintain proper UB branching and glomerular morphogenesis. Overexpression of Robo2 leads to reduced UB branching caused by fewer surrounding MM cells, but MM cell apoptosis is not involved in this effect. Our study demonstrates that overexpression of Robo2 by microinjection in embryonic kidneys is an effective approach to study the function of Robo2.

Overexpression of Robo2 causes defects in the recruitment of metanephric mesenchymal cells and ureteric bud branching morphogenesis

Energy Technology Data Exchange (ETDEWEB)

Ji, Jiayao [Institute of Nephrology, State Key Laboratory of Kidney Disease (2011DAV00088), The Chinese PLA General Hospital, Beijing 100853 (China); Medical College of NanKai University, Tianjin (China); Li, Qinggang; Xie, Yuansheng; Zhang, Xueguang; Cui, Shaoyuan; Shi, Suozhu [Institute of Nephrology, State Key Laboratory of Kidney Disease (2011DAV00088), The Chinese PLA General Hospital, Beijing 100853 (China); Chen, Xiangmei, E-mail: xmchen301@126.com [Institute of Nephrology, State Key Laboratory of Kidney Disease (2011DAV00088), The Chinese PLA General Hospital, Beijing 100853 (China); Medical College of NanKai University, Tianjin (China)

2012-05-11

Highlights: Black-Right-Pointing-Pointer Overexpression of Robo2 caused reduced UB branching and glomerular number. Black-Right-Pointing-Pointer Fewer MM cells surrounding the UB after overexpression of Robo2 in vitro. Black-Right-Pointing-Pointer No abnormal Epithelial Morphology of UB or apoptosis of mm cells in the kidney. Black-Right-Pointing-Pointer Overexpression of Robo2 affected MM cells migration and caused UB deficit. Black-Right-Pointing-Pointer The reduced glomerular number can also be caused by fewer MM cells. -- Abstract: Roundabout 2 (Robo2) is a member of the membrane protein receptor family. The chemorepulsive effect of Slit2-Robo2 signaling plays vital roles in nervous system development and neuron migration. Slit2-Robo2 signaling is also important for maintaining the normal morphogenesis of the kidney and urinary collecting system, especially for the branching of the ureteric bud (UB) at the proper site. Slit2 or Robo2 mouse mutants exhibit multilobular kidneys, multiple ureters, and dilatation of the ureter, renal pelvis, and collecting duct system, which lead to vesicoureteral reflux. To understand the effect of Robo2 on kidney development, we used microinjection and electroporation to overexpress GFP-Robo2 in an in vitro embryonic kidney model. Our results show reduced UB branching and decreased glomerular number after in vitro Robo2 overexpression in the embryonic kidneys. We found fewer metanephric mesenchymal (MM) cells surrounding the UB but no abnormal morphology in the branching epithelial UB. Meanwhile, no significant change in MM proliferation or apoptosis was observed. These findings indicate that Robo2 is involved in the development of embryonic kidneys and that the normal expression of Robo2 can help maintain proper UB branching and glomerular morphogenesis. Overexpression of Robo2 leads to reduced UB branching caused by fewer surrounding MM cells, but MM cell apoptosis is not involved in this effect. Our study demonstrates that

Inhibitory Effects of Robo2 on Nephrin: A Crosstalk between Positive and Negative Signals Regulating Podocyte Structure

Directory of Open Access Journals (Sweden)

Xueping Fan

2012-07-01

Full Text Available Robo2 is the cell surface receptor for the repulsive guidance cue Slit and is involved in axon guidance and neuronal migration. Nephrin is a podocyte slit-diaphragm protein that functions in the kidney glomerular filtration barrier. Here, we report that Robo2 is expressed at the basal surface of mouse podocytes and colocalizes with nephrin. Biochemical studies indicate that Robo2 forms a complex with nephrin in the kidney through adaptor protein Nck. In contrast to the role of nephrin that promotes actin polymerization, Slit2-Robo2 signaling inhibits nephrin-induced actin polymerization. In addition, the amount of F-actin associated with nephrin is increased in Robo2 knockout mice that develop an altered podocyte foot process structure. Genetic interaction study further reveals that loss of Robo2 alleviates the abnormal podocyte structural phenotype in nephrin null mice. These results suggest that Robo2 signaling acts as a negative regulator on nephrin to influence podocyte foot process architecture.

Co-overexpression of bacterial GroESL chaperonins partly overcomes non-productive folding and tetramer assembly of E. coli-expressed human medium-chain acyl-CoA dehydrogenase (MCAD) carrying the prevalent disease-causing K304E mutation

DEFF Research Database (Denmark)

Bross, P; Andresen, B S; Winter, V

1993-01-01

underlying MCAD deficiency caused by the prevalent K304E mutation. Depending on which of the three amino acids--lysine (wild-type), glutamic acid (K304E) or glutamine (K304Q) are present at position 304 of the mature polypeptide, three different patterns were observed in our assay system: (i) solubility...... in Western blotting. In a first attempt to estimate the specific activity, we show that tetrameric K304E and K304Q mutant MCAD display a specific activity in the range of the wild-type enzyme. Taken together, our results strongly suggest, that the K304E mutation primarily impairs the rate of folding...... with negative charge at position 304 (glutamic acid) but not with a neutral charge (glutamine) negatively affects conversion to active tetramers. A possible explanation for this latter effect--charge repulsion upon subunit docking--is discussed....

Site-specific perturbations of alpha-synuclein fibril structure by the Parkinson's disease associated mutations A53T and E46K.

Directory of Open Access Journals (Sweden)

Luisel R Lemkau

Full Text Available Parkinson's disease (PD is pathologically characterized by the presence of Lewy bodies (LBs in dopaminergic neurons of the substantia nigra. These intracellular inclusions are largely composed of misfolded α-synuclein (AS, a neuronal protein that is abundant in the vertebrate brain. Point mutations in AS are associated with rare, early-onset forms of PD, although aggregation of the wild-type (WT protein is observed in the more common sporadic forms of the disease. Here, we employed multidimensional solid-state NMR experiments to assess A53T and E46K mutant fibrils, in comparison to our recent description of WT AS fibrils. We made de novo chemical shift assignments for the mutants, and used these chemical shifts to empirically determine secondary structures. We observe significant perturbations in secondary structure throughout the fibril core for the E46K fibril, while the A53T fibril exhibits more localized perturbations near the mutation site. Overall, these results demonstrate that the secondary structure of A53T has some small differences from the WT and the secondary structure of E46K has significant differences, which may alter the overall structural arrangement of the fibrils.

36 CFR 3.19 - May I operate a submersible within park waters?

Science.gov (United States)

2010-07-01

... 36 Parks, Forests, and Public Property 1 2010-07-01 2010-07-01 false May I operate a submersible within park waters? 3.19 Section 3.19 Parks, Forests, and Public Property NATIONAL PARK SERVICE... waters? The use of manned or unmanned submersibles may only occur in accordance with a permit issued by...

MPL W515L/K Mutations in Chronic Myeloproliferative Neoplasms.

Science.gov (United States)

Akpınar, Timur Selçuk; Hançer, Veysel Sabri; Nalçacı, Meliha; Diz-Küçükkaya, Reyhan

2013-03-01

The MPL gene encodes the thrombopoietin receptor. Recently MPL mutations (MPL W515L or MPL W515K) were described in patients with essential thrombocythemia (ET) and primary (idiopathic) myelofibrosis (PMF). The prevalence and the clinical importance of these mutations are not clear. In the present study, we aimed to investigate the frequency and clinical significance of MPL W515L/K mutations in our patients with ET and PMF. A total of 77 patients (66 were diagnosed with ET and 11 with PMF) and 42 healthy controls were included in the study. Using peripheral blood samples, the presence of MPL W515L/K mutations and JAK-2 V617F mutation were analyzed by real-time polymerase chain reaction. In our study, MPL W515L/K or JAK-2 V617F mutations were not observed in healthy controls. JAK-2 V617F mutation was present in 35 patients, of whom 29 had ET (43.9%, 29/66) and 6 had PMF (54.5%, 6/11). In the patient group, MPL W515L/K mutations were found in only 2 PMF cases, and these cases were negative for JAK-2 V617F mutation. The prevalence of MPL W515L/K mutations in the patient group was 2.6%, and the prevalence of MPL W515L/K mutations among the cases negative for the JAK-2 V617F mutation was found to be 4.8%. The 2 cases with MPL W515L/K mutations had long follow-up times (124 months and 71 months, respectively), had no thrombotic or hemorrhagic complications, and had no additional cytogenetic anomalies. MPL W515L/K mutations may be helpful for identifying clonal disease in MPN patients with no established Ph chromosome or JAK-2 V617F mutation. None declared.

Radioimmunotherapy of small cell lung cancer xenograft mice with a 90Y anti-ROBO1 monoclonal antibody: Pathological study of effects on tumor and normal organs

International Nuclear Information System (INIS)

Fujiwara, K.; Koyama, K.; Kitada, T.; Takahashi, M.; Momose, T.; Suga, K.

2015-01-01

Full text of publication follows. ROBO1 is a membrane protein that is concerned about axon guidance. It is reported that ROBO1 contributes to tumor metastasis and angio genesis. ROBO1 is specifically expressed at high levels in small cell lung cancer (SCLC). In this study, we performed radioimmunotherapy (RIT) to SCLC models, and analyzed pathological alteration of tumor and organs. Methods: For the biodistribution study, 111 In-DOTA anti-ROBO1 IgG (about 370 kBq, 111 In anti-ROBO1) was injected into NCI-H69 xenograft mice via tail vein. To evaluate antitumor effect, RIT study was performed. 90 Y-DOTA anti-ROBO1 IgG (about 7.4 MBq, 90 Y anti-ROBO1) was injected. The experiments measured tumor volume, mouse weights and blood cell counts periodically. The tumors and organs (liver, kidney, intestine, spleen, femoral and sternum) of mice were obtained, and histopathologic analysis were carried out. Results: as a result of biodistribution study, the specific accumulation in the tumor of 111 In anti-ROBO1 was observed. Liver, kidney, spleen and lung showed comparatively high accumulation of 111 In anti-ROBO1. In the RIT study, 90 Y anti-ROBO1 significantly reduced tumor volume compared with original volume and increased median survival time to 58 days (p<0.01, versus saline, 28 days), while 90 Y anti-ROBO1 induced transient pancytopenia. Histopathologic analysis of tumors and organs further validated the therapeutic efficacy and the systemic toxicity of 90 Y anti-ROBO1. In day 7 when tumor volume reduced to 60% compared with original volume, irreversible nuclear denaturation and fibrosis were observed. The percentage of TUNEL-positive cells increased to 11.4%±5.1 in the day 7 (p<0.01, versus control, 4.14%±1.4), which showed increase of DNA fragmentation and apoptosis in the tumor tissues. Normal organs excluding spleen and sternum showed no significant injury. In day 7 post injection, spleen showed transient reduction of hematopoietic cells. Hematopoietic cells in

Spectrum of K ras mutations in Pakistani colorectal cancer patients

International Nuclear Information System (INIS)

Murtaza, B.N.; Bibi, A.; Rashid, M.U.; Khan, Y.I.; Chaudri, M.S.; Shakoori, A.R.

2013-01-01

The incidence of colorectal cancer (CRC) is increasing daily worldwide. Although different aspects of CRC have been studied in other parts of the world, relatively little or almost no information is available in Pakistan about different aspects of this disease at the molecular level. The present study was aimed at determining the frequency and prevalence of K ras gene mutations in Pakistani CRC patients. Tissue and blood samples of 150 CRC patients (64% male and 36% female) were used for PCR amplification of K ras and detection of mutations by denaturing gradient gel electrophoresis, restriction fragment length polymorphism analysis, and nucleotide sequencing. The K ras mutation frequency was found to be 13%, and the most prevalent mutations were found at codons 12 and 13. A novel mutation was also found at codon 31. The dominant mutation observed was a G to A transition. Female patients were more susceptible to K ras mutations, and these mutations were predominant in patients with a nonmetastatic stage of CRC. No significant differences in the prevalence of K ras mutations were observed for patient age, gender, or tumor type. It can be inferred from this study that Pakistani CRC patients have a lower frequency of K ras mutations compared to those observed in other parts of the world, and that K ras mutations seemed to be significantly associated with female patients

Spectrum of K ras mutations in Pakistani colorectal cancer patients

Energy Technology Data Exchange (ETDEWEB)

Murtaza, B.N.; Bibi, A. [School of Biological Sciences, University of the Punjab, Quaid-i-Azam Campus, Lahore (Pakistan); Rashid, M.U.; Khan, Y.I. [Shaukat Khanum Memorial Cancer Hospital and Research Centre, Johar Town, Lahore (Pakistan); Chaudri, M.S. [Services Institute of Medical Sciences, Lahore (Pakistan); Shakoori, A.R. [School of Biological Sciences, University of the Punjab, Quaid-i-Azam Campus, Lahore (Pakistan)

2013-11-29

The incidence of colorectal cancer (CRC) is increasing daily worldwide. Although different aspects of CRC have been studied in other parts of the world, relatively little or almost no information is available in Pakistan about different aspects of this disease at the molecular level. The present study was aimed at determining the frequency and prevalence of K ras gene mutations in Pakistani CRC patients. Tissue and blood samples of 150 CRC patients (64% male and 36% female) were used for PCR amplification of K ras and detection of mutations by denaturing gradient gel electrophoresis, restriction fragment length polymorphism analysis, and nucleotide sequencing. The K ras mutation frequency was found to be 13%, and the most prevalent mutations were found at codons 12 and 13. A novel mutation was also found at codon 31. The dominant mutation observed was a G to A transition. Female patients were more susceptible to K ras mutations, and these mutations were predominant in patients with a nonmetastatic stage of CRC. No significant differences in the prevalence of K ras mutations were observed for patient age, gender, or tumor type. It can be inferred from this study that Pakistani CRC patients have a lower frequency of K ras mutations compared to those observed in other parts of the world, and that K ras mutations seemed to be significantly associated with female patients.

Radiative K{sub e3} decays revisited

Energy Technology Data Exchange (ETDEWEB)

Gasser, J. [Universitaet Bern, Institut fuer Theoretische Physik, Bern (Switzerland); Kubis, B. [Universitaet Bern, Institut fuer Theoretische Physik, Bern (Switzerland); Universitaet Bonn, Helmholtz-Institut fuer Strahlen- und Kernphysik, Bonn (Germany); Paver, N. [Universita degli Studi di Trieste, Dipartimento di Fisica Teorica, Trieste (Italy); INFN-Trieste, Trieste (Italy); Verbeni, M. [Universidad de Granada, Departamento de Fisica Teorica y del Cosmos, Granada (Spain)

2005-03-01

Motivated by recent experimental results and ongoing measurements, we review the chiral perturbation theory prediction for K{sub L}{yields}{pi}{sup -+}e{sup {+-}}{nu}{sub e}{gamma} decays. Special emphasis is given to the stability of the inner bremsstrahlung-dominated relative branching ratio versus the K{sub e3} form factors, and on the separation of the structure-dependent amplitude in differential distributions over the phase space. For the structure-dependent terms, an assessment of the order p{sup 6} corrections is given, in particular, a full next-to-leading order calculation of the axial component is performed. The experimental analysis of the photon energy spectrum is discussed, and other potentially useful distributions are introduced. (orig.)

MPL W515L/K Mutations in Chronic Myeloproliferative Neoplasms

Directory of Open Access Journals (Sweden)

Timur Selçuk Akpınar

2013-03-01

Full Text Available OBJECTIVE: The MPL gene encodes the thrombopoietin receptor. Recently MPL mutations (MPL W515L or MPL W515K were described in patients with essential thrombocythemia (ET and primary (idiopathic myelofibrosis (PMF. The prevalence and the clinical importance of these mutations are not clear. In the present study, we aimed to investigate the frequency and clinical significance of MPL W515L/K mutations in our patients with ET and PMF. METHODS: A total of 77 patients (66 were diagnosed with ET and 11 with PMF and 42 healthy controls were included in the study. Using peripheral blood samples, the presence of MPL W515L/K mutations and JAK-2 V617F mutation were analyzed by real-time polymerase chain reaction. RESULTS: In our study, MPL W515L/K or JAK-2 V617F mutations were not observed in healthy controls. JAK-2 V617F mutation was present in 35 patients, of whom 29 had ET (43.9%, 29/66 and 6 had PMF (54.5%, 6/11. In the patient group, MPL W515L/K mutations were found in only 2 PMF cases, and these cases were negative for JAK-2 V617F mutation. The prevalence of MPL W515L/K mutations in the patient group was 2.6%, and the prevalence of MPL W515L/K mutations among the cases negative for the JAK-2 V617F mutation was found to be 4.8%. The 2 cases with MPL W515L/K mutations had long follow-up times (124 months and 71 months, respectively, had no thrombotic or hemorrhagic complications, and had no additional cytogenetic anomalies. CONCLUSION: MPL W515L/K mutations may be helpful for identifying clonal disease in MPN patients with no established Ph chromosome or JAK-2 V617F mutation.

A robo-pigeon based on an innovative multi-mode telestimulation system.

Science.gov (United States)

Yang, Junqing; Huai, Ruituo; Wang, Hui; Lv, Changzhi; Su, Xuecheng

2015-01-01

In this paper, we describe a new multi-mode telestimulation system for brain-microstimulation for the navigation of a robo-pigeon, a new type of bio-robot based on Brain-Computer Interface (BCI) techniques. The multi-mode telestimulation system overcomes neuron adaptation that was a key shortcoming of the previous single-mode stimulation by the use of non-steady TTL biphasic pulses accomplished by randomly alternating pulse modes. To improve efficiency, a new behavior model ("virtual fear") is proposed and applied to the robo-pigeon. Unlike the previous "virtual reward" model, the "virtual fear" behavior model does not require special training. The performance and effectiveness of the system to alleviate the adaptation of neurons was verified by a robo-pigeon navigation test, simultaneously confirming the practicality of the "virtual fear" behavioral model.

7 CFR 319.74-3 - Importations by the Department.

Science.gov (United States)

2010-01-01

... INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE FOREIGN QUARANTINE NOTICES Cut Flowers § 319.74-3 Importations by the Department. The U.S. Department of Agriculture may import cut flowers for experimental or...

RoboTAP: Target priorities for robotic microlensing observations

Science.gov (United States)

Hundertmark, M.; Street, R. A.; Tsapras, Y.; Bachelet, E.; Dominik, M.; Horne, K.; Bozza, V.; Bramich, D. M.; Cassan, A.; D'Ago, G.; Figuera Jaimes, R.; Kains, N.; Ranc, C.; Schmidt, R. W.; Snodgrass, C.; Wambsganss, J.; Steele, I. A.; Mao, S.; Ment, K.; Menzies, J.; Li, Z.; Cross, S.; Maoz, D.; Shvartzvald, Y.

2018-01-01

Context. The ability to automatically select scientifically-important transient events from an alert stream of many such events, and to conduct follow-up observations in response, will become increasingly important in astronomy. With wide-angle time domain surveys pushing to fainter limiting magnitudes, the capability to follow-up on transient alerts far exceeds our follow-up telescope resources, and effective target prioritization becomes essential. The RoboNet-II microlensing program is a pathfinder project, which has developed an automated target selection process (RoboTAP) for gravitational microlensing events, which are observed in real time using the Las Cumbres Observatory telescope network. Aims: Follow-up telescopes typically have a much smaller field of view compared to surveys, therefore the most promising microlensing events must be automatically selected at any given time from an annual sample exceeding 2000 events. The main challenge is to select between events with a high planet detection sensitivity, with the aim of detecting many planets and characterizing planetary anomalies. Methods: Our target selection algorithm is a hybrid system based on estimates of the planet detection zones around a microlens. It follows automatic anomaly alerts and respects the expected survey coverage of specific events. Results: We introduce the RoboTAP algorithm, whose purpose is to select and prioritize microlensing events with high sensitivity to planetary companions. In this work, we determine the planet sensitivity of the RoboNet follow-up program and provide a working example of how a broker can be designed for a real-life transient science program conducting follow-up observations in response to alerts; we explore the issues that will confront similar programs being developed for the Large Synoptic Survey Telescope (LSST) and other time domain surveys.

A novel NR2E3 gene mutation in autosomal recessive retinitis pigmentosa with cystic maculopathy

OpenAIRE

Mahajan, D.; Votruba, Marcela

2017-01-01

NR2E3 is a gene that encodes for photoreceptor cell specific nuclear receptor, which is involved in cone proliferation. The splice site mutation 119-2A>C in NR2E3 (15q23) has been previously reported to underlie recessive enhanced cone S sensitivity syndrome, clumped pigmentary retinal degeneration, Goldman-Favre syndrome and also autosomal dominant and autosomal recessive retinitis pigmentosa (RP). However, the mutation c 571 + 2 T > C in NR2E3 has not been previously reported with retinal d...

March of the Robo-advisors : The potential for global expansion of digital asset management platforms

OpenAIRE

Rättyä, Jere

2016-01-01

This thesis looks into the robo-advisory market in the U.S. and Europe, with the goal of determining the international potential for a Finnish robo-advisor service and inspecting the interest of foreign service providers in the Finnish market. Fintech is becoming increasingly disruptive for the traditional and conservative financial sector, which has resulted in start-ups building their own robo-advisor platform around the world. Traditional wealth management is both expensive and exclusi...

The rapid-onset dystonia parkinsonism mutation D923N of the Na+, K+-ATPase alpha3 isoform disrupts Na+ interaction at the third Na+ site.

Science.gov (United States)

Einholm, Anja Pernille; Toustrup-Jensen, Mads S; Holm, Rikke; Andersen, Jens Peter; Vilsen, Bente

2010-08-20

Rapid-onset dystonia parkinsonism (RDP), a rare neurological disorder, is caused by mutation of the neuron-specific alpha3-isoform of Na(+), K(+)-ATPase. Here, we present the functional consequences of RDP mutation D923N. Relative to the wild type, the mutant exhibits a remarkable approximately 200-fold reduction of Na(+) affinity for activation of phosphorylation from ATP, reflecting a defective interaction of the E(1) form with intracellular Na(+). This is the largest effect on Na(+) affinity reported so far for any Na(+), K(+)-ATPase mutant. D923N also affects the interaction with extracellular Na(+) normally driving the E(1)P to E(2)P conformational transition backward. However, no impairment of K(+) binding was observed for D923N, leading to the conclusion that Asp(923) is specifically associated with the third Na(+) site that is selective toward Na(+). The crystal structure of the Na(+), K(+)-ATPase in E(2) form shows that Asp(923) is located in the cytoplasmic half of transmembrane helix M8 inside a putative transport channel, which is lined by residues from the transmembrane helices M5, M7, M8, and M10 and capped by the C terminus, recently found involved in recognition of the third Na(+) ion. Structural modeling of the E(1) form of Na(+), K(+)-ATPase based on the Ca(2+)-ATPase crystal structure is consistent with the hypothesis that Asp(923) contributes to a site binding the third Na(+) ion. These results in conjunction with our previous findings with other RDP mutants suggest that a selective defect in the handling of Na(+) may be a general feature of the RDP disorder.

Low prevalence of transmitted K65R and other tenofovir resistance mutations across different HIV-1 subtypes: implications for pre-exposure prophylaxis.

Science.gov (United States)

Chan, Philip A; Huang, Austin; Kantor, Rami

2012-10-15

Tenofovir-containing regimens have demonstrated potential efficacy as pre-exposure prophylaxis (PrEP) in preventing HIV-1 infection. Transmitted drug resistance mutations associated with tenofovir, specifically the reverse transcriptase (RT) mutation K65R, may impact the effectiveness of PrEP. The worldwide prevalence of transmitted tenofovir resistance in different HIV-1 subtypes is unknown. Sequences from treatment-naïve studies and databases were aggregated and analyzed by Stanford Database tools and as per the International AIDS Society (IAS-USA) resistance criteria. RT sequences were collected from GenBank, the Stanford HIV Sequence Database and the Los Alamos HIV Sequence Database. Sequences underwent rigorous quality control measures. Tenofovir-associated resistance mutations included K65R, K70E, T69-insertion and ≥3 thymidine analogue mutations (TAMs), inclusive of M41L or L210W. A total of 19,823 sequences were evaluated across diverse HIV-1 subtypes (Subtype A: 1549 sequences, B: 9783, C: 3198, D: 483, F: 372, G: 594, H: 41, J: 69, K: 239, CRF01_AE: 1797 and CRF02_AG: 1698). Overall, tenofovir resistance prevalence was 0.4% (n=77/19,823, 95% confidence interval or CI: 0.3 to 0.5). K65R was found in 20 sequences (0.1%, 95% CI: 0.06 to 0.15). Differences in the prevalence of K65R between HIV-1 subtypes were not statistically significant. K70E and ≥3 TAMs were found in 0.015% (95% CI: 0.004 to 0.04) and 0.27% (95% CI: 0.2 to 0.4) of sequences, respectively. Prevalence of transmitted K65R and other tenofovir resistance mutations across diverse HIV-1 subtypes and recombinants is low, suggesting minimal effect on tenofovir-containing PrEP regimens.

Machine Learning for RealisticBall Detection in RoboCup SPL

OpenAIRE

Bloisi, Domenico; Del Duchetto, Francesco; Manoni, Tiziano; Suriani, Vincenzo

2017-01-01

In this technical report, we describe the use of a machine learning approach for detecting the realistic black and white ball currently in use in the RoboCup Standard Platform League. Our aim is to provide a ready-to-use software module that can be useful for the RoboCup SPL community. To this end, the approach is integrated within the official B-Human code release 2016. The complete code for the approach presented in this work can be downloaded from the SPQR Team homepage at http://spqr.diag...

Impact of somatic PI3K pathway and ERBB family mutations on pathological complete response (pCR) in HER2-positive breast cancer patients who received neoadjuvant HER2-targeted therapies.

LENUS (Irish Health Repository)

Toomey, Sinead

2017-07-27

The Cancer Genome Atlas analysis revealed that somatic EGFR, receptor tyrosine-protein kinase erbB-2 (ERBB2), Erb-B2 receptor tyrosine kinase 3 (ERBB3) and Erb-B2 receptor tyrosine kinase 4 (ERBB4) gene mutations (ERBB family mutations) occur alone or co-occur with somatic mutations in the gene encoding the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (PIK3CA) in 19% of human epidermal growth factor receptor 2 (HER2)-positive breast cancers. Because ERBB family mutations can activate the PI3K\\/AKT pathway and likely have similar canonical signalling effects to PI3K pathway mutations, we investigated their combined impact on response to neoadjuvant HER2-targeted therapies.

Brief Report: Robo1 Regulates the Migration of Human Subventricular Zone Neural Progenitor Cells During Development.

Science.gov (United States)

Guerrero-Cazares, Hugo; Lavell, Emily; Chen, Linda; Schiapparelli, Paula; Lara-Velazquez, Montserrat; Capilla-Gonzalez, Vivian; Clements, Anna Christina; Drummond, Gabrielle; Noiman, Liron; Thaler, Katrina; Burke, Anne; Quiñones-Hinojosa, Alfredo

2017-07-01

Human neural progenitor cell (NPC) migration within the subventricular zone (SVZ) of the lateral ganglionic eminence is an active process throughout early brain development. The migration of human NPCs from the SVZ to the olfactory bulb during fetal stages resembles what occurs in adult rodents. As the human brain develops during infancy, this migratory stream is drastically reduced in cell number and becomes barely evident in adults. The mechanisms regulating human NPC migration are unknown. The Slit-Robo signaling pathway has been defined as a chemorepulsive cue involved in axon guidance and neuroblast migration in rodents. Slit and Robo proteins expressed in the rodent brain help guide neuroblast migration from the SVZ through the rostral migratory stream to the olfactory bulb. Here, we present the first study on the role that Slit and Robo proteins play in human-derived fetal neural progenitor cell migration (hfNPC). We describe that Robo1 and Robo2 isoforms are expressed in the human fetal SVZ. Furthermore, we demonstrate that Slit2 is able to induce a chemorepellent effect on the migration of hfNPCs derived from the human fetal SVZ. In addition, when Robo1 expression is inhibited, hfNPCs are unable to migrate to the olfactory bulb of mice when injected in the anterior SVZ. Our findings indicate that the migration of human NPCs from the SVZ is partially regulated by the Slit-Robo axis. This pathway could be regulated to direct the migration of NPCs in human endogenous neural cell therapy. Stem Cells 2017;35:1860-1865. © 2017 AlphaMed Press.

RoboCup Rescue Robot and Simulation Leagues

NARCIS (Netherlands)

Akin, H.L.; Ito, N.; Jacoff, A.; Kleiner, A.; Pellenz, J.; Visser, A.

2013-01-01

The RoboCup Rescue Robot and Simulation competitions have been held since 2000. The experience gained during these competitions has increased the maturity level of the field, which allowed deploying robots after real disasters (for example, Fukushima Daiichi nuclear disaster). This article provides

Rescue of Na+ affinity in aspartate 928 mutants of Na+,K+-ATPase by secondary mutation of glutamate 314.

Science.gov (United States)

Holm, Rikke; Einholm, Anja P; Andersen, Jens P; Vilsen, Bente

2015-04-10

The Na(+),K(+)-ATPase binds Na(+) at three transport sites denoted I, II, and III, of which site III is Na(+)-specific and suggested to be the first occupied in the cooperative binding process activating phosphorylation from ATP. Here we demonstrate that the asparagine substitution of the aspartate associated with site III found in patients with rapid-onset dystonia parkinsonism or alternating hemiplegia of childhood causes a dramatic reduction of Na(+) affinity in the α1-, α2-, and α3-isoforms of Na(+),K(+)-ATPase, whereas other substitutions of this aspartate are much less disruptive. This is likely due to interference by the amide function of the asparagine side chain with Na(+)-coordinating residues in site III. Remarkably, the Na(+) affinity of site III aspartate to asparagine and alanine mutants is rescued by second-site mutation of a glutamate in the extracellular part of the fourth transmembrane helix, distant to site III. This gain-of-function mutation works without recovery of the lost cooperativity and selectivity of Na(+) binding and does not affect the E1-E2 conformational equilibrium or the maximum phosphorylation rate. Hence, the rescue of Na(+) affinity is likely intrinsic to the Na(+) binding pocket, and the underlying mechanism could be a tightening of Na(+) binding at Na(+) site II, possibly via movement of transmembrane helix four. The second-site mutation also improves Na(+),K(+) pump function in intact cells. Rescue of Na(+) affinity and Na(+) and K(+) transport by second-site mutation is unique in the history of Na(+),K(+)-ATPase and points to new possibilities for treatment of neurological patients carrying Na(+),K(+)-ATPase mutations. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

The translation initiation factor 3 subunit eIF3K interacts with PML and associates with PML nuclear bodies

Energy Technology Data Exchange (ETDEWEB)

Salsman, Jayme; Pinder, Jordan; Tse, Brenda [Department of Pathology, Dalhousie University, P.O. Box 15000, Halifax, Nova Scotia, Canada B3H 4R2 (Canada); Corkery, Dale [Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia (Canada); Dellaire, Graham, E-mail: dellaire@dal.ca [Department of Pathology, Dalhousie University, P.O. Box 15000, Halifax, Nova Scotia, Canada B3H 4R2 (Canada); Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia (Canada)

2013-10-15

The promyelocytic leukemia protein (PML) is a tumor suppressor protein that regulates a variety of important cellular processes, including gene expression, DNA repair and cell fate decisions. Integral to its function is the ability of PML to form nuclear bodies (NBs) that serve as hubs for the interaction and modification of over 90 cellular proteins. There are seven canonical isoforms of PML, which encode diverse C-termini generated by alternative pre-mRNA splicing. Recruitment of specific cellular proteins to PML NBs is mediated by protein–protein interactions with individual PML isoforms. Using a yeast two-hybrid screen employing peptide sequences unique to PML isoform I (PML-I), we identified an interaction with the eukaryotic initiation factor 3 subunit K (eIF3K), and in the process identified a novel eIF3K isoform, which we term eIF3K-2. We further demonstrate that eIF3K and PML interact both in vitro via pull-down assays, as well as in vivo within human cells by co-immunoprecipitation and co-immunofluorescence. In addition, eIF3K isoform 2 (eIF3K-2) colocalizes to PML bodies, particularly those enriched in PML-I, while eIF3K isoform 1 associates poorly with PML NBs. Thus, we report eIF3K as the first known subunit of the eIF3 translation pre-initiation complex to interact directly with the PML protein, and provide data implicating alternative splicing of both PML and eIF3K as a possible regulatory mechanism for eIF3K localization at PML NBs. - Highlights: • The PML-I C-terminus, encoded by exon 9, interacts with translation factor eIF3K. • We identify a novel eIF3K isoform that excludes exon 2 (eIF3K-2). • eIF3K-2 preferentially associates with PML bodies enriched in PML-I vs. PML-IV. • Alternative splicing of eIF3K regulates association with PML bodies.

Variable clinical expressivity of STAT3 mutation in hyperimmunoglobulin E syndrome: genetic and clinical studies of six patients

NARCIS (Netherlands)

Wolach, Ofir; Kuijpers, Taco; Ben-Ari, Josef; Gavrieli, Ronit; Feinstein-Goren, Neta; Alders, Marielle; Garty, Ben Zion; Wolach, Baruch

2014-01-01

Autosomal dominant Hyper IgE syndrome (AD-HIES) is a rare and complex primary immunodeficiency that affects multiple systems. Mutations in signal transducer and activator of transcription 3 (STAT3) gene cause AD-HIES. These mutations have a dominant-negative effect and the presence of such mutations

Aspects of radiative K{sup +}{sub e3} decays

Energy Technology Data Exchange (ETDEWEB)

Kubis, B. [Universitaet Bonn, Helmholtz-Institut fuer Strahlen- und Kernphysik, Bonn (Germany); Mueller, E.H. [Universitaet Bonn, Helmholtz-Institut fuer Strahlen- und Kernphysik, Bonn (Germany); University of Edinburgh, School of Physics, Edinburgh (United Kingdom); Gasser, J.; Schmid, M. [Universitaet Bern, Institut fuer theoretische Physik, Bern (Switzerland)

2007-04-15

We re-investigate the radiative charged kaon decay K{sup {+-}}{yields}{pi}{sup 0}e{sup {+-}}{nu}{sub e}{gamma} [K{sub e3{gamma}}{sup {+-}}] in chiral perturbation theory, merging the chiral expansion with Low's theorem. We thoroughly analyze the precision of the predicted branching ratio relative to the non-radiative decay channel. Structure dependent terms and their impact on differential decay distributions are investigated in detail, and the possibility to see effects of the chiral anomaly in this decay channel is emphasized. (orig.)

Online‐Geldanlageberatung mit Robo Advice

OpenAIRE

Bahlinger, Thomas

2016-01-01

Der Robo Advisor‐Markt in Deutschland zeigt ein deutliches Aufholpotenzial zum US‐Markt, nicht nur im Hinblick auf das Marktvolumen, sondern auch auf das angebotene Leistungsspektrum. Die 15 untersuchten deutschen Anbieter weisen zum Teil erhebliche Unterschiede in den 20 analysierten Kriterien auf, allerdings ohne dass einzelne Anbieter durchgängig über alle Kriterien hinweg ausschließlich gute oder schlechte Bewertungen erhalten. Dies macht eine differenzierte Herangehensweise der Anbiet...

Herramienta para la evaluación del riesgo de robo en el autotransporte de carga

OpenAIRE

Elizabeth De la Torre; Carlos Martner; Eric Moreno Quintero; José Luis Martínez; Elías Olivares Benítez

2014-01-01

Introducción: En México el robo se ha convertido en uno de los riesgos más importantes para la eficiencia y la competitividad de las cadenas de suministro. Esta propuesta busca identificar las variables que influyen sobre el riesgo de robo en el autotransporte como paso previo de una metodología para evaluar cuantitativamente la influencia de las variables identificadas y crear una aplicación que permita evaluar el riesgo de robo, apoyando así a la toma de decisiones en la creación de esquema...

Characteristics and clinical correlates of MPL 515W>L/K mutation in essential thrombocythemia.

Science.gov (United States)

Vannucchi, Alessandro M; Antonioli, Elisabetta; Guglielmelli, Paola; Pancrazzi, Alessandro; Guerini, Vittoria; Barosi, Giovanni; Ruggeri, Marco; Specchia, Giorgina; Lo-Coco, Francesco; Delaini, Federica; Villani, Laura; Finotto, Silvia; Ammatuna, Emanuele; Alterini, Renato; Carrai, Valentina; Capaccioli, Gloria; Di Lollo, Simonetta; Liso, Vincenzo; Rambaldi, Alessandro; Bosi, Alberto; Barbui, Tiziano

2008-08-01

Among 994 patients with essential thrombocythemia (ET) who were genotyped for the MPLW515L/K mutation, 30 patients carrying the mutation were identified (3.0%), 8 of whom also displayed the JAK2V671F mutation. MPLW515L/K patients presented lower hemoglobin levels and higher platelet counts than did wild type (wt) MPL; these differences were highly significant compared with MPLwt/JAK2V617F-positive patients. Reduced hemoglobin and increased platelet levels were preferentially associated with the W515L and W515K alleles, respectively. MPL mutation was a significant risk factor for microvessel disturbances, suggesting platelet hyperreactivity associated with constitutively active MPL; arterial thromboses were increased only in comparison to MPLwt/JAK2wt patients. MPLW515L/K patients presented reduced total and erythroid bone marrow cellularity, whereas the numbers of megakaryocytes, megakaryocytic clusters, and small-sized megakaryocytes were all significantly increased. These data indicate that MPLW515L/K mutations do not define a distinct phenotype in ET, although some differences depended on the JAK2V617F mutational status of the counterpart.

Effect of the G375C and G346E achondroplasia mutations on FGFR3 activation.

Directory of Open Access Journals (Sweden)

Lijuan He

Full Text Available Two mutations in FGFR3, G380R and G375C are known to cause achondroplasia, the most common form of human dwarfism. The G380R mutation accounts for 98% of the achondroplasia cases, and thus has been studied extensively. Here we study the effect of the G375C mutation on the phosphorylation and the cross-linking propensity of full-length FGFR3 in HEK 293 cells, and we compare the results to previously published results for the G380R mutant. We observe identical behavior of the two achondroplasia mutants in these experiments, a finding which supports a direct link between the severity of dwarfism phenotypes and the level and mechanism of FGFR3 over-activation. The mutations do not increase the cross-linking propensity of FGFR3, contrary to previous expectations that the achondroplasia mutations stabilize the FGFR3 dimers. Instead, the phosphorylation efficiency within un-liganded FGFR3 dimers is increased, and this increase is likely the underlying cause for pathogenesis in achondroplasia. We further investigate the G346E mutation, which has been reported to cause achondroplasia in one case. We find that this mutation does not increase FGFR3 phosphorylation and decreases FGFR3 cross-linking propensity, a finding which raises questions whether this mutation is indeed a genetic cause for human dwarfism.

Effect of the G375C and G346E achondroplasia mutations on FGFR3 activation.

Science.gov (United States)

He, Lijuan; Serrano, Christopher; Niphadkar, Nitish; Shobnam, Nadia; Hristova, Kalina

2012-01-01

Two mutations in FGFR3, G380R and G375C are known to cause achondroplasia, the most common form of human dwarfism. The G380R mutation accounts for 98% of the achondroplasia cases, and thus has been studied extensively. Here we study the effect of the G375C mutation on the phosphorylation and the cross-linking propensity of full-length FGFR3 in HEK 293 cells, and we compare the results to previously published results for the G380R mutant. We observe identical behavior of the two achondroplasia mutants in these experiments, a finding which supports a direct link between the severity of dwarfism phenotypes and the level and mechanism of FGFR3 over-activation. The mutations do not increase the cross-linking propensity of FGFR3, contrary to previous expectations that the achondroplasia mutations stabilize the FGFR3 dimers. Instead, the phosphorylation efficiency within un-liganded FGFR3 dimers is increased, and this increase is likely the underlying cause for pathogenesis in achondroplasia. We further investigate the G346E mutation, which has been reported to cause achondroplasia in one case. We find that this mutation does not increase FGFR3 phosphorylation and decreases FGFR3 cross-linking propensity, a finding which raises questions whether this mutation is indeed a genetic cause for human dwarfism.

Coexistence of K-ras mutations and HPV infection in colon cancer

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Tezol Ayda

2006-05-01

Full Text Available Abstract Background Activation of the ras genes or association with human papillomavirus infection have been extensively studied in colorectal cancer. However, the correlation between K-ras mutations and HPV in colorectal cancer has not been investigated yet. In this study we aimed to investigate the presence of K-ras mutations and their correlation with HPV infection in colon cancer. Methods K-ras mutations were analyzed by a mutagenic PCR assay and digestion with specific restriction enzymes to distinguish the wild-type and mutant codons. HPV infection was analyzed by PCR amplification and hybridization with specific probes by Southern blotting. Stattistical analyses were performed by the chi-square and Fisher's exact tests Results HPV gene fragments were detected in 43 tumors and 17 normal tissue samples. HPV 18 was the prevalent type in the tumor tissue. A mutation at codon 12 of the K-ras gene was present in 31 patients. 56% of the HPV-positive tumors also harbored a K-ras mutation. Codon 13 mutations were not observed. These data indicate that infection with high risk HPV types and mutational activation of the K-ras gene are frequent events in colorectal carcinogenesis. Conclusion Our findings suggest that mutational activation of the K-ras gene is a common event in colon carcinogenesis and that HPV infection may represent an important factor in the development of the premalignant lesions leading to the neoplastic phenotype.

Sequential emergence and clinical implications of viral mutants with K70E and K65R mutation in reverse transcriptase during prolonged tenofovir monotherapy in rhesus macaques with chronic RT-SHIV infection

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Pedersen Niels C

2007-04-01

Full Text Available Abstract Background We reported previously on the emergence and clinical implications of simian immunodeficiency virus (SIVmac251 mutants with a K65R mutation in reverse transcriptase (RT, and the role of CD8+ cell-mediated immune responses in suppressing viremia during tenofovir therapy. Because of significant sequence differences between SIV and HIV-1 RT that affect drug susceptibilities and mutational patterns, it is unclear to what extent findings with SIV can be extrapolated to HIV-1 RT. Accordingly, to model HIV-1 RT responses, 12 macaques were inoculated with RT-SHIV, a chimeric SIV containing HIV-1 RT, and started on prolonged tenofovir therapy 5 months later. Results The early virologic response to tenofovir correlated with baseline viral RNA levels and expression of the MHC class I allele Mamu-A*01. For all animals, sensitive real-time PCR assays detected the transient emergence of K70E RT mutants within 4 weeks of therapy, which were then replaced by K65R mutants within 12 weeks of therapy. For most animals, the occurrence of these mutations preceded a partial rebound of plasma viremia to levels that remained on average 10-fold below baseline values. One animal eventually suppressed K65R viremia to undetectable levels for more than 4 years; sequential experiments using CD8+ cell depletion and tenofovir interruption demonstrated that both CD8+ cells and continued tenofovir therapy were required for sustained suppression of viremia. Conclusion This is the first evidence that tenofovir therapy can select directly for K70E viral mutants in vivo. The observations on the clinical implications of the K65R RT-SHIV mutants were consistent with those of SIVmac251, and suggest that for persons infected with K65R HIV-1 both immune-mediated and drug-dependent antiviral activities play a role in controlling viremia. These findings suggest also that even in the presence of K65R virus, continuation of tenofovir treatment as part of HAART may be

The expression of the Slit-Robo signal in the retina of diabetic rats and the vitreous or fibrovascular retinal membranes of patients with proliferative diabetic retinopathy.

Science.gov (United States)

Zhou, Weiyan; Wang, Hongya; Yu, Wenzhen; Xie, Wankun; Zhao, Min; Huang, Lvzhen; Li, Xiaoxin

2017-01-01

The Slit-Robo signal has an important role in vasculogenesis and angiogenesis. Our study examined the expression of Slit2 and its receptor, Robo1, in a rat model of streptozotocin-induced diabetes and in patients with proliferative diabetic retinopathy. Diabetes was induced in male Sprague-Dawley rats via a single, intraperitoneal injection of streptozotocin. The rats were sacrificed 1, 3 or 6 months after the injection. The expression of Slit2 and Robo1 in retinal tissue was measured by real-time reverse transcription polymerase chain reaction (RT-PCR), and protein levels were measured by western blotting and immunohistochemistry. Recombinant N-Slit2 protein was used to study the effects of Slit2 on the expression of VEGF in vivo. The concentration of Slit2 protein in human eyes was measured by enzyme-linked immunosorbent assay in 27 eyes with proliferative diabetic retinopathy and 28 eyes in control group. The expression of Slit2, Robo1 and VEGF in the excised human fibrovascular membranes was examined by fluorescence immunostaining and semi-quantitative RT-PCR. The expression of Slit2 and Robo1 in the retina was altered after STZ injection. Recombinant N-Slit2 protein did not increase the retinal VEGF expression. Vitreous concentrations of Slit2 were significantly higher in the study group than in the control group. In the human fibrovascular membranes of the study group, the co-localization of VEGF with the markers for Slit2 and Robo1was observed. The expression of Slit2 mRNA, Robo1 mRNA, and VEGF mRNA was significantly higher in human fibrovascular proliferative diabetic retinopathy membranes than in the control membranes. The alteration of Slit2 and Robo1 expression in the retinas of diabetic rats and patients with proliferative diabetic retinopathy suggests a role for the Slit-Robo signal in the various stages diabetic retinopathy. Further studies should address the possible involvement of the Slit-Robo signal in the pathophysiological progress of diabetic

Mutation at Glu23 eliminates the neuron growth inhibitory activity of human metallothionein-3

International Nuclear Information System (INIS)

Ding Zhichun; Teng Xinchen; Cai Bin; Wang Hui; Zheng Qi; Wang Yang; Zhou Guoming; Zhang Mingjie; Wu Houming; Sun Hongzhe; Huang Zhongxian

2006-01-01

Human metallothionein-3 (hMT3), first isolated and identified as a neuronal growth inhibitory factor (GIF), is a metalloprotein expressed predominantly in brain. However, untill now, the exact mechanism of the bioactivity of hMT3 is still unknown. In order to study the influence of acid-base catalysis on S-nitrosylation of hMT3, we constructed the E23K mutant of hMT3. During the course of bioassay, we found out unexpectedly that mutation at E23 of hMT3 eliminates the neuronal growth inhibitory activity completely. To the best of our knowledge, it is First report that other residues, besides the TCPCP motif, in the β-domain can alter the bioactivity of hMT3. In order to figure out the causes for the loss of bioactivity of the E23K mutant, the biochemical properties were characterized by UV-vis spectroscopy, CD spectroscopy, pH titration, DTNB reaction, EDTA reaction, and SNOC reaction. All data demonstrated that stability of the metal-thiolate cluster and overall structure of the E23K mutant were not altered too much. However, the reaction of the E23K mutant with SNOC exhibited biphasic kinetics and the mutant protein released zinc ions much faster than hMT3 in the initial step, while hMT3 exhibited single kinetic process. The 2D [ 1 H- 15 N] HSQC was also employed to characterize structural changes during the reaction of hMT3 with varying mounts of nitric oxide. It was shown that the resonance of Glu23 disappeared at a molar ratio of NO to protein of 4. Based on these results, we suggest that mutation at Glu23 may alter the NO metabolism and/or affect zinc homeostasis in brain, thus altering the neuronal growth inhibitory activity

31 CFR 575.319 - United States.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false United States. 575.319 Section 575.319 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE OF....319 United States. The term United States means the United States, its territories and possessions...

Diet, Lifestyle and risk of K-ras mutation-positive and -negative colorectal adenomas

NARCIS (Netherlands)

Wark, P.A.; Kuil, van der W.; Ploemacher, J.; Muijen, van G.N.P.; Mulder, Ch.J.J.; Weijenberg, M.P.; Kok, F.J.; Kampman, E.

2006-01-01

K-ras mutation-positive (K-ras+) and -negative (K-ras-) colorectal adenomas may differ clinically and pathologically. As environmental compounds may cause mutations in the growth-related K-ras oncogene or affect clonal selection depending on mutational status, we evaluated whether the aetiology of

A mutational comparison of adult and adolescent and young adult (AYA) colon cancer.

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Tricoli, James V; Boardman, Lisa A; Patidar, Rajesh; Sindiri, Sivasish; Jang, Jin S; Walsh, William D; McGregor, Paul M; Camalier, Corinne E; Mehaffey, Michele G; Furman, Wayne L; Bahrami, Armita; Williams, P Mickey; Lih, Chih-Jian; Conley, Barbara A; Khan, Javed

2018-03-01

It is possible that the relative lack of progress in treatment outcomes among adolescent and young adult (AYA) patients with cancer is caused by a difference in disease biology compared with the corresponding diseases in younger and older individuals. There is evidence that colon cancer is more aggressive and has a poorer prognosis in AYA patients than in older adult patients. To further understand the molecular basis for this difference, whole-exome sequencing was conducted on a cohort of 30 adult, 30 AYA, and 2 pediatric colon cancers. A statistically significant difference in mutational frequency was observed between AYA and adult samples in 43 genes, including ROBO1, MYC binding protein 2 (MYCBP2), breast cancer 2 (early onset) (BRCA2), MAP3K3, MCPH1, RASGRP3, PTCH1, RAD9B, CTNND1, ATM, NF1; KIT, PTEN, and FBXW7. Many of these mutations were nonsynonymous, missense, stop-gain, or frameshift mutations that were damaging. Next, RNA sequencing was performed on a subset of the samples to confirm the mutations identified by exome sequencing. This confirmation study verified the presence of a significantly greater frequency of damaging mutations in AYA compared with adult colon cancers for 5 of the 43 genes (MYCBP2, BRCA2, PHLPP1, TOPORS, and ATR). The current results provide the rationale for a more comprehensive study with a larger sample set and experimental validation of the functional impact of the identified variants along with their contribution to the biologic and clinical characteristics of AYA colon cancer. Cancer 2018;124:1070-82. © 2017 American Cancer Society. © 2017 American Cancer Society.

K-ras mutations in sinonasal cancers in relation to wood dust exposure

International Nuclear Information System (INIS)

Bornholdt, Jette; Vogel, Ulla; Husgafvel-Pursiainen, Kirsti; Wallin, Håkan; Hansen, Johnni; Steiniche, Torben; Dictor, Michael; Antonsen, Annemarie; Wolff, Henrik; Schlünssen, Vivi; Holmila, Reetta; Luce, Danièle

2008-01-01

Cancer in the sinonasal tract is rare, but persons who have been occupationally exposed to wood dust have a substantially increased risk. It has been estimated that approximately 3.6 million workers are exposed to inhalable wood dust in EU. In previous small studies of this cancer, ras mutations were suggested to be related to wood dust exposure, but these studies were too limited to detect statistically significant associations. We examined 174 cases of sinonasal cancer diagnosed in Denmark in the period from 1991 to 2001. To ensure uniformity, all histological diagnoses were carefully reviewed pathologically before inclusion. Paraffin embedded tumour samples from 58 adenocarcinomas, 109 squamous cell carcinomas and 7 other carcinomas were analysed for K-ras codon 12, 13 and 61 point mutations by restriction fragment length polymorphisms and direct sequencing. Information on occupational exposure to wood dust and to potential confounders was obtained from telephone interviews and from registry data. Among the patients in this study, exposure to wood dust was associated with a 21-fold increased risk of having an adenocarcinoma than a squamous cell carcinoma compared to unexposed [OR = 21.0, CI = 8.0–55.0]. K-ras was mutated in 13% of the adenocarcinomas (seven patients) and in 1% of squamous cell carcinomas (one patient). Of these eight mutations, five mutations were located in the codon 12. The exact sequence change of remaining three could not be identified unambiguously. Among the five identified mutations, the G→A transition was the most common, and it was present in tumour tissue from two wood dust exposed adenocarcinoma patients and one patient with unknown exposure. Previously published studies of sinonasal cancer also identify the GGT → GAT transition as the most common and often related to wood dust exposure. Patients exposed to wood dust seemed more likely to develop adenocarcinoma compared to squamous cell carcinomas. K-ras mutations were detected

L-3-n-Butylphthalide Protects HSPB8 K141N Mutation-Induced Oxidative Stress by Modulating the Mitochondrial Apoptotic and Nrf2 Pathways

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Xiao-Dong Yang

2017-07-01

Full Text Available Charcot–Marie–Tooth disease (CMT, also known as hereditary motor and sensory neuropathy, is the most common inherited peripheral nerve disorder. Missense mutations, such as K141N, in the small heat shock protein HSPB8 are known to cause distal hereditary motor neuropathy 2A (dHMN2A or Charcot-Marie-Tooth neuropathy type 2L (CMT2L. However, of critical clinical significance, very few specific therapies for this disease exist. In the present study, we investigated the impact of mutant K141N HSPB8 on mitochondrial distribution and function in a cellular model of CMT2L. Our results indicate that K141N HSPB8 induced mitochondrial aggregation and caused increased oxidative stress injury. As an extraction from Chinese celery Apium graveolens Linn seeds, L-3-n-Butylphthalide (NBP, has been reported to exert many neuroprotective effects, we interrogated whether NBP could elicit a protective effect on the cell injury typically caused by HSPB8 K141N mutations. We found NBP could reverse the pathological processes induced by HSPB8 K141N mutation via an antioxidant effect, modulation of the Bax/Bcl-2 mitochondrial apoptotic and Nrf2 pathways. We propose a novel function of HSPB8, highlighting the consequence of the K141N pathogenic mutation. Furthermore, we suggest NBP may have promising therapeutic potential in the treatment of CMT2L.

Slit-Robo signalling in heart development

OpenAIRE

Zhao, J; Mommersteeg, MTM

2018-01-01

The Slit ligands and their Robo receptors are well-known for their roles during axon guidance in the central nervous system, but are still relatively unknown in the cardiac field. However, data from different animal models suggest a broad involvement of the pathway in many aspects of heart development, from cardiac cell migration and alignment, lumen formation, chamber formation, to the formation of the ventricular septum, semilunar and atrioventricular valves, caval veins and pericardium. Ab...

Experimental validation of the predicted binding site of Escherichia coli K1 outer membrane protein A to human brain microvascular endothelial cells: identification of critical mutations that prevent E. coli meningitis.

Science.gov (United States)

Pascal, Tod A; Abrol, Ravinder; Mittal, Rahul; Wang, Ying; Prasadarao, Nemani V; Goddard, William A

2010-11-26

Escherichia coli K1, the most common cause of meningitis in neonates, has been shown to interact with GlcNAc1-4GlcNAc epitopes of Ecgp96 on human brain microvascular endothelial cells (HBMECs) via OmpA (outer membrane protein A). However, the precise domains of extracellular loops of OmpA interacting with the chitobiose epitopes have not been elucidated. We report the loop-barrel model of these OmpA interactions with the carbohydrate moieties of Ecgp96 predicted from molecular modeling. To test this model experimentally, we generated E. coli K1 strains expressing OmpA with mutations of residues predicted to be critical for interaction with the HBMEC and tested E. coli invasion efficiency. For these same mutations, we predicted the interaction free energies (including explicit calculation of the entropy) from molecular dynamics (MD), finding excellent correlation (R(2) = 90%) with experimental invasion efficiency. Particularly important is that mutating specific residues in loops 1, 2, and 4 to alanines resulted in significant inhibition of E. coli K1 invasion in HBMECs, which is consistent with the complete lack of binding found in the MD simulations for these two cases. These studies suggest that inhibition of the interactions of these residues of Loop 1, 2, and 4 with Ecgp96 could provide a therapeutic strategy to prevent neonatal meningitis due to E. coli K1.

Effect of the uvr D3 mutation on ultraviolet radiation-induced DNA-repair replication in Escherichia coli K12

International Nuclear Information System (INIS)

Carlson, K.M.; Smith, K.C.

1981-01-01

Ultraviolet-radiation-induced DNA-repair replication was measured in wild-type, polA1, uvrD3, and polA1 uvrD3 strains of Escherichia coli K 12. A large stimulation of repair replication was observed in the uvrD3 strain, compared to the wild-type and polA1 strains. This enhanced repair replication was reduced in the polA1 uvrD3 strain. Therefore, a uvrD3 mutation appears to affect the amount of repair replication performed by DNA polymerase I. In the polA1 strain, there also appears to be an effect of the uvrD3 mutation on the amount of repair replication performed by DNA polymerase III (and/or II). The enhanced repair replication observed for the uvrD3 strains appears to be in response to the enhanced DNA degradation observed for these strains. (orig.)

Recurrent Skin and Lung Infections in Autosomal Dominant Hyper IgE Syndrome with Transactivation Domain STAT3 Mutation

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Chad J. Cooper

2014-01-01

Full Text Available Background. Hyper IgE is a rare systemic disease characterized by the clinical triad of high serum levels of IgE (>2000 IU/mL, eczema, and recurrent staphylococcal skin and lung infections. The presentation of hyper IgE syndrome is highly variable, which makes it easy to confuse the diagnosis with that of severe atopy or other rare immunodeficiency disorders. Case Report. A 23-year-old Hispanic presented with history of frequent respiratory and gastrointestinal infections as a child and multiple episodes of skin and lung infections (abscess with Staphylococcus aureus throughout his adult life. He had multiple eczematous lesions and folliculitis over his entire body, oral/esophageal candidiasis, and retention of his primary teeth. The IgE was elevated (>5000 IU/mL. Genetic mutation analysis revealed a mutation affecting the transactivation domain of the STAT3 gene. Conclusion. The hallmark of hyper IgE syndrome is serum IgE of >2000 IU/mL. Hyper IgE syndrome is a genetic disorder that is either autosomal dominant or recessive. A definite diagnosis can be made with genetic mutation analysis, and in this case, it revealed a very rare finding of the transactivation domain STAT3 mutation. Hyper IgE syndrome is a challenge for clinicians in establishing a diagnosis in suspected cases.

Razor clam to RoboClam: burrowing drag reduction mechanisms and their robotic adaptation

International Nuclear Information System (INIS)

Winter, A G; V; Dorsch, D S; Slocum, A H; Hosoi, A E; Deits, R L H

2014-01-01

Estimates based on the strength, size, and shape of the Atlantic razor clam (Ensis directus) indicate that the animal's burrow depth should be physically limited to a few centimeters; yet razor clams can dig as deep as 70 cm. By measuring soil deformations around burrowing E. directus, we have found the animal reduces drag by contracting its valves to initially fail, and then fluidize, the surrounding substrate. The characteristic contraction time to achieve fluidization can be calculated directly from soil properties. The geometry of the fluidized zone is dictated by two commonly-measured geotechnical parameters: coefficient of lateral earth pressure and friction angle. Calculations using full ranges for both parameters indicate that the fluidized zone is a local effect, occurring between 1–5 body radii away from the animal. The energy associated with motion through fluidized substrate—characterized by a depth-independent density and viscosity—scales linearly with depth. In contrast, moving through static soil requires energy that scales with depth squared. For E. directus, this translates to a 10X reduction in the energy required to reach observed burrow depths. For engineers, localized fluidization offers a mechanically simple and purely kinematic method to dramatically reduce energy costs associated with digging. This concept is demonstrated with RoboClam, an E. directus-inspired robot. Using a genetic algorithm to find optimal digging kinematics, RoboClam has achieved localized fluidization burrowing performance comparable to that of the animal, with a linear energy-depth relationship, in both idealized granular glass beads and E. directus' native cohesive mudflat habitat. (paper)

Mutations in Plasmodium falciparum K13 propeller gene from Bangladesh (2009-2013).

Science.gov (United States)

Mohon, Abu Naser; Alam, Mohammad Shafiul; Bayih, Abebe Genetu; Folefoc, Asongna; Shahinas, Dea; Haque, Rashidul; Pillai, Dylan R

2014-11-18

Bangladesh is a malaria hypo-endemic country sharing borders with India and Myanmar. Artemisinin combination therapy (ACT) remains successful in Bangladesh. An increase of artemisinin-resistant malaria parasites on the Thai-Cambodia and Thai-Myanmar borders is worrisome. K13 propeller gene (PF3D7_1343700 or PF13_0238) mutations have been linked to both in vitro artemisinin resistance and in vivo slow parasite clearance rates. This group undertook to evaluate if mutations seen in Cambodia have emerged in Bangladesh where ACT use is now standard for a decade. Samples were obtained from Plasmodium falciparum-infected malaria patients from Upazila health complexes (UHC) between 2009 and 2013 in seven endemic districts of Bangladesh. These districts included Khagrachari (Matiranga UHC), Rangamati (Rajasthali UHC), Cox's Bazar (Ramu and Ukhia UHC), Bandarban (Lama UHC), Mymensingh (Haluaghat UHC), Netrokona (Durgapur and Kalmakanda UHC), and Moulvibazar (Sreemangal and Kamalganj UHC). Out of 296 microscopically positive P. falciparum samples, 271 (91.6%) were confirmed as mono-infections by both real-time PCR and nested PCR. The K13 propeller gene from 253 (93.4%) samples was sequenced bi-directionally. One non-synonymous mutation (A578S) was found in Bangladeshi clinical isolates. The A578S mutation was confirmed and lies adjacent to the C580Y mutation, the major mutation causing delayed parasite clearance in Cambodia. Based on computational modeling A578S should have a significant effect on tertiary structure of the protein. The data suggest that P. falciparum in Bangladesh remains free of the C580Y mutation linked to delayed parasite clearance. However, the mutation A578S is present and based on structural analysis could affect K13 gene function. Further in vivo clinical studies are required to validate the effect of this mutation.

Measurements of the absolute branching fractions for D→anti Kπe+νe, D→anti K*e+νe and determination of Γ(D+→anti K*0e+νe)/Γ(D+→anti K0e+νe)

International Nuclear Information System (INIS)

Ablikim, M.; Bai, J.Z.; Ban, Y.

2006-01-01

Using the data of about 33 pb -1 collected at and around 3.773 GeV with the BES-II detector at the BEPC collider, we have studied the exclusive semileptonic decays D + →K - π + e + ν e , D 0 →anti K 0 π - e + ν e , D + →anti K *0 e + ν e and D 0 →K *- e + ν e . The absolute branching fractions for the decays are measured to be BF(D + →K - π + e + ν e )=(3.50±0.75±0.27)%, BF(D 0 →anti K 0 π - e + ν e )=(2.61±1.04±0.28)%, BF(D + →anti K *0 e + ν e )=(5.06±1.21±0.40)% and BF(D 0 →K *- e + ν e )=(2.87±1.48±0.39)%. The ratio of the vector to pseudoscalar semileptonic decay rates Γ(D + →anti K *0 e + ν e )/Γ(D + →anti K 0 e + ν e ) is determined to be 0.57±0.17±0.02. (orig.)

Activation of PI3K/Akt signaling by n-terminal SH2 domain mutants of the p85α regulatory subunit of PI3K is enhanced by deletion of its c-terminal SH2 domain.

Science.gov (United States)

Hofmann, Bianca T; Jücker, Manfred

2012-10-01

The phosphoinositide 3-kinase (PI3K) is frequently activated in human cancer cells due to gain of function mutations in the catalytic (p110) and the regulatory (p85) subunits. The regulatory subunit consists of an SH3 domain and two SH2 domains. An oncogenic form of p85α named p65 lacking the c-terminal SH2 domain (cSH2) has been cloned from an irradiation-induced murine thymic lymphoma and transgenic mice expressing p65 in T lymphocytes develop a lymphoproliferative disorder. We have recently detected a c-terminal truncated form of p85α named p76α in a human lymphoma cell line lacking most of the cSH2 domain due to a frame shift mutation. Here, we report that the deletion of the cSH2 domain enhances the activating effects of the n-terminal SH2 domain (nSH2) mutants K379E and R340E on the PI3K/Akt pathway and micro tumor formation in a focus assay. Further analysis revealed that this transforming effect is mediated by activation of the catalytic PI3K isoform p110α and downstream signaling through mTOR. Our data further support a mechanistic model in which mutations of the cSH2 domain of p85α can abrogate its negative regulatory function on PI3K activity via the nSH2 domain of p85α. Copyright © 2012 Elsevier Inc. All rights reserved.

Acanthosis nigricans in a Japanese boy with hypochondroplasia due to a K650T mutation in FGFR3

Science.gov (United States)

Hirai, Hiroki; Hamada, Junpei; Hasegawa, Kosei; Ishii, Eiichi

2017-01-01

Abstract. Acanthosis nigricans (AN) is observed in some cases of skeletal dysplasia. However, AN has occasionally been reported in patients with hypochondroplasia (HCH), and a clinical diagnosis is sometimes difficult when its physical and radiological features are mild. Mutations in the gene encoding the fibroblast growth factor receptor 3 (FGFR3) have been identified as the cause of some types of skeletal dysplasia, which is diagnostically useful. Here, we report the case of a 3-yr-old Japanese boy who presented with AN. His height, weight, head circumference, and arm span were 91.7 cm (–1.95 SD), 16.3 kg, 54.0 cm (+2.6 SD), and 88.0 cm, respectively. In addition to the AN, he also exhibited a mild height deficit and macrocephaly, which prompted a search for FGFR3 mutations, although no skeletal disproportion, exaggerated lumbar lordosis, or facial dysmorphism was observed, and only slight radiological abnormalities were noted. A definitive diagnosis of HCH was made based on FGFR3 gene analysis, which detected a heterozygous K650T mutation. Insulin insensitivity was not found to have contributed to the development of AN. In individuals with AN, careful assessments for symptoms of HCH are important, regardless of the presence or absence of a short stature, and FGFR3 gene analysis is recommended in such cases. PMID:29026271

An integrative genomic and proteomic analysis of PIK3CA, PTEN and AKT mutations in breast cancer

Energy Technology Data Exchange (ETDEWEB)

Stemke-Hale, Katherine; Gonzalez-Angulo, Ana Maria; Lluch, Ana; Neve, Richard M.; Kuo, Wen-Lin; Davies, Michael; Carey, Mark; Hu, Zhi; Guan, Yinghui; Sahin, Aysegul; Symmans, W. Fraser; Pusztai, Lajos; Nolden, Laura K.; Horlings, Hugo; Berns, Katrien; Hung, Mien-Chie; van de Vijver, Marc J.; Valero, Vicente; Gray, Joe W.; Bernards, Rene; Mills, Gordon B.; Hennessy, Bryan T.

2008-05-06

Phosphatidylinositol-3-kinase (PI3K)/AKT pathway aberrations are common in cancer. By applying mass spectroscopy-based sequencing and reverse phase protein arrays to 547 human breast cancers and 41 cell lines, we determined the subtype specificity and signaling effects of PIK3CA, AKT and PTEN mutations, and the effects of PIK3CA mutations on responsiveness to PI3K inhibition in-vitro and on outcome after adjuvant tamoxifen. PIK3CA mutations were more common in hormone receptor positive (33.8%) and HER2-positive (24.6%) than in basal-like tumors (8.3%). AKT1 (1.4%) and PTEN (2.3%) mutations were restricted to hormone receptor-positive cancers with PTEN protein levels also being significantly lower in hormone receptor-positive cancers. Unlike AKT1 mutations, PIK3CA (39%) and PTEN (20%) mutations were more common in cell lines than tumors, suggesting a selection for these but not AKT1 mutations during adaptation to culture. PIK3CA mutations did not have a significant impact on outcome in 166 hormone receptor-positive breast cancer patients after adjuvant tamoxifen. PIK3CA mutations, in comparison with PTEN loss and AKT1 mutations, were associated with significantly less and indeed inconsistent activation of AKT and of downstream PI3K/AKT signaling in tumors and cell lines, and PTEN loss and PIK3CA mutation were frequently concordant, suggesting different contributions to pathophysiology. PTEN loss but not PIK3CA mutations rendered cells sensitive to growth inhibition by the PI3K inhibitor LY294002. Thus, PI3K pathway aberrations likely play a distinct role in the pathogenesis of different breast cancer subtypes. The specific aberration may have implications for the selection of PI3K-targeted therapies in hormone receptor-positive breast cancer.

Study of the process e+e- → K+K- in the center-of-mass energy range 1010-1060 MeV with the CMD-3 detector

Science.gov (United States)

Kozyrev, E. A.; Solodov, E. P.; Akhmetshin, R. R.; Amirkhanov, A. N.; Anisenkov, A. V.; Aulchenko, V. M.; Banzarov, V. S.; Bashtovoy, N. S.; Berkaev, D. E.; Bondar, A. E.; Bragin, A. V.; Eidelman, S. I.; Epifanov, D. A.; Epshteyn, L. B.; Erofeev, A. L.; Fedotovich, G. V.; Gayazov, S. E.; Grebenuk, A. A.; Gribanov, S. S.; Grigoriev, D. N.; Ignatov, F. V.; Ivanov, V. L.; Karpov, S. V.; Kasaev, A. S.; Kazanin, V. F.; Korobov, A. A.; Koop, I. A.; Kozyrev, A. N.; Krokovny, P. P.; Kuzmenko, A. E.; Kuzmin, A. S.; Logashenko, I. B.; Lukin, P. A.; Lysenko, A. P.; Mikhailov, K. Yu.; Okhapkin, V. S.; Perevedentsev, E. A.; Pestov, Yu. N.; Popov, A. S.; Razuvaev, G. P.; Rogovsky, Yu. A.; Ruban, A. A.; Ryskulov, N. M.; Ryzhenenkov, A. E.; Shebalin, V. E.; Shemyakin, D. N.; Shwartz, B. A.; Shwartz, D. B.; Sibidanov, A. L.; Shatunov, Yu. M.; Talyshev, A. A.; Vorobiov, A. I.; Yudin, Yu. V.

2018-04-01

The process e+e- →K+K- has been studied using 1.7 ×106 events from a data sample corresponding to an integrated luminosity of 5.7 pb-1 collected with the CMD-3 detector in the center-of-mass energy range 1010-1060 MeV. The cross section is measured with about 2% systematic uncertainty and is used to calculate the contribution to the anomalous magnetic moment of the muon aμK+K- = (19.33 ± 0.40) ×10-10, and to obtain the ϕ (1020) meson parameters. We consider the relationship between the e+e- →K+K- and e+e- → KS0 KL0 cross sections and compare it to the theoretical prediction.

Analysis of PIK3CA Mutations and Activation Pathways in Triple Negative Breast Cancer.

Directory of Open Access Journals (Sweden)

Paolo Cossu-Rocca

Full Text Available Triple Negative Breast Cancer (TNBC accounts for 12-24% of all breast carcinomas, and shows worse prognosis compared to other breast cancer subtypes. Molecular studies demonstrated that TNBCs are a heterogeneous group of tumors with different clinical and pathologic features, prognosis, genetic-molecular alterations and treatment responsivity. The PI3K/AKT is a major pathway involved in the regulation of cell survival and proliferation, and is the most frequently altered pathway in breast cancer, apparently with different biologic impact on specific cancer subtypes. The most common genetic abnormality is represented by PIK3CA gene activating mutations, with an overall frequency of 20-40%. The aims of our study were to investigate PIK3CA gene mutations on a large series of TNBC, to perform a wider analysis on genetic alterations involving PI3K/AKT and BRAF/RAS/MAPK pathways and to correlate the results with clinical-pathologic data.PIK3CA mutation analysis was performed by using cobas® PIK3CA Mutation Test. EGFR, AKT1, BRAF, and KRAS genes were analyzed by sequencing. Immunohistochemistry was carried out to identify PTEN loss and to investigate for PI3K/AKT pathways components.PIK3CA mutations were detected in 23.7% of TNBC, whereas no mutations were identified in EGFR, AKT1, BRAF, and KRAS genes. Moreover, we observed PTEN loss in 11.3% of tumors. Deregulation of PI3K/AKT pathways was revealed by consistent activation of pAKT and p-p44/42 MAPK in all PIK3CA mutated TNBC.Our data shows that PIK3CA mutations and PI3K/AKT pathway activation are common events in TNBC. A deeper investigation on specific TNBC genomic abnormalities might be helpful in order to select patients who would benefit from current targeted therapy strategies.

Analysis of PIK3CA Mutations and Activation Pathways in Triple Negative Breast Cancer.

Science.gov (United States)

Cossu-Rocca, Paolo; Orrù, Sandra; Muroni, Maria Rosaria; Sanges, Francesca; Sotgiu, Giovanni; Ena, Sara; Pira, Giovanna; Murgia, Luciano; Manca, Alessandra; Uras, Maria Gabriela; Sarobba, Maria Giuseppina; Urru, Silvana; De Miglio, Maria Rosaria

2015-01-01

Triple Negative Breast Cancer (TNBC) accounts for 12-24% of all breast carcinomas, and shows worse prognosis compared to other breast cancer subtypes. Molecular studies demonstrated that TNBCs are a heterogeneous group of tumors with different clinical and pathologic features, prognosis, genetic-molecular alterations and treatment responsivity. The PI3K/AKT is a major pathway involved in the regulation of cell survival and proliferation, and is the most frequently altered pathway in breast cancer, apparently with different biologic impact on specific cancer subtypes. The most common genetic abnormality is represented by PIK3CA gene activating mutations, with an overall frequency of 20-40%. The aims of our study were to investigate PIK3CA gene mutations on a large series of TNBC, to perform a wider analysis on genetic alterations involving PI3K/AKT and BRAF/RAS/MAPK pathways and to correlate the results with clinical-pathologic data. PIK3CA mutation analysis was performed by using cobas® PIK3CA Mutation Test. EGFR, AKT1, BRAF, and KRAS genes were analyzed by sequencing. Immunohistochemistry was carried out to identify PTEN loss and to investigate for PI3K/AKT pathways components. PIK3CA mutations were detected in 23.7% of TNBC, whereas no mutations were identified in EGFR, AKT1, BRAF, and KRAS genes. Moreover, we observed PTEN loss in 11.3% of tumors. Deregulation of PI3K/AKT pathways was revealed by consistent activation of pAKT and p-p44/42 MAPK in all PIK3CA mutated TNBC. Our data shows that PIK3CA mutations and PI3K/AKT pathway activation are common events in TNBC. A deeper investigation on specific TNBC genomic abnormalities might be helpful in order to select patients who would benefit from current targeted therapy strategies.

Colon Cancer Tumorigenesis Initiated by the H1047R Mutant PI3K.

Directory of Open Access Journals (Sweden)

Alexander E Yueh

Full Text Available The phosphoinositide 3-kinase (PI3K signaling pathway is critical for multiple important cellular functions, and is one of the most commonly altered pathways in human cancers. We previously developed a mouse model in which colon cancers were initiated by a dominant active PI3K p110-p85 fusion protein. In that model, well-differentiated mucinous adenocarcinomas developed within the colon and initiated through a non-canonical mechanism that is not dependent on WNT signaling. To assess the potential relevance of PI3K mutations in human cancers, we sought to determine if one of the common mutations in the human disease could also initiate similar colon cancers. Mice were generated expressing the Pik3caH1047R mutation, the analog of one of three human hotspot mutations in this gene. Mice expressing a constitutively active PI3K, as a result of this mutation, develop invasive adenocarcinomas strikingly similar to invasive adenocarcinomas found in human colon cancers. These tumors form without a polypoid intermediary and also lack nuclear CTNNB1 (β-catenin, indicating a non-canonical mechanism of tumor initiation mediated by the PI3K pathway. These cancers are sensitive to dual PI3K/mTOR inhibition indicating dependence on the PI3K pathway. The tumor tissue remaining after treatment demonstrated reduction in cellular proliferation and inhibition of PI3K signaling.

7 CFR 319.73-3 - Conditions for transit movement of certain products through Puerto Rico or Hawaii.

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2010-01-01

... through Puerto Rico or Hawaii. 319.73-3 Section 319.73-3 Agriculture Regulations of the Department of... or Hawaii. (a) Mail. Samples of unroasted coffee that are transiting Hawaii or Puerto Rico en route.... These samples must be returned to origin or forwarded to a destination outside Hawaii or Puerto Rico in...

Noninvasive Assessment of Antenatal Hydronephrosis in Mice Reveals a Critical Role for Robo2 in Maintaining Anti-Reflux Mechanism

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Wang, Hang; Li, Qinggang; Liu, Juan; Mendelsohn, Cathy; Salant, David J.; Lu, Weining

2011-01-01

Antenatal hydronephrosis and vesicoureteral reflux (VUR) are common renal tract birth defects. We recently showed that disruption of the Robo2 gene is associated with VUR in humans and antenatal hydronephrosis in knockout mice. However, the natural history, causal relationship and developmental origins of these clinical conditions remain largely unclear. Although the hydronephrosis phenotype in Robo2 knockout mice has been attributed to the coexistence of ureteral reflux and obstruction in the same mice, this hypothesis has not been tested experimentally. Here we used noninvasive high-resolution micro-ultrasonography and pathological analysis to follow the progression of antenatal hydronephrosis in individual Robo2-deficient mice from embryo to adulthood. We found that hydronephrosis progressed continuously after birth with no spontaneous resolution. With the use of a microbubble ultrasound contrast agent and ultrasound-guided percutaneous aspiration, we demonstrated that antenatal hydronephrosis in Robo2-deficient mice is caused by high-grade VUR resulting from a dilated and incompetent ureterovesical junction rather than ureteral obstruction. We further documented Robo2 expression around the developing ureterovesical junction and identified early dilatation of ureteral orifice structures as a potential fetal origin of antenatal hydronephrosis and VUR. Our results thus demonstrate that Robo2 is crucial for the formation of a normal ureteral orifice and for the maintenance of an effective anti-reflux mechanism. This study also establishes a reproducible genetic mouse model of progressive antenatal hydronephrosis and primary high-grade VUR. PMID:21949750

Homozygous EDNRB mutation in a patient with Waardenburg syndrome type 1.

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Morimoto, Noriko; Mutai, Hideki; Namba, Kazunori; Kaneko, Hiroki; Kosaki, Rika; Matsunaga, Tatsuo

2018-04-01

To examine and expand the genetic spectrum of Waardenburg syndrome type 1 (WS1). Clinical features related to Waardenburg syndrome (WS) were examined in a five-year old patient. Mutation analysis of genes related to WS was performed in the proband and her parents. Molecular modeling of EDNRB and the p.R319W mutant was conducted to predict the pathogenicity of the mutation. The proband showed sensorineural hearing loss, heterochromia iridis, and dystopia canthorum, fulfilling the clinical criteria of WS1. Genetic analyses revealed that the proband had no mutation in PAX3 which has been known as the cause of WS1, but had a homozygous missense mutation (p.R319W) in endothelin receptor type B (EDNRB) gene. The asymptomatic parents had the mutation in a heterozygote state. This mutation has been previously reported in a heterozygous state in a patient with Hirschsprung's disease unaccompanied by WS, but the patient and her parents did not show any symptoms in gastrointestinal tract. Molecular modeling of EDNRB with the p.R319W mutation demonstrated reduction of the positively charged surface area in this region, which might reduce binding ability of EDNRB to G protein and lead to abnormal signal transduction underlying the WS phenotype. Our findings suggested that autosomal recessive mutation in EDNRB may underlie a part of WS1 with the current diagnostic criteria, and supported that Hirschsprung's disease is a multifactorial genetic disease which requires additional factors. Further molecular analysis is necessary to elucidate the gene interaction and to reappraise the current WS classification. Copyright © 2017 Elsevier B.V. All rights reserved.

Microbial profile and critical control points during processing of 'robo ...

African Journals Online (AJOL)

Microbial profile and critical control points during processing of 'robo' snack from ... the relevant critical control points especially in relation to raw materials and ... to the quality of the various raw ingredients used were the roasting using earthen

Mutations Phe785Leu and Thr618Met in Na+, K+-ATPase, Associated with Familial Rapid-Onset Dystonia Parkinsonism, Interfere with Na+ Interaction by Distinct Mechanisms

DEFF Research Database (Denmark)

Schack, Vivien Rodacker; Toustrup-Jensen, Mads Schak; Vilsen, Bente

The Na+, K+-ATPase plays key roles in brain function. Recently, missense mutations in the Na+, K+-ATPase were found associated with familial rapid-onset dystonia parkinsonism (FRDP). Here, we have characterized the functional consequences of FRDP mutations Phe785Leu and Thr618Met. Both mutations...... lead to functionally altered, but active, Na+, K+-pumps that display reduced apparent affinity for cytoplasmic Na+, but the underlying mechanism differs between the mutants. In Phe785Leu, the interaction of the E1 form with Na+ is defective, and the E1-E2 equilibrium is not displaced. In Thr618Met......, the Na+ affinity is reduced because of displacement of the conformational equilibrium in favor of the K+-occluded E2(K2) form. In both mutants, K+ interaction at the external activating sites of the E2P phosphoenzyme is normal. The change of cellular Na+ homeostasis is likely a major factor contributing...

Mutations Phe785Leu and Thr618Met in Na+, K+-ATPase, Associated with Familial Rapid-Onset Dystonia Parkinsonism, Interfere with Na+ Interaction by Distinct Mechanisms

DEFF Research Database (Denmark)

Schack, Vivien Rodacker; Toustrup-Jensen, Mads Schak; Vilsen, Bente

The Na+, K+-ATPase plays key roles in brain function. Recently, missense mutations in the Na+, K+-ATPase were found associated with familial rapid-onset dystonia parkinsonism (FRDP). We have characterized the functional consequences of FRDP mutations Phe785Leu and Thr618Met. Both mutations lead...... to functionally altered, but active, Na+, K+-pumps that display reduced apparent affinity for cytoplasmic Na+, but the underlying mechanism differs between the mutants. In Phe785Leu, the interaction of the E1 form with Na+ is defective, and the E1-E2 equilibrium is not displaced. In Thr618Met, the Na+ affinity...... is reduced because of displacement of the conformational equilibrium in favor of the K+-occluded E2(K2) form. In both mutants, K+ interaction at the external activating sites of the E2P phosphoenzyme is normal. The change of cellular Na+ homeostasis is likely a major factor contributing to the development...

Spinning-Up: the Case of the Symbiotic X-Ray Binary 3A 1954+319

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Fuerst, F.; Marcu, D. M.; Pottschmidt, K.; Grinberg, V.; Wilms, J.; CadolleBel, M.

2011-01-01

We present a timing and spectral analysis of the variable X-ray source 3A 1954+319. Our analysis is mainly based on an outburst serendipitously observed during INTEGRAL Key Program observations of the Cygnus region in 2008 fall and on the Swift/BAT longterm light curve. Previous observations, though sparse, have identified the source to be one of only nine known symbiotic X-ray binaries, i.e., systems composed of an accreting neutron star orbiting in a highly inhomogeneous medium around an M-giant companion. The spectrum of3A 1954+319 above > 20 keV can be best described by a broken power law model. The extremely long pulse period of approx.5.3 hours is clearly visible in the INTEGRAL/ISGRI light curve and confirmed through an epoch folding period search. Furthermore, the light curve allows us to determine a very strong spin up of -2 x 10(exp -4) h/h during the outburst. This spin up is confirmed by the pulse period evolution calculated from Swift/BAT data. The Swift/BAT data also show a long spin-down trend prior to the 2008 outburst, which is confirmed in archival INTEGRAL/ISGRI data. We discuss possible accretion models and geometries allowing for the transfer of such large amounts of angular momentum and investigate the harder spectrum of this outburst compared to previously published results.

7 CFR 319.59-3 - Articles prohibited importation pending risk evaluation.

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2010-01-01

... 7 Agriculture 5 2010-01-01 2010-01-01 false Articles prohibited importation pending risk... Diseases § 319.59-3 Articles prohibited importation pending risk evaluation. The articles listed in...(b), pending the completion of an evaluation by APHIS of the potential pest risks associated with the...

Rescue of Na+ and H+ binding in Na+,K+-ATPase M8 aspartate mutants by secondary mutation

DEFF Research Database (Denmark)

Holm, Rikke; Einholm, Anja P.; Andersen, Jens Peter

A mutation replacing the aspartate in transmembrane segment M8 in the a3-isoform of Na,K-ATPase with asparagine has been found in patients with rapid-onset dystonia parkinsonism or alternating hemiplegia of childhood. This aspartate may be a critical Na+ coordinating residue, but the crystal......-isoforms of Na,K-ATPase, and much smaller effects were seen for other mutations to the M8 aspartate, which were less disruptive of Na+ binding than mutations to other residues related to Na+ site III. The D928 (rat a1 numbering) mutations strongly diminished the cooperativity of Na+ binding. Moreover the p......H optimum of Na,K-ATPase activity was left-shifted, again with D928N being most disruptive. The reduced affinity for activating Na+ and for inhibitory protons, caused by D928N and D928A mutations, could be rescued by introduction of an additional mutation of a glutamate located far away from D928....

Mutations in PIK3CA are infrequent in neuroblastoma

International Nuclear Information System (INIS)

Dam, Vincent; Morgan, Brian T; Mazanek, Pavel; Hogarty, Michael D

2006-01-01

Neuroblastoma is a frequently lethal pediatric cancer in which MYCN genomic amplification is highly correlated with aggressive disease. Deregulated MYC genes require co-operative lesions to foster tumourigenesis and both direct and indirect evidence support activated Ras signaling for this purpose in many cancers. Yet Ras genes and Braf, while often activated in cancer cells, are infrequent targets for activation in neuroblastoma. Recently, the Ras effector PIK3CA was shown to be activated in diverse human cancers. We therefore assessed PIK3CA for mutation in human neuroblastomas, as well as in neuroblastomas arising in transgenic mice with MYCN overexpressed in neural-crest tissues. In this murine model we additionally surveyed for Ras family and Braf mutations as these have not been previously reported. Sixty-nine human neuroblastomas (42 primary tumors and 27 cell lines) were sequenced for PIK3CA activating mutations within the C2, helical and kinase domain 'hot spots' where 80% of mutations cluster. Constitutional DNA was sequenced in cases with confirmed alterations to assess for germline or somatic acquisition. Additionally, Ras family members (Hras1, Kras2 and Nras) and the downstream effectors Pik3ca and Braf, were sequenced from twenty-five neuroblastomas arising in neuroblastoma-prone transgenic mice. We identified mutations in the PIK3CA gene in 2 of 69 human neuroblastomas (2.9%). Neither mutation (R524M and E982D) has been studied to date for effects on lipid kinase activity. Though both occurred in tumors with MYCN amplification the overall rate of PIK3CA mutations in MYCN amplified and single-copy tumors did not differ appreciably (2 of 31 versus 0 of 38, respectively). Further, no activating mutations were identified in a survey of Ras signal transduction genes (including Hras1, Kras2, Nras, Pik3ca, or Braf genes) in twenty-five neuroblastic tumors arising in the MYCN-initiated transgenic mouse model. These data suggest that activating

Use of the RoboFlag synthetic task environment to investigate workload and stress responses in UAV operation.

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Guznov, Svyatoslav; Matthews, Gerald; Funke, Gregory; Dukes, Allen

2011-09-01

Use of unmanned aerial vehicles (UAVs) is an increasingly important element of military missions. However, controlling UAVs may impose high stress and workload on the operator. This study evaluated the use of the RoboFlag simulated environment as a means for profiling multiple dimensions of stress and workload response to a task requiring control of multiple vehicles (robots). It tested the effects of two workload manipulations, environmental uncertainty (i.e., UAV's visual view area) and maneuverability, in 64 participants. The findings confirmed that the task produced substantial workload and elevated distress. Dissociations between the stress and performance effects of the manipulations confirmed the utility of a multivariate approach to assessment. Contrary to expectations, distress and some aspects of workload were highest in the low-uncertainty condition, suggesting that overload of information may be an issue for UAV interface designers. The strengths and limitations of RoboFlag as a methodology for investigating stress and workload responses are discussed.

Identification of a novel STAT3 mutation in a patient with hyper-IgE syndrome

DEFF Research Database (Denmark)

Mogensen, Trine H; Jakobsen, Marianne; Larsen, Carsten S

2013-01-01

Here we describe a patient with hyper-IgE syndrome presenting with recurrent staphylococcal abscesses, pneumonia, and chronic mucocutaneous candidiasis, and report the identification of a novel STAT3 mutation at amino acid position 621, which has not previously been described. In addition, we...

Hox paralog group 2 genes control the migration of mouse pontine neurons through slit-robo signaling.

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Marc J Geisen

2008-06-01

Full Text Available The pontine neurons (PN represent a major source of mossy fiber projections to the cerebellum. During mouse hindbrain development, PN migrate tangentially and sequentially along both the anteroposterior (AP and dorsoventral (DV axes. Unlike DV migration, which is controlled by the Netrin-1/Dcc attractive pathway, little is known about the molecular mechanisms guiding PN migration along the AP axis. Here, we show that Hoxa2 and Hoxb2 are required both intrinsically and extrinsically to maintain normal AP migration of subsets of PN, by preventing their premature ventral attraction towards the midline. Moreover, the migration defects observed in Hoxa2 and Hoxb2 mutant mice were phenocopied in compound Robo1;Robo2, Slit1;Slit2, and Robo2;Slit2 knockout animals, indicating that these guidance molecules act downstream of Hox genes to control PN migration. Indeed, using chromatin immunoprecipitation assays, we further demonstrated that Robo2 is a direct target of Hoxa2 in vivo and that maintenance of high Robo and Slit expression levels was impaired in Hoxa2 mutant mice. Lastly, the analysis of Phox2b-deficient mice indicated that the facial motor nucleus is a major Slit signaling source required to prevent premature ventral migration of PN. These findings provide novel insights into the molecular control of neuronal migration from transcription factor to regulation of guidance receptor and ligand expression. Specifically, they address the question of how exposure to multiple guidance cues along the AP and DV axes is regulated at the transcriptional level and in turn translated into stereotyped migratory responses during tangential migration of neurons in the developing mammalian brain.

Common FLG mutation K4671X not associated with atopic dermatitis in Han Chinese in a family association study.

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Ruhong Cheng

Full Text Available BACKGROUND: Filaggrin gene (FLG mutations have been identified as the cause of ichthyosis vulgaris (IV and major predisposing factors for atopic dermatitis (AD. The relationship among AD, IV and FLG mutations has not been clarified yet. Mutations 3321delA and K4671X, two of the most common mutations in Chinese patients, were both statistically associated with AD in case-control studies. MATERIALS AND METHODS: A group of 100 family trios (a total of 300 members with one affected AD proband and both parents were recruited and screened for three filaggrin null mutations (3222del4, 3321delA and K4671X. The subjects' manifestations of AD and IV were assessed by two experienced dermatologists and recorded in detail. The relationship of common mutations to AD were assessed using both case-control and family-based tests of association. Filaggrin expression was measured in skin of 3 subjects with K4671X heterozygote and the normal control using quantitative real-time RT-PCR and immunohistochemistry. RESULTS: Of 100 probands for AD, 22 were carriers for common FLG mutations and only 2 of them were from 40 none-IV family trios (5.00%, consistent with that of the healthy control group (3.99%, P>0.05. Significant statistical associations were revealed between AD and 3321delA (P<0.001, odds ratio 12.28, 95% confidence interval 3.35-44.98 as well as K4671X (P = 0.002, odds ratio 4.53, 95% confidence interval 1.77-11.60. The family-based approach revealed that 3321delA was over-transmitted to AD offspring from parents (T:U = 12∶1, P = 0.003 but failed to demonstrate transmission disequilibrium between K4671X and AD (T:U = 10∶8, P = 0.815. Moreover, compared to the normal control, filaggrin expression at both mRNA and protein levels in epidermis of subjects with K4671X(heter was not reduced. CONCLUSIONS: AD patients from none-IV family trios have low probability of carrying FLG mutations. The present family samples confirmed the

UvA Rescue - Team Description Paper - Infrastructure competition - Rescue Simulation League RoboCup 2014 - João Pessoa - Brazil

NARCIS (Netherlands)

Visser, A.

2014-01-01

The UvA Rescue Team has several innovative ideas to further improve the infrastructure of the RoboCup Rescue Simulation League. Those ideas range from providing USARSim an interface compatible with the RoboCup@Home Simulation, to provide the possibility to specify robots in the URDF format, to

Reduced H3K27me3 expression in Merkel cell polyoma virus-positive tumors.

Science.gov (United States)

Busam, Klaus J; Pulitzer, Melissa P; Coit, Daniel C; Arcila, Maria; Leng, Danielle; Jungbluth, Achim A; Wiesner, Thomas

2017-06-01

Merkel cell carcinoma is a primary cutaneous neuroendocrine carcinoma, which once metastatic is difficult to treat. Recent mutation analyses of Merkel cell carcinoma revealed a low number of mutations in Merkel cell polyomavirus-associated tumors, and a high number of mutations in virus-negative combined squamous cell and neuroendocrine carcinomas of chronically sun-damaged skin. We speculated that the paucity of mutations in virus-positive Merkel cell carcinoma may reflect a pathomechanism that depends on derangements of chromatin without alterations in the DNA sequence (epigenetic dysregulation). One central epigenetic regulator is the Polycomb repressive complex 2 (PRC2), which silences genomic regions by trimethylating (me3) lysine (K) 27 of histone H3, and thereby establishes the histone mark H3K27me3. Recent experimental research data demonstrated that PRC2 loss in mice skin results in the formation of Merkel cells. Prompted by these findings, we explored a possible contribution of PRC2 loss in human Merkel cell carcinoma. We examined the immunohistochemical expression of H3K27me3 in 35 Merkel cell carcinomas with pure histological features (22 primary and 13 metastatic lesions) and in 5 combined squamous and neuroendocrine carcinomas of the skin. We found a strong reduction of H3K27me3 staining in tumors with pure histologic features and virus-positive Merkel cell carcinomas. Combined neuroendocrine carcinomas had no or only minimal loss of H3K27me3 labeling. Our findings suggest that a PRC2-mediated epigenetic deregulation may play a role in the pathogenesis of virus-positive Merkel cell carcinomas and in tumors with pure histologic features.

PIK3CA mutations frequently coexist with RAS and BRAF mutations in patients with advanced cancers.

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Filip Janku

Full Text Available Oncogenic mutations of PIK3CA, RAS (KRAS, NRAS, and BRAF have been identified in various malignancies, and activate the PI3K/AKT/mTOR and RAS/RAF/MEK pathways, respectively. Both pathways are critical drivers of tumorigenesis.Tumor tissues from 504 patients with diverse cancers referred to the Clinical Center for Targeted Therapy at MD Anderson Cancer Center starting in October 2008 were analyzed for PIK3CA, RAS (KRAS, NRAS, and BRAF mutations using polymerase chain reaction-based DNA sequencing.PIK3CA mutations were found in 54 (11% of 504 patients tested; KRAS in 69 (19% of 367; NRAS in 19 (8% of 225; and BRAF in 31 (9% of 361 patients. PIK3CA mutations were most frequent in squamous cervical (5/14, 36%, uterine (7/28, 25%, breast (6/29, 21%, and colorectal cancers (18/105, 17%; KRAS in pancreatic (5/9, 56%, colorectal (49/97, 51%, and uterine cancers (3/20, 15%; NRAS in melanoma (12/40, 30%, and uterine cancer (2/11, 18%; BRAF in melanoma (23/52, 44%, and colorectal cancer (5/88, 6%. Regardless of histology, KRAS mutations were found in 38% of patients with PIK3CA mutations compared to 16% of patients with wild-type (wtPIK3CA (p = 0.001. In total, RAS (KRAS, NRAS or BRAF mutations were found in 47% of patients with PIK3CA mutations vs. 24% of patients wtPIK3CA (p = 0.001. PIK3CA mutations were found in 28% of patients with KRAS mutations compared to 10% with wtKRAS (p = 0.001 and in 20% of patients with RAS (KRAS, NRAS or BRAF mutations compared to 8% with wtRAS (KRAS, NRAS or wtBRAF (p = 0.001.PIK3CA, RAS (KRAS, NRAS, and BRAF mutations are frequent in diverse tumors. In a wide variety of tumors, PIK3CA mutations coexist with RAS (KRAS, NRAS and BRAF mutations.

Potyviral resistance derived from cultivars of Phaseolus vulgaris carrying bc-3 co-segregates with homozygotic presence of a mutated eIF4E allele

DEFF Research Database (Denmark)

Naderpour, M; Lund, O Søgaard; Larsen, R

2008-01-01

-binding proteins, eIF4E, eIF(iso)4E and nCBP. In cultivars reported to carry bc-3 resistance, eIF4E was found to display non-silent mutations at codons 53, 65, 76 and 111 closely resembling a pattern of eIF4E mutations determining potyvirus resistance in other plant species. By application of a molecular marker...

A novel missense HGD gene mutation, K57N, in a patient with alkaptonuria.

Science.gov (United States)

Grasko, Jonathan M; Hooper, Amanda J; Brown, Jeffrey W; McKnight, C James; Burnett, John R

2009-05-01

Alkaptonuria is a rare recessive disorder of phenylalanine/tyrosine metabolism due to a defect in the enzyme homogentisate 1,2-dioxygenase (HGD) caused by mutations in the HGD gene. We report the case of a 38 year-old male with known alkaptonuria who was referred to an adult metabolic clinic after initially presenting to an emergency department with renal colic and subsequently passing black ureteric calculi. He complained of severe debilitating lower back pain, worsening over the last few years. A CT scan revealed marked degenerative changes and severe narrowing of the disc spaces along the entire lumbar spine. Sequencing of the HGD gene revealed that he was a compound heterozygote for a previously described missense mutation in exon 13 (G360R) and a novel missense mutation in exon 3 (K57N). Lys(57) is conserved among species and mutation of this residue is predicted to affect HGD protein function by interfering with substrate traffic at the active site. In summary, we describe an alkaptonuric patient and report a novel missense HGD mutation, K57N.

New truncation mutation of the NR2E3 gene in a Japanese patient with enhanced S-cone syndrome.

Science.gov (United States)

Kuniyoshi, Kazuki; Hayashi, Takaaki; Sakuramoto, Hiroyuki; Mishima, Hiroshi; Tsuneoka, Hiroshi; Tsunoda, Kazushige; Iwata, Takeshi; Shimomura, Yoshikazu

2016-11-01

The enhanced S-cone syndrome (ESCS) is a rare hereditary retinal degeneration that has enhanced short wavelength-sensitive cone (S-cone) functions. The longitudinal clinical course of this disease has been rarely reported, and the genetic aspects of ESCS have not been well investigated in the Japanese population. In this report, we present our clinical and genetic findings for 2 patients with ESCS. The patients were 2 unrelated Japanese men. Standard ophthalmic examinations and mutation screening for the NR2E3 gene were performed. Patient 1 was a 36-year-old man, and his clinical findings were typical of ESCS. His decimal best-corrected visual acuity (BCVA) was 1.0 OD and 0.5 OS after removal of cataracts. Genetic investigations revealed a homozygous truncation frameshift, the p.I307LfsX33 mutation. Patient 2 was an 11-year-old boy when he was first examined by us. His clinical findings were typical of ESCS except for uveitis in the left eye. His decimal BCVA at the age of 39 years was maintained at 1.5 in each eye, although the retinal degeneration and visual field impairments had progressed during the follow-up period. The genetic investigations revealed homozygous mutations of p.R104Q in the NR2E3 gene. The frameshift mutation, p.I307LfsX33, in the NR2E3 gene is a new causative mutation for ESCS. The clinical observations for patient 2 are the longest ever reported. The retinal degeneration caused by this mutation is slowly progressive, and these patients maintained good vision with maintenance of the foveal structure until their late thirties.

Mutations in the DNA-binding domain of NR2E3 affect in vivo dimerization and interaction with CRX.

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Raphael Roduit

Full Text Available BACKGROUND: NR2E3 (PNR is an orphan nuclear receptor essential for proper photoreceptor determination and differentiation. In humans, mutations in NR2E3 have been associated with the recessively inherited enhanced short wavelength sensitive (S- cone syndrome (ESCS and, more recently, with autosomal dominant retinitis pigmentosa (adRP. NR2E3 acts as a suppressor of the cone generation program in late mitotic retinal progenitor cells. In adult rod photoreceptors, NR2E3 represses cone-specific gene expression and acts in concert with the transcription factors CRX and NRL to activate rod-specific genes. NR2E3 and CRX have been shown to physically interact in vitro through their respective DNA-binding domains (DBD. The DBD also contributes to homo- and heterodimerization of nuclear receptors. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed NR2E3 homodimerization and NR2E3/CRX complex formation in an in vivo situation by Bioluminescence Resonance Energy Transfer (BRET(2. NR2E3 wild-type protein formed homodimers in transiently transfected HEK293T cells. NR2E3 homodimerization was impaired in presence of disease-causing mutations in the DBD, except for the p.R76Q and p.R104W mutant proteins. Strikingly, the adRP-linked p.G56R mutant protein interacted with CRX with a similar efficiency to that of NR2E3 wild-type and p.R311Q proteins. In contrast, all other NR2E3 DBD-mutant proteins did not interact with CRX. The p.G56R mutant protein was also more effective in abolishing the potentiation of rhodospin gene transactivation by the NR2E3 wild-type protein. In addition, the p.G56R mutant enhanced the transrepression of the M- and S-opsin promoter, while all other NR2E3 DBD-mutants did not. CONCLUSIONS/SIGNIFICANCE: These results suggest different disease mechanisms in adRP- and ESCS-patients carrying NR2E3 mutations. Titration of CRX by the p.G56R mutant protein acting as a repressor in trans may account for the severe clinical phenotype in adRP patients.

Herramienta para la evaluación del riesgo de robo en el autotransporte de carga

Directory of Open Access Journals (Sweden)

Elizabeth De la Torre

2014-01-01

Full Text Available Introducción: En México el robo se ha convertido en uno de los riesgos más importantes para la eficiencia y la competitividad de las cadenas de suministro. Esta propuesta busca identificar las variables que influyen sobre el riesgo de robo en el autotransporte como paso previo de una metodología para evaluar cuantitativamente la influencia de las variables identificadas y crear una aplicación que permita evaluar el riesgo de robo, apoyando así a la toma de decisiones en la creación de esquemas de seguridad. Metodología: El proceso para identificar estas variables de riesgo fue el análisis estadístico de la información disponible de robos de carga mediante el método de Análisis de Componentes Principales, determinando un primer conjunto de variables de interés para el diseño de una encuesta que se aplicó a expertos en seguridad de la cadena de suministro empleando la metodología Delphi y estableciendo ponderaciones a través del Proceso de Jerarquización Analítica. Resultados: Con la metodología propuesta se obtuvieron los factores más relevantes en el riesgo de robo en el autotransporte y se construyó una función para obtener un índice del riesgo. La función propuesta se programó en una aplicación computacional que facilita el cálculo del indicador propuesto con información de pares origen-destino determinados. Los resultados de la metodología permitirán confirmar las variables usadas o identificar nuevas variables considerando las cuantificaciones de su influencia en el riesgo. Discusión y Conclusión: Obtener información confiable sobre robos de carga es muy difícil, por lo sensible del tema y la inexactitud de los datos publicados. Estas imprecisiones y las percepciones subjetivas asociadas se atenúan con esta metodología basada en opiniones de expertos y en las técnicas cuantitativas referidas para integrar el índice de riesgo propuesto. Este índice permite dimensionar y comparar estrategias de

Microstructural evolution and thixoformability of semi-solid aluminum 319s alloy during re-melting

International Nuclear Information System (INIS)

Hu, X.G.; Zhu, Q.; Lu, H.X.; Zhang, F.; Li, D.Q.; Midson, S.P.

2015-01-01

The aim of this paper is to characterize both microstructural evolution and thixoformability during partial melting of semi-solid 319s alloy. The thixoformability criteria of 319s was initially investigated by thermodynamic analysis. In-situ observation of partial re-melting was performed by a Confocal Laser Scanning Microscope to determine the effect of heating rate on melting characteristics. Meanwhile, the microstructural evolution of 319s alloy at extremely low heating rate was also investigated in order to understand the mechanism of re-melting process. The studies demonstrated that 319s alloy is suitable for thixocasting because of the controllable liquid fraction in the operating window of 15 °C. The process window was effected by both temperature and heating time. The primary particles evolution in 319s alloy can be divided into four stages, and the coarsening rate during isothermal test is 227 μm 3 /s. The effective method to obtain desirable microstructure is to manage the time in the semi-solid state by controlling heating rate and soaking time. - Highlights: • The thixoformability of 319s is discussed by using SPSC and thermodynamic analysis. • The re-melting processes at different heating rate are in-situ observed. • We identified the four stages of microstructural evolution during re-melting. • The coarsening rate K for 319s during isothermal test is identified. • The variation tendency of Si particle size with increasing time is reported

Exome Sequencing Identifies a Novel MAP3K14 Mutation in Recessive Atypical Combined Immunodeficiency

Directory of Open Access Journals (Sweden)

Nikola Schlechter

2017-11-01

Full Text Available Primary immunodeficiency disorders (PIDs render patients vulnerable to infection with a wide range of microorganisms and thus provide good in vivo models for the assessment of immune responses during infectious challenges. Priming of the immune system, especially in infancy, depends on different environmental exposures and medical practices. This may determine the timing and phenotype of clinical appearance of immune deficits as exemplified with early exposure to Bacillus Calmette-Guérin (BCG vaccination and dissemination in combined immunodeficiencies. Varied phenotype expression poses a challenge to identification of the putative immune deficit. Without the availability of genomic diagnosis and data analysis resources and with limited capacity for functional definition of immune pathways, it is difficult to establish a definitive diagnosis and to decide on appropriate treatment. This study describes the use of exome sequencing to identify a homozygous recessive variant in MAP3K14, NIKVal345Met, in a patient with combined immunodeficiency, disseminated BCG-osis, and paradoxically elevated lymphocytes. Laboratory testing confirmed hypogammaglobulinemia with normal CD19, but failed to confirm a definitive diagnosis for targeted treatment decisions. NIKVal345Met is predicted to be deleterious and pathogenic by two in silico prediction tools and is situated in a gene crucial for effective functioning of the non-canonical nuclear factor-kappa B signaling pathway. Functional analysis of NIKVal345Met- versus NIKWT-transfected human embryonic kidney-293T cells showed that this mutation significantly affects the kinase activity of NIK leading to decreased levels of phosphorylated IkappaB kinase-alpha (IKKα, the target of NIK. BCG-stimulated RAW264.7 cells transfected with NIKVal345Met also presented with reduced levels of phosphorylated IKKα, significantly increased p100 levels and significantly decreased p52 levels compared to cells transfected

The role of MAP4K3 in lifespan regulation of Caenorhabditiselegans

International Nuclear Information System (INIS)

Khan, Maruf H.; Hart, Matthew J.; Rea, Shane L.

2012-01-01

Highlights: ► Inhibition of MAP4K3 by RNAi leads to increased mean lifespan in Caenorhabditis elegans. ► Mutation in the citron homology domain of MAP4K3 leads to increased mean lifespan. ► Mutation in the kinase domain of MAP4K3 has no significant effect on mean lifespan. -- Abstract: The TOR pathway is a kinase signaling pathway that regulates cellular growth and proliferation in response to nutrients and growth factors. TOR signaling is also important in lifespan regulation – when this pathway is inhibited, either naturally, by genetic mutation, or by pharmacological means, lifespan is extended. MAP4K3 is a Ser/Thr kinase that has recently been found to be involved in TOR activation. Unexpectedly, the effect of this protein is not mediated via Rheb, the more widely known TOR activation pathway. Given the role of TOR in growth and lifespan control, we looked at how inhibiting MAP4K3 in Caenorhabditiselegans affects lifespan. We used both feeding RNAi and genetic mutants to look at the effect of MAP4K3 deficiency. Our results show a small but significant increase in mean lifespan in MAP4K3 deficient worms. MAP4K3 thus represents a new target in the TOR pathway that can be targeted for pharmacological intervention to control lifespan.

The role of MAP4K3 in lifespan regulation of Caenorhabditiselegans

Energy Technology Data Exchange (ETDEWEB)

Khan, Maruf H. [Barshop Institute for Longevity and Aging Studies, Department of Physiology, University of Texas Health Science Center, San Antonio, TX 78240 (United States); Hart, Matthew J., E-mail: HartMJ@uthscsa.edu [Barshop Institute for Longevity and Aging Studies, Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX 78240 (United States); Rea, Shane L., E-mail: reas3@uthscsa.edu [Barshop Institute for Longevity and Aging Studies, Department of Physiology, University of Texas Health Science Center, San Antonio, TX 78240 (United States)

2012-08-24

Highlights: Black-Right-Pointing-Pointer Inhibition of MAP4K3 by RNAi leads to increased mean lifespan in Caenorhabditis elegans. Black-Right-Pointing-Pointer Mutation in the citron homology domain of MAP4K3 leads to increased mean lifespan. Black-Right-Pointing-Pointer Mutation in the kinase domain of MAP4K3 has no significant effect on mean lifespan. -- Abstract: The TOR pathway is a kinase signaling pathway that regulates cellular growth and proliferation in response to nutrients and growth factors. TOR signaling is also important in lifespan regulation - when this pathway is inhibited, either naturally, by genetic mutation, or by pharmacological means, lifespan is extended. MAP4K3 is a Ser/Thr kinase that has recently been found to be involved in TOR activation. Unexpectedly, the effect of this protein is not mediated via Rheb, the more widely known TOR activation pathway. Given the role of TOR in growth and lifespan control, we looked at how inhibiting MAP4K3 in Caenorhabditiselegans affects lifespan. We used both feeding RNAi and genetic mutants to look at the effect of MAP4K3 deficiency. Our results show a small but significant increase in mean lifespan in MAP4K3 deficient worms. MAP4K3 thus represents a new target in the TOR pathway that can be targeted for pharmacological intervention to control lifespan.

Structural Analysis of a Vehicle Dynamics Model for Fault Detection and Isolation on the ROboMObil

OpenAIRE

Ho, Lok Man

2013-01-01

The ROboMObil, a mobility prototype under development at the DLR, differs from most current road vehicles with its high degree of overactuation with regards to the vehicle dynamics. This is due to the independent traction motor drives and steering actuators in each wheel, as well as one brake-by-wire actuator for each axle. Together with the large number of sensors, these provide opportunities for control and also lead to challenges for fault detection and isolation. In this study, the ROboMO...

Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors

DEFF Research Database (Denmark)

Goriely, Anne; Hansen, Ruth M S; Taylor, Indira B

2009-01-01

Genes mutated in congenital malformation syndromes are frequently implicated in oncogenesis, but the causative germline and somatic mutations occur in separate cells at different times of an organism's life. Here we unify these processes to a single cellular event for mutations arising in male germ...... cells that show a paternal age effect. Screening of 30 spermatocytic seminomas for oncogenic mutations in 17 genes identified 2 mutations in FGFR3 (both 1948A>G, encoding K650E, which causes thanatophoric dysplasia in the germline) and 5 mutations in HRAS. Massively parallel sequencing of sperm DNA...... a common 'selfish' pathway supporting proliferation in the testis, leading to diverse phenotypes in the next generation including fetal lethality, congenital syndromes and cancer predisposition....

Mutation and genomic amplification of the PIK3CA proto-oncogene in pituitary adenomas

International Nuclear Information System (INIS)

Murat, C.B.; Braga, P.B.S.; Fortes, M.A.H.Z.; Bronstein, M.D.; Corrêa-Giannella, M.L.C.; Giorgi, R.R.

2012-01-01

The tumorigenesis of pituitary adenomas is poorly understood. Mutations of the PIK3CA proto-oncogene, which encodes the p110-α catalytic subunit of PI3K, have been reported in various types of human cancers regarding the role of the gene in cell proliferation and survival through activation of the PI3K/Akt signaling pathway. Only one Chinese study described somatic mutations and amplification of the PIK3CA gene in a large series of pituitary adenomas. The aim of the present study was to determine genetic alterations of PIK3CA in a second series that consisted of 33 pituitary adenomas of different subtypes diagnosed by immunohistochemistry: 6 adrenocorticotropic hormone-secreting microadenomas, 5 growth hormone-secreting macroadenomas, 7 prolactin-secreting macroadenomas, and 15 nonfunctioning macroadenomas. Direct sequencing of exons 9 and 20 assessed by qPCR was employed to investigate the presence of mutations and genomic amplification defined as a copy number ≥4. Previously identified PIK3CA mutations (exon 20) were detected in four cases (12.1%). Interestingly, the Chinese study reported mutations only in invasive tumors, while we found a PIK3CA mutation in one noninvasive corticotroph microadenoma. PIK3CA amplification was observed in 21.2% (7/33) of the cases. This study demonstrates the presence of somatic mutations and amplifications of the PIK3CA gene in a second series of pituitary adenomas, corroborating the previously described involvement of the PI3K/Akt signaling pathway in the tumorigenic process of this gland

Mutation and genomic amplification of the PIK3CA proto-oncogene in pituitary adenomas

Energy Technology Data Exchange (ETDEWEB)

Murat, C.B.; Braga, P.B.S.; Fortes, M.A.H.Z. [Laboratório de Endocrinologia Celular e Molecular (LIM-25), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Bronstein, M.D. [Unidade de Neuroendocrinologia, Serviço de Endocrinologia, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Corrêa-Giannella, M.L.C.; Giorgi, R.R. [Laboratório de Endocrinologia Celular e Molecular (LIM-25), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil)

2012-07-13

The tumorigenesis of pituitary adenomas is poorly understood. Mutations of the PIK3CA proto-oncogene, which encodes the p110-α catalytic subunit of PI3K, have been reported in various types of human cancers regarding the role of the gene in cell proliferation and survival through activation of the PI3K/Akt signaling pathway. Only one Chinese study described somatic mutations and amplification of the PIK3CA gene in a large series of pituitary adenomas. The aim of the present study was to determine genetic alterations of PIK3CA in a second series that consisted of 33 pituitary adenomas of different subtypes diagnosed by immunohistochemistry: 6 adrenocorticotropic hormone-secreting microadenomas, 5 growth hormone-secreting macroadenomas, 7 prolactin-secreting macroadenomas, and 15 nonfunctioning macroadenomas. Direct sequencing of exons 9 and 20 assessed by qPCR was employed to investigate the presence of mutations and genomic amplification defined as a copy number ≥4. Previously identified PIK3CA mutations (exon 20) were detected in four cases (12.1%). Interestingly, the Chinese study reported mutations only in invasive tumors, while we found a PIK3CA mutation in one noninvasive corticotroph microadenoma. PIK3CA amplification was observed in 21.2% (7/33) of the cases. This study demonstrates the presence of somatic mutations and amplifications of the PIK3CA gene in a second series of pituitary adenomas, corroborating the previously described involvement of the PI3K/Akt signaling pathway in the tumorigenic process of this gland.

Perspectiva psicosocial en adolescentes acusados por delitos contra la salud y robo

Directory of Open Access Journals (Sweden)

José Guadalupe Salazar Estrada

2009-01-01

Full Text Available Nuestro objetivo en este estudio es identificar condiciones de vida de los sujetos adolescentes acusados de cometer delitos contra la salud y robo, desde una perspectiva psicosocial. Se estudiaron un total de 122 expedientes, de los cuales el 50% son acusados y acusadas por delitos contra la salud, y el otro 50% por robo; el 70% de los hombres y el 68.2% de las mujeres han consumido un tipo drogas, un 66 % del total de la muestra presentó poca tolerancia a la frustración, el 60 % tiene un manejo inadecuado de la afectividad, con una diferencia significativa cuando se estudia por tipo de delito. Entre las diferencias encontradas, las condiciones psicológicas como la personalidad, están más asociadas a la delincuencia juvenil.

Mutations in Plasmodium falciparum K13 propeller gene from Bangladesh (2009–2013)

OpenAIRE

Mohon, Abu Naser; Alam, Mohammad Shafiul; Bayih, Abebe Genetu; Folefoc, Asongna; Shahinas, Dea; Haque, Rashidul; Pillai, Dylan R

2014-01-01

Background Bangladesh is a malaria hypo-endemic country sharing borders with India and Myanmar. Artemisinin combination therapy (ACT) remains successful in Bangladesh. An increase of artemisinin-resistant malaria parasites on the Thai-Cambodia and Thai-Myanmar borders is worrisome. K13 propeller gene (PF3D7_1343700 or PF13_0238) mutations have been linked to both in vitro artemisinin resistance and in vivo slow parasite clearance rates. This group undertook to evaluate if mutations seen in Ca...

RoboCup@Home Scientific Competition and Benchmarking for Domestic Service Robots

NARCIS (Netherlands)

Wisspeintner, Thomas; van der Zant, Tijn; Iocchi, Luca; Schiffer, Stefan

2009-01-01

Being part of the RoboCup initiative, the ROBOCUP@HOME league targets the development and deployment of autonomous service and assistive robot technology being essential for future personal domestic applications. The domain of domestic service and assistive robotics implicates a wide range of

[Mutation analysis of FGFR3 gene in a family featuring hereditary dwarfism].

Science.gov (United States)

Zhang, Qiong; Jiang, Hai-ou; Quan, Qing-li; Li, Jun; He, Ting; Huang, Xue-shuang

2011-12-01

To investigate the clinical symptoms and potential mutation in FGFR3 gene for a family featuring hereditary dwarfism in order to attain diagnosis and provide prenatal diagnosis. Five patients and two unaffected relatives from the family, in addition with 100 healthy controls, were recruited. Genome DNA was extracted. Exons 10 and 13 of the FGFR3 gene were amplified using polymerase chain reaction (PCR). PCR products were sequenced in both directions. All patients had similar features including short stature, short limbs, lumbar hyperlordosis but normal craniofacial features. A heterozygous mutation G1620T (N540K) was identified in the cDNA from all patients but not in the unaffected relatives and 100 control subjects. A heterozygous G380R mutation was excluded. The hereditary dwarfism featured by this family has been caused by hypochondroplasia (HCH) due to a N540K mutation in the FGFR3 gene.

On the effect of hyperaldosteronism-inducing mutations in Na/K pumps.

Science.gov (United States)

Meyer, Dylan J; Gatto, Craig; Artigas, Pablo

2017-11-06

Primary aldosteronism, a condition in which too much aldosterone is produced and that leads to hypertension, is often initiated by an aldosterone-producing adenoma within the zona glomerulosa of the adrenal cortex. Somatic mutations of ATP1A1, encoding the Na/K pump α1 subunit, have been found in these adenomas. It has been proposed that a passive inward current transported by several of these mutant pumps is a "gain-of-function" activity that produces membrane depolarization and concomitant increases in aldosterone production. Here, we investigate whether the inward current through mutant Na/K pumps is large enough to induce depolarization of the cells that harbor them. We first investigate inward currents induced by these mutations in Xenopus Na/K pumps expressed in Xenopus oocytes and find that these inward currents are similar in amplitude to wild-type outward Na/K pump currents. Subsequently, we perform a detailed functional evaluation of the human Na/K pump mutants L104R, delF100-L104, V332G, and EETA963S expressed in Xenopus oocytes. By combining two-electrode voltage clamp with [ 3 H]ouabain binding, we measure the turnover rate of these inward currents and compare it to the turnover rate for outward current through wild-type pumps. We find that the turnover rate of the inward current through two of these mutants (EETA963S and L104R) is too small to induce significant cell depolarization. Electrophysiological characterization of another hyperaldosteronism-inducing mutation, G99R, reveals the absence of inward currents under many different conditions, including in the presence of the regulator FXYD1 as well as with mammalian ionic concentrations and body temperatures. Instead, we observe robust outward currents, but with significantly reduced affinities for intracellular Na + and extracellular K + Collectively, our results point to loss-of-function as the common mechanism for the hyperaldosteronism induced by these Na/K pump mutants. © 2017 Meyer et al.

31 CFR 538.319 - U.S. registered money transmitter.

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false U.S. registered money transmitter. 538.319 Section 538.319 Money and Finance: Treasury Regulations Relating to Money and Finance... General Definitions § 538.319 U.S. registered money transmitter. The term U.S. registered money...

CRUSER 2015, TechCon, Robots in the Roses, Robo-Ethics [video

OpenAIRE

2015-01-01

CRUSER 2015 events Technical Consortium Robots in the Roses Robo-Ethics Ray Buettner, CRUSER Director Tim Chung, CRUSER Deputy Director LT Raymond Davis, Systems Engineering student LT Patrick Livesay, Systems Engineering student LT Eric Beaty, National Security Affairs student Matt Kiefer, recent distance learning graduate

The wavy Mutation Maps to the Inositol 1,4,5-Trisphosphate 3-Kinase 2 (IP3K2) Gene of Drosophila and Interacts with IP3R to Affect Wing Development.

Science.gov (United States)

Dean, Derek M; Maroja, Luana S; Cottrill, Sarah; Bomkamp, Brent E; Westervelt, Kathleen A; Deitcher, David L

2015-11-27

Inositol 1,4,5-trisphosphate (IP3) regulates a host of biological processes from egg activation to cell death. When IP3-specific receptors (IP3Rs) bind to IP3, they release calcium from the ER into the cytoplasm, triggering a variety of cell type- and developmental stage-specific responses. Alternatively, inositol polyphosphate kinases can phosphorylate IP3; this limits IP3R activation by reducing IP3 levels, and also generates new signaling molecules altogether. These divergent pathways draw from the same IP3 pool yet cause very different cellular responses. Therefore, controlling the relative rates of IP3R activation vs. phosphorylation of IP3 is essential for proper cell functioning. Establishing a model system that sensitively reports the net output of IP3 signaling is crucial for identifying the controlling genes. Here we report that mutant alleles of wavy (wy), a classic locus of the fruit fly Drosophila melanogaster, map to IP3 3-kinase 2 (IP3K2), a member of the inositol polyphosphate kinase gene family. Mutations in wy disrupt wing structure in a highly specific pattern. RNAi experiments using GAL4 and GAL80(ts) indicated that IP3K2 function is required in the wing discs of early pupae for normal wing development. Gradations in the severity of the wy phenotype provide high-resolution readouts of IP3K2 function and of overall IP3 signaling, giving this system strong potential as a model for further study of the IP3 signaling network. In proof of concept, a dominant modifier screen revealed that mutations in IP3R strongly suppress the wy phenotype, suggesting that the wy phenotype results from reduced IP4 levels, and/or excessive IP3R signaling. Copyright © 2016 Dean et al.

The wavy Mutation Maps to the Inositol 1,4,5-Trisphosphate 3-Kinase 2 (IP3K2 Gene of Drosophila and Interacts with IP3R to Affect Wing Development

Directory of Open Access Journals (Sweden)

Derek M. Dean

2016-02-01

Full Text Available Inositol 1,4,5-trisphosphate (IP3 regulates a host of biological processes from egg activation to cell death. When IP3-specific receptors (IP3Rs bind to IP3, they release calcium from the ER into the cytoplasm, triggering a variety of cell type- and developmental stage-specific responses. Alternatively, inositol polyphosphate kinases can phosphorylate IP3; this limits IP3R activation by reducing IP3 levels, and also generates new signaling molecules altogether. These divergent pathways draw from the same IP3 pool yet cause very different cellular responses. Therefore, controlling the relative rates of IP3R activation vs. phosphorylation of IP3 is essential for proper cell functioning. Establishing a model system that sensitively reports the net output of IP3 signaling is crucial for identifying the controlling genes. Here we report that mutant alleles of wavy (wy, a classic locus of the fruit fly Drosophila melanogaster, map to IP3 3-kinase 2 (IP3K2, a member of the inositol polyphosphate kinase gene family. Mutations in wy disrupt wing structure in a highly specific pattern. RNAi experiments using GAL4 and GAL80ts indicated that IP3K2 function is required in the wing discs of early pupae for normal wing development. Gradations in the severity of the wy phenotype provide high-resolution readouts of IP3K2 function and of overall IP3 signaling, giving this system strong potential as a model for further study of the IP3 signaling network. In proof of concept, a dominant modifier screen revealed that mutations in IP3R strongly suppress the wy phenotype, suggesting that the wy phenotype results from reduced IP4 levels, and/or excessive IP3R signaling.

The glucocerobrosidase E326K variant predisposes to Parkinson's disease, but does not cause Gaucher's disease.

Science.gov (United States)

Duran, Raquel; Mencacci, Niccolo E; Angeli, Aikaterini V; Shoai, Maryam; Deas, Emma; Houlden, Henry; Mehta, Atul; Hughes, Derralynn; Cox, Timothy M; Deegan, Patrick; Schapira, Anthony H; Lees, Andrew J; Limousin, Patricia; Jarman, Paul R; Bhatia, Kailash P; Wood, Nicholas W; Hardy, John; Foltynie, Tom

2013-02-01

Heterozygous loss-of-function mutations in the acid beta-glucocerebrosidase (GBA1) gene, responsible for the recessive lysosomal storage disorder, Gaucher's disease (GD), are the strongest known risk factor for Parkinson's disease (PD). Our aim was to assess the contribution of GBA1 mutations in a series of early-onset PD. One hundred and eighty-five PD patients (with an onset age of ≤50) and 283 age-matched controls were screened for GBA1 mutations by Sanger sequencing. We show that the frequency of GBA1 mutations is much higher in this patient series than in typical late-onset patient cohorts. Furthermore, our results reveal that the most prevalent PD-associated GBA1 mutation is E326K, a variant that does not, when homozygous, cause GD. Our results confirm recent reports that the mutation, E326K, predisposes to PD and suggest that, in addition to reduced GBA1 activity, other molecular mechanisms may contribute to the development of the disease. Copyright © 2012 Movement Disorders Society.

Tech United Eindhoven, winner RoboCup 2014 MSL : Middle Size League

NARCIS (Netherlands)

Lopez Martinez, C.; Schoenmakers, F.; Naus, G.; Meessen, K.; Douven, Y.; van de Loo, H.; Bruijnen, D.J.H.; Aangenent, W.; Groenen, J.P.J.; van Ninhuijs, B.; Briegel, M.; Hoogendijk, R.; van Brakel, P.; Van Den Berg, R.; Hendriks, O.; Arts, R.R.M.J.W.; Botden, F.J.B.M.; Houtman, W.; van 't Klooster, M.E.; van der Velden, J.R.; Beeren, C.; de Koning, C.K.M.; Klooster, O.F.C.; Soetens, R.; van de Molengraft, R.; Bianchi, R.A.C.; Levent Akin, H.; Ramamoorthy, S.; Sugiura, K.

2015-01-01

In this paper we discuss improvements in mechanical, electrical and software design, which we did to become RoboCup 2014 world champion. Regarding hardware and control our progress includes first steps towards improved passing accuracy via velocity feedback control on the shooting lever. In terms of

Measurement of the $K_{L} \\to e^{+}e^{-}e^{+} e^{-}$ Decay Rate

CERN Document Server

Lai, A; Marras, D; Batley, J Richard; Dosanjh, R S; Gershon, T J; Kalmus, George Ernest; Lazzeroni, C; Munday, D J; Olaiya, E; Parker, M A; White, T O; Wotton, S A; Arcidiacono, R; Barr, G; Bocquet, G; Ceccucci, Augusto; Çuhadar-Dönszelmann, T; Cundy, Donald C; Doble, Niels T; Falaleev, V P; Gatignon, L; Gonidec, A; Gorini, B; Grafström, P; Kubischta, Werner; Lacourt, A; Norton, A; Panzer-Steindel, B; Tatishvili, G T; Wahl, H; Cheshkov, C; Khristov, P Z; Kekelidze, V D; Madigozhin, D T; Molokanova, N A; Potrebenikov, Yu K; Zinchenko, A I; Martin, V; Rubin, P; Sacco, R; Walker, A; Contalbrigo, M; Dalpiaz, Pietro; Duclos, J; Frabetti, P L; Gianoli, A; Martini, M; Petrucci, F; Savrié, M; Bizzeti, A; Calvetti, M; Collazuol, G; Graziani, G; Iacopini, E; Lenti, M; Martelli, F; Veltri, M; Eppard, M; Hirstius, A; Holtz, K; Kleinknecht, K; Koch, U; Köpke, L; Lopes da Silva, P; Marouelli, P; Mestvirishvili, I; Pellmann, I A; Peters, A; Schmidt, S A; Schönharting, V; Schué, Yu; Wanke, R; Winhart, A; Wittgen, M; Chollet, J C; Fayard, Louis; Iconomidou-Fayard, L; Unal, G; Wingerter-Seez, I; Anzivino, Giuseppina; Cenci, P; Imbergamo, E; Lubrano, P; Mestvirishvili, A; Nappi, A; Pepé, M; Piccini, M; Casali, R; Cerri, C; Cirilli, M; Costantini, F; Fantechi, R; Fiorini, Luca; Giudici, Sergio; Mannelli, I; Pierazzini, G M; Sozzi, M; Chèze, J B; De Beer, M; Debu, P; Derue, F; Formica, A; Granier de Cassagnac, R; Gouge, G; Marel, Gérard; Mazzucato, E; Peyaud, B; Turlay, René; Vallage, B; Holder, M; Maier, A; Ziolkowski, M; Biino, C; Cartiglia, N; Marchetto, F; Menichetti, E; Pastrone, N; Nassalski, J P; Rondio, Ewa; Szleper, M; Wislicki, W; Wronka, S; Dibon, Heinz; Jeitler, Manfred; Markytan, Manfred; Mikulec, I; Neuhofer, Günther; Pernicka, Manfred; Taurok, Anton; Widhalm, L; Beavis, D; Besliu, C; Budick, B; Bøggild, H; Chasman, C; Christensen, C H; Christiansen, P; Cibor, J; Debbe, R; Enger, E; Gaardhøje, J J; Germinario, M; Hagel, K; Ito, H; Jipa, A; Jundt, F; Jordre, J I; Jorgensen, C E; Karabowicz, R; Kim, E J; Kozik, T; Larsen, T M; Lee, J H; Lee, Y K; Lindal, S; Lystad, R; Løvhøiden, G; Majka, Z; Makeev, A; Mikelsen, M; Murray, M; Natowitz, J B; Neumann, B; Nielsen, B S; Ouerdane, D; Planeta, R; Rami, F; Ristea, C; Ristea, O; Röhrich, D; Samset, B H; Sandberg, D; Sanders, S J; Scheetz, R A; Staszel, P; Tveter, T S; Videbaek, F; Wada, R; Yin, Z; Zgura, I S

2005-01-01

The decay rate of the long-lived neutral K meson into the e^+ e^- e^+ e^- final state has been measured with the NA48 detector at the CERN SPS. Using data collected in 1998 and 1999, a total of 200 events has been observed with negligible background. This observation corresponds to a branching ratio of Br(K_L -> e^+ e^- e^+ e^-) = (3.30 + - 0.24_stat + - 0.23_sys + - 0.10_norm) x 10^-8.

Concurrent mutation in exons 1 and 2 of the K-ras oncogene in colorectal cancer

Directory of Open Access Journals (Sweden)

Fiorella Guadagni

2012-01-01

Full Text Available The K-ras gene is frequently mutated in colorectal cancer and has been associated with tumor initiation and progression; approximately 90% of the activating mutations are found in codons 12 and 13 of exon 1 and just under 5% in codon 61 located in exon 2. These mutations determine single aminoacidic substitutions in the GTPase pocket leading to a block of the GTP hydrolytic activity of the K-ras p21 protein, and therefore to its constitutive activation. Point mutations in sites of the K-ras gene, other than codons 12, 13 and 61, and other types of genetic alterations, may occur in a minority of cases, such as in the less frequent cases of double mutations in the K-ras gene. However, all mutations in this gene, even those which occur in non-canonical sites or double mutations, are relevant oncogenic alterations in colorectal cancer and may underlie K-ras pathway hyperactivation. In the present study, we report the case of a patient with colorectal cancer presenting a concurrent point mutation in exons 1 and 2 of the K-ras gene, a GGT to TGT substitution (Glycine to Cysteine at codon 12, and a GAC to AAC substitution (Aspartic Acid to Asparagine at codon 57. In addition, we found in the same patient’s sample a silent polymorphism at codon 11 (Ala11Ala of exon 1. (Folia Histochemica et Cytobiologica 2011; Vol. 49, No. 4, pp. 729–733

Up-regulation of Robo1 in dorsal root ganglia after sciatic nerve ...

African Journals Online (AJOL)

Yomi

2012-01-05

Jan 5, 2012 ... bers of the immunoglobulin superfamily of cell adhesion molecules (CAM). .... 20 g) were used (Xiangya Center of Experimental Animals, Central .... Expression of Robo1 was detected in large (25 to 40 µm), medium (25 to 15 ...

High-throughput genotyping in metastatic esophageal squamous cell carcinoma identifies phosphoinositide-3-kinase and BRAF mutations.

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Chi Hoon Maeng

Full Text Available Given the high incidence of metastatic esophageal squamous cell carcinoma, especially in Asia, we screened for the presence of somatic mutations using OncoMap platform with the aim of defining subsets of patients who may be potential candidate for targeted therapy.We analyzed 87 tissue specimens obtained from 80 patients who were pathologically confirmed with esophageal squamous cell carcinoma and received 5-fluoropyrimidine/platinum-based chemotherapy. OncoMap 4.0, a mass-spectrometry based assay, was used to interrogate 471 oncogenic mutations in 41 commonly mutated genes. Tumor specimens were prepared from primary cancer sites in 70 patients and from metastatic sites in 17 patients. In order to test the concordance between primary and metastatic sites from the patient for mutations, we analyzed 7 paired (primary-metastatic specimens. All specimens were formalin-fixed paraffin embedded tissues and tumor content was >70%.In total, we have detected 20 hotspot mutations out of 80 patients screened. The most frequent mutation was PIK3CA mutation (four E545K, five H1047R and one H1047L (N = 10, 11.5% followed by MLH1 V384D (N = 7, 8.0%, TP53 (R306, R175H and R273C (N = 3, 3.5%, BRAF V600E (N = 1, 1.2%, CTNNB1 D32N (N = 1, 1.2%, and EGFR P733L (N = 1, 1.2%. Distributions of somatic mutations were not different according to anatomic sites of esophageal cancer (cervical/upper, mid, lower. In addition, there was no difference in frequency of mutations between primary-metastasis paired samples.Our study led to the detection of potentially druggable mutations in esophageal SCC which may guide novel therapies in small subsets of esophageal cancer patients.

Mutations in galactosemia

Energy Technology Data Exchange (ETDEWEB)

Reichardt, J.K.V. [Univ. of Southern California School of Medicine, Los Angeles, CA (United States)

1995-10-01

This Letter raises four issues concerning two papers on galactosemia published in the March 1995 of the Journal. First, table 2 in the paper by Elsas et al. incorrectly attributes seven galactose-l-phosphate uridyl transferase (GALT) mutations (S135L, L195P, K285N, N314D, R333W, R333G, and K334R). The table also fails to mention that others have reported the same two findings attributed to {open_quotes}Leslie et al.; Elsas et al. and in press{close_quotes} and {open_quotes}Leslie et al.; Elsas et al.{close_quotes} The first finding on the prevalence of the Q188R galactosemia mutation in the G/G Caucasian population has also been described by Ng et al., and the second finding on the correlation of the N314D GALT mutation with the Duarte variant was reported by Lin et al. Second, Elsas et al. suggest that the E203K and N314D mutations may {open_quotes}produce intra-allelic complementation when in cis{close_quotes}. This speculation is supported by the activity data of individual III-2 but is inconsistent with the activities of three other individuals I-1, II-1, and III-1 of the same pedigree. The GALT activity measured in these three individuals suggests a dominant negative effect of E203K in E203K-N314D chromosomes, since they all have less than normal activity. Thus, the preponderance of the data in this paper is at odds with the authors speculation. It is worth recalling that Lin et al. also identified four N314D GALT mutations on 95 galactosemic chromosomes examined. A similar situation also appears to be the case in proband III-1 (with genotype E203K-N314D/IVSC) in the Elsas et al. paper. 9 refs.

NR2E3 mutations in enhanced S-cone sensitivity syndrome (ESCS), Goldmann-Favre syndrome (GFS), clumped pigmentary retinal degeneration (CPRD), and retinitis pigmentosa (RP).

Science.gov (United States)

Schorderet, Daniel F; Escher, Pascal

2009-11-01

NR2E3, also called photoreceptor-specific nuclear receptor (PNR), is a transcription factor of the nuclear hormone receptor superfamily whose expression is uniquely restricted to photoreceptors. There, its physiological activity is essential for proper rod and cone photoreceptor development and maintenance. Thirty-two different mutations in NR2E3 have been identified in either homozygous or compound heterozygous state in the recessively inherited enhanced S-cone sensitivity syndrome (ESCS), Goldmann-Favre syndrome (GFS), and clumped pigmentary retinal degeneration (CPRD). The clinical phenotype common to all these patients is night blindness, rudimental or absent rod function, and hyperfunction of the "blue" S-cones. A single p.G56R mutation is inherited in a dominant manner and causes retinitis pigmentosa (RP). We have established a new locus-specific database for NR2E3 (www.LOVD.nl/eye), containing all reported mutations, polymorphisms, and unclassified sequence variants, including novel ones. A high proportion of mutations are located in the evolutionarily-conserved DNA-binding domains (DBDs) and ligand-binding domains (LBDs) of NR2E3. Based on homology modeling of these NR2E3 domains, we propose a structural localization of mutated residues. The high variability of clinical phenotypes observed in patients affected by NR2E3-linked retinal degenerations may be caused by different disease mechanisms, including absence of DNA-binding, altered interactions with transcriptional coregulators, and differential activity of modifier genes.

ATP1A3 Mutation in Adult Rapid-Onset Ataxia.

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Kathleen J Sweadner

Full Text Available A 21-year old male presented with ataxia and dysarthria that had appeared over a period of months. Exome sequencing identified a de novo missense variant in ATP1A3, the gene encoding the α3 subunit of Na,K-ATPase. Several lines of evidence suggest that the variant is causative. ATP1A3 mutations can cause rapid-onset dystonia-parkinsonism (RDP with a similar age and speed of onset, as well as severe diseases of infancy. The patient's ATP1A3 p.Gly316Ser mutation was validated in the laboratory by the impaired ability of the expressed protein to support the growth of cultured cells. In a crystal structure of Na,K-ATPase, the mutated amino acid was directly apposed to a different amino acid mutated in RDP. Clinical evaluation showed that the patient had many characteristics of RDP, however he had minimal fixed dystonia, a defining symptom of RDP. Successive magnetic resonance imaging (MRI revealed progressive cerebellar atrophy, explaining the ataxia. The absence of dystonia in the presence of other RDP symptoms corroborates other evidence that the cerebellum contributes importantly to dystonia pathophysiology. We discuss the possibility that a second de novo variant, in ubiquilin 4 (UBQLN4, a ubiquitin pathway component, contributed to the cerebellar neurodegenerative phenotype and differentiated the disease from other manifestations of ATP1A3 mutations. We also show that a homozygous variant in GPRIN1 (G protein-regulated inducer of neurite outgrowth 1 deletes a motif with multiple copies and is unlikely to be causative.

Robo-AO Kepler Survey. IV. The Effect of Nearby Stars on 3857 Planetary Candidate Systems

Science.gov (United States)

Ziegler, Carl; Law, Nicholas M.; Baranec, Christoph; Riddle, Reed; Duev, Dmitry A.; Howard, Ward; Jensen-Clem, Rebecca; Kulkarni, S. R.; Morton, Tim; Salama, Maïssa

2018-04-01

We present the overall statistical results from the Robo-AO Kepler planetary candidate survey, comprising of 3857 high-angular resolution observations of planetary candidate systems with Robo-AO, an automated laser adaptive optics system. These observations reveal previously unknown nearby stars blended with the planetary candidate host stars that alter the derived planetary radii or may be the source of an astrophysical false positive transit signal. In the first three papers in the survey, we detected 440 nearby stars around 3313 planetary candidate host stars. In this paper, we present observations of 532 planetary candidate host stars, detecting 94 companions around 88 stars; 84 of these companions have not previously been observed in high resolution. We also report 50 more-widely separated companions near 715 targets previously observed by Robo-AO. We derive corrected planetary radius estimates for the 814 planetary candidates in systems with a detected nearby star. If planetary candidates are equally likely to orbit the primary or secondary star, the radius estimates for planetary candidates in systems with likely bound nearby stars increase by a factor of 1.54, on average. We find that 35 previously believed rocky planet candidates are likely not rocky due to the presence of nearby stars. From the combined data sets from the complete Robo-AO KOI survey, we find that 14.5 ± 0.5% of planetary candidate hosts have a nearby star with 4″, while 1.2% have two nearby stars, and 0.08% have three. We find that 16% of Earth-sized, 13% of Neptune-sized, 14% of Saturn-sized, and 19% of Jupiter-sized planet candidates have detected nearby stars.

Role of H3K4 demethylases in complex neurodevelopmental diseases.

Science.gov (United States)

Wynder, Christopher; Stalker, Leanne; Doughty, Martin L

2010-06-01

Significant neurological disorders can result from subtle perturbations of gene regulation that are often linked to epigenetic regulation. Proteins that regulate the methylation of lysine 4 of histone H3 (H3K4) and play a central role in epigenetic regulation, and mutations in genes encoding these enzymes have been identified in both autism and Rett syndrome. The H3K4 demethylases remove methyl groups from lysine 4 leading to loss of RNA polymerase binding and transcriptional repression. When these proteins are mutated, brain development is altered. Currently, little is known regarding how these gene regulators function at the genomic level. In this article, we will discuss findings that link H3K4 demethylases to neurodevelopment and neurological disease.

Cross Sections for the Reactions e+e to K+ K- pi+pi-, K+ K- pi0pi0, and K+ K- K+ K- Measured Using Initial-State Radiation

Energy Technology Data Exchange (ETDEWEB)

Lees, J.P.; Poireau, V.; Prencipe, E.; Tisserand, V.; /Annecy, LAPP; Garra Tico, J.; Grauges, E.; /Barcelona U., ECM; Martinelli, M.; /INFN, Trieste /Trieste U.; Milanes, D.A.; /INFN, Trieste /Trieste U.; Palano, A.; /INFN, Trieste /Trieste U.; Pappagallo, M.; /INFN, Trieste /Trieste U. /INFN, Bari /Bari U. /Bari U. /INFN, Bari; Eigen, G.; Stugu, B.; Sun, L.; /Bergen U.; Brown, D.N.; Kerth, L.T.; Kolomensky, Yu.G.; Lynch, G.; Osipenkov, I.L.; /LBL, Berkeley /UC, Berkeley; Koch, H.; Schroeder, T.; /Ruhr U., Bochum; Asgeirsson, D.J.; /British Columbia U. /Brunel U. /Novosibirsk, IYF /UC, Irvine /UC, Riverside /UC, Santa Barbara /UC, Santa Cruz /Caltech /Cincinnati U. /Colorado U. /Colorado State U. /Dortmund U. /Dresden, Tech. U. /Ecole Polytechnique /Edinburgh U. /INFN, Trieste /INFN, Trieste /INFN, Trieste /Trieste U. /INFN, Trieste /Trieste U. /INFN, Trieste /Trieste U. /INFN, Trieste /Trieste U. /INFN, Trieste /Trieste U. /INFN, Trieste /Trieste U. /INFN, Trieste /Trieste U. /INFN, Trieste /INFN, Ferrara /Ferrara U. /Frascati /INFN, Trieste /Trieste U. /INFN, Trieste /Trieste U. /INFN, Trieste /Trieste U. /INFN, Trieste /Trieste U. /INFN, Trieste /INFN, Trieste /Trieste U. /INFN, Trieste /INFN, Genoa /Genoa U. /Indian Inst. Tech., Guwahati /Harvard U. /Harvey Mudd Coll. /Heidelberg U. /Humboldt U., Berlin /Imperial Coll., London /Iowa State U. /Iowa State U. /Johns Hopkins U. /Orsay, LAL /LLNL, Livermore /Liverpool U. /Queen Mary, U. of London /Royal Holloway, U. of London /Louisville U. /Mainz U., Inst. Kernphys. /Manchester U., Comp. Sci. Dept. /Maryland U. /Massachusetts U., Amherst /MIT /McGill U. /INFN, Trieste /Trieste U. /INFN, Trieste /Trieste U. /INFN, Trieste /INFN, Trieste /Trieste U. /INFN, Trieste /Trieste U. /INFN, Milan /Milan U. /Mississippi U. /Montreal U. /INFN, Trieste /Trieste U. /INFN, Trieste /Trieste U. /INFN, Trieste /Trieste U. /INFN, Trieste /Trieste U. /INFN, Naples /Naples U. /NIKHEF, Amsterdam /Notre Dame U. /Ohio State U. /Oregon U. /INFN, Trieste /Trieste U. /INFN, Trieste /Trieste U. /INFN, Trieste /Trieste U. /INFN, Trieste /Trieste U. /INFN, Trieste /INFN, Trieste /INFN, Trieste /INFN, Trieste /Trieste U. /INFN, Trieste /Trieste U. /INFN, Padua /Padua U. /Paris U., VI-VII /INFN, Trieste /Trieste U. /INFN, Trieste /Trieste U. /INFN, Trieste /Trieste U. /INFN, Perugia /Perugia U. /INFN, Trieste /Trieste U. /INFN, Trieste /Trieste U. /INFN, Trieste /Trieste U. /INFN, Trieste /Trieste U. /INFN, Trieste /Trieste U. /INFN, Trieste /Trieste U. /INFN, Trieste /Trieste U. /INFN, Trieste /Trieste U. /INFN, Trieste /Trieste U. /INFN, Trieste /Trieste U. /INFN, Trieste /INFN, Pisa /Princeton U. /INFN, Trieste /INFN, Trieste /INFN, Trieste /Trieste U. /INFN, Trieste /INFN, Trieste /Trieste U. /INFN, Trieste /Trieste U. /INFN, Trieste /INFN, Trieste /INFN, Trieste /INFN, Rome /Rome U. /Rostock U. /Rutherford /DAPNIA, Saclay /SLAC /South Carolina U. /Southern Methodist U. /Stanford U., Phys. Dept. /SUNY, Albany /Tel Aviv U. /Tennessee U. /Texas U. /Texas U., Dallas /INFN, Trieste /Trieste U. /INFN, Trieste /Trieste U. /INFN, Trieste /Trieste U. /INFN, Turin /Turin U. /INFN, Trieste /Trieste U. /INFN, Trieste /Trieste U. /INFN, Trieste /Trieste U. /Valencia U., IFIC /Victoria U. /Warwick U. /Wisconsin U., Madison

2011-08-19

We study the processes e{sup +}e{sup -} {yields} K{sup +}K{sup -}{pi}{sup +}{pi}-{gamma}, K{sup +}K{sup -}{pi}{sup 0}{pi}{sup 0}{gamma}, and K{sup +}K{sup -}K{sup +}K{sup -}{gamma}, where the photon is radiated from the initial state. About 84000, 8000, and 4200 fully reconstructed events, respectively, are selected from 454 fb{sup -1} of BABAR data. The invariant mass of the hadronic final state defines the e{sup +}e{sup -} center-of-mass energy, so that the K{sup +}K{sup -}{pi}{sup +}{pi}{sup -}{gamma} data can be compared with direct measurements of the e{sup +}e{sup -} {yields} K{sup +}K{sup -}{pi}{sup +}{pi}{sup -} reaction. No direct measurements exist for the e{sup +}e{sup -} {yields} K{sup +}K{sup -}{pi}{sup 0}{pi}{sup 0} or e{sup +}e{sup -} {yields} K{sup +}K{sup -}K{sup +}K{sup -} reactions, and we present an update of our previous result with doubled statistics. Studying the structure of these events, we find contributions from a number of intermediate states, and extract their cross sections. In particular, we perform a more detailed study of the e{sup +}e{sup -} {yields} {phi}(1020){pi}{pi}{gamma} reaction, and confirm the presence of the Y (2175) resonance in the {phi}(1020)f{sub 0}(980) and K{sup +}K{sup -} f{sub 0}(980) modes. In the charmonium region, we observe the J/{psi} in all three final states and in several intermediate states, as well as the {phi}(2S) in some modes, and measure the corresponding branching fractions.

48 CFR 319.501 - General.

Science.gov (United States)

2010-10-01

... BUSINESS PROGRAMS Set-Asides for Small Business 319.501 General. (e) Subsequent to the Contracting Officer's recommendation on Form HHS 653, HHS Small Business Review Form, the SBS shall review each proposed acquisition strategy and either concur or not concur with the Contracting Officer's recommendation. The PCR...

9 CFR 319.145 - Italian sausage products.

Science.gov (United States)

2010-01-01

... Section 319.145 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE... accordance with § 319.6. When pork muscle tissue is combined with beef or veal, or both, in the preparation... unsmoked product. The product before cooking or smoking shall contain no more than 3 percent water as...

Fat and K-ras mutations in sporadic colorectal cancer in The Netherlands Cohort Study

NARCIS (Netherlands)

Brink, M.; Weijenberg, M.P.; Goeij, A.F.P.M. de; Schouten, L.J.; Koedijk, F.D.H.; Roemen, G.M.J.M.; Lentjes, M.H.F.M.; Bruïne, A.P. de; Goldbohm, R.A.; Brandt, P.A. van den

2004-01-01

Associations between dietary intake of various fats and specific K-ras mutations in colorectal cancer (CRC) were investigated within the framework of The Netherlands Cohort Study on diet and cancer (NLCS). After 7.3 years of follow-up and with exclusion of the first 2.3 years, 448 colon and 160

K13 mutations and pfmdr1 copy number variation in Plasmodium falciparum malaria in Myanmar.

Science.gov (United States)

Win, Aye A; Imwong, Mallika; Kyaw, Myat P; Woodrow, Charles J; Chotivanich, Kesinee; Hanboonkunupakarn, Borimas; Pukrittayakamee, Sasithon

2016-02-24

Artemisinin-based combination therapy has been first-line treatment for falciparum malaria in Myanmar since 2005. The wide extent of artemisinin resistance in the Greater Mekong sub-region and the presence of mefloquine resistance at the Myanmar-Thailand border raise concerns over resistance patterns in Myanmar. The availability of molecular markers for resistance to both drugs enables assessment even in remote malaria-endemic areas. A total of 250 dried blood spot samples collected from patients with Plasmodium falciparum malarial infection in five malaria-endemic areas across Myanmar were analysed for kelch 13 sequence (k13) and pfmdr1 copy number variation. K13 mutations in the region corresponding to amino acids 210-726 (including the propeller region of the protein) were detected by nested PCR amplification and sequencing, and pfmdr1 copy number variation by real-time PCR. In two sites, a sub-set of patients were prospectively followed up for assessment of day-3 parasite clearance rates after a standard course of artemether-lumefantrine. K13 mutations and pfmdr1 amplification were successfully analysed in 206 and 218 samples, respectively. Sixty-nine isolates (33.5 %) had mutations within the k13 propeller region with 53 of these (76.8 %) having mutations already known to be associated with artemisinin resistance. F446I (32 isolates) and P574L (15 isolates) were the most common examples. K13 mutation was less common in sites in western border regions (29 of 155 isolates) compared to samples from the east and north (40 of 51 isolates; p Myanmar. There is a low prevalence of parasites with multiple pfmdr1 copies across the country. The efficacy of artemisinin-based combination therapy containing mefloquine and lumefantrine is, therefore, expected to be high, although regular monitoring of efficacy will be important.

Mutation Processes in 293-Based Clones Overexpressing the DNA Cytosine Deaminase APOBEC3B.

Directory of Open Access Journals (Sweden)

Monica K Akre

Full Text Available Molecular, cellular, and clinical studies have combined to demonstrate a contribution from the DNA cytosine deaminase APOBEC3B (A3B to the overall mutation load in breast, head/neck, lung, bladder, cervical, ovarian, and other cancer types. However, the complete landscape of mutations attributable to this enzyme has yet to be determined in a controlled human cell system. We report a conditional and isogenic system for A3B induction, genomic DNA deamination, and mutagenesis. Human 293-derived cells were engineered to express doxycycline-inducible A3B-eGFP or eGFP constructs. Cells were subjected to 10 rounds of A3B-eGFP exposure that each caused 80-90% cell death. Control pools were subjected to parallel rounds of non-toxic eGFP exposure, and dilutions were done each round to mimic A3B-eGFP induced population fluctuations. Targeted sequencing of portions of TP53 and MYC demonstrated greater mutation accumulation in the A3B-eGFP exposed pools. Clones were generated and microarray analyses were used to identify those with the greatest number of SNP alterations for whole genome sequencing. A3B-eGFP exposed clones showed global increases in C-to-T transition mutations, enrichments for cytosine mutations within A3B-preferred trinucleotide motifs, and more copy number aberrations. Surprisingly, both control and A3B-eGFP clones also elicited strong mutator phenotypes characteristic of defective mismatch repair. Despite this additional mutational process, the 293-based system characterized here still yielded a genome-wide view of A3B-catalyzed mutagenesis in human cells and a system for additional studies on the compounded effects of simultaneous mutation mechanisms in cancer cells.

The N355K atlastin 1 mutation is associated with hereditary sensory neuropathy and pyramidal tract features.

Science.gov (United States)

Leonardis, L; Auer-Grumbach, M; Papić, L; Zidar, J

2012-07-01

  Mutations in atlastin-1 (ATL-1), a gene known to cause pure, early-onset autosomal dominant hereditary spastic paraplegia SPG3A, have been recently reported to cause hereditary sensory neuropathy I (HSN I). We describe the detailed clinical and electrophysiologic findings in the first family with ulcero-mutilating sensory neuropathy carrying the c. C1065A, p.N355K mutation in ATL-1.   Detailed clinical and electrophysiologic studies were performed in affected and at-risk family members. Motor and sensory nerve conductions studies (NCS) were carried out in upper and lower limbs. ATL-1 was screened for mutations by direct sequencing.   Ten patients were found to carry the N355K mutation. With the exception of the two youngest patients, all had trophic skin changes in the feet consisting mainly of painless ulcers. Frequently, amputation of toes, feet, or even more proximal parts of the lower legs became necessary. A variable degree of increased muscle tone was observed in younger patients, whilst some older affected individuals only presented with hyperreflexia of patellar tendon reflexes. NCS revealed signs of an axonal motor and sensory neuropathies.   Our family carrying the N355K ATL1 mutation, which was initially diagnosed as HSN I, enlarges the SPG3A phenotype. We therefore suggest that patients with HSN I excluded for more common causes of HSN I, and in particular, affected individuals who exhibit additional pyramidal tract features should also be screened for mutations in ATL1. © 2012 The Author(s) European Journal of Neurology © 2012 EFNS.

Investigation of $K_{L,S} \\rightarrow \\pi^{+}\\pi^{-}e^{+}e^{-}$ decays

CERN Document Server

Lai, A; Arcidiacono, R; Barr, G; Becker, H G; Bevan, A; Biino, C; Bizzeti, A; Bocquet, G; Calvetti, M; Cartiglia, N; Casali, R; Ceccucci, Augusto; Cenci, P; Cerri, C; Cheshkov, C; Chollet, J C; Chèze, J B; Cirilli, M; Clemencic, M; Cogan, J; Collazuol, G; Contalbrigo, M; Costantini, F; Cundy, Donald C; Dalpiaz, Pietro; De Beer, M; Debu, P; Doble, Niels T; Dosanjh, R S; Duclos, J; Eppard, M; Falaleev, V P; Fantechi, R; Fayard, Louis; Fischer, G; Formica, A; Fox, H; Frabetti, P L; Gaponenko, A N; Gatignon, L; Gershon, T J; Gianoli, A; Giudici, Sergio; Gonidec, A; Gorini, B; Govi, G; Grafström, P; Granier de Cassagnac, R; Graziani, G; Hay, B; Holder, M; Holtz, K; Iacopini, E; Iconomidou-Fayard, L; Imbergamo, E; Jeitler, Manfred; Kalmus, George Ernest; Kalter, A; Kekelidze, V D; Khristov, P Z; Kleinknecht, K; Knowles, I; Koch, U; Kubischta, Werner; Köpke, L; Lazzeroni, C; Lenti, M; Lopes da Silva, P; Lubrano, P; Luitz, S; Madigozhin, D T; Maier, A; Mannelli, I; Marchetto, F; Markytan, Manfred; Marouelli, P; Marras, D; Martin, V; Martini, M; Masetti, L; Mazzucato, E; Menichetti, E; Mestvirishvili, A; Mikulec, I; Munday, D J; Nappi, A; Nassalski, J P; Needham, M D; Neuhofer, Günther; Norton, A; Ocariz, J; Olaiya, E; Palestini, S; Panzer-Steindel, B; Parker, M A; Pellmann, I A; Pepé, M; Pernicka, Manfred; Peters, A; Petrucci, F; Peyaud, B; Piccini, M; Pierazzini, G M; Potrebenikov, Yu K; Rondio, Ewa; Sacco, R; Savrié, M; Schmidt, S; Schué, Yu; Schönharting, V; Sozzi, M; Szleper, M; Tatishvili, G T; Taureg, Hans; Taurok, Anton; Turlay, René; Unal, G; Vallage, B; Velasco, M; Veltri, M; Wahl, H; Walker, A; Wanke, R; White, T O; Widhalm, L; Wingerter-Seez, I; Winhart, A; Wislicki, W; Wittgen, M; Wotton, S A; Wronka, S; Zinchenko, A I; Ziolkowski, M

2003-01-01

The K_L -> pi+pi-e+e- and K_S -> pi+pi-e+e- decay modes have been studied in detail using the NA48 detector at CERN SPS. Based on the data collected during the 1998 and 1999 run periods, a sample of 1162 K_L -> pi+pi-e+e- candidates has been observed with an expected background level of 36.9 events, yielding the branching ratio measurement BR(K_L -> pi+pi-e+e-)=(3.08+-0.20)x10^-7. The distribution of events in the sin\\phicos\\phi variable, where \\phi is the angle between the pi+pi- and the e+e- decay planes in the kaon centre of mass, is found to exhibit a large CP-violating asymmetry with the value A_\\phi(14.2+-3.6)%. For the K_S -> pi+pi-e+e- decay channel, 621 candidates have been identified in the 1999 data sample with an estimated background contribution of 0.7 event. The corresponding branching ratio has been determined to be BR(K_S -> pi+pi-e+e-)=(4.71+-0.32)x10^-5. The combined value of this measurement with the published 1998 result id BR(K_S -> pi+pi-e+e-)=4.69+-0.30)x10^-5. No asymmetry is observed ...

7 CFR 319.56-30 - Hass avocados from Michoacan, Mexico.

Science.gov (United States)

2010-01-01

... 7 Agriculture 5 2010-01-01 2010-01-01 false Hass avocados from Michoacan, Mexico. 319.56-30... § 319.56-30 Hass avocados from Michoacan, Mexico. Fresh Hass variety avocados (Persea americana) may be imported from Michoacan, Mexico, into the United States in accordance with the requirements of § 319.56-3...

Novel CREB3L3 Nonsense Mutation in a Family With Dominant Hypertriglyceridemia.

Science.gov (United States)

Cefalù, Angelo B; Spina, Rossella; Noto, Davide; Valenti, Vincenza; Ingrassia, Valeria; Giammanco, Antonina; Panno, Maria D; Ganci, Antonina; Barbagallo, Carlo M; Averna, Maurizio R

2015-12-01

Cyclic AMP responsive element-binding protein 3-like 3 (CREB3L3) is a novel candidate gene for dominant hypertriglyceridemia. To date, only 4 kindred with dominant hypertriglyceridemia have been found to be carriers of 2 nonsense mutations in CREB3L3 gene (245fs and W46X). We investigated a family in which hypertriglyceridemia displayed an autosomal dominant pattern of inheritance. The proband was a 49-year-old woman with high plasma triglycerides (≤1300 mg/dL; 14.68 mmol/L). Her father had a history of moderate hypertriglyceridemia, and her 51-year-old brother had triglycerides levels as high as 1600 mg/dL (18.06 mmol/L). To identify the causal mutation in this family, we analyzed the candidate genes of recessive and dominant forms of primary hypertriglyceridemia by direct sequencing. The sequencing of CREB3L3 gene led to the discovery of a novel minute frame shift mutation in exon 3 of CREB3L3 gene, predicted to result in the formation of a truncated protein devoid of function (c.359delG-p.K120fsX20). Heterozygosity for the c.359delG mutation resulted in a severe phenotype occurring later in life in the proband and her brother and a good response to diet and a hypotriglyceridemic treatment. The same mutation was detected in a 13-year-old daughter who to date is normotriglyceridemic. We have identified a novel pathogenic mutation in CREB3L3 gene in a family with dominant hypertriglyceridemia with a variable pattern of penetrance. © 2015 American Heart Association, Inc.

S6K1 and 4E-BP1 are independent regulated and control cellular growth in bladder cancer.

Directory of Open Access Journals (Sweden)

Roman Nawroth

Full Text Available Aberrant activation and mutation status of proteins in the phosphatidylinositol-3-kinase (PI3K/Akt/mammalian target of rapamycin (mTOR and the mitogen activated protein kinase (MAPK signaling pathways have been linked to tumorigenesis in various tumors including urothelial carcinoma (UC. However, anti-tumor therapy with small molecule inhibitors against mTOR turned out to be less successful than expected. We characterized the molecular mechanism of this pathway in urothelial carcinoma by interfering with different molecular components using small chemical inhibitors and siRNA technology and analyzed effects on the molecular activation status, cell growth, proliferation and apoptosis. In a majority of tested cell lines constitutive activation of the PI3K was observed. Manipulation of mTOR or Akt expression or activity only regulated phosphorylation of S6K1 but not 4E-BP1. Instead, we provide evidence for an alternative mTOR independent but PI3K dependent regulation of 4E-BP1. Only the simultaneous inhibition of both S6K1 and 4E-BP1 suppressed cell growth efficiently. Crosstalk between PI3K and the MAPK signaling pathway is mediated via PI3K and indirect by S6K1 activity. Inhibition of MEK1/2 results in activation of Akt but not mTOR/S6K1 or 4E-BP1. Our data suggest that 4E-BP1 is a potential new target molecule and stratification marker for anti cancer therapy in UC and support the consideration of a multi-targeting approach against PI3K, mTORC1/2 and MAPK.

Antitumor Efficacy of the Dual PI3K/mTOR Inhibitor PF-04691502 in a Human Xenograft Tumor Model Derived from Colorectal Cancer Stem Cells Harboring a PIK3CA Mutation.

Directory of Open Access Journals (Sweden)

Douglas D Fang

Full Text Available PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide mutations can help predict the antitumor activity of phosphatidylinositol-3-kinase (PI3K/mammalian target of rapamycin (mTOR pathway inhibitors in both preclinical and clinical settings. In light of the recent discovery of tumor-initiating cancer stem cells (CSCs in various tumor types, we developed an in vitro CSC model from xenograft tumors established in mice from a colorectal cancer patient tumor in which the CD133+/EpCAM+ population represented tumor-initiating cells. CD133+/EpCAM+ CSCs were enriched under stem cell culture conditions and formed 3-dimensional tumor spheroids. Tumor spheroid cells exhibited CSC properties, including the capability for differentiation and self-renewal, higher tumorigenic potential and chemo-resistance. Genetic analysis using an OncoCarta™ panel revealed a PIK3CA (H1047R mutation in these cells. Using a dual PI3K/mTOR inhibitor, PF-04691502, we then showed that blockage of the PI3K/mTOR pathway inhibited the in vitro proliferation of CSCs and in vivo xenograft tumor growth with manageable toxicity. Tumor growth inhibition in mice was accompanied by a significant reduction of phosphorylated Akt (pAKT (S473, a well-established surrogate biomarker of PI3K/mTOR signaling pathway inhibition. Collectively, our data suggest that PF-04691502 exhibits potent anticancer activity in colorectal cancer by targeting both PIK3CA (H1047R mutant CSCs and their derivatives. These results may assist in the clinical development of PF-04691502 for the treatment of a subpopulation of colorectal cancer patients with poor outcomes.

Frequent alterations of SLIT2–ROBO1–CDC42 signalling pathway ...

Indian Academy of Sciences (India)

breast cancer; alterations of SLIT2–ROBO1 signalling; active CDC42; ... proportion of four subtypes were tested for molecular alterations of SLIT2, ... reduced expression of phospho Serine-71 CDC42 predicted poor survival of BC patients.

PI3K pathway activation results in low efficacy of both trastuzumab and lapatinib

International Nuclear Information System (INIS)

Wang, Leiping; Hu, Xichun; Zhang, Qunling; Zhang, Jian; Sun, Si; Guo, Haiyi; Jia, Zhen; Wang, Biyun; Shao, Zhimin; Wang, Zhonghua

2011-01-01

Human epidermal growth factor receptor 2 (HER2) is the most crucial ErbB receptor tyrosine kinase (RTK) family member in HER2-positive (refered to HER2-overexpressing) breast cancer which are dependent on or 'addictive' to the Phosphatidylinositol-3-kinase (PI3K) pathway. HER2-related target drugs trastuzumab and lapatinib have been the foundation of treatment of HER2--positive breast cancer. This study was designed to explore the relationship between PI3K pathway activation and the sensitivity to lapatinib in HER2--positive metastatic breast cancer patients pretreated with anthracyclins, taxanes and trastuzumab. Sixty-seven HER2-positive metastatic breast cancer patients were recruited into a global lapatinib Expanded Access Program and 57 patients have primary tumor specimens available for determination of PI3K pathway status. PTEN status was determined by immunohistochemical staining and PIK3CA mutations were detected via PCR sequencing. All patients were treated with lapatinib 1250 mg/day continuously and capecitabine 1000 mg/m 2 twice daily on a 2-week-on and 1-week-off schedule until disease progression, death, withdrawal of informed consent, or intolerable toxicity. PIK3CA mutations and PTEN loss were detected in 12.3% (7/57) and 31.6% (18/57) of the patients, respectively. Twenty-two patients with PI3K pathway activation (defined as PIK3CA mutation and/or PTEN expression loss) had a lower clinical benefit rate (36.4% versus 68.6%, P = 0.017) and a lower overall response rate (9.1% versus 31.4%, P = 0.05), when compared with the 35 patients with no activation. A retrospective analysis of first trastuzumab-containing regimen treatment data showed that PI3K pathway activation correlated with a shorter median progression-free survival (4.5 versus 9.0 months, P = 0.013). PIK3CA mutations occur more frequently in elder patients for HER2-positive breast cancer. PIK3CA mutations and PTEN loss are not mutually exclusive. PI3K pathway activation resulting

Electrophysiological analysis of the mutated Na,K-ATPase cation binding pocket.

NARCIS (Netherlands)

Koenderink, J.B.; Geibel, S.; Grabsch, E.; Pont, J.J.H.H.M. de; Bamberg, E.; Friedrich, T.

2003-01-01

Na,K-ATPase mediates net electrogenic transport by extruding three Na+ ions and importing two K+ ions across the plasma membrane during each reaction cycle. We mutated putative cation coordinating amino acids in transmembrane hairpin M5-M6 of rat Na,K-ATPase: Asp776 (Gln, Asp, Ala), Glu779 (Asp,

Molecular analysis of formaldehyde-induced mutations in human lymphoblasts and E. coli

International Nuclear Information System (INIS)

Crosby, R.M.; Richardson, K.K.; Craft, T.R.; Benforado, K.B.; Liber, H.L.; Skopek, T.R.

1988-01-01

The molecular nature of formaldehyde (HCHO)-induced mutations was studied in both human lymphoblasts and E. coli. Thirty HPRT - human lymphoblast colonies induced by eight repetitive 150 μM HCHO treatments were characterized by Southern blot analysis. Fourteen of these mutants (47%) had visible deletions of some or all of the X-linked HPRT bands, indicating that HCHO can induce large losses of DNA in human lymphoblasts. In E. coli., DNA alterations induced by HCHO were characterized with use of the xanthine guanine phosphoribosyl transferase (gpt) gene as the genetic target. Exposure of E. coli to 4 mM HCHO for 1 hr induced large insertions (41%), large deletions (18%), and point mutations (41%). Dideoxy DNA sequencing revealed that most of the point mutations were transversions at GC base pairs. In contrast, exposure of E. coli to 40 mM HCHO for 1 hr produced 92% point mutations, 62% of which were transitions at a single AT base pair in the gene. Therefore, HCHO is capable of producing different genetic alterations in E. coli at different concentrations, suggesting fundamental differences in the mutagenic mechanisms operating at the two concentrations used. Naked pSV2gpt plasmid DNA was exposed to 3.3 or 10 mM HCHO and transformed into E. coli. Most of the resulting mutations were frameshifts, again suggesting a different mutagenic mechanism

AKT Inhibition in Solid Tumors With AKT1 Mutations.

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Hyman, David M; Smyth, Lillian M; Donoghue, Mark T A; Westin, Shannon N; Bedard, Philippe L; Dean, Emma J; Bando, Hideaki; El-Khoueiry, Anthony B; Pérez-Fidalgo, José A; Mita, Alain; Schellens, Jan H M; Chang, Matthew T; Reichel, Jonathan B; Bouvier, Nancy; Selcuklu, S Duygu; Soumerai, Tara E; Torrisi, Jean; Erinjeri, Joseph P; Ambrose, Helen; Barrett, J Carl; Dougherty, Brian; Foxley, Andrew; Lindemann, Justin P O; McEwen, Robert; Pass, Martin; Schiavon, Gaia; Berger, Michael F; Chandarlapaty, Sarat; Solit, David B; Banerji, Udai; Baselga, José; Taylor, Barry S

2017-07-10

Purpose AKT1 E17K mutations are oncogenic and occur in many cancers at a low prevalence. We performed a multihistology basket study of AZD5363, an ATP-competitive pan-AKT kinase inhibitor, to determine the preliminary activity of AKT inhibition in AKT-mutant cancers. Patients and Methods Fifty-eight patients with advanced solid tumors were treated. The primary end point was safety; secondary end points were progression-free survival (PFS) and response according to Response Evaluation Criteria in Solid Tumors (RECIST). Tumor biopsies and plasma cell-free DNA (cfDNA) were collected in the majority of patients to identify predictive biomarkers of response. Results In patients with AKT1 E17K-mutant tumors (n = 52) and a median of five lines of prior therapy, the median PFS was 5.5 months (95% CI, 2.9 to 6.9 months), 6.6 months (95% CI, 1.5 to 8.3 months), and 4.2 months (95% CI, 2.1 to 12.8 months) in patients with estrogen receptor-positive breast, gynecologic, and other solid tumors, respectively. In an exploratory biomarker analysis, imbalance of the AKT1 E17K-mutant allele, most frequently caused by copy-neutral loss-of-heterozygosity targeting the wild-type allele, was associated with longer PFS (hazard ratio [HR], 0.41; P = .04), as was the presence of coincident PI3K pathway hotspot mutations (HR, 0.21; P = .045). Persistent declines in AKT1 E17K in cfDNA were associated with improved PFS (HR, 0.18; P = .004) and response ( P = .025). Responses were not restricted to patients with detectable AKT1 E17K in pretreatment cfDNA. The most common grade ≥ 3 adverse events were hyperglycemia (24%), diarrhea (17%), and rash (15.5%). Conclusion This study provides the first clinical data that AKT1 E17K is a therapeutic target in human cancer. The genomic context of the AKT1 E17K mutation further conditioned response to AZD5363.

The Frequency and Type of K-RAS Mutations in Mexican Patients With Colorectal Cancer: A National Study.

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Cárdenas-Ramos, Susana G; Alcázar-González, Gregorio; Reyes-Cortés, Luisa M; Torres-Grimaldo, Abdiel A; Calderón-Garcidueñas, Ana L; Morales-Casas, José; Flores-Sánchez, Patricia; De León-Escobedo, Raúl; Gómez-Díaz, Antonio; Moreno-Bringas, Carmen; Sánchez-Guillén, Jorge; Ramos-Salazar, Pedro; González-de León, César; Barrera-Saldaña, Hugo A

2017-06-01

Current metastatic colorectal cancer (mCRC) therapy uses monoclonal antibodies against the epidermal growth factor receptor. This treatment is only useful in the absence of K-RAS gene mutations; therefore the study of such mutations is part of a personalized treatment. The aim of this work is to determine the frequency and type of the most common K-RAS mutations in Mexican patients with metastatic disease by nucleotide sequencing. We studied 888 patients with mCRC from different regions of Mexico. The presence of mutations in exon 2, codons 12 and 13, of the K-RAS gene was determined by nucleotide sequencing. Patients exhibited K-RAS gene mutations in 35% (310/888) of cases. Mutation frequency of codons 12 and 13 was 71% (221/310) and 29% (89/310), respectively. The most common mutation (45.7%) in codon 12 was c.35G>A (p.G12D), whereas the one in codon 13 was c.38G>A (p.G13D) (78.7%). Given the frequency of K-RAS mutations in Mexicans, making a genetic study before deciding to treat mCRC patients with monoclonal antibodies is indispensable.

The Glucocerobrosidase E326K Variant Predisposes to Parkinson’s Disease, But Does Not Cause Gaucher’s Disease

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Angeli, Aikaterini V.; Shoai, Maryam; Deas, Emma; Houlden, Henry; Mehta, Atul; Hughes, Derralynn; Cox, Timothy M.; Deegan, Patrick; Schapira, Anthony H.; Lees, Andrew J.; Limousin, Patricia; Jarman, Paul R.; Bhatia, Kailash P.; Wood, Nicholas W.; Hardy, John; Foltynie, Tom

2014-01-01

Background Heterozygous loss-of-function mutations in the acid beta-glucocerebrosidase (GBA1) gene, responsible for the recessive lysosomal storage disorder, Gaucher’s disease (GD), are the strongest known risk factor for Parkinson’s disease (PD). Our aim was to assess the contribution of GBA1 mutations in a series of early-onset PD. Methods One hundred and eighty-five PD patients (with an onset age of ≤50) and 283 age-matched controls were screened for GBA1 mutations by Sanger sequencing. Results We show that the frequency of GBA1 mutations is much higher in this patient series than in typical late-onset patient cohorts. Furthermore, our results reveal that the most prevalent PD-associated GBA1 mutation is E326K, a variant that does not, when homozygous, cause GD. Conclusions Our results confirm recent reports that the mutation, E326K, predisposes to PD and suggest that, in addition to reduced GBA1 activity, other molecular mechanisms may contribute to the development of the disease. PMID:23225227

31 CFR 597.319 - U.S. financial institution.

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2010-07-01

... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false U.S. financial institution. 597.319 Section 597.319 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE... financial institution's foreign branches; (b) Any financial institution operating or doing business in the...

31 CFR 560.319 - United States depository institution.

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2010-07-01

... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false United States depository institution. 560.319 Section 560.319 Money and Finance: Treasury Regulations Relating to Money and Finance... entity, that is engaged primarily in the business of banking (for example, banks, savings banks, savings...

31 CFR 537.319 - U.S. depository institution.

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2010-07-01

... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false U.S. depository institution. 537.319 Section 537.319 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE..., that is engaged primarily in the business of banking (for example, banks, savings banks, savings...

Activation of the PI3K/AKT pathway in Merkel cell carcinoma.

Directory of Open Access Journals (Sweden)

Christian Hafner

Full Text Available Merkel cell carcinoma (MCC is a highly aggressive skin cancer with an increasing incidence. The understanding of the molecular carcinogenesis of MCC is limited. Here, we scrutinized the PI3K/AKT pathway, one of the major pathways activated in human cancer, in MCC. Immunohistochemical analysis of 41 tumor tissues and 9 MCC cell lines revealed high levels of AKT phosphorylation at threonine 308 in 88% of samples. Notably, the AKT phosphorylation was not correlated with the presence or absence of the Merkel cell polyoma virus (MCV. Accordingly, knock-down of the large and small T antigen by shRNA in MCV positive MCC cells did not affect phosphorylation of AKT. We also analyzed 46 MCC samples for activating PIK3CA and AKT1 mutations. Oncogenic PIK3CA mutations were found in 2/46 (4% MCCs whereas mutations in exon 4 of AKT1 were absent. MCC cell lines demonstrated a high sensitivity towards the PI3K inhibitor LY-294002. This finding together with our observation that the PI3K/AKT pathway is activated in the majority of human MCCs identifies PI3K/AKT as a potential new therapeutic target for MCC patients.

DNA replication origin function is promoted by H3K4 di-methylation in Saccharomyces cerevisiae.

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Rizzardi, Lindsay F; Dorn, Elizabeth S; Strahl, Brian D; Cook, Jeanette Gowen

2012-10-01

DNA replication is a highly regulated process that is initiated from replication origins, but the elements of chromatin structure that contribute to origin activity have not been fully elucidated. To identify histone post-translational modifications important for DNA replication, we initiated a genetic screen to identify interactions between genes encoding chromatin-modifying enzymes and those encoding proteins required for origin function in the budding yeast Saccharomyces cerevisiae. We found that enzymes required for histone H3K4 methylation, both the histone methyltransferase Set1 and the E3 ubiquitin ligase Bre1, are required for robust growth of several hypomorphic replication mutants, including cdc6-1. Consistent with a role for these enzymes in DNA replication, we found that both Set1 and Bre1 are required for efficient minichromosome maintenance. These phenotypes are recapitulated in yeast strains bearing mutations in the histone substrates (H3K4 and H2BK123). Set1 functions as part of the COMPASS complex to mono-, di-, and tri-methylate H3K4. By analyzing strains lacking specific COMPASS complex members or containing H2B mutations that differentially affect H3K4 methylation states, we determined that these replication defects were due to loss of H3K4 di-methylation. Furthermore, histone H3K4 di-methylation is enriched at chromosomal origins. These data suggest that H3K4 di-methylation is necessary and sufficient for normal origin function. We propose that histone H3K4 di-methylation functions in concert with other histone post-translational modifications to support robust genome duplication.

Somatic mutations of the histone H3K27 demethylase, UTX, in human cancer

Science.gov (United States)

van Haaften, Gijs; Dalgliesh, Gillian L; Davies, Helen; Chen, Lina; Bignell, Graham; Greenman, Chris; Edkins, Sarah; Hardy, Claire; O’Meara, Sarah; Teague, Jon; Butler, Adam; Hinton, Jonathan; Latimer, Calli; Andrews, Jenny; Barthorpe, Syd; Beare, Dave; Buck, Gemma; Campbell, Peter J; Cole, Jennifer; Dunmore, Rebecca; Forbes, Simon; Jia, Mingming; Jones, David; Kok, Chai Yin; Leroy, Catherine; Lin, Meng-Lay; McBride, David J; Maddison, Mark; Maquire, Simon; McLay, Kirsten; Menzies, Andrew; Mironenko, Tatiana; Lee, Mulderrig; Mudie, Laura; Pleasance, Erin; Shepherd, Rebecca; Smith, Raffaella; Stebbings, Lucy; Stephens, Philip; Tang, Gurpreet; Tarpey, Patrick S; Turner, Rachel; Turrell, Kelly; Varian, Jennifer; West, Sofie; Widaa, Sara; Wray, Paul; Collins, V Peter; Ichimura, Koichi; Law, Simon; Wong, John; Yuen, Siu Tsan; Leung, Suet Yi; Tonon, Giovanni; DePinho, Ronald A; Tai, Yu-Tzu; Anderson, Kenneth C; Kahnoski, Richard J.; Massie, Aaron; Khoo, Sok Kean; Teh, Bin Tean; Stratton, Michael R; Futreal, P Andrew

2010-01-01

Somatically acquired epigenetic changes are present in many cancers. Epigenetic regulation is maintained via post-translational modifications of core histones. Here, we describe inactivating somatic mutations in the histone lysine demethylase, UTX, pointing to histone H3 lysine methylation deregulation in multiple tumour types. UTX reintroduction into cancer cells with inactivating UTX mutations resulted in slowing of proliferation and marked transcriptional changes. These data identify UTX as a new human cancer gene. PMID:19330029

Common mutations in the fibroblast growth factor receptor 3 (FGFR 3) gene account for achondroplasia, hypochondroplasia, and thanatophoric dwarfism

Energy Technology Data Exchange (ETDEWEB)

Bonaventure, J.; Rousseau, F.; Legeai-Mallet, L.; LeMerrer, M.; Munnich, A.; Maroteaux, P. [INSERM, Paris (France)

1996-05-03

The mapping of the achondroplasia locus to the short arm of chromosome 4 and the subsequent identification of a recurrent missense mutation (G380R) in the fibroblast growth factor receptor 3 (FGFR-3) gene has been followed by the detection of common FGFR-3 mutations in two clinically related disorders: thanatophoric dwarfism (types I and II) and hypochondroplasia. The relative clinical homogeneity of achondroplasia was substantiated by demonstration of its genetic homogeneity as more than 98% of all patients hitherto reported exhibit mutations in the transmembrane receptor domain. Although most hypochondroplasia cases were accounted for by a recurrent missense substitution (N540K) in the first tyrosine kinase (TK 1) domain of the receptor, a significant proportion (40%) of our patients did not harbor the N540K mutation and three hypochondroplasia families were not linked to the FGFR-3 locus, thus supporting clinical heterogeneity of this condition. In thanatophoric dwarfism (TD), a recurrent FGFR-3 mutation located in the second tyrosine kinase (TK 2) domain of the receptor was originally detected in 100% of TD II cases; in our series, seven distinct mutations in three different protein domains were identified in 25 of 26 TD I patients, suggesting that TD, like achondroplasia, is a genetically homogenous skeletal disorder. 31 refs., 4 figs., 2 tabs.

Clinical significance of BRAF non-V600E mutations on the therapeutic effects of anti-EGFR monoclonal antibody treatment in patients with pretreated metastatic colorectal cancer: the Biomarker Research for anti-EGFR monoclonal Antibodies by Comprehensive Cancer genomics (BREAC) study.

Science.gov (United States)

Shinozaki, Eiji; Yoshino, Takayuki; Yamazaki, Kentaro; Muro, Kei; Yamaguchi, Kensei; Nishina, Tomohiro; Yuki, Satoshi; Shitara, Kohei; Bando, Hideaki; Mimaki, Sachiyo; Nakai, Chikako; Matsushima, Koutatsu; Suzuki, Yutaka; Akagi, Kiwamu; Yamanaka, Takeharu; Nomura, Shogo; Fujii, Satoshi; Esumi, Hiroyasu; Sugiyama, Masaya; Nishida, Nao; Mizokami, Masashi; Koh, Yasuhiro; Abe, Yukiko; Ohtsu, Atsushi; Tsuchihara, Katsuya

2017-11-07

Patients with BRAF V600E -mutated metastatic colorectal cancer (mCRC) have a poorer prognosis as well as resistance to anti-EGFR antibodies. However, it is unclear whether BRAF mutations other than BRAF V600E (BRAF non-V600E mutations) contribute to anti-EGFR antibody resistance. This study was composed of exploratory and inference cohorts. Candidate biomarkers identified by whole exome sequencing from super-responders and nonresponders in the exploratory cohort were validated by targeted resequencing for patients who received anti-EGFR antibody in the inference cohort. In the exploratory cohort, 31 candidate biomarkers, including KRAS/NRAS/BRAF mutations, were identified. Targeted resequencing of 150 patients in the inference cohort revealed 40 patients with RAS (26.7%), 9 patients with BRAF V600E (6.0%), and 7 patients with BRAF non-V600E mutations (4.7%), respectively. The response rates in RAS, BRAF V600E , and BRAF non-V600E were lower than those in RAS/BRAF wild-type (2.5%, 0%, and 0% vs 31.9%). The median PFS in BRAF non-V600E mutations was 2.4 months, similar to that in RAS or BRAF V600E mutations (2.1 and 1.6 months) but significantly worse than that in wild-type RAS/BRAF (5.9 months). Although BRAF non-V600E mutations identified were a rare and unestablished molecular subtype, certain BRAF non-V600E mutations might contribute to a lesser benefit of anti-EGFR monoclonal antibody treatment.

Son of sevenless directly links the Robo receptor to rac activation to control axon repulsion at the midline.

Science.gov (United States)

Yang, Long; Bashaw, Greg J

2006-11-22

Son of sevenless (Sos) is a dual specificity guanine nucleotide exchange factor (GEF) that regulates both Ras and Rho family GTPases and thus is uniquely poised to integrate signals that affect both gene expression and cytoskeletal reorganization. Here, using genetics, biochemistry, and cell biology, we demonstrate that Sos is recruited to the plasma membrane, where it forms a ternary complex with the Roundabout receptor and the SH3-SH2 adaptor protein Dreadlocks (Dock) to regulate Rac-dependent cytoskeletal rearrangement in response to the Slit ligand. Intriguingly, the Ras and Rac-GEF activities of Sos can be uncoupled during Robo-mediated axon repulsion; Sos axon guidance function depends on its Rac-GEF activity, but not its Ras-GEF activity. These results provide in vivo evidence that the Ras and RhoGEF domains of Sos are separable signaling modules and support a model in which Robo recruits Sos to the membrane via Dock to activate Rac during midline repulsion.

31 CFR 540.319 - U.S. financial institution.

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2010-07-01

... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false U.S. financial institution. 540.319... CONTROL REGULATIONS General Definitions § 540.319 U.S. financial institution. The term U.S. financial... financial institutions that are located in the United States, but not such institutions' foreign branches...

Frequent alterations of SLIT2–ROBO1–CDC42 signalling pathway ...

Indian Academy of Sciences (India)

2016-09-07

Sep 7, 2016 ... Keywords. breast cancer; alterations of SLIT2–ROBO1 signalling; active CDC42; pSer71-CDC42 . Journal of ... have already been studied in head and neck squamous cell ...... lung, oral, cervical, breast, kidney (Dallol et al.

Synergistic effects of targeted PI3K signaling inhibition and chemotherapy in liposarcoma.

Directory of Open Access Journals (Sweden)

Shang Guo

Full Text Available While liposarcoma is the second most common soft tissue malignant tumor, the molecular pathogenesis in this malignancy is poorly understood. Our goal was therefore to expand the understanding of molecular mechanisms that drive liposarcoma and identify therapeutically-susceptible genetic alterations. We studied a cohort of high-grade liposarcomas and benign lipomas across multiple disease sites, as well as two liposarcoma cell lines, using multiplexed mutational analysis. Nucleic acids extracted from diagnostic patient tissue were simultaneously interrogated for 150 common mutations across 15 essential cancer genes using a clinically-validated platform for cancer genotyping. Western blot analysis was implemented to detect activation of downstream pathways. Liposarcoma cell lines were used to determine the effects of PI3K targeted drug treatment with or without chemotherapy. We identified mutations in the PIK3CA gene in 4 of 18 human liposarcoma patients (22%. No PIK3CA mutations were identified in benign lipomas. Western blot analysis confirmed downstream activation of AKT in both PIK3CA mutant and non-mutant liposarcoma samples. PI-103, a dual PI3K/mTOR inhibitor, effectively inhibited the activation of the PI3K/AKT in liposarcoma cell lines and induced apoptosis. Importantly, combination with PI-103 treatment strongly synergized the growth-inhibitory effects of the chemotherapy drugs doxorubicin and cisplatin in liposarcoma cells. Taken together, these findings suggest that activation of the PI3K/AKT pathway is an important cancer mechanism in liposarcoma. Targeting the PI3K/AKT/pathway with small molecule inhibitors in combination with chemotherapy could be exploited as a novel strategy in the treatment of liposarcoma.

31 CFR 598.319 - U.S. financial institution.

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2010-07-01

... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false U.S. financial institution. 598.319... General Definitions § 598.319 U.S. financial institution. The term U.S. financial institution means any U..., offices, and agencies of foreign financial institutions which are located in the United States, but not...

The LRRK2 Variant E193K Prevents Mitochondrial Fission Upon MPP+ Treatment by Altering LRRK2 Binding to DRP1

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Maria Perez Carrion

2018-02-01

Full Text Available Mutations in leucine-rich repeat kinase 2 gene (LRRK2 are associated with familial and sporadic Parkinson’s disease (PD. LRRK2 is a complex protein that consists of multiple domains, including 13 putative armadillo-type repeats at the N-terminus. In this study, we analyzed the functional and molecular consequences of a novel variant, E193K, identified in an Italian family. E193K substitution does not influence LRRK2 kinase activity. Instead it affects LRRK2 biochemical properties, such as phosphorylation at Ser935 and affinity for 14-3-3ε. Primary fibroblasts obtained from an E193K carrier demonstrated increased cellular toxicity and abnormal mitochondrial fission upon 1-methyl-4-phenylpyridinium treatment. We found that E193K alters LRRK2 binding to DRP1, a crucial mediator of mitochondrial fission. Our data support a role for LRRK2 as a scaffolding protein influencing mitochondrial fission.

Cancer3D: understanding cancer mutations through protein structures.

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Porta-Pardo, Eduard; Hrabe, Thomas; Godzik, Adam

2015-01-01

The new era of cancer genomics is providing us with extensive knowledge of mutations and other alterations in cancer. The Cancer3D database at http://www.cancer3d.org gives an open and user-friendly way to analyze cancer missense mutations in the context of structures of proteins in which they are found. The database also helps users analyze the distribution patterns of the mutations as well as their relationship to changes in drug activity through two algorithms: e-Driver and e-Drug. These algorithms use knowledge of modular structure of genes and proteins to separately study each region. This approach allows users to find novel candidate driver regions or drug biomarkers that cannot be found when similar analyses are done on the whole-gene level. The Cancer3D database provides access to the results of such analyses based on data from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE). In addition, it displays mutations from over 14,700 proteins mapped to more than 24,300 structures from PDB. This helps users visualize the distribution of mutations and identify novel three-dimensional patterns in their distribution. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

JAK and MPL mutations in myeloid malignancies.

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Tefferi, Ayalew

2008-03-01

The Janus family of non-receptor tyrosine kinases (JAK1, JAK2, JAK3 and tyrosine kinase 2) transduces signals downstream of type I and II cytokine receptors via signal transducers and activators of transcription (STATs). JAK3 is important in lymphoid and JAK2 in myeloid cell proliferation and differentiation. The thrombopoietin receptor MPL is one of several JAK2 cognate receptors and is essential for myelopoiesis in general and megakaryopoiesis in particular. Germline loss-of-function (LOF) JAK3 and MPL mutations cause severe combined immunodeficiency and congenital amegakaryocytic thrombocytopenia, respectively. Germline gain-of-function (GOF) MPL mutation (MPLS505N) causes familial thrombocytosis. Somatic JAK3 (e.g. JAK3A572V, JAK3V722I, JAK3P132T) and fusion JAK2 (e.g. ETV6-JAK2, PCM1-JAK2, BCR-JAK2) mutations have respectively been described in acute megakaryocytic leukemia and acute leukemia/chronic myeloid malignancies. However, current attention is focused on JAK2 (e.g. JAK2V617F, JAK2 exon 12 mutations) and MPL (e.g. MPLW515L/K/S, MPLS505N) mutations associated with myeloproliferative neoplasms (MPNs). A JAK2 mutation, primarily JAK2V617F, is invariably associated with polycythemia vera (PV). The latter mutation also occurs in the majority of patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF). MPL mutational frequency in MPNs is substantially less (<10%). In general, despite a certain degree of genotype - phenotype correlations, the prognostic relevance of harbouring one of these mutations, or their allele burden when present, remains dubious. Regardless, based on the logical assumption that amplified JAK-STAT signalling is central to the pathogenesis of PV, ET and PMF, several anti-JAK2 tyrosine kinase inhibitors have been developed and are currently being tested in humans with these disorders.

Synergistic effects of concurrent blockade of PI3K and MEK pathways in pancreatic cancer preclinical models.

Directory of Open Access Journals (Sweden)

Hua Zhong

Full Text Available Patients with pancreatic cancer have dismal prognoses, and novel therapies are urgently needed. Mutations of the KRAS oncogene occur frequently in pancreatic cancer and represent an attractive target. Direct targeting of the predominant KRAS pathways have been challenging and research into therapeutic strategies have been now refocused on pathways downstream of KRAS, phosphoinositide 3-kinase (PI3K and mitogen-activated protein kinase (MAPK [MEK]. We hypothesized that concurrent inhibition of the PI3K and MEK pathways would result in synergistic antitumor activity, as it would circumvent the compensatory feedback loop between the two pathways. We investigated the combined effect of the PI3K inhibitor, GDC0941, and the MEK inhibitor, AZD6244, on cell viability, apoptosis and cell signaling in a panel of pancreatic cancer cell lines. An in vivo analysis was conducted on pancreatic cancer xenografts. While BxPC-3 (KRAS wild type and MIA PaCa-2 (KRAS mutated cell lines were sensitive to GDC0941 and AZD6244 as single agents, synergistic inhibition of tumor cell growth and induction of apoptosis were observed in both cell lines when the two drugs were combined. Interestingly, phosphorylation of the cap-dependent translational components, 4E-binding protein (p-4E-BP1 and S6 was found to be closely associated with sensitivity to GDC0941 and AZD6244. In BxPC-3 cell xenografts, survival differences were observed between the control and the AZD6244, GDC0941, and combination groups. Our study provides the rationale for concurrent targeting of the PI3K and MEK pathways, regardless of KRAS status, and suggests that phosphorylation of 4E-BP1and S6 can serve as a predictive biomarker for response to treatment.

A novel de novo activating mutation in STAT3 identified in a patient with common variable immunodeficiency (CVID).

Science.gov (United States)

Russell, Mark A; Pigors, Manuela; Houssen, Maha E; Manson, Ania; Kelsell, David; Longhurst, Hilary; Morgan, Noel G

2018-02-01

Common variable immunodeficiency (CVID) is characterised by repeated infection associated with primary acquired hypogammaglobulinemia. CVID frequently has a complex aetiology but, in certain cases, it has a monogenic cause. Recently, variants within the gene encoding the transcription factor STAT3 were implicated in monogenic CVID. Here, we describe a patient presenting with symptoms synonymous with CVID, who displayed reduced levels of IgG and IgA, repeated viral infections and multiple additional co-morbidities. Whole-exome sequencing revealed a de novo novel missense mutation in the coiled-coil domain of STAT3 (c.870A>T; p.K290N). Accordingly, the K290N variant of STAT3 was generated, and a STAT3 responsive dual-luciferase reporter assay revealed that the variant strongly enhances STAT3 transcriptional activity both under basal and stimulated (with IL-6) conditions. Overall, these data complement earlier studies in which CVID-associated STAT3 mutations are predicted to enhance transcriptional activity, suggesting that such patients may respond favourably to IL-6 receptor antagonists (e.g. tocilizumab). Copyright © 2017 Elsevier Inc. All rights reserved.

P53, K-RAS, β-CATENIN, C-KIT and BAK mutations in the lung cancer of Chinese and Japanese patients

International Nuclear Information System (INIS)

Shuo Xing; Nobotoshi Nawa; Kazuhiro Tanabe; Tadashi Hongyo; Li- Ya Li; Jing-Tian Tang; Mitsunori Ohta

2005-01-01

Seventeen Chinese (Beijing) and 24 Japanese (Osaka) lung cancer cases were analyzed for mutations of p53, K-ras, β-catenin, c-kit and bak genes by PCR-SSCP analysis followed by direct sequencing. Significantly higher mutation frequency of p53 gene, one of key genes for radiation sensitivity, was found in Chinese cases (11/17; 64.7 %) than Japanese cases (8/24; 33.3 %) (p< O.O5). Fourteen of the 16 mutations found in the Chinese cases were transitions at exon 4,5 and intron 4. In the Japanese cases, of the total of 11 mutations, 5 were transitions and 5 were transversions and one was deletion. Six β-catenin mutations were found in 6 Chinese cases (35.3 % ) at codon 53 and 58, and 4 were found in 3 Japanese cases (12.5 %). C-kit mutations were detected in 5 Chinese cases (29.4 %), while no mutations were found in Japanese cases (p< O.O5). No K-ras mutation was found in both Chinese and Japanese cases. For the first time, we report on bak mutation in human lung cancer in Chinese (2/17; 11.8% ) and Japanese cases (2/24; 8.3% ). C-kit and bak genes are also definitive factors to radiosensitivity. These data thus suggest that there were apparent differences in frequency and/or mutational types of p53, β-catenin and c-kit? genes between Chinese and Japanese cases. The differences can be attributed to factors such as lifestyles including smoking and racial and/or environmental factors, and also to the prediction of the response to radiotherapy. (author)

Genotyping of K-ras codons 12 and 13 mutations in colorectal cancer by capillary electrophoresis.

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Chen, Yen-Ling; Chang, Ya-Sian; Chang, Jan-Gowth; Wu, Shou-Mei

2009-06-26

Point mutations of the K-ras gene located in codons 12 and 13 cause poor responses to the anti-epidermal growth factor receptor (anti-EGFR) therapy of colorectal cancer (CRC) patients. Besides, mutations of K-ras gene have also been proven to play an important role in human tumor progression. We established a simple and effective capillary electrophoresis (CE) method for simultaneous point mutation detection in codons 12 and 13 of K-ras gene. We combined one universal fluorescence-based nonhuman-sequence primer and two fragment-oriented primers in one tube, and performed this two-in-one polymerase chain reaction (PCR). PCR fragments included wild type and seven point mutations at codons 12 and 13 of K-ras gene. The amplicons were analyzed by single-strand conformation polymorphism (SSCP)-CE method. The CE analysis was performed by using a 1x Tris-borate-EDTA (TBE) buffer containing 1.5% (w/v) hydroxyethylcellulose (HEC) (MW 250,000) under reverse polarity with 15 degrees C and 30 degrees C. Ninety colorectal cancer patients were blindly genotyped using this developed method. The results showed good agreement with those of DNA sequencing method. The SSCP-CE was feasible for mutation screening of K-ras gene in populations.

Role of BRAFV600E Mutation Analysis for Thyroid Nodules Classified as Indeterminate on Ultrasonography

International Nuclear Information System (INIS)

Nam, Sang Yu; Shin, Jung Hee; Han, Boo Kyung; Ko, Eun Young; Kang, Seok Seon; Hahn, Soo Yeon; Hwang, Ji Young; Nam, Mee Young; Kim, Jong Won; Chung, Jae Hoon

2010-01-01

We aimed to evaluate a possible role for BRAFV600E mutation analysis of aspiration specimens in the work up of thyroid nodules classified as indeterminate on US. A total of 122 nodules from 122 patients were prospectively classified as indeterminate nodules based on US findings. US-guided fine needle aspiration (FNA) was done for all 122 nodules. The presence of a BRAFV600E mutation in FNA specimens was determined by allele-specific PCR. US-indeterminate nodules were confirmed as malignant in 20.5% (25/122) of cases and benign in 76.2% (93/122) after FNA or surgery. A few (3.3% (4/122), remained indeterminate. A BRAFV600E mutation was identified in 14.8% (18/122) of US indeterminate nodules. Of those 18 nodules, three were benign and 13 were malignant after the initial FNA. One (0.8%, 1/122) with an initially benign cytology and a BRAFV600E mutation was confirmed to be malignant after surgery. The remaining two benign nodules with a mutation were not followed-up. All 9 initial FNA-nondiagnostic nodules were mutation negative but 2 (11.8%) of 17 indeterminate nodules on initial FNAs were mutation positive. BRAFV600E mutation analysis prevents false negative cytology for only 0.8% of cases and reduces ambiguous diagnoses for 1.6% of all US-indeterminate thyroid nodules. Therefore, adding BRAFV600E mutation analysis to FNA for US-indeterminate nodules is of limited usefulness

Microstructure and mechanical properties of thixoformed A319 aluminium alloy

International Nuclear Information System (INIS)

Salleh, M.S.; Omar, M.Z.; Syarif, J.; Alhawari, K.S.; Mohammed, M.N.

2014-01-01

Highlights: • A319 was successfully thixoformed at 50% liquid, i.e. at 571 °C. • T6 heat treatment has increased the strength and hardness of the thixoformed alloy. • The elongation after T6 heat treatment is even significantly improved. • The iron-rich intermetallic phase reduces the strength of the thixoformed alloy. - Abstract: Thixoforming is a viable technology for forming alloys in a semisolid state into near net-shaped products. In the present study, the effect of a thixoforming process on the microstructure and mechanical properties of A319 aluminium alloy was investigated. The ingots obtained from the cooling slope were thixoformed in a press after they remained at 571 °C for 5 min, yielding a microstructure predominantly composed of α-Al globules and inter-globular Si particles. Some of the thixoformed samples were treated with an ageing process (T6) and then, hardness and tensile samples were prepared from the as-cast, as-thixoformed and thixoformed T6. All the thixoformed samples were characterised using optical microscopy, scanning electron microscopy (SEM), energy dispersive X-ray (EDX) and X-ray diffraction (XRD) as well as hardness measurements and tensile tests. The results indicate that the mechanical properties of the thixoformed A319 alloy increased after the T6 heat treatment (hardness of 124.2 ± 3.2 HV, tensile strength of 298 ± 3.0 MPa, yield strength of 201 ± 2.6 MPa and elongation to fracture of 4.5 ± 0.3%). The fracture samples from the tensile test were analysed, revealing that the iron-rich intermetallic observed in the samples reduced the tensile strength and ductility of the thixoformed A319 alloys

Loss of function mutations in PTPN6 promote STAT3 deregulation via JAK3 kinase in diffuse large B-cell lymphoma

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Demosthenous, Christos; Han, Jing Jing; Hu, Guangzhen; Stenson, Mary; Gupta, Mamta

2015-01-01

PTPN6 (SHP1) is a tyrosine phosphatase that negatively controls the activity of multiple signaling pathways including STAT signaling, however role of mutated PTPN6 is not much known. Here we investigated whether PTPN6 might also be a potential target for diffuse large B cell lymphoma (DLBCL) and performed Sanger sequencing of the PTPN6 gene. We have identified missense mutations within PTPN6 (N225K and A550V) in 5% (2/38) of DLBCL tumors. Site directed mutagenesis was performed to mutate wild type (WT) PTPN6 and stable cell lines were generated by lentiviral transduction of PTPN6WT, PTPN6N225K and PTPN6A550V constructs, and effects of WT or mutated PTPN6 on STAT3 signaling were analyzed. WT PTPN6 dephosphorylated STAT3, but had no effect on STAT1, STAT5 or STAT6 phosphorylation. Both PTPN6 mutants were unable to inhibit constitutive, as well as cytokines induced STAT3 activation. Both PTPN6 mutants also demonstrated reduced tyrosine phosphatase activity and exhibited enhanced STAT3 transactivation activity. Intriguingly, a lack of direct binding between STAT3 and WT or mutated PTPN6 was observed. However, compared to WT PTPN6, cells expressing PTPN6 mutants exhibited increased binding between JAK3 and PTPN6 suggesting a more dynamic interaction of PTPN6 with upstream regulators of STAT3. Consistent with this notion, both the mutants demonstrated increased resistance to JAK3 inhibitor, WHIP-154 relative to WT PTPN6. Overall, this is the first study, which demonstrates that N225K and A550V PTPN6 mutations cause loss-of-function leading to JAK3 mediated deregulation of STAT3 pathway and uncovers a mechanism that tumor cells can use to control PTPN6 substrate specificity. PMID:26565811

Spectrum of EGFR gene mutations in Vietnamese patients with non-small cell lung cancer.

Science.gov (United States)

Vu, Hoang Anh; Xinh, Phan Thi; Ha, Hua Thi Ngoc; Hanh, Ngo Thi Tuyet; Bach, Nguyen Duc; Thao, Doan Thi Phuong; Dat, Ngo Quoc; Trung, Nguyen Sao

2016-03-01

Epidermal growth factor receptor (EGFR) mutational status is a crucial biomarker for prediction of response to tyrosine kinase inhibitors in patients with non-small cell lung cancer (NSCLC). Although these mutations have been well characterized in other countries, little is known about the frequency or spectrum of EGFR mutations in Vietnamese NSCLC patients. Using Sanger DNA sequencing, we investigated mutations in EGFR exons 18-21 from 332 patients diagnosed with NSCLC at University of Medicine and Pharmacy, Ho Chi Minh City, Vietnam. DNA was extracted from formalin-fixed, paraffin-embedded tissues, followed by PCR amplification and sequencing. EGFR mutations were detected in 135 samples (40.7%), of which eight samples carried double mutations. In total, 46 different types of EGFR mutations were found, including six novel mutations (p.K713E, p.K714R, p.P794S, p.R803W, p.P848S, and p.K867E). Among the four exons investigated, exon 19 was most frequently mutated (63 out of 332 patients, 19%), with the p.E746_A750del appearing in 43 samples. Exon 21 was mutated in 56 samples (16.9%), of which 47 were p.L858R. Each of exons 18 and 20 was mutated in 12 samples (3.6%). The frequency of EGFR mutations was higher in females than in males (48.9% vs 35%, P = 0.012), but not statistically different between adenocarcinomas and other histological types of NSCLC (41.3% vs 34.5%, P = 0.478). DNA sequencing detected EGFR mutations with high frequency and revealed a broad spectrum of mutation type in Vietnamese patients with NSCLC. © 2015 Wiley Publishing Asia Pty Ltd.

Identification and sequence analysis of Sulfolobus solfataricus purE and purK genes

DEFF Research Database (Denmark)

Sørensen, Iben Schildt; Dandanell, Gert

1997-01-01

From a genomic library of Sulfolobus solfataricus DSM1617 we have isolated and identified the purEK locus. Two open reading frames are identified as homologs of the purE and purK purine biosynthetic genes in Escherichia coli. The C-terminus of purE overlaps with the N-terminus of purK. When either...... of the genes is expressed from an E. coli promoter they can complement the corresponding purE and purK mutations in E. coli. PurE seems to be more closely related to eubacteria than to other archaea and to eukaryotes. Also the purK gene, which has not yet been found in other archaea, is more closely related...

S.P.Q.R. + Sicilia RoboCup 2005 Report

OpenAIRE

Iocchi , L; Nardi , D; Cherubini , Andrea; Marchetti , L; Ziparo , V.

2005-01-01

International audience; The Italian Robot Team SPQR+Sicilia is the result of a joint effort of two Italian research groups: S.P.Q.R. (Soccer Player Quadruped Robots, but also Senatus PopolusQue Romanus): the group of the Faculty of Engineering at University of Rome “La Sapienza” in Italy, that is involved in RoboCup competitions since 1998 in different leagues (Middle-size 1998-2002, Four-legged since 2001, Real-rescue-robots since 2003). The members of S.P.Q.R. are: Luca Iocchi (Team Leader)...

Driver mutations (JAK2V617F, MPLW515L/K or CALR), pentraxin-3 and C-reactive protein in essential thrombocythemia and polycythemia vera.

Science.gov (United States)

Lussana, Federico; Carobbio, Alessandra; Salmoiraghi, Silvia; Guglielmelli, Paola; Vannucchi, Alessandro Maria; Bottazzi, Barbara; Leone, Roberto; Mantovani, Alberto; Barbui, Tiziano; Rambaldi, Alessandro

2017-02-22

The driver mutations JAK2V617F, MPLW515L/K and CALR influence disease phenotype of myeloproliferative neoplasms (MPNs) and might sustain a condition of chronic inflammation. Pentraxin 3 (PTX3) and high-sensitivity C-reactive protein (hs-CRP) are inflammatory biomarkers potentially useful for refining prognostic classification of MPNs. We evaluated 305 with essential thrombocythemia (ET) and 172 polycythemia vera (PV) patients diagnosed according to the 2016 WHO criteria and with full molecular characterization for driver mutations. PTX3 levels were significantly increased in carriers of homozygous JAK2V617F mutation compared to all the other genotypes and triple negative ET patients, while hs-CRP levels were independent of the mutational profile. The risk of haematological evolution and death from any cause was about 2- and 1.5-fold increased in individuals with high PTX-3 levels, while the thrombosis rate tended to be lower. High hs-CRP levels were associated with risk of haematological evolution, death and also major thrombosis. After sequential adjustment for potential confounders (age, gender, diagnosis and treatments) and the presence of JAK2V617F homozygous status, high hs-CRP levels remained significant for all outcomes, while JAK2V617F homozygous status as well as treatments were the factors independently accounting for adverse outcomes among patients with high PTX3 levels. These results provide evidence that JAK2V617F mutation influences MPN-associated inflammation with a strong correlation between allele burden and PTX3 levels. Plasma levels of hs-CRP and PTX3 might be of prognostic value for patients with ET and PV, but their validation in future prospective studies is needed.

Central Vehicle Dynamics Control of the Robotic Research Platform ROboMObil

OpenAIRE

Bünte, Tilman; Ho, Lok Man; Satzger, Clemens; Brembeck, Jonathan

2014-01-01

The ROboMObil is DLR’s space-robotics driven by-wire electro-mobile research platform for mechatronic actuators, vehicle dynamics control, human machine interfaces, and autonomous driving (DLR = German Aerospace Center). Due to its four highly integrated identical Wheel Robots it exhibits an extraordinary manoeuvrability even allowing for driving sideward or rotating on the spot. Topics related to vehicle dynamics control are addressed in this article.

CMS-dependent prognostic impact of KRAS and BRAFV600E mutations in primary colorectal cancer.

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Smeby, J; Sveen, A; Merok, M A; Danielsen, S A; Eilertsen, I A; Guren, M G; Dienstmann, R; Nesbakken, A; Lothe, R A

2018-05-01

The prognostic impact of KRAS and BRAFV600E mutations in primary colorectal cancer (CRC) varies with microsatellite instability (MSI) status. The gene expression-based consensus molecular subtypes (CMSs) of CRC define molecularly and clinically distinct subgroups, and represent a novel stratification framework in biomarker analysis. We investigated the prognostic value of these mutations within the CMS groups. Totally 1197 primary tumors from a Norwegian series of CRC stage I-IV were analyzed for MSI and mutation status in hotspots in KRAS (codons 12, 13 and 61) and BRAF (codon 600). A subset was analyzed for gene expression and confident CMS classification was obtained for 317 samples. This cohort was expanded with clinical and molecular data, including CMS classification, from 514 patients in the publically available dataset GSE39582. Gene expression signatures associated with KRAS and BRAFV600E mutations were used to evaluate differential impact of mutations on gene expression among the CMS groups. BRAFV600E and KRAS mutations were both associated with inferior 5-year overall survival (OS) exclusively in MSS tumors (BRAFV600E mutation versus KRAS/BRAF wild-type: Hazard ratio (HR) 2.85, P CMS1, leading to negative prognostic impact in this subtype (OS: BRAFV600E mutation versus wild-type: HR 7.73, P = 0.001). In contrast, the poor prognosis of KRAS mutations was limited to MSS tumors with CMS2/CMS3 epithelial-like gene expression profiles (OS: KRAS mutation versus wild-type: HR 1.51, P = 0.011). The subtype-specific prognostic associations were substantiated by differential effects of BRAFV600E and KRAS mutations on gene expression signatures according to the MSI status and CMS group. BRAFV600E mutations are enriched and associated with metastatic disease in CMS1 MSS tumors, leading to poor prognosis in this subtype. KRAS mutations are associated with adverse outcome in epithelial (CMS2/CMS3) MSS tumors.

Study of hTERT and Histone 3 Mutations in Medulloblastoma.

Science.gov (United States)

Viana-Pereira, Marta; Almeida, Gisele Caravina; Stavale, João Norberto; Malheiro, Susana; Clara, Carlos; Lobo, Patrícia; Pimentel, José; Reis, Rui Manuel

2017-01-01

Hotspot activating mutations of the telomerase reverse transcriptase (hTERT) promoter region were recently described in several tumor types. These mutations lead to enhanced expression of telomerase, being responsible for telomere maintenance and allowing continuous cell division. Additionally, there are alternative telomere maintenance mechanisms, associated with histone H3 mutations, responsible for disrupting the histone code and affecting the regulation of transcription. Here, we investigated the clinical relevance of these mechanistically related molecules in medulloblastoma. Sixty-nine medulloblastomas, formalin fixed and paraffin embedded, from a cohort of patients aged 1.5-70 years, were used to investigate the hotspot mutations of the hTERT promoter region, i.e. H3F3A and HIST1H3B, using Sanger sequencing. We successfully sequenced hTERT in all 69 medulloblastoma samples and identified a total of 19 mutated cases (27.5%). c.-124:G>A and c.-146:G>A mutations were detected, respectively, in 16 and 3 samples. Similar to previous reports, hTERT mutations were more frequent in older patients (p < 0.0001), being found only in 5 patients <20 years of age. In addition, hTERT-mutated tumors were more frequently recurrent (p = 0.026) and hTERT mutations were significantly enriched in tumors located in the right cerebellar hemisphere (p = 0.039). No mutations were found on the H3F3A or HIST1H3B genes. hTERT promoter mutations are frequent in medulloblastoma and are associated with older patients, prone to recurrence and located in the right cerebellar hemisphere. On the other hand, histone 3 mutations do not seem to be present in medulloblastoma. © 2016 S. Karger AG, Basel.

A 3-day-old neonate with severe hypertriglyceridemia from novel mutations of the GPIHBP1 gene.

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Buonuomo, Paola Sabrina; Bartuli, Andrea; Rabacchi, Claudio; Bertolini, Stefano; Calandra, Sebastiano

2015-01-01

Familial chylomicronemia is a genetic defect of the intravascular lipolysis of triglyceride (TG)-rich lipoproteins. Intravascular lipolysis involves the TG-hydrolase lipoprotein lipase (LPL) as well as other factors such as apolipoprotein CII and apolipoprotein AV (activators of LPL), GPIHBP1 (the molecular platform required for LPL activity on endothelial surface), and LMF1 (a factor required for intracellular formation of active LPL). We sequenced the familial chylomicronemia candidate genes in a neonate with chylomicronemia. A 3-day-old newborn was found to have chylomicronemia (plasma TG 18.8 mmol/L, 1.667 mg/dL). The discontinuation of breastfeeding for 24 hours reduced plasma TG to 2.3 mmol/L (201 mg/dL), whereas its resumption induced a sharp TG increase (7.9 mmol/L, 690 mg/dL). The child was switched to a low-fat diet, which was effective in maintaining TG level below 3.5 mmol/L (294 mg/dL) during the first months of life. The child was found to be a compound heterozygous for 2 novel mutations in GPIHBP1 gene. The first mutation was a 9-bp deletion and 4-bp insertion in exon 2, causing a frameshift that abolished the canonical termination codon TGA. The predicted translation product of the mutant messenger RNA is a peptide that contains 51 amino acids of the N-terminal end of the wild-type protein followed by 252 novel amino acids. The second mutation was a nucleotide change (c.319T>C), causing an amino acid substitution p.(Ser107Pro) predicted in silico to be damaging. GPIHBP1 mutations should be considered in neonates with chylomicronemia negative for mutations in LPL gene. Copyright © 2015 National Lipid Association. Published by Elsevier Inc. All rights reserved.

7 CFR 319.73-4 - Costs.

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2010-01-01

... 7 Agriculture 5 2010-01-01 2010-01-01 false Costs. 319.73-4 Section 319.73-4 Agriculture..., DEPARTMENT OF AGRICULTURE FOREIGN QUARANTINE NOTICES Coffee § 319.73-4 Costs. All costs of inspection... duty will be furnished without cost to the importer. ...

Systematic Functional Characterization of Resistance to PI3K Inhibition in Breast Cancer.

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Le, Xiuning; Antony, Rajee; Razavi, Pedram; Treacy, Daniel J; Luo, Flora; Ghandi, Mahmoud; Castel, Pau; Scaltriti, Maurizio; Baselga, Jose; Garraway, Levi A

2016-10-01

PIK3CA (which encodes the PI3K alpha isoform) is the most frequently mutated oncogene in breast cancer. Small-molecule PI3K inhibitors have shown promise in clinical trials; however, intrinsic and acquired resistance limits their utility. We used a systematic gain-of-function approach to identify genes whose upregulation confers resistance to the PI3K inhibitor BYL719 in breast cancer cells. Among the validated resistance genes, Proviral Insertion site in Murine leukemia virus (PIM) kinases conferred resistance by maintaining downstream PI3K effector activation in an AKT-independent manner. Concurrent pharmacologic inhibition of PIM and PI3K overcame this resistance mechanism. We also observed increased PIM expression and activity in a subset of breast cancer biopsies with clinical resistance to PI3K inhibitors. PIM1 overexpression was mutually exclusive with PIK3CA mutation in treatment-naïve breast cancers, suggesting downstream functional redundancy. Together, these results offer new insights into resistance to PI3K inhibitors and support clinical studies of combined PIM/PI3K inhibition in a subset of PIK3CA-mutant cancers. PIM kinase overexpression confers resistance to small-molecule PI3K inhibitors. Combined inhibition of PIM and PI3K may therefore be warranted in a subset of breast cancers. Cancer Discov; 6(10); 1134-47. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1069. ©2016 American Association for Cancer Research.

Evidence for a role of srGAP3 in the positioning of commissural axons within the ventrolateral funiculus of the mouse spinal cord.

Directory of Open Access Journals (Sweden)

Claire Bacon

Full Text Available Slit-Robo signaling guides commissural axons away from the floor-plate of the spinal cord and into the longitudinal axis after crossing the midline. In this study we have evaluated the role of the Slit-Robo GTPase activating protein 3 (srGAP3 in commissural axon guidance using a knockout (KO mouse model. Co-immunoprecipitation experiments confirmed that srGAP3 interacts with the Slit receptors Robo1 and Robo2 and immunohistochemistry studies showed that srGAP3 co-localises with Robo1 in the ventral and lateral funiculus and with Robo2 in the lateral funiculus. Stalling axons have been reported in the floor-plate of Slit and Robo mutant spinal cords but our axon tracing experiments revealed no dorsal commissural axon stalling in the floor plate of the srGAP3 KO mouse. Interestingly we observed a significant thickening of the ventral funiculus and a thinning of the lateral funiculus in the srGAP3 KO spinal cord, which has also recently been reported in the Robo2 KO. However, axons in the enlarged ventral funiculus of the srGAP3 KO are Robo1 positive but do not express Robo2, indicating that the thickening of the ventral funiculus in the srGAP3 KO is not a Robo2 mediated effect. We suggest a role for srGAP3 in the lateral positioning of post crossing axons within the ventrolateral funiculus.

Assessing PIK3CA and PTEN in Early-Phase Trials with PI3K/AKT/mTOR Inhibitors

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Filip Janku

2014-01-01

Full Text Available Despite a wealth of preclinical studies, it is unclear whether PIK3CA or phosphatase and tensin homolog (PTEN gene aberrations are actionable in the clinical setting. Of 1,656 patients with advanced, refractory cancers tested for PIK3CA or PTEN abnormalities, PIK3CA mutations were found in 9% (146/1,589, and PTEN loss and/or mutation was found in 13% (149/1,157. In multicovariable analysis, treatment with a phosphatidylinositol 3-kinase (PI3K/AKT/mammalian target of rapamycin (mTOR inhibitor was the only independent factor predicting response to therapy in individuals harboring a PIK3CA or PTEN aberration. The rate of stable disease ≥6 months/partial response reached 45% in a subgroup of individuals with H1047R PIK3CA mutations. Aberrations in the PI3K/AKT/mTOR pathway are common and potentially actionable in patients with diverse advanced cancers. This work provides further important clinical validation for continued and accelerated use of biomarker-driven trials incorporating rational drug combinations.

Regulation of the PI3K pathway through a p85α monomer–homodimer equilibrium

KAUST Repository

Cheung, Lydia W T; Walkiewicz, Katarzyna Wiktoria; Besong, Tabot M.D.; Guo, Huifang; Hawke, David H.; Arold, Stefan T.; Mills, Gordon B.

2015-01-01

The canonical action of the p85α regulatory subunit of phosphatidylinositol 3-kinase (PI3K) is to associate with the p110α catalytic subunit to allow stimuli-dependent activation of the PI3K pathway. We elucidate a p110α-independent role of homodimerized p85α in the positive regulation of PTEN stability and activity. p110α-free p85α homodimerizes via two intermolecular interactions (SH3:proline-rich region and BH:BH) to selectively bind unphosphorylated activated PTEN. As a consequence, homodimeric but not monomeric p85α suppresses the PI3K pathway by protecting PTEN from E3 ligase WWP2-mediated proteasomal degradation. Further, the p85α homodimer enhances the lipid phosphatase activity and membrane association of PTEN. Strikingly, we identified cancer patient-derived oncogenic p85α mutations that target the homodimerization or PTEN interaction surface. Collectively, our data suggest the equilibrium of p85α monomerdimers regulates the PI3K pathway and disrupting this equilibrium could lead to disease development. © Cheung et al.

Regulation of the PI3K pathway through a p85α monomer–homodimer equilibrium

KAUST Repository

Cheung, Lydia W T

2015-07-29

The canonical action of the p85α regulatory subunit of phosphatidylinositol 3-kinase (PI3K) is to associate with the p110α catalytic subunit to allow stimuli-dependent activation of the PI3K pathway. We elucidate a p110α-independent role of homodimerized p85α in the positive regulation of PTEN stability and activity. p110α-free p85α homodimerizes via two intermolecular interactions (SH3:proline-rich region and BH:BH) to selectively bind unphosphorylated activated PTEN. As a consequence, homodimeric but not monomeric p85α suppresses the PI3K pathway by protecting PTEN from E3 ligase WWP2-mediated proteasomal degradation. Further, the p85α homodimer enhances the lipid phosphatase activity and membrane association of PTEN. Strikingly, we identified cancer patient-derived oncogenic p85α mutations that target the homodimerization or PTEN interaction surface. Collectively, our data suggest the equilibrium of p85α monomerdimers regulates the PI3K pathway and disrupting this equilibrium could lead to disease development. © Cheung et al.

Driver mutations (JAK2V617F, MPLW515L/K or CALR), pentraxin-3 and C-reactive protein in essential thrombocythemia and polycythemia vera

OpenAIRE

Lussana, Federico; Carobbio, Alessandra; Salmoiraghi, Silvia; Guglielmelli, Paola; Vannucchi, Alessandro Maria; Bottazzi, Barbara; Leone, Roberto; Mantovani, Alberto; Barbui, Tiziano; Rambaldi, Alessandro

2017-01-01

Abstract Background The driver mutations JAK2V617F, MPLW515L/K and CALR influence disease phenotype of myeloproliferative neoplasms (MPNs) and might sustain a condition of chronic inflammation. Pentraxin 3 (PTX3) and high-sensitivity C-reactive protein (hs-CRP) are inflammatory biomarkers potentially useful for refining prognostic classification of MPNs. Methods We evaluated 305 with essential thrombocythemia (ET) and 172 polycythemia vera (PV) patients diagnosed according to the 2016 WHO cri...

Normosmic congenital hypogonadotropic hypogonadism due to TAC3/TACR3 mutations: characterization of neuroendocrine phenotypes and novel mutations.

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Bruno Francou

Full Text Available CONTEXT: TAC3/TACR3 mutations have been reported in normosmic congenital hypogonadotropic hypogonadism (nCHH (OMIM #146110. In the absence of animal models, studies of human neuroendocrine phenotypes associated with neurokinin B and NK3R receptor dysfunction can help to decipher the pathophysiology of this signaling pathway. OBJECTIVE: To evaluate the prevalence of TAC3/TACR3 mutations, characterize novel TACR3 mutations and to analyze neuroendocrine profiles in nCHH caused by deleterious TAC3/TACR3 biallelic mutations. RESULTS: From a cohort of 352 CHH, we selected 173 nCHH patients and identified nine patients carrying TAC3 or TACR3 variants (5.2%. We describe here 7 of these TACR3 variants (1 frameshift and 2 nonsense deleterious mutations and 4 missense variants found in 5 subjects. Modeling and functional studies of the latter demonstrated the deleterious consequence of one missense mutation (Tyr267Asn probably caused by the misfolding of the mutated NK3R protein. We found a statistically significant (p<0.0001 higher mean FSH/LH ratio in 11 nCHH patients with TAC3/TACR3 biallelic mutations than in 47 nCHH patients with either biallelic mutations in KISS1R, GNRHR, or with no identified mutations and than in 50 Kallmann patients with mutations in KAL1, FGFR1 or PROK2/PROKR2. Three patients with TAC3/TACR3 biallelic mutations had an apulsatile LH profile but low-frequency alpha-subunit pulses. Pulsatile GnRH administration increased alpha-subunit pulsatile frequency and reduced the FSH/LH ratio. CONCLUSION: The gonadotropin axis dysfunction associated with nCHH due to TAC3/TACR3 mutations is related to a low GnRH pulsatile frequency leading to a low frequency of alpha-subunit pulses and to an elevated FSH/LH ratio. This ratio might be useful for pre-screening nCHH patients for TAC3/TACR3 mutations.

Driver mutations (JAK2V617F, MPLW515L/K or CALR, pentraxin-3 and C-reactive protein in essential thrombocythemia and polycythemia vera

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Federico Lussana

2017-02-01

Full Text Available Abstract Background The driver mutations JAK2V617F, MPLW515L/K and CALR influence disease phenotype of myeloproliferative neoplasms (MPNs and might sustain a condition of chronic inflammation. Pentraxin 3 (PTX3 and high-sensitivity C-reactive protein (hs-CRP are inflammatory biomarkers potentially useful for refining prognostic classification of MPNs. Methods We evaluated 305 with essential thrombocythemia (ET and 172 polycythemia vera (PV patients diagnosed according to the 2016 WHO criteria and with full molecular characterization for driver mutations. Results PTX3 levels were significantly increased in carriers of homozygous JAK2V617F mutation compared to all the other genotypes and triple negative ET patients, while hs-CRP levels were independent of the mutational profile. The risk of haematological evolution and death from any cause was about 2- and 1.5-fold increased in individuals with high PTX-3 levels, while the thrombosis rate tended to be lower. High hs-CRP levels were associated with risk of haematological evolution, death and also major thrombosis. After sequential adjustment for potential confounders (age, gender, diagnosis and treatments and the presence of JAK2V617F homozygous status, high hs-CRP levels remained significant for all outcomes, while JAK2V617F homozygous status as well as treatments were the factors independently accounting for adverse outcomes among patients with high PTX3 levels. Conclusions These results provide evidence that JAK2V617F mutation influences MPN-associated inflammation with a strong correlation between allele burden and PTX3 levels. Plasma levels of hs-CRP and PTX3 might be of prognostic value for patients with ET and PV, but their validation in future prospective studies is needed.

Compounding of vitamin A, D3, E and K3 supplements for cystic fibrosis patients: formulation and stability study.

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Huyghebaert, N; De Beer, J; Vervaet, C; Remon, J P

2007-10-01

Cystic fibrosis (CF) patients suffer from malabsorption of fat-soluble vitamins (A, D, E and K). These vitamins are available as water-dispersible (A, D(3) and E) or water-soluble grades (K(3)), which is favoured in CF patients as they fail to absorb oil-based products. The objective of this study was to determine stability of these raw materials after opening the original package and to develop a compounded formulation of acceptable quality, stability and taste, allowing flexible dose adaptation and being appropriate for administration to children and elderly people. The raw materials were stored after opening their original package for 8 months at 8 degrees C and room temperature (RT). Stability was assessed using a validated HPLC method after extraction of the vitamin from the cold water-soluble matrix (vitamin A acetate, D(3) and E) or using a spectrophotometrical method (vitamin K(3)). These materials were mixed with an appropriate lactose grade (lactose 80 m for vitamins A and D(3); lactose 90 m for vitamin E, lactose very fine powder for vitamin K(3)) and filled in hard gelatin capsules. Mass and content uniformity were determined and stability of the vitamins in the capsules was assessed after 2 months storage at 8 degrees C and RT. All raw materials showed good stability during storage in the opened original package for 8 months storage at 8 degrees C as well as RT (>95% of the initial content). The compounded formulations complied with the requirements of the European Pharmacopoeia for mass and content uniformity and can be stored for 2 months at 8 degrees C or RT while maintaining the vitamin content between 90% and 110%. As these fat-soluble vitamins are not commercially available on the Belgian market, compounded formulations are a valuable alternative for prophylactic administration of these vitamins to CF patients, i.e. a stable formulation, having an acceptable taste, allowing flexible dose adaptation and being appropriate for administration to

Quail FMO3 gene cloning, tissue expression profiling, polymorphism detection and association analysis with fishy taint in eggs.

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Fengtao Mo

Full Text Available Quail eggs comprise a significant and favourable part of table eggs in certain countries. Some quail eggs, however, present fishy off-flavor which directly influences their quality. It is reported that flavin-containing monooxygenase 3 (FMO3 is associated with fish-odour trait in human and animal products. FMO3 is responsible for the degradation of trimethylamine (TMA in vivo. Loss-of-function mutations in FMO3 gene can result in defective TMA N-oxygenation, giving rise to disorder known as "fish-odour syndrome" in human, as well as the fishy off-flavor in cow milk and chicken eggs. In order to reveal the genetic factor of fishy taint in quail eggs, we cloned the cDNA sequence of quail FMO3 gene, investigated FMO3 mRNA expression level in various tissues, detected SNPs in the coding region of the gene and conducted association analysis between a mutation and the TMA content in quail egg yolks. The 1888 bp cDNA sequence of quail FMO3 gene encoding 532 amino acids was obtained and characterized. The phylogenetic analysis revealed quail FMO3 had a closer relationship with chicken FMO3. The FMO3 mRNA was highly expressed in liver and kidney of quail. Nine SNPs were detected in the coding sequence of quail FMO3 gene, including a nonsense mutation (Q319X which was significantly associated with the elevated TMA content in quail egg yolks. Genotype TT at Q319X mutation loci was sensitive to choline. With addition of choline in the feed, the quails with homozygote TT at the Q319X mutation loci laid fish-odour eggs, indicating an interaction between genotype and diet. The results indicated that Q319X mutation was associated with the fishy off-flavor in quail eggs. Identification of the unfavorable allele T of quail FMO3 gene can be applied in future quail breeding to eliminate fishy off-flavor trait in quail eggs.

Animal products and K-ras codon 12 and 13 mutations in colon carcinomas

NARCIS (Netherlands)

Kampman, E.; Voskuil, D.W.; Kraats, A.A. van; Balder, H.F.; Muijen, G.N.P. van; Goldbohm, R.A.; Veer, P. van 't

2000-01-01

K-ras gene mutations (codons 12 and 13) were determined by PCR-based mutant allele-specific amplification (MASA) in tumour tissue of 185 colon cancer patients: 36% harboured mutations, of which 82% were located in codon 12. High intakes of animal protein, calcium and poultry were differently

Discordance of Mutation Statuses of Epidermal Growth Factor Receptor and K-ras between Primary Adenocarcinoma of Lung and Brain Metastasis

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Kun-Ming Rau

2016-04-01

Full Text Available Mutations on epidermal growth factor receptor (EGFR of adenocarcinomas of lung have been found to be associated with increased sensitivity to EGFR tyrosine kinase inhibitors and K-ras mutations may correlate with primary resistance. We aimed to explore the discordant mutation statuses of EGFR and K-ras between primary tumors and matched brain metastases in adenocarcinomas of lung. We used a sensitive Scorpion ARMS method to analyze EGFR mutation, and Sanger sequencing followed by allele-specific real-time polymerase chain reaction to analyze K-ras mutation. Forty-nine paired tissues with both primary adenocarcinoma of lung and matched brain metastasis were collected. Thirteen patients (26.5% were discordant for the status of EGFR between primary and metastatic sites. K-ras gene could be checked in paired specimens from 33 patients, thirteen patients (39.6% were discordant for the status of K-ras. In primary lung adenocarcinoma, there were 14 patients of mutant EGFR had mutant K-ras synchronously. This study revealed that the status of EGFR mutation in lung adenocarcinomas is relatively consistent between primary and metastatic sites compared to K-ras mutation. However, there are still a few cases of adenocarcinoma of lung showing discordance for the status of EGFR mutation. Repeated analysis of EGFR mutation is highly recommended if tissue from metastatic or recurrent site is available for the evaluation of target therapy.

Evaluating maps produced by urban search and rescue robots: Lessons learned from RoboCup

NARCIS (Netherlands)

Balaguer, B.; Balakirsky, S.; Carpin, S.; Visser, A.

2009-01-01

This paper presents the map evaluation methodology developed for the Virtual Robots Rescue competition held as part of RoboCup. The procedure aims to evaluate the quality of maps produced by multi-robot systems with respect to a number of factors, including usability, exploration, annotation and

9 CFR 319.80 - Barbecued meats.

Science.gov (United States)

2010-01-01

... CERTIFICATION DEFINITIONS AND STANDARDS OF IDENTITY OR COMPOSITION Cooked Meats § 319.80 Barbecued meats. Barbecued meats, such as product labeled “Beef Barbecue” or “Barbecued Pork,” shall be cooked by the direct... 9 Animals and Animal Products 2 2010-01-01 2010-01-01 false Barbecued meats. 319.80 Section 319.80...

Enhanced Production of Vitamin K2 from Bacillus subtilis (nattoby Mutation and Optimization of the Fermentation Medium

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Junying Song

2014-08-01

Full Text Available The aim of this study was to enhance the production of vitamin K2 by using N-methyl-N-nitro-N-nitroso-guanidine (NTG and low energy ion beam implantation and optimizing the fermentation medium. Mutation resulted in 1.66-fold higher production of vitamin K2 than that of the parentl strain. The production by the mutant BN-P15-11-1was increased 55% and reached 3.593±0.107 mg/L by using the Plackett-Burman and Box-Behnken designs to optimize the fermentation medium. The optimal fermentation culture medium was composed of (g/L glycerol 69.6, sucrose 34.5, K2HPO4 4.0, peptone 20, yeast extract 25 and fermented at 37 °C and 150 rpm for 72 h. The results showed that the NTG and low energy ion beam implantation mutations and optimizing fermentation medium were effective methods to enhance vitamin K2production.

The non-small cell lung cancer EGFR extracellular domain mutation, M277E, is oncogenic and drug-sensitive

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Yu S

2017-09-01

Full Text Available Su Yu,1,2 Yang Zhang,1 Yunjian Pan,1 Chao Cheng,1,3 Yihua Sun,1,3 Haiquan Chen1–4 1Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; 2Cancer Research Center, Fudan University Shanghai Cancer Center, Shanghai, China; 3Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; 4Institutes of Biomedical Sciences, Fudan University, Shanghai, China Purpose: To identify novel oncogenic mutations in non-small cell lung cancer patient specimens that lack mutations in known targetable genes (“pan-negative” patients.Methods: Comprehensive mutational analyses were performed on 1,356 lung adenocarcinoma specimens. In this cohort of patients, common lung cancer oncogenic driver mutations were detected in the epidermal growth factor receptor (EGFR kinase domain, the human epidermal growth factor receptor 2 kinase domain, as well as the KRAS, BRAF, ALK, ROS1 and RET genes. A sub-cohort of pan-negative patient specimens was assayed for mutations in the EGFR extracellular domain (ECD. Additionally, EGFR mutant NIH-3T3 stable cell lines were constructed and assessed for protein content, anchorage-independent growth, and tumor formation in xenograft models to identify oncogenic mutations. BaF3 lymphocytes were also used to test sensitivities of the mutations to tyrosine kinase inhibitors.Results: In pan-negative lung adenocarcinoma cases, a novel oncogenic EGFR ECD mutation was identified (M277E. EGFR M277E mutations encoded oncoproteins that transformed NIH-3T3 cells to grow in the absence of exogenous epidermal growth factor. Transformation was further evidenced by anchorage-independent growth and tumor formation in immunocompromised xenograft mouse models. Finally, as seen in the canonical EGFR L858R mutation, the M277E mutation conferred sensitivity to both erlotinib and cetuximab in BaF3 cell lines and to erlotinib in xenograft models.Conclusion: Here, a new EGFR driver mutation, M277E

Frequent alterations of the PI3K/AKT/mTOR pathways in hereditary nonpolyposis colorectal cancer

DEFF Research Database (Denmark)

Ekstrand, Anna Isinger; Jönsson, Mats; Lindblom, Annika

2010-01-01

The phosphatidylinositol 3-kinases-AKT-mammalian target of rapamycin pathway (PI3K/AKT/mTOR) is central in colorectal tumors. Data on its role in hereditary cancers are, however, scarce and we therefore characterized mutations in PIK3CA and KRAS, and expression of PIK3CA, phosphorylated AKT......, and PTEN in colorectal cancers linked to hereditary nonpolyposis colorectal cancer (HNPCC). Sequencing was used to identify mutations in PIK3CA, a real-time PCR-based method to identify KRAS mutations, and immunohistochemical staining was used to evaluate the expression of PIK3CA, phosphorylated AKT...... and PTEN in 58 HNPCC-associated colorectal cancers. Derangements of at least one of the PI3K/AKT/mTOR components analyzed were found in 51/58 (88%) tumors. Mutations in PIK3CA and KRAS were identified in 14 and 31% of the tumors respectively. Overexpression of PIK3CA and phosphorylated AKT occurred in 59...

Indian hedgehog mutations causing brachydactyly type A1 impair Hedgehog signal transduction at multiple levels

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Ma, Gang; Yu, Jiang; Xiao, Yue; Chan, Danny; Gao, Bo; Hu, Jianxin; He, Yongxing; Guo, Shengzhen; Zhou, Jian; Zhang, Lingling; Gao, Linghan; Zhang, Wenjuan; Kang, Yan; Cheah, Kathryn SE; Feng, Guoyin; Guo, Xizhi; Wang, Yujiong; Zhou, Cong-zhao; He, Lin

2011-01-01

Brachydactyly type A1 (BDA1), the first recorded Mendelian autosomal dominant disorder in humans, is characterized by a shortening or absence of the middle phalanges. Heterozygous missense mutations in the Indian Hedgehog (IHH) gene have been identified as a cause of BDA1; however, the biochemical consequences of these mutations are unclear. In this paper, we analyzed three BDA1 mutations (E95K, D100E, and E131K) in the N-terminal fragment of Indian Hedgehog (IhhN). Structural analysis showed that the E95K mutation changes a negatively charged area to a positively charged area in a calcium-binding groove, and that the D100E mutation changes the local tertiary structure. Furthermore, we showed that the E95K and D100E mutations led to a temperature-sensitive and calcium-dependent instability of IhhN, which might contribute to an enhanced intracellular degradation of the mutant proteins via the lysosome. Notably, all three mutations affected Hh binding to the receptor Patched1 (PTC1), reducing its capacity to induce cellular differentiation. We propose that these are common features of the mutations that cause BDA1, affecting the Hh tertiary structure, intracellular fate, binding to the receptor/partners, and binding to extracellular components. The combination of these features alters signaling capacity and range, but the impact is likely to be variable and mutation-dependent. The potential variation in the signaling range is characterized by an enhanced interaction with heparan sulfate for IHH with the E95K mutation, but not the E131K mutation. Taken together, our results suggest that these IHH mutations affect Hh signaling at multiple levels, causing abnormal bone development and abnormal digit formation. PMID:21537345

PIK3CA activating mutation in colorectal carcinoma: associations with molecular features and survival.

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Christophe Rosty

Full Text Available Mutations in PIK3CA are present in 10 to 15% of colorectal carcinomas. We aimed to examine how PIK3CA mutations relate to other molecular alterations in colorectal carcinoma, to pathologic phenotype and survival. PIK3CA mutation testing was carried out using direct sequencing on 757 incident tumors from the Melbourne Collaborative Cohort Study. The status of O-6-methylguanine-DNA methyltransferase (MGMT was assessed using both immunohistochemistry and methyLight techniques. Microsatellite instability, CpG island phenotype (CIMP, KRAS and BRAF V600E mutation status, and pathology review features were derived from previous reports. PIK3CA mutation was observed in 105 of 757 (14% of carcinomas, characterized by location in the proximal colon (54% vs. 34%; P<0.001 and an increased frequency of KRAS mutation (48% vs. 25%; P<0.001. High-levels of CIMP were more frequently found in PIK3CA-mutated tumors compared with PIK3CA wild-type tumors (22% vs. 11%; P = 0.004. There was no difference in the prevalence of BRAF V600E mutation between these two tumor groups. PIK3CA-mutated tumors were associated with loss of MGMT expression (35% vs. 20%; P = 0.001 and the presence of tumor mucinous differentiation (54% vs. 32%; P<0.001. In patients with wild-type BRAF tumors, PIK3CA mutation was associated with poor survival (HR 1.51 95% CI 1.04-2.19, P = 0.03. In summary, PIK3CA-mutated colorectal carcinomas are more likely to develop in the proximal colon, to demonstrate high levels of CIMP, KRAS mutation and loss of MGMT expression. PIK3CA mutation also contributes to significantly decreased survival for patients with wild-type BRAF tumors.

TOX3 mutations in breast cancer.

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James Owain Jones

Full Text Available TOX3 maps to 16q12, a region commonly lost in breast cancers and recently implicated in the risk of developing breast cancer. However, not much is known of the role of TOX3 itself in breast cancer biology. This is the first study to determine the importance of TOX3 mutations in breast cancers. We screened TOX3 for mutations in 133 breast tumours and identified four mutations (three missense, one in-frame deletion of 30 base pairs in six primary tumours, corresponding to an overall mutation frequency of 4.5%. One potentially deleterious missense mutation in exon 3 (Leu129Phe was identified in one tumour (genomic DNA and cDNA. Whilst copy number changes of 16q12 are common in breast cancer, our data show that mutations of TOX3 are present at low frequency in tumours. Our results support that TOX3 should be further investigated to elucidate its role in breast cancer biology.

Mutations in the Bacterial Ribosomal Protein L3 and Their Association with Antibiotic Resistance

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Klitgaard, Rasmus N.; Ntokou, Eleni; Nørgaard, Katrine; Biltoft, Daniel; Hansen, Lykke H.; Trædholm, Nicolai M.; Kongsted, Jacob

2015-01-01

Different groups of antibiotics bind to the peptidyl transferase center (PTC) in the large subunit of the bacterial ribosome. Resistance to these groups of antibiotics has often been linked with mutations or methylations of the 23S rRNA. In recent years, there has been a rise in the number of studies where mutations have been found in the ribosomal protein L3 in bacterial strains resistant to PTC-targeting antibiotics but there is often no evidence that these mutations actually confer antibiotic resistance. In this study, a plasmid exchange system was used to replace plasmid-carried wild-type genes with mutated L3 genes in a chromosomal L3 deletion strain. In this way, the essential L3 gene is available for the bacteria while allowing replacement of the wild type with mutated L3 genes. This enables investigation of the effect of single mutations in Escherichia coli without a wild-type L3 background. Ten plasmid-carried mutated L3 genes were constructed, and their effect on growth and antibiotic susceptibility was investigated. Additionally, computational modeling of the impact of L3 mutations in E. coli was used to assess changes in 50S structure and antibiotic binding. All mutations are placed in the loops of L3 near the PTC. Growth data show that 9 of the 10 mutations were well accepted in E. coli, although some of them came with a fitness cost. Only one of the mutants exhibited reduced susceptibility to linezolid, while five exhibited reduced susceptibility to tiamulin. PMID:25845869

Detecting BRAF Mutations in Formalin-Fixed Melanoma: Experiences with TwoState-of-the-Art Techniques

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Nicola L. Schoenewolf

2012-06-01

Full Text Available Background: Melanoma is characterized by a high frequency of BRAF mutations. It is unknown if the BRAF mutation status has any predictive value for therapeutic approaches such as angiogenesis inhibition. Patients and Methods: We used 2 methods to analyze the BRAF mutation status in 52 of 62 melanoma patients. Method 1 (mutation-specific real-time PCR specifically detects the most frequent BRAF mutations, V600E and V600K. Method 2 (denaturing gel gradient electrophoresis and direct sequencing identifies any mutations affecting exons 11 and 15. Results: Eighteen BRAF mutations and 15 wild-type mutations were identified with both methods. One tumor had a double mutation (GAA in codon 600. Results of 3 samples were discrepant. Additional mutations (V600M, K601E were detected using method 2. Sixteen DNA samples were analyzable with either method 1 or method 2. There was a significant association between BRAF V600E mutation and survival. Conclusion: Standardized tissue fixation protocols are needed to optimize BRAF mutation analysis in melanoma. For melanoma treatment decisions, the availability of a fast and reliable BRAF V600E screening method may be sufficient. If other BRAF mutations in exons 11 and 15 are found to be of predictive value, a combination of the 2 methods would be useful.

Meat consumption and K-ras mutations in sporadic colon and rectal cancer in The Netherlands Cohort Study

NARCIS (Netherlands)

Brink, M.; Weijenberg, M.P.; Goeij, A.F.P.M. de; Roemen, G.M.J.M.; Lentjes, M.H.F.M.; Bruïne, A.P. de; Goldbohm, R.A.; Brandt, P.A. van den

2005-01-01

Case-cohort analyses were performed on meat and fish consumption in relation to K-ras mutations in 448 colon and 160 rectal cancers that occurred during 7.3 years of follow-up, excluding the first 2.3 years, and 2948 subcohort members of The Netherlands Cohort Study on diet and cancer. Adjusted

Functional analysis of Waardenburg syndrome-associated PAX3 and SOX10 mutations: report of a dominant-negative SOX10 mutation in Waardenburg syndrome type II.

Science.gov (United States)

Zhang, Hua; Chen, Hongsheng; Luo, Hunjin; An, Jing; Sun, Lin; Mei, Lingyun; He, Chufeng; Jiang, Lu; Jiang, Wen; Xia, Kun; Li, Jia-Da; Feng, Yong

2012-03-01

Waardenburg syndrome (WS) is an auditory-pigmentary disorder resulting from melanocyte defects, with varying combinations of sensorineural hearing loss and abnormal pigmentation of the hair, skin, and inner ear. WS is classified into four subtypes (WS1-WS4) based on additional symptoms. PAX3 and SOX10 are two transcription factors that can activate the expression of microphthalmia-associated transcription factor (MITF), a critical transcription factor for melanocyte development. Mutations of PAX3 are associated with WS1 and WS3, while mutations of SOX10 cause WS2 and WS4. Recently, we identified some novel WS-associated mutations in PAX3 and SOX10 in a cohort of Chinese WS patients. Here, we further identified an E248fsX30 SOX10 mutation in a family of WS2. We analyzed the subcellular distribution, expression and in vitro activity of two PAX3 mutations (p.H80D, p.H186fsX5) and four SOX10 mutations (p.E248fsX30, p.G37fsX58, p.G38fsX69 and p.R43X). Except H80D PAX3, which retained partial activity, the other mutants were unable to activate MITF promoter. The H80D PAX3 and E248fsX30 SOX10 were localized in the nucleus as wild type (WT) proteins, whereas the other mutant proteins were distributed in both cytoplasm and nucleus. Furthermore, E248fsX30 SOX10 protein retained the DNA-binding activity and showed dominant-negative effect on WT SOX10. However, E248fsX30 SOX10 protein seems to decay faster than the WT one, which may underlie the mild WS2 phenotype caused by this mutation.

A SURVEY OF THE HIGH ORDER MULTIPLICITY OF NEARBY SOLAR-TYPE BINARY STARS WITH Robo-AO

Energy Technology Data Exchange (ETDEWEB)

Riddle, Reed L.; Bui, Khanh; Dekany, Richard G.; Kulkarni, Shrinivas; Tendulkar, Shriharsh P. [Division of Physics, Mathematics, and Astronomy, California Institute of Technology, Pasadena, CA 91125 (United States); Tokovinin, Andrei [Cerro Tololo Inter-American Observatory, Casilla 603, La Serena (Chile); Mason, Brian D.; Hartkopf, William I. [U.S. Naval Observatory, 3450 Massachusetts Avenue, Washington, DC 20392-5420 (United States); Roberts, Lewis C. Jr. [Jet Propulsion Laboratory, California Institute of Technology, 4800 Oak Grove Drive, Pasadena, CA 91109 (United States); Baranec, Christoph [Institute for Astronomy, University of Hawai" i at Mānoa, Hilo, HI 96720-2700 (United States); Law, Nicholas M. [Department of Physics and Astronomy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3255 (United States); Burse, Mahesh P.; Das, H. K.; Punnadi, Sujit; Ramaprakash, A. N. [Inter-University Centre for Astronomy and Astrophysics, Ganeshkhind, Pune, 411007 (India)

2015-01-20

We conducted a survey of nearby binary systems composed of main sequence stars of spectral types F and G in order to improve our understanding of the hierarchical nature of multiple star systems. Using Robo-AO, the first robotic adaptive optics instrument, we collected high angular resolution images with deep and well-defined detection limits in the Sloan Digital Sky Survey i' band. A total of 695 components belonging to 595 systems were observed. We prioritized observations of faint secondary components with separations over 10'' to quantify the still poorly constrained frequency of their subsystems. Of the 214 secondaries observed, 39 contain such subsystems; 19 of those were discovered with Robo-AO. The selection-corrected frequency of secondary subsystems with periods from 10{sup 3.5} to 10{sup 5} days is 0.12 ± 0.03, the same as the frequency of such companions to the primary. Half of the secondary pairs belong to quadruple systems where the primary is also a close pair, showing that the presence of subsystems in both components of the outer binary is correlated. The relatively large abundance of 2+2 quadruple systems is a new finding, and will require more exploration of the formation mechanism of multiple star systems. We also targeted close binaries with periods less than 100 yr, searching for their distant tertiary components, and discovered 17 certain and 2 potential new triples. In a subsample of 241 close binaries, 71 have additional outer companions. The overall frequency of tertiary components is not enhanced, compared to all (non-binary) targets, but in the range of outer periods from 10{sup 6} to 10{sup 7.5} days (separations on the order of 500 AU), the frequency of tertiary components is 0.16 ± 0.03, exceeding the frequency of similar systems among all targets (0.09) by almost a factor of two. Measurements of binary stars with Robo-AO allowed us to compute first orbits for 9 pairs and to improve orbits of another 11 pairs.

Tumorigenesis of K-ras mutation in human endometrial carcinoma via upregulation of estrogen receptor.

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Tu, Zheng; Gui, Liming; Wang, Jianliu; Li, Xiaoping; Sun, Pengming; Wei, Lihui

2006-05-01

To investigate the tumorigenesis of mutant [12Asp]-K-ras in endometrial carcinoma and its relationship with ER. We constructed pcDI-[12Asp]K-ras4B by inserting full-length [12Asp]K-ras4B from human endometrial carcinoma Hec-1A cells, into pcDI vector. Cell proliferation of NIH3T3 after transfection with pcDI-[12Asp]K-ras4B was measured by MTT assay. The cell transformation was determined by colony formation and tumor nodule development. [12Asp]-K-ras4B-NIH3T3 cells were transfected with constitutively active pCMV-RafCAAX and dominant-negative pCMV-RafS621A. Cell growth was measured by MTT assay and [3H]thymidine incorporation. After transfected with pcDI-[12Asp]K-ras4B or pCMV-RafS621A, the cells were harvested for Western blot and reporter assay to determine the expression and transcriptional activity of ERalpha and ERbeta, respectively. [12Asp]-K-ras4B enhanced NIH3T3 cells proliferation after 48 h post-transfection (P ras4B-NIH3T3 cells (13.48%) than pcDI-NIH3T3 (4.26%) or untreated NIH3T3 (2.33%). The pcDI-[12Asp]-K-ras4B-NIH3T3 cells injected to the nude mice Balb/C developed tumor nodules with poor-differentiated cells after 12 days. An increase of ERalpha and ERbeta was observed in pcDI-[12Asp]-K-ras4B-NIH3T3 cells. RafS621A downregulated ERalpha and ERbeta expression. Estrogen induced the ER transcriptional activity by 5-fold in pcDI-NIH3T3 cells, 13-fold in pcDI-[12Asp]K-ras4B-NIH3T3 and 19-fold in HEC-1A. RafS621A suppressed the ER transcriptional activity. K-ras mutation induces tumorigenesis in endometrium, and this malignant transformation involves Raf signaling pathway and ER.

Association of folate intake, dietary habits, smoking and COX-2 promotor -765G>C polymorphism with K-ras mutation in patients with colorectal cancer.

Science.gov (United States)

Kamal, Manal M; Youssef, Omar Z; Lotfy, Ahmed N; Elsaed, Eman T; Fawzy, May M T

2012-09-01

Understanding the role of environmental and molecular influences on the nature and rate of K-ras mutations in colorectal neoplasms is crucial. COX-2 polymorphisms -765G>C may play a role in carcinogenic processes in combination with specific life-style conditions or dependent on the racial composition of a particular population. If mutational events play an important role in colorectal carcinogenesis sequence, one can hypothesize that modification of these events by life-style or other factors would be a useful prevention strategy. To explore the association between K-ras mutation and potential variables known or suspected to be related to the risk of colorectal cancer (CRC) as well as determining the possible modulating effect of the COX-2 polymorphism, -765G>C. The study was conducted on 80 patients with colorectal cancer from Tropical Medicine and Gastrointestinal Tract endoscopy Departments and those attending clinic of the National Cancer Institute, Cairo University during the period extending from April 2009 to March 2010. Full history taking with emphasis on the risk factors of interest, namely age, sex, family history, smoking and dietary history. Serum CEA and CA19-9, RBCs folic acid and occult blood in stool were done to all samples. K-ras protooncogene mutation at codon 12 (exon 1) and cyclooxygenase 2 (COX-2) -765G>C polymorphism were determined by PCR-RFLP. The K-ras mutation was positive in 23 (28.7%) patients. COX-2 polymorphism revealed GG in 62.5%, GC in 26.2 % and CC genotype was found in 11.3 % of cases. The mean red blood cell folic acid level was lower in the K-ras positive group (100.96±51.3 ng/ml) than the negative group (216.6±166.4 ng/ml), (P<0.01). Higher folate levels were found in males than females (median=173 ng/ml and 85 ng/ml; respectively, P=0.002) with adjusted odds ratio (OR) of 0.984. Only, the RBCs folate (P=0.0018) followed by gender (P=0.036) contributed significantly in the discrimination between patients prone to develop K

Association of folate intake, dietary habits, smoking and COX-2 promotor-765G > C polymorphism with K-ras mutation in patients with colorectal cancer

International Nuclear Information System (INIS)

Kamal, M.M.; Youssef, O.Z.; Lotfy, A.N.; Elsaed, E.T.; Fawzy, M.M.T.

2012-01-01

Background: Understanding the role of environmental and molecular influences on the nature and rate of K-ras mutations in colorectal neoplasms is crucial. COX-2 polymorphisms -765G > C may play a role in carcinogenic processes in combination with specific life-style conditions or dependent on the racial composition of a particular population. If mutational events play an important role in colorectal carcinogenesis sequence, one can hypothesize that modification of these events by life-style or other factors would be a useful prevention strategy. Aim of work: To explore the association between K-ras mutation and potential variables known or suspected to be related to the risk of colorectal cancer (CRC) as well as determining the possible modulating effect of the COX-2 polymorphism, —765G > C. Subjects and methods: The study was conducted on 80 patients with colorectal cancer from Tropical Medicine and Gastrointestinal Tract endoscopy Departments and those attending clinic of the National Cancer Institute, Cairo University during the period extending from April 2009 to March 2010. Full history taking with emphasis on the risk factors of interest, namely age, sex, family history, smoking and dietary history. Serum CEA and CA19-9, RBCs folic acid and occult blood in stool were done to all samples. K-ras protooncogene mutation at codon 12 (exon 1) and cyclooxygenase 2 (COX-2) —765G > C polymorphism were determined by PCR-RFLP. Results: The K-ras mutation was positive in 23 (28.7%) patients. COX-2 polymorphism revealed GG in 62.5%, GC in 26.2 % and CC genotype was found in 11.3 % of cases. The mean red blood cell folic acid level was lower in the K-ras positive group (100.96 ± 51.3 ng/ml) than the negative group (216.6 ± 166.4 ng/ml), (P < 0.01). Higher folate levels were found in males than females (median = 173 ng/ml and 85 ng/ml; respectively, P = 0.002) with adjusted odds ratio (OR) of 0.984. Only, the RBCs folate (P = 0.0018) followed by gender (P = 0

GTP Binding and Oncogenic Mutations May Attenuate Hypervariable Region (HVR)-Catalytic Domain Interactions in Small GTPase K-Ras4B, Exposing the Effector Binding Site*

Science.gov (United States)

Lu, Shaoyong; Banerjee, Avik; Jang, Hyunbum; Zhang, Jian; Gaponenko, Vadim; Nussinov, Ruth

2015-01-01

K-Ras4B, a frequently mutated oncogene in cancer, plays an essential role in cell growth, differentiation, and survival. Its C-terminal membrane-associated hypervariable region (HVR) is required for full biological activity. In the active GTP-bound state, the HVR interacts with acidic plasma membrane (PM) headgroups, whereas the farnesyl anchors in the membrane; in the inactive GDP-bound state, the HVR may interact with both the PM and the catalytic domain at the effector binding region, obstructing signaling and nucleotide exchange. Here, using molecular dynamics simulations and NMR, we aim to figure out the effects of nucleotides (GTP and GDP) and frequent (G12C, G12D, G12V, G13D, and Q61H) and infrequent (E37K and R164Q) oncogenic mutations on full-length K-Ras4B. The mutations are away from or directly at the HVR switch I/effector binding site. Our results suggest that full-length wild-type GDP-bound K-Ras4B (K-Ras4BWT-GDP) is in an intrinsically autoinhibited state via tight HVR-catalytic domain interactions. The looser association in K-Ras4BWT-GTP may release the HVR. Some of the oncogenic mutations weaken the HVR-catalytic domain association in the K-Ras4B-GDP/-GTP bound states, which may facilitate the HVR disassociation in a nucleotide-independent manner, thereby up-regulating oncogenic Ras signaling. Thus, our results suggest that mutations can exert their effects in more than one way, abolishing GTP hydrolysis and facilitating effector binding. PMID:26453300

Importance of Leu99 in transmembrane segment M1 of the Na+, K+ -ATPase in the binding and occlusion of K+

DEFF Research Database (Denmark)

Einholm, Anja P.; Andersen, Jens Peter; Vilsen, Bente

2007-01-01

Twenty-six point mutations were introduced into the N-terminal and middle parts of transmembrane segment M1 of the Na+, K+ -ATPase and its cytosolic extension. None of the alterations to charged and polar residues in the N-terminal part of M1 and its cytosolic extension had any major effect...... on the cation binding properties, thus rejecting the hypothesis that these residues are involved in cation selectivity. By contrast, specific residues in the middle part of M1, particularly Leu(99), were found critical to K+ interaction of the enzyme. Hence, mutation L99A reduced the affinity for K+ activation...... of E2P dephosphorylation 17-fold, and L99F reduced the equilibrium level of the K+-occluded intermediate [K2]E2 and increased the rate of K+ deocclusion 39-fold, i.e. more than seen for mutation E329Q of the cation-binding glutamate in M4. L99Q affected K+ interaction in yet another way...

X-ray-induced mutations in Escherichia coli K-12 strains with altered DNA polymerase I activities

International Nuclear Information System (INIS)

Nagata, Yuki; Kawata, Masakado; Komura, Jun-ichiro; Ono, Tetsuya; Yamamoto, Kazuo

2003-01-01

Spectra of ionizing radiation mutagenesis were determined by sequencing X-ray-induced endogenous tonB gene mutations in Escherichia coli polA strains. We used two polA alleles, the polA1 mutation, defective for Klenow domain, and the polA107 mutation, defective for flap domain. We demonstrated that irradiation of 75 and 50 Gy X-rays could induce 3.8- and 2.6-fold more of tonB mutation in polA1 and polA107 strains, respectively, than spontaneous level. The radiation induced spectrum of 51 tonB mutations in polA1 and 51 in polA107 indicated that minus frameshift, A:T→T:A transversion and G:C→T:A transversion were the types of mutations increased. Previously, we have reported essentially the same X-ray-induced tonB mutation spectra in the wild-type strain. These results indicate that (1) X-rays can induce minus frameshift, A:T→T:A transversion and G:C→T:A transversion in E. coli and (2) presence or absence of polymerase I (PolI) of E. coli does not have any effects on the process of X-ray mutagenesis

Unusual presentations in patients with E200K familial Creutzfeldt-Jakob disease.

Science.gov (United States)

Cohen, O S; Kimiagar, I; Korczyn, A D; Nitsan, Z; Appel, S; Hoffmann, C; Rosenmann, H; Kahana, E; Chapman, J

2016-05-01

Familial Creutzfeldt-Jakob disease (fCJD) in Jews of Libyan ancestry is caused by an E200K mutation in the PRNP gene. The typical presenting symptoms include cognitive decline, behavioral changes and gait disturbances; however, some patients may have an unusual presentation such as a stroke-like presentation, alien hand syndrome or visual disturbances. The aim of this paper is to describe uncommon presentations in our series of consecutive patients with E200K fCJD. The study group included consecutive fCJD patients followed up as part of a longitudinal prospective study ongoing since 2003 or hospitalized since 2005. The clinical diagnosis of probable CJD was based on accepted diagnostic criteria and supported by typical magnetic resonance imaging, electroencephalographic findings, elevated cerebrospinal fluid tau protein levels and by genetic testing for the E200K mutation. Disease symptoms and signs were retrieved from the medical files. The study population included 77 patients (42 men) with a mean age of disease onset of 60.6 ± 7.2 years. The most prevalent presenting symptoms were cognitive decline followed by gait impairment and behavioral changes. However, six patients had an unusual presentation including auditory agnosia, monoparesis, stroke-like presentation, facial nerve palsy, pseudobulbar syndrome and alien hand syndrome. Our case series illustrates the wide phenotypic variability of the clinical presentation of patients with fCJD and widens the clinical spectrum of the disease. A high level of clinical suspicion may prove useful in obtaining early diagnosis and therefore avoiding costly and inefficient diagnostic and therapeutic strategies. © 2016 EAN.

Alternating hemiplegia of childhood-related neural and behavioural phenotypes in Na+,K+-ATPase α3 missense mutant mice.

Directory of Open Access Journals (Sweden)

Greer S Kirshenbaum

Full Text Available Missense mutations in ATP1A3 encoding Na(+,K(+-ATPase α3 have been identified as the primary cause of alternating hemiplegia of childhood (AHC, a motor disorder with onset typically before the age of 6 months. Affected children tend to be of short stature and can also have epilepsy, ataxia and learning disability. The Na(+,K(+-ATPase has a well-known role in maintaining electrochemical gradients across cell membranes, but our understanding of how the mutations cause AHC is limited. Myshkin mutant mice carry an amino acid change (I810N that affects the same position in Na(+,K(+-ATPase α3 as I810S found in AHC. Using molecular modelling, we show that the Myshkin and AHC mutations display similarly severe structural impacts on Na(+,K(+-ATPase α3, including upon the K(+ pore and predicted K(+ binding sites. Behavioural analysis of Myshkin mice revealed phenotypic abnormalities similar to symptoms of AHC, including motor dysfunction and cognitive impairment. 2-DG imaging of Myshkin mice identified compromised thalamocortical functioning that includes a deficit in frontal cortex functioning (hypofrontality, directly mirroring that reported in AHC, along with reduced thalamocortical functional connectivity. Our results thus provide validation for missense mutations in Na(+,K(+-ATPase α3 as a cause of AHC, and highlight Myshkin mice as a starting point for the exploration of disease mechanisms and novel treatments in AHC.

Robo advisor, your reliable partner? Building a trustworthy digital investment management service

OpenAIRE

Salo, Anni

2017-01-01

Investment management services have strongly relied on traditional face-to-face business models, causing the services being highly expensive and therefore available only for the wealthiest population. Recently a new digital business model, robo advisors, entered the market and are predicted to democratise the entire industry by bringing investment management services available to a wider public than ever before. Although the business models in financial services are changing, customer tr...

RoboGlove: Initial Work Toward a Robotically Assisted EVA Glove

Science.gov (United States)

Rogers, Jonathan

2015-01-01

The RoboGlove is a device designed to provide additional grip strength or endurance for a user. In applying this Robonaut 2 spinoff technology to the Phase VI Space Suit glove, the project is using robotic tendons and actuators to regain some of the hand performance that is lost when wearing a pressurized glove. An array of sensors embedded into the finger softgoods provides input to the control system which retracts the tendons, helping to close the user's hand. While active, this system provides augmentation, but is nonintrusive to glove usage when disabled.

7 CFR 1205.319 - Cotton-producing region.

Science.gov (United States)

2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false Cotton-producing region. 1205.319 Section 1205.319... Cotton Research and Promotion Order Definitions § 1205.319 Cotton-producing region. Cotton-producing region means each of the following groups of cotton-producing States: (a) Southeast Region: Alabama...

Phosphatidylinositol 3-Kinase (PI3K) and phosphatidylinositol 3-kinase-related kinase (PIKK) inhibitors: importance of the morpholine ring

Czech Academy of Sciences Publication Activity Database

Andrs, M.; Kobarecny, J.; Jun, D.; Hodný, Zdeněk; Bartek, Jiří; Kuca, K.

2015-01-01

Roč. 58, č. 1 (2015), s. 41-71 ISSN 0022-2623 R&D Projects: GA MŠk(CZ) CZ.1.07/2.3.00/30.0044 Grant - others:University Hospital Hradec Kralove(CZ) 00179906; Faculty of Military Health Sciences, University of Defence(CZ) SV/FVZ201402 Institutional support: RVO:68378050 Keywords : DEPENDENT PROTEIN-KINASE * STRAND BREAK REPAIR * SELECTIVE PI3K-BETA INHIBITORS * TELANGIECTASIA MUTATED KINASE Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.589, year: 2015

Novel ENAM and LAMB3 mutations in Chinese families with hypoplastic amelogenesis imperfecta.

Science.gov (United States)

Wang, Xin; Zhao, Yuming; Yang, Yuan; Qin, Man

2015-01-01

Amelogenesis imperfecta is a group of inherited diseases affecting the quality and quantity of dental enamel. To date, mutations in more than ten genes have been associated with non-syndromic amelogenesis imperfecta (AI). Among these, ENAM and LAMB3 mutations are known to be parts of the etiology of hypoplastic AI in human cases. When both alleles of LAMB3 are defective, it could cause junctional epidermolysis bullosa (JEB), while with only one mutant allele in the C-terminus of LAMB3, it could result in severe hypoplastic AI without skin fragility. We enrolled three Chinese families with hypoplastic autosomal-dominant AI. Despite the diagnosis falling into the same type, the characteristics of their enamel hypoplasia were different. Screening of ENAM and LAMB3 genes was performed by direct sequencing of genomic DNA from blood samples. Disease-causing mutations were identified and perfectly segregated with the enamel defects in three families: a 19-bp insertion mutation in the exon 7 of ENAM (c.406_407insTCAAAAAAGCCGACCACAA, p.K136Ifs*16) in Family 1, a single-base deletion mutation in the exon 5 of ENAM (c. 139delA, p. M47Cfs*11) in Family 2, and a LAMB3 nonsense mutation in the last exon (c.3466C>T, p.Q1156X) in Family 3. Our results suggest that heterozygous mutations in ENAM and LAMB3 genes can cause hypoplastic AI with markedly different phenotypes in Chinese patients. And these findings extend the mutation spectrum of both genes and can be used for mutation screening of AI in the Chinese population.

Novel ENAM and LAMB3 mutations in Chinese families with hypoplastic amelogenesis imperfecta.

Directory of Open Access Journals (Sweden)

Xin Wang

Full Text Available Amelogenesis imperfecta is a group of inherited diseases affecting the quality and quantity of dental enamel. To date, mutations in more than ten genes have been associated with non-syndromic amelogenesis imperfecta (AI. Among these, ENAM and LAMB3 mutations are known to be parts of the etiology of hypoplastic AI in human cases. When both alleles of LAMB3 are defective, it could cause junctional epidermolysis bullosa (JEB, while with only one mutant allele in the C-terminus of LAMB3, it could result in severe hypoplastic AI without skin fragility. We enrolled three Chinese families with hypoplastic autosomal-dominant AI. Despite the diagnosis falling into the same type, the characteristics of their enamel hypoplasia were different. Screening of ENAM and LAMB3 genes was performed by direct sequencing of genomic DNA from blood samples. Disease-causing mutations were identified and perfectly segregated with the enamel defects in three families: a 19-bp insertion mutation in the exon 7 of ENAM (c.406_407insTCAAAAAAGCCGACCACAA, p.K136Ifs*16 in Family 1, a single-base deletion mutation in the exon 5 of ENAM (c. 139delA, p. M47Cfs*11 in Family 2, and a LAMB3 nonsense mutation in the last exon (c.3466C>T, p.Q1156X in Family 3. Our results suggest that heterozygous mutations in ENAM and LAMB3 genes can cause hypoplastic AI with markedly different phenotypes in Chinese patients. And these findings extend the mutation spectrum of both genes and can be used for mutation screening of AI in the Chinese population.

Study of the following decays: K{sub l,s} {yields} {pi}{sup +}{pi}{sup -}e{sup +}e{sup -}; Etude des desintegrations K{sub l,s} {yields} {pi}{sup +}{pi}{sup -}e{sup +}e{sup -}

Energy Technology Data Exchange (ETDEWEB)

Cogan, J

2001-12-01

The study of the K{sub L,S} {yields} {pi}{sup +}{pi}{sup -}e{sup +}e{sup -} decay modes in the NA48 experiment at CERN is presented in this thesis. Using the full data samples collected in 1998 and 1999, 1285 {+-} 37 events K{sub L} {yields} {pi}{sup +}{pi}{sup -}e{sup +}e{sup -} have been extracted over a background of 41 events. The measured branching ratio is: BR(K{sub L} {yields} {pi}{sup +}{pi}{sup -}e{sup +}e{sup -})=[3,16{+-}0,09(stat.){+-}0,16(syst.)] x 10{sup -7}. Concerning the K{sub S} mode, a signal of 768 {+-} 28 candidates has been observed over a negligible background. The obtained branching ratio is: BR(K{sub S} {yields} {pi}{sup +}{pi}{sup -}e{sup +}e{sup -})=[4,28{+-}0,18(stat.){+-}0,26(syst.)] x 10{sup -5}. Both results are in very good agreement with the values predicted by phenomenological models where the processes K{sub L,S} {yields} {pi}{sup +}{pi}{sup -}e{sup +}e{sup -} are described in terms of inner Bremsstrahlung and direct emission contributions. In the K{sub L} mode, the presence of two components with opposed CP states leads to a large asymmetry A in the distribution of the angle {phi} between the decay planes of the two pions and the two electrons. The detailed analysis of the K{sub L} {yields} {pi}{sup +}{pi}{sup -}e{sup +}e{sup -} mode ends up to a non-zero value of the asymmetry with more than 4 standard deviations: A(K{sub L} {yields} {pi}{sup +}{pi}{sup -}e{sup +}e{sup -})=[13,8{+-}2,8(stat.){+-}2,3(syst.)]%. This result is a clear manifestation of CP violation in this channel. The large value of this asymmetry, in excellent agreement with theoretical prediction, accounts for CP violation in the K{sup 0}-K-bar{sup 0} mixing. Furthermore, it was verified that in the K{sub S} {yields} {pi}{sup +}{pi}{sup -}e{sup +}e{sup -} mode which is dominated by the inner Bremsstrahlung component, the asymmetry is compatible with zero: A(K{sub S} {yields} {pi}{sup +}{pi}{sup -}e{sup +}e{sup -})=[-0,8{+-}3,6(stat.){+-}1,2(syst.)]%. (author)

PI3K: A Crucial Piece in the RAS Signaling Puzzle.

Science.gov (United States)

Krygowska, Agata Adelajda; Castellano, Esther

2018-06-01

RAS proteins are key signaling switches essential for control of proliferation, differentiation, and survival of eukaryotic cells. RAS proteins are mutated in 30% of human cancers. In addition, mutations in upstream or downstream signaling components also contribute to oncogenic activation of the pathway. RAS proteins exert their functions through activation of several signaling pathways and dissecting the contributions of these effectors in normal cells and in cancer is an ongoing challenge. In this review, we summarize our current knowledge about how RAS regulates type I phosphatidylinositol 3-kinase (PI3K), one of the main RAS effectors. RAS signaling through PI3K is necessary for normal lymphatic vasculature development and for RAS-induced transformation in vitro and in vivo, especially in lung cancer, where it is essential for tumor initiation and necessary for tumor maintenance. Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved.

Conformational alterations resulting from mutations in cytoplasmic domains of the alpha subunit of the Na,K-ATPase

DEFF Research Database (Denmark)

Blostein, R; Daly, S E; MacAulay, Nanna

1998-01-01

This paper summarizes experiments concerned with the functional consequences of mutations in cytoplasmic regions of the alpha 1 subunit of the Na,K-ATPase, in particular the amino terminus, the first cytoplasmic loop between transmembrane segments M2 and M3, and the major cytoplasmic loop between...

32 CFR 644.319 - Protection of wetlands.

Science.gov (United States)

2010-07-01

... 32 National Defense 4 2010-07-01 2010-07-01 true Protection of wetlands. 644.319 Section 644.319... ESTATE HANDBOOK Disposal § 644.319 Protection of wetlands. The requirements of Executive Order 11990, Protection of Wetlands, 42 FR 26961, (24 May 1977) are applicable to the disposal of Federal lands and...

MAP2K1 and MAP3K1 mutations in langerhans cell histiocytosis

NARCIS (Netherlands)

Nelson, David S.; van Halteren, Astrid; Quispel, Willemijn T.; van den Bos, Cor; Bovée, Judith V. M. G.; Patel, Bhumi; Badalian-Very, Gayane; van Hummelen, Paul; Ducar, Matthew; Lin, Ling; MacConaill, Laura E.; Egeler, R. Maarten; Rollins, Barrett J.

2015-01-01

Langerhans cell histiocytosis (LCH) is now understood to be a neoplastic disease in which over 50% of cases have somatic activating mutations of BRAF. However, the extracellular signal-related (ERK) pathway is activated in all cases including those with wild type BRAF alleles. Here, we applied a

49 CFR 238.319 - Running brake test.

Science.gov (United States)

2010-10-01

... 49 Transportation 4 2010-10-01 2010-10-01 false Running brake test. 238.319 Section 238.319... Requirements for Tier I Passenger Equipment § 238.319 Running brake test. (a) As soon as conditions safely permit, a running brake test shall be performed on each passenger train after the train has received, or...

Whole genomes redefine the mutational landscape of pancreatic cancer.

Science.gov (United States)

Waddell, Nicola; Pajic, Marina; Patch, Ann-Marie; Chang, David K; Kassahn, Karin S; Bailey, Peter; Johns, Amber L; Miller, David; Nones, Katia; Quek, Kelly; Quinn, Michael C J; Robertson, Alan J; Fadlullah, Muhammad Z H; Bruxner, Tim J C; Christ, Angelika N; Harliwong, Ivon; Idrisoglu, Senel; Manning, Suzanne; Nourse, Craig; Nourbakhsh, Ehsan; Wani, Shivangi; Wilson, Peter J; Markham, Emma; Cloonan, Nicole; Anderson, Matthew J; Fink, J Lynn; Holmes, Oliver; Kazakoff, Stephen H; Leonard, Conrad; Newell, Felicity; Poudel, Barsha; Song, Sarah; Taylor, Darrin; Waddell, Nick; Wood, Scott; Xu, Qinying; Wu, Jianmin; Pinese, Mark; Cowley, Mark J; Lee, Hong C; Jones, Marc D; Nagrial, Adnan M; Humphris, Jeremy; Chantrill, Lorraine A; Chin, Venessa; Steinmann, Angela M; Mawson, Amanda; Humphrey, Emily S; Colvin, Emily K; Chou, Angela; Scarlett, Christopher J; Pinho, Andreia V; Giry-Laterriere, Marc; Rooman, Ilse; Samra, Jaswinder S; Kench, James G; Pettitt, Jessica A; Merrett, Neil D; Toon, Christopher; Epari, Krishna; Nguyen, Nam Q; Barbour, Andrew; Zeps, Nikolajs; Jamieson, Nigel B; Graham, Janet S; Niclou, Simone P; Bjerkvig, Rolf; Grützmann, Robert; Aust, Daniela; Hruban, Ralph H; Maitra, Anirban; Iacobuzio-Donahue, Christine A; Wolfgang, Christopher L; Morgan, Richard A; Lawlor, Rita T; Corbo, Vincenzo; Bassi, Claudio; Falconi, Massimo; Zamboni, Giuseppe; Tortora, Giampaolo; Tempero, Margaret A; Gill, Anthony J; Eshleman, James R; Pilarsky, Christian; Scarpa, Aldo; Musgrove, Elizabeth A; Pearson, John V; Biankin, Andrew V; Grimmond, Sean M

2015-02-26

Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.

Whole genomes redefine the mutational landscape of pancreatic cancer

Science.gov (United States)

Waddell, Nicola; Pajic, Marina; Patch, Ann-Marie; Chang, David K.; Kassahn, Karin S.; Bailey, Peter; Johns, Amber L.; Miller, David; Nones, Katia; Quek, Kelly; Quinn, Michael C. J.; Robertson, Alan J.; Fadlullah, Muhammad Z. H.; Bruxner, Tim J. C.; Christ, Angelika N.; Harliwong, Ivon; Idrisoglu, Senel; Manning, Suzanne; Nourse, Craig; Nourbakhsh, Ehsan; Wani, Shivangi; Wilson, Peter J; Markham, Emma; Cloonan, Nicole; Anderson, Matthew J.; Fink, J. Lynn; Holmes, Oliver; Kazakoff, Stephen H.; Leonard, Conrad; Newell, Felicity; Poudel, Barsha; Song, Sarah; Taylor, Darrin; Waddell, Nick; Wood, Scott; Xu, Qinying; Wu, Jianmin; Pinese, Mark; Cowley, Mark J.; Lee, Hong C.; Jones, Marc D.; Nagrial, Adnan M.; Humphris, Jeremy; Chantrill, Lorraine A.; Chin, Venessa; Steinmann, Angela M.; Mawson, Amanda; Humphrey, Emily S.; Colvin, Emily K.; Chou, Angela; Scarlett, Christopher J.; Pinho, Andreia V.; Giry-Laterriere, Marc; Rooman, Ilse; Samra, Jaswinder S.; Kench, James G.; Pettitt, Jessica A.; Merrett, Neil D.; Toon, Christopher; Epari, Krishna; Nguyen, Nam Q.; Barbour, Andrew; Zeps, Nikolajs; Jamieson, Nigel B.; Graham, Janet S.; Niclou, Simone P.; Bjerkvig, Rolf; Grützmann, Robert; Aust, Daniela; Hruban, Ralph H.; Maitra, Anirban; Iacobuzio-Donahue, Christine A.; Wolfgang, Christopher L.; Morgan, Richard A.; Lawlor, Rita T.; Corbo, Vincenzo; Bassi, Claudio; Falconi, Massimo; Zamboni, Giuseppe; Tortora, Giampaolo; Tempero, Margaret A.; Gill, Anthony J.; Eshleman, James R.; Pilarsky, Christian; Scarpa, Aldo; Musgrove, Elizabeth A.; Pearson, John V.; Biankin, Andrew V.; Grimmond, Sean M.

2015-01-01

Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded. PMID:25719666

Slit-Robo GTPase-Activating Protein 2 as a metastasis suppressor in osteosarcoma

OpenAIRE

Marko, Tracy A.; Shamsan, Ghaidan A.; Edwards, Elizabeth N.; Hazelton, Paige E.; Rathe, Susan K.; Cornax, Ingrid; Overn, Paula R.; Varshney, Jyotika; Diessner, Brandon J.; Moriarity, Branden S.; O?Sullivan, M. Gerard; Odde, David J.; Largaespada, David A.

2016-01-01

Osteosarcoma is the most common primary bone tumor, with metastatic disease responsible for most treatment failure and patient death. A forward genetic screen utilizing Sleeping Beauty mutagenesis in mice previously identified potential genetic drivers of osteosarcoma metastasis, including Slit-Robo GTPase-Activating Protein 2 (Srgap2). This study evaluates the potential role of SRGAP2 in metastases-associated properties of osteosarcoma cell lines through Srgap2 knockout via the CRISPR/Cas9 n...

Specific regulation of point-mutated K-ras-immortalized cell proliferation by a photodynamic antisense strategy.

Science.gov (United States)

Higuchi, Maiko; Yamayoshi, Asako; Kato, Kiyoko; Kobori, Akio; Wake, Norio; Murakami, Akira

2010-02-01

It has been reported that point mutations in genes are responsible for various cancers, and the selective regulation of gene expression is an important factor in developing new types of anticancer drugs. To develop effective drugs for the regulation of point-mutated genes, we focused on photoreactive antisense oligonucleotides. Previously, we reported that photoreactive oligonucleotides containing 2'-O-psoralenylmethoxyethyl adenosine (2'-Ps-eom) showed drastic photoreactivity in a strictly sequence-specific manner. Here, we demonstrated the specific gene regulatory effects of 2'-Ps-eom on [(12)Val]K-ras mutant (GGT --> GTT). Photo-cross-linking between target mRNAs and 2'-Ps-eom was sequence-specific, and the effect was UVA irradiation-dependent. Furthermore, 2'-Ps-eom was able to inhibit K-ras-immortalized cell proliferation (K12V) but not Vco cells that have the wild-type K-ras gene. These results suggest that the 2'-Ps-eom will be a powerful nucleic acid drug to inhibit the expression of disease-causing point mutation genes, and has great therapeutic potential in the treatment of cancer.

Dietary folate intake and K-ras mutations in sporadic colon and rectal cancer in the Netherlands Cohort Study

NARCIS (Netherlands)

Brink, M.; Weijenberg, M.P.; Goeij, A.F.P.M. de; Roemen, G.M.J.M.; Lentjes, M.H.F.M.; Bruïne, A.P. de; Engeland, M. van; Goldbohm, R.A.; Brandt, P.A. van den

2005-01-01

We studied the association between dietary folate and specific K-ras mutations in colon and rectal cancer in The Netherlands Cohort Study on diet and cancer. After 7.3 years of follow-up, 448 colon and 160 rectal cancer patients and 3,048 sub-cohort members (55-69 years at baseline) were available

GTP Binding and Oncogenic Mutations May Attenuate Hypervariable Region (HVR)-Catalytic Domain Interactions in Small GTPase K-Ras4B, Exposing the Effector Binding Site.

Science.gov (United States)

Lu, Shaoyong; Banerjee, Avik; Jang, Hyunbum; Zhang, Jian; Gaponenko, Vadim; Nussinov, Ruth

2015-11-27

K-Ras4B, a frequently mutated oncogene in cancer, plays an essential role in cell growth, differentiation, and survival. Its C-terminal membrane-associated hypervariable region (HVR) is required for full biological activity. In the active GTP-bound state, the HVR interacts with acidic plasma membrane (PM) headgroups, whereas the farnesyl anchors in the membrane; in the inactive GDP-bound state, the HVR may interact with both the PM and the catalytic domain at the effector binding region, obstructing signaling and nucleotide exchange. Here, using molecular dynamics simulations and NMR, we aim to figure out the effects of nucleotides (GTP and GDP) and frequent (G12C, G12D, G12V, G13D, and Q61H) and infrequent (E37K and R164Q) oncogenic mutations on full-length K-Ras4B. The mutations are away from or directly at the HVR switch I/effector binding site. Our results suggest that full-length wild-type GDP-bound K-Ras4B (K-Ras4B(WT)-GDP) is in an intrinsically autoinhibited state via tight HVR-catalytic domain interactions. The looser association in K-Ras4B(WT)-GTP may release the HVR. Some of the oncogenic mutations weaken the HVR-catalytic domain association in the K-Ras4B-GDP/-GTP bound states, which may facilitate the HVR disassociation in a nucleotide-independent manner, thereby up-regulating oncogenic Ras signaling. Thus, our results suggest that mutations can exert their effects in more than one way, abolishing GTP hydrolysis and facilitating effector binding. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Screening of three Mediterranean phenylketonuria mutations in ...

Indian Academy of Sciences (India)

as the most frequent mutation (Dahri et al. 2010). The. E280K mutation was also reported in Mediterranean popu- lations (Guldberg et al. 1993). Since Tunisia is a Mediter- ranean country, patients with PKU are presumed to have these mutations. The aim of this study was to assess prevalence of the three above mutations ...

9 CFR 319.308 - Tripe with milk.

Science.gov (United States)

2010-01-01

... 9 Animals and Animal Products 2 2010-01-01 2010-01-01 false Tripe with milk. 319.308 Section 319... Products § 319.308 Tripe with milk. “Tripe with Milk” shall be prepared so that the finished canned article, exclusive of the cooked-out juices and milk, will contain at least 65 percent tripe. The product shall be...

DETECTION OF K-RAS AND P53 MUTATIONS IN SPUTUM SAMPLES OF LUNG CANCER PATIENTS USING LASER CAPTURE MICRODISSECTION MICROSCOPE AND MUTATION ANALYSIS

Science.gov (United States)

Detection of K-ras and p53 Mutations in Sputum Samples of Lung Cancer Patients Using Laser Capture Microdissection Microscope and Mutation AnalysisPhouthone Keohavong a,*, Wei-Min Gao a, Kui-Cheng Zheng a, Hussam Mady b, Qing Lan c, Mona Melhem b, and Judy Mumford d.<...

Two Finnish USH1B patients with three novel mutations in myosin VIIA.

Science.gov (United States)

Vastinsalo, Hanna; Isosomppi, Juha; Aittakorpi, Anne; Sankila, Eeva-Marja

2006-09-21

Usher syndrome (USH) is an autosomal recessive disorder resulting in retinal degeneration and sensorineural deafness caused by mutations in at least 10 gene loci. USH is divided into three main clinical types: USH1 (33-44%), USH2 (56-67%), and USH3. Worldwide, USH1 and USH2 account for most of the Usher syndrome cases with rare occurrence of USH3. In Finland, however, USH3 is the most common type (40%), explained by genetic and geographical isolation accompanied with a founder mutation, while USH1 is estimated to comprise 34% and USH2 12% of all USH cases. We examined two unrelated Finnish USH1 patients by sequencing. We found three new myosin VIIA (MYO7A) mutations: p.K923AfsX8, p.Q1896X, and p.E1349K. The p.K923AfsX8 mutation was present in both patients as well as in one of 200 Finnish control chromosomes. This is the first molecular genetic study of USH1 in Finland. We have found three new pathological mutations causing either premature termination of translation or replacement of an evolutionary conserved MYO7A amino acid.

A new experimental system for study on adaptive mutations

Institute of Scientific and Technical Information of China (English)

Lü; Zhong; (

2001-01-01

［1］Luria, S. E., Delbrück, M., Mutation of bacteria from virus sensitivity to virus resistance, Genetics, 1943, 28: 491.［2］Lederberg, J., Lederberg, E. M., Replica plating and indirect selection of bacteria mutants, J. Bacteriol., 1952, 63: 399.［3］Carins, J., Overbaugh, J., Miller, S., The origin of mutants, Nature, 1988, 355: 142.［4］Foster, P. L., Adaptive mutation: the uses of adversity, Annu. Rev. Microbiol., 1993, 47: 467.［5］Hall, B. G., Adaptive mutagenesis: a process that generates almost exclusively beneficient mutations, Genetica, 1998, 102/103: 109.［6］Kasak, L., Horak, R., Kivisaar, M., Promotor-creating mutations in Psuedmonas putida: A model system for the study of mutation in starving bacteria, PNAS, 1997, 94: 3134.［7］Steele, D. F., Jinks-Robertson, An examination of adaptive reversion in Saccharomyces cerevisiae, Genetics, 1992, 132: 9.［8］Davis, R. W., Botstein, Roth, J. R., Advanced Bacterial Genetics--A Manual for Genetic Engineering, New York: Cold Spring Harbor Laboratory Press, 1980, 13.［9］Miller, J. H., Experiments in Molecular Genetics, New York: Cold Spring Harbor Laboratory Press, 1972, 352.［10］ Lea, D. E., Coulson, C. A., The distribution of the numbers of mutants in bacterial populations, J. Genetics, 1949, 49: 264.［11］ Hughes, K. T., Roth, J. R., Transitory cis complementation: a method for provided transposition function to defective transposons, Genetics, 1988, 119: 9.［12］ Sanderson, K. E., Roth J., Linkage map of Salmonella typhimurium, Microbiol. Rev., 1988, 52: 485.［13］ He, B., Shiau, A., Choi, K. Y., Genes of the E. coli pur region are negatively controlled by a repressor-operator interaction, J. Bacteriol., 1990, 172: 4555.［14］ Liu, B., Huang, Y., Wang, A. Q., Regulation of purine biosynthetic genes expression in Salmonella typhimurium (IV)--Oc mutation site of purG and its function analysis, Science in China, Ser. C, 1997, 40(3): 238.［15］ Tang, H., Qin, J. C., Wang, A. Q

RoboSCell: An automated single cell arraying and analysis instrument

KAUST Repository

Sakaki, Kelly

2009-09-09

Single cell research has the potential to revolutionize experimental methods in biomedical sciences and contribute to clinical practices. Recent studies suggest analysis of single cells reveals novel features of intracellular processes, cell-to-cell interactions and cell structure. The methods of single cell analysis require mechanical resolution and accuracy that is not possible using conventional techniques. Robotic instruments and novel microdevices can achieve higher throughput and repeatability; however, the development of such instrumentation is a formidable task. A void exists in the state-of-the-art for automated analysis of single cells. With the increase in interest in single cell analyses in stem cell and cancer research the ability to facilitate higher throughput and repeatable procedures is necessary. In this paper, a high-throughput, single cell microarray-based robotic instrument, called the RoboSCell, is described. The proposed instrument employs a partially transparent single cell microarray (SCM) integrated with a robotic biomanipulator for in vitro analyses of live single cells trapped at the array sites. Cells, labeled with immunomagnetic particles, are captured at the array sites by channeling magnetic fields through encapsulated permalloy channels in the SCM. The RoboSCell is capable of systematically scanning the captured cells temporarily immobilized at the array sites and using optical methods to repeatedly measure extracellular and intracellular characteristics over time. The instrument\\'s capabilities are demonstrated by arraying human T lymphocytes and measuring the uptake dynamics of calcein acetoxymethylester-all in a fully automated fashion. © 2009 Springer Science+Business Media, LLC.

High rate of mutation K103N causing resistance to nevirapine in Indian children with acquired immunodeficiency syndrome

Directory of Open Access Journals (Sweden)

Sehgal S

2008-01-01

Full Text Available In north India the number of paediatric cases with acquired immunodeficiency syndrome (AIDS is on the rise. Most drug combinations used for treatment of AIDS incorporate nevirapine, resistance to which develops very fast if given singly or because of unplanned interruptions. This paper investigates presence of mutations at codon 103 and codon 215 of the HIV pol gene causing resistance to nevirapine and zidovudine (AZT respectively in 25 children with AIDS. Mutations T215Y and K103N were detected by a nested cum amplification refractory mutation system polymerase chain reaction (ARMS PCR and the results were confirmed by direct sequencing in five randomly selected cases. Nineteen patients had received nevirapine containing regimen and six were drug naive. Mutation K103N was observed in 56% (14/25 of the children while mutation T215Y was found in none. Two of the six drug naοve children also showed K103N mutation. Thus, Indian children drug naοve or treated with nevirapine containing regimens show a high rate of mutation conferring resistance to nevirapine which calls for a judicious use of nevirapine both in antenatal and postnatal setting.

Mutations in a novel gene with transmembrane domains underlie Usher syndrome type 3.

Science.gov (United States)

Joensuu, T; Hämäläinen, R; Yuan, B; Johnson, C; Tegelberg, S; Gasparini, P; Zelante, L; Pirvola, U; Pakarinen, L; Lehesjoki, A E; de la Chapelle, A; Sankila, E M

2001-10-01

Usher syndrome type 3 (USH3) is an autosomal recessive disorder characterized by progressive hearing loss, severe retinal degeneration, and variably present vestibular dysfunction, assigned to 3q21-q25. Here, we report on the positional cloning of the USH3 gene. By haplotype and linkage-disequilibrium analyses in Finnish carriers of a putative founder mutation, the critical region was narrowed to 250 kb, of which we sequenced, assembled, and annotated 207 kb. Two novel genes-NOPAR and UCRP-and one previously identified gene-H963-were excluded as USH3, on the basis of mutational analysis. USH3, the candidate gene that we identified, encodes a 120-amino-acid protein. Fifty-two Finnish patients were homozygous for a termination mutation, Y100X; patients in two Finnish families were compound heterozygous for Y100X and for a missense mutation, M44K, whereas patients in an Italian family were homozygous for a 3-bp deletion leading to an amino acid deletion and substitution. USH3 has two predicted transmembrane domains, and it shows no homology to known genes. As revealed by northern blotting and reverse-transcriptase PCR, it is expressed in many tissues, including the retina.

Volumetric properties of binary mixtures of {difluoromethane (R32) + trans-1,3,3,3-tetrafluoropropene (R1234ze(E))} at temperatures from 283.15 K to 363.15 K and pressures up to 100 MPa

International Nuclear Information System (INIS)

Jia, Tao; Bi, Shengshan; Hu, Xiaozhen; Meng, Xianyang; Wu, Jiangtao

2016-01-01

Highlights: • Densities of R32+R1234ze(E) mixtures were measured with a vibrating-tube densimeter. • Densities of mixtures were conducted from (283 to 363) K, at pressures up to 100 MPa. • Excess molar volumes were correlated with the Redlich–Kister equation. - Abstract: Values of experimental density of difluoromethane (R32) and five compositions of {R32 + trans-1,3,3,3-tetrafluoropropene (R1234ze(E))} binary mixtures are reported over the temperature range from 283 K to 363 K and at pressures up to 100 MPa with a vibrating-tube densimeter. The excess molar volumes were calculated from experimental results and fitted to the Redlich–Kister equation. The maximum standard deviation and average standard deviations of the experimental and calculated values of excess molar volume from Redlich–Kister equation are 0.07789 cm"3·mol"−"1 and 0.01645 cm"3·mol"−"1, respectively.

miR319, miR390, and miR393 Are Involved in Aluminum Response in Flax (Linum usitatissimum L.).

Science.gov (United States)

Dmitriev, Alexey A; Kudryavtseva, Anna V; Bolsheva, Nadezhda L; Zyablitsin, Alexander V; Rozhmina, Tatiana A; Kishlyan, Natalya V; Krasnov, George S; Speranskaya, Anna S; Krinitsina, Anastasia A; Sadritdinova, Asiya F; Snezhkina, Anastasiya V; Fedorova, Maria S; Yurkevich, Olga Yu; Muravenko, Olga V; Belenikin, Maxim S; Melnikova, Nataliya V

2017-01-01

Acid soils limit agricultural production worldwide. Major reason of crop losses in acid soils is the toxicity of aluminum (Al). In the present work, we investigated expression alterations of microRNAs in flax ( Linum usitatissimum L.) plants under Al stress. Flax seedlings of resistant (TMP1919 and G1071/4_k) and sensitive (Lira and G1071/4_o) to Al cultivars and lines were exposed to AlCl 3 solution for 4 and 24 hours. Twelve small RNA libraries were constructed and sequenced using Illumina platform. In total, 97 microRNAs from 18 conserved families were identified. miR319, miR390, and miR393 revealed expression alterations associated with Al treatment of flax plants. Moreover, for miR390 and miR393, the alterations were distinct in sensitive and resistant to Al genotypes. Expression level changes of miR319 and miR390 were confirmed using qPCR analysis. In flax, potential targets of miR319 are TCPs, miR390-TAS3 and GRF5, and miR393-AFB2-coding transcripts. TCPs, TAS3, GRF5, and AFB2 participate in regulation of plant growth and development. The involvement of miR319, miR390, and miR393 in response to Al stress in flax was shown here for the first time. We speculate that these microRNAs play an important role in Al response via regulation of growth processes in flax plants.

Synergistic Interactions with PI3K Inhibition that Induce Apoptosis. | Office of Cancer Genomics

Science.gov (United States)

Activating mutations involving the PI3K pathway occur frequently in human cancers. However, PI3K inhibitors primarily induce cell cycle arrest, leaving a significant reservoir of tumor cells that may acquire or exhibit resistance. We searched for genes that are required for the survival of PI3K mutant cancer cells in the presence of PI3K inhibition by conducting a genome scale shRNA-based apoptosis screen in a PIK3CA mutant human breast cancer cell. We identified 5 genes (PIM2, ZAK, TACC1, ZFR, ZNF565) whose suppression induced cell death upon PI3K inhibition.

High frequency of mutation G377S in Brazilian type 3 Gaucher disease patients

Directory of Open Access Journals (Sweden)

R. Rozenberg

2006-09-01

Full Text Available Gaucher disease (GD, the most prevalent lysosome storage disorder, presents an autosomal recessive mode of inheritance. It is a paradigm for therapeutic intervention in medical genetics due to the existence of effective enzyme replacement therapy. We report here the analysis of GD in 262 unrelated Brazilian patients, carried out in order to establish the frequency of the most common mutations and to provide prognostic information based on genotype-phenotype correlations. Among 247 type 1 GD patients, mutation N370S was detected in 47% of all the alleles, but N370S/N370S homozygosity was found in only 10% of the patients, a much lower frequency than expected, suggesting that most individuals presenting this genotype may not receive medical attention. Recombinant alleles were detected at a high frequency: 44% of the chromosomes bearing mutation L444P had other mutations derived from the pseudogene sequence, present in 25% of patients. Three neuronopathic type 2 patients were homozygous for L444P, all presenting additional mutations (E326K or recombinant alleles that probably lead to the more severe phenotypes. Six children, classified as type 1 GD patients, had a L444P/L444P genotype, showing that neuronopathic symptoms may only manifest later in life. This would indicate the need for a higher treatment dose during enzyme replacement therapy. Finally, mutation G377S was present in 4 homozygous type 1 patients and also in compound heterozygosity in 5 (42% type 3 patients. These findings indicate that G377S cannot be unambiguously classified as mild and suggest an allele-dose effect for this mutation.

Gain-of-function mutations in the gene encoding the tyrosine phosphatase SHP2 induce hydrocephalus in a catalytically dependent manner.

Science.gov (United States)

Zheng, Hong; Yu, Wen-Mei; Waclaw, Ronald R; Kontaridis, Maria I; Neel, Benjamin G; Qu, Cheng-Kui

2018-03-20

Catalytically activating mutations in Ptpn11 , which encodes the protein tyrosine phosphatase SHP2, cause 50% of Noonan syndrome (NS) cases, whereas inactivating mutations in Ptpn11 are responsible for nearly all cases of the similar, but distinct, developmental disorder Noonan syndrome with multiple lentigines (NSML; formerly called LEOPARD syndrome). However, both types of disease mutations are gain-of-function mutations because they cause SHP2 to constitutively adopt an open conformation. We found that the catalytic activity of SHP2 was required for the pathogenic effects of gain-of-function, disease-associated mutations on the development of hydrocephalus in the mouse. Targeted pan-neuronal knockin of a Ptpn11 allele encoding the active SHP2 E76K mutant resulted in hydrocephalus due to aberrant development of ependymal cells and their cilia. These pathogenic effects of the E76K mutation were suppressed by the additional mutation C459S, which abolished the catalytic activity of SHP2. Moreover, ependymal cells in NSML mice bearing the inactive SHP2 mutant Y279C were also unaffected. Mechanistically, the SHP2 E76K mutant induced developmental defects in ependymal cells by enhancing dephosphorylation and inhibition of the transcription activator STAT3. Whereas STAT3 activity was reduced in Ptpn11 E76K/+ cells, the activities of the kinases ERK and AKT were enhanced, and neural cell-specific Stat3 knockout mice also manifested developmental defects in ependymal cells and cilia. These genetic and biochemical data demonstrate a catalytic-dependent role of SHP2 gain-of-function disease mutants in the pathogenesis of hydrocephalus. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

FGFR3, PIK3CA and RAS mutations in benign lichenoid keratosis.

Science.gov (United States)

Groesser, L; Herschberger, E; Landthaler, M; Hafner, C

2012-04-01

Benign lichenoid keratoses (BLKs) are solitary skin lesions which have been proposed to represent a regressive form of pre-existent epidermal tumours such as solar lentigo or seborrhoeic keratosis. However, the genetic basis of BLK is unknown. FGFR3, PIK3CA and RAS mutations have been shown to be involved in the pathogenesis of seborrhoeic keratosis and solar lentigo. We thus investigated whether these mutations are also present in BLK. After manual microdissection and DNA isolation, 52 BLKs were screened for FGFR3, PIK3CA and RAS hotspot mutations using SNaPshot(®) multiplex assays. We identified 6/52 (12%) FGFR3 mutations, 10/52 (19%) PIK3CA mutations, 6/52 (12%) HRAS mutations and 2/52 (4%) KRAS mutations. FGFR3 and RAS mutations were mutually exclusive. One BLK showed a simultaneous PIK3CA and HRAS mutation. In nine BLKs with a mutation, nonlesional control tissue from the epidermal margin and the dermal lymphocytic infiltrate were wild-type, indicating that these mutations are somatic. To demonstrate that these findings are specific, 10 samples of lichen planus were analysed without evidence for FGFR3, PIK3CA or RAS mutations. Our results indicate that FGFR3, PIK3CA and RAS mutations are present in approximately 50% of BLKs. These findings support the concept on the molecular genetic level that at least a proportion of BLKs represents regressive variants resulting from former benign epidermal tumours such as seborrhoeic keratosis and solar lentigo. © 2011 The Authors. BJD © 2011 British Association of Dermatologists 2011.

Analysis of mutations in DNA gyrase and topoisomerase IV of Ureaplasma urealyticum and Ureaplasma parvum serovars resistant to fluoroquinolones.

Science.gov (United States)

Piccinelli, Giorgio; Gargiulo, Franco; Biscaro, Valeria; Caccuri, Francesca; Caruso, Arnaldo; De Francesco, Maria Antonia

2017-01-01

This study aims to determine the prevalence of fluoroquinolone resistance of Ureaplasma biovars and serovars isolated from urogenital clinical samples and determine the underlying molecular mechanism for quinolone resistance for all resistant isolates. Of 105 samples confirmed as positive for U. urealyticum/U. parvum, 85 were resistant to quinolones by the Mycoplasma-IST2 kit. However, only 43 out of 85 quinolone resistant isolates had amino acid substitutions in GyrA, GyrB, ParC and ParE proteins underlining that this assay have mis-identified as fluoroquinolone resistant 42 isolates. The known ParC E87K and ParC S83L mutations were found in 1 and 10 isolates, respectively. An original mutation of ureaplasmal ParC (E87Q, 1 isolate) was found. Furthermore, we found a ParE R448K mutation in one isolate, already described. Among the additional alterations detected, the most prevalent mutation found was L176F in GyrA protein in 18 isolates with single infection and in 3 isolates with mixed ureaplasma infections. Mutations in GyrB (E502Q, 4 isolates), ParE (Q412K, Q412P, Q412T, 3 independent isolates), whose role is unknown, were also found. Other sporadic mutations in the four genes were identified. This investigation is the result of monitoring the data for molecular fluoroquinone resistance in Ureaplasma spp. in Italy. Resulting that this acquired resistance is high and that continued local epidemiological studies are essential to monitor and document their antimicrobial resistance trends. Copyright © 2016 Elsevier B.V. All rights reserved.

Preliminary Engineering Report contaminated groundwater seeps 317/319/ENE area

International Nuclear Information System (INIS)

1996-01-01

When the Resource Conservation and Recovery Act Facility Investigation (RFI) in the 317/319/ENE Area of Argonne National Laboratory-East (ANL-E) was being completed, groundwater was discovered moving to the surface through a series of seeps. The seeps are located approximately 600 ft south of the ANL fence line in Waterfall Glen Forest Preserve. Samples of this water were collected and analyzed for selected parameters. Two of five seeps sampled were found to contain detectable levels of organic contaminants. Three chemical species were identified: chloroform (14-25 μg/L), carbon tetrachloride (56-340 μg/L), and tetrachloroethylene (3-6 μg/L). The other seeps did not contain detectable levels of volatile organic compounds (VOCs). The water issuing from these two contaminated seeps flows into a narrow ravine, where it is visible as a trickle of water flowing through sand and gravel deposits on the floor of the ravine. Approximately 100-ft downstream of the seep area, the contaminated water is no longer visible, having drained back into the soil in the bed of the ravine. Figure 1 shows the location of the 317/319/ENE Area in relation to the ANL-E site and the Waterfall Glen Forest Preserve

Spectrum of CFTR gene mutations in Ecuadorian cystic fibrosis patients: the second report of the p.H609R mutation.

Science.gov (United States)

Ortiz, Sofía C; Aguirre, Santiago J; Flores, Sofía; Maldonado, Claudio; Mejía, Juan; Salinas, Lilian

2017-11-01

High heterogeneity in the CFTR gene mutations disturbs the molecular diagnosis of cystic fibrosis (CF). In order to improve the diagnosis of CF in our country, the present study aims to define a panel of common CFTR gene mutations by sequencing 27 exons of the gene in Ecuadorian Cystic Fibrosis patients. Forty-eight Ecuadorian individuals with suspected/confirmed CF diagnosis were included. Twenty-seven exons of CFTR gene were sequenced to find sequence variations. Prevalence of pathogenic variations were determined and compared with other countries' data. We found 70 sequence variations. Eight of these are CF-causing mutations: p.F508del, p.G85E, p.G330E, p.A455E, p.G970S, W1098X, R1162X, and N1303K. Also this study is the second report of p.H609R in Ecuadorian population. Mutation prevalence differences between Ecuadorian population and other Latin America countries were found. The panel of mutations suggested as an initial screening for the Ecuadorian population with cystic fibrosis should contain the mutations: p.F508del, p.G85E, p.G330E, p.A455E, p.G970S, W1098X, R1162X, and N1303K. © 2017 NETLAB Laboratorios Especializados. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.

High-momentum components in 3He(e,e') and (e,e'p)

International Nuclear Information System (INIS)

Sick, I.

1984-01-01

In this talk, the author discusses the properties of the 3 He spectral function S(K,E) at large momentum K and large separation energy E. He deals in particular with the question how to measure S, and how to understand the physics connected to it. As experimental input he uses (e,e') data. He starts by discussing how to understand (e,e') in terms of properties of S(K,E). For this purpose, an extensive discussion of the scaling function F(y) is needed. When once it is found out how to exploit inclusive scattering, he comes back to exclusive reactions and discusses the relative merits of (e,e'p) and (e,e') in order to investigate how these tools can best complement each other. Some conclusions on the properties of S(K,E) at large K and E, together with some suggestions for future activities follows. (Auth.)

Fatal Prion Disease in a Mouse Model of Genetic E200K Creutzfeldt-Jakob Disease

Science.gov (United States)

Friedman-Levi, Yael; Meiner, Zeev; Canello, Tamar; Frid, Kati; Kovacs, Gabor G.; Budka, Herbert; Avrahami, Dana; Gabizon, Ruth

2011-01-01

Genetic prion diseases are late onset fatal neurodegenerative disorders linked to pathogenic mutations in the prion protein-encoding gene, PRNP. The most prevalent of these is the substitution of Glutamate for Lysine at codon 200 (E200K), causing genetic Creutzfeldt-Jakob disease (gCJD) in several clusters, including Jews of Libyan origin. Investigating the pathogenesis of genetic CJD, as well as developing prophylactic treatments for young asymptomatic carriers of this and other PrP mutations, may well depend upon the availability of appropriate animal models in which long term treatments can be evaluated for efficacy and toxicity. Here we present the first effective mouse model for E200KCJD, which expresses chimeric mouse/human (TgMHu2M) E199KPrP on both a null and a wt PrP background, as is the case for heterozygous patients and carriers. Mice from both lines suffered from distinct neurological symptoms as early as 5–6 month of age and deteriorated to death several months thereafter. Histopathological examination of the brain and spinal cord revealed early gliosis and age-related intraneuronal deposition of disease-associated PrP similarly to human E200K gCJD. Concomitantly we detected aggregated, proteinase K resistant, truncated and oxidized PrP forms on immunoblots. Inoculation of brain extracts from TgMHu2ME199K mice readily induced, the first time for any mutant prion transgenic model, a distinct fatal prion disease in wt mice. We believe that these mice may serve as an ideal platform for the investigation of the pathogenesis of genetic prion disease and thus for the monitoring of anti-prion treatments. PMID:22072968

Fatal prion disease in a mouse model of genetic E200K Creutzfeldt-Jakob disease.

Directory of Open Access Journals (Sweden)

Yael Friedman-Levi

2011-11-01

Full Text Available Genetic prion diseases are late onset fatal neurodegenerative disorders linked to pathogenic mutations in the prion protein-encoding gene, PRNP. The most prevalent of these is the substitution of Glutamate for Lysine at codon 200 (E200K, causing genetic Creutzfeldt-Jakob disease (gCJD in several clusters, including Jews of Libyan origin. Investigating the pathogenesis of genetic CJD, as well as developing prophylactic treatments for young asymptomatic carriers of this and other PrP mutations, may well depend upon the availability of appropriate animal models in which long term treatments can be evaluated for efficacy and toxicity. Here we present the first effective mouse model for E200KCJD, which expresses chimeric mouse/human (TgMHu2M E199KPrP on both a null and a wt PrP background, as is the case for heterozygous patients and carriers. Mice from both lines suffered from distinct neurological symptoms as early as 5-6 month of age and deteriorated to death several months thereafter. Histopathological examination of the brain and spinal cord revealed early gliosis and age-related intraneuronal deposition of disease-associated PrP similarly to human E200K gCJD. Concomitantly we detected aggregated, proteinase K resistant, truncated and oxidized PrP forms on immunoblots. Inoculation of brain extracts from TgMHu2ME199K mice readily induced, the first time for any mutant prion transgenic model, a distinct fatal prion disease in wt mice. We believe that these mice may serve as an ideal platform for the investigation of the pathogenesis of genetic prion disease and thus for the monitoring of anti-prion treatments.

The Performance of the Robo-AO Laser Guide Star Adaptive Optics System at the Kitt Peak 2.1 m Telescope

Science.gov (United States)

Jensen-Clem, Rebecca; Duev, Dmitry A.; Riddle, Reed; Salama, Maïssa; Baranec, Christoph; Law, Nicholas M.; Kulkarni, S. R.; Ramprakash, A. N.

2018-01-01

Robo-AO is an autonomous laser guide star adaptive optics (AO) system recently commissioned at the Kitt Peak 2.1 m telescope. With the ability to observe every clear night, Robo-AO at the 2.1 m telescope is the first dedicated AO observatory. This paper presents the imaging performance of the AO system in its first 18 months of operations. For a median seeing value of 1.″44, the average Strehl ratio is 4% in the i\\prime band. After post processing, the contrast ratio under sub-arcsecond seeing for a 2≤slant i\\prime ≤slant 16 primary star is five and seven magnitudes at radial offsets of 0.″5 and 1.″0, respectively. The data processing and archiving pipelines run automatically at the end of each night. The first stage of the processing pipeline shifts and adds the rapid frame rate data using techniques optimized for different signal-to-noise ratios. The second “high-contrast” stage of the pipeline is eponymously well suited to finding faint stellar companions. Currently, a range of scientific programs, including the synthetic tracking of near-Earth asteroids, the binarity of stars in young clusters, and weather on solar system planets are being undertaken with Robo-AO.

EGFR Exon 18 Mutations in Lung Cancer: Molecular Predictors of Augmented Sensitivity to Afatinib or Neratinib as Compared with First- or Third-Generation TKIs.

Science.gov (United States)

Kobayashi, Yoshihisa; Togashi, Yosuke; Yatabe, Yasushi; Mizuuchi, Hiroshi; Jangchul, Park; Kondo, Chiaki; Shimoji, Masaki; Sato, Katsuaki; Suda, Kenichi; Tomizawa, Kenji; Takemoto, Toshiki; Hida, Toyoaki; Nishio, Kazuto; Mitsudomi, Tetsuya

2015-12-01

Lung cancers harboring common EGFR mutations respond to EGFR tyrosine kinase inhibitors (TKI), whereas exon 20 insertions (Ins20) are resistant to them. However, little is known about mutations in exon 18. Mutational status of lung cancers between 2001 and 2015 was reviewed. Three representative mutations in exon 18, G719A, E709K, and exon 18 deletion (Del18: delE709_T710insD) were retrovirally introduced into Ba/F3 and NIH/3T3 cells. The 90% inhibitory concentrations (IC90s) of first-generation (1G; gefitinib and erlotinib), second-generation (2G; afatinib, dacomitinib, and neratinib), and third-generation TKIs (3G; AZD9291 and CO1686) were determined. Among 1,402 EGFR mutations, Del19, L858R, and Ins20 were detected in 40%, 47%, and 4%, respectively. Exon 18 mutations, including G719X, E709X, and Del18, were present in 3.2%. Transfected Ba/F3 cells grew in the absence of IL3, and NIH/3T3 cells formed foci with marked pile-up, indicating their oncogenic abilities. IC90s of 1G and 3G TKIs in G719A, E709K, and Del18 were much higher than those in Del19 (by >11-50-fold), whereas IC90s of afatinib were only 3- to 7-fold greater than those for Del19. Notably, cells transfected with G719A and E709K exhibited higher sensitivity to neratinib (by 5-25-fold) than those expressing Del19. Patients with lung cancers harboring G719X exhibited higher response rate to afatinib or neratinib (∼ 80%) than to 1G TKIs (35%-56%) by compilation of data in the literature. Lung cancers harboring exon 18 mutations should not be overlooked in clinical practice. These cases can be best treated with afatinib or neratinib, although the currently available in vitro diagnostic kits cannot detect all exon 18 mutations. ©2015 American Association for Cancer Research.

Decreased Sensitivity to Changes in the Concentration of Metal Ions as the Basis for the Hyperactivity of DtxR(E175K)

Energy Technology Data Exchange (ETDEWEB)

D’Aquino, J. Alejandro; Denninger, Andrew R.; Moulin, Aaron G.; D’Aquino, Katharine E.; Ringe, Dagmar; (Harvard-Med); (Brandeis)

2010-01-12

The metal-ion-activated diphtheria toxin repressor (DtxR) is responsible for the regulation of virulence and other genes in Corynebacterium diphtheriae. A single point mutation in DtxR, DtxR(E175K), causes this mutant repressor to have a hyperactive phenotype. Mice infected with Mycobacterium tuberculosis transformed with plasmids carrying this mutant gene show reduced signs of the tuberculosis infection. Corynebacterial DtxR is able to complement mycobacterial IdeR and vice versa. To date, an explanation for the hyperactivity of DtxR(E175K) has remained elusive. In an attempt to address this issue, we have solved the first crystal structure of DtxR(E175K) and characterized this mutant using circular dichroism, isothermal titration calorimetry, and other biochemical techniques. The results show that although DtxR(E175K) and the wild type have similar secondary structures, DtxR(E175K) gains additional thermostability upon activation with metal ions, which may lead to this mutant requiring a lower concentration of metal ions to reach the same levels of thermostability as the wild-type protein. The E175K mutation causes binding site 1 to retain metal ion bound at all times, which can only be removed by incubation with an ion chelator. The crystal structure of DtxR(E175K) shows an empty binding site 2 without evidence of oxidation of Cys102. The association constant for this low-affinity binding site of DtxR(E175K) obtained from calorimetric titration with Ni(II) is K{sub a} = 7.6 {+-} 0.5 x 10{sup 4}, which is very similar to the reported value for the wild-type repressor, K{sub a} = 6.3 x 10{sup 4}. Both the wild type and DtxR(E175K) require the same amount of metal ion to produce a shift in the electrophoretic mobility shift assay, but unlike the wild type, DtxR(E175K) binding to its cognate DNA [tox promoter-operator (toxPO)] does not require metal-ion supplementation in the running buffer. In the timescale of these experiments, the Mn(II)-DtxR(E175K)-toxPO complex

Mutation K42E in dehydrodolichol diphosphate synthase (DHDDS) causes recessive retinitis pigmentosa.

Science.gov (United States)

Lam, Byron L; Züchner, Stephan L; Dallman, Julia; Wen, Rong; Alfonso, Eduardo C; Vance, Jeffery M; Peričak-Vance, Margaret A

2014-01-01

A single-nucleotide mutation in the gene that encodes DHDDS has been identified by whole exome sequencing as the cause of the non-syndromic recessive retinitis pigmentosa (RP) in a family of Ashkenazi Jewish origin in which three of the four siblings have early onset retinal degeneration. The peripheral retinal degeneration in the affected siblings was evident in the initial examination in 1992 and only one had detectable electroretinogram (ERG) that suggested cone-rod dysfunction. The pigmentary retinal degeneration subsequently progressed rapidly. The identified mutation changes the highly conserved residue Lys42 to Glu, resulting in lower catalytic efficiency. Patterns of plasma transferrin isoelectric focusing gel were normal in all family members, indicating no significant abnormality in protein glycosylation. Dolichols have been shown to influence the fluidity and of the membrane and promote vesicle fusion. Considering that photoreceptor outer segments contain stacks of membrane discs, we believe that the mutation may lead to low dolichol levels in photoreceptor outer segments, resulting in unstable membrane structure that leads to photoreceptor degeneration.

BPS open strings and A-D-E-singularities in F-theory on K3

NARCIS (Netherlands)

Bergshoeff, Eric A.; Hartong, Jelle

We improve on a recently constructed graphical representation of the supergravity 7-brane solution and apply this refined representation to re-study the open string description of the A-D-E-singularities in F-theory on K3. A noteworthy feature of the graphical representation is that it provides the

Analysis of PI3K/mTOR Pathway Biomarkers and Their Prognostic Value in Women with Hormone Receptor–Positive, HER2-Negative Early Breast Cancer

Directory of Open Access Journals (Sweden)

Hamdy A. Azim

2016-04-01

.6%, respectively. PIK3CA mutations were found in 7 patients (29.2%. PI3K mutations were correlated with nuclear localization of pAKT (i.e., decreased cytoplasmic pAKT, P = .04; and increased nuclear pAKT, P = .10. There was a tendency toward an inverse correlation between PI3K mutations and the expression of pS6RP (P = .10 and p4EBP1 (P = .19. Nuclear LKB1 expression was a marker of good prognosis. It was associated with smaller tumors (P = .05, more ER (P = .08 and progesteron receptor (PgR positivity (P = .002. In the Kaplan Meier (KM model, patients with high nuclear LKB1 had longer DFS (hazard ratio = 0.36; 95% confidence interval, 0.15-1.10; P = .08. Nuclear pAKT high expression also carried a tendency toward longer DFS (hazard ratio = 0.51; 95% confidence interval, 0.11-1.16; P = .13. The expression of p4EBP1, pS6RP, and the PI3K mutational status did not show any prognostic significance in our cohort. CONCLUSION: Among the studied biomarkers, only nuclear expression of LKB1 and pAKT tended to predict better survival in breast cancer patients. PI3K mutation was correlated with the expression of nuclear pAKT but not pS6RP or p4EBP1.

7 CFR 319.69-2 - Freedom from pests.

Science.gov (United States)

2010-01-01

... 7 Agriculture 5 2010-01-01 2010-01-01 false Freedom from pests. 319.69-2 Section 319.69-2 Agriculture Regulations of the Department of Agriculture (Continued) ANIMAL AND PLANT HEALTH INSPECTION... § 319.69-2 Freedom from pests. All packing materials allowed entry under restriction shall be free from...

7 CFR 319.75-2 - Restricted articles. 1

Science.gov (United States)

2010-01-01

... 7 Agriculture 5 2010-01-01 2010-01-01 false Restricted articles. 1 319.75-2 Section 319.75-2... SERVICE, DEPARTMENT OF AGRICULTURE FOREIGN QUARANTINE NOTICES Khapra Beetle § 319.75-2 Restricted articles. 1 1 The importation of restricted articles may be subject to prohibitions or restrictions under...

7 CFR 319.40-6 - Universal importation options.

Science.gov (United States)

2010-01-01

... 7 Agriculture 5 2010-01-01 2010-01-01 false Universal importation options. 319.40-6 Section 319.40-6 Agriculture Regulations of the Department of Agriculture (Continued) ANIMAL AND PLANT HEALTH... Unmanufactured Wood Articles § 319.40-6 Universal importation options. (a) Logs. Logs may be imported if prior to...

7 CFR 319.37-10 - Marking and identity.

Science.gov (United States)

2010-01-01

... 7 Agriculture 5 2010-01-01 2010-01-01 false Marking and identity. 319.37-10 Section 319.37-10 Agriculture Regulations of the Department of Agriculture (Continued) ANIMAL AND PLANT HEALTH INSPECTION..., and Other Plant Products 1,2 § 319.37-10 Marking and identity. (a) Any restricted article for...

BRAF V600E mutational status in bile duct adenomas and hamartomas.

Science.gov (United States)

Pujals, Anaïs; Bioulac-Sage, Paulette; Castain, Claire; Charpy, Cécile; Zafrani, Elie Serge; Calderaro, Julien

2015-10-01

Bile duct adenomas (BDA) and bile duct hamartomas (BDH) are benign bile duct lesions considered neoplastic or secondary to ductal plate malformation, respectively. We have reported previously a high prevalence of BRAF V600E mutations detected by allele-specific polymerase chain reaction assay in BDA, and suggested that BDA may be precursors to a subset of intrahepatic cholangiocarcinomas harbouring V600E mutations. The aim of the present study was to assess the existence of BRAF V600E mutations, using immunohistochemical methods, in additional BDA as well as in BDH. Fifteen BDA and 35 BDH were retrieved from the archives of the pathology departments of two French university hospitals. All cases were reviewed by two pathologists specialized in liver diseases. BRAF V600E mutational status was investigated by immunohistochemistry. Mutated BRAF mutant protein was detected in 53% of the BDA and in none of the cases of BDH. Our findings suggest that BDA and BDH are different processes, and that BDA represent true benign neoplasms. They also support the hypothesis that mutated BDA might precede the development of the subset of intrahepatic cholangiocarcinomas harbouring BRAF V600E mutations. © 2015 John Wiley & Sons Ltd.

A Fast, Sensitive and Accurate High Resolution Melting (HRM Technology-Based Assay to Screen for Common K-ras Mutations

Directory of Open Access Journals (Sweden)

D. Kramer

2009-01-01

Full Text Available Background: Increasing evidence points to a negative correlation between K-ras mutations and patient’s response to, or survival benefit after, treatment with EGFR-inhibitors. Therefore, rapid and reliable assays for mutational analysis of the K-ras gene are strongly needed.

PIK3CA, HRAS and PTEN in human papillomavirus positive oropharyngeal squamous cell carcinoma

International Nuclear Information System (INIS)

Chiosea, Simion I; Nikiforova, Marina N; Grandis, Jennifer R; Lui, Vivian W Y; Diergaarde, Brenda; Maxwell, Jessica H; Ferris, Robert L; Kim, Seungwon W; Luvison, Alyssa; Miller, Megan

2013-01-01

Recent genomic evidence suggests frequent phosphatidylinositide 3-kinase (PI3K) pathway activation in human papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma. Mutations/amplification of the gene encoding p110α catalytic subunit of phosphoinositide 3-kinase (PIK3CA), loss of phosphatase and tensin homolog (PTEN) and HRAS mutations are known to activate PI3K pathway. PIK3CA mutations were identified by Sanger sequencing in 23 of 75 (31%) HPV-positive oropharyngeal carcinomas, including exon 9 (p.E545K [n = 10] and p.E542K [n = 5]) or exon 20 (p.H1047Y, n = 2) mutations. Five rare and one novel (p.R537Q) PIK3CA mutations were identified. HRAS mutation (p.Q61L) was detected in 1 of 62 tested cases. PIK3CA amplification by fluorescence in situ hybridization (FISH) was identified in 4 cases (4/21, 20%), while PTEN loss was seen in 7 (7/21, 33%) cases (chromosome 10 monosomy [n = 4], homozygous deletion [n = 3]). Overall, genetic alterations that likely lead to PI3K pathway activation were identified in 34 of 75 cases (45%) and did not correlate with disease specific survival. These findings offer a molecular rationale for therapeutic targeting of PI3K pathway in patients with HPV-positive oropharyngeal carcinoma

Distributed active traction control system applied to the RoboCup middle size league

OpenAIRE

Almeida, José; Dias, André; Sequeira, João; Martins, Alfredo; Silva, Eduardo

2013-01-01

This work addresses the problem of traction control in mobile wheeled robots in the particular case of the RoboCup Middle Size League (MSL). The slip control problem is formulated using simple friction models for ISePorto Team robots with a differential wheel configuration. Traction was also characterized experimentally in the MSL scenario for relevant game events. This work proposes a hierarchical traction control architecture which relies in local slip detection and con...

9 CFR 319.261 - Meat loaf.

Science.gov (United States)

2010-01-01

... 9 Animals and Animal Products 2 2010-01-01 2010-01-01 false Meat loaf. 319.261 Section 319.261... ORGANIZATION AND TERMINOLOGY; MANDATORY MEAT AND POULTRY PRODUCTS INSPECTION AND VOLUNTARY INSPECTION AND CERTIFICATION DEFINITIONS AND STANDARDS OF IDENTITY OR COMPOSITION Luncheon Meat, Loaves and Jellied Products...

9 CFR 319.500 - Meat pies.

Science.gov (United States)

2010-01-01

... 9 Animals and Animal Products 2 2010-01-01 2010-01-01 false Meat pies. 319.500 Section 319.500... ORGANIZATION AND TERMINOLOGY; MANDATORY MEAT AND POULTRY PRODUCTS INSPECTION AND VOLUNTARY INSPECTION AND CERTIFICATION DEFINITIONS AND STANDARDS OF IDENTITY OR COMPOSITION Meat Food Entree Products, Pies, and...

9 CFR 319.304 - Meat stews.

Science.gov (United States)

2010-01-01

... 9 Animals and Animal Products 2 2010-01-01 2010-01-01 false Meat stews. 319.304 Section 319.304... ORGANIZATION AND TERMINOLOGY; MANDATORY MEAT AND POULTRY PRODUCTS INSPECTION AND VOLUNTARY INSPECTION AND CERTIFICATION DEFINITIONS AND STANDARDS OF IDENTITY OR COMPOSITION Canned, Frozen, or Dehydrated Meat Food...

9 CFR 319.260 - Luncheon meat.

Science.gov (United States)

2010-01-01

... 9 Animals and Animal Products 2 2010-01-01 2010-01-01 false Luncheon meat. 319.260 Section 319.260... ORGANIZATION AND TERMINOLOGY; MANDATORY MEAT AND POULTRY PRODUCTS INSPECTION AND VOLUNTARY INSPECTION AND CERTIFICATION DEFINITIONS AND STANDARDS OF IDENTITY OR COMPOSITION Luncheon Meat, Loaves and Jellied Products...

α3Na+/K+-ATPase deficiency causes brain ventricle dilation and abrupt embryonic motility in zebrafish

DEFF Research Database (Denmark)

Doğanli, Canan; Beck, Hans Christian; Ribera, Angeles B

2013-01-01

Na(+)/K(+)-ATPases are transmembrane ion pumps that maintain ion gradients across the basolateral plasma membrane in all animal cells to facilitate essential biological functions. Mutations in the Na(+)/K(+)-ATPase α3 subunit gene (ATP1A3) cause rapid-onset dystonia-parkinsonism, a rare movement ...

Measurement of the $B^0 \\to K^{*0}e^+e^-$ branching fraction at low dilepton mass

CERN Document Server

INSPIRE-00258707; Abellan Beteta, C; Adametz, A; Adeva, B; Adinolfi, M; Adrover, C; Affolder, A; Ajaltouni, Z; Albrecht, J; Alessio, F; Alexander, M; Ali, S; Alkhazov, G; Alvarez Cartelle, P; Alves Jr, A A; Amato, S; Amhis, Y; Anderlini, L; Anderson, J; Andreassen, R; Appleby, R B; Aquines Gutierrez, O; Archilli, F; Artamonov, A; Artuso, M; Aslanides, E; Auriemma, G; Bachmann, S; Back, J J; Baesso, C; Balagura, V; Baldini, W; Barlow, R J; Barschel, C; Barsuk, S; Barter, W; Bauer, Th; Bay, A; Beddow, J; Bediaga, I; Belogurov, S; Belous, K; Belyaev, I; Ben-Haim, E; Benayoun, M; Bencivenni, G; Benson, S; Benton, J; Berezhnoy, A; Bernet, R; Bettler, M -O; van Beuzekom, M; Bien, A; Bifani, S; Bird, T; Bizzeti, A; Bjørnstad, P M; Blake, T; Blanc, F; Blanks, C; Blouw, J; Blusk, S; Bobrov, A; Bocci, V; Bondar, A; Bondar, N; Bonivento, W; Borghi, S; Borgia, A; Bowcock, T J V; Bowen, E; Bozzi, C; Brambach, T; van den Brand, J; Bressieux, J; Brett, D; Britsch, M; Britton, T; Brook, N H; Brown, H; Burducea, I; Bursche, A; Buytaert, J; Cadeddu, S; Callot, O; Calvi, M; Calvo Gomez, M; Camboni, A; Campana, P; Carbone, A; Carboni, G; Cardinale, R; Cardini, A; Carranza-Mejia, H; Carson, L; Carvalho Akiba, K; Casse, G; Cattaneo, M; Cauet, Ch; Charles, M; Charpentier, Ph; Chen, P; Chiapolini, N; Chrzaszcz, M; Ciba, K; Cid Vidal, X; Ciezarek, G; Clarke, P E L; Clemencic, M; Cliff, H V; Closier, J; Coca, C; Coco, V; Cogan, J; Cogneras, E; Collins, P; Comerma-Montells, A; Contu, A; Cook, A; Coombes, M; Coquereau, S; Corti, G; Couturier, B; Cowan, G A; Craik, D; Cunliffe, S; Currie, R; D'Ambrosio, C; David, P; David, P N Y; De Bonis, I; De Bruyn, K; De Capua, S; De Cian, M; De Miranda, J M; De Paula, L; De Silva, W; De Simone, P; Decamp, D; Deckenhoff, M; Degaudenzi, H; Del Buono, L; Deplano, C; Derkach, D; Deschamps, O; Dettori, F; Di Canto, A; Dickens, J; Dijkstra, H; Dogaru, M; Domingo Bonal, F; Donleavy, S; Dordei, F; Dosil Suárez, A; Dossett, D; Dovbnya, A; Dupertuis, F; Dzhelyadin, R; Dziurda, A; Dzyuba, A; Easo, S; Egede, U; Egorychev, V; Eidelman, S; van Eijk, D; Eisenhardt, S; Eitschberger, U; Ekelhof, R; Eklund, L; El Rifai, I; Elsasser, Ch; Elsby, D; Falabella, A; Färber, C; Fardell, G; Farinelli, C; Farry, S; Fave, V; Ferguson, D; Fernandez Albor, V; Ferreira Rodrigues, F; Ferro-Luzzi, M; Filippov, S; Fitzpatrick, C; Fontana, M; Fontanelli, F; Forty, R; Francisco, O; Frank, M; Frei, C; Frosini, M; Furcas, S; Furfaro, E; Gallas Torreira, A; Galli, D; Gandelman, M; Gandini, P; Gao, Y; Garofoli, J; Garosi, P; Garra Tico, J; Garrido, L; Gaspar, C; Gauld, R; Gersabeck, E; Gersabeck, M; Gershon, T; Ghez, Ph; Gibson, V; Gligorov, V V; Göbel, C; Golubkov, D; Golutvin, A; Gomes, A; Gordon, H; Grabalosa Gándara, M; Graciani Diaz, R; Granado Cardoso, L A; Graugés, E; Graziani, G; Grecu, A; Greening, E; Gregson, S; Grünberg, O; Gui, B; Gushchin, E; Guz, Yu; Gys, T; Hadjivasiliou, C; Haefeli, G; Haen, C; Haines, S C; Hall, S; Hampson, T; Hansmann-Menzemer, S; Harnew, N; Harnew, S T; Harrison, J; Harrison, P F; Hartmann, T; He, J; Heijne, V; Hennessy, K; Henrard, P; Hernando Morata, J A; van Herwijnen, E; Hicks, E; Hill, D; Hoballah, M; Hombach, C; Hopchev, P; Hulsbergen, W; Hunt, P; Huse, T; Hussain, N; Hutchcroft, D; Hynds, D; Iakovenko, V; Ilten, P; Jacobsson, R; Jaeger, A; Jans, E; Jansen, F; Jaton, P; Jing, F; John, M; Johnson, D; Jones, C R; Jost, B; Kaballo, M; Kandybei, S; Karacson, M; Karbach, T M; Kenyon, I R; Kerzel, U; Ketel, T; Keune, A; Khanji, B; Kochebina, O; Komarov, I; Koopman, R F; Koppenburg, P; Korolev, M; Kozlinskiy, A; Kravchuk, L; Kreplin, K; Kreps, M; Krocker, G; Krokovny, P; Kruse, F; Kucharczyk, M; Kudryavtsev, V; Kvaratskheliya, T; La Thi, V N; Lacarrere, D; Lafferty, G; Lai, A; Lambert, D; Lambert, R W; Lanciotti, E; Lanfranchi, G; Langenbruch, C; Latham, T; Lazzeroni, C; Le Gac, R; van Leerdam, J; Lees, J -P; Lefèvre, R; Leflat, A; Lefrançois, J; Leroy, O; Li, Y; Li Gioi, L; Liles, M; Lindner, R; Linn, C; Liu, B; Liu, G; von Loeben, J; Lopes, J H; Lopez Asamar, E; Lopez-March, N; Lu, H; Luisier, J; Luo, H; Machefert, F; Machikhiliyan, I V; Maciuc, F; Maev, O; Malde, S; Manca, G; Mancinelli, G; Mangiafave, N; Marconi, U; Märki, R; Marks, J; Martellotti, G; Martens, A; Martin, L; Martín Sánchez, A; Martinelli, M; Martinez Santos, D; Martins Tostes, D; Massafferri, A; Matev, R; Mathe, Z; Matteuzzi, C; Matveev, M; Maurice, E; Mazurov, A; McCarthy, J; McNulty, R; Meadows, B; Meier, F; Meissner, M; Merk, M; Milanes, D A; Minard, M -N; Molina Rodriguez, J; Monteil, S; Moran, D; Morawski, P; Mountain, R; Mous, I; Muheim, F; Müller, K; Muresan, R; Muryn, B; Muster, B; Naik, P; Nakada, T; Nandakumar, R; Nasteva, I; Needham, M; Neufeld, N; Nguyen, A D; Nguyen, T D; Nguyen-Mau, C; Nicol, M; Niess, V; Niet, R; Nikitin, N; Nikodem, T; Nisar, S; Nomerotski, A; Novoselov, A; Oblakowska-Mucha, A; Obraztsov, V; Oggero, S; Ogilvy, S; Okhrimenko, O; Oldeman, R; Orlandea, M; Otalora Goicochea, J M; Owen, P; Pal, B K; Palano, A; Palutan, M; Panman, J; Papanestis, A; Pappagallo, M; Parkes, C; Parkinson, C J; Passaleva, G; Patel, G D; Patel, M; Patrick, G N; Patrignani, C; Pavel-Nicorescu, C; Pazos Alvarez, A; Pellegrino, A; Penso, G; Pepe Altarelli, M; Perazzini, S; Perego, D L; Perez Trigo, E; Pérez-Calero Yzquierdo, A; Perret, P; Perrin-Terrin, M; Pessina, G; Petridis, K; Petrolini, A; Phan, A; Picatoste Olloqui, E; Pietrzyk, B; Pilař, T; Pinci, D; Playfer, S; Plo Casasus, M; Polci, F; Polok, G; Poluektov, A; Polycarpo, E; Popov, D; Popovici, B; Potterat, C; Powell, A; Prisciandaro, J; Pugatch, V; Puig Navarro, A; Qian, W; Rademacker, J H; Rakotomiaramanana, B; Rangel, M S; Raniuk, I; Rauschmayr, N; Raven, G; Redford, S; Reid, M M; dos Reis, A C; Ricciardi, S; Richards, A; Rinnert, K; Rives Molina, V; Roa Romero, D A; Robbe, P; Rodrigues, E; Rodriguez Perez, P; Rogers, G J; Roiser, S; Romanovsky, V; Romero Vidal, A; Rouvinet, J; Ruf, T; Ruiz, H; Sabatino, G; Saborido Silva, J J; Sagidova, N; Sail, P; Saitta, B; Salzmann, C; Sanmartin Sedes, B; Sannino, M; Santacesaria, R; Santamarina Rios, C; Santovetti, E; Sapunov, M; Sarti, A; Satriano, C; Satta, A; Savrie, M; Savrina, D; Schaack, P; Schiller, M; Schindler, H; Schleich, S; Schlupp, M; Schmelling, M; Schmidt, B; Schneider, O; Schopper, A; Schune, M -H; Schwemmer, R; Sciascia, B; Sciubba, A; Seco, M; Semennikov, A; Senderowska, K; Sepp, I; Serra, N; Serrano, J; Seyfert, P; Shapkin, M; Shapoval, I; Shatalov, P; Shcheglov, Y; Shears, T; Shekhtman, L; Shevchenko, O; Shevchenko, V; Shires, A; Silva Coutinho, R; Skwarnicki, T; Smith, N A; Smith, E; Smith, M; Sobczak, K; Sokoloff, M D; Soler, F J P; Soomro, F; Souza, D; Souza De Paula, B; Spaan, B; Sparkes, A; Spradlin, P; Stagni, F; Stahl, S; Steinkamp, O; Stoica, S; Stone, S; Storaci, B; Straticiuc, M; Straumann, U; Subbiah, V K; Swientek, S; Syropoulos, V; Szczekowski, M; Szczypka, P; Szumlak, T; T'Jampens, S; Teklishyn, M; Teodorescu, E; Teubert, F; Thomas, C; Thomas, E; van Tilburg, J; Tisserand, V; Tobin, M; Tolk, S; Tonelli, D; Topp-Joergensen, S; Torr, N; Tournefier, E; Tourneur, S; Tran, M T; Tresch, M; Tsaregorodtsev, A; Tsopelas, P; Tuning, N; Ubeda Garcia, M; Ukleja, A; Urner, D; Uwer, U; Vagnoni, V; Valenti, G; Vazquez Gomez, R; Vazquez Regueiro, P; Vecchi, S; Velthuis, J J; Veltri, M; Veneziano, G; Vesterinen, M; Viaud, B; Vieira, D; Vilasis-Cardona, X; Vollhardt, A; Volyanskyy, D; Voong, D; Vorobyev, A; Vorobyev, V; Voß, C; Voss, H; Waldi, R; Wallace, R; Wandernoth, S; Wang, J; Ward, D R; Watson, N K; Webber, A D; Websdale, D; Whitehead, M; Wicht, J; Wiechczynski, J; Wiedner, D; Wiggers, L; Wilkinson, G; Williams, M P; Williams, M; Wilson, F F; Wishahi, J; Witek, M; Wotton, S A; Wright, S; Wu, S; Wyllie, K; Xie, Y; Xing, F; Xing, Z; Yang, Z; Young, R; Yuan, X; Yushchenko, O; Zangoli, M; Zavertyaev, M; Zhang, F; Zhang, L; Zhang, W C; Zhang, Y; Zhelezov, A; Zhong, L; Zvyagin, A

2013-01-01

The branching fraction of the rate decay $B^0 \\rightarrow K^{*0}e^+e^-$ in the dilepton mass region from 30 to 1000 MeV$/c^2$ has been measured by the LHCb experiment, using $pp$ collision data, corresponding to an integrated luminosity of 1.0 fb$^{-1}$, at a centre-of-mass energy of 7 TeV. The decay mode $B^0 \\rightarrow J/\\psi(e^+e^-) K^{*0}$ is utilized as a normalization channel. The branching fraction $B^0 \\rightarrow K^{*0}e^+e^-$ is measured to be $$ B(B^0 \\rightarrow K^{*0}e^+e^-)^{30-1000 MeV/c^2}= (3.1\\, ^{+0.9\\mbox{} +0.2}_{-0.8\\mbox{}-0.3} \\pm 0.2)\\times 10^{-7}, $$ where the first error is statistical, the second is systematic, and the third comes from the uncertainties on the $B^0 \\rightarrow J/\\psi K^{*0}$ and $J/\\psi \\rightarrow e^+e^- $ branching fractions.

k-RAS mutations in non-small cell lung cancer patients treated with TKIs among smokers and non-smokers: a meta-analysis

Directory of Open Access Journals (Sweden)

Ai-Gui Jiang

2016-06-01

Full Text Available Aim of the study : Recent studies have suggested that k-RAS mutations are related to the response to epidermal growth factor receptor (EGFR tyrosine-kinase inhibitions (TKIs in advanced non-small cell lung cancer (NSCLC treatment. The aim of this meta-analysis was to assess the relationship between smoking history and k-RAS mutations in NSCLC treated with TKIs. Material and methods : We searched MEDLINE and Web of Science up to 15 March 2014. The pooled relative risk (RR was estimated by using fixed effect model or random effect model, according to heterogeneity between studies. We also carried out power analyses. Results : We identified 12 studies with 1193 patients, including 196 patients (16.4% with k-RAS mutations. The pooled k-RAS mutations incidence was 22.8% (174/764 in patients with smoke expose vs. 5.4% (23/429 in those with no smoke exposure. The pooled RR was 2.991 (95% CI: 1.884–4.746; Z = 4.65, p = 0.000. No publication bias was found (Begg’s test: z = 1.09, p = 0.274 and Egger’s test: t = 1.38, p = 0.201. In subgroup analyses, the pooled RR was 3.336 (95% CI: 1.925–5.779; Z = 4.30, p = 0.000 in the Caucasian subgroup, while in the Asian subgroup the pooled RR was 2.093 (95% CI: 0.909–4.822; Z = 1.73, p = 0.083, but the sample size was underpowered (0.465. Conclusions : The current meta-analysis found that smoking was related to increased incidence of k-RAS mutations in non-small cell lung cancer treated with TKIs. This may be further evidence that smoking will lead to a worse prognosis in NSCLC patients treated with TKIs.

RPA-Mediated Recruitment of the E3 Ligase RFWD3 Is Vital for Interstrand Crosslink Repair and Human Health.

Science.gov (United States)

Feeney, Laura; Muñoz, Ivan M; Lachaud, Christophe; Toth, Rachel; Appleton, Paul L; Schindler, Detlev; Rouse, John

2017-06-01

Defects in the repair of DNA interstrand crosslinks (ICLs) are associated with the genome instability syndrome Fanconi anemia (FA). Here we report that cells with mutations in RFWD3, an E3 ubiquitin ligase that interacts with and ubiquitylates replication protein A (RPA), show profound defects in ICL repair. An amino acid substitution in the WD40 repeats of RFWD3 (I639K) found in a new FA subtype abolishes interaction of RFWD3 with RPA, thereby preventing RFWD3 recruitment to sites of ICL-induced replication fork stalling. Moreover, single point mutations in the RPA32 subunit of RPA that abolish interaction with RFWD3 also inhibit ICL repair, demonstrating that RPA-mediated RFWD3 recruitment to stalled replication forks is important for ICL repair. We also report that unloading of RPA from sites of ICL induction is perturbed in RFWD3-deficient cells. These data reveal important roles for RFWD3 localization in protecting genome stability and preserving human health. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Association between nucleotide mutation of eNOS gene and serum ...

African Journals Online (AJOL)

Various mutation on endothelial nitric oxide synthase (eNOs) gene cause reduced production of NO, the expansion factor (VEF) and may accelerate the process of atherosclerosis. The study was designed to investigate the frequency of T-786C polymorphism of the gene or nucleotide mutation of eNOS gene in patients ...

7 CFR 319.56-5 - Pest-free areas.

Science.gov (United States)

2010-01-01

... 7 Agriculture 5 2010-01-01 2010-01-01 false Pest-free areas. 319.56-5 Section 319.56-5 Agriculture..., DEPARTMENT OF AGRICULTURE FOREIGN QUARANTINE NOTICES Fruits and Vegetables § 319.56-5 Pest-free areas. As... provided that the fruits or vegetables originate from an area that is free of a specific pest or pests. In...

7 CFR 319.8-13 - From Northwest Mexico.

Science.gov (United States)

2010-01-01

... 7 Agriculture 5 2010-01-01 2010-01-01 false From Northwest Mexico. 319.8-13 Section 319.8-13... for the Entry of Cotton and Covers from Mexico § 319.8-13 From Northwest Mexico. Contingent upon continued freedom of Northwest Mexico and of the West Coast of Mexico from infestations of the pink bollworm...

Frequent alterations of the PI3K/AKT/mTOR pathways in hereditary nonpolyposis colorectal cancer

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Ekstrand, Anna Isinger; Jönsson, Mats; Lindblom, Annika

2010-01-01

The phosphatidylinositol 3-kinases-AKT-mammalian target of rapamycin pathway (PI3K/AKT/mTOR) is central in colorectal tumors. Data on its role in hereditary cancers are, however, scarce and we therefore characterized mutations in PIK3CA and KRAS, and expression of PIK3CA, phosphorylated AKT...... and PTEN in 58 HNPCC-associated colorectal cancers. Derangements of at least one of the PI3K/AKT/mTOR components analyzed were found in 51/58 (88%) tumors. Mutations in PIK3CA and KRAS were identified in 14 and 31% of the tumors respectively. Overexpression of PIK3CA and phosphorylated AKT occurred in 59...... and 75% and were strongly associated (P = 0.005). Reduced/lost PTEN expression was found in 63% of the tumors. Though HNPCC-associated colorectal cancers show simple genetic profiles with few chromosomal alterations, we demonstrate frequent and repeated targeting of the PI3K/AKT/mTOR pathway, which...

PI3K inhibition to overcome endocrine resistance in breast cancer.

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Keegan, Niamh M; Gleeson, Jack P; Hennessy, Bryan T; Morris, Patrick G

2018-01-01

Activation of the phosphatidylinositol-3 kinase (PI3K) pathway is a critical step in oncogenesis and plays a role in the development of treatment resistance for both estrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2) positive breast cancers. Hence, there have been efforts to therapeutically inhibit this pathway. Areas covered: Several inhibitors of PI3K are now progressing through clinical trials with varying degrees of efficacy and toxicity to date. Numerous unresolved questions remain concerning the optimal isoform selectivity of PI3K inhibitors and use of predictive biomarkers. This review examines the most important PI3K inhibitors in ER positive breast cancer to date, with a particular focus on their role in overcoming endocrine therapy resistance and the possible use of PIK3CA mutations as a predictive biomarker. Expert opinion: We discuss some of the emerging challenges and questions encountered during the development of PI3K inhibitors from preclinical to phase III studies, including other novel biomarkers and future combinations to overcome endocrine resistance.

7 CFR 319.8-23 - Treatment.

Science.gov (United States)

2010-01-01

... 7 Agriculture 5 2010-01-01 2010-01-01 false Treatment. 319.8-23 Section 319.8-23 Agriculture....8-23 Treatment. (a)(1) Vacuum fumigation as required in this subpart shall consist of fumigation, in... the substitution of processing, utilization, or other form of treatment for vacuum fumigation when in...

EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas

DEFF Research Database (Denmark)

Mohammad, Faizaan; Weissmann, Simon; Leblanc, Benjamin Olivier

2017-01-01

Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain tumor that is located in the pons and primarily affects children. Nearly 80% of DIPGs harbor mutations in histone H3 genes, wherein lysine 27 is substituted with methionine (H3K27M). H3K27M has been shown to inhibit polycomb repressiv...

Trithorax monomethylates histone H3K4 and interacts directly with CBP to promote H3K27 acetylation and antagonize Polycomb silencing

Science.gov (United States)

Tie, Feng; Banerjee, Rakhee; Saiakhova, Alina R.; Howard, Benny; Monteith, Kelsey E.; Scacheri, Peter C.; Cosgrove, Michael S.; Harte, Peter J.

2014-01-01

Trithorax (TRX) antagonizes epigenetic silencing by Polycomb group (PcG) proteins, stimulates enhancer-dependent transcription, and establishes a ‘cellular memory’ of active transcription of PcG-regulated genes. The mechanisms underlying these TRX functions remain largely unknown, but are presumed to involve its histone H3K4 methyltransferase activity. We report that the SET domains of TRX and TRX-related (TRR) have robust histone H3K4 monomethyltransferase activity in vitro and that Tyr3701 of TRX and Tyr2404 of TRR prevent them from being trimethyltransferases. The trxZ11 missense mutation (G3601S), which abolishes H3K4 methyltransferase activity in vitro, reduces the H3K4me1 but not the H3K4me3 level in vivo. trxZ11 also suppresses the impaired silencing phenotypes of the Pc3 mutant, suggesting that H3K4me1 is involved in antagonizing Polycomb silencing. Polycomb silencing is also antagonized by TRX-dependent H3K27 acetylation by CREB-binding protein (CBP). We show that perturbation of Polycomb silencing by TRX overexpression requires CBP. We also show that TRX and TRR are each physically associated with CBP in vivo, that TRX binds directly to the CBP KIX domain, and that the chromatin binding patterns of TRX and TRR are highly correlated with CBP and H3K4me1 genome-wide. In vitro acetylation of H3K27 by CBP is enhanced on K4me1-containing H3 substrates, and independently altering the H3K4me1 level in vivo, via the H3K4 demethylase LSD1, produces concordant changes in H3K27ac. These data indicate that the catalytic activities of TRX and CBP are physically coupled and suggest that both activities play roles in antagonizing Polycomb silencing, stimulating enhancer activity and cellular memory. PMID:24550119

[Expression of JAK2V617F and MPLW515L/K mutation in 30 suspected cases of early myeloproliferative disorders].

Science.gov (United States)

Fan, Zheng; Zhang, Ri; Shen, Yi-Min; Fei, Hai-Rong; Zhu, Zi-Ling; Cen, Jian-Nong

2008-09-01

To investigate the prevalence of JAK2V617F and MPLW515L/K mutation in patients with slightly elevated platelets (BPC) or hemoglobin (Hb) not meeting the criteria of polycythemia vera (PV) or essential thrombocythemia (ET). Genomic DNA from bone marrow or blood mononuclear cells was screened with allele specific polymerase chain reaction (AS-PCR) for JAK2V617F and MPLW515L/K mutation. The history of thrombosis was assessed retrospectively by patients files. Of 30 patients, 14 (46.7%) were positive for the JAK2V617F mutation, none of them had the MPLW515L/ K. Five of these 14 patients had a history of thrombosis. Follow-up results were available in 22 patients. Among them, 12 patients with JAK2V617F mutation turned out to be MPD in 6-24 months; only 2 out of 10 patients without this mutation evolved to MPD. JAK2V617F mutation could be one of the diagnosis criteria of early MPD. No MPLW515L/K expression was found in early MPD.

TOR and S6K1 promote translation reinitiation of uORF-containing mRNAs via phosphorylation of eIF3h.

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Schepetilnikov, Mikhail; Dimitrova, Maria; Mancera-Martínez, Eder; Geldreich, Angèle; Keller, Mario; Ryabova, Lyubov A

2013-04-17

Mammalian target-of-rapamycin (mTOR) triggers S6 kinase (S6K) activation to phosphorylate targets linked to translation in response to energy, nutrients, and hormones. Pathways of TOR activation in plants remain unknown. Here, we uncover the role of the phytohormone auxin in TOR signalling activation and reinitiation after upstream open reading frame (uORF) translation, which in plants is dependent on translation initiation factor eIF3h. We show that auxin triggers TOR activation followed by S6K1 phosphorylation at T449 and efficient loading of uORF-mRNAs onto polysomes in a manner sensitive to the TOR inhibitor Torin-1. Torin-1 mediates recruitment of inactive S6K1 to polysomes, while auxin triggers S6K1 dissociation and recruitment of activated TOR instead. A putative target of TOR/S6K1-eIF3h-is phosphorylated and detected in polysomes in response to auxin. In TOR-deficient plants, polysomes were prebound by inactive S6K1, and loading of uORF-mRNAs and eIF3h was impaired. Transient expression of eIF3h-S178D in plant protoplasts specifically upregulates uORF-mRNA translation. We propose that TOR functions in polysomes to maintain the active S6K1 (and thus eIF3h) phosphorylation status that is critical for translation reinitiation.

alpha-Adducin mutations increase Na/K pump activity in renal cells by affecting constitutive endocytosis: implications for tubular Na reabsorption.

Science.gov (United States)

Torielli, Lucia; Tivodar, Simona; Montella, Rosa Chiara; Iacone, Roberto; Padoani, Gloria; Tarsini, Paolo; Russo, Ornella; Sarnataro, Daniela; Strazzullo, Pasquale; Ferrari, Patrizia; Bianchi, Giuseppe; Zurzolo, Chiara

2008-08-01

Genetic variation in alpha-adducin cytoskeletal protein is implicated in the polymerization and bundling of actin and alteration of the Na/K pump, resulting in abnormal renal sodium transport and hypertension in Milan hypertensive rats and humans. To investigate the molecular involvement of alpha-adducin in controlling Na/K pump activity, wild-type or mutated rat and human alpha-adducin forms were, respectively, transfected into several renal cell lines. Through multiple experimental approaches (microscopy, enzymatic assays, coimmunoprecipitation), we showed that rat and human mutated forms increased Na/K pump activity and the number of pump units; moreover, both variants coimmunoprecipitate with Na/K pump. The increased Na/K pump activity was not due to changes in its basolateral localization, but to an alteration of Na/K pump residential time on the plasma membrane. Indeed, both rat and human mutated variants reduced constitutive Na/K pump endocytosis and similarly affected transferrin receptor trafficking and fluid-phase endocytosis. In fact, alpha-adducin was detected in clathrin-coated vesicles and coimmunoprecipitated with clathrin. These results indicate that adducin, besides its modulatory effects on actin cytoskeleton dynamics, might play a direct role in clathrin-dependent endocytosis. The constitutive reduction of the Na/K pump endocytic rate induced by mutated adducin variants may be relevant in Na-dependent hypertension.

Robo-AO Kepler Asteroseismic Survey. I. Adaptive Optics Imaging of 99 Asteroseismic Kepler Dwarfs and Subgiants

Energy Technology Data Exchange (ETDEWEB)

Schonhut-Stasik, Jessica S.; Baranec, Christoph; Huber, Daniel; Atkinson, Dani; Hagelberg, Janis; Marel, Nienke van der; Hodapp, Klaus W. [Institute for Astronomy, University of Hawai‘i at Mānoa, Hilo, HI 96720-2700 (United States); Ziegler, Carl; Law, Nicholas M. [Department of Physics and Astronomy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3255 (United States); Gaidos, Eric [Department of Geology and Geophysics, University of Hawai‘i at Mānoa, Honolulu, HI 96822 (United States); Riddle, Reed, E-mail: jstasik@hawaii.edu [Division of Physics, Mathematics, and Astronomy, California Institute of Technology, Pasadena, CA 91125 (United States)

2017-10-01

We used the Robo-AO laser adaptive optics (AOs) system to image 99 main sequence and subgiant stars that have Kepler -detected asteroseismic signals. Robo-AO allows us to resolve blended secondary sources at separations as close as ∼0.″15 that may contribute to the measured Kepler light curves and affect asteroseismic analysis and interpretation. We report eight new secondary sources within 4.″0 of these Kepler asteroseismic stars. We used Subaru and Keck AOs to measure differential infrared photometry for these candidate companion systems. Two of the secondary sources are likely foreground objects, while the remaining six are background sources; however, we cannot exclude the possibility that three of the objects may be physically associated. We measured a range of i ′-band amplitude dilutions for the candidate companion systems from 0.43% to 15.4%. We find that the measured amplitude dilutions are insufficient to explain the previously identified excess scatter in the relationship between asteroseismic oscillation amplitude and the frequency of maximum power.

Detection of K76T Mutation in pfcrt Gene as an Applicable Ge-netic Marker for Prediction of Chloroquine Resistant falciparum Malaria in Isolates from an Endemic District of Iran

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A Raeisi

2008-04-01

Full Text Available Background: This study investigated the association between pfcrt, T76 allele and chloroquine resistance in patients with falciparum malaria. Molecular assays for point mutations on drugs resistance-related genes are applied tools for monitoring emerging resistance and surveillance malaria control strategies in endemic areas. The mutant genotype at codon 76 of Plasmodium falciparum chloroquine resistance transporter gene (pfcrt has been proposed as a molecular marker for the faster detection of chloroquine resistance in field. Methods: In 64 samples from patients with uncomplicated falciparum malaria from Sarbaz district in southeast of Iran,  the clinical response to chloroquine and the prevalence of K76T  mutations in pfcrt gene were investigated by in vivo and nested-PCR  followed restriction enzyme digestion methods. Results:  The occurrence of the K76T mutation was very high (60 of 64, i.e. 93.75% among these filed isolates. Only 4 of 64 isolates harbored wild type K76 codon and no case was a mixed of K76 and 76T codons. All of the 22 (100% chloroquine-resistant and 16.7% of sensitive isolates were found to harbor the 76T mutation and none was found to contain the wild type (K76 allele. Conclusions: The frequency of chloroquine resistance associated point mutation K76T, in pfcrt gene in this region suggest that detection of this mutation can be applied for predicting chloroquine resistance in epidemiologic settings with sufficiently high sensitivity to make it an attractive alternative to time and labor-consuming in vivo trials.

Minor abnormalities of testis development in mice lacking the gene encoding the MAPK signalling component, MAP3K1.

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Nick Warr

2011-05-01

Full Text Available In mammals, the Y chromosome is a dominant male determinant, causing the bipotential gonad to develop as a testis. Recently, cases of familial and spontaneous 46,XY disorders of sex development (DSD have been attributed to mutations in the human gene encoding mitogen-activated protein kinase kinase kinase 1, MAP3K1, a component of the mitogen-activated protein kinase (MAPK signal transduction pathway. In individuals harbouring heterozygous mutations in MAP3K1, dysregulation of MAPK signalling was observed in lymphoblastoid cell lines, suggesting a causal role for these mutations in disrupting XY sexual development. Mice lacking the cognate gene, Map3k1, are viable and exhibit the eyes open at birth (EOB phenotype on a mixed genetic background, but on the C57BL/6J genetic background most mice die at around 14.5 dpc due to a failure of erythropoiesis in the fetal liver. However, no systematic examination of sexual development in Map3k1-deficient mice has been described, an omission that is especially relevant in the case of C57BL/6J, a genetic background that is sensitized to disruptions to testis determination. Here, we report that on a mixed genetic background mice lacking Map3k1 are fertile and exhibit no overt abnormalities of testis development. On C57BL/6J, significant non-viability is observed with very few animals surviving to adulthood. However, an examination of development in Map3k1-deficient XY embryos on this genetic background revealed no significant defects in testis determination, although minor abnormalities were observed, including an increase in gonadal length. Based on these observations, we conclude that MAP3K1 is not required for mouse testis determination. We discuss the significance of these data for the functional interpretation of sex-reversing MAP3K1 mutations in humans.

Investigation of K sub L , sub S-> pi sup +pi sup - e sup + e sup - decays

CERN Document Server

Lai, A; Bevan, A

2003-01-01

The K sub L-> pi sup +pi sup - e sup + e sup - and K sub S-> pi sup +pi sup - e sup + e sup - decay modes have been studied in detail using the NA48 detector at the CERN SPS. Based on the data collected during the 1998 and 1999 run periods, a sample of 1162 K sub L-> pi sup +pi sup - e sup + e sup - candidates has been observed with an expected background level of 36.9 events, yielding the branching ratio measurement BR(K sub L -> pi sup +pi sup - e sup + e sup -)=(3.08+-0.20) x 10 sup - sup 7. The distribution of events in the sin phi cos phi variable, where phi is the angle between the pi sup +pi sup - and the e sup + e sup - decay planes in the kaon centre of mass, is found to exhibit a large CP-violating asymmetry with the value A subphi=(14.2+-3.6)%. For the K sub S-> pi sup +pi sup - e sup + e sup - decay channel, 621 candidates have been identified in the 1999 data sample with an estimated background contribution of 0.7 event. The corresponding branching ratio has been determined to be BR(K sub S-> pi ...

Mutations in Mll2, an H3K4 Methyltransferase, Result in Insulin Resistance and Impaired Glucose Tolerance in Mice

Science.gov (United States)

Schröter, David; Matthews, Helen C.; Bogani, Debora; Moir, Lee; Long, Anna; Church, Christopher; Hugill, Alison; Anstee, Quentin M.; Goldin, Rob; Thursz, Mark; Hollfelder, Florian; Cox, Roger D.

2013-01-01

We employed a random mutagenesis approach to identify novel monogenic determinants of type 2 diabetes. Here we show that haplo-insufficiency of the histone methyltransferase myeloid-lineage leukemia (Mll2/Wbp7) gene causes type 2 diabetes in the mouse. We have shown that mice heterozygous for two separate mutations in the SET domain of Mll2 or heterozygous Mll2 knockout mice were hyperglycaemic, hyperinsulinaemic and developed non-alcoholic fatty liver disease. Consistent with previous Mll2 knockout studies, mice homozygous for either ENU mutation (or compound heterozygotes) died during embryonic development at 9.5–14.5 days post coitum. Heterozygous deletion of Mll2 induced in the adult mouse results in a normal phenotype suggesting that changes in chromatin methylation during development result in the adult phenotype. Mll2 has been shown to regulate a small subset of genes, a number of which Neurod1, Enpp1, Slc27a2, and Plcxd1 are downregulated in adult mutant mice. Our results demonstrate that histone H3K4 methyltransferase Mll2 is a component of the genetic regulation necessary for glucose homeostasis, resulting in a specific disease pattern linking chromatin modification with causes and progression of type 2 diabetes, providing a basis for its further understanding at the molecular level. PMID:23826075

Mutations in Mll2, an H3K4 methyltransferase, result in insulin resistance and impaired glucose tolerance in mice.

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Michelle Goldsworthy

Full Text Available We employed a random mutagenesis approach to identify novel monogenic determinants of type 2 diabetes. Here we show that haplo-insufficiency of the histone methyltransferase myeloid-lineage leukemia (Mll2/Wbp7 gene causes type 2 diabetes in the mouse. We have shown that mice heterozygous for two separate mutations in the SET domain of Mll2 or heterozygous Mll2 knockout mice were hyperglycaemic, hyperinsulinaemic and developed non-alcoholic fatty liver disease. Consistent with previous Mll2 knockout studies, mice homozygous for either ENU mutation (or compound heterozygotes died during embryonic development at 9.5-14.5 days post coitum. Heterozygous deletion of Mll2 induced in the adult mouse results in a normal phenotype suggesting that changes in chromatin methylation during development result in the adult phenotype. Mll2 has been shown to regulate a small subset of genes, a number of which Neurod1, Enpp1, Slc27a2, and Plcxd1 are downregulated in adult mutant mice. Our results demonstrate that histone H3K4 methyltransferase Mll2 is a component of the genetic regulation necessary for glucose homeostasis, resulting in a specific disease pattern linking chromatin modification with causes and progression of type 2 diabetes, providing a basis for its further understanding at the molecular level.

Radiation-induced mutations in sweet cherry (Prunus avium L.)

Energy Technology Data Exchange (ETDEWEB)

Saamin, S [Cocoa and Coconut Research Division, Malaysian Agricultural Research and Development Institute (Malaysia); Thompson, M M [Department of Horticulture, Oregon State University, Corvallis, OR (United States)

1989-01-01

Full text: Dormant scions of 'Bing' were exposed to 1-2.5 kR gamma radiation. The main buds were excised and the scions grafted to allow the growth of accessory buds into primary shoots. The frequency and types of mutations were described in a population of 3307 M{sub 1}V{sub 2} shoot. The overall mutation frequency was 2.7% incl. 0.15% growth-reduced mutants. The experiment was repeated using 3kR and 4kR fractionated doses in water. Differences in mutation frequency at 3kR and 4kR were not significant. Of 2765 surviving M{sub 1}V{sub 2} shoots derived from irradiation of accessory buds of both standard and V{sub 1} shoots, the overall mutation frequency was 3.3% incl. 1.7% partial leaf mutants, 1.0% leaf mutants, and 0.54% growth-reduced mutants. For maximum mutation rate with adequate survival we suggest acute irradiation of accessory buds in air at dosages approximating LD50. Mutant sectors in M{sub 1}V{sub 1} shoots derived from accessory buds are larger than those from main buds, as revealed by the higher number of mutant repeats. (author)

9 CFR 319.701 - Mixed fat shortening.

Science.gov (United States)

2010-01-01

... 9 Animals and Animal Products 2 2010-01-01 2010-01-01 false Mixed fat shortening. 319.701 Section... § 319.701 Mixed fat shortening. Shortening prepared with a mixture of meat fats and vegetable oils may... descending order of predominance. ...

A novel fully automated molecular diagnostic system (AMDS for colorectal cancer mutation detection.

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