Aberrant location of inhibitory synaptic marker proteins in the hippocampus of dystrophin-deficient mice: implications for cognitive impairment in duchenne muscular dystrophy.

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Elżbieta Krasowska

Full Text Available Duchenne muscular dystrophy (DMD is a neuromuscular disease that arises from mutations in the dystrophin-encoding gene. Apart from muscle pathology, cognitive impairment, primarily of developmental origin, is also a significant component of the disorder. Convergent lines of evidence point to an important role for dystrophin in regulating the molecular machinery of central synapses. The clustering of neurotransmitter receptors at inhibitory synapses, thus impacting on synaptic transmission, is of particular significance. However, less is known about the role of dystrophin in influencing the precise expression patterns of proteins located within the pre- and postsynaptic elements of inhibitory synapses. To this end, we exploited molecular markers of inhibitory synapses, interneurons and dystrophin-deficient mouse models to explore the role of dystrophin in determining the stereotypical patterning of inhibitory connectivity within the cellular networks of the hippocampus CA1 region. In tissue from wild-type (WT mice, immunoreactivity of neuroligin2 (NL2, an adhesion molecule expressed exclusively in postsynaptic elements of inhibitory synapses, and the vesicular GABA transporter (VGAT, a marker of GABAergic presynaptic elements, were predictably enriched in strata pyramidale and lacunosum moleculare. In acute contrast, NL2 and VGAT immunoreactivity was relatively evenly distributed across all CA1 layers in dystrophin-deficient mice. Similar changes were evident with the cannabinoid receptor 1, vesicular glutamate transporter 3, parvalbumin, somatostatin and the GABAA receptor alpha1 subunit. The data show that in the absence of dystrophin, there is a rearrangement of the molecular machinery, which underlies the precise spatio-temporal pattern of GABAergic synaptic transmission within the CA1 sub-field of the hippocampus.

Platelet function and activation in Cavalier King Charles Spaniels with subclinical chronic valvular heart disease.

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Tong, Linda J; Hosgood, Giselle L; French, Anne T; Irwin, Peter J; Shiel, Robert E

2016-08-01

OBJECTIVE To assess platelet closure time (CT), mean platelet component (MPC) concentration, and platelet component distribution width (PCDW) in dogs with subclinical chronic valvular heart disease. ANIMALS 89 Cavalier King Charles Spaniels (CKCSs) and 39 control dogs (not CKCSs). PROCEDURES Platelet count, MPC concentration, PCDW, and Hct were measured by use of a hematology analyzer, and CT was measured by use of a platelet function analyzer. Murmur grade and echocardiographic variables (mitral valve regurgitant jet size relative to left atrial area, left atrial-to-aortic diameter ratio, and left ventricular internal dimensions) were recorded. Associations between explanatory variables (sex, age, murmur grade, echocardiographic variables, platelet count, and Hct) and outcomes (CT, MPC concentration, and PCDW) were examined by use of multivariate regression models. RESULTS A model with 5 variables best explained variation in CT (R(2), 0.74), with > 60% of the variance of CT explained by mitral valve regurgitant jet size. The model of best fit to explain variation in MPC concentration included only platelet count (R(2), 0.24). The model of best fit to explain variation in PCDW included platelet count and sex (R(2), 0.25). CONCLUSIONS AND CLINICAL RELEVANCE In this study, a significant effect of mitral valve regurgitant jet size on CT was consistent with platelet dysfunction. However, platelet activation, as assessed on the basis of the MPC concentration and PCDW, was not a feature of subclinical chronic valvular heart disease in CKCSs.

Fetal skeletal muscle progenitors have regenerative capacity after intramuscular engraftment in dystrophin deficient mice.

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Hiroshi Sakai

Full Text Available Muscle satellite cells (SCs are stem cells that reside in skeletal muscles and contribute to regeneration upon muscle injury. SCs arise from skeletal muscle progenitors expressing transcription factors Pax3 and/or Pax7 during embryogenesis in mice. However, it is unclear whether these fetal progenitors possess regenerative ability when transplanted in adult muscle. Here we address this question by investigating whether fetal skeletal muscle progenitors (FMPs isolated from Pax3(GFP/+ embryos have the capacity to regenerate muscle after engraftment into Dystrophin-deficient mice, a model of Duchenne muscular dystrophy. The capacity of FMPs to engraft and enter the myogenic program in regenerating muscle was compared with that of SCs derived from adult Pax3(GFP/+ mice. Transplanted FMPs contributed to the reconstitution of damaged myofibers in Dystrophin-deficient mice. However, despite FMPs and SCs having similar myogenic ability in culture, the regenerative ability of FMPs was less than that of SCs in vivo. FMPs that had activated MyoD engrafted more efficiently to regenerate myofibers than MyoD-negative FMPs. Transcriptome and surface marker analyses of these cells suggest the importance of myogenic priming for the efficient myogenic engraftment. Our findings suggest the regenerative capability of FMPs in the context of muscle repair and cell therapy for degenerative muscle disease.

Volume reduction of the jugular foramina in Cavalier King Charles Spaniels with syringomyelia.

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Schmidt, Martin Jürgen; Ondreka, Nele; Sauerbrey, Maren; Volk, Holger Andreas; Rummel, Christoph; Kramer, Martin

2012-09-06

Understanding the pathogenesis of the chiari-like malformation in the Cavalier King Charles Spaniel (CKCS) is incomplete, and current hypotheses do not fully explain the development of syringomyelia (SM) in the spinal cords of affected dogs. This study investigates an unconventional pathogenetic theory for the development of cerebrospinal fluid (CSF) pressure waves in the subarachnoid space in CKCS with SM, by analogy with human diseases. In children with achondroplasia the shortening of the skull base can lead to a narrowing of the jugular foramina (JF) between the cranial base synchondroses. This in turn has been reported to cause a congestion of the major venous outflow tracts of the skull and consequently to an increase in the intracranial pressure (ICP). Amongst brachycephalic dog breeds the CKCS has been identified as having an extremely short and wide braincase. A stenosis of the JF and a consequential vascular compromise in this opening could contribute to venous hypertension, raising ICP and causing CSF jets in the spinal subarachnoid space of the CKCS. In this study, JF volumes in CKCSs with and without SM were compared to assess a possible role of this pathologic mechanism in the development of SM in this breed. Computed tomography (CT) scans of 40 CKCSs > 4 years of age were used to create three-dimensional (3D) models of the skull and the JF. Weight matched groups (7-10 kg) of 20 CKCSs with SM and 20 CKCSs without SM were compared. CKCSs without SM presented significantly larger JF -volumes (median left JF: 0.0633 cm3; median right JF: 0.0703 cm3; p stenosis of the JF and consecutive venous congestion may explain the aetiology of CSF pressure waves in the subarachnoid space, independent of cerebellar herniation, as an additional pathogenetic factor for the development of SM in this breed.

Marginal level dystrophin expression improves clinical outcome in a strain of dystrophin/utrophin double knockout mice.

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Dejia Li

2010-12-01

Full Text Available Inactivation of all utrophin isoforms in dystrophin-deficient mdx mice results in a strain of utrophin knockout mdx (uko/mdx mice. Uko/mdx mice display severe clinical symptoms and die prematurely as in Duchenne muscular dystrophy (DMD patients. Here we tested the hypothesis that marginal level dystrophin expression may improve the clinical outcome of uko/mdx mice. It is well established that mdx3cv (3cv mice express a near-full length dystrophin protein at ∼5% of the normal level. We crossed utrophin-null mutation to the 3cv background. The resulting uko/3cv mice expressed the same level of dystrophin as 3cv mice but utrophin expression was completely eliminated. Surprisingly, uko/3cv mice showed a much milder phenotype. Compared to uko/mdx mice, uko/3cv mice had significantly higher body weight and stronger specific muscle force. Most importantly, uko/3cv outlived uko/mdx mice by several folds. Our results suggest that a threshold level dystrophin expression may provide vital clinical support in a severely affected DMD mouse model. This finding may hold clinical implications in developing novel DMD therapies.

Volume reduction of the jugular foramina in Cavalier King Charles Spaniels with syringomyelia

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Schmidt Martin

2012-09-01

Full Text Available Abstract Background Understanding the pathogenesis of the chiari-like malformation in the Cavalier King Charles Spaniel (CKCS is incomplete, and current hypotheses do not fully explain the development of syringomyelia (SM in the spinal cords of affected dogs. This study investigates an unconventional pathogenetic theory for the development of cerebrospinal fluid (CSF pressure waves in the subarachnoid space in CKCS with SM, by analogy with human diseases. In children with achondroplasia the shortening of the skull base can lead to a narrowing of the jugular foramina (JF between the cranial base synchondroses. This in turn has been reported to cause a congestion of the major venous outflow tracts of the skull and consequently to an increase in the intracranial pressure (ICP. Amongst brachycephalic dog breeds the CKCS has been identified as having an extremely short and wide braincase. A stenosis of the JF and a consequential vascular compromise in this opening could contribute to venous hypertension, raising ICP and causing CSF jets in the spinal subarachnoid space of the CKCS. In this study, JF volumes in CKCSs with and without SM were compared to assess a possible role of this pathologic mechanism in the development of SM in this breed. Results Computed tomography (CT scans of 40 CKCSs > 4 years of age were used to create three-dimensional (3D models of the skull and the JF. Weight matched groups (7–10 kg of 20 CKCSs with SM and 20 CKCSs without SM were compared. CKCSs without SM presented significantly larger JF -volumes (median left JF: 0.0633 cm3; median right JF: 0.0703 cm3; p 3; median right JF: 0.0434 cm3; p Conclusion A stenosis of the JF and consecutive venous congestion may explain the aetiology of CSF pressure waves in the subarachnoid space, independent of cerebellar herniation, as an additional pathogenetic factor for the development of SM in this breed.

Dystrophin-deficient cardiomyocytes derived from human urine: New biologic reagents for drug discovery

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Xuan Guan

2014-03-01

Full Text Available The ability to extract somatic cells from a patient and reprogram them to pluripotency opens up new possibilities for personalized medicine. Induced pluripotent stem cells (iPSCs have been employed to generate beating cardiomyocytes from a patient's skin or blood cells. Here, iPSC methods were used to generate cardiomyocytes starting from the urine of a patient with Duchenne muscular dystrophy (DMD. Urine was chosen as a starting material because it contains adult stem cells called urine-derived stem cells (USCs. USCs express the canonical reprogramming factors c-myc and klf4, and possess high telomerase activity. Pluripotency of urine-derived iPSC clones was confirmed by immunocytochemistry, RT-PCR and teratoma formation. Urine-derived iPSC clones generated from healthy volunteers and a DMD patient were differentiated into beating cardiomyocytes using a series of small molecules in monolayer culture. Results indicate that cardiomyocytes retain the DMD patient's dystrophin mutation. Physiological assays suggest that dystrophin-deficient cardiomyocytes possess phenotypic differences from normal cardiomyocytes. These results demonstrate the feasibility of generating cardiomyocytes from a urine sample and that urine-derived cardiomyocytes retain characteristic features that might be further exploited for mechanistic studies and drug discovery.

Increased susceptibility of dystrophin-deficient brain to mild hypoxia

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Wallis, T.; Rae, C.; Bubb, W.A.; Head, S.I.

2002-01-01

Full text: Duchenne muscular dystrophy is an X-linked disorder resulting from total absence of the 427 kDa protein dystrophin. Dystrophin is normally expressed in the brain mainly in a neuronal subpopulation: cortical pyramidal cells, hippocampal CA1 neurons and cerebellar Purkinje cells. One suggested role for dystrophin is in colocalising mitochondrial creatine kinase with ADP translocase and ATP synthase in mitochondria. Brain tissue slices in the murine model of Duchenne dystrophy, the mdx mouse, have been shown to be more sensitive to hypoxia than control. In this work, we used 13 C NMR to monitor the metabolic response of mdx cortical brain tissue slices to normoxia (95%O 2 /5% CO 2 ) and mild hypoxia (95%air/5% CO 2 ). Under normoxic conditions, mdx cortical slices displayed increased net flux through the Krebs cycle and glutamate/glutamine cycle, consistent with the proposed GABA A lesion which results in decreased inhibitory input. By contrast, mild hypoxia resulted in a significant increase in the total pool size of lactate and decreased net flux of 13 C from [3- 13 C]pyruvate into glutamate C4, GABA C2 and Ala C2, as well as decreased anaplerotic activity as measured by the ratio of Asp C2: Asp C3 label. Mild hypoxia has a significantly greater effect on brain oxidative metabolism in mdx mice, than in control

Voluntary wheel running in dystrophin-deficient (mdx) mice: Relationships between exercise parameters and exacerbation of the dystrophic phenotype

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Smythe, Gayle M; White, Jason D

2012-01-01

Voluntary wheel running can potentially be used to exacerbate the disease phenotype in dystrophin-deficient mdx mice. While it has been established that voluntary wheel running is highly variable between individuals, the key parameters of wheel running that impact the most on muscle pathology have not been examined in detail. We conducted a 2-week test of voluntary wheel running by mdx mice and the impact of wheel running on disease pathology. There was significant individual variation in the...

Clinical and genetic characterisation of dystrophin-deficient muscular dystrophy in a family of Miniature Poodle dogs.

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Lluís Sánchez

Full Text Available Four full-sibling intact male Miniature Poodles were evaluated at 4-19 months of age. One was clinically normal and three were affected. All affected dogs were reluctant to exercise and had generalised muscle atrophy, a stiff gait and a markedly elevated serum creatine kinase activity. Two affected dogs also showed poor development, learning difficulties and episodes of abnormal behaviour. In these two dogs, investigations into forebrain structural and metabolic diseases were unremarkable; electromyography demonstrated fibrillation potentials and complex repetitive discharges in the infraspinatus, supraspinatus and epaxial muscles. Histopathological, immunohistochemical and immunoblotting analyses of muscle biopsies were consistent with dystrophin-deficient muscular dystrophy. DNA samples were obtained from all four full-sibling male Poodles, a healthy female littermate and the dam, which was clinically normal. Whole genome sequencing of one affected dog revealed a >5 Mb deletion on the X chromosome, encompassing the entire DMD gene. The exact deletion breakpoints could not be experimentally ascertained, but we confirmed that this region was deleted in all affected males, but not in the unaffected dogs. Quantitative polymerase chain reaction confirmed all three affected males were hemizygous for the mutant X chromosome, while the wildtype chromosome was observed in the unaffected male littermate. The female littermate and the dam were both heterozygous for the mutant chromosome. Forty-four Miniature Poodles from the general population were screened for the mutation and were homozygous for the wildtype chromosome. The finding represents a naturally-occurring mutation causing dystrophin-deficient muscular dystrophy in the dog.

Carrier detection of duchenne and becker muscular dystrophy using muscle dystrophin immunohistochemistry

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Acary S. Bulle Oliveira

1992-12-01

Full Text Available To ascertain whether dystrophin immunohistochemistry could improve DMD/ BMD carrier detection, we analyzed 14 muscle biopsies from 13 DMD and one BMD probable and possible carriers. All women were also evaluated using conventional methods, including genetic analysis, clinical and neurological evaluation, serum CK levels, KMG, and muscle biopsy. In 6 cases, there was a mosaic of dystrophin-positive and dystrophin-deficient fibers that allowed to make the diagnosis of a carrier state. Comparing dystrophin immunohistochemistry to the traditional methods, it was noted that this method is less sensitive than serum CK measuremens, but is more sensitive than EMG and muscle biopsy. The use of dystrophin immunohistochemistry in addition to CK, EMG and muscle biopsy improved the accuracy of carrier detection. This method is also helpful to distinguish manifesting DMD carriers from patients with other neuromuscular diseases like limb-girdle muscular dystrophy and spinal muscular atrophy.

Increased NT-proANP predicts risk of congestive heart failure in Cavalier King Charles spaniels with mitral regurgitation caused by myxomatous valve disease.

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Eriksson, Anders S; Häggström, Jens; Pedersen, Henrik Duelund; Hansson, Kerstin; Järvinen, Anna-Kaisa; Haukka, Jari; Kvart, Clarence

2014-09-01

To evaluate the predictive value of plasma N-terminal pro-atrial natriuretic peptide (NT-proANP) and nitric oxide end-products (NOx) as markers for progression of mitral regurgitation caused by myxomatous mitral valve disease. Seventy-eight privately owned Cavalier King Charles spaniels with naturally occurring myxomatous mitral valve disease. Prospective longitudinal study comprising 312 measurements over a 4.5 year period. Clinical values were recorded, NT-proANP concentrations were measured by radioimmunoassay, and NOx were analyzed colorimetrically. To predict congestive heart failure (CHF), Cox proportional hazards models with time-varying covariates were constructed. The hazard ratio for NT-proANP (per 1000 pmol/l increase) to predict future CHF was 6.7 (95% confidence interval, 3.6-12.5; p 1000 pmol/l was 11 months (95% confidence interval, 5.6-12.6 months), compared to 54 months (46 - infinity) for dogs with concentrations ≤ 1000 pmol/l (p 130 beats per minute) and grade of murmur (≥ 3/6). The risk of CHF due to mitral regurgitation is increased in dogs with blood NT-proANP concentrations above 1000 pmol/l. Measurement of NT-proANP can be a valuable tool to identify dogs that may develop CHF within months. Copyright © 2014 Elsevier B.V. All rights reserved.

Motor physical therapy affects muscle collagen type I and decreases gait speed in dystrophin-deficient dogs.

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Thaís P Gaiad

Full Text Available Golden Retriever Muscular Dystrophy (GRMD is a dystrophin-deficient canine model genetically homologous to Duchenne Muscular Dystrophy (DMD in humans. Muscular fibrosis secondary to cycles of degeneration/regeneration of dystrophic muscle tissue and muscular weakness leads to biomechanical adaptation that impairs the quality of gait. Physical therapy (PT is one of the supportive therapies available for DMD, however, motor PT approaches have controversial recommendations and there is no consensus regarding the type and intensity of physical therapy. In this study we investigated the effect of physical therapy on gait biomechanics and muscular collagen deposition types I and III in dystrophin-deficient dogs. Two dystrophic dogs (treated dogs-TD underwent a PT protocol of active walking exercise, 3×/week, 40 minutes/day, 12 weeks. Two dystrophic control dogs (CD maintained their routine of activities of daily living. At t0 (pre and t1 (post-physical therapy, collagen type I and III were assessed by immunohistochemistry and gait biomechanics were analyzed. Angular displacement of shoulder, elbow, carpal, hip, stifle and tarsal joint and vertical (Fy, mediolateral (Fz and craniocaudal (Fx ground reaction forces (GRF were assessed. Wilcoxon test was used to verify the difference of biomechanical variables between t0 and t1, considering p<.05. Type I collagen of endomysium suffered the influence of PT, as well as gait speed that had decreased from t0 to t1 (p<.000. The PT protocol employed accelerates morphological alterations on dystrophic muscle and promotes a slower velocity of gait. Control dogs which maintained their routine of activities of daily living seem to have found a better balance between movement and preservation of motor function.

Motor Physical Therapy Affects Muscle Collagen Type I and Decreases Gait Speed in Dystrophin-Deficient Dogs

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Gaiad, Thaís P.; Araujo, Karla P. C.; Serrão, Júlio C.; Miglino, Maria A.; Ambrósio, Carlos Eduardo

2014-01-01

Golden Retriever Muscular Dystrophy (GRMD) is a dystrophin-deficient canine model genetically homologous to Duchenne Muscular Dystrophy (DMD) in humans. Muscular fibrosis secondary to cycles of degeneration/regeneration of dystrophic muscle tissue and muscular weakness leads to biomechanical adaptation that impairs the quality of gait. Physical therapy (PT) is one of the supportive therapies available for DMD, however, motor PT approaches have controversial recommendations and there is no consensus regarding the type and intensity of physical therapy. In this study we investigated the effect of physical therapy on gait biomechanics and muscular collagen deposition types I and III in dystrophin-deficient dogs. Two dystrophic dogs (treated dogs-TD) underwent a PT protocol of active walking exercise, 3×/week, 40 minutes/day, 12 weeks. Two dystrophic control dogs (CD) maintained their routine of activities of daily living. At t0 (pre) and t1 (post-physical therapy), collagen type I and III were assessed by immunohistochemistry and gait biomechanics were analyzed. Angular displacement of shoulder, elbow, carpal, hip, stifle and tarsal joint and vertical (Fy), mediolateral (Fz) and craniocaudal (Fx) ground reaction forces (GRF) were assessed. Wilcoxon test was used to verify the difference of biomechanical variables between t0 and t1, considering p<.05. Type I collagen of endomysium suffered the influence of PT, as well as gait speed that had decreased from t0 to t1 (p<.000). The PT protocol employed accelerates morphological alterations on dystrophic muscle and promotes a slower velocity of gait. Control dogs which maintained their routine of activities of daily living seem to have found a better balance between movement and preservation of motor function. PMID:24713872

Assessing the relative importance of health and conformation traits in the cavalier king Charles spaniel.

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Wijnrocx, Katrien; François, Liesbeth; Goos, Peter; Buys, Nadine; Janssens, Steven

2018-01-01

The selection of a future breeding dog is a complicated task, in which disease characteristics and different traits have to be combined and weighed against one another. Truncation selection, that is the exclusion of affected animals, may be very inefficient when selecting on a large number of traits, and may result in a reduction of the genetic diversity in a population or breed. Selection could be facilitated by the use of a selection index that combines multiple traits or breeding values into one score. This however requires a consideration of their relative value according to their economic weight, which is difficult to express in monetary units for health traits. The use of a choice experiment to derive non-market values might be a solution to this problem. This is a pilot study to assess the potential use of choice experiments to ascertain the public preference and relative importance attached to health- and conformation traits in the selection of a Cavalier King Charles spaniel. The focus was on two prevalent disorders, mitral valve disease and syringomyelia, and on several important conformation traits such as muzzle length and eye shape. Based on available prior information, a Bayesian D-optimal design approach was used to develop a choice experiment and the resulting choice sets. Every participant (breeder or owner) in the choice experiment was presented with a total of 17 choice sets, in which at most four traits could vary to reduce the cognitive burden. A total of 114 respondents participated in the choice experiment and results showed that respondents (breeders/owners) current attitudes were directed towards health (syringomyelia and mitral valve disease), followed by eye shape and level of inbreeding. This approach identifies the value breeders and owners attach to certain traits in the breeding objective. The resulting relative weights, represented as the logworths obtained from the choice experiment, could be an alternative to economic weights. They

Defects in mitochondrial ATP synthesis in dystrophin-deficient mdx skeletal muscles may be caused by complex I insufficiency.

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Emma Rybalka

Full Text Available Duchenne Muscular Dystrophy is a chronic, progressive and ultimately fatal skeletal muscle wasting disease characterised by sarcolemmal fragility and intracellular Ca2+ dysregulation secondary to the absence of dystrophin. Mounting literature also suggests that the dysfunction of key energy systems within the muscle may contribute to pathological muscle wasting by reducing ATP availability to Ca2+ regulation and fibre regeneration. No study to date has biochemically quantified and contrasted mitochondrial ATP production capacity by dystrophic mitochondria isolated from their pathophysiological environment such to determine whether mitochondria are indeed capable of meeting this heightened cellular ATP demand, or examined the effects of an increasing extramitochondrial Ca2+ environment. Using isolated mitochondria from the diaphragm and tibialis anterior of 12 week-old dystrophin-deficient mdx and healthy control mice (C57BL10/ScSn we have demonstrated severely depressed Complex I-mediated mitochondrial ATP production rate in mdx mitochondria that occurs irrespective of the macronutrient-derivative substrate combination fed into the Kreb's cycle, and, which is partially, but significantly, ameliorated by inhibition of Complex I with rotenone and stimulation of Complex II-mediated ATP-production with succinate. There was no difference in the MAPR response of mdx mitochondria to increasing extramitochondrial Ca2+ load in comparison to controls, and 400 nM extramitochondrial Ca2+ was generally shown to be inhibitory to MAPR in both groups. Our data suggests that DMD pathology is exacerbated by a Complex I deficiency, which may contribute in part to the severe reductions in ATP production previously observed in dystrophic skeletal muscle.

Angiotensin-converting enzyme activity in Cavalier King Charles Spaniels with an ACE gene polymorphism and myxomatous mitral valve disease.

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Meurs, Kathryn M; Olsen, Lisbeth H; Reimann, Maria J; Keene, Bruce W; Atkins, Clarke E; Adin, Darcy; Aona, Brent; Condit, Julia; DeFrancesco, Teresa; Reina-Doreste, Yamir; Stern, Joshua A; Tou, Sandra; Ward, Jessica; Woodruff, Kathleen

2018-02-01

Myxomatous mitral valve disease (MMVD) is the most common heart disease in the dog. It is particularly common in the Cavalier King Charles Spaniel (CKCS) breed and affected dogs are frequently managed with angiotensin-converting enzyme inhibitors (ACE-I). We have previously identified a canine ACE gene polymorphism associated with a decrease in angiotensin-converting enzyme (ACE) activity. The aim of this study was to evaluate for the prevalence of the ACE polymorphism in CKCS with mitral valve disease and to determine whether the presence of the polymorphism is associated with alterations in ACE activity at different stages of cardiac disease. Seventy-three dogs with a diagnosis of mitral valve disease were evaluated and a blood sample was drawn for ACE polymorphism genotyping and ACE activity measurement. Forty-three dogs were homozygous for the ACE polymorphism; five were heterozygous and 25 were homozygous wild type. The mean age and the median severity of disease were not different for dogs with the polymorphism and dogs with the wild-type sequence. The median baseline ACE activity was significantly lower for the ACE polymorphism (27.0 U/l) than the wild-type sequence dogs (31.0 U/l) (P=0.02). Dogs with more severe disease and the ACE polymorphism had significantly lower levels of ACE activity than dogs with the wild-type sequence (P=0.03). The CKCS appears to have a high prevalence of the ACE variant. Dogs with the ACE variant had lower levels of ACE activity even in more advanced mitral valve disease than dogs without the variant. The clinical significance of this finding and its impact on the need for ACE-I in dogs with the polymorphism and heart disease deserves further study.

Dystrophin-deficient dogs with reduced myostatin have unequal muscle growth and greater joint contractures.

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Kornegay, Joe N; Bogan, Daniel J; Bogan, Janet R; Dow, Jennifer L; Wang, Jiahui; Fan, Zheng; Liu, Naili; Warsing, Leigh C; Grange, Robert W; Ahn, Mihye; Balog-Alvarez, Cynthia J; Cotten, Steven W; Willis, Monte S; Brinkmeyer-Langford, Candice; Zhu, Hongtu; Palandra, Joe; Morris, Carl A; Styner, Martin A; Wagner, Kathryn R

2016-01-01

Myostatin (Mstn) is a negative regulator of muscle growth whose inhibition promotes muscle growth and regeneration. Dystrophin-deficient mdx mice in which myostatin is knocked out or inhibited postnatally have a less severe phenotype with greater total mass and strength and less fibrosis and fatty replacement of muscles than mdx mice with wild-type myostatin expression. Dogs with golden retriever muscular dystrophy (GRMD) have previously been noted to have increased muscle mass and reduced fibrosis after systemic postnatal myostatin inhibition. Based partly on these results, myostatin inhibitors are in development for use in human muscular dystrophies. However, persisting concerns regarding the effects of long-term and profound myostatin inhibition will not be easily or imminently answered in clinical trials. To address these concerns, we developed a canine (GRippet) model by crossbreeding dystrophin-deficient GRMD dogs with Mstn-heterozygous (Mstn (+/-)) whippets. A total of four GRippets (dystrophic and Mstn (+/-)), three GRMD (dystrophic and Mstn wild-type) dogs, and three non-dystrophic controls from two litters were evaluated. Myostatin messenger ribonucleic acid (mRNA) and protein levels were downregulated in both GRMD and GRippet dogs. GRippets had more severe postural changes and larger (more restricted) maximal joint flexion angles, apparently due to further exaggeration of disproportionate effects on muscle size. Flexors such as the cranial sartorius were more hypertrophied on magnetic resonance imaging (MRI) in the GRippets, while extensors, including the quadriceps femoris, underwent greater atrophy. Myostatin protein levels negatively correlated with relative cranial sartorius muscle cross-sectional area on MRI, supporting a role in disproportionate muscle size. Activin receptor type IIB (ActRIIB) expression was higher in dystrophic versus control dogs, consistent with physiologic feedback between myostatin and ActRIIB. However, there was no

Sparing of the dystrophin-deficient cranial sartorius muscle is associated with classical and novel hypertrophy pathways in GRMD dogs.

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Nghiem, Peter P; Hoffman, Eric P; Mittal, Priya; Brown, Kristy J; Schatzberg, Scott J; Ghimbovschi, Svetlana; Wang, Zuyi; Kornegay, Joe N

2013-11-01

Both Duchenne and golden retriever muscular dystrophy (GRMD) are caused by dystrophin deficiency. The Duchenne muscular dystrophy sartorius muscle and orthologous GRMD cranial sartorius (CS) are relatively spared/hypertrophied. We completed hierarchical clustering studies to define molecular mechanisms contributing to this differential involvement and their role in the GRMD phenotype. GRMD dogs with larger CS muscles had more severe deficits, suggesting that selective hypertrophy could be detrimental. Serial biopsies from the hypertrophied CS and other atrophied muscles were studied in a subset of these dogs. Myostatin showed an age-dependent decrease and an inverse correlation with the degree of GRMD CS hypertrophy. Regulators of myostatin at the protein (AKT1) and miRNA (miR-539 and miR-208b targeting myostatin mRNA) levels were altered in GRMD CS, consistent with down-regulation of myostatin signaling, CS hypertrophy, and functional rescue of this muscle. mRNA and proteomic profiling was used to identify additional candidate genes associated with CS hypertrophy. The top-ranked network included α-dystroglycan and like-acetylglucosaminyltransferase. Proteomics demonstrated increases in myotrophin and spectrin that could promote hypertrophy and cytoskeletal stability, respectively. Our results suggest that multiple pathways, including decreased myostatin and up-regulated miRNAs, α-dystroglycan/like-acetylglucosaminyltransferase, spectrin, and myotrophin, contribute to hypertrophy and functional sparing of the CS. These data also underscore the muscle-specific responses to dystrophin deficiency and the potential deleterious effects of differential muscle involvement. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Immobilization of Dystrophin and Laminin α2-Chain Deficient Zebrafish Larvae In Vivo Prevents the Development of Muscular Dystrophy.

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Mei Li

Full Text Available Muscular dystrophies are often caused by genetic alterations in the dystrophin-dystroglycan complex or its extracellular ligands. These structures are associated with the cell membrane and provide mechanical links between the cytoskeleton and the matrix. Mechanical stress is considered a pathological mechanism and muscle immobilization has been shown to be beneficial in some mouse models of muscular dystrophy. The zebrafish enables novel and less complex models to examine the effects of extended immobilization or muscle relaxation in vivo in different dystrophy models. We have examined effects of immobilization in larvae from two zebrafish strains with muscular dystrophy, the Sapje dystrophin-deficient and the Candyfloss laminin α2-chain-deficient strains. Larvae (4 days post fertilization, dpf of both mutants have significantly lower active force in vitro, alterations in the muscle structure with gaps between muscle fibers and altered birefringence patterns compared to their normal siblings. Complete immobilization (18 hrs to 4 dpf was achieved using a small molecular inhibitor of actin-myosin interaction (BTS, 50 μM. This treatment resulted in a significantly weaker active contraction at 4 dpf in both mutated larvae and normal siblings, most likely reflecting a general effect of immobilization on myofibrillogenesis. The immobilization also significantly reduced the structural damage in the mutated strains, showing that muscle activity is an important pathological mechanism. Following one-day washout of BTS, muscle tension partly recovered in the Candyfloss siblings and caused structural damage in these mutants, indicating activity-induced muscle recovery and damage, respectively.

The proton pump inhibitor lansoprazole improves the skeletal phenotype in dystrophin deficient mdx mice.

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Arpana Sali

Full Text Available In Duchenne muscular dystrophy (DMD, loss of the membrane stabilizing protein dystrophin results in myofiber damage. Microinjury to dystrophic myofibers also causes secondary imbalances in sarcolemmic ion permeability and resting membrane potential, which modifies excitation-contraction coupling and increases proinflammatory/apoptotic signaling cascades. Although glucocorticoids remain the standard of care for the treatment of DMD, there is a need to investigate the efficacy of other pharmacological agents targeting the involvement of imbalances in ion flux on dystrophic pathology.We designed a preclinical trial to investigate the effects of lansoprazole (LANZO administration, a proton pump inhibitor, on the dystrophic muscle phenotype in dystrophin deficient (mdx mice. Eight to ten week-old female mice were assigned to one of four treatment groups (n = 12 per group: (1 vehicle control; (2 5 mg/kg/day LANZO; (3 5 mg/kg/day prednisolone; and (4 combined treatment of 5 mg/kg/day prednisolone (PRED and 5 mg/kg/day LANZO. Treatment was administered orally 5 d/wk for 3 months. At the end of the study, behavioral (Digiscan and functional outcomes (grip strength and Rotarod were assessed prior to sacrifice. After sacrifice, body, tissue and organ masses, muscle histology, in vitro muscle force, and creatine kinase levels were measured. Mice in the combined treatment groups displayed significant reductions in the number of degenerating muscle fibers and number of inflammatory foci per muscle field relative to vehicle control. Additionally, mice in the combined treatment group displayed less of a decline in normalized forelimb and hindlimb grip strength and declines in in vitro EDL force after repeated eccentric contractions.Together our findings suggest that combined treatment of LANZO and prednisolone attenuates some components of dystrophic pathology in mdx mice. Our findings warrant future investigation of the clinical efficacy of LANZO and

A comparative study of N-glycolylneuraminic acid (Neu5Gc and cytotoxic T cell (CT carbohydrate expression in normal and dystrophin-deficient dog and human skeletal muscle.

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Paul T Martin

Full Text Available The expression of N-glycolylneuraminic acid (Neu5Gc and the cytotoxic T cell (CT carbohydrate can impact the severity of muscular dystrophy arising from the loss of dystrophin in mdx mice. Here, we describe the expression of these two glycans in skeletal muscles of dogs and humans with or without dystrophin-deficiency. Neu5Gc expression was highly reduced (>95% in muscle from normal golden retriever crosses (GR, n = 3 and from golden retriever with muscular dystrophy (GRMD, n = 5 dogs at multiple ages (3, 6 and 13 months when compared to mouse muscle, however, overall sialic acid expression in GR and GRMD muscles remained high at all ages. Neu5Gc was expressed on only a minority of GRMD satellite cells, CD8⁺ T lymphocytes and macrophages. Human muscle from normal (no evident disease, n = 3, Becker (BMD, n = 3 and Duchenne (DMD, n = 3 muscular dystrophy individuals had absent to very low Neu5Gc staining, but some punctate intracellular muscle staining was present in BMD and DMD muscles. The CT carbohydrate was localized to the neuromuscular junction in GR muscle, while GRMD muscles had increased expression on a subset of myofibers and macrophages. In humans, the CT carbohydrate was ectopically expressed on the sarcolemmal membrane of some BMD muscles, but not normal human or DMD muscles. These data are consistent with the notion that altered Neu5Gc and CT carbohydrate expression may modify disease severity resulting from dystrophin deficiency in dogs and humans.

Evaluation of skeletal and cardiac muscle function after chronic administration of thymosin beta-4 in the dystrophin deficient mouse.

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Christopher F Spurney

2010-01-01

Full Text Available Thymosin beta-4 (Tbeta4 is a ubiquitous protein with many properties relating to cell proliferation and differentiation that promotes wound healing and modulates inflammatory mediators. We studied the effects of chronic administration of Tbeta4 on the skeletal and cardiac muscle of dystrophin deficient mdx mice, the mouse model of Duchenne muscular dystrophy. Female wild type (C57BL10/ScSnJ and mdx mice, 8-10 weeks old, were treated with 150 microg of Tbeta4 twice a week for 6 months. To promote muscle pathology, mice were exercised for 30 minutes twice a week. Skeletal and cardiac muscle function were assessed via grip strength and high frequency echocardiography. Localization of Tbeta4 and amount of fibrosis were quantified using immunohistochemistry and Gomori's tri-chrome staining, respectively. Mdx mice treated with Tbeta4 showed a significant increase in skeletal muscle regenerating fibers compared to untreated mdx mice. Tbeta4 stained exclusively in the regenerating fibers of mdx mice. Although untreated mdx mice had significantly decreased skeletal muscle strength compared to untreated wild type, there were no significant improvements in mdx mice after treatment. Systolic cardiac function, measured as percent shortening fraction, was decreased in untreated mdx mice compared to untreated wild type and there was no significant difference after treatment in mdx mice. Skeletal and cardiac muscle fibrosis were also significantly increased in untreated mdx mice compared to wild type, but there was no significant improvement in treated mdx mice. In exercised dystrophin deficient mice, chronic administration of Tbeta4 increased the number of regenerating fibers in skeletal muscle and could have a potential role in treatment of skeletal muscle disease in Duchenne muscular dystrophy.

Serum cholinesterases are differentially regulated in normal and dystrophin-deficient mutant mice

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Andrea R. Durrant

2012-06-01

Full Text Available The cholinesterases, acetylcholinesterase and butyrylcholinesterase (pseudocholinesterase, are abundant in the nervous system and in other tissues. The role of acetylcholinesterase in terminating transmitter action in the peripheral and central nervous system is well understood. However, both knowledge of the function(s of the cholinesterases in serum, and of their metabolic and endocrine regulation under normal and pathological conditions, is limited. This study investigates acetylcholinesterase and butyrylcholinesterase in sera of dystrophin-deficient mdx mutant mice, an animal model for the human Duchenne muscular dystrophy and in control healthy mice. The data show systematic and differential variations in the concentrations of both enzymes in the sera, and specific changes dictated by alteration of hormonal balance in both healthy and dystrophic mice. While acetylcholinesterase in mdx-sera is elevated, butyrylcholinesterase is markedly diminished, resulting in an overall cholinesterase decrease compared to sera of healthy controls. The androgen testosterone (T is a negative modulator of butyrylcholinesterase, but not of acetylcholinesterase, in male mouse sera. T-removal elevated both butyrylcholinesterase activity and the butyrylcholinesterase/acetylcholinesterase ratio in mdx male sera to values resembling those in healthy control male mice. Mechanisms of regulation of the circulating cholinesterases and their impairment in the dystrophic mice are suggested, and clinical implications for diagnosis and treatment are considered.

Dystrophin Immunity in Duchenne’s Muscular Dystrophy

OpenAIRE

Mendell, Jerry R.; Campbell, Katherine; Rodino-Klapac, Louise; Sahenk, Zarife; Shilling, Chris; Lewis, Sarah; Bowles, Dawn; Gray, Steven; Li, Chengwen; Galloway, Gloria; Malik, Vinod; Coley, Brian; Clark, K. Reed; Li, Juan; Xiao, Xiao

2010-01-01

We report on delivery of a functional dystrophin transgene to skeletal muscle in six patients with Duchenne’s muscular dystrophy. Dystrophin-specific T cells were detected after treatment, providing evidence of transgene expression even when the functional protein was not visualized in skeletal muscle. Circulating dystrophin-specific T cells were unexpectedly detected in two patients before vector treatment. Revertant dystrophin fibers, which expressed functional, truncated dystrophin from th...

Dystrophin Immunity in Duchenne’s Muscular Dystrophy

Science.gov (United States)

Mendell, Jerry R.; Campbell, Katherine; Rodino-Klapac, Louise; Sahenk, Zarife; Shilling, Chris; Lewis, Sarah; Bowles, Dawn; Gray, Steven; Li, Chengwen; Galloway, Gloria; Malik, Vinod; Coley, Brian; Clark, K. Reed; Li, Juan; Xiao, Xiao; Samulski, Jade; McPhee, Scott W.; Samulski, R. Jude; Walker, Christopher M.

2010-01-01

SUMMARY We report on delivery of a functional dystrophin transgene to skeletal muscle in six patients with Duchenne’s muscular dystrophy. Dystrophin-specific T cells were detected after treatment, providing evidence of transgene expression even when the functional protein was not visualized in skeletal muscle. Circulating dystrophin-specific T cells were unexpectedly detected in two patients before vector treatment. Revertant dystrophin fibers, which expressed functional, truncated dystrophin from the deleted endogenous gene after spontaneous in-frame splicing, contained epitopes targeted by the autoreactive T cells. The potential for T-cell immunity to self and nonself dystrophin epitopes should be considered in designing and monitoring experimental therapies for this disease. (Funded by the Muscular Dystrophy Association and others; ClinicalTrials.gov number, NCT00428935.) PMID:20925545

Dystrophin Expressing Chimeric (DEC) Human Cells Provide a Potential Therapy for Duchenne Muscular Dystrophy.

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Siemionow, Maria; Cwykiel, Joanna; Heydemann, Ahlke; Garcia, Jesus; Marchese, Enza; Siemionow, Krzysztof; Szilagyi, Erzsebet

2018-06-01

Duchenne Muscular Dystrophy (DMD) is a progressive and lethal disease caused by mutations of the dystrophin gene. Currently no cure exists. Stem cell therapies targeting DMD are challenged by limited engraftment and rejection despite the use of immunosuppression. There is an urgent need to introduce new stem cell-based therapies that exhibit low allogenic profiles and improved cell engraftment. In this proof-of-concept study, we develop and test a new human stem cell-based approach to increase engraftment, limit rejection, and restore dystrophin expression in the mdx/scid mouse model of DMD. We introduce two Dystrophin Expressing Chimeric (DEC) cell lines created by ex vivo fusion of human myoblasts (MB) derived from two normal donors (MB N1 /MB N2 ), and normal and DMD donors (MB N /MB DMD ). The efficacy of fusion was confirmed by flow cytometry and confocal microscopy based on donor cell fluorescent labeling (PKH26/PKH67). In vitro, DEC displayed phenotype and genotype of donor parent cells, expressed dystrophin, and maintained proliferation and myogenic differentiation. In vivo, local delivery of both DEC lines (0.5 × 10 6 ) restored dystrophin expression (17.27%±8.05-MB N1 /MB N2 and 23.79%±3.82-MB N /MB DMD ) which correlated with significant improvement of muscle force, contraction and tolerance to fatigue at 90 days after DEC transplant to the gastrocnemius muscles (GM) of dystrophin-deficient mdx/scid mice. This study establishes DEC as a potential therapy for DMD and other types of muscular dystrophies.

Use of Morphometric Mapping to Characterise Symptomatic Chiari-Like Malformation, Secondary Syringomyelia and Associated Brachycephaly in the Cavalier King Charles Spaniel.

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Susan P Knowler

Full Text Available To characterise the symptomatic phenotype of Chiari-like malformation (CM, secondary syringomyelia (SM and brachycephaly in the Cavalier King Charles Spaniel using morphometric measurements on mid-sagittal Magnetic Resonance images (MRI of the brain and craniocervical junction.This retrospective study, based on a previous quantitative analysis in the Griffon Bruxellois (GB, used 24 measurements taken on 130 T1-weighted MRI of hindbrain and cervical region. Associated brachycephaly was estimated using 26 measurements, including rostral forebrain flattening and olfactory lobe rotation, on 72 T2-weighted MRI of the whole brain. Both study cohorts were divided into three groups; Control, CM pain and SM and their morphometries compared with each other.Fourteen significant traits were identified in the hindbrain study and nine traits in the whole brain study, six of which were similar to the GB and suggest a common aetiology. The Control cohort had the most elliptical brain (p = 0.010, least olfactory bulb rotation (p = 0.003 and a protective angle (p = 0.004 compared to the other groups. The CM pain cohort had the greatest rostral forebrain flattening (p = 0.007, shortest basioccipital (p = 0.019, but a greater distance between the atlas and basioccipital (p = 0.002 which was protective for SM. The SM cohort had two conformation anomalies depending on the severity of craniocervical junction incongruities; i the proximity of the dens (p <0.001 ii increased airorhynchy with a smaller, more ventrally rotated olfactory bulb (p <0.001. Both generated 'concertina' flexures of the brain and craniocervical junction.Morphometric mapping provides a diagnostic tool for quantifying symptomatic CM, secondary SM and their relationship with brachycephaly. It is hypothesized that CM pain is associated with increased brachycephaly and SM can result from different combinations of abnormalities of the forebrain, caudal fossa and craniocervical junction which compromise

Flux wire measurements in Cavalier for verifying computer code applications

International Nuclear Information System (INIS)

Fehr, M.; Stubbs, J.; Hosticka, B.

1988-01-01

The Cavalier and UVAR research reactors are to be converted from high-enrichment uranium (HEU) to low-enrichment uranium (LEU) fuel. As a first step, an extensive set of gold wire activation measurements has been taken on the Cavalier reactor. Axial traverses show internal consistency to the order of ±5%, while horizontal traverses show somewhat larger deviations. The activation measurements will be converted to flux measurements via the Thermos code and will then be used to verify the Leopard-2DB codes. The codes will ultimately be used to design an upgraded LEU core for the UVAR

Craniometric Analysis of the Hindbrain and Craniocervical Junction of Chihuahua, Affenpinscher and Cavalier King Charles Spaniel Dogs With and Without Syringomyelia Secondary to Chiari-Like Malformation.

Science.gov (United States)

Knowler, Susan P; Kiviranta, Anna-Mariam; McFadyen, Angus K; Jokinen, Tarja S; La Ragione, Roberto M; Rusbridge, Clare

2017-01-01

To characterize and compare the phenotypic variables of the hindbrain and craniocervical junction associated with syringomyelia (SM) in the Chihuahua, Affenpinscher and Cavalier King Charles Spaniel (CKCS). Analysis of 273 T1-weighted mid-sagittal DICOM sequences of the hindbrain and craniocervical junction from 99 Chihuahuas, 42 Affenpinschers and 132 CKCSs. The study compared 22 morphometric features (11 lines, eight angles and three ratios) of dogs with and without SM using refined techniques based on previous studies of the Griffon Bruxellois (GB) using Discriminant Function Analysis and ANOVA with post-hoc corrections. The analysis identified 14/22 significant traits for SM in the three dog breeds, five of which were identical to those reported for the GB and suggest inclusion of a common aetiology. One ratio, caudal fossa height to the length of the skull base extended to an imaginary point of alignment between the atlas and supraoccipital bones, was common to all three breeds (p values 0.029 to Chihuahua had a smaller angle between the dens, atlas and basioccipital bone (p value < 0.001); Affenpinschers had a smaller distance from atlas to dens (p value 0.009); CKCS had a shorter distance between the spheno-occipital synchondrosis and atlas (p value 0.007). The selected morphometries successfully characterised conformational changes in the brain and craniocervical junction that might form the basis of a diagnostic tool for all breeds. The severity of SM involved a spectrum of abnormalities, incurred by changes in both angulation and size that could alter neural parenchyma compliance and/or impede cerebrospinal fluid channels.

Cognitive dysfunction in the dystrophin-deficient mouse model of Duchenne muscular dystrophy: A reappraisal from sensory to executive processes.

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Chaussenot, Rémi; Edeline, Jean-Marc; Le Bec, Benoit; El Massioui, Nicole; Laroche, Serge; Vaillend, Cyrille

2015-10-01

Duchenne muscular dystrophy (DMD) is associated with language disabilities and deficits in learning and memory, leading to intellectual disability in a patient subpopulation. Recent studies suggest the presence of broader deficits affecting information processing, short-term memory and executive functions. While the absence of the full-length dystrophin (Dp427) is a common feature in all patients, variable mutation profiles may additionally alter distinct dystrophin-gene products encoded by separate promoters. However, the nature of the cognitive dysfunctions specifically associated with the loss of distinct brain dystrophins is unclear. Here we show that the loss of the full-length brain dystrophin in mdx mice does not modify the perception and sensorimotor gating of auditory inputs, as assessed using auditory brainstem recordings and prepulse inhibition of startle reflex. In contrast, both acquisition and long-term retention of cued and trace fear memories were impaired in mdx mice, suggesting alteration in a functional circuit including the amygdala. Spatial learning in the water maze revealed reduced path efficiency, suggesting qualitative alteration in mdx mice learning strategy. However, spatial working memory performance and cognitive flexibility challenged in various behavioral paradigms in water and radial-arm mazes were unimpaired. The full-length brain dystrophin therefore appears to play a role during acquisition of associative learning as well as in general processes involved in memory consolidation, but no overt involvement in working memory and/or executive functions could be demonstrated in spatial learning tasks. Copyright © 2015 Elsevier Inc. All rights reserved.

Diseased muscles that lack dystrophin or laminin-α2 have altered compositions and proliferation of mononuclear cell populations

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Miller Jeffrey

2005-04-01

Full Text Available Abstract Background Multiple types of mononucleate cells reside among the multinucleate myofibers in skeletal muscles and these mononucleate cells function in muscle maintenance and repair. How neuromuscular disease might affect different types of muscle mononucleate cells had not been determined. In this study, therefore, we examined how two neuromuscular diseases, dystrophin-deficiency and laminin-α2-deficiency, altered the proliferation and composition of different subsets of muscle-derived mononucleate cells. Methods We used fluorescence-activated cell sorting combined with bromodeoxyuridine labeling to examine proliferation rates and compositions of mononuclear cells in diseased and healthy mouse skeletal muscle. We prepared mononucleate cells from muscles of mdx (dystrophin-deficient or Lama2-/- (laminin-α2-deficient mice and compared them to cells from healthy control muscles. We enumerated subsets of resident muscle cells based on Sca-1 and CD45 expression patterns and determined the proliferation of each cell subset in vivo by BrdU incorporation. Results We found that the proliferation and composition of the mononucleate cells in dystrophin-deficient and laminin-α2-deficient diseased muscles are different than in healthy muscle. The mdx and Lama2-/- muscles showed similar significant increases in CD45+ cells compared to healthy muscle. Changes in proliferation, however, differed between the two diseases with proliferation increased in mdx and decreased in Lama2-/- muscles compared to healthy muscles. In particular, the most abundant Sca-1-/CD45- subset, which contains muscle precursor cells, had increased proliferation in mdx muscle but decreased proliferation in Lama2-/- muscles. Conclusion The similar increases in CD45+ cells, but opposite changes in proliferation of muscle precursor cells, may underlie aspects of the distinct pathologies in the two diseases.

Black bear parathyroid hormone has greater anabolic effects on trabecular bone in dystrophin-deficient mice than in wild type mice.

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Gray, Sarah K; McGee-Lawrence, Meghan E; Sanders, Jennifer L; Condon, Keith W; Tsai, Chung-Jui; Donahue, Seth W

2012-09-01

Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease that has deleterious consequences in muscle and bone, leading to decreased mobility, progressive osteoporosis, and premature death. Patients with DMD experience a higher-than-average fracture rate, particularly in the proximal and distal femur and proximal tibia. The dystrophin-deficient mdx mouse is a model of DMD that demonstrates muscle degeneration and fibrosis and osteoporosis. Parathyroid hormone, an effective anabolic agent for post-menopausal and glucocorticoid-induced osteoporosis, has not been explored for DMD. Black bear parathyroid hormone (bbPTH) has been implicated in the maintenance of bone properties during extended periods of disuse (hibernation). We cloned bbPTH and found 9 amino acid residue differences from human PTH. Apoptosis was mitigated and cAMP was activated by bbPTH in osteoblast cultures. We administered 28nmol/kg of bbPTH 1-84 to 4-week old male mdx and wild type mice via daily (5×/week) subcutaneous injection for 6 weeks. Vehicle-treated mdx mice had 44% lower trabecular bone volume fraction than wild type mice. No changes were found in femoral cortical bone geometry or mechanical properties with bbPTH treatment in wild type mice, and only medio-lateral moment of inertia changed with bbPTH treatment in mdx femurs. However, μCT analyses of the trabecular regions of the distal femur and proximal tibia showed marked increases in bone volume fraction with bbPTH treatment, with a greater anabolic response (7-fold increase) in mdx mice than wild type mice (2-fold increase). Trabecular number increased in mdx long bone, but not wild type bone. Additionally, greater osteoblast area and decreased osteoclast area were observed with bbPTH treatment in mdx mice. The heightened response to PTH in mdx bone compared to wild type suggests a link between dystrophin deficiency, altered calcium signaling, and bone. These findings support further investigation of PTH as an anabolic

Characterization of dystrophin deficient rats: a new model for Duchenne muscular dystrophy.

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Larcher, Thibaut; Lafoux, Aude; Tesson, Laurent; Remy, Séverine; Thepenier, Virginie; François, Virginie; Le Guiner, Caroline; Goubin, Helicia; Dutilleul, Maéva; Guigand, Lydie; Toumaniantz, Gilles; De Cian, Anne; Boix, Charlotte; Renaud, Jean-Baptiste; Cherel, Yan; Giovannangeli, Carine; Concordet, Jean-Paul; Anegon, Ignacio; Huchet, Corinne

2014-01-01

A few animal models of Duchenne muscular dystrophy (DMD) are available, large ones such as pigs or dogs being expensive and difficult to handle. Mdx (X-linked muscular dystrophy) mice only partially mimic the human disease, with limited chronic muscular lesions and muscle weakness. Their small size also imposes limitations on analyses. A rat model could represent a useful alternative since rats are small animals but 10 times bigger than mice and could better reflect the lesions and functional abnormalities observed in DMD patients. Two lines of Dmd mutated-rats (Dmdmdx) were generated using TALENs targeting exon 23. Muscles of animals of both lines showed undetectable levels of dystrophin by western blot and less than 5% of dystrophin positive fibers by immunohistochemistry. At 3 months, limb and diaphragm muscles from Dmdmdx rats displayed severe necrosis and regeneration. At 7 months, these muscles also showed severe fibrosis and some adipose tissue infiltration. Dmdmdx rats showed significant reduction in muscle strength and a decrease in spontaneous motor activity. Furthermore, heart morphology was indicative of dilated cardiomyopathy associated histologically with necrotic and fibrotic changes. Echocardiography showed significant concentric remodeling and alteration of diastolic function. In conclusion, Dmdmdx rats represent a new faithful small animal model of DMD.

Muscular dystrophy in a family of Labrador Retrievers with no muscle dystrophin and a mild phenotype.

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Vieira, Natassia M; Guo, Ling T; Estrela, Elicia; Kunkel, Louis M; Zatz, Mayana; Shelton, G Diane

2015-05-01

Animal models of dystrophin deficient muscular dystrophy, most notably canine X-linked muscular dystrophy, play an important role in developing new therapies for human Duchenne muscular dystrophy. Although the canine disease is a model of the human disease, the variable severity of clinical presentations in the canine may be problematic for pre-clinical trials, but also informative. Here we describe a family of Labrador Retrievers with three generations of male dogs having markedly increased serum creatine kinase activity, absence of membrane dystrophin, but with undetectable clinical signs of muscle weakness. Clinically normal young male Labrador Retriever puppies were evaluated prior to surgical neuter by screening laboratory blood work, including serum creatine kinase activity. Serum creatine kinase activities were markedly increased in the absence of clinical signs of muscle weakness. Evaluation of muscle biopsies confirmed a dystrophic phenotype with both degeneration and regeneration. Further evaluations by immunofluorescence and western blot analysis confirmed the absence of muscle dystrophin. Although dystrophin was not identified in the muscles, we did not find any detectable deletions or duplications in the dystrophin gene. Sequencing is now ongoing to search for point mutations. Our findings in this family of Labrador Retriever dogs lend support to the hypothesis that, in exceptional situations, muscle with no dystrophin may be functional. Unlocking the secrets that protect these dogs from a severe clinical myopathy is a great challenge which may have important implications for future treatment of human muscular dystrophies. Copyright © 2015 Elsevier B.V. All rights reserved.

Detection of new paternal dystrophin gene mutations in isolated cases of dystrophinopathy in females

Energy Technology Data Exchange (ETDEWEB)

Pegoraro, E.; Wessel, H.B.; Schwartz, L.; Hoffman, E.P. (Univ. of Pittsburgh, PA (United States)); Schimke, R.N. (Kansas Univ. Medical Center, Kansas City (United States)); Arahata, Kiichi; Hayashi, Yukiko (National Institute of Neurosciences, Tokyo (Japan)); Stern, H. (Children' s National Medical Center, Washington, DC (United States)); Marks, H. (A.I. duPont Institute, Wilmington (United States)); Glasberg, M.R. (Henry Ford Hospital, Detroit, MI (United States)) (and others)

1994-06-01

Duchenne muscular dystrophy is one of the most common lethal monogenic disorders and is caused by dystrophin deficiency. The disease is transmitted as an X-linked recessive trait; however, recent biochemical and clinical studies have shown that many girls and women with a primary myopathy have an underlying dystrophinopathy, despite a negative family history for Duchenne dystrophy. These isolated female dystrophinopathy patients carried ambiguous diagnoses with presumed autosomal recessive inheritance (limb-girdle muscular dystrophy) prior to biochemical detection of dystrophin abnormalities in their muscle biopsy. It has been assumed that these female dystrophinopathy patients are heterozygous carries who show preferential inactivation of the X chromosome harboring the normal dystrophin gene, although this has been shown for only a few X:autosome translocations and for two cases of discordant monozygotic twin female carriers. Here the authors study X-inactivation patterns of 13 female dystrophinopathy patients - 10 isolated cases and 3 cases with a positive family history for Duchenne dystrophy in males. They show that all cases have skewed X-inactivation patterns in peripheral blood DNA. Of the nine isolated cases informative in the assay, eight showed inheritance of the dystrophin gene mutation from the paternal germ line. Only a single case showed maternal inheritance. The 10-fold higher incidence of paternal transmission of dystrophin gene mutations in these cases is at 30-fold variance with Bayesian predictions and gene mutation rates. Thus, the results suggest some mechanistic interaction between new dystrophin gene mutations, paternal inheritance, and skewed X inactivation. The results provide both empirical risk data and a molecular diagnostic test method, which permit genetic counseling and prenatal diagnosis of this new category of patients. 58 refs., 7 figs., 2 tabs.

Possible influences on the expression of X chromosome-linked dystrophin abnormalities by heterozygosity for autosomal recessive Fukuyama congenital muscular dystrophy

Energy Technology Data Exchange (ETDEWEB)

Beggs, A.H.; Neumann, P.E.; Anderson, M.S.; Kunkel, L.M. (Harvard Medical School, Boston, MA (United States)); Arahata, Kiichi; Arikawa, Eri; Nonaka, Ikuya (National Inst. of Neuroscience, Tokyo (Japan))

1992-01-15

Abnormalities of dystrophin, a cytoskeletal protein of muscle and nerve, are generally considered specific for Duchenne and Becker muscular dystrophy. However, several patients have recently been identified with dystrophin deficiency who, before dystrophin testing, were considered to have Fukuyama congenital muscular dystrophy (FCMD) on the basis of clinical findings. Epidemiologic data suggest that only 1/3,500 males with autosomal recessive FCMD should have abnormal dystrophin. To explain the observation of 3/23 FCMD males with abnormal dystrophin, the authors propose that dystrophin and the FCMD gene product interact and that the earlier onset and greater severity of these patients' phenotype (relative to Duchenne muscular dystrophy) are due to their being heterozygous for the FCMD mutation in addition to being hemizygous for Duchenne muscular dystrophy, a genotype that is predicted to occur in 1/175,000 Japanese males. This model may help explain the genetic basis for some of the clinical and pathological variability seen among patients with FCMD, and it has potential implications for understanding the inheritance of other autosomal recessive disorders in general. For example, sex ratios for rare autosomal recessive disorders caused by mutations in proteins that interact with X chromosome-linked gene products may display predictable deviation from 1:1.

Changes in serum progesterone concentrations in Bernese mountain dogs and Cavalier King Charles Spaniels during pregnancy.

Science.gov (United States)

Thejll Kirchhoff, K; Goericke-Pesch, S

2016-10-15

Progesterone (P4) concentrations during canine pregnancy follow a specific pattern. Although the general pattern is similar, it is likely that breed-specific differences exist. Detailed knowledge about the physiological range of P4 concentrations may be helpful in cases of suspected hypoluteoidism. The aim of this study was to investigate P4 changes during pregnancy in a small and a large breed, to obtain reference values for specific intervals during pregnancy and to test for breed- or body weight-specific differences. We studied P4 concentrations in pregnancies from healthy Bernese mountain dogs (BMDs, n = 6) and Cavalier King Charles Spaniels (CKCSs, n = 6) with a normal reproductive history. Blood samples for P4 were taken to determine the day of ovulation and after confirmation of pregnancy in regular intervals from Days 23 to 29 to Days 60 to 64. Bernese mountain dogs delivered 6.2 ± 2.6 puppies (range: 3-9) 63.4 ± 1.5 (range: 61-65) days after ovulation (excluding data from one BMD with elective c-section) and CKCS delivered 3.3 ± 1.9 puppies (range: 1-5) 63.5 ± 1.1 (range: 62-65) days after ovulation. In general, the P4 concentrations of individual dogs continuously decreased from the first to the last sampling during pregnancy. Respective mean concentrations were Days 23 to 29: 19.2 ± 4.3/22.2 ± 3.9 ng/mL (BMD/CKCS), Days 30 to 34: 15.6 ± 2.3/17.7 ± 5.8 ng/mL, Days 35 to 39: 12.5 ± 2.8/14.1 ± 3.4 ng/mL, Days 40 to 44: 8.9 ± 1.4/11.8 ± 3.7 ng/mL, Days 45 to 49: 7.7 ± 1.6/8.9 ± 1.9 ng/mL, Days 50 to 54: 6.0 ± 1.3/8.7 ± 7.1 ng/mL, Days 55 to 59: 4.7 ± 1.2/5.3 ± 2.8 ng/mL, and Days 60 to 64: 3.69 ± 1.86/2.62 ± 0.42 ng/mL. ANOVA indicated significant differences over time within each breed when considered individually (P parturition). Other than expected, we failed to proof significant differences in P4 between CKCS and BMD. Further studies are required to confirm the results on a larger

Proteomic analysis reveals new cardiac-specific dystrophin-associated proteins.

Directory of Open Access Journals (Sweden)

Eric K Johnson

Full Text Available Mutations affecting the expression of dystrophin result in progressive loss of skeletal muscle function and cardiomyopathy leading to early mortality. Interestingly, clinical studies revealed no correlation in disease severity or age of onset between cardiac and skeletal muscles, suggesting that dystrophin may play overlapping yet different roles in these two striated muscles. Since dystrophin serves as a structural and signaling scaffold, functional differences likely arise from tissue-specific protein interactions. To test this, we optimized a proteomics-based approach to purify, identify and compare the interactome of dystrophin between cardiac and skeletal muscles from as little as 50 mg of starting material. We found selective tissue-specific differences in the protein associations of cardiac and skeletal muscle full length dystrophin to syntrophins and dystrobrevins that couple dystrophin to signaling pathways. Importantly, we identified novel cardiac-specific interactions of dystrophin with proteins known to regulate cardiac contraction and to be involved in cardiac disease. Our approach overcomes a major challenge in the muscular dystrophy field of rapidly and consistently identifying bona fide dystrophin-interacting proteins in tissues. In addition, our findings support the existence of cardiac-specific functions of dystrophin and may guide studies into early triggers of cardiac disease in Duchenne and Becker muscular dystrophies.

Compensation for dystrophin-deficiency: ADAM12 overexpression in skeletal muscle results in increased alpha 7 integrin, utrophin and associated glycoproteins

DEFF Research Database (Denmark)

Moghadaszadeh, Behzad; Albrechtsen, Reidar; Guo, Ling T

2003-01-01

Mouse models for genetic diseases are among the most powerful tools available for developing and testing new treatment strategies. ADAM12 is a disintegrin and metalloprotease, previously demonstrated to significantly alleviate the pathology of mdx mice, a model for Duchenne muscular dystrophy...... in humans. More specifically ADAM12 appeared to prevent muscle cell necrosis in the mdx mice as evidenced by morphological analysis and by the reduced levels of serum creatine kinase. In the present study we demonstrated that ADAM12 may compensate for the dystrophin deficiency in mdx mice by increasing...... the expression and redistribution of several components of the muscle cell-adhesion complexes. First, we analyzed transgenic mice that overexpress ADAM12 and found mild myopathic changes and accelerated regeneration following acute injury. We then analyzed changes in gene-expression profiles in mdx/ADAM12...

A genome-wide association study identifies candidate loci associated to syringomyelia secondary to Chiari-like malformation in Cavalier King Charles Spaniels.

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Ancot, Frédéric; Lemay, Philippe; Knowler, Susan P; Kennedy, Karen; Griffiths, Sandra; Cherubini, Giunio Bruto; Sykes, Jane; Mandigers, Paul J J; Rouleau, Guy A; Rusbridge, Clare; Kibar, Zoha

2018-03-22

Syringomyelia (SM) is a common condition affecting brachycephalic toy breed dogs and is characterized by the development of fluid-filled cavities within the spinal cord. It is often concurrent with a complex developmental malformation of the skull and craniocervical vertebrae called Chiari-like malformation (CM) characterized by a conformational change and overcrowding of the brain and cervical spinal cord particularly at the craniocervical junction. CM and SM have a polygenic mode of inheritance with variable penetrance. We identified six cranial T1-weighted sagittal MRI measurements that were associated to maximum transverse diameter of the syrinx cavity. Increased syrinx transverse diameter has been correlated previously with increased likelihood of behavioral signs of pain. We next conducted a whole genome association study of these traits in 65 Cavalier King Charles Spaniel (CKCS) dogs (33 controls, 32 with extreme phenotypes). Two loci on CFA22 and CFA26 were found to be significantly associated to two traits associated with a reduced volume and altered orientation of the caudal cranial fossa. Their reconstructed haplotypes defined two associated regions that harbor only two genes: PCDH17 on CFA22 and ZWINT on CFA26. PCDH17 codes for a cell adhesion molecule expressed specifically in the brain and spinal cord. ZWINT plays a role in chromosome segregation and its expression is increased with the onset of neuropathic pain. Targeted genomic sequencing of these regions identified respectively 37 and 339 SNPs with significantly associated P values. Genotyping of tagSNPs selected from these 2 candidate loci in an extended cohort of 461 CKCS (187 unaffected, 274 SM affected) identified 2 SNPs on CFA22 that were significantly associated to SM strengthening the candidacy of this locus in SM development. We identified 2 loci on CFA22 and CFA26 that contained only 2 genes, PCDH17 and ZWINT, significantly associated to two traits associated with syrinx transverse

Metabolic remodeling agents show beneficial effects in the dystrophin-deficient mdx mouse model

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Jahnke Vanessa E

2012-08-01

Full Text Available Abstract Background Duchenne muscular dystrophy is a genetic disease involving a severe muscle wasting that is characterized by cycles of muscle degeneration/regeneration and culminates in early death in affected boys. Mitochondria are presumed to be involved in the regulation of myoblast proliferation/differentiation; enhancing mitochondrial activity with exercise mimetics (AMPK and PPAR-delta agonists increases muscle function and inhibits muscle wasting in healthy mice. We therefore asked whether metabolic remodeling agents that increase mitochondrial activity would improve muscle function in mdx mice. Methods Twelve-week-old mdx mice were treated with two different metabolic remodeling agents (GW501516 and AICAR, separately or in combination, for 4 weeks. Extensive systematic behavioral, functional, histological, biochemical, and molecular tests were conducted to assess the drug(s' effects. Results We found a gain in body and muscle weight in all treated mice. Histologic examination showed a decrease in muscle inflammation and in the number of fibers with central nuclei and an increase in fibers with peripheral nuclei, with significantly fewer activated satellite cells and regenerating fibers. Together with an inhibition of FoXO1 signaling, these results indicated that the treatments reduced ongoing muscle damage. Conclusions The three treatments produced significant improvements in disease phenotype, including an increase in overall behavioral activity and significant gains in forelimb and hind limb strength. Our findings suggest that triggering mitochondrial activity with exercise mimetics improves muscle function in dystrophin-deficient mdx mice.

Deletion of Galgt2 (B4Galnt2) reduces muscle growth in response to acute injury and increases muscle inflammation and pathology in dystrophin-deficient mice.

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Xu, Rui; Singhal, Neha; Serinagaoglu, Yelda; Chandrasekharan, Kumaran; Joshi, Mandar; Bauer, John A; Janssen, Paulus M L; Martin, Paul T

2015-10-01

Transgenic overexpression of Galgt2 (official name B4Galnt2) in skeletal muscle stimulates the glycosylation of α dystroglycan (αDG) and the up-regulation of laminin α2 and dystrophin surrogates known to inhibit muscle pathology in mouse models of congenital muscular dystrophy 1A and Duchenne muscular dystrophy. Skeletal muscle Galgt2 gene expression is also normally increased in the mdx mouse model of Duchenne muscular dystrophy compared with the wild-type mice. To assess whether this increased endogenous Galgt2 expression could affect disease, we quantified muscular dystrophy measures in mdx mice deleted for Galgt2 (Galgt2(-/-)mdx). Galgt2(-/-) mdx mice had increased heart and skeletal muscle pathology and inflammation, and also worsened cardiac function, relative to age-matched mdx mice. Deletion of Galgt2 in wild-type mice also slowed skeletal muscle growth in response to acute muscle injury. In each instance where Galgt2 expression was elevated (developing muscle, regenerating muscle, and dystrophic muscle), Galgt2-dependent glycosylation of αDG was also increased. Overexpression of Galgt2 failed to inhibit skeletal muscle pathology in dystroglycan-deficient muscles, in contrast to previous studies in dystrophin-deficient mdx muscles. This study demonstrates that Galgt2 gene expression and glycosylation of αDG are dynamically regulated in muscle and that endogenous Galgt2 gene expression can ameliorate the extent of muscle pathology, inflammation, and dysfunction in mdx mice. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Dramatic elevation in urinary amino terminal titin fragment excretion quantified by immunoassay in Duchenne muscular dystrophy patients and in dystrophin deficient rodents.

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Robertson, Alan S; Majchrzak, Mark J; Smith, Courtney M; Gagnon, Robert C; Devidze, Nino; Banks, Glen B; Little, Sean C; Nabbie, Fizal; Bounous, Denise I; DiPiero, Janet; Jacobsen, Leslie K; Bristow, Linda J; Ahlijanian, Michael K; Stimpson, Stephen A

2017-07-01

Enzyme-linked and electrochemiluminescence immunoassays were developed for quantification of amino (N-) terminal fragments of the skeletal muscle protein titin (N-ter titin) and qualified for use in detection of urinary N-ter titin excretion. Urine from normal subjects contained a small but measurable level of N-ter titin (1.0 ± 0.4 ng/ml). A 365-fold increase (365.4 ± 65.0, P = 0.0001) in urinary N-ter titin excretion was seen in Duchene muscular dystrophy (DMD) patients. Urinary N-ter titin was also evaluated in dystrophin deficient rodent models. Mdx mice exhibited low urinary N-ter titin levels at 2 weeks of age followed by a robust and sustained elevation starting at 3 weeks of age, coincident with the development of systemic skeletal muscle damage in this model; fold elevation could not be determined because urinary N-ter titin was not detected in age-matched wild type mice. Levels of serum creatine kinase and serum skeletal muscle troponin I (TnI) were also low at 2 weeks, elevated at later time points and were significantly correlated with urinary N-ter titin excretion in mdx mice. Corticosteroid treatment of mdx mice resulted in improved exercise performance and lowering of both urinary N-ter titin and serum skeletal muscle TnI concentrations. Low urinary N-ter titin levels were detected in wild type rats (3.0 ± 0.6 ng/ml), while Dmd mdx rats exhibited a 556-fold increase (1652.5 ± 405.7 ng/ml, P = 0.002) (both at 5 months of age). These results suggest that urinary N-ter titin is present at low basal concentrations in normal urine and increases dramatically coincident with muscle damage produced by dystrophin deficiency. Urinary N-ter titin has potential as a facile, non-invasive and translational biomarker for DMD. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Craniometric Analysis of the Hindbrain and Craniocervical Junction of Chihuahua, Affenpinscher and Cavalier King Charles Spaniel Dogs With and Without Syringomyelia Secondary to Chiari-Like Malformation.

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Susan P Knowler

Full Text Available To characterize and compare the phenotypic variables of the hindbrain and craniocervical junction associated with syringomyelia (SM in the Chihuahua, Affenpinscher and Cavalier King Charles Spaniel (CKCS.Analysis of 273 T1-weighted mid-sagittal DICOM sequences of the hindbrain and craniocervical junction from 99 Chihuahuas, 42 Affenpinschers and 132 CKCSs. The study compared 22 morphometric features (11 lines, eight angles and three ratios of dogs with and without SM using refined techniques based on previous studies of the Griffon Bruxellois (GB using Discriminant Function Analysis and ANOVA with post-hoc corrections.The analysis identified 14/22 significant traits for SM in the three dog breeds, five of which were identical to those reported for the GB and suggest inclusion of a common aetiology. One ratio, caudal fossa height to the length of the skull base extended to an imaginary point of alignment between the atlas and supraoccipital bones, was common to all three breeds (p values 0.029 to <0.001. Associated with SM were a reduced occipital crest and two acute changes in angulation i 'sphenoid flexure' at the spheno-occipital synchondrosis ii 'cervical flexure' at the foramen magnum allied with medulla oblongata elevation. Comparing dogs with and without SM, each breed had a unique trait: Chihuahua had a smaller angle between the dens, atlas and basioccipital bone (p value < 0.001; Affenpinschers had a smaller distance from atlas to dens (p value 0.009; CKCS had a shorter distance between the spheno-occipital synchondrosis and atlas (p value 0.007.The selected morphometries successfully characterised conformational changes in the brain and craniocervical junction that might form the basis of a diagnostic tool for all breeds. The severity of SM involved a spectrum of abnormalities, incurred by changes in both angulation and size that could alter neural parenchyma compliance and/or impede cerebrospinal fluid channels.

Twelve years of chiari-like malformation and syringomyelia scanning in Cavalier King Charles Spaniels in the Netherlands: Towards a more precise phenotype.

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Katrien Wijnrocx

Full Text Available Chiari-like malformation (CM, syringomyelia (SM and middle ear effusion (also called PSOM are three conditions that frequently occur in Cavalier King Charles Spaniels (CKCS. Both CM and SM are currently screened in the Netherlands prior to breeding and are graded according to the British Veterinary Association's Kennel Club (BVA/KC scheme. This study evaluated the prevalence and estimated genetic parameter of CM, SM and middle ear effusion from 12 years of screening results. For SM, the classical method using the BVA/KC scheme, was compared with exact measuring of the central canal dilation. For CM, the BVA/KC scheme was compared with a more detailed scheme. Next to this the presence of microchip artifacts was assessed. 1249 screening of 1020 dogs were re-evaluated. Results indicated the presence of CM in all dogs, suggesting it has become a breed-specific characteristic. And although different grades of CM were observed, the condition did not deteriorate over time. SM was present in 39% of the dogs and a clear age effect was demonstrated, with SM increasing with age. This emphasizes the importance of screening at appropriate age, since SM can worsen with increasing age. One alternative is to promote repeated measures. The presence of middle ear effusion in this study was 19%-21% for dogs younger than 3 years, and 32%-38% for dogs older than 3 years. In as much as 60%, microchip artifacts were noticed, leading to the recommendation to place microchips in another location in breeds that are susceptible to developing SM. Finally, this study estimated the heritability of CM in this population, due to the lack of phenotypic variance, to be very low at 0.02-0.03. The heritability for SM central canal dilatation to be 0.30, compared to 0.13 for the classical BVA/KC method, using a model including the age effect and the combined effect of veterinary clinic and year of the evaluation. Genetic correlations were rather small, ranging from 0.16-0.33. As a

Improvement of cardiac contractile function by peptide-based inhibition of NF-κB in the utrophin/dystrophin-deficient murine model of muscular dystrophy

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Guttridge Denis C

2011-05-01

Full Text Available Abstract Background Duchenne muscular dystrophy (DMD is an inherited and progressive disease causing striated muscle deterioration. Patients in their twenties generally die from either respiratory or cardiac failure. In order to improve the lifespan and quality of life of DMD patients, it is important to prevent or reverse the progressive loss of contractile function of the heart. Recent studies by our labs have shown that the peptide NBD (Nemo Binding Domain, targeted at blunting Nuclear Factor κB (NF-κB signaling, reduces inflammation, enhances myofiber regeneration, and improves contractile deficits in the diaphragm in dystrophin-deficient mdx mice. Methods To assess whether cardiac function in addition to diaphragm function can be improved, we investigated physiological and histological parameters of cardiac muscle in mice deficient for both dystrophin and its homolog utrophin (double knockout = dko mice treated with NBD peptide. These dko mice show classic pathophysiological hallmarks of heart failure, including myocyte degeneration, an impaired force-frequency response and a severely blunted β-adrenergic response. Cardiac contractile function at baseline and frequencies and pre-loads throughout the in vivo range as well as β-adrenergic reserve was measured in isolated cardiac muscle preparations. In addition, we studied histopathological and inflammatory markers in these mice. Results At baseline conditions, active force development in cardiac muscles from NBD treated dko mice was more than double that of vehicle-treated dko mice. NBD treatment also significantly improved frequency-dependent behavior of the muscles. The increase in force in NBD-treated dko muscles to β-adrenergic stimulation was robustly restored compared to vehicle-treated mice. However, histological features, including collagen content and inflammatory markers were not significantly different between NBD-treated and vehicle-treated dko mice. Conclusions We conclude

Context Dependent Effects of Chimeric Peptide Morpholino Conjugates Contribute to Dystrophin Exon-skipping Efficiency

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HaiFang Yin; Prisca Boisguerin; Hong M Moulton; Corinne Betts; Yiqi Seow; Jordan Boutilier; Qingsong Wang; Anthony Walsh; Bernard Lebleu; Matthew JA Wood

2013-01-01

We have recently reported that cell-penetrating peptides (CPPs) and novel chimeric peptides containing CPP (referred as B peptide) and muscle-targeting peptide (referred as MSP) motifs significantly improve the systemic exon-skipping activity of morpholino phosphorodiamidate oligomers (PMOs) in dystrophin-deficient mdx mice. In the present study, the general mechanistic significance of the chimeric peptide configuration on the activity and tissue uptake of peptide conjugated PMOs in vivo was ...

Creation of Dystrophin Expressing Chimeric Cells of Myoblast Origin as a Novel Stem Cell Based Therapy for Duchenne Muscular Dystrophy.

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Siemionow, M; Cwykiel, J; Heydemann, A; Garcia-Martinez, J; Siemionow, K; Szilagyi, E

2018-04-01

Over the past decade different stem cell (SC) based approaches were tested to treat Duchenne Muscular Dystrophy (DMD), a lethal X-linked disorder caused by mutations in dystrophin gene. Despite research efforts, there is no curative therapy for DMD. Allogeneic SC therapies aim to restore dystrophin in the affected muscles; however, they are challenged by rejection and limited engraftment. Thus, there is a need to develop new more efficacious SC therapies. Chimeric Cells (CC), created via ex vivo fusion of donor and recipient cells, represent a promising therapeutic option for tissue regeneration and Vascularized Composite Allotransplantation (VCA) due to tolerogenic properties that eliminate the need for lifelong immunosuppression. This proof of concept study tested feasibility of myoblast fusion for Dystrophin Expressing. Chimeric Cell (DEC) therapy through in vitro characterization and in vivo assessment of engraftment, survival, and efficacy in the mdx mouse model of DMD. Murine DEC were created via ex vivo fusion of normal (snj) and dystrophin-deficient (mdx) myoblasts using polyethylene glycol. Efficacy of myoblast fusion was confirmed by flow cytometry and dystrophin immunostaining, while proliferative and myogenic differentiation capacity of DEC were assessed in vitro. Therapeutic effect after DEC transplant (0.5 × 10 6 ) into the gastrocnemius muscle (GM) of mdx mice was assessed by muscle functional tests. At 30 days post-transplant dystrophin expression in GM of injected mdx mice increased to 37.27 ± 12.1% and correlated with improvement of muscle strength and function. Our study confirmed feasibility and efficacy of DEC therapy and represents a novel SC based approach for treatment of muscular dystrophies.

Targeted Exon Skipping to Address “Leaky” Mutations in the Dystrophin Gene

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Sue Fletcher

2012-01-01

Full Text Available Protein-truncating mutations in the dystrophin gene lead to the progressive muscle wasting disorder Duchenne muscular dystrophy, whereas in-frame deletions typically manifest as the milder allelic condition, Becker muscular dystrophy. Antisense oligomer-induced exon skipping can modify dystrophin gene expression so that a disease-associated dystrophin pre-mRNA is processed into a Becker muscular dystrophy-like mature transcript. Despite genomic deletions that may encompass hundreds of kilobases of the gene, some dystrophin mutations appear “leaky”, and low levels of high molecular weight, and presumably semi-functional, dystrophin are produced. A likely causative mechanism is endogenous exon skipping, and Duchenne individuals with higher baseline levels of dystrophin may respond more efficiently to the administration of splice-switching antisense oligomers. We optimized excision of exons 8 and 9 in normal human myoblasts, and evaluated several oligomers in cells from eight Duchenne muscular dystrophy patients with deletions in a known “leaky” region of the dystrophin gene. Inter-patient variation in response to antisense oligomer induced skipping in vitro appeared minimal. We describe oligomers targeting exon 8, that unequivocally increase dystrophin above baseline in vitro, and propose that patients with leaky mutations are ideally suited for participation in antisense oligomer mediated splice-switching clinical studies.

Eosinophilia of dystrophin-deficient muscle is promoted by perforin-mediated cytotoxicity by T cell effectors

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Cai, B.; Spencer, M. J.; Nakamura, G.; Tseng-Ong, L.; Tidball, J. G.

2000-01-01

Previous investigations have shown that cytotoxic T lymphocytes (CTLs) contribute to muscle pathology in the dystrophin-null mutant mouse (mdx) model of Duchenne muscular dystrophy through perforin-dependent and perforin-independent mechanisms. We have assessed whether the CTL-mediated pathology includes the promotion of eosinophilia in dystrophic muscle, and thereby provides a secondary mechanism through which CTLs contribute to muscular dystrophy. Quantitative immunohistochemistry confirmed that eosinophilia is a component of the mdx dystrophy. In addition, electron microscopic observations show that eosinophils traverse the basement membrane of mdx muscle fibers and display sites of close apposition of eosinophil and muscle membranes. The close membrane apposition is characterized by impingement of eosinophilic rods of major basic protein into the muscle cell membrane. Transfer of mdx splenocytes and mdx muscle extracts to irradiated C57 mice by intraperitoneal injection resulted in muscle eosinophilia in the recipient mice. Double-mutant mice lacking dystrophin and perforin showed less eosinophilia than was displayed by mdx mice that expressed perforin. Finally, administration of prednisolone, which has been shown previously to reduce the concentration of CTLs in dystrophic muscle, produced a significant reduction in eosinophilia. These findings indicate that eosinophilia is a component of the mdx pathology that is promoted by perforin-dependent cytotoxicity of effector T cells. However, some eosinophilia of mdx muscle is independent of perforin-mediated processes.

Dystrophin quantification and clinical correlations in Becker muscular dystrophy: implications for clinical trials.

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Anthony, Karen; Cirak, Sebahattin; Torelli, Silvia; Tasca, Giorgio; Feng, Lucy; Arechavala-Gomeza, Virginia; Armaroli, Annarita; Guglieri, Michela; Straathof, Chiara S; Verschuuren, Jan J; Aartsma-Rus, Annemieke; Helderman-van den Enden, Paula; Bushby, Katherine; Straub, Volker; Sewry, Caroline; Ferlini, Alessandra; Ricci, Enzo; Morgan, Jennifer E; Muntoni, Francesco

2011-12-01

Duchenne muscular dystrophy is caused by mutations in the DMD gene that disrupt the open reading frame and prevent the full translation of its protein product, dystrophin. Restoration of the open reading frame and dystrophin production can be achieved by exon skipping using antisense oligonucleotides targeted to splicing elements. This approach aims to transform the Duchenne muscular dystrophy phenotype to that of the milder disorder, Becker muscular dystrophy, typically caused by in-frame dystrophin deletions that allow the production of an internally deleted but partially functional dystrophin. There is ongoing debate regarding the functional properties of the different internally deleted dystrophins produced by exon skipping for different mutations; more insight would be valuable to improve and better predict the outcome of exon skipping clinical trials. To this end, we have characterized the clinical phenotype of 17 patients with Becker muscular dystrophy harbouring in-frame deletions relevant to on-going or planned exon skipping clinical trials for Duchenne muscular dystrophy and correlated it to the levels of dystrophin, and dystrophin-associated protein expression. The cohort of 17 patients, selected exclusively on the basis of their genotype, included 4 asymptomatic, 12 mild and 1 severe patient. All patients had dystrophin levels of >40% of control and significantly higher dystrophin (P = 0.013), β-dystroglycan (P = 0.025) and neuronal nitric oxide synthase (P = 0.034) expression was observed in asymptomatic individuals versus symptomatic patients with Becker muscular dystrophy. Furthermore, grouping the patients by deletion, patients with Becker muscular dystrophy with deletions with an end-point of exon 51 (the skipping of which could rescue the largest group of Duchenne muscular dystrophy deletions) showed significantly higher dystrophin levels (P = 0.034) than those with deletions ending with exon 53. This is the first quantitative study on both

Exon skipping and translation in patients with frameshift deletions in the dystrophin gene

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Sherratt, T.G.; Dubowitz, V.; Sewry, C.A.; Strong, P.N. (Royal Postgraduate Medical School, London (United Kingdom)); Vulliamy, T. (Hammersmith Hospital, London (United Kingdom))

1993-11-01

Although many Duchenne muscular dystrophy patients have a deletion in the dystrophin gene which disrupts the translational reading frame, they express dystrophin in a small proportion of skeletal muscle fibers ([open quotes]revertant fibers[close quotes]). Antibody studies have shown, indirectly, that dystrophin synthesis in revertant fibers is facilitated by a frame-restoring mechanism; in the present study, the feasibility of mRNA splicing was investigated. Dystrophin transcripts were analyzed in skeletal muscle from individuals possessing revertant fibers and a frameshift deletion in the dystrophin gene. In each case a minor in-frame transcript was detected, in which exons adjacent to those deleted from the genome had been skipped. There appeared to be some correlation between the levels of in-frame transcripts and the predicted translation products. Low levels of alternatively spliced transcripts were also present in normal muscle. The results provide further evidence of exon skipping in the dystrophin gene and indicate that this may be involved in the synthesis of dystrophin by revertant fibers. 44 refs., 12 figs.

Dystrophin analysis in carriers of Duchenne and Becker muscular dystrophy

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Hoogerwaard, Edo M.; Ginjaar, Ieke B.; Bakker, Egbert; de Visser, Marianne

2005-01-01

Associations between clinical phenotype (muscle weakness, dilated cardiomyopathy) and dystrophin abnormalities in muscle tissue among definite carriers of Duchenne (DMD) and Becker muscular dystrophy (BMD) were investigated. No associations between dystrophin abnormalities and clinical variables in

Metabolic dysfunction and altered mitochondrial dynamics in the utrophin-dystrophin deficient mouse model of duchenne muscular dystrophy.

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Meghna Pant

Full Text Available The utrophin-dystrophin deficient (DKO mouse model has been widely used to understand the progression of Duchenne muscular dystrophy (DMD. However, it is unclear as to what extent muscle pathology affects metabolism. Therefore, the present study was focused on understanding energy expenditure in the whole animal and in isolated extensor digitorum longus (EDL muscle and to determine changes in metabolic enzymes. Our results show that the 8 week-old DKO mice consume higher oxygen relative to activity levels. Interestingly the EDL muscle from DKO mouse consumes higher oxygen per unit integral force, generates less force and performs better in the presence of pyruvate thus mimicking a slow twitch muscle. We also found that the expression of hexokinase 1 and pyruvate kinase M2 was upregulated several fold suggesting increased glycolytic flux. Additionally, there is a dramatic increase in dynamin-related protein 1 (Drp 1 and mitofusin 2 protein levels suggesting increased mitochondrial fission and fusion, a feature associated with increased energy demand and altered mitochondrial dynamics. Collectively our studies point out that the dystrophic disease has caused significant changes in muscle metabolism. To meet the increased energetic demand, upregulation of metabolic enzymes and regulators of mitochondrial fusion and fission is observed in the dystrophic muscle. A better understanding of the metabolic demands and the accompanied alterations in the dystrophic muscle can help us design improved intervention therapies along with existing drug treatments for the DMD patients.

Structure of a WW domain-containing fragment of dystrophin complexed with {beta}-dystroglycan.

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Huang, X.; Poy, F.; Zhang, R.; Joachimiak, A.; Sudol, M.; Eck, M. J.; Biosciences Division; Dana Farber Cancer Inst.; Harvard Medical School; Mount Sinai School of Medicine

2000-08-01

Dystrophin and {beta}-dystroglycan are components of the dystrophin--glycoprotein complex (DGC), a multimolecular assembly that spans the cell membrane and links the actin cytoskeleton to the extracellular basal lamina. Defects in the dystrophin gene are the cause of Duchenne and Becker muscular dystrophies. The C-terminal region of dystrophin binds the cytoplasmic tail of {beta}-dystroglycan, in part through the interaction of its WW domain with a proline-rich motif in the tail of {beta}-dystroglycan. Here we report the crystal structure of this portion of dystrophin in complex with the proline-rich binding site in {beta}-dystroglycan. The structure shows that the dystrophin WW domain is embedded in an adjacent helical region that contains two EF-hand-like domains. The {beta}-dystroglycan peptide binds a composite surface formed by the WW domain and one of these EF-hands. Additionally, the structure reveals striking similarities in the mechanisms of proline recognition employed by WW domains and SH3 domains.

TNF-α-Induced microRNAs Control Dystrophin Expression in Becker Muscular Dystrophy.

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Fiorillo, Alyson A; Heier, Christopher R; Novak, James S; Tully, Christopher B; Brown, Kristy J; Uaesoontrachoon, Kitipong; Vila, Maria C; Ngheim, Peter P; Bello, Luca; Kornegay, Joe N; Angelini, Corrado; Partridge, Terence A; Nagaraju, Kanneboyina; Hoffman, Eric P

2015-09-08

The amount and distribution of dystrophin protein in myofibers and muscle is highly variable in Becker muscular dystrophy and in exon-skipping trials for Duchenne muscular dystrophy. Here, we investigate a molecular basis for this variability. In muscle from Becker patients sharing the same exon 45-47 in-frame deletion, dystrophin levels negatively correlate with microRNAs predicted to target dystrophin. Seven microRNAs inhibit dystrophin expression in vitro, and three are validated in vivo (miR-146b/miR-374a/miR-31). microRNAs are expressed in dystrophic myofibers and increase with age and disease severity. In exon-skipping-treated mdx mice, microRNAs are significantly higher in muscles with low dystrophin rescue. TNF-α increases microRNA levels in vitro whereas NFκB inhibition blocks this in vitro and in vivo. Collectively, these data show that microRNAs contribute to variable dystrophin levels in muscular dystrophy. Our findings suggest a model where chronic inflammation in distinct microenvironments induces pathological microRNAs, initiating a self-sustaining feedback loop that exacerbates disease progression. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

TNF-α-Induced microRNAs Control Dystrophin Expression in Becker Muscular Dystrophy

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Alyson A. Fiorillo

2015-09-01

Full Text Available The amount and distribution of dystrophin protein in myofibers and muscle is highly variable in Becker muscular dystrophy and in exon-skipping trials for Duchenne muscular dystrophy. Here, we investigate a molecular basis for this variability. In muscle from Becker patients sharing the same exon 45–47 in-frame deletion, dystrophin levels negatively correlate with microRNAs predicted to target dystrophin. Seven microRNAs inhibit dystrophin expression in vitro, and three are validated in vivo (miR-146b/miR-374a/miR-31. microRNAs are expressed in dystrophic myofibers and increase with age and disease severity. In exon-skipping-treated mdx mice, microRNAs are significantly higher in muscles with low dystrophin rescue. TNF-α increases microRNA levels in vitro whereas NFκB inhibition blocks this in vitro and in vivo. Collectively, these data show that microRNAs contribute to variable dystrophin levels in muscular dystrophy. Our findings suggest a model where chronic inflammation in distinct microenvironments induces pathological microRNAs, initiating a self-sustaining feedback loop that exacerbates disease progression.

Evolutionary study of vertebrate and invertebrate members of the dystrophin and utrophin gene family

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Roberts, R.G.; Nicholson, L.; Bobrow, M. [Paediatric Research Unit, London (United Kingdom)] [and others

1994-09-01

Vertebrates express two members of the dystrophin gene family. The prototype, dystrophin, is expressed in muscle and neural tissue, and is defective in the human disorders Duchenne and Becker muscular dystrophy (DMD, BMD). The dystrophin homologue utrophin is more generally expressed but has not yet been associated with a genetic disorder. The function of neither protein is clear. A comparison of human utrophin with the known dystrophins (human, mouse, chicken, Torpedo) suggests that dystrophin and utrophin diverged before the vertebrate radiation. We have used reverse-transcript PCR (RT-PCR) directed by degenerate primers to characterize dystrophin and utrophin transcripts from a range of vertebrate and invertebrate animals. Our results suggest that the duplication leading to distinct dystrophin and utrophin genes occurred close to the point of divergence of urochordates from the cephalochordate-vertebrate lineage. This divergence may have occurred to fulfill a novel role which arose at this point, or may reflect a need for separate regulation of the neuromuscular and other functions of the ancient dystrophin. Our data include sequences of the first non-human utrophins to be characterized, and show these to be substantially more divergent than their cognate dystrophins. In addition, our results provide a large body of information regarding the tolerance of amino acid positions in the cysteine-rich and C-terminal domains to substitution. This will aid the interpretations of DMD and BMD missense mutations in these regions.

T cell cytokine gene polymorphisms in canine diabetes mellitus.

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Short, Andrea D; Catchpole, Brian; Kennedy, Lorna J; Barnes, Annette; Lee, Andy C; Jones, Chris A; Fretwell, Neale; Ollier, William E R

2009-03-15

Insulin-deficiency diabetes in dogs shares some similarities with human latent autoimmune diabetes of adults (LADA). Canine diabetes is likely to have a complex pathogenesis with multiple genes contributing to overall susceptibility and/or disease progression. An association has previously been shown between canine diabetes and MHC class II genes, although other genes are also likely to contribute to the genetic risk. Potential diabetes susceptibility genes include immuno-regulatory TH1/TH2 cytokines such as IFNgamma, IL-12, IL-4 and IL-10. We screened these candidate genes for single nucleotide polymorphisms (SNPs) in a range of different dog breeds using dHPLC analysis and DNA sequencing. Thirty-eight of the SNPs were genotyped in crossbreed dogs and seven other breed groups (Labrador Retriever, West Highland White Terrier, Collie, Schnauzer, Cairn Terrier, Samoyed and Cavalier King Charles Spaniel), which demonstrated substantial intra-breed differences in allele frequencies. When SNPs were examined for an association with diabetes by case:control analysis significant associations were observed for IL-4 in three breeds, the Collie, Cairn Terrier and Schnauzer and for IL-10 in the Cavalier King Charles Spaniel. These results suggest that canine cytokine genes regulating the TH1/TH2 immune balance might play a contributory role in determining susceptibility to diabetes in some breeds.

Fetal microchimeric cells in a fetus-treats-its-mother paradigm do not contribute to dystrophin production in serially parous mdx females.

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Seppanen, Elke Jane; Hodgson, Samantha Susan; Khosrotehrani, Kiarash; Bou-Gharios, George; Fisk, Nicholas M

2012-10-10

Throughout every pregnancy, genetically distinct fetal microchimeric stem/progenitor cells (FMCs) engraft in the mother, persist long after delivery, and may home to damaged maternal tissues. Phenotypically normal fetal lymphoid progenitors have been described to develop in immunodeficient mothers in a fetus-treats-its-mother paradigm. Since stem cells contribute to muscle repair, we assessed this paradigm in the mdx mouse model of Duchenne muscular dystrophy. mdx females were bred serially to either ROSAeGFP males or mdx males to obtain postpartum microchimeras that received either wild-type FMCs or dystrophin-deficient FMCs through serial gestations. To enhance regeneration, notexin was injected into the tibialis anterior of postpartum mice. FMCs were detected by qPCR at a higher frequency in injected compared to noninjected side muscle (P=0.02). However, the number of dystrophin-positive fibers was similar in mothers delivering wild-type compared to mdx pups. In addition, there was no correlation between FMC detection and percentage dystrophin, and no GFP+ve FMCs were identified that expressed dystrophin. In 10/11 animals, GFP+ve FMCs were detected by immunohistochemistry, of which 60% expressed CD45 with 96% outside the basal lamina defining myofiber contours. Finally we confirmed lack of FMC contribution to statellite cells in postpartum mdx females mated with Myf5-LacZ males. We conclude that the FMC contribution to regenerating muscles is insufficient to have a functional impact.

Voluntary wheel running in dystrophin-deficient (mdx) mice: Relationships between exercise parameters and exacerbation of the dystrophic phenotype.

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Smythe, Gayle M; White, Jason D

2011-12-18

Voluntary wheel running can potentially be used to exacerbate the disease phenotype in dystrophin-deficient mdx mice. While it has been established that voluntary wheel running is highly variable between individuals, the key parameters of wheel running that impact the most on muscle pathology have not been examined in detail. We conducted a 2-week test of voluntary wheel running by mdx mice and the impact of wheel running on disease pathology. There was significant individual variation in the average daily distance (ranging from 0.003 ± 0.005 km to 4.48 ± 0.96 km), culminating in a wide range (0.040 km to 67.24 km) of total cumulative distances run by individuals. There was also variation in the number and length of run/rest cycles per night, and the average running rate. Correlation analyses demonstrated that in the quadriceps muscle, a low number of high distance run/rest cycles was the most consistent indicator for increased tissue damage. The amount of rest time between running bouts was a key factor associated with gastrocnemius damage. These data emphasize the need for detailed analysis of individual running performance, consideration of the length of wheel exposure time, and the selection of appropriate muscle groups for analysis, when applying the use of voluntary wheel running to disease exacerbation and/or pre-clinical testing of the efficacy of therapeutic agents in the mdx mouse.

Cavalier perspective plots of two-dimensional matrices. Program Stereo

International Nuclear Information System (INIS)

Los Arcos Merino, J.M.

1978-01-01

The program Stereo allows representation of a two-dimensional matrix containing numerical data, in the form of a cavalier perspective, isometric or not, with an angle variable between 0 deg and 180 deg. The representation is in histogram form for each matrix row and those curves which fall behind higher curves and therefore would not be seen are suppressed. It has been written in Fortran V for a Calcomp-936 digital plotter operating off-line with a Univac 1106 computer. Drawing method, subroutine structure and running instructions are described in this paper. (author)

Computational study of the human dystrophin repeats: interaction properties and molecular dynamics.

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Baptiste Legrand

Full Text Available Dystrophin is a large protein involved in the rare genetic disease Duchenne muscular dystrophy (DMD. It functions as a mechanical linker between the cytoskeleton and the sarcolemma, and is able to resist shear stresses during muscle activity. In all, 75% of the dystrophin molecule consists of a large central rod domain made up of 24 repeat units that share high structural homology with spectrin-like repeats. However, in the absence of any high-resolution structure of these repeats, the molecular basis of dystrophin central domain's functions has not yet been deciphered. In this context, we have performed a computational study of the whole dystrophin central rod domain based on the rational homology modeling of successive and overlapping tandem repeats and the analysis of their surface properties. Each tandem repeat has very specific surface properties that make it unique. However, the repeats share enough electrostatic-surface similarities to be grouped into four separate clusters. Molecular dynamics simulations of four representative tandem repeats reveal specific flexibility or bending properties depending on the repeat sequence. We thus suggest that the dystrophin central rod domain is constituted of seven biologically relevant sub-domains. Our results provide evidence for the role of the dystrophin central rod domain as a scaffold platform with a wide range of surface features and biophysical properties allowing it to interact with its various known partners such as proteins and membrane lipids. This new integrative view is strongly supported by the previous experimental works that investigated the isolated domains and the observed heterogeneity of the severity of dystrophin related pathologies, especially Becker muscular dystrophy.

Ex vivo gene editing of the dystrophin gene in muscle stem cells mediated by peptide nucleic acid single stranded oligodeoxynucleotides induces stable expression of dystrophin in a mouse model for Duchenne muscular dystrophy.

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Nik-Ahd, Farnoosh; Bertoni, Carmen

2014-07-01

Duchenne muscular dystrophy (DMD) is a fatal disease caused by mutations in the dystrophin gene, which result in the complete absence of dystrophin protein throughout the body. Gene correction strategies hold promise to treating DMD. Our laboratory has previously demonstrated the ability of peptide nucleic acid single-stranded oligodeoxynucleotides (PNA-ssODNs) to permanently correct single-point mutations at the genomic level. In this study, we show that PNA-ssODNs can target and correct muscle satellite cells (SCs), a population of stem cells capable of self-renewing and differentiating into muscle fibers. When transplanted into skeletal muscles, SCs transfected with correcting PNA-ssODNs were able to engraft and to restore dystrophin expression. The number of dystrophin-positive fibers was shown to significantly increase over time. Expression was confirmed to be the result of the activation of a subpopulation of SCs that had undergone repair as demonstrated by immunofluorescence analyses of engrafted muscles using antibodies specific to full-length dystrophin transcripts and by genomic DNA analysis of dystrophin-positive fibers. Furthermore, the increase in dystrophin expression detected over time resulted in a significant improvement in muscle morphology. The ability of transplanted cells to return into quiescence and to activate upon demand was confirmed in all engrafted muscles following injury. These results demonstrate the feasibility of using gene editing strategies to target and correct SCs and further establish the therapeutic potential of this approach to permanently restore dystrophin expression into muscle of DMD patients. © 2014 AlphaMed Press.

Mismatched single stranded antisense oligonucleotides can induce efficient dystrophin splice switching

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Kole Ryszard

2011-10-01

Full Text Available Abstract Background Antisense oligomer induced exon skipping aims to reduce the severity of Duchenne muscular dystrophy by redirecting splicing during pre-RNA processing such that the causative mutation is by-passed and a shorter but partially functional Becker muscular dystrophy-like dystrophin isoform is produced. Normal exons are generally targeted to restore the dystrophin reading frame however, an appreciable subset of dystrophin mutations are intra-exonic and therefore have the potential to compromise oligomer efficiency, necessitating personalised oligomer design for some patients. Although antisense oligomers are easily personalised, it remains unclear whether all patient polymorphisms within antisense oligomer target sequences will require the costly process of producing and validating patient specific compounds. Methods Here we report preclinical testing of a panel of splice switching antisense oligomers, designed to excise exon 25 from the dystrophin transcript, in normal and dystrophic patient cells. These patient cells harbour a single base insertion in exon 25 that lies within the target sequence of an oligomer shown to be effective at removing exon 25. Results It was anticipated that such a mutation would compromise oligomer binding and efficiency. However, we show that, despite the mismatch an oligomer, designed and optimised to excise exon 25 from the normal dystrophin mRNA, removes the mutated exon 25 more efficiently than the mutation-specific oligomer. Conclusion This raises the possibility that mismatched AOs could still be therapeutically applicable in some cases, negating the necessity to produce patient-specific compounds.

Analysis of Dystrophin Gene Deletions by Multiplex PCR in Moroccan Patients

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Aziza Sbiti

2002-01-01

Full Text Available Duchenne and Becker muscular dystrophy (DMD and BMD are X-linked diseases resulting from a defect in the dystrophin gene located on Xp21. DMD is the most frequent neuromuscular disease in humans (1/3500 male newborn. Deletions in the dystrophin gene represent 65% of mutations in DMD/BMD patients. We have analyzed DNA from 72 Moroccan patients with DMD/BMD using the multiplex polymerase chain reaction (PCR to screen for exon deletions within the dystrophin gene, and to estimate the frequency of these abnormalities. We found dystrophin gene deletions in 37 cases. Therefore the frequency in Moroccan DMD/BMD patients is about 51.3%. All deletions were clustered in the two known hot-spots regions, and in 81% of cases deletions were detected in the region from exon 43 to exon 52. These findings are comparable to those reported in other studies. It is important to note that in our population, we can first search for deletions of DMD gene in the most frequently deleted exons determined by this study. This may facilitate the molecular diagnosis of DMD and BMD in our country.

Dystrophin in frameshift deletion patients with Becker Muscular Dystrophy

Energy Technology Data Exchange (ETDEWEB)

Gangopadhyay, S.B.; Ray, P.N.; Worton, R.G.; Sherratt, T.G.; Heckmatt, J.Z.; Dubowitz, V.; Strong, P.N.; Miller, G. (Penn State College of Medicine, Hershey, PA (United States)); Shokeir, M. (Univ. Hospital, Saskatchewan (Canada))

1992-09-01

In a previous study the authors identified 14 cases with Duchenne muscular dystrophy (DMD) or its milder variant, Becker muscular dystrophy (BMD), with a deletion of exons 3-7, a deletion that would be expected to shift the translational reading frame of the mRNA and give a severe phenotype. They have examined dystrophin and its mRNA from muscle biopsies of seven cases with either mild or intermediate phenotypes. In all cases they detected slightly lower-molecular-weight dystrophin in 12%-15% abundance relative to the normal. By sequencing amplified mRNA they have found that exon 2 is spliced to exon 8, a splice that produces a frameshifted mRNA, and have found no evidence for alternate splicing that might be involved in restoration of dystrophin mRNA reading frame in the patients with a mild phenotype. Other transcriptional and posttranscriptional mechanisms such as cryptic promoter, ribosomal frameshifting, and reinitiation are suggested that might play some role in restoring the reading frame. 34 refs., 5 figs. 1 tab.

A Translational Pathway Toward a Clinical Trial Using the Second-Generation AAV Micro-Dystrophin Vector

Science.gov (United States)

2016-09-01

mune system a few weeks later. It is now clear that the gene delivery vehicle (AAV virus capsid), cargo (transgene), or the protein produced from the...Ideally, delivery of a full-length dystrophin cDNA will yield the production of a full- length dystrophin protein and the maximum pro- tection of...investigational new drug (IND) application can be filed for a gene therapy trial with systemic delivery of dystrophin? Dr. Duan: A number of IND

Correlation of Utrophin Levels with the Dystrophin Protein Complex and Muscle Fibre Regeneration in Duchenne and Becker Muscular Dystrophy Muscle Biopsies.

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Janghra, Narinder; Morgan, Jennifer E; Sewry, Caroline A; Wilson, Francis X; Davies, Kay E; Muntoni, Francesco; Tinsley, Jonathon

2016-01-01

Duchenne muscular dystrophy is a severe and currently incurable progressive neuromuscular condition, caused by mutations in the DMD gene that result in the inability to produce dystrophin. Lack of dystrophin leads to loss of muscle fibres and a reduction in muscle mass and function. There is evidence from dystrophin-deficient mouse models that increasing levels of utrophin at the muscle fibre sarcolemma by genetic or pharmacological means significantly reduces the muscular dystrophy pathology. In order to determine the efficacy of utrophin modulators in clinical trials, it is necessary to accurately measure utrophin levels and other biomarkers on a fibre by fibre basis within a biopsy section. Our aim was to develop robust and reproducible staining and imaging protocols to quantify sarcolemmal utrophin levels, sarcolemmal dystrophin complex members and numbers of regenerating fibres within a biopsy section. We quantified sarcolemmal utrophin in mature and regenerating fibres and the percentage of regenerating muscle fibres, in muscle biopsies from Duchenne, the milder Becker muscular dystrophy and controls. Fluorescent immunostaining followed by image analysis was performed to quantify utrophin intensity and β-dystrogylcan and ɣ -sarcoglycan intensity at the sarcolemma. Antibodies to fetal and developmental myosins were used to identify regenerating muscle fibres allowing the accurate calculation of percentage regeneration fibres in the biopsy. Our results indicate that muscle biopsies from Becker muscular dystrophy patients have fewer numbers of regenerating fibres and reduced utrophin intensity compared to muscle biopsies from Duchenne muscular dystrophy patients. Of particular interest, we show for the first time that the percentage of regenerating muscle fibres within the muscle biopsy correlate with the clinical severity of Becker and Duchenne muscular dystrophy patients from whom the biopsy was taken. The ongoing development of these tools to quantify

Correlation of Utrophin Levels with the Dystrophin Protein Complex and Muscle Fibre Regeneration in Duchenne and Becker Muscular Dystrophy Muscle Biopsies.

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Narinder Janghra

Full Text Available Duchenne muscular dystrophy is a severe and currently incurable progressive neuromuscular condition, caused by mutations in the DMD gene that result in the inability to produce dystrophin. Lack of dystrophin leads to loss of muscle fibres and a reduction in muscle mass and function. There is evidence from dystrophin-deficient mouse models that increasing levels of utrophin at the muscle fibre sarcolemma by genetic or pharmacological means significantly reduces the muscular dystrophy pathology. In order to determine the efficacy of utrophin modulators in clinical trials, it is necessary to accurately measure utrophin levels and other biomarkers on a fibre by fibre basis within a biopsy section. Our aim was to develop robust and reproducible staining and imaging protocols to quantify sarcolemmal utrophin levels, sarcolemmal dystrophin complex members and numbers of regenerating fibres within a biopsy section. We quantified sarcolemmal utrophin in mature and regenerating fibres and the percentage of regenerating muscle fibres, in muscle biopsies from Duchenne, the milder Becker muscular dystrophy and controls. Fluorescent immunostaining followed by image analysis was performed to quantify utrophin intensity and β-dystrogylcan and ɣ -sarcoglycan intensity at the sarcolemma. Antibodies to fetal and developmental myosins were used to identify regenerating muscle fibres allowing the accurate calculation of percentage regeneration fibres in the biopsy. Our results indicate that muscle biopsies from Becker muscular dystrophy patients have fewer numbers of regenerating fibres and reduced utrophin intensity compared to muscle biopsies from Duchenne muscular dystrophy patients. Of particular interest, we show for the first time that the percentage of regenerating muscle fibres within the muscle biopsy correlate with the clinical severity of Becker and Duchenne muscular dystrophy patients from whom the biopsy was taken. The ongoing development of these

Use of epitope libraries to identify exon-specific monoclonal antibodies for characterization of altered dystrophins in muscular dystrophy

Energy Technology Data Exchange (ETDEWEB)

Nguyen thi Man; Morris, G.E. (North East Wales Inst., Clwyd (United Kingdom))

1993-06-01

The majority of mutations in Xp21-linked muscular dystrophy (MD) can be identified by PCR or Southern blotting, as deletions or duplications of groups of exons in the dystrophin gene, but it is not always possible to predict how much altered dystrophin, if any, will be produced. Use of exon-specific monoclonal antibodies (mAbs) on muscle biopsies from MD patients can, in principle, provide information on both the amount of altered dystrophin produced and, when dystrophin is present, the nature of the genetic deletion or point mutation. For this purpose, mAbs which recognize regions of dystrophin encoded by known exons and whose binding is unaffected by the absence of adjacent exons are required. To map mAbs to specific exons, random [open quotes]libraries[close quotes] of expressed dystrophin fragments were created by cloning DNAseI digestion fragments of a 4.3-kb dystrophin cDNA into a pTEX expression vector. The libraries were then used to locate the epitopes recognized by 48 mAbs to fragments of 25--60 amino acids within the 1,434-amino-acid dystrophin fragment used to produce the antibodies. This is sufficiently detailed to allow further refinement by using synthetic peptides and, in many cases, to identify the exon in the DMD (Duchenne MD) gene which encodes the epitope. To illustrate their use in dystrophin analysis, a Duchenne patient with a frameshift deletion of exons 42 and 43 makes a truncated dystrophin encoded by exons 1--41, and the authors now show that this can be detected in the sarcolemma by mAbs up to and including those specific for exon 41 epitopes but not by mAbs specific for exon 43 or later epitopes. 38 refs., 2 figs., 4 tabs.

Concurrent Label-Free Mass Spectrometric Analysis of Dystrophin Isoform Dp427 and the Myofibrosis Marker Collagen in Crude Extracts from mdx-4cv Skeletal Muscles

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Murphy, Sandra; Zweyer, Margit; Mundegar, Rustam R.; Henry, Michael; Meleady, Paula; Swandulla, Dieter; Ohlendieck, Kay

2015-01-01

The full-length dystrophin protein isoform of 427 kDa (Dp427), the absence of which represents the principal abnormality in X-linked muscular dystrophy, is difficult to identify and characterize by routine proteomic screening approaches of crude tissue extracts. This is probably related to its large molecular size, its close association with the sarcolemmal membrane, and its existence within a heterogeneous glycoprotein complex. Here, we used a careful extraction procedure to isolate the total protein repertoire from normal versus dystrophic mdx-4cv skeletal muscles, in conjunction with label-free mass spectrometry, and successfully identified Dp427 by proteomic means. In contrast to a considerable number of previous comparative studies of the total skeletal muscle proteome, using whole tissue proteomics we show here for the first time that the reduced expression of this membrane cytoskeletal protein is the most significant alteration in dystrophinopathy. This agrees with the pathobiochemical concept that the almost complete absence of dystrophin is the main defect in Duchenne muscular dystrophy and that the mdx-4cv mouse model of dystrophinopathy exhibits only very few revertant fibers. Significant increases in collagens and associated fibrotic marker proteins, such as fibronectin, biglycan, asporin, decorin, prolargin, mimecan, and lumican were identified in dystrophin-deficient muscles. The up-regulation of collagen in mdx-4cv muscles was confirmed by immunofluorescence microscopy and immunoblotting. Thus, this is the first mass spectrometric study of crude tissue extracts that puts the proteomic identification of dystrophin in its proper pathophysiological context. PMID:28248273

Targeted Exon Skipping to Correct Exon Duplications in the Dystrophin Gene

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Kane L Greer

2014-01-01

Full Text Available Duchenne muscular dystrophy is a severe muscle-wasting disease caused by mutations in the dystrophin gene that ablate functional protein expression. Although exonic deletions are the most common Duchenne muscular dystrophy lesion, duplications account for 10–15% of reported disease-causing mutations, and exon 2 is the most commonly duplicated exon. Here, we describe the in vitro evaluation of phosphorodiamidate morpholino oligomers coupled to a cell-penetrating peptide and 2′-O-methyl phosphorothioate oligonucleotides, using three distinct strategies to reframe the dystrophin transcript in patient cells carrying an exon 2 duplication. Differences in exon-skipping efficiencies in vitro were observed between oligomer analogues of the same sequence, with the phosphorodiamidate morpholino oligomer coupled to a cell-penetrating peptide proving the most effective. Differences in exon 2 excision efficiency between normal and exon 2 duplication cells, were apparent, indicating that exon context influences oligomer-induced splice switching. Skipping of a single copy of exon 2 was induced in the cells carrying an exon 2 duplication, the simplest strategy to restore the reading frame and generate a normal dystrophin transcript. In contrast, multiexon skipping of exons 2–7 to generate a Becker muscular dystrophy-like dystrophin transcript was more challenging and could only be induced efficiently with the phosphorodiamidate morpholino oligomer chemistry.

Early dystrophin loss is coincident with the transition of compensated cardiac hypertrophy to heart failure.

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Fernanda P Prado

Full Text Available Hypertension causes cardiac hypertrophy, one of the most important risk factors for heart failure (HF. Despite the importance of cardiac hypertrophy as a risk factor for the development of HF, not all hypertrophied hearts will ultimately fail. Alterations of cytoskeletal and sarcolemma-associated proteins are considered markers cardiac remodeling during HF. Dystrophin provides mechanical stability to the plasma membrane through its interactions with the actin cytoskeleton and, indirectly, to extracellular matrix proteins. This study was undertaken to evaluate dystrophin and calpain-1 in the transition from compensated cardiac hypertrophy to HF. Wistar rats were subjected to abdominal aorta constriction and killed at 30, 60 and 90 days post surgery (dps. Cardiac function and blood pressure were evaluated. The hearts were collected and Western blotting and immunofluorescence performed for dystrophin, calpain-1, alpha-fodrin and calpastatin. Statistical analyses were performed and considered significant when p<0.05. After 90 dps, 70% of the animals showed hypertrophic hearts (HH and 30% hypertrophic+dilated hearts (HD. Systolic and diastolic functions were preserved at 30 and 60 dps, however, decreased in the HD group. Blood pressure, cardiomyocyte diameter and collagen content were increased at all time points. Dystrophin expression was lightly increased at 30 and 60 dps and HH group. HD group showed decreased expression of dystrophin and calpastatin and increased expression of calpain-1 and alpha-fodrin fragments. The first signals of dystrophin reduction were observed as early as 60 dps. In conclusion, some hearts present a distinct molecular pattern at an early stage of the disease; this pattern could provide an opportunity to identify these failure-prone hearts during the development of the cardiac disease. We showed that decreased expression of dystrophin and increased expression of calpains are coincident and could work as possible

Heteroduplex analysis of the dystrophin gene: Application to point mutation and carrier detection

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Prior, T.W.; Papp, A.C.; Snyder, P.J.; Sedra, M.S.; Western, L.M.; Bartolo, C.; Mendell, J.R. [Ohio State Univ., Columbus, OH (United States); Moxley, R.T. [Univ. of Rochester Medical Center, NY (United States)

1994-03-01

Approximately one-third of Duchenne muscular dystrophy patients have undefined mutations in the dystrophin gene. For carrier and prenatal studies in families without detectable mutations, the indirect restriction fragment length polymorphism linkage approach is used. Using a multiplex amplification and heteroduplex analysis of dystrophin exons, the authors identified nonsense mutations in two DMD patients. Although the nonsense mutations are predicted to severely truncate the dystrophin protein, both patients presented with mild clinical courses of the disease. As a result of identifying the mutation in the affected boys, direct carrier studies by heteroduplex analysis were extended to other relatives. The authors conclude that the technique is not only ideal for mutation detection but is also useful for diagnostic testing. 29 refs., 4 figs.

Multiple Species Comparison of Cardiac Troponin T and Dystrophin: Unravelling the DNA behind Dilated Cardiomyopathy.

Science.gov (United States)

England, Jennifer; Loughna, Siobhan; Rutland, Catrin Sian

2017-07-07

Animals have frequently been used as models for human disorders and mutations. Following advances in genetic testing and treatment options, and the decreasing cost of these technologies in the clinic, mutations in both companion and commercial animals are now being investigated. A recent review highlighted the genes associated with both human and non-human dilated cardiomyopathy. Cardiac troponin T and dystrophin were observed to be associated with both human and turkey (troponin T) and canine (dystrophin) dilated cardiomyopathies. This review gives an overview of the work carried out in cardiac troponin T and dystrophin to date in both human and animal dilated cardiomyopathy.

Evaluation of point mutations in dystrophin gene in Iranian ...

Indian Academy of Sciences (India)

5Department of Biology, Science and Research Branch, Islamic Azad ... Dystrophin protein is found ... Duchenne and Becker muscular dystrophy; neuromuscular disorder; point mutation. ..... modern diagnostic techniques to a large cohort.

A sensitive, reproducible and objective immunofluorescence analysis method of dystrophin in individual fibers in samples from patients with duchenne muscular dystrophy.

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Chantal Beekman

Full Text Available Duchenne muscular dystrophy (DMD is characterized by the absence or reduced levels of dystrophin expression on the inner surface of the sarcolemmal membrane of muscle fibers. Clinical development of therapeutic approaches aiming to increase dystrophin levels requires sensitive and reproducible measurement of differences in dystrophin expression in muscle biopsies of treated patients with DMD. This, however, poses a technical challenge due to intra- and inter-donor variance in the occurrence of revertant fibers and low trace dystrophin expression throughout the biopsies. We have developed an immunofluorescence and semi-automated image analysis method that measures the sarcolemmal dystrophin intensity per individual fiber for the entire fiber population in a muscle biopsy. Cross-sections of muscle co-stained for dystrophin and spectrin have been imaged by confocal microscopy, and image analysis was performed using Definiens software. Dystrophin intensity has been measured in the sarcolemmal mask of spectrin for each individual muscle fiber and multiple membrane intensity parameters (mean, maximum, quantiles per fiber were calculated. A histogram can depict the distribution of dystrophin intensities for the fiber population in the biopsy. This method was tested by measuring dystrophin in DMD, Becker muscular dystrophy, and healthy muscle samples. Analysis of duplicate or quadruplicate sections of DMD biopsies on the same or multiple days, by different operators, or using different antibodies, was shown to be objective and reproducible (inter-assay precision, CV 2-17% and intra-assay precision, CV 2-10%. Moreover, the method was sufficiently sensitive to detect consistently small differences in dystrophin between two biopsies from a patient with DMD before and after treatment with an investigational compound.

Multiple Species Comparison of Cardiac Troponin T and Dystrophin: Unravelling the DNA behind Dilated Cardiomyopathy

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Jennifer England

2017-07-01

Full Text Available Animals have frequently been used as models for human disorders and mutations. Following advances in genetic testing and treatment options, and the decreasing cost of these technologies in the clinic, mutations in both companion and commercial animals are now being investigated. A recent review highlighted the genes associated with both human and non-human dilated cardiomyopathy. Cardiac troponin T and dystrophin were observed to be associated with both human and turkey (troponin T and canine (dystrophin dilated cardiomyopathies. This review gives an overview of the work carried out in cardiac troponin T and dystrophin to date in both human and animal dilated cardiomyopathy.

The polyproline site in hinge 2 influences the functional capacity of truncated dystrophins.

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Glen B Banks

2010-05-01

Full Text Available Mutations in dystrophin can lead to Duchenne muscular dystrophy or the more mild form of the disease, Becker muscular dystrophy. The hinge 3 region in the rod domain of dystrophin is particularly prone to deletion mutations. In-frame deletions of hinge 3 are predicted to lead to BMD, however the severity of disease can vary considerably. Here we performed extensive structure-function analyses of truncated dystrophins with modified hinges and spectrin-like repeats in mdx mice. We found that the polyproline site in hinge 2 profoundly influences the functional capacity of a microdystrophin(DeltaR4-R23/DeltaCT with a large deletion in the hinge 3 region. Inclusion of polyproline in microdystrophin(DeltaR4-R23/DeltaCT led to small myofibers (12% smaller than wild-type, Achilles myotendinous disruption, ringed fibers, and aberrant neuromuscular junctions in the mdx gastrocnemius muscles. Replacing hinge 2 of microdystrophin(DeltaR4-R23/DeltaCT with hinge 3 significantly improved the functional capacity to prevent muscle degeneration, increase muscle fiber area, and maintain the junctions. We conclude that the rigid alpha-helical structure of the polyproline site significantly impairs the functional capacity of truncated dystrophins to maintain appropriate connections between the cytoskeleton and extracellular matrix.

Comparative Analysis of Vertebrate Dystrophin Loci Indicate Intron Gigantism as a Common Feature

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Pozzoli, Uberto; Elgar, Greg; Cagliani, Rachele; Riva, Laura; Comi, Giacomo P.; Bresolin, Nereo; Bardoni, Alessandra; Sironi, Manuela

2003-01-01

The human DMD gene is the largest known to date, spanning > 2000 kb on the X chromosome. The gene size is mainly accounted for by huge intronic regions. We sequenced 190 kb of Fugu rubripes (pufferfish) genomic DNA corresponding to the complete dystrophin gene (FrDMD) and provide the first report of gene structure and sequence comparison among dystrophin genomic sequences from different vertebrate organisms. Almost all intron positions and phases are conserved between FrDMD and its mammalian counterparts, and the predicted protein product of the Fugu gene displays 55% identity and 71% similarity to human dystrophin. In analogy to the human gene, FrDMD presents several-fold longer than average intronic regions. Analysis of intron sequences of the human and murine genes revealed that they are extremely conserved in size and that a similar fraction of total intron length is represented by repetitive elements; moreover, our data indicate that intron expansion through repeat accumulation in the two orthologs is the result of independent insertional events. The hypothesis that intron length might be functionally relevant to the DMD gene regulation is proposed and substantiated by the finding that dystrophin intron gigantism is common to the three vertebrate genes. [Supplemental material is available online at www.genome.org.] PMID:12727896

Skeletal Muscle Differentiation on a Chip Shows Human Donor Mesoangioblasts' Efficiency in Restoring Dystrophin in a Duchenne Muscular Dystrophy Model.

Science.gov (United States)

Serena, Elena; Zatti, Susi; Zoso, Alice; Lo Verso, Francesca; Tedesco, F Saverio; Cossu, Giulio; Elvassore, Nicola

2016-12-01

: Restoration of the protein dystrophin on muscle membrane is the goal of many research lines aimed at curing Duchenne muscular dystrophy (DMD). Results of ongoing preclinical and clinical trials suggest that partial restoration of dystrophin might be sufficient to significantly reduce muscle damage. Different myogenic progenitors are candidates for cell therapy of muscular dystrophies, but only satellite cells and pericytes have already entered clinical experimentation. This study aimed to provide in vitro quantitative evidence of the ability of mesoangioblasts to restore dystrophin, in terms of protein accumulation and distribution, within myotubes derived from DMD patients, using a microengineered model. We designed an ad hoc experimental strategy to miniaturize on a chip the standard process of muscle regeneration independent of variables such as inflammation and fibrosis. It is based on the coculture, at different ratios, of human dystrophin-positive myogenic progenitors and dystrophin-negative myoblasts in a substrate with muscle-like physiological stiffness and cell micropatterns. Results showed that both healthy myoblasts and mesoangioblasts restored dystrophin expression in DMD myotubes. However, mesoangioblasts showed unexpected efficiency with respect to myoblasts in dystrophin production in terms of the amount of protein produced (40% vs. 15%) and length of the dystrophin membrane domain (210-240 µm vs. 40-70 µm). These results show that our microscaled in vitro model of human DMD skeletal muscle validated previous in vivo preclinical work and may be used to predict efficacy of new methods aimed at enhancing dystrophin accumulation and distribution before they are tested in vivo, reducing time, costs, and variability of clinical experimentation. This study aimed to provide in vitro quantitative evidence of the ability of human mesoangioblasts to restore dystrophin, in terms of protein accumulation and distribution, within myotubes derived from

The influence of low dystrophin levels on disease pathology in mouse models for Duchenne Muscular Dystrophy

NARCIS (Netherlands)

Putten, Maaike van

2013-01-01

Duchenne muscular dystrophy (DMD) is the most prevalent neuromuscular disorder, caused by mutations in the DMD gene that prevent synthesis of dystrophin. Fibers that lack dystrophin are sensitive to exercise-induced damage, resulting in progressive muscle wasting, loss of ambulation and premature

Immobilization and therapeutic passive stretching generate thickening and increase the expression of laminin and dystrophin in skeletal muscle

International Nuclear Information System (INIS)

Cação-Benedini, L.O.; Ribeiro, P.G.; Prado, C.M.; Chesca, D.L.; Mattiello-Sverzut, A.C.

2014-01-01

Extracellular matrix and costamere proteins transmit the concentric, isometric, and eccentric forces produced by active muscle contraction. The expression of these proteins after application of passive tension stimuli to muscle remains unknown. This study investigated the expression of laminin and dystrophin in the soleus muscle of rats immobilized with the right ankle in plantar flexion for 10 days and subsequent remobilization, either by isolated free movement in a cage or associated with passive stretching for up to 10 days. The intensity of the macrophage response was also evaluated. One hundred and twenty-eight female Wistar rats were divided into 8 groups: free for 10 days; immobilized for 10 days; immobilized/free for 1, 3, or 10 days; or immobilized/stretched/free for 1, 3, or 10 days. After the experimental procedures, muscle tissue was processed for immunofluorescence (dystrophin/laminin/CD68) and Western blot analysis (dystrophin/laminin). Immobilization increased the expression of dystrophin and laminin but did not alter the number of macrophages in the muscle. In the stretched muscle groups, there was an increase in dystrophin and the number of macrophages after 3 days compared with the other groups; dystrophin showed a discontinuous labeling pattern, and laminin was found in the intracellular space. The amount of laminin was increased in the muscles treated by immobilization followed by free movement for 10 days. In the initial stages of postimmobilization (1 and 3 days), an exacerbated macrophage response and an increase of dystrophin suggested that the therapeutic stretching technique induced additional stress in the muscle fibers and costameres

Immobilization and therapeutic passive stretching generate thickening and increase the expression of laminin and dystrophin in skeletal muscle

Energy Technology Data Exchange (ETDEWEB)

Cação-Benedini, L.O.; Ribeiro, P.G. [Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Medicina e Reabilitação do Aparelho Locomotor, Departamento de Biomecânica, Ribeirão Preto, SP, Brasil, Departamento de Biomecânica, Medicina e Reabilitação do Aparelho Locomotor, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Prado, C.M.; Chesca, D.L. [Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Departamento de Patologia, Ribeirão Preto, SP, Brasil, Departamento de Patologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Mattiello-Sverzut, A.C. [Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Medicina e Reabilitação do Aparelho Locomotor, Departamento de Biomecânica, Ribeirão Preto, SP, Brasil, Departamento de Biomecânica, Medicina e Reabilitação do Aparelho Locomotor, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil)

2014-05-09

Extracellular matrix and costamere proteins transmit the concentric, isometric, and eccentric forces produced by active muscle contraction. The expression of these proteins after application of passive tension stimuli to muscle remains unknown. This study investigated the expression of laminin and dystrophin in the soleus muscle of rats immobilized with the right ankle in plantar flexion for 10 days and subsequent remobilization, either by isolated free movement in a cage or associated with passive stretching for up to 10 days. The intensity of the macrophage response was also evaluated. One hundred and twenty-eight female Wistar rats were divided into 8 groups: free for 10 days; immobilized for 10 days; immobilized/free for 1, 3, or 10 days; or immobilized/stretched/free for 1, 3, or 10 days. After the experimental procedures, muscle tissue was processed for immunofluorescence (dystrophin/laminin/CD68) and Western blot analysis (dystrophin/laminin). Immobilization increased the expression of dystrophin and laminin but did not alter the number of macrophages in the muscle. In the stretched muscle groups, there was an increase in dystrophin and the number of macrophages after 3 days compared with the other groups; dystrophin showed a discontinuous labeling pattern, and laminin was found in the intracellular space. The amount of laminin was increased in the muscles treated by immobilization followed by free movement for 10 days. In the initial stages of postimmobilization (1 and 3 days), an exacerbated macrophage response and an increase of dystrophin suggested that the therapeutic stretching technique induced additional stress in the muscle fibers and costameres.

Mouse models of two missense mutations in actin-binding domain 1 of dystrophin associated with Duchenne or Becker muscular dystrophy.

Science.gov (United States)

McCourt, Jackie L; Talsness, Dana M; Lindsay, Angus; Arpke, Robert W; Chatterton, Paul D; Nelson, D'anna M; Chamberlain, Christopher M; Olthoff, John T; Belanto, Joseph J; McCourt, Preston M; Kyba, Michael; Lowe, Dawn A; Ervasti, James M

2018-02-01

Missense mutations in the dystrophin protein can cause Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) through an undefined pathomechanism. In vitro studies suggest that missense mutations in the N-terminal actin-binding domain (ABD1) cause protein instability, and cultured myoblast studies reveal decreased expression levels that can be restored to wild-type with proteasome inhibitors. To further elucidate the pathophysiology of missense dystrophin in vivo, we generated two transgenic mdx mouse lines expressing L54R or L172H mutant dystrophin, which correspond to missense mutations identified in human patients with DMD or BMD, respectively. Our biochemical, histologic and physiologic analysis of the L54R and L172H mice show decreased levels of dystrophin which are proportional to the phenotypic severity. Proteasome inhibitors were ineffective in both the L54R and L172H mice, yet mice homozygous for the L172H transgene were able to express even higher levels of dystrophin which caused further improvements in muscle histology and physiology. Given that missense dystrophin is likely being degraded by the proteasome but whole body proteasome inhibition was not possible, we screened for ubiquitin-conjugating enzymes involved in targeting dystrophin to the proteasome. A myoblast cell line expressing L54R mutant dystrophin was screened with an siRNA library targeting E1, E2 and E3 ligases which identified Amn1, FBXO33, Zfand5 and Trim75. Our study establishes new mouse models of dystrophinopathy and identifies candidate E3 ligases that may specifically regulate dystrophin protein turnover in vivo. © The Author(s) 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Spectrum of small mutations in the dystrophin coding region

Energy Technology Data Exchange (ETDEWEB)

Prior, T.W.; Bartolo, C.; Pearl, D.K. [Ohio State Univ., Columbus, OH (United States)] [and others

1995-07-01

Duchenne and Becker muscular dystrophies (DMD and BMD) are caused by defects in the dystrophin gene. About two-thirds of the affected patients have large deletions or duplications, which occur in the 5` and central portion of the gene. The nondeletion/duplication cases are most likely the result of smaller mutations that cannot be identified by current diagnostic screening strategies. We screened {approximately} 80% of the dystrophin coding sequence for small mutations in 158 patients without deletions or duplications and identified 29 mutations. The study indicates that many of the DMD and the majority of the BMD small mutations lie in noncoding regions of the gene. All of the mutations identified were unique to single patients, and most of the mutations resulted in protein truncation. We did not find a clustering of small mutations similar to the deletion distribution but found > 40% of the small mutations 3` of exon 55. The extent of protein truncation caused by the 3` mutations did not determine the phenotype, since even the exon 76 nonsense mutation resulted in the severe DMD phenotype. Our study confirms that the dystrophin gene is subject to a high rate of mutation in CpG sequences. As a consequence of not finding any hotspots or prevalent small mutations, we conclude that it is presently not possible to perform direct carrier and prenatal diagnostics for many families without deletions or duplications. 71 refs., 2 figs., 2 tabs.

Dystroglycan and muscular dystrophies related to the dystrophin-glycoprotein complex.

Science.gov (United States)

Sciandra, Francesca; Bozzi, Manuela; Bianchi, Marzia; Pavoni, Ernesto; Giardina, Bruno; Brancaccio, Andrea

2003-01-01

Dystroglycan (DG) is an adhesion molecule composed of two subunits, alpha and beta, that are produced by the post-translational cleavage of a single precursor molecule. DG is a pivotal component of the dystrophin-glycoprotein complex (DGC), which connects the extracellular matrix to the cytoskeleton in skeletal muscle and many other tissues. Some muscular dystrophies are caused by mutations of DGC components, such as dystrophin, sarcoglycan or laminin-2, or also of DGC-associated molecules, such as caveolin-3. DG-null mice died during early embriogenesis and no neuromuscular diseases directly associated to genetic abnormalities of DG were identified so far. However, DG plays a crucial role for muscle integrity since its targeting at the sarcolemma is often perturbed in DGC-related neuromuscular disorders.

Assessment of the structural and functional impact of in-frame mutations of the DMD gene, using the tools included in the eDystrophin online database

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Nicolas Aurélie

2012-07-01

Full Text Available Abstract Background Dystrophin is a large essential protein of skeletal and heart muscle. It is a filamentous scaffolding protein with numerous binding domains. Mutations in the DMD gene, which encodes dystrophin, mostly result in the deletion of one or several exons and cause Duchenne (DMD and Becker (BMD muscular dystrophies. The most common DMD mutations are frameshift mutations resulting in an absence of dystrophin from tissues. In-frame DMD mutations are less frequent and result in a protein with partial wild-type dystrophin function. The aim of this study was to highlight structural and functional modifications of dystrophin caused by in-frame mutations. Methods and results We developed a dedicated database for dystrophin, the eDystrophin database. It contains 209 different non frame-shifting mutations found in 945 patients from a French cohort and previous studies. Bioinformatics tools provide models of the three-dimensional structure of the protein at deletion sites, making it possible to determine whether the mutated protein retains the typical filamentous structure of dystrophin. An analysis of the structure of mutated dystrophin molecules showed that hybrid repeats were reconstituted at the deletion site in some cases. These hybrid repeats harbored the typical triple coiled-coil structure of native repeats, which may be correlated with better function in muscle cells. Conclusion This new database focuses on the dystrophin protein and its modification due to in-frame deletions in BMD patients. The observation of hybrid repeat reconstitution in some cases provides insight into phenotype-genotype correlations in dystrophin diseases and possible strategies for gene therapy. The eDystrophin database is freely available: http://edystrophin.genouest.org/.

Novel dystrophin mutations revealed by analysis of dystrophin mRNA: alternative splicing suppresses the phenotypic effect of a nonsense mutation

Czech Academy of Sciences Publication Activity Database

Fajkusová, L.; Lukáš, Z.; Tvrdíková, M.; Kuhrová, V.; Hájek, J.; Fajkus, Jiří

2001-01-01

Roč. 11, č. 2 (2001), s. 133-138 ISSN 0960-8966 R&D Projects: GA MZd IZ3700; GA MZd NM19; GA MZd NA5227 Institutional research plan: CEZ:AV0Z5004920 Keywords : Duchenne muscular dystrophy * Becker muscular dystrophy * dystrophin mRNA Subject RIV: BO - Biophysics Impact factor: 2.547, year: 2001

Becker muscular dystrophy severity is linked to the structure of dystrophin.

Science.gov (United States)

Nicolas, Aurélie; Raguénès-Nicol, Céline; Ben Yaou, Rabah; Ameziane-Le Hir, Sarah; Chéron, Angélique; Vié, Véronique; Claustres, Mireille; Leturcq, France; Delalande, Olivier; Hubert, Jean-François; Tuffery-Giraud, Sylvie; Giudice, Emmanuel; Le Rumeur, Elisabeth

2015-03-01

In-frame exon deletions of the Duchenne muscular dystrophy (DMD) gene produce internally truncated proteins that typically lead to Becker muscular dystrophy (BMD), a milder allelic disorder of DMD. We hypothesized that differences in the structure of mutant dystrophin may be responsible for the clinical heterogeneity observed in Becker patients and we studied four prevalent in-frame exon deletions, i.e. Δ45-47, Δ45-48, Δ45-49 and Δ45-51. Molecular homology modelling revealed that the proteins corresponding to deletions Δ45-48 and Δ45-51 displayed a similar structure (hybrid repeat) than the wild-type dystrophin, whereas deletions Δ45-47 and Δ45-49 lead to proteins with an unrelated structure (fractional repeat). All four proteins in vitro expressed in a fragment encoding repeats 16-21 were folded in α-helices and remained highly stable. Refolding dynamics were slowed and molecular surface hydrophobicity were higher in fractional repeat containing Δ45-47 and Δ45-49 deletions compared with hybrid repeat containing Δ45-48 and Δ45-51 deletions. By retrospectively collecting data for a series of French BMD patients, we showed that the age of dilated cardiomyopathy (DCM) onset was delayed by 11 and 14 years in Δ45-48 and Δ45-49 compared with Δ45-47 patients, respectively. A clear trend toward earlier wheelchair dependency (minimum of 11 years) was also observed in Δ45-47 and Δ45-49 patients compared with Δ45-48 patients. Muscle dystrophin levels were moderately reduced in most patients without clear correlation with the deletion type. Disease progression in BMD patients appears to be dependent on the deletion itself and associated with a specific structure of dystrophin at the deletion site. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Deletion of Dystrophin In-Frame Exon 5 Leads to a Severe Phenotype: Guidance for Exon Skipping Strategies.

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Zhi Yon Charles Toh

Full Text Available Duchenne and Becker muscular dystrophy severity depends upon the nature and location of the DMD gene lesion and generally correlates with the dystrophin open reading frame. However, there are striking exceptions where an in-frame genomic deletion leads to severe pathology or protein-truncating mutations (nonsense or frame-shifting indels manifest as mild disease. Exceptions to the dystrophin reading frame rule are usually resolved after molecular diagnosis on muscle RNA. We report a moderate/severe Becker muscular dystrophy patient with an in-frame genomic deletion of DMD exon 5. This mutation has been reported by others as resulting in Duchenne or Intermediate muscular dystrophy, and the loss of this in-frame exon in one patient led to multiple splicing events, including omission of exon 6, that disrupts the open reading frame and is consistent with a severe phenotype. The patient described has a deletion of dystrophin exon 5 that does not compromise recognition of exon 6, and although the deletion does not disrupt the reading frame, his clinical presentation is more severe than would be expected for classical Becker muscular dystrophy. We suggest that the dystrophin isoform lacking the actin-binding sequence encoded by exon 5 is compromised, reflected by the phenotype resulting from induction of this dystrophin isoform in mouse muscle in vivo. Hence, exon skipping to address DMD-causing mutations within DMD exon 5 may not yield an isoform that confers marked clinical benefit. Additional studies will be required to determine whether multi-exon skipping strategies could yield more functional dystrophin isoforms, since some BMD patients with larger in-frame deletions in this region have been reported with mild phenotypes.

Studying the role of dystrophin-associated proteins in influencing Becker muscular dystrophy disease severity.

Science.gov (United States)

van den Bergen, J C; Wokke, B H A; Hulsker, M A; Verschuuren, J J G M; Aartsma-Rus, A M

2015-03-01

Becker muscular dystrophy is characterized by a variable disease course. Many factors have been implicated to contribute to this diversity, among which the expression of several components of the dystrophin associated glycoprotein complex. Together with dystrophin, most of these proteins anchor the muscle fiber cytoskeleton to the extracellular matrix, thus protecting the muscle from contraction induced injury, while nNOS is primarily involved in inducing vasodilation during muscle contraction, enabling adequate muscle oxygenation. In the current study, we investigated the role of three components of the dystrophin associated glycoprotein complex (beta-dystroglycan, gamma-sarcoglycan and nNOS) and the dystrophin homologue utrophin on disease severity in Becker patients. Strength measurements, data about disease course and fresh muscle biopsies of the anterior tibial muscle were obtained from 24 Becker patients aged 19 to 66. The designation of Becker muscular dystrophy in this study was based on the mutation and not on the clinical severity. Contrary to previous studies, we were unable to find a relationship between expression of nNOS, beta-dystroglycan and gamma-sarcoglycan at the sarcolemma and disease severity, as measured by muscle strength in five muscle groups and age at reaching several disease milestones. Unexpectedly, we found an inverse correlation between utrophin expression at the sarcolemma and age at reaching disease milestones. Copyright © 2015 Elsevier B.V. All rights reserved.

Intellectual Ability in the Duchenne Muscular Dystrophy and Dystrophin Gene Mutation Location

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Rasic Milic V.

2014-12-01

Full Text Available Duchenne muscular dystrophy (DMD is the most common form of muscular dystrophy during childhood. Mutations in dystrophin (DMD gene are also recognized as a cause of cognitive impairment. We aimed to determine the association between intelligence level and mutation location in DMD genes in Serbian patients with DMD. Forty-one male patients with DMD, aged 3 to 16 years, were recruited at the Clinic for Neurology and Psychiatry for Children and Youth in Belgrade, Serbia. All patients had defined DMD gene deletions or duplications [multiplex ligation- dependent probe amplification (MLPA, polymerase chain reaction (PCR] and cognitive status assessment (Wechsler Intelligence Scale for Children, Brunet-Lezine scale, Vineland-Doll scale. In 37 patients with an estimated full scale intelligence quotient (FSIQ, six (16.22% had borderline intelligence (70dystrophin isoforms and when mutations in the 5’-untranslated region (5’UTR of Dp140 (exons 45-50 were assigned to affect only Dp427 and Dp260. Mutations affecting Dp140 and Dp71/Dp40 have been associated with more frequent and more severe cognitive impairment. Finally, the same classification of mutations explained the greater proportion of FSIQ variability associated with cumulative loss of dystrophin isoforms. In conclusion, cumulative loss of dystrophin isoforms increases the risk of intellectual impairment in DMD and characterizing the genotype can define necessity of early cognitive interventions in DMD patients.

Myoblots: dystrophin quantification by in-cell western assay for a streamlined development of Duchenne muscular dystrophy (DMD) treatments.

Science.gov (United States)

Ruiz-Del-Yerro, E; Garcia-Jimenez, I; Mamchaoui, K; Arechavala-Gomeza, V

2017-10-31

New therapies for neuromuscular disorders are often mutation specific and require to be studied in patient's cell cultures. In Duchenne muscular dystrophy (DMD) dystrophin restoration drugs are being developed but as muscle cell cultures from DMD patients are scarce and do not grow or differentiate well, only a limited number of candidate drugs are tested. Moreover, dystrophin quantification by western blotting requires a large number of cultured cells; so fewer compounds are as thoroughly screened as is desirable. We aimed to develop a quantitative assessment tool using fewer cells to contribute in the study of dystrophin and to identify better drug candidates. An 'in-cell western' assay is a quantitative immunofluorescence assay performed in cell culture microplates that allows protein quantification directly in culture, allowing a higher number of experimental repeats and throughput. We have optimized the assay ('myoblot') to be applied to the study of differentiated myoblast cultures. After an exhaustive optimization of the technique to adapt it to the growth and differentiation rates of our cultures and the low intrinsic expression of our proteins of interests, our myoblot protocol allows the quantification of dystrophin and other muscle-associated proteins in muscle cell cultures. We are able to distinguish accurately between the different sets of patients based on their dystrophin expression and detect dystrophin restoration after treatment. We expect that this new tool to quantify muscle proteins in DMD and other muscle disorders will aid in their diagnosis and in the development of new therapies. © 2017 British Neuropathological Society.

Gene therapies that restore dystrophin expression for the treatment of Duchenne muscular dystrophy

Science.gov (United States)

Robinson-Hamm, Jacqueline N.; Gersbach, Charles A.

2016-01-01

Duchenne muscular dystrophy is one of the most common inherited genetic diseases and is caused by mutations to the DMD gene that encodes the dystrophin protein. Recent advances in genome editing and gene therapy offer hope for the development of potential therapeutics. Truncated versions of the DMD gene can be delivered to the affected tissues with viral vectors and show promising results in a variety of animal models. Genome editing with the CRISPR/Cas9 system has recently been used to restore dystrophin expression by deleting one or more exons of the DMD gene in patient cells and in a mouse model that led to functional improvement of muscle strength. Exon skipping with oligonucleotides has been successful in several animal models and evaluated in multiple clinical trials. Next-generation oligonucleotide formulations offer significant promise to build on these results. All these approaches to restoring dystrophin expression are encouraging, but many hurdles remain. This review summarizes the current state of these technologies and summarizes considerations for their future development. PMID:27542949

Characterization of genetic deletions in Becker muscular dystrophy using monoclonal antibodies against a deletion-prone region of dystrophin

Energy Technology Data Exchange (ETDEWEB)

Thanh, L.T.; Man, Nguyen Thi; Morris, G.E. [Wales Institute, Clwyd (United Kingdom)] [and others

1995-08-28

We have produced a new panel of 20 monoclonal antibodies (mAbs) against a region of the dystrophin protein corresponding to a deletion-prone region of the Duchenne muscular dystrophy gene (exons 45-50). We show that immunohistochemistry or Western blotting with these {open_quotes}exon-specific{close_quotes} mAbs can provide a valuable addition to Southern blotting or PCR methods for the accurate identification of genetic deletions in Becker muscular dystrophy patients. The antibodies were mapped to the following exons: exon 45 (2 mAbs), exon 46 (6), exon 47 (1), exons 47/48 (4), exons 48-50 (6), and exon 50 (1). PCR amplification of single exons or groups of exons was used both to produce specific dystrophin immunogens and to map the mAbs obtained. PCR-mediated mutagenesis was also used to identify regions of dystrophin important for mAb binding. Because the mAbs can be used to characterize the dystrophin produced by individual muscle fibres, they will also be useful for studying {open_quotes}revertant{close_quotes} fibres in Duchenne muscle and for monitoring the results of myoblast therapy trials in MD patients with deletions in this region of the dystrophin gene. 27 refs., 7 figs., 3 tabs.

Dual exon skipping in myostatin and dystrophin for Duchenne muscular dystrophy

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van Ommen Gert Jan B

2011-04-01

Full Text Available Abstract Background Myostatin is a potent muscle growth inhibitor that belongs to the Transforming Growth Factor-β (TGF-β family. Mutations leading to non functional myostatin have been associated with hypermuscularity in several organisms. By contrast, Duchenne muscular dystrophy (DMD is characterized by a loss of muscle fibers and impaired regeneration. In this study, we aim to knockdown myostatin by means of exon skipping, a technique which has been successfully applied to reframe the genetic defect of dystrophin gene in DMD patients. Methods We targeted myostatin exon 2 using antisense oligonucleotides (AON in healthy and DMD-derived myotubes cultures. We assessed the exon skipping level, transcriptional expression of myostatin and its target genes, and combined myostatin and several dystrophin AONs. These AONs were also applied in the mdx mice models via intramuscular injections. Results Myostatin AON induced exon 2 skipping in cell cultures and to a lower extent in the mdx mice. It was accompanied by decrease in myostatin mRNA and enhanced MYOG and MYF5 expression. Furthermore, combination of myostatin and dystrophin AONs induced simultaneous skipping of both genes. Conclusions We conclude that two AONs can be used to target two different genes, MSTN and DMD, in a straightforward manner. Targeting multiple ligands of TGF-beta family will be more promising as adjuvant therapies for DMD.

Viking stranger kings

DEFF Research Database (Denmark)

Dobat, Andres S.

2015-01-01

as a materialization of a stranger king myth, with the ship‐setting reproducing the narrative of the founding of the dynasty by an immigrant forefather, and the burial mounds conveying the idea of the foreign king taking possession of the locals’ land. In a broader erspective, the stranger king concept and the special...

ADAM12 overexpression does not improve outcome in mice with laminin alpha2-deficient muscular dystrophy

DEFF Research Database (Denmark)

Guo, Ling T; Shelton, G Diane; Wewer, Ulla M

2005-01-01

We have recently shown that overexpression of ADAM12 results in increased muscle regeneration and significantly reduced pathology in mdx, dystrophin deficient mice. In the present study, we tested the effect of overexpressing ADAM12 in dy(W) laminin-deficient mice. dy mice have a very severe...... clinical phenotype and would be expected to benefit greatly from enhanced regeneration. We found that dy(W) mice overexpressing ADAM12 indeed have increased muscle regeneration, as evidenced by increased numbers of muscle fibers expressing fetal myosin. However, overexpression of ADAM12 had no significant...

Nanopolymers improve delivery of exon skipping oligonucleotides and concomitant dystrophin expression in skeletal muscle of mdx mice

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Sirsi Shashank R

2008-04-01

Full Text Available Abstract Background Exon skipping oligonucleotides (ESOs of 2'O-Methyl (2'OMe and morpholino chemistry have been shown to restore dystrophin expression in muscle fibers from the mdx mouse, and are currently being tested in phase I clinical trials for Duchenne Muscular Dystrophy (DMD. However, ESOs remain limited in their effectiveness because of an inadequate delivery profile. Synthetic cationic copolymers of poly(ethylene imine (PEI and poly(ethylene glycol (PEG are regarded as effective agents for enhanced delivery of nucleic acids in various applications. Results We examined whether PEG-PEI copolymers can facilitate ESO-mediated dystrophin expression after intramuscular injections into tibialis anterior (TA muscles of mdx mice. We utilized a set of PEG-PEI copolymers containing 2 kDa PEI and either 550 Da or 5 kDa PEG, both of which bind 2'OMe ESOs with high affinity and form stable nanoparticulates with a relatively low surface charge. Three weekly intramuscular injections of 5 μg of ESO complexed with PEI2K-PEG550 copolymers resulted in about 500 dystrophin-positive fibers and about 12% of normal levels of dystrophin expression at 3 weeks after the initial injection, which is significantly greater than for injections of ESO alone, which are known to be almost completely ineffective. In an effort to enhance biocompatibility and cellular uptake, the PEI2K-PEG550 and PEI2K-PEG5K copolymers were functionalized by covalent conjugation with nanogold (NG or adsorbtion of colloidal gold (CG, respectively. Surprisingly, using the same injection and dosing regimen, we found no significant difference in dystrophin expression by Western blot between the NG-PEI2K-PEG550, CG-PEI2K-PEG5K, and non-functionalized PEI2K-PEG550 copolymers. Dose-response experiments using the CG-PEI2K-PEG5K copolymer with total ESO ranging from 3–60 μg yielded a maximum of about 15% dystrophin expression. Further improvements in dystrophin expression up to 20% of normal

Context Dependent Effects of Chimeric Peptide Morpholino Conjugates Contribute to Dystrophin Exon-skipping Efficiency.

Science.gov (United States)

Yin, Haifang; Boisguerin, Prisca; Moulton, Hong M; Betts, Corinne; Seow, Yiqi; Boutilier, Jordan; Wang, Qingsong; Walsh, Anthony; Lebleu, Bernard; Wood, Matthew Ja

2013-09-24

We have recently reported that cell-penetrating peptides (CPPs) and novel chimeric peptides containing CPP (referred as B peptide) and muscle-targeting peptide (referred as MSP) motifs significantly improve the systemic exon-skipping activity of morpholino phosphorodiamidate oligomers (PMOs) in dystrophin-deficient mdx mice. In the present study, the general mechanistic significance of the chimeric peptide configuration on the activity and tissue uptake of peptide conjugated PMOs in vivo was investigated. Four additional chimeric peptide-PMO conjugates including newly identified peptide 9 (B-9-PMO and 9-B-PMO) and control peptide 3 (B-3-PMO and 3-B-PMO) were tested in mdx mice. Immunohistochemical staining, RT-PCR and western blot results indicated that B-9-PMO induced significantly higher level of exon skipping and dystrophin restoration than its counterpart (9-B-PMO), further corroborating the notion that the activity of chimeric peptide-PMO conjugates is dependent on relative position of the tissue-targeting peptide motif within the chimeric peptide with respect to PMOs. Subsequent mechanistic studies showed that enhanced cellular uptake of B-MSP-PMO into muscle cells leads to increased exon-skipping activity in comparison with MSP-B-PMO. Surprisingly, further evidence showed that the uptake of chimeric peptide-PMO conjugates of both orientations (B-MSP-PMO and MSP-B-PMO) was ATP- and temperature-dependent and also partially mediated by heparan sulfate proteoglycans (HSPG), indicating that endocytosis is likely the main uptake pathway for both chimeric peptide-PMO conjugates. Collectively, our data demonstrate that peptide orientation in chimeric peptides is an important parameter that determines cellular uptake and activity when conjugated directly to oligonucleotides. These observations provide insight into the design of improved cell targeting compounds for future therapeutics studies.Molecular Therapy-Nucleic Acids (2013) 2, e124; doi:10.1038/mtna.2013

Context Dependent Effects of Chimeric Peptide Morpholino Conjugates Contribute to Dystrophin Exon-skipping Efficiency

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HaiFang Yin

2013-01-01

Full Text Available We have recently reported that cell-penetrating peptides (CPPs and novel chimeric peptides containing CPP (referred as B peptide and muscle-targeting peptide (referred as MSP motifs significantly improve the systemic exon-skipping activity of morpholino phosphorodiamidate oligomers (PMOs in dystrophin-deficient mdx mice. In the present study, the general mechanistic significance of the chimeric peptide configuration on the activity and tissue uptake of peptide conjugated PMOs in vivo was investigated. Four additional chimeric peptide-PMO conjugates including newly identified peptide 9 (B-9-PMO and 9-B-PMO and control peptide 3 (B-3-PMO and 3-B-PMO were tested in mdx mice. Immunohistochemical staining, RT-PCR and western blot results indicated that B-9-PMO induced significantly higher level of exon skipping and dystrophin restoration than its counterpart (9-B-PMO, further corroborating the notion that the activity of chimeric peptide-PMO conjugates is dependent on relative position of the tissue-targeting peptide motif within the chimeric peptide with respect to PMOs. Subsequent mechanistic studies showed that enhanced cellular uptake of B-MSP-PMO into muscle cells leads to increased exon-skipping activity in comparison with MSP-B-PMO. Surprisingly, further evidence showed that the uptake of chimeric peptide-PMO conjugates of both orientations (B-MSP-PMO and MSP-B-PMO was ATP- and temperature-dependent and also partially mediated by heparan sulfate proteoglycans (HSPG, indicating that endocytosis is likely the main uptake pathway for both chimeric peptide-PMO conjugates. Collectively, our data demonstrate that peptide orientation in chimeric peptides is an important parameter that determines cellular uptake and activity when conjugated directly to oligonucleotides. These observations provide insight into the design of improved cell targeting compounds for future therapeutics studies.

Complete restoration of multiple dystrophin isoforms in genetically corrected Duchenne muscular dystrophy patient–derived cardiomyocytes

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Susi Zatti

2014-01-01

Full Text Available Duchenne muscular dystrophy (DMD–associated cardiac diseases are emerging as a major cause of morbidity and mortality in DMD patients, and many therapies for treatment of skeletal muscle failed to improve cardiac function. The reprogramming of patients' somatic cells into pluripotent stem cells, combined with technologies for correcting the genetic defect, possesses great potential for the development of new treatments for genetic diseases. In this study, we obtained human cardiomyocytes from DMD patient–derived, induced pluripotent stem cells genetically corrected with a human artificial chromosome carrying the whole dystrophin genomic sequence. Stimulation by cytokines was combined with cell culturing on hydrogel with physiological stiffness, allowing an adhesion-dependent maturation and a proper dystrophin expression. The obtained cardiomyocytes showed remarkable sarcomeric organization of cardiac troponin T and α-actinin, expressed cardiac-specific markers, and displayed electrically induced calcium transients lasting less than 1 second. We demonstrated that the human artificial chromosome carrying the whole dystrophin genomic sequence is stably maintained throughout the cardiac differentiation process and that multiple promoters of the dystrophin gene are properly activated, driving expression of different isoforms. These dystrophic cardiomyocytes can be a valuable source for in vitro modeling of DMD-associated cardiac disease. Furthermore, the derivation of genetically corrected, patient-specific cardiomyocytes represents a step toward the development of innovative cell and gene therapy approaches for DMD.

Single Cell Analysis of Dystrophin and SRY Gene by Using Whole Genome Amplification

Institute of Scientific and Technical Information of China (English)

徐晨明; 金帆; 黄荷凤; 陶冶; 叶英辉

2001-01-01

Objective To develop a reliable and sensitive method for detection of sex and multiloci of Duchenne muscular dystrophy (DMD) gene in single cell Materials & methods Whole genome of single cell were amplified by using 15-base random primers (primer extension preamplification, PEP), then a small aliquot of PEP product were analyzed by using locus-specific nest PCR amplification. The procedure was evaluated by detection dystrophin exons 8, 17, 19, 44, 45, 48 and human testis-determining gene (SRY)in single lymphocytes from known sources and single blastomeres from the couples with no family history of DMD.Results The amplification efficiency rate of six dystrophin exons from single lymphocytes and single blastomeres were 97. 2% (175/180) and 100% (60/60) respectively.Results of SRY showed that 100% (15/15) amplification in single male-derived lymphocytes and 0% (0/15) amplification in single female-derived lymphocytes. Conclusion The technique of single cell PEP-nest PCR for dystrophin exons 8, 17,19, 44, 45, 48 and SRY is highly specifc. PEP-nest PCR is suitable for Preimplantation genetic diagnosis (PGD) of DMD at single cell level.

Screening of Dystrophin Gene Deletions in Egyptian Patients with DMD/BMD Muscular Dystrophies

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Laila K. Effat

2000-01-01

Full Text Available Duchenne muscular dystrophy (DMD and Becker muscular dystrophy (BMD are allelic disorders caused by mutations within the dystrophin gene. Our study has identified 100 Egyptian families collected from the Human Genetics Clinic, National Research Center, Cairo. All cases were subjected to complete clinical evaluation pedigree analysis, electromyography studies, estimation of serum creatine phosphokinase enzyme (CPK levels and DNA analysis. Multiplex PCR using 18 pairs of specific primers were used for screening of deletion mutations within the dystrophin gene. A frequency of 55% among the families. Sixty per cent of detected deletions involved multiple exons spanning the major or the minor hot spot of the dystrophin gene. The remainder 40% which mainly involved exon 45. Comparing these findings with frequencies of other countries it was found that our figures fall within the reported range of 40%– for deletions. The distribution of deletions in our study and other different studies was variable and specific ethnic differences do not apparently account for specific deletions. In addition this study concluded that employment of the 18 exon analysis is a cost effective and a highly accurate (97% to launch a nationwide program.

Phase 2a study of ataluren-mediated dystrophin production in patients with nonsense mutation Duchenne muscular dystrophy.

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Richard S Finkel

Full Text Available Approximately 13% of boys with Duchenne muscular dystrophy (DMD have a nonsense mutation in the dystrophin gene, resulting in a premature stop codon in the corresponding mRNA and failure to generate a functional protein. Ataluren (PTC124 enables ribosomal readthrough of premature stop codons, leading to production of full-length, functional proteins.This Phase 2a open-label, sequential dose-ranging trial recruited 38 boys with nonsense mutation DMD. The first cohort (n = 6 received ataluren three times per day at morning, midday, and evening doses of 4, 4, and 8 mg/kg; the second cohort (n = 20 was dosed at 10, 10, 20 mg/kg; and the third cohort (n = 12 was dosed at 20, 20, 40 mg/kg. Treatment duration was 28 days. Change in full-length dystrophin expression, as assessed by immunostaining in pre- and post-treatment muscle biopsy specimens, was the primary endpoint.Twenty three of 38 (61% subjects demonstrated increases in post-treatment dystrophin expression in a quantitative analysis assessing the ratio of dystrophin/spectrin. A qualitative analysis also showed positive changes in dystrophin expression. Expression was not associated with nonsense mutation type or exon location. Ataluren trough plasma concentrations active in the mdx mouse model were consistently achieved at the mid- and high- dose levels in participants. Ataluren was generally well tolerated.Ataluren showed activity and safety in this short-term study, supporting evaluation of ataluren 10, 10, 20 mg/kg and 20, 20, 40 mg/kg in a Phase 2b, double-blind, long-term study in nonsense mutation DMD.ClinicalTrials.gov NCT00264888.

mRNA and microRNA transcriptomics analyses in a murine model of dystrophin loss and therapeutic restoration

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Thomas C. Roberts

2016-03-01

Full Text Available Duchenne muscular dystrophy (DMD is a pediatric, X-linked, progressive muscle-wasting disorder caused by loss of function mutations affecting the gene encoding the dystrophin protein. While the primary genetic insult in DMD is well described, many details of the molecular and cellular pathologies that follow dystrophin loss are incompletely understood. To investigate gene expression in dystrophic muscle we have applied mRNA and microRNA (miRNA microarray technology to the mdx mouse model of DMD. This study was designed to generate a complete description of gene expression changes associated with dystrophic pathology and the response to an experimental therapy which restores dystrophin protein function. These datasets have enabled (1 the determination of gene expression changes associated with dystrophic pathology, (2 identification of differentially expressed genes that are restored towards wild-type levels after therapeutic dystrophin rescue, (3 investigation of the correlation between mRNA and protein expression (determined by parallel mass spectrometry proteomics analysis, and (4 prediction of pathology associated miRNA-target interactions. Here we describe in detail how the data were generated including the basic analysis as contained in the manuscript published in Human Molecular Genetics with PMID 26385637. The data have been deposited in the Gene Expression Omnibus (GEO with the accession number GSE64420.

Becker muscular dystrophy due to an intronic splicing mutation inducing a dual dystrophin transcript.

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Todeschini, Alice; Gualandi, Francesca; Trabanelli, Cecilia; Armaroli, Annarita; Ravani, Anna; Fanin, Marina; Rota, Silvia; Bello, Luca; Ferlini, Alessandra; Pegoraro, Elena; Padovani, Alessandro; Filosto, Massimiliano

2016-10-01

We describe a 29-year-old patient who complained of left thigh muscle weakness since he was 23 and of moderate proximal weakness of both lower limbs with difficulty in climbing stairs and running since he was 27. Mild weakness of iliopsoas and quadriceps muscles and muscle atrophy of both the distal forearm and thigh were observed upon clinical examination. He harboured a novel c.1150-3C>G substitution in the DMD gene, affecting the intron 10 acceptor splice site and causing exon 11 skipping and an out-of-frame transcript. However, protein of normal molecular weight but in reduced amounts was observed on Western Blot analysis. Reverse transcription analysis on muscle RNA showed production, via alternative splicing, of a transcript missing exon 11 as well as a low abundant full-length transcript which is enough to avoid the severe Duchenne phenotype. Our study showed that a reduced amount of full length dystrophin leads to a mild form of Becker muscular dystrophy. These results confirm earlier findings that low amounts of dystrophin can be associated with a milder phenotype, which is promising for therapies aiming at dystrophin restoration. Copyright © 2016 Elsevier B.V. All rights reserved.

Duchenne muscular dystrophy diagnosed by dystrophin gene deletion test: A case report

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Rathod Kishor G, Dawre Rahul M, Kamble Milind B,Tambe Saleem H

2014-04-01

Full Text Available Duchenne muscular dystrophy (DMD is an X-linked recessive disease affecting 1 in 3600—6000 live male births. A muscle biopsy is not necessary if a genetic diagnosis is secured first, particularly as some families might view the procedure as traumatic. DMD occurs as a result of mutations (mainly deletions in the dystrophin gene (DMD; locus Xp21.2. Mutations lead to an absence of or defect in the protein dystrophin, which results in progressive muscle degeneration leading to loss of independent ambulation. Ninety percent of out frame mutations result in DMD, while 90% of in-frame mutations result in BMD. Electron microscopy is not required to confirm DMD. Genetic testing is mandatory irrespective of biopsy results. But the muscle biopsy is not required if the diagnosis is secured first by genetic testing.

A case report: Becker muscular dystrophy presenting with epilepsy and dysgnosia induced by duplication mutation of Dystrophin gene.

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Miao, Jing; Feng, Jia-Chun; Zhu, Dan; Yu, Xue-Fan

2016-12-12

Becker muscular dystrophy (BMD), a genetic disorder of X-linked recessive inheritance, typically presents with gradually progressive muscle weakness. The condition is caused by mutations of Dystrophin gene located at Xp21.2. Epilepsy is an infrequent manifestation of BMD, while cases of BMD with dysgnosia are extremely rare. We describe a 9-year-old boy with BMD, who presented with epilepsy and dysgnosia. Serum creatine kinase level was markedly elevated (3665 U/L). Wechsler intelligence tests showed a low intelligence quotient (IQ = 65). Electromyogram showed slight myogenic changes and skeletal muscle biopsy revealed muscular dystrophy. Immunohistochemical staining showed partial positivity of sarcolemma for dystrophin-N. Multiplex ligation-dependent probe amplification revealed a duplication mutation in exons 37-44 in the Dystrophin gene. The present case report helps to better understand the clinical and genetic features of BMD.

Use of capillary Western immunoassay (Wes) for quantification of dystrophin levels in skeletal muscle of healthy controls and individuals with Becker and Duchenne muscular dystrophy.

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Beekman, Chantal; Janson, Anneke A; Baghat, Aabed; van Deutekom, Judith C; Datson, Nicole A

2018-01-01

Duchenne muscular dystrophy (DMD) is a neuromuscular disease characterized by progressive weakness of the skeletal and cardiac muscles. This X-linked disorder is caused by open reading frame disrupting mutations in the DMD gene, resulting in strong reduction or complete absence of dystrophin protein. In order to use dystrophin as a supportive or even surrogate biomarker in clinical studies on investigational drugs aiming at correcting the primary cause of the disease, the ability to reliably quantify dystrophin expression in muscle biopsies of DMD patients pre- and post-treatment is essential. Here we demonstrate the application of the ProteinSimple capillary immunoassay (Wes) method, a gel- and blot-free method requiring less sample, antibody and time to run than conventional Western blot assay. We optimized dystrophin quantification by Wes using 2 different antibodies and found it to be highly sensitive, reproducible and quantitative over a large dynamic range. Using a healthy control muscle sample as a reference and α-actinin as a protein loading/muscle content control, a panel of skeletal muscle samples consisting of 31 healthy controls, 25 Becker Muscle dystrophy (BMD) and 17 DMD samples was subjected to Wes analysis. In healthy controls dystrophin levels varied 3 to 5-fold between the highest and lowest muscle samples, with the reference sample representing the average of all 31 samples. In BMD muscle samples dystrophin levels ranged from 10% to 90%, with an average of 33% of the healthy muscle average, while for the DMD samples the average dystrophin level was 1.3%, ranging from 0.7% to 7% of the healthy muscle average. In conclusion, Wes is a suitable, efficient and reliable method for quantification of dystrophin expression as a biomarker in DMD clinical drug development.

Why do people buy dogs with potential welfare problems related to extreme conformation and inherited disease? A representative study of Danish owners of four small dog breeds.

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Sandøe, P; Kondrup, S V; Bennett, P C; Forkman, B; Meyer, I; Proschowsky, H F; Serpell, J A; Lund, T B

2017-01-01

A number of dog breeds suffer from welfare problems due to extreme phenotypes and high levels of inherited diseases but the popularity of such breeds is not declining. Using a survey of owners of two popular breeds with extreme physical features (French Bulldog and Chihuahua), one with a high load of inherited diseases not directly related to conformation (Cavalier King Charles Spaniel), and one representing the same size range but without extreme conformation and with the same level of disease as the overall dog population (Cairn Terrier), we investigated this seeming paradox. We examined planning and motivational factors behind acquisition of the dogs, and whether levels of experienced health and behavior problems were associated with the quality of the owner-dog relationship and the intention to re-procure a dog of the same breed. Owners of each of the four breeds (750/breed) were randomly drawn from a nationwide Danish dog registry and invited to participate. Of these, 911 responded, giving a final sample of 846. There were clear differences between owners of the four breeds with respect to degree of planning prior to purchase, with owners of Chihuahuas exhibiting less. Motivations behind choice of dog were also different. Health and other breed attributes were more important to owners of Cairn Terriers, whereas the dog's personality was reported to be more important for owners of French Bulldogs and Cavalier King Charles Spaniels but less important for Chihuahua owners. Higher levels of health and behavior problems were positively associated with a closer owner-dog relationship for owners of Cavalier King Charles Spaniels and Chihuahuas but, for owners of French Bulldogs, high levels of problems were negatively associated with an intention to procure the same breed again. In light of these findings, it appears less paradoxical that people continue to buy dogs with welfare problems.

The King Tapestries at Kronborg Castle

DEFF Research Database (Denmark)

Reindel, Ulrik

2015-01-01

In the 1580s, Frederik II (Danish-Norwegian king, reigned 1559-1588) had the Great Hall at Kronborg Castle, Elsinore, furnished with 43 tapestries portraying no fewer than 100 Danish kings. The tapestries were arranged chronologically, beginning with King Dan, the mythological founder of the king...

Modulation of splicing of the preceding intron by antisense oligonucleotide complementary to intra-exon sequence deleted in dystrophin Kobe

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Takeshima, Y.; Matuso, M.; Sakamoto, H.; Nishio, H. [Kobe Univ. School of Medicine and Science (Japan)

1994-09-01

Molecular analysis of dystrophin Kobe showed that exon 19 of the dystrophin gene bearing a 52 bp deletion was skipped during splicing, although the known consensus sequences at the 5{prime} and 3{prime} splice site of exon 19 were maintained. These data suggest that the deleted sequence of exon 19 may function as a cis-acting factor for exact splicing for the upstream intron. To investigate this potential role, an in vitro splicing system using dystrophin precursors was established. A two-exon precursor containing exon 18, truncated intron 18, and exon 19 was accurately spliced. However, splicing of intron 18 was dramatically inhibited when wild exon 19 was replaced with mutated exon 19. Even though the length of exon 19 was restored to normal by replacing the deleted sequence with other sequence, splicing of intron 18 was not fully reactivated. Characteristically, splicing of intron 18 was inactivated more markedly when the replaced sequence contained less polypurine stretches. These data suggested that modification of the exon sequence would result in a splicing abnormality. Antisense 31 mer 2`-O-methyl ribonucleotide was targeted against 5{prime} end of deleted region of exon 19 to modulate splicing of the mRNA precursor. Splicing of intron 18 was inhibited in a dose- and time-dependent manner. This is the first in vitro evidence to show splicing of dystrophin pre-mRNA can be managed by antisense oligonucleotides. These experiments represent an approach in which antisense oligonucleotides are used to restore the function of a defective dystrophin gene in Duchenne muscular dystrophy by inducing skipping of certain exons during splicing.

Targeting artificial transcription factors to the utrophin A promoter: effects on dystrophic pathology and muscle function.

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Lu, Yifan; Tian, Chai; Danialou, Gawiyou; Gilbert, Rénald; Petrof, Basil J; Karpati, George; Nalbantoglu, Josephine

2008-12-12

Duchenne muscular dystrophy is caused by a genetic defect in the dystrophin gene. The absence of dystrophin results in muscle fiber necrosis and regeneration, leading to progressive muscle fiber loss. Utrophin is a close analogue of dystrophin. A substantial, ectopic expression of utrophin in the extrasynaptic sarcolemma of dystrophin-deficient muscle fibers can prevent deleterious effects of dystrophin deficiency. An alternative approach for the extrasynaptic up-regulation of utrophin involves the augmentation of utrophin transcription via the endogenous utrophin A promoter using custom-designed transcriptional activator proteins with zinc finger (ZFP) motifs. We tested a panel of custom-designed ZFP for their ability to activate the utrophin A promoter. Expression of one such ZFP efficiently increased, in a time-dependent manner, utrophin transcript and protein levels both in vitro and in vivo. In dystrophic mouse (mdx) muscles, administration of adenoviral vectors expressing this ZFP led to significant enhancement of muscle function with decreased necrosis, restoration of the dystrophin-associated proteins, and improved resistance to eccentric contractions. These studies provide evidence that specifically designed ZFPs can act as strong transcriptional activators of the utrophin A promoter. These may thus serve as attractive therapeutic agents for dystrophin deficiency states such as Duchenne muscular dystrophy.

[King Injo's disease and burnt needle therapy].

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Kim, In-Sook

2004-12-01

This paper investigates an interrelationship between burnt needle therapy and King Injo's disease. From 1633 (Year 11 in King Injo's reign) to May 5, 1649 (Year 27 in King Injo's reign), right before his death, King Injo was treated with burnt needles by Yi Hyeongik, an acupuncturist when the king had health problems. This study arises from two questions: why was King Injo often treated with burnt needles? and what effect did burnt needles have?Burnt needle therapy is a combined form of acupuncture and moxibustion. Yi Hyeongik was famous for eradicating pathogenic factors. He was appointed as a doctor in the Royal Hospital. The medical definition for pathogenic factors is that they are disease-causing factors. Understanding the pathogenic factor for King Injo's disease could make it possible to find the interrelationship between burnt needles and the king's disease. In the Joseon ear, the prevalent belief about diseases was that diseases could be caused by homeopathic magic. Some people thought homeopathic magic caused King Injo's disease. The actual reasons for King Injo's disease were the participation in the excessive rites of Queen Mother Inmok's funeral and the constant oppression from the Ching Dynasty after disgraceful defeat in the war. When King Injo started to be sick, homeopathic magic cases were found in the royal palace. The king's incurable disease was believed to have happened as a result of homeopathic magic. King Injo's suspicion toward Princess Jeongmyeong derived from her mother, Queen Mother Inmok. Moral justification for King Injo's coup was Gwanghaegun or Prince Gwanghae's immoral conduct toward Queen Mothe Inmok. After he was installed, King Injo obeyed the Queen Mother and showed her every attention. Meanwhile, he treated Princess Jeongmyeong with respect, maximized the moral justification for the coup, and solidified the royal authority. However, constant rebellions and treasons threatened King Injo. The king suspected that Queen Mother

God our king

African Journals Online (AJOL)

p1243322

metaphor of king is used with a realistic claim in the Biblical texts and in the. Christian ..... love their king, whatever emotional bond there might occasionally be between them. .... green” and it would be senseless to ask what kind of power God has. It does ... attitude and behavior towards God, the focus here will be on God.

The True Lion King of Africa: The Epic History of Sundiata, King of Old Mali.

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Paterno, Domenica R.

David Wisniewski's 1992 picture book version of the African epic of "Sundiata, Lion King of Mali" and the actual historical account of the 13th century Lion King, Sundiata, are both badly served by Disney's "The Lion King." Disney has been praised for using African animals as story characters; for using the African landscape as…

King Injo's Disease and Burnt Needle Therapy

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KIM In-Sook

2004-12-01

Full Text Available This paper investigates an interrelationship between burnt needle therapy(번침 and King Injo'sdisease. From 1633 (Year 11 in King Injo's reign to May 5, 1649 (Year 27 King in Injo's reign, right before his death, King Injo(인조 was treated with burnt needles by Yi Hyeongik(이형익, an acupuncturist when the king had health problems. This study arises from two questions: why was King Injo often treated with burnt needles? and what effect did burnt needles have? Burnt needle therapy is a combined form of acupuncture and moxibustion. Yi Hyeongik was famous for eradicating pathogenic factors. He was appointed as a doctor in the Royal Hospital. The medical definition for pathogenic factors is that they are disease-causing factors. Understanding the pathogenic factor for King Injo's disease could make it possible to find the interrelationship between burnt needles and the king's disease. In the Joseon era, the prevalent belief about diseases was that diseases could be caused by homeopathic magic. Some people thought homeopathic magic caused King Injo's disease.　 The actual reasons for King Injo's disease were the participation in the excessive rites of Queen Mother Inmok's funeral and the constant oppression from the Ching Dynasty after disgraceful defeat in the war. When King Injo started to be sick, homeopathic magic cases were found in the royal palace. The king's incurable disease was believed to have happened as a result of homeopathic magic. King Injo's suspicion toward Princess Jeongmyeong(정명공주 derived from her mother, Queen Mother Inmok(인목대비. Moral justification for King Injo's coup was Gwanghaegun(광해군 or Prince Gwanghae's immoral conduct toward Queen Mother Inmok. After he was installed, King Injo obeyed the Queen Mother and showed her every attention. Meanwhile, he treated Princess Jeongmyeong with respect, maximized the moral justification for the coup, and solidified the royal authority. However, constant

Adhalin, the 50 kD dystrophin associated protein, is not the locus for severe childhood autosomal recessive dystrophy (SCARMD)

Energy Technology Data Exchange (ETDEWEB)

McNally, E.M.; Selig, S.; Kunkel, L.M. [Children`s Hospital, Boston, MA (United States)

1994-09-01

Mutations in the carboxyl-terminus in dystrophin are normally sufficient to produce severely dystrophic muscle. This portion of dystrophin binds a complex of dystrophin-associated glycoproteins (DAGs). The genes encoding these DAGs are candidate genes for causing neuromuscular disease. Immunoreactivity for adhalin, the 50 kD DAG, is absent in muscle biopsies from patients with SCARMD, a form of dystrophy clinically similar Duchenne muscular dystrophy. Prior linkage analysis in SCARMD families revealed that the disease gene segregates with markers on chromosome 13. To determine the molecular role that adhalin may play in SCARMD, human cDNA and genomic sequences were isolated. Primers were designed based on predicted areas of conservation in rabbit adhalin and used in RT-PCR with human skeletal and cardiac muscle. RT-PCR products were confirmed by sequence as human adhalin and then used as probes for screening human cDNA and genomic libraries. Human and rabbit adhalin are 90% identical, and among the cDNAs, a novel splice form of adhalin was seen which may encode part of the 35 kD component of the dystrophin-glycoprotein complex. To our surprise, only human/rodent hybrids containing human chromosome 17 amplified adhalin sequences in a PCR analysis. FISH analysis with three overlapping genomic sequences confirmed the chromosome 17 location and further delineated the map position to 17q21. Therefore, adhalin is excluded as the gene causing SCARMD.

Dual AAV Gene Therapy for Duchenne Muscular Dystrophy with a 7-kb Mini-Dystrophin Gene in the Canine Model.

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Kodippili, Kasun; Hakim, Chady H; Pan, Xiufang; Yang, Hsiao T; Yue, Yongping; Zhang, Yadong; Shin, Jin-Hong; Yang, N Nora; Duan, Dongsheng

2018-03-01

Dual adeno-associated virus (AAV) technology was developed in 2000 to double the packaging capacity of the AAV vector. The proof of principle has been demonstrated in various mouse models. Yet, pivotal evidence is lacking in large animal models of human diseases. Here we report expression of a 7-kb canine ΔH2-R15 mini-dystrophin gene using a pair of dual AAV vectors in the canine model of Duchenne muscular dystrophy (DMD). The ΔH2-R15 minigene is by far the most potent synthetic dystrophin gene engineered for DMD gene therapy. We packaged minigene dual vectors in Y731F tyrosine-modified AAV-9 and delivered to the extensor carpi ulnaris muscle of a 12-month-old affected dog at the dose of 2 × 10 13 viral genome particles/vector/muscle. Widespread mini-dystrophin expression was observed 2 months after gene transfer. The missing dystrophin-associated glycoprotein complex was restored. Treatment also reduced muscle degeneration and fibrosis and improved myofiber size distribution. Importantly, dual AAV therapy greatly protected the muscle from eccentric contraction-induced force loss. Our data provide the first clear evidence that dual AAV therapy can be translated to a diseased large mammal. Further development of dual AAV technology may lead to effective therapies for DMD and many other diseases in human patients.

Contribution of oxidative stress to pathology in diaphragm and limb muscles with Duchenne muscular dystrophy.

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Kim, Jong-Hee; Kwak, Hyo-Bum; Thompson, LaDora V; Lawler, John M

2013-02-01

Duchenne muscular dystrophy (DMD) is a degenerative skeletal muscle disease that makes walking and breathing difficult. DMD is caused by an X-linked (Xp21) mutation in the dystrophin gene. Dystrophin is a scaffolding protein located in the sarcolemmal cytoskeleton, important in maintaining structural integrity and regulating muscle cell (muscle fiber) growth and repair. Dystrophin deficiency in mouse models (e.g., mdx mouse) destabilizes the interface between muscle fibers and the extracellular matrix, resulting in profound damage, inflammation, and weakness in diaphragm and limb muscles. While the link between dystrophin deficiency with inflammation and pathology is multi-factorial, elevated oxidative stress has been proposed as a central mediator. Unfortunately, the use of non-specific antioxidant scavengers in mouse and human studies has led to inconsistent results, obscuring our understanding of the importance of redox signaling in pathology of muscular dystrophy. However, recent studies with more mechanistic approaches in mdx mice suggest that NAD(P)H oxidase and nuclear factor-kappaB are important in amplifying dystrophin-deficient muscle pathology. Therefore, more targeted antioxidant therapeutics may ameliorate damage and weakness in human population, thus promoting better muscle function and quality of life. This review will focus upon the pathobiology of dystrophin deficiency in diaphragm and limb muscle primarily in mouse models, with a rationale for development of targeted therapeutic antioxidants in DMD patients.

Long-term rescue of dystrophin expression and improvement in muscle pathology and function in dystrophic mdx mice by peptide-conjugated morpholino.

Science.gov (United States)

Wu, Bo; Lu, Peijuan; Cloer, Caryn; Shaban, Mona; Grewal, Snimar; Milazi, Stephanie; Shah, Sapana N; Moulton, Hong M; Lu, Qi Long

2012-08-01

Exon skipping is capable of correcting frameshift and nonsense mutations in Duchenne muscular dystrophy. Phase 2 clinical trials in the United Kingdom and the Netherlands have reported induction of dystrophin expression in muscle of Duchenne muscular dystrophy patients by systemic administration of both phosphorodiamidate morpholino oligomers (PMO) and 2'-O-methyl phosphorothioate. Peptide-conjugated phosphorodiamidate morpholino offers significantly higher efficiency than phosphorodiamidate morpholino, with the ability to induce near-normal levels of dystrophin, and restores function in both skeletal and cardiac muscle. We examined 1-year systemic efficacy of peptide-conjugated phosphorodiamidate morpholino targeting exon 23 in dystrophic mdx mice. The LD(50) of peptide-conjugated phosphorodiamidate morpholino was determined to be approximately 85 mg/kg. The half-life of dystrophin expression was approximately 2 months in skeletal muscle, but shorter in cardiac muscle. Biweekly injection of 6 mg/kg peptide-conjugated phosphorodiamidate morpholino produced >20% dystrophin expression in all skeletal muscles and ≤5% in cardiac muscle, with improvement in muscle function and pathology and reduction in levels of serum creatine kinase. Monthly injections of 30 mg/kg peptide-conjugated phosphorodiamidate morpholino restored dystrophin to >50% normal levels in skeletal muscle, and 15% in cardiac muscle. This was associated with greatly reduced serum creatine kinase levels, near-normal histology, and functional improvement of skeletal muscle. Our results demonstrate for the first time that regular 1-year administration of peptide-conjugated phosphorodiamidate morpholino can be safely applied to achieve significant therapeutic effects in an animal model. Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Simultaneous Pathoproteomic Evaluation of the Dystrophin-Glycoprotein Complex and Secondary Changes in the mdx-4cv Mouse Model of Duchenne Muscular Dystrophy

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Sandra Murphy

2015-06-01

Full Text Available In skeletal muscle, the dystrophin-glycoprotein complex forms a membrane-associated assembly of relatively low abundance, making its detailed proteomic characterization in normal versus dystrophic tissues technically challenging. To overcome this analytical problem, we have enriched the muscle membrane fraction by a minimal differential centrifugation step followed by the comprehensive label-free mass spectrometric analysis of microsomal membrane preparations. This organelle proteomic approach successfully identified dystrophin and its binding partners in normal versus dystrophic hind limb muscles. The introduction of a simple pre-fractionation step enabled the simultaneous proteomic comparison of the reduction in the dystrophin-glycoprotein complex and secondary changes in the mdx-4cv mouse model of dystrophinopathy in a single analytical run. The proteomic screening of the microsomal fraction from dystrophic hind limb muscle identified the full-length dystrophin isoform Dp427 as the most drastically reduced protein in dystrophinopathy, demonstrating the remarkable analytical power of comparative muscle proteomics. Secondary pathoproteomic expression patterns were established for 281 proteins, including dystrophin-associated proteins and components involved in metabolism, signalling, contraction, ion-regulation, protein folding, the extracellular matrix and the cytoskeleton. Key findings were verified by immunoblotting. Increased levels of the sarcolemmal Na+/K+-ATPase in dystrophic leg muscles were also confirmed by immunofluorescence microscopy. Thus, the reduction of sample complexity in organelle-focused proteomics can be advantageous for the profiling of supramolecular protein complexes in highly intricate systems, such as skeletal muscle tissue.

Interdependence of laminin-mediated clustering of lipid rafts and the dystrophin complex in astrocytes.

Science.gov (United States)

Noël, Geoffroy; Tham, Daniel Kai Long; Moukhles, Hakima

2009-07-17

Astrocyte endfeet surrounding blood vessels are active domains involved in water and potassium ion transport crucial to the maintenance of water and potassium ion homeostasis in brain. A growing body of evidence points to a role for dystroglycan and its interaction with perivascular laminin in the targeting of the dystrophin complex and the water-permeable channel, aquaporin 4 (AQP4), at astrocyte endfeet. However, the mechanisms underlying such compartmentalization remain poorly understood. In the present study we found that AQP4 resided in Triton X-100-insoluble fraction, whereas dystroglycan was recovered in the soluble fraction in astrocytes. Cholesterol depletion resulted in the translocation of a pool of AQP4 to the soluble fraction indicating that its distribution is indeed associated with cholesterol-rich membrane domains. Upon laminin treatment AQP4 and the dystrophin complex, including dystroglycan, reorganized into laminin-associated clusters enriched for the lipid raft markers GM1 and flotillin-1 but not caveolin-1. Reduced diffusion rates of GM1 in the laminin-induced clusters were indicative of the reorganization of raft components in these domains. In addition, both cholesterol depletion and dystroglycan silencing reduced the number and area of laminin-induced clusters of GM1, AQP4, and dystroglycan. These findings demonstrate the interdependence between laminin binding to dystroglycan and GM1-containing lipid raft reorganization and provide novel insight into the dystrophin complex regulation of AQP4 polarization in astrocytes.

Electroporation Enhanced Effect of Dystrophin Splice Switching PNA Oligomers in Normal and Dystrophic Muscle

DEFF Research Database (Denmark)

Hjortkjær, Camilla Brolin; Shiraishi, Takehiko; Hojman, Pernille

2015-01-01

for improvement of in vivo cellular availability, we have investigated the effect of electrotransfer upon intramuscular (i.m.) PNA administration in vivo. Antisense PNA targeting exon 23 of the murine dystrophin gene was administered by i.m. injection to the tibialis anterior (TA) muscle of normal NMRI......Peptide nucleic acid (PNA) is a synthetic DNA mimic that has shown potential for discovery of novel splice switching antisense drugs. However, in vivo cellular delivery has been a limiting factor for development, and only few successful studies have been reported. As a possible modality...... switching was detected at the RNA level up to 4 weeks after a single-dose treatment. In dystrophic muscles of the MDX mouse, electroporation increased the number of dystrophin-positive fibers about 2.5-fold at 2 weeks after a single PNA administration compared to injection only. In conclusion, we find...

Tissue distribution of the dystrophin-related gene product and expression in the mdx and dy mouse

Energy Technology Data Exchange (ETDEWEB)

Love, D.R.; Marsden, R.F.; Bloomfield, J.F.; Davies, K.E. (John Radcliffe Hospital, Oxford (England)); Morris, G.E.; Ellis, J.M. (North East Wales Inst., Deeside, Wales (England)); Fairbrother, U.; Edwards, Y.H. (Univ. College London (England)); Slater, C.P. (Newcastle General Hospital, Newcastle-upon-Tyne (England)); Parry, D.J. (Univ. of Ottawa, Ontario (Canada))

1991-04-15

The authors have previously reported a dystrophin-related locus (DMDL for Duchenne muscular dystrophy-like) on human chromosome 6 that maps close to the dy mutation on mouse chromosome 10. Here they show that this gene is expressed in a wide range of tissues at varying levels. The transcript is particularly abundant in several human fetal tissues, including heart, placenta, and intestine. Studies with antisera raised against a DMDL fusion protein identify a 400,000 M{sub r} protein in all mouse tissues tested, including those of mdx and dy mice. Unlike the dystrophin gene, the DMDL gene transcript is not differentially spliced at the 3{prime} end in either fetal muscle or brain.

Screening of point mutations by multiple SSCP analysis in the dystrophin gene

Energy Technology Data Exchange (ETDEWEB)

Lasa, A.; Baiget, M.; Gallano, P. [Hospital Sant Pau, Barcelona (Spain)

1994-09-01

Duchenne muscular dystrophy (DMD) is a lethal, X-linked neuromuscular disorder. The population frequency of DMD is one in approximately 3500 boys, of which one third is thought to be a new mutant. The DMD gene is the largest known to date, spanning over 2,3 Mb in band Xp21.2; 79 exons are transcribed into a 14 Kb mRNA coding for a protein of 427 kD which has been named dystrophin. It has been shown that about 65% of affected boys have a gene deletion with a wide variation in localization and size. The remaining affected individuals who have no detectable deletions or duplications would probably carry more subtle mutations that are difficult to detect. These mutations occur in several different exons and seem to be unique to single patients. Their identification represents a formidable goal because of the large size and complexity of the dystrophin gene. SSCP is a very efficient method for the detection of point mutations if the parameters that affect the separation of the strands are optimized for a particular DNA fragment. The multiple SSCP allows the simultaneous study of several exons, and implies the use of different conditions because no single set of conditions will be optimal for all fragments. Seventy-eight DMD patients with no deletion or duplication in the dystrophin gene were selected for the multiple SSCP analysis. Genomic DNA from these patients was amplified using the primers described for the diagnosis procedure (muscle promoter and exons 3, 8, 12, 16, 17, 19, 32, 45, 48 and 51). We have observed different mobility shifts in bands corresponding to exons 8, 12, 43 and 51. In exons 17 and 45, altered electrophoretic patterns were found in different samples identifying polymorphisms already described.

Protein truncation test: analysis of two novel point mutations at the carboxy-terminus of the human dystrophin gene associated with mental retardation.

Science.gov (United States)

Tuffery, S; Lenk, U; Roberts, R G; Coubes, C; Demaille, J; Claustres, M

1995-01-01

Approximately one-third of the mutations responsible for Duchenne muscular dytrophy (DMD) do not involve gross rearrangements of the dystrophin gene. Methods for intensive mutation screening have recently been applied to this immense gene, which resulted in the identification of a number of point mutations in DMD patients, mostly translation-terminating mutations. A number of data raised the possibility that the C-terminal region of dystrophin might be involved in some cases of mental retardation associated with DMD. Using single-strand conformation analysis of products amplified by polymerase chain reaction (PCR-SSCA) to screen the terminal domains of the dystrophin gene (exons 60-79) of 20 unrelated patients with DMD or BMD, we detected two novel point mutations in two mentally retarded DMD patients: a 1-bp deletion in exon 70 (10334delC) and a 5' splice donor site alteration in intron 69 (10294 + 1G-->T). Both mutations should result in a premature translation termination of dystrophin. The possible effects on the reading frame were analyzed by the study of reverse transcripts amplified from peripheral blood lymphocytes mRNA and by the protein truncation test.

Restoration of half the normal dystrophin sequence in a double-deletion Duchenne muscular dystrophy family

Energy Technology Data Exchange (ETDEWEB)

Hoop, R.C.; Schwartz, L.S.; Hoffman, E.P. [Univ. of Pittsburgh School of Medicine, Pittsburgh, PA (United States); Russo, L.S. [Univ. of Florida, Jacksonville, FL (United States); Riconda, D.L. [Orlando Regional Medical Center, Orlando, FL (United States)

1994-02-01

Two male cousins with Duchenne muscular dystrophy were found to have different maternal dystrophin gene haplotypes and different deletion mutations. One propositus showed two noncontiguous deletions-one in the 5{prime}, proximal deletional hotspot region, and the other in the 3{prime}, more distal deletional hotspot region. The second propositus showed only the 5{prime} deletion. Using multiple fluorescent exon dosage and fluorescent multiplex CA repeat linkage analyses, the authors show that the mother of each propositus carries both deletions on the same grandmaternal X chromosome. This paradox is explained by a single recombinational event between the 2 deleted regions of one of the carrier`s dystrophin genes, giving rise to a son with a partially {open_quotes}repaired{close_quotes} gene retaining only the 5{prime} deletion. 20 refs., 4 figs.

Kings Today, Rich Tomorrow

DEFF Research Database (Denmark)

Fattoum, Asma

2013-01-01

This study investigates the King vs. Rich dilemma that founder-CEOs face at IPO. When undertaking IPO, founders face two options. They can either get rich, but then run the risk of losing the control over their firms; or they can remain kings by introducing defensive mechanisms, but this is likel...

Deletion of exon 26 of the dystrophin gene is associated with a mild Becker muscular dystrophy phenotype

DEFF Research Database (Denmark)

Witting, Nanna; Duno, Morten; Vissing, John

2011-01-01

With the possible introduction of exon skipping therapy in Duchenne muscular dystrophy, it has become increasingly important to know the role of each exon of the dystrophin gene to protein expression, and thus the phenotype. In this report, we present two related men with an unusually mild BMD...... calf hypertrophy was noted. Creatine kinase was normal or raised maximally to 500 U/l. The muscle biopsy was myopathic with increased fiber size variation and many internal nuclei, but no dystrophy. No comorbidity was found. In both cases, western blot showed a reduced dystrophin band. Genetic...... skipping therapy for Duchenne muscular dystrophy. This report also shows that BMD may present with a normal CK....

The King and I

Science.gov (United States)

Gallagher, Mary Grace

2009-01-01

This year marks the 40th anniversary of the first Coretta Scott King Book Award, which encourages "the artistic expression of the black experience via literature and the graphic arts." The award, which began honoring illustrators in 1974, added the John Steptoe Award for New Talent in 1995. No doubt, past King award winners like Sharon Flake,…

Identification of small molecule and genetic modulators of AON-induced dystrophin exon skipping by high-throughput screening.

Directory of Open Access Journals (Sweden)

Debra A O'Leary

Full Text Available One therapeutic approach to Duchenne Muscular Dystrophy (DMD recently entering clinical trials aims to convert DMD phenotypes to that of a milder disease variant, Becker Muscular Dystrophy (BMD, by employing antisense oligonucleotides (AONs targeting splice sites, to induce exon skipping and restore partial dystrophin function. In order to search for small molecule and genetic modulators of AON-dependent and independent exon skipping, we screened approximately 10,000 known small molecule drugs, >17,000 cDNA clones, and >2,000 kinase- targeted siRNAs against a 5.6 kb luciferase minigene construct, encompassing exon 71 to exon 73 of human dystrophin. As a result, we identified several enhancers of exon skipping, acting on both the reporter construct as well as endogenous dystrophin in mdx cells. Multiple mechanisms of action were identified, including histone deacetylase inhibition, tubulin modulation and pre-mRNA processing. Among others, the nucleolar protein NOL8 and staufen RNA binding protein homolog 2 (Stau2 were found to induce endogenous exon skipping in mdx cells in an AON-dependent fashion. An unexpected but recurrent theme observed in our screening efforts was the apparent link between the inhibition of cell cycle progression and the induction of exon skipping.

Gentamicin treatment in exercised mdx mice: Identification of dystrophin-sensitive pathways and evaluation of efficacy in work-loaded dystrophic muscle.

Science.gov (United States)

De Luca, Annamaria; Nico, Beatrice; Rolland, Jean-François; Cozzoli, Anna; Burdi, Rosa; Mangieri, Domenica; Giannuzzi, Viviana; Liantonio, Antonella; Cippone, Valentina; De Bellis, Michela; Nicchia, Grazia Paola; Camerino, Giulia Maria; Frigeri, Antonio; Svelto, Maria; Camerino, Diana Conte

2008-11-01

Aminoglycosides force read through of premature stop codon mutations and introduce new mutation-specific gene-corrective strategies in Duchenne muscular dystrophy. A chronic treatment with gentamicin (32 mg/kg/daily i.p., 8-12 weeks) was performed in exercised mdx mice with the dual aim to clarify the dependence on dystrophin of the functional, biochemical and histological alterations present in dystrophic muscle and to verify the long term efficiency of small molecule gene-corrective strategies in work-loaded dystrophic muscle. The treatment counteracted the exercise-induced impairment of in vivo forelimb strength after 6-8 weeks. We observed an increase in dystrophin expression level in all the fibers, although lower than that observed in normal fibers, and found a concomitant recovery of aquaporin-4 at sarcolemma. A significant reduction in centronucleated fibers, in the area of necrosis and in the percentage of nuclear factor-kB-positive nuclei was observed in gastrocnemious muscle of treated animals. Plasma creatine kinase was reduced by 70%. Ex vivo, gentamicin restored membrane ionic conductance in mdx diaphragm and limb muscle fibers. No effects were observed on the altered calcium homeostasis and sarcolemmal calcium permeability, detected by electrophysiological and microspectrofluorimetric approaches. Thus, the maintenance of a partial level of dystrophin is sufficient to reinforce sarcolemmal stability, reducing leakiness, inflammation and fiber damage, while correction of altered calcium homeostasis needs greater expression of dystrophin or direct interventions on the channels involved.

Views of Dr. Martin Luther King, Jr.

Science.gov (United States)

Davis, Alan H.

1990-01-01

Discusses views of Martin Luther King, Jr., including concepts of human rights, related counseling approaches, and ethics. Claims King's views provide helpful insights for counselors and clients. Concludes King invited individuals to view challenging life situations as moral opportunities. (Author/ABL)

Nonmechanical Roles of Dystrophin and Associated Proteins in Exercise, Neuromuscular Junctions, and Brains

Directory of Open Access Journals (Sweden)

Bailey Nichols

2015-07-01

Full Text Available Dystrophin-glycoprotein complex (DGC is an important structural unit in skeletal muscle that connects the cytoskeleton (f-actin of a muscle fiber to the extracellular matrix (ECM. Several muscular dystrophies, such as Duchenne muscular dystrophy, Becker muscular dystrophy, congenital muscular dystrophies (dystroglycanopathies, and limb-girdle muscular dystrophies (sarcoglycanopathies, are caused by mutations in the different DGC components. Although many early studies indicated DGC plays a crucial mechanical role in maintaining the structural integrity of skeletal muscle, recent studies identified novel roles of DGC. Beyond a mechanical role, these DGC members play important signaling roles and act as a scaffold for various signaling pathways. For example, neuronal nitric oxide synthase (nNOS, which is localized at the muscle membrane by DGC members (dystrophin and syntrophins, plays an important role in the regulation of the blood flow during exercise. DGC also plays important roles at the neuromuscular junction (NMJ and in the brain. In this review, we will focus on recently identified roles of DGC particularly in exercise and the brain.

Consecutive analysis of mutation spectrum in the dystrophin gene of 507 Korean boys with Duchenne/Becker muscular dystrophy in a single center.

Science.gov (United States)

Cho, Anna; Seong, Moon-Woo; Lim, Byung Chan; Lee, Hwa Jeen; Byeon, Jung Hye; Kim, Seung Soo; Kim, Soo Yeon; Choi, Sun Ah; Wong, Ai-Lynn; Lee, Jeongho; Kim, Jon Soo; Ryu, Hye Won; Lee, Jin Sook; Kim, Hunmin; Hwang, Hee; Choi, Ji Eun; Kim, Ki Joong; Hwang, Young Seung; Hong, Ki Ho; Park, Seungman; Cho, Sung Im; Lee, Seung Jun; Park, Hyunwoong; Seo, Soo Hyun; Park, Sung Sup; Chae, Jong Hee

2017-05-01

Duchenne and Becker muscular dystrophies (DMD and BMD) are allelic X-linked recessive muscle diseases caused by mutations in the large and complex dystrophin gene. We analyzed the dystrophin gene in 507 Korean DMD/BMD patients by multiple ligation-dependent probe amplification and direct sequencing. Overall, 117 different deletions, 48 duplications, and 90 pathogenic sequence variations, including 30 novel variations, were identified. Deletions and duplications accounted for 65.4% and 13.3% of Korean dystrophinopathy, respectively, suggesting that the incidence of large rearrangements in dystrophin is similar among different ethnic groups. We also detected sequence variations in >100 probands. The small variations were dispersed across the whole gene, and 12.3% were nonsense mutations. Precise genetic characterization in patients with DMD/BMD is timely and important for implementing nationwide registration systems and future molecular therapeutic trials in Korea and globally. Muscle Nerve 55: 727-734, 2017. © 2016 Wiley Periodicals, Inc.

[Clinical features of patients with Becker muscular dystrophy and deletions of the rod domain of dystrophin gene].

Science.gov (United States)

Wang, Yanyun; Zhu, Yuling; Yang, Juan; Li, Yaqin; Sun, Jiangwen; Zhan, Yixin; Zhang, Cheng

2018-02-10

OBJECTIVE To explore the clinical features of patients carrying deletions of the rod domain of the dystrophin gene. METHODS Clinical data of 12 Chinese patients with Becker muscular dystrophy (BMD) and such deletions was reviewed. RESULTS Most patients complained of muscle weakness of lower limbs. Two patients had muscle cramps, one had increased creatine kinase (CK) level, and one had dilated cardiomyopathy. CONCLUSION Compared with DMD, the clinical features of BMD are much more variable, particularly for those carrying deletions of the rod domain of the dystrophin gene. Muscular weakness may not be the sole complaint of BMD. The diagnosis of BMD cannot be excluded by moderately elevated CK. For male patients with dilated cardiomyopathy, the possibility of BMD should be considered.

King and Eye

DEFF Research Database (Denmark)

Suwannakij, Sing

King and Eye explores the visual formation of kingship in Siam in its multifarious aspects. This dissertation identifies the leitmotifs in the dynamics between seeing the king and being seen by him, which burst forth in different eras. The visual sense has been a repository for the ontologization...... devices, most significantly the photographic and the cine cameras, but also encompassing other ocular apparatuses. The images produced through the contraptions were brought together under the royal eye at the apex, which in turn claimed its supremacy over space, time, and the vast and diverse population...

Relatively low proportion of dystrophin gene deletions in Israeili Duchenne and Becker muscular dystrophy patients

Energy Technology Data Exchange (ETDEWEB)

Shomrat, R.; Gluck, E.; Legum, C.; Shiloh, Y. [Tel Aviv Univ. (Israel)

1994-02-15

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are allelic disorders caused by mutations in the X-linked dystrophin gene. The most common mutations in western populations are deletions that are spread non-randomly throughout the gene. Molecular analysis of the dystrophin gene structure by hybridization of the full length cDNA to Southern blots and by PCR in 62 unrelated Israeli male DMD/BMD patients showed deletions in 23 (37%). This proportion is significantly lower than that found in European and North American populations (55-65%). Seventy-eight percent of the deletions were confined to exons 44-52, half of these exons 44-45, and the remaining 22% to exons 1 and 19. There was no correlation between the size of the deletion and the severity of the disease. All the deletions causing frameshift resulted in the DMD phenotypes. 43 refs., 1 fig., 1 tab.

Optimization of Peptide Nucleic Acid Antisense Oligonucleotides for Local and Systemic Dystrophin Splice Correction in the mdx Mouse

Science.gov (United States)

Yin, HaiFang; Betts, Corinne; Saleh, Amer F; Ivanova, Gabriela D; Lee, Hyunil; Seow, Yiqi; Kim, Dalsoo; Gait, Michael J; Wood, Matthew JA

2010-01-01

Antisense oligonucleotides (AOs) have the capacity to alter the processing of pre-mRNA transcripts in order to correct the function of aberrant disease-related genes. Duchenne muscular dystrophy (DMD) is a fatal X-linked muscle degenerative disease that arises from mutations in the DMD gene leading to an absence of dystrophin protein. AOs have been shown to restore the expression of functional dystrophin via splice correction by intramuscular and systemic delivery in animal models of DMD and in DMD patients via intramuscular administration. Major challenges in developing this splice correction therapy are to optimize AO chemistry and to develop more effective systemic AO delivery. Peptide nucleic acid (PNA) AOs are an alternative AO chemistry with favorable in vivo biochemical properties and splice correcting abilities. Here, we show long-term splice correction of the DMD gene in mdx mice following intramuscular PNA delivery and effective splice correction in aged mdx mice. Further, we report detailed optimization of systemic PNA delivery dose regimens and PNA AO lengths to yield splice correction, with 25-mer PNA AOs providing the greatest splice correcting efficacy, restoring dystrophin protein in multiple peripheral muscle groups. PNA AOs therefore provide an attractive candidate AO chemistry for DMD exon skipping therapy. PMID:20068555

Critical appraisal of discriminant formulas for distinguishing thalassemia from iron deficiency in patients with microcytic anemia.

Science.gov (United States)

Urrechaga, Eloísa; Hoffmann, Johannes J M L

2017-08-28

Many discriminant formulas have been reported for distinguishing thalassemia trait from iron deficiency in patients with microcytic anemia. Independent verification of several discriminant formulas is deficient or even lacking. Therefore, we have retrospectively investigated discriminant formulas in a large, well-characterized patient population. The investigational population consisted of 2664 patients with microcytic anemia: 1259 had iron deficiency, 1196 'pure' thalassemia trait (877 β- and 319 α-thalassemia), 150 had thalassemia trait with concomitant iron deficiency or anemia of chronic disease, and 36 had other diseases. We investigated 25 discriminant formulas that only use hematologic parameters available on all analyzers; formulas with more advanced parameters were disregarded. The diagnostic performance was investigated using ROC analysis. The three best performing formulas were the Jayabose (RDW index), Janel (11T), and Green and King formulas. The differences between them were not statistically significant (p>0.333), but each of them had significantly higher area under the ROC curve than any other formula. The Jayabose and Green and King formulas had the highest sensitivities: 0.917 both. The highest specificity, 0.925, was found for the Janel formula, which is a composite score of 11 other formulas. All investigated formulas performed significantly better in distinguishing β- than α-thalassemia from iron deficiency. In our patient population, the Jayabose RDW index, the Green and King formula and the Janel 11T score are superior to all other formulas examined for distinguishing between thalassemia trait and iron deficiency anemia. We confirmed that all formulas perform much better in β- than in α-thalassemia carriers and also that they incorrectly classify approximately 30% of thalassemia carriers with concomitant other anemia as not having thalassemia. The diagnostic performance of even the best formulas is not high enough for making a final

Precise correction of the dystrophin gene in duchenne muscular dystrophy patient induced pluripotent stem cells by TALEN and CRISPR-Cas9.

Science.gov (United States)

Li, Hongmei Lisa; Fujimoto, Naoko; Sasakawa, Noriko; Shirai, Saya; Ohkame, Tokiko; Sakuma, Tetsushi; Tanaka, Michihiro; Amano, Naoki; Watanabe, Akira; Sakurai, Hidetoshi; Yamamoto, Takashi; Yamanaka, Shinya; Hotta, Akitsu

2015-01-13

Duchenne muscular dystrophy (DMD) is a severe muscle-degenerative disease caused by a mutation in the dystrophin gene. Genetic correction of patient-derived induced pluripotent stem cells (iPSCs) by TALENs or CRISPR-Cas9 holds promise for DMD gene therapy; however, the safety of such nuclease treatment must be determined. Using a unique k-mer database, we systematically identified a unique target region that reduces off-target sites. To restore the dystrophin protein, we performed three correction methods (exon skipping, frameshifting, and exon knockin) in DMD-patient-derived iPSCs, and found that exon knockin was the most effective approach. We further investigated the genomic integrity by karyotyping, copy number variation array, and exome sequencing to identify clones with a minimal mutation load. Finally, we differentiated the corrected iPSCs toward skeletal muscle cells and successfully detected the expression of full-length dystrophin protein. These results provide an important framework for developing iPSC-based gene therapy for genetic disorders using programmable nucleases. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

King, Prof. Sir David Anthony

Indian Academy of Sciences (India)

Elected: 1998 Honorary. King, Prof. Sir David Anthony Sc.D., FRS. Date of birth: 12 August 1939. Address: Chief Scientific Adivser & Head, Office of Science and Innovation, London SW1H 0ET, U.K.. Contact: Office: (+44-020) 7215 3821. Fax: (+44-020) 7215 0314. Email: mpst.king@dti.gsi.gov.uk, dak10@cus.cam.ac.uk.

The leaders King Sverre and King Haakon : analysis of King Sverre Sigurdsson and King Haakon Haakonsson in Sverris Saga and Haakonar Saga Haakonarsonar through Max Weber's and John Gardner's models

OpenAIRE

Osornio, Ismael Jose Duran

2004-01-01

The leadership of the Norwegian Kings during the Medieval ‘Civil War’ plays a prominent part in social, political and economical life in high Medieval Norway. The objective of the present dissertation discusses how King Sverre Sigurdsson (1177-1202) and Haakon Haakonsson (1217-1263) are depicted in their Sagas. The work will be focus on four analytical tools: 1. The Kings’ Charisma; 2. The Kings’ Personal Abilities; 3. The Kings’ Bureaucracy; 4. The King’s closest Fellows. The thesis goal wil...

Dystrophin is required for the normal function of the cardio-protective K(ATP channel in cardiomyocytes.

Directory of Open Access Journals (Sweden)

Laura Graciotti

Full Text Available Duchenne and Becker muscular dystrophy patients often develop a cardiomyopathy for which the pathogenesis is still unknown. We have employed the murine animal model of Duchenne muscular dystrophy (mdx, which develops a cardiomyopathy that includes some characteristics of the human disease, to study the molecular basis of this pathology. Here we show that the mdx mouse heart has defects consistent with alteration in compounds that regulate energy homeostasis including a marked decrease in creatine-phosphate (PC. In addition, the mdx heart is more susceptible to anoxia than controls. Since the cardio-protective ATP sensitive potassium channel (K(ATP complex and PC have been shown to interact we investigated whether deficits in PC levels correlate with other molecular events including K(ATP ion channel complex presence, its functionality and interaction with dystrophin. We found that this channel complex is present in the dystrophic cardiac cell membrane but its ability to sense a drop in the intracellular ATP concentration and consequently open is compromised by the absence of dystrophin. We further demonstrate that the creatine kinase muscle isoform (CKm is displaced from the plasma membrane of the mdx cardiac cells. Considering that CKm is a determinant of K(ATP channel complex function we hypothesize that dystrophin acts as a scaffolding protein organizing the K(ATP channel complex and the enzymes necessary for its correct functioning. Therefore, the lack of proper functioning of the cardio-protective K(ATP system in the mdx cardiomyocytes may be part of the mechanism contributing to development of cardiac disease in dystrophic patients.

Syringomyelia and Craniocervical Junction Abnormalities in Chihuahuas

OpenAIRE

Kiviranta, A.‐M.; Rusbridge, C.; Laitinen‐Vapaavuori, O.; Hielm‐Björkman, A.; Lappalainen, A.K.; Knowler, S.P.; Jokinen, T.S.

2017-01-01

Background: Chiari-like malformation (CM) and syringomyelia (SM) are widely reported in Cavalier King Charles Spaniels and Griffon Bruxellois dogs. Increasing evidence indicates that CM and SM also occur in other small and toy breed dogs, such as Chihuahuas. Objectives: To describe the presence of SM and craniocervical junction (CCJ) abnormalities in Chihuahuas and to evaluate the possible association of CCJ abnormalities with SM. To describe CM/SM-related clinical signs and neuro...

Sarcospan: a small protein with large potential for Duchenne muscular dystrophy

Science.gov (United States)

2013-01-01

Purification of the proteins associated with dystrophin, the gene product responsible for Duchenne muscular dystrophy, led to the discovery of the dystrophin-glycoprotein complex. Sarcospan, a 25-kDa transmembrane protein, was the last component to be identified and its function in skeletal muscle has been elusive. This review will focus on progress over the last decade revealing that sarcospan is an important regulator of muscle cell adhesion, strength, and regeneration. Investigations using several transgenic mouse models demonstrate that overexpression of sarcospan in the mouse model for Duchenne muscular dystrophy ameliorates pathology and restores muscle cell binding to laminin. Sarcospan improves cell surface expression of the dystrophin- and utrophin-glycoprotein complexes as well as α7β1 integrin, which are the three major laminin-binding complexes in muscle. Utrophin and α7β1 integrin compensate for the loss of dystrophin and the finding that sarcospan increases their abundance at the extra-synaptic sarcolemma supports the use of sarcospan as a therapeutic target. Newly discovered phenotypes in sarcospan-deficient mice, including a reduction in specific force output and increased drop in force in the diaphragm muscle, result from decreased utrophin and dystrophin expression and further reveal sarcospan’s role in determining abundance of these complexes. Dystrophin protein levels and the specific force output of the diaphragm muscle are further reduced upon genetic removal of α7 integrin (Itga7) in SSPN-deficient mice, demonstrating that interactions between integrin and sarcospan are critical for maintenance of the dystrophin-glycoprotein complex and force production of the diaphragm muscle. Sarcospan is a major regulator of Akt signaling pathways and sarcospan-deficiency significantly impairs muscle regeneration, a process that is dependent on Akt activation. Intriguingly, sarcospan regulates glycosylation of a specific subpopulation of �

Characterization of the complete mitochondrial genome of the king pigeon (Columba livia breed king).

Science.gov (United States)

Zhang, Rui-Hua; He, Wen-Xiao; Xu, Tong

2015-06-01

The king pigeon is a breed of pigeon developed over many years of selective breeding primarily as a utility breed. In the present work, we report the complete mitochondrial genome sequence of king pigeon for the first time. The total length of the mitogenome was 17,221 bp with the base composition of 30.14% for A, 24.05% for T, 31.82% for C, and 13.99% for G and an A-T (54.22 %)-rich feature was detected. It harbored 13 protein-coding genes, two ribosomal RNA genes, 22 transfer RNA genes, and one non-coding control region (D-loop region). The arrangement of all genes was identical to the typical mitochondrial genomes of pigeon. The complete mitochondrial genome sequence of king pigeon would serve as an important data set of the germplasm resources for further study.

Sulfur and Oxygen Isotopic Composition of Sulfate in the Fresh Water, King Sejong Station, King George Island, Antarctica

Science.gov (United States)

Kim, M.; Lee, I.; Lee, J.; Park, B.; Mayer, B.; Kaufman, A. J.; Park, S.; Kim, G.; Lee, K.

2008-12-01

Isotopic compositions of sulfur (δ34S) and oxygen (δ18O) were measured for the sulfate of the fresh water near the King Sejong Station, King George Island, Antarctica. Sejong station is located in the Barton peninsular of the King George Island. The geology around King Sejong station mainly composed of basalt-andesite, quart monzodiorite, and granodiorite. Lapilli tuff, conglomerate, sandstone, and siltstone occur along the southern and eastern shore of the Barton peninsula. Lapilli tuff also occurs on the highland located on southeastern part of the Barton peninsula. The δ34S values of sulfate extracted from fresh water samples at King Sejong Station range from 13.7 to 16.3 per mil excluding 1 sample. These sulfur values are very narrow in their range compared with those from anthropogenic sources. These sulfur values are 5 to 7 per mil lower than those of typical present seawater. Considering the rocks occurring near the King Sejong station, these sulfur isotopic values do not seem to be related to any evaporites of certain age. In Antarctic region the natural source of sulfate dissolved in water could be originated from marine biogenic source (DMS), sea-salt, volcanic source, or other continental sources. Most of the δ34S values of sulfate at King Sejong station seems to indicate the dominance of marine biogenic origin for the source of sulfur. The δ18O values of sulfate extracted from fresh water samples at King Sejong Station range from 1.9 to 6.4 per mil excluding 1 sample. These oxygen isotope values are lower than those of the sulfate in the present seawater by 6 per mil. However, both sulfur and oxygen isotope values strongly represent the influence of the seawater sulfate. One sample have 2.6 and -1.1 per mil in its δ34S and δ18O values, respectively, that are quite different from the isotopic values of other samples. This sample was collected in the highland far from the King Sejong station. Therefore this sample might reflect the composition of

Delivery of AAV2/9-microdystrophin genes incorporating helix 1 of the coiled-coil motif in the C-terminal domain of dystrophin improves muscle pathology and restores the level of α1-syntrophin and α-dystrobrevin in skeletal muscles of mdx mice.

Science.gov (United States)

Koo, Taeyoung; Malerba, Alberto; Athanasopoulos, Takis; Trollet, Capucine; Boldrin, Luisa; Ferry, Arnaud; Popplewell, Linda; Foster, Helen; Foster, Keith; Dickson, George

2011-11-01

Duchenne muscular dystrophy is a severe X-linked inherited muscle wasting disorder caused by mutations in the dystrophin gene. Adeno-associated virus (AAV) vectors have been extensively used to deliver genes efficiently for dystrophin expression in skeletal muscles. To overcome limited packaging capacity of AAV vectors (pathology of dystrophic mdx mice. However, the CT domain of dystrophin is thought to recruit part of the dystrophin-associated protein complex, which acts as a mediator of signaling between extracellular matrix and cytoskeleton in muscle fibers. In this study, we extended the ΔR4-23/ΔCT microdystrophin by incorporating helix 1 of the coiled-coil motif in the CT domain of dystrophin (MD2), which contains the α1-syntrophin and α-dystrobrevin binding sites. Intramuscular injection of AAV2/9 expressing CT domain-extended microdystrophin showed efficient dystrophin expression in tibialis anterior muscles of mdx mice. The presence of the CT domain of dystrophin in MD2 increased the recruitment of α1-syntrophin and α-dystrobrevin at the sarcolemma and significantly improved the muscle resistance to lengthening contraction-induced muscle damage in the mdx mice compared with MD1. These results suggest that the incorporation of helix 1 of the coiled-coil motif in the CT domain of dystrophin to the microdystrophins will substantially improve their efficiency in restoring muscle function in patients with Duchenne muscular dystrophy.

Brain Function in Duchenne Muscular Dystrophy

Directory of Open Access Journals (Sweden)

J. Gordon Millichap

2002-02-01

Full Text Available The role of dystrophin disorders in the CNS function of boys with Duchenne muscular dystrophy (DMD and the dystrophin-deficient mdx mouse, an animal model of DMD, is reviewed at the University of New South Wales, University of Sydney, Australia.

Current Translational Research and Murine Models For Duchenne Muscular Dystrophy

Science.gov (United States)

Rodrigues, Merryl; Echigoya, Yusuke; Fukada, So-ichiro; Yokota, Toshifumi

2016-01-01

Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder characterized by progressive muscle degeneration. Mutations in the DMD gene result in the absence of dystrophin, a protein required for muscle strength and stability. Currently, there is no cure for DMD. Since murine models are relatively easy to genetically manipulate, cost effective, and easily reproducible due to their short generation time, they have helped to elucidate the pathobiology of dystrophin deficiency and to assess therapies for treating DMD. Recently, several murine models have been developed by our group and others to be more representative of the human DMD mutation types and phenotypes. For instance, mdx mice on a DBA/2 genetic background, developed by Fukada et al., have lower regenerative capacity and exhibit very severe phenotype. Cmah-deficient mdx mice display an accelerated disease onset and severe cardiac phenotype due to differences in glycosylation between humans and mice. Other novel murine models include mdx52, which harbors a deletion mutation in exon 52, a hot spot region in humans, and dystrophin/utrophin double-deficient (dko), which displays a severe dystrophic phenotype due the absence of utrophin, a dystrophin homolog. This paper reviews the pathological manifestations and recent therapeutic developments in murine models of DMD such as standard mdx (C57BL/10), mdx on C57BL/6 background (C57BL/6-mdx), mdx52, dystrophin/utrophin double-deficient (dko), mdxβgeo, Dmd-null, humanized DMD (hDMD), mdx on DBA/2 background (DBA/2-mdx), Cmah-mdx, and mdx/mTRKO murine models. PMID:27854202

Why do people buy dogs with potential welfare problems related to extreme conformation and inherited disease? A representative study of Danish owners of four small dog breeds

OpenAIRE

Sand?e, P.; Kondrup, S. V.; Bennett, P. C.; Forkman, B.; Meyer, I; Proschowsky, H. F.; Serpell, J. A.; Lund, T. B.

2017-01-01

number of dog breeds suffer from welfare problems due to extreme phenotypes and high levels of inherited diseases but the popularity of such breeds is not declining. Using a survey of owners of two popular breeds with extreme physical features (French Bulldog and Chihuahua), one with a high load of inherited diseases not directly related to conformation (Cavalier King Charles Spaniel), and one representing the same size range but without extreme conformation and with the same level of disease...

Goldie Brangman Remembers the Operation to Save Dr King.

Science.gov (United States)

Koch, Evan; Brangman, Goldie

2015-12-01

In September 1958 the Rev Dr Martin Luther King Jr was stabbed and nearly assassinated. Surgeons at Harlem Hospital in New York City removed a 17.8-cm (7-in)-long letter opener from Dr King's chest. Certified Registered Nurse Anesthetist Goldie Brangman remembers this event because she participated in Dr King's anesthetic. This article correlates Brangman's memories with published accounts of the event. It also places the event within the context of the modern civil rights movement that Dr King led.

John Davies of Hereford, the King of Denmark & Shakespeare's Meeting of Kings: Praise Beyond Praise

DEFF Research Database (Denmark)

Sterrett, Joseph William

2016-01-01

This article traces the response and style of John Davies of Hereford, 'an ordinary man' as he celebrated an extraordinary event, the state visit of the King of Denmark to the court of James I in 1606. It then draws comparisons to Shakespeare's meeting of kings some seven or eight years later...... at the beginning of the late history play, All is True, suggesting that the earlier poet's experience influenced the latter....

Identification of a novel first exon in the human dystrophin gene and of a new promoter located more than 500 kb upstream of the nearest known promoter

Energy Technology Data Exchange (ETDEWEB)

Yanagawa, H.; Nishio, H.; Takeshima, Y. [Kobe Univ. School of Medicine (Japan)] [and others

1994-09-01

The dystrophin gene, which is muted in patients with Duchenne and Becker muscular dystrophies, is the largest known human gene. Five alternative promoters have been characterized until now. Here we show that a novel dystrophin isoform with a different first exon can be produced through transcription initiation at a previously-unidentified alternative promoter. The case study presented is that of patient with Duchenne muscular dystrophy who had a deletion extending from 5{prime} end of the dystrophin gene to exon 2, including all promoters previously mapped in the 5{prime} part of the gene. Transcripts from lymphoblastoid cells were found to contain sequences corresponding to exon 3, indicating the presence of new promoter upstream of this exon. The nucleotide sequence of amplified cDNA corresponding to the 5{prime} end of the new transcript indicated that the 5{prime} end of exon 3 was extended by 9 codons, only the last (most 3{prime}) of which codes for methionine. The genomic nucleotide sequence upstream from the new exon, as determined using inverse polymerase chain reaction, revealed the presence of sequences similar to a TATA box, an octamer motif and an MEF-2 element. The identified promoter/exon did not map to intron 2, as might have been expected, but to a position more than 500 kb upstream of the most 5{prime} of the previously-identified promoters, thereby adding 500 kb to the dystrophin gene. The sequence of part of the new promoter region is very similar to that of certain medium reiteration frequency repetitive sequences. These findings may help us understand the molecular evolution of the dystrophin gene.

King Kong tuli unenäost / Alar Niineväli

Index Scriptorium Estoniae

Niineväli, Alar

2005-01-01

Hiigelgorilla King Kongi sünd kinolinal 1933.a. Merian C. Cooperi õudusfilmis "King Kong" ja koletise hilisemad tulemised, ka koos jaapanlaste Godzillaga (1962) ja Tarzaniga india filmis "Tarzan ja King Kong" (1965)

PITX2 Enhances the Regenerative Potential of Dystrophic Skeletal Muscle Stem Cells.

Science.gov (United States)

Vallejo, Daniel; Hernández-Torres, Francisco; Lozano-Velasco, Estefanía; Rodriguez-Outeiriño, Lara; Carvajal, Alejandra; Creus, Carlota; Franco, Diego; Aránega, Amelia Eva

2018-04-10

Duchenne muscular dystrophy (DMD), one of the most lethal genetic disorders, involves progressive muscle degeneration resulting from the absence of DYSTROPHIN. Lack of DYSTROPHIN expression in DMD has critical consequences in muscle satellite stem cells including a reduced capacity to generate myogenic precursors. Here, we demonstrate that the c-isoform of PITX2 transcription factor modifies the myogenic potential of dystrophic-deficient satellite cells. We further show that PITX2c enhances the regenerative capability of mouse DYSTROPHIN-deficient satellite cells by increasing cell proliferation and the number of myogenic committed cells, but importantly also increasing dystrophin-positive (revertant) myofibers by regulating miR-31. These PITX2-mediated effects finally lead to improved muscle function in dystrophic (DMD/mdx) mice. Our studies reveal a critical role for PITX2 in skeletal muscle repair and may help to develop therapeutic strategies for muscular disorders. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

New Dystrophin/Dystroglycan interactors control neuron behavior in Drosophila eye

Directory of Open Access Journals (Sweden)

Rishko Valentyna M

2011-09-01

Full Text Available Abstract Background The Dystrophin Glycoprotein Complex (DGC is a large multi-component complex that is well known for its function in muscle tissue. When the main components of the DGC, Dystrophin (Dys and Dystroglycan (Dg are affected cognitive impairment and mental retardation in addition to muscle degeneration can occur. Previously we performed an array of genetic screens using a Drosophila model for muscular dystrophy in order to find novel DGC interactors aiming to elucidate the signaling role(s in which the complex is involved. Since the function of the DGC in the brain and nervous system has not been fully defined, we have here continued to analyze the DGC modifiers' function in the developing Drosophila brain and eye. Results Given that disruption of Dys and Dg leads to improper photoreceptor axon projections into the lamina and eye neuron elongation defects during development, we have determined the function of previously screened components and their genetic interaction with the DGC in this tissue. Our study first found that mutations in chif, CG34400, Nrk, Lis1, capt and Cam cause improper axon path-finding and loss of SP2353, Grh, Nrk, capt, CG34400, vimar, Lis1 and Cam cause shortened rhabdomere lengths. We determined that Nrk, mbl, capt and Cam genetically interact with Dys and/or Dg in these processes. It is notable that most of the neuronal DGC interacting components encountered are involved in regulation of actin dynamics. Conclusions Our data indicate possible DGC involvement in the process of cytoskeletal remodeling in neurons. The identification of new components that interact with the DGC not only helps to dissect the mechanism of axon guidance and eye neuron differentiation but also provides a great opportunity for understanding the signaling mechanisms by which the cell surface receptor Dg communicates via Dys with the actin cytoskeleton.

A novel point mutation (G[sup [minus]1] to T) in a 5[prime] splice donor site of intron 13 of the dystrophin gene results in exon skipping and is responsible for Becker Muscular Dystrophy

Energy Technology Data Exchange (ETDEWEB)

Hagiwara, Yoko; Nishio, Hisahide; Kitoh, Yoshihiko; Takeshima, Yasuhiro; Narita, Naoko; Wada, Hiroko; Yokoyama, Mitsuhiro; Nakamura, Hajime; Matsuo, Masafumi (Kobe Univ. School of Medicine (Japan))

1994-01-01

The mutations in one-third of Duchenne and Becker muscular dystrophy patients remain unknown, as they do not involve gross rearrangements of the dystrophin gene. The authors now report a defect in the splicing of precursor mRNA (pre-mRNA), resulting from a maternally inherited mutation of the dystrophin gene in a patient with Becker muscular dystrophy. This defect results from a G-to-T transversion at the terminal nucleotide of exon 13, within the 5[prime] splice site of intron 13, and causes complete skipping of exon 13 during processing of dystrophin pre-mRNA. The predicted polypeptide encoded by the aberrant mRNA is a truncated dystrophin lacking 40 amino acids from the amino-proximal end of the rod domain. This is the first report of an intraexon point mutation that completely inactivates a 5[prime] splice donor site in dystrophin pre-mRNA. Analysis of the genomic context of the G[sup [minus]1]-to-T mutation at the 5[prime] splice site supports the exon-definition model of pre-mRNA splicing and contributes to the understanding of splice-site selection. 48 refs., 5 figs.

MLPA based detection of mutations in the dystrophin gene of 180 Polish families with Duchenne/Becker muscular dystrophy.

Science.gov (United States)

Zimowski, Janusz G; Massalska, Diana; Holding, Mariola; Jadczak, Sylwia; Fidziańska, Elżbieta; Lusakowska, Anna; Kostera-Pruszczyk, Anna; Kamińska, Anna; Zaremba, Jacek

2014-01-01

Duchenne/Becker muscular dystrophy (DMD/BMD) is a recessive, X-linked disorder caused by a mutation in the dystrophin gene. Deletions account for approximately 60-65% of mutations, duplications for 5-10%. The remaining cases are mainly point mutations. According to Monaco theory clinical form of the disease depends on maintaining or disrupting the reading frame. The purpose of the study was to determine frequency and location of deletions and duplications in the dystrophin gene, to determine the compliance between maintaining/disrupting the reading frame and clinical form of the disease and to check the effectiveness of MLPA (multiplex ligation-dependent probe amplification) in the detection of these mutations in hemizygous patients and heterozygous female carriers. The material is composed of combined results of molecular diagnosis carried out in years 2009-2012 in 180 unrelated patients referred with the diagnosis of DMD/BMD tested by use of MLPA. We identified 110 deletions, 22 duplication (in one patient two different duplications were detected) and 2 point mutations. Deletions involved mainly exons 45-54 and 3-21, whereas most duplications involved exons 3-18. The compliance with Monaco theory was 95% for deletions and 76% for duplications. Most of mutations in the dystrophin gene were localized in the hot spots - different for deletions and duplications. MLPA enabled their quick identification, exact localization and determination whether or not they maintained or disrupted the reading frame. MLPA was also effective in detection of deletions and duplications in female carriers. Copyright © 2014 Polish Neurological Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Electroporation Enhanced Effect of Dystrophin Splice Switching PNA Oligomers in Normal and Dystrophic Muscle

Directory of Open Access Journals (Sweden)

Camilla Brolin

2015-01-01

Full Text Available Peptide nucleic acid (PNA is a synthetic DNA mimic that has shown potential for discovery of novel splice switching antisense drugs. However, in vivo cellular delivery has been a limiting factor for development, and only few successful studies have been reported. As a possible modality for improvement of in vivo cellular availability, we have investigated the effect of electrotransfer upon intramuscular (i.m. PNA administration in vivo. Antisense PNA targeting exon 23 of the murine dystrophin gene was administered by i.m. injection to the tibialis anterior (TA muscle of normal NMRI and dystrophic mdx mice with or without electroporation. At low, single PNA doses (1.5, 3, or 10 µg/TA, electroporation augmented the antisense exon skipping induced by an unmodified PNA by twofold to fourfold in healthy mouse muscle with optimized electric parameters, measured after 7 days. The PNA splice switching was detected at the RNA level up to 4 weeks after a single-dose treatment. In dystrophic muscles of the MDX mouse, electroporation increased the number of dystrophin-positive fibers about 2.5-fold at 2 weeks after a single PNA administration compared to injection only. In conclusion, we find that electroporation can enhance PNA antisense effects in muscle tissue.

Pessoa’s myth of the King Sebastian reinterpreted

OpenAIRE

Monika Świda

2013-01-01

The present paper depicts alterations undergone by the sleeping king motif (sebastianism) in the writings of Fernando Pessoa. The data to conduct the study were collected in thematic anthologies and several unpublished pieces. The myth of the King Sebastian was given a congregational dimension by Pessoa, thus conveying his cultural and identity project subsumed under the metaphor of the spiritual empire. Pessoa introduces some readjustments in the way the historical king is to be conceived of...

75 FR 34307 - King Kamehameha Day, 2010

Science.gov (United States)

2010-06-16

... Kamehameha Day, 2010 By the President of the United States of America A Proclamation Two hundred years ago, King Kamehameha the Great brought the Hawaiian Islands together under a unified government. His courage...'s concern for public safety.'' On this bicentennial King Kamehameha Day, we celebrate the history...

Persistent Dystrophin Protein Restoration 90 Days after a Course of Intraperitoneally Administered Naked 2′OMePS AON and ZM2 NP-AON Complexes in mdx Mice

Directory of Open Access Journals (Sweden)

Elena Bassi

2012-01-01

Full Text Available In Duchenne muscular dystrophy, the exon-skipping approach has obtained proof of concept in animal models, myogenic cell cultures, and following local and systemic administration in Duchenne patients. Indeed, we have previously demonstrated that low doses (7.5 mg/Kg/week of 2′-O-methyl-phosphorothioate antisense oligoribonucleotides (AONs adsorbed onto ZM2 nanoparticles provoke widespread dystrophin restoration 7 days after intraperitoneal treatment in mdx mice. In this study, we went on to test whether this dystrophin restoration was still measurable 90 days from the end of the same treatment. Interestingly, we found that both western blot and immunohistochemical analysis (up to 7% positive fibres were still able to detect dystrophin protein in the skeletal muscles of ZM2-AON-treated mice at this time, and the level of exon-23 skipping could still be assessed by RT real-time PCR (up to 10% of skipping percentage. In contrast, the protein was undetectable by western blot analysis in the skeletal muscles of mdx mice treated with an identical dose of naked AON, and the percentage of dystrophin-positive fibres and exon-23 skipping were reminiscent of those of untreated mdx mice. Our data therefore demonstrate the long-term residual efficacy of this systemic low-dose treatment and confirm the protective effect nanoparticles exert on AON molecules.

Dragon-Kings, Black-Swans and Prediction (Invited)

Science.gov (United States)

Sornette, D.

2010-12-01

Extreme fluctuations or events are often associated with power law statistics. Indeed, it is a popular belief that "wild randomness'' is deeply associated with distributions with power law tails characterized by small exponents. In other words, power law tails are often seen as the epitome of extreme events (the "Black Swan'' story). Here, we document in very different systems that there is life beyond power law tails: power laws can be superseded by "dragon-kings'', monster events that occur beyond (or changing) the power law tail. Dragon-kings reveal hidden mechanisms that are only transiently active and that amplify the normal fluctuations (often described by the power laws of the normal regime). The goal of this lecture is to catalyze the interest of the community of geophysicists across all fields of geosciences so that the "invisible gorilla" fallacy may be avoided. Our own research illustrates that new statistics or representation of data are often necessary to identify dragon-kings, with strategies guided by the underlying mechanisms. Paradoxically, the monsters may be ignored or hidden by the use of inappropriate analysis or statistical tools that amount to cut a mamooth in small pieces, so as to lead to the incorrect belief that only mice exist. In order to stimulate further research, we will document and discuss the dragon-king phenomenon on the statistics of financial losses, economic geography, hydrodynamic turbulence, mechanical ruptures, avalanches in complex heterogeneous media, earthquakes, and epileptic seizures. The special status of dragon-kings open a new research program on their predictability, based on the fact that they belong to a different class of their own and express specific mechanisms amplifying the normal dynamics via positive feedbacks. We will present evidence of these claims for the predictions of material rupture, financial crashes and epileptic seizures. As a bonus, a few remarks will be offered at the end on how the dragon-king

The King's Ring: A Matter of Trust

DEFF Research Database (Denmark)

Sterrett, Joseph William

2018-01-01

This essay examines the material and social effects of an exchange of trust between a king, Henry VIII, and his counsellor, Thomas Cranmer in Shakespeare and Fletcher’s All is True. The ring that the King gives Cranmer is both nothing and everything: nothing in that it could be anything, any ring...

Safety Evaluation Report related to renewal of the operating license for the CAVALIER Training Reactor at the University of Virginia (Docket No. 50-396)

International Nuclear Information System (INIS)

1985-05-01

This Safety Evaluation Report for the application filed by the University of Virginia for a renewal of Operating License R-123 to continue to operate the CAVALIER (Cooperatively Assembled Virginia Low Intensity Educational Reactor) has been prepared by the Office of Nuclear Reactor Regulation of the US Nuclear Regulatory Commission. The facility is owned and operated by the University of Virginia and is located on the campus in Charlottesville, Virginia. Based on its technical review, the staff concludes that the reactor facility can continue to be operated by the university without endangering the health and safety of the public or the environment

Short (16-mer locked nucleic acid splice-switching oligonucleotides restore dystrophin production in Duchenne Muscular Dystrophy myotubes.

Directory of Open Access Journals (Sweden)

Vanessa Borges Pires

Full Text Available Splice-switching antisense oligonucleotides (SSOs offer great potential for RNA-targeting therapies, and two SSO drugs have been recently approved for treating Duchenne Muscular Dystrophy (DMD and Spinal Muscular Atrophy (SMA. Despite promising results, new developments are still needed for more efficient chemistries and delivery systems. Locked nucleic acid (LNA is a chemically modified nucleic acid that presents several attractive properties, such as high melting temperature when bound to RNA, potent biological activity, high stability and low toxicity in vivo. Here, we designed a series of LNA-based SSOs complementary to two sequences of the human dystrophin exon 51 that are most evolutionary conserved and evaluated their ability to induce exon skipping upon transfection into myoblasts derived from a DMD patient. We show that 16-mers with 60% of LNA modification efficiently induce exon skipping and restore synthesis of a truncated dystrophin isoform that localizes to the plasma membrane of patient-derived myotubes differentiated in culture. In sum, this study underscores the value of short LNA-modified SSOs for therapeutic applications.

Quantitative analysis of the dystrophin gene by real-time PCR

Directory of Open Access Journals (Sweden)

Maksimovic Nela

2012-01-01

Full Text Available Duchenne and Becker muscular dystrophy (DMD/BMD are severe X-linked neuromuscular disorders caused by mutations in the dystrophin gene. Our aim was to optimize a quantitative real-time PCR method based on SYBR® Green I chemistry for routine diagnostics of DMD/BMD deletion carriers. Twenty female relatives of DMD/BMD patients with previously detected partial gene deletions were studied. The relative quantity of the target exons was calculated by a comparative threshold cycle method (ΔΔCt. The carrier status of all subjects was successfully determined. The gene dosage ratio for non-carriers was 1.07±0.20, and for carriers 0.56±0.11. This assay proved to be simple, rapid, reliable and cost-effective.

78 FR 5247 - Martin Luther King, Jr., Federal Holiday, 2013

Science.gov (United States)

2013-01-24

..., 2013 Martin Luther King, Jr., Federal Holiday, 2013 By the President of the United States of America A... thousands upon thousands rallying for jobs and freedom, the Reverend Dr. Martin Luther King, Jr., delivered... Constitution and the laws of the United States, do hereby proclaim January 21, 2013, as the Martin Luther King...

The Newest Monument: The Martin Luther King, Jr. National Memorial

Science.gov (United States)

Social Studies and the Young Learner, 2011

2011-01-01

This article features the newest monument, the Martin Luther King, Jr. National Memorial. The memorial on the National Mall in Washington, D.C., honoring Dr. Martin Luther King, Jr. will be an engaging landscape experience to convey four fundamental and recurring themes throughout Dr. King's life--democracy, justice, hope, and love. Natural…

God our king

African Journals Online (AJOL)

p1243322

the “king” metaphor for God is conceptually explained in terms of the relationship ... key metaphors, then it is essential to a God-talk that is grounded in the .... Jesus are both king (cf Eph 5:5), which means that God shares his kingship with the ...

Multiple species comparison of cardiac troponin T and dystrophin: unravelling the DNA behind dilated cardiomyopathy

OpenAIRE

England, Jennifer; Loughna, Siobhan; Rutland, Catrin S.

2017-01-01

Animals have frequently been used as models for human disorders and mutations. Following advances in genetic testing and treatment options, and the decreasing cost of these technologies in the clinic, mutations in both companion and commercial animals are now being investigated. A recent review highlighted the genes associated with both human and non-human dilated cardiomyopathy. Cardiac troponin T and dystrophin were observed to be associated with both human and turkey (troponin T) and canin...

[A study of treatise on medicine by King Sejo].

Science.gov (United States)

Hwang, Im-kyung; Hwang, Sang-lk

2003-12-01

This paper explores historical backgrounds and contents of Treatise on Medicine written by King Sejo (r. 1455-1468) including his views on traditional medicine and pharmacy in the early Chosen period. The Treatise declared by King Sejo in 1463 has been considered as an important and unique manual of medicine because it was the exclusive example written by the king of Chosen. It was the King Sejo' s era when the medical milieu in both social and medical aspects was highly encouraged thanks to the previous achievements by King Sejong the Great (r.1418-1450). King Sejo, in particular, who was much interested in practical learning called 'Miscellaneous Studies', emphasized on court medicine. His writing can be understood in such historical frame. Another reason why he wrote the Treatise can be said that he felt necessary for establishing the medical ethic codes for inefficient court medicine-officials. In personal background, he tried to find available remedies since he had been suffered from some chronic diseases. The contents of the Treatise can be broadly fallen to the clinical and ethical aspects. In the former one, the Treatise focuses on treatment without hesitation through the sharp and exact diagnosis by medical doctors. In the latter one, eight categories of medical doctors are discussed according to their moral degrees: sim'eui, sik'eui, yak'eui, hon'eui, kwang eui, mang'eui, sa'eui, and sal'eui. Finally, musim' ji-eui was supplemented. Among them, sal'eui, medicine-official lacking both medical ability and ethical attitude, was classified as the lowest degree; sim'eui, medicine-official sincerely making his all efforts for patients, was thought to be a paragon of medical morality. In conclusion, the Treatise on Medicine by King Sejo played an important role as a manual for the principle of medical practice and for the instruction to enhance ethical attitude among medicine-officials.

The city of the divine king

DEFF Research Database (Denmark)

Barnow, Niels Finn

2001-01-01

The City of the Divine King deals with urban systems and urban architecture in the river kingdoms of the Near East and the agrarian societies of the Orient. The book is part of a larger work comprising studies of the antique Greek world and the Roman Empire and the later developments of cities...... and villages in medieval Europe. The City of the Divine King is followed by volume 2: The City of the Landowner, about the Greco-Roman World, and volume 3: The City of the Merchant, about the medieval urban development in Europe....

Effective myotube formation in human adipose tissue-derived stem cells expressing dystrophin and myosin heavy chain by cellular fusion with mouse C2C12 myoblasts

Energy Technology Data Exchange (ETDEWEB)

Eom, Young Woo [Cell Therapy and Tissue Engineering Center, Wonju College of Medicine, Yonsei Univ., Wonju (Korea, Republic of); Biomedical Research Institute, Lifeliver Co., Ltd., Suwon (Korea, Republic of); Lee, Jong Eun; Yang, Mal Sook; Jang, In Keun; Kim, Hyo Eun; Lee, Doo Hoon; Kim, Young Jin [Biomedical Research Institute, Lifeliver Co., Ltd., Suwon (Korea, Republic of); Park, Won Jin [Dr. Park' s Aesthetic Clinic, Seoul (Korea, Republic of); Kong, Jee Hyun; Shim, Kwang Yong [Department of Hematology-Oncology, Wonju College of Medicine, Yonsei Univ., Wonju (Korea, Republic of); Lee, Jong In, E-mail: oncochem@yonsei.ac.kr [Department of Hematology-Oncology, Wonju College of Medicine, Yonsei Univ., Wonju (Korea, Republic of); Kim, Hyun Soo, E-mail: khsmd@unitel.co.kr [Department of Hematology-Oncology, Wonju College of Medicine, Yonsei Univ., Wonju (Korea, Republic of)

2011-04-29

Highlights: {yields} hASCs were differentiated into skeletal muscle cells by treatment with 5-azacytidine, FGF-2, and the supernatant of cultured hASCs. {yields} Dystrophin and MyHC were expressed in late differentiation step by treatment with the supernatant of cultured hASCs. {yields} hASCs expressing dystrophin and MyHC contributed to myotube formation during co-culture with mouse myoblast C2C12 cells. -- Abstract: Stem cell therapy for muscular dystrophies requires stem cells that are able to participate in the formation of new muscle fibers. However, the differentiation steps that are the most critical for this process are not clear. We investigated the myogenic phases of human adipose tissue-derived stem cells (hASCs) step by step and the capability of myotube formation according to the differentiation phase by cellular fusion with mouse myoblast C2C12 cells. In hASCs treated with 5-azacytidine and fibroblast growth factor-2 (FGF-2) for 1 day, the early differentiation step to express MyoD and myogenin was induced by FGF-2 treatment for 6 days. Dystrophin and myosin heavy chain (MyHC) expression was induced by hASC conditioned medium in the late differentiation step. Myotubes were observed only in hASCs undergoing the late differentiation step by cellular fusion with C2C12 cells. In contrast, hASCs that were normal or in the early stage were not involved in myotube formation. Our results indicate that stem cells expressing dystrophin and MyHC are more suitable for myotube formation by co-culture with myoblasts than normal or early differentiated stem cells expressing MyoD and myogenin.

Effective myotube formation in human adipose tissue-derived stem cells expressing dystrophin and myosin heavy chain by cellular fusion with mouse C2C12 myoblasts

International Nuclear Information System (INIS)

Eom, Young Woo; Lee, Jong Eun; Yang, Mal Sook; Jang, In Keun; Kim, Hyo Eun; Lee, Doo Hoon; Kim, Young Jin; Park, Won Jin; Kong, Jee Hyun; Shim, Kwang Yong; Lee, Jong In; Kim, Hyun Soo

2011-01-01

Highlights: → hASCs were differentiated into skeletal muscle cells by treatment with 5-azacytidine, FGF-2, and the supernatant of cultured hASCs. → Dystrophin and MyHC were expressed in late differentiation step by treatment with the supernatant of cultured hASCs. → hASCs expressing dystrophin and MyHC contributed to myotube formation during co-culture with mouse myoblast C2C12 cells. -- Abstract: Stem cell therapy for muscular dystrophies requires stem cells that are able to participate in the formation of new muscle fibers. However, the differentiation steps that are the most critical for this process are not clear. We investigated the myogenic phases of human adipose tissue-derived stem cells (hASCs) step by step and the capability of myotube formation according to the differentiation phase by cellular fusion with mouse myoblast C2C12 cells. In hASCs treated with 5-azacytidine and fibroblast growth factor-2 (FGF-2) for 1 day, the early differentiation step to express MyoD and myogenin was induced by FGF-2 treatment for 6 days. Dystrophin and myosin heavy chain (MyHC) expression was induced by hASC conditioned medium in the late differentiation step. Myotubes were observed only in hASCs undergoing the late differentiation step by cellular fusion with C2C12 cells. In contrast, hASCs that were normal or in the early stage were not involved in myotube formation. Our results indicate that stem cells expressing dystrophin and MyHC are more suitable for myotube formation by co-culture with myoblasts than normal or early differentiated stem cells expressing MyoD and myogenin.

A BanI RFLP at a deletion hotspot in the human dystrophin gene

Energy Technology Data Exchange (ETDEWEB)

Read, A P; Mountford, R [St. Mary' s Hospital, Manchester (England)

1990-01-25

Cf56a is a 0.9 kb EcoRI fragment of dystrophin cDNA in pUC13. Cf56a is identical to Kunkel's cDNA probe 8. Constant bands of 14.4, 11.0, 8.1, 6.2 and 1.3 kb correspond to exons I, N, L, N and K respectively. The polymorphic band is exon J (exon 48, 1.2+3.9 kb HindIII bands). This exon is deleted in 25% of all Duchenne/Becker dystrophy boys. Therefore this RFLP is useful for determining carrier status of at-risk females by showing heterozygosity or apparent non-maternity.

Long-Term Efficacy of Systemic Multiexon Skipping Targeting Dystrophin Exons 45–55 With a Cocktail of Vivo-Morpholinos in Mdx52 Mice

Directory of Open Access Journals (Sweden)

Yusuke Echigoya

2015-01-01

Full Text Available Antisense-mediated exon skipping, which can restore the reading frame, is a most promising therapeutic approach for Duchenne muscular dystrophy. Remaining challenges include the limited applicability to patients and unclear function of truncated dystrophin proteins. Multiexon skipping targeting exons 45–55 at the mutation hotspot of the dystrophin gene could overcome both of these challenges. Previously, we described the feasibility of exons 45–55 skipping with a cocktail of Vivo-Morpholinos in vivo; however, the long-term efficacy and safety of Vivo-Morpholinos remains to be determined. In this study, we examined the efficacy and toxicity of exons 45–55 skipping by intravenous injections of 6 mg/kg 10-Vivo-Morpholino cocktail (0.6 mg/kg each vPMO every 2 weeks for 18 weeks to dystrophic exon-52 knockout (mdx52 mice. Systemic skipping of the entire exons 45–55 region was induced, and the Western blot analysis exhibited the restoration of 5–27% of normal levels of dystrophin protein in skeletal muscles, accompanied by improvements in histopathology and muscle strength. No obvious immune response and renal and hepatic toxicity were detected at the end-point of the treatment. We demonstrate our new regimen with the 10-Vivo-Morpholino cocktail is effective and safe for long-term repeated systemic administration in the dystrophic mouse model.

MicroRNA-486–dependent modulation of DOCK3/PTEN/AKT signaling pathways improves muscular dystrophy–associated symptoms

Science.gov (United States)

Alexander, Matthew S.; Casar, Juan Carlos; Motohashi, Norio; Vieira, Natássia M.; Eisenberg, Iris; Marshall, Jamie L.; Gasperini, Molly J.; Lek, Angela; Myers, Jennifer A.; Estrella, Elicia A.; Kang, Peter B.; Shapiro, Frederic; Rahimov, Fedik; Kawahara, Genri; Widrick, Jeffrey J.; Kunkel, Louis M.

2014-01-01

Duchenne muscular dystrophy (DMD) is caused by mutations in the gene encoding dystrophin, which results in dysfunctional signaling pathways within muscle. Previously, we identified microRNA-486 (miR-486) as a muscle-enriched microRNA that is markedly reduced in the muscles of dystrophin-deficient mice (Dmdmdx-5Cv mice) and in DMD patient muscles. Here, we determined that muscle-specific transgenic overexpression of miR-486 in muscle of Dmdmdx-5Cv mice results in reduced serum creatine kinase levels, improved sarcolemmal integrity, fewer centralized myonuclei, increased myofiber size, and improved muscle physiology and performance. Additionally, we identified dedicator of cytokinesis 3 (DOCK3) as a miR-486 target in skeletal muscle and determined that DOCK3 expression is induced in dystrophic muscles. DOCK3 overexpression in human myotubes modulated PTEN/AKT signaling, which regulates muscle hypertrophy and growth, and induced apoptosis. Furthermore, several components of the PTEN/AKT pathway were markedly modulated by miR-486 in dystrophin-deficient muscle. Skeletal muscle–specific miR-486 overexpression in Dmdmdx-5Cv animals decreased levels of DOCK3, reduced PTEN expression, and subsequently increased levels of phosphorylated AKT, which resulted in an overall beneficial effect. Together, these studies demonstrate that stable overexpression of miR-486 ameliorates the disease progression of dystrophin-deficient skeletal muscle. PMID:24789910

Evolution of king crabs from hermit crab ancestors

Science.gov (United States)

Cunningham, C. W.; Blackstone, N. W.; Buss, L. W.

1992-02-01

KING crabs (Family Lithodidae) are among the world's largest arthropods, having a crab-like morphology and a strongly calcified exoskeleton1-6. The hermit crabs, by contrast, have depended on gastropod shells for protection for over 150 million years5,7. Shell-living has constrained the morphological evolution of hermit crabs by requiring a decalcified asymmetrical abdomen capable of coiling into gastropod shells and by preventing crabs from growing past the size of the largest available shells1-6. Whereas reduction in shell-living and acquisition of a crab-like morphology (carcinization) has taken place independently in several hermit crab lineages, and most dramatically in king crabs1-6, the rate at which this process has occurred was entirely unknown2,7. We present molecular evidence that king crabs are not only descended from hermit crabs, but are nested within the hermit crab genus Pagurus. We estimate that loss of the shell-living habit and the complete carcinization of king crabs has taken between 13 and 25 million years.

Human resources managers as custodians of the King III code

Directory of Open Access Journals (Sweden)

Frank de Beer

2015-05-01

Full Text Available The objective of this research was to perform an exploratory study on the knowledge and understanding of the King III code among Human Resources (HR managers in South African companies. The King III code is a comprehensive international corporate governance regime which addresses the financial, social, ethical and environmental practices of organisations. HR management plays a role in managing corporate governance by using the King III code as a guideline. The main research questions were: Does HR management know, understand, apply, and have the ability to use the King III code in terms of ethical decision-making? What role does HR management play in corporate governance? A random sample of available HR managers, senior HR consultants and HR directors was taken and semi-structured interviews were conducted. The results indicated that the respondents had no in-depth knowledge of the King III code. They did not fully understand the King III code and its implications nor did they use it to ensure ethical management. The themes most emphasised by the participants were: culture, reward and remuneration, policies and procedures and performance management. The participants emphasised the importance of these items  and HR’s role in managing them.

Dual Myostatin and Dystrophin Exon Skipping by Morpholino Nucleic Acid Oligomers Conjugated to a Cell-penetrating Peptide Is a Promising Therapeutic Strategy for the Treatment of Duchenne Muscular Dystrophy

Directory of Open Access Journals (Sweden)

Alberto Malerba

2012-01-01

Full Text Available The knockdown of myostatin, a negative regulator of skeletal muscle mass may have important implications in disease conditions accompanied by muscle mass loss like cancer, HIV/AIDS, sarcopenia, muscle atrophy, and Duchenne muscular dystrophy (DMD. In DMD patients, where major muscle loss has occurred due to a lack of dystrophin, the therapeutic restoration of dystrophin expression alone in older patients may not be sufficient to restore the functionality of the muscles. We recently demonstrated that phosphorodiamidate morpholino oligomers (PMOs can be used to re-direct myostatin splicing and promote the expression of an out-of-frame transcript so reducing the amount of the synthesized myostatin protein. Furthermore, the systemic administration of the same PMO conjugated to an octaguanidine moiety (Vivo-PMO led to a significant increase in the mass of soleus muscle of treated mice. Here, we have further optimized the use of Vivo-PMO in normal mice and also tested the efficacy of the same PMO conjugated to an arginine-rich cell-penetrating peptide (B-PMO. Similar experiments conducted in mdx dystrophic mice showed that B-PMO targeting myostatin is able to significantly increase the tibialis anterior (TA muscle weight and when coadministered with a B-PMO targeting the dystrophin exon 23, it does not have a detrimental interaction. This study confirms that myostatin knockdown by exon skipping is a potential therapeutic strategy to counteract muscle wasting conditions and dual myostatin and dystrophin skipping has potential as a therapy for DMD.

Haplotypes in the Dystrophin DNA Segment Point to a Mosaic Origin of Modern Human Diversity

OpenAIRE

Ziętkiewicz, Ewa; Yotova, Vania; Gehl, Dominik; Wambach, Tina; Arrieta, Isabel; Batzer, Mark; Cole, David E.C.; Hechtman, Peter; Kaplan, Feige; Modiano, David; Moisan, Jean-Paul; Michalski, Roman; Labuda, Damian

2003-01-01

Although Africa has played a central role in human evolutionary history, certain studies have suggested that not all contemporary human genetic diversity is of recent African origin. We investigated 35 simple polymorphic sites and one Tn microsatellite in an 8-kb segment of the dystrophin gene. We found 86 haplotypes in 1,343 chromosomes from around the world. Although a classical out-of-Africa topology was observed in trees based on the variant frequencies, the tree of haplotype sequences re...

Widespread and evolutionary analysis of a MITE family Monkey King in Brassicaceae.

Science.gov (United States)

Dai, Shutao; Hou, Jinna; Long, Yan; Wang, Jing; Li, Cong; Xiao, Qinqin; Jiang, Xiaoxue; Zou, Xiaoxiao; Zou, Jun; Meng, Jinling

2015-06-19

Miniature inverted repeat transposable elements (MITEs) are important components of eukaryotic genomes, with hundreds of families and many copies, which may play important roles in gene regulation and genome evolution. However, few studies have investigated the molecular mechanisms involved. In our previous study, a Tourist-like MITE, Monkey King, was identified from the promoter region of a flowering time gene, BnFLC.A10, in Brassica napus. Based on this MITE, the characteristics and potential roles on gene regulation of the MITE family were analyzed in Brassicaceae. The characteristics of the Tourist-like MITE family Monkey King in Brassicaceae, including its distribution, copies and insertion sites in the genomes of major Brassicaceae species were analyzed in this study. Monkey King was actively amplified in Brassica after divergence from Arabidopsis, which was indicated by the prompt increase in copy number and by phylogenetic analysis. The genomic variations caused by Monkey King insertions, both intra- and inter-species in Brassica, were traced by PCR amplification. Genomic sequence analysis showed that most complete Monkey King elements are located in gene-rich regions, less than 3kb from genes, in both the B. rapa and A. thaliana genomes. Sixty-seven Brassica expressed sequence tags carrying Monkey King fragments were also identified from the NCBI database. Bisulfite sequencing identified specific DNA methylation of cytosine residues in the Monkey King sequence. A fragment containing putative TATA-box motifs in the MITE sequence could bind with nuclear protein(s) extracted from leaves of B. napus plants. A Monkey King-related microRNA, bna-miR6031, was identified in the microRNA database. In transgenic A. thaliana, when the Monkey King element was inserted upstream of 35S promoter, the promoter activity was weakened. Monkey King, a Brassicaceae Tourist-like MITE family, has amplified relatively recently and has induced intra- and inter-species genomic

Somatic mosaicism of a point mutation in the dystrophin gene in a patient presenting with an asymmetrical muscle weakness and contractures

NARCIS (Netherlands)

Helderman-van den Enden, A. T. J. M.; Ginjaar, H. B.; Kneppers, A. L. J.; Bakker, E.; Breuning, M. H.; de Visser, M.

2003-01-01

We describe a patient with somatic mosaicism of a point mutation in the dystrophin gene causing benign muscular dystrophy with an unusual asymmetrical distribution of muscle weakness and contractures. To our knowledge this is the first patient with asymmetrical weakness and contractures in an

100-fold but not 50-fold dystrophin overexpression aggravates electrocardiographic defects in the mdx model of Duchenne muscular dystrophy

Directory of Open Access Journals (Sweden)

Yongping Yue

2016-01-01

Full Text Available Dystrophin gene replacement holds the promise of treating Duchenne muscular dystrophy. Supraphysiological expression is a concern for all gene therapy studies. In the case of Duchenne muscular dystrophy, Chamberlain and colleagues found that 50-fold overexpression did not cause deleterious side effect in skeletal muscle. To determine whether excessive dystrophin expression in the heart is safe, we studied two lines of transgenic mdx mice that selectively expressed a therapeutic minidystrophin gene in the heart at 50-fold and 100-fold of the normal levels. In the line with 50-fold overexpression, minidystrophin showed sarcolemmal localization and electrocardiogram abnormalities were corrected. However, in the line with 100-fold overexpression, we not only detected sarcolemmal minidystrophin expression but also observed accumulation of minidystrophin vesicles in the sarcoplasm. Excessive minidystrophin expression did not correct tachycardia, a characteristic feature of Duchenne muscular dystrophy. Importantly, several electrocardiogram parameters (QT interval, QRS duration and the cardiomyopathy index became worse than that of mdx mice. Our data suggests that the mouse heart can tolerate 50-fold minidystrophin overexpression, but 100-fold overexpression leads to cardiac toxicity.

Den radikale Kings skandinaviske drøm

DEFF Research Database (Denmark)

Brøndal, Jørn

2013-01-01

I dag forgudes Martin Luther King for sin racemæssige vision. Derimod aner de fleste amerikanere ikke noget om hans økonomiske ideer, og hvis de gjorde, ville mange af dem utvivlsomt affeje dem som alt for radikale......I dag forgudes Martin Luther King for sin racemæssige vision. Derimod aner de fleste amerikanere ikke noget om hans økonomiske ideer, og hvis de gjorde, ville mange af dem utvivlsomt affeje dem som alt for radikale...

The philosophical premises of the second King Report on corporate governance

Directory of Open Access Journals (Sweden)

G.J. Rossouw

2005-07-01

Full Text Available This article focuses on the philosophical presuppositions of the second King Report on corporate governance for South Africa (hereafter referred to as the King II Report. Especially in the “Introduction and Background” section of the King II Report it is clear that the Report is premised upon a specific understanding of the present-day corporation and its moral obligations. The purpose of this article is to commit what Charles Taylor called “an act of retrieval” in which the philosophical premises of the King II Report will be unearthed and exposed. It will be argued that the view of the present-day corporation that underlies the King II Report could be related back to a number of debates on the notion of the comtemporary corporation and its moral responsibilities that have been played out since the 1970s. It will be indicated how these debates provide the philosophical foundations for the view of the comtemporary corporation and its moral obligations that is espoused in the King II Report. The claim made in the Report that the African world view and culture influenced the Report’s notion of corporate governance will also be critically reviewed. Finally it will be attempted to evaluate to what extent the recommendations of the King II Report live up to its own philosophical premises.

Chilean Antarctic Stations on King George Island

Directory of Open Access Journals (Sweden)

Katsutada Kaminuma

2000-07-01

Full Text Available The purpose of my visit to Chilean Antarctic Stations was to assess the present status of geophysical observations and research, as the South Shetland Island, West Antarctica, where the stations are located, are one of the most active tectonic regions on the Antarctic plate. The Instituto Antartico Chileno (INACH kindly gave me a chance to stay in Frei/Escudero Bases as an exchange scientist under the Antarctic Treaty for two weeks in January 2000. I stayed in Frei Base as a member of a geological survey group named "Tectonic Evolution of the Antarctic Peninsula" which was organized by Prof. F. Herve, University of Chile, from January 05 to 19,2000. All my activity in the Antarctic was organized by INACH. During my stay in Frei Base, I also visited Bellingshausen (Russian, Great Wall (China and Artigas (Uruguay stations. All these stations are located within walking distance of Frei Base. King Sejong Station (Korea, located 10km east from Frei Base, and Jubany Base (Argentine, another 6km south-east from King Sejong Station, were also visited with the aid of a zodiac boat that was kindly operated for us by King Sejong Station. All stations except Escudero Base carry out meteorological observations. The seismological observations in Frei Base are operated by Washington State University of the U. S. monitoring of earthquake activity and three-component geomagnetic observations are done at King Sejong and Great Wall stations. Earth tide is monitored at Artigas Base. Continuous monitoring of GPS and gravity change are planned at King Sejong Station in the near future. Scientific research activities of each country in the area in the 1999/2000 Antarctic summer season were studied and the logistic ability of all stations was also assessed for our future international cooperation.

Rama in the royal title of the Hungarian kings

Directory of Open Access Journals (Sweden)

Živković Tibor D.

2004-01-01

Full Text Available The region (župa of Rama was enlisted in the official title of the Hungarian kings around 1138, as it is known from an official document. The exact answer to the question under which circumstances it happened has never been reached. It is most probable that Rama was not just other name for Bosnia as it was proposed in historiography, neither was a part of Bosnia conquered by military action of the Hungarian king around 1135. Having in mind that Rama was a part of the principality of Raška during the Early Middle Ages, it is quite possible that Rama became part of the official title of the Hungarian kings through some direct connections between ruling families of Hungary and Raška. The most probable answer could be reached through the examination of these relations. Namely, a daughter of Raška's župan, Uroš I, Helena, was married to the Hungarian crown prince Bela in 1129, when Rama was, most probably, part of Helena's dowry. When the crown prince became king of Hungary in 1131, Rama was included in his royal title. Later on during the Middle Ages Rama became part of Bosnia giving ground to the Hungarian kings to claim whole Bosnia as their heritage. .

76 FR 3819 - Martin Luther King, Jr., Federal Holiday, 2011

Science.gov (United States)

2011-01-20

... with the same strength, persistence, and determination exhibited by Dr. King, guided by the enduring... closer to Dr. King's vision of all Americans living and working together as one beloved community. NOW...

Dr. Martin Luther King, Jr. as Spiritual Leader

Directory of Open Access Journals (Sweden)

Andrea Pierce

2013-09-01

Full Text Available The purpose of this paper is to explore Dr. Martin Luther King Jr.’s spiritual leadership through his “I Have a Dream” speech. The paper explores the three characteristics of spiritual leadership as posed by Fry’s (2003 spiritual leadership theory: vision, hope/faith and altruistic love. The research draws upon these characteristics through qualitative content analysis of Dr. Martin Luther King Jr.’s “I Have a Dream” speech to illustrate Dr. King’s leadership as that of a spiritual leader. The research advances the spiritual leadership theory by establishing Dr. Martin Luther King Jr. as a spiritual leader. Through the illustration of Dr. King’s spiritual leadership, the characteristics of a spiritual leader are given tangible understanding.

Meet EPA researcher Dawn King

Science.gov (United States)

Research microbiologist Dawn King works in EPA’s National Exposure Research Laboratory where she identifies and assesses the health risk of microbial pathogens in water. This is her researchers at work profile.

A BanI RFLP at a deletion hotspot in the human dystrophin gene

Energy Technology Data Exchange (ETDEWEB)

Read, A.P.; Mountford, R. (St. Mary' s Hospital, Manchester (England))

1990-01-25

Cf56a is a 0.9 kb EcoRI fragment of dystrophin cDNA in pUC13. Cf56a is identical to Kunkel's cDNA probe 8. Constant bands of 14.4, 11.0, 8.1, 6.2 and 1.3 kb correspond to exons I, N, L, N and K respectively. The polymorphic band is exon J (exon 48, 1.2+3.9 kb HindIII bands). This exon is deleted in 25% of all Duchenne/Becker dystrophy boys. Therefore this RFLP is useful for determining carrier status of at-risk females by showing heterozygosity or apparent non-maternity.

A Palisade Fit for a King: Ideal architecture in King Harald Bluetooth's Jelling

DEFF Research Database (Denmark)

Jessen, Mads Dengsø; Holst, Mads Kähler; Lindblom, Charlotta

2014-01-01

family named on the rune stones in Jelling and in particular to the reign of King Harald Bluetooth. In addition to the structure and date of the palisade, the article will present the tentative results from a series of analyses regarding the construction, composition, function and demolition...

Of Gods and Kings

DEFF Research Database (Denmark)

Brisch, Nicole

2013-01-01

throughout history. This is not a new point but remains all too often underappreciated when discussing the blurring of lines between human and god as evidenced in the deification of kings. In ancient Mesopotamia, one of the oldest high civilizations in the world, it was a short-lived but nevertheless...

Black swans and dragon kings: A unified model

Science.gov (United States)

Eliazar, Iddo

2017-09-01

The term “black swan” is a metaphor for outlier events whose statistics are characterized by Pareto's Law and by Zipf's Law; namely, statistics governed by power-law tails. The term “dragon king” is a metaphor for a singular outlier event which, in comparison with all other outlier events, is in a league of its own. As an illustrative example consider the wealth of a family that is sampled at random from a medieval society: the nobility constitutes the black-swan category, and the royal family constitutes the dragon-king category. In this paper we present and analyze a dynamical model that generates, universally and jointly, black swans and dragon kings. According to this model, growing from the microscopic scale to the macroscopic scale, black swans and dragon kings emerge together and invariantly with respect to initial conditions.

Distal mdx muscle groups exhibiting up-regulation of utrophin and rescue of dystrophin-associated glycoproteins exemplify a protected phenotype in muscular dystrophy

Science.gov (United States)

Dowling, Paul; Culligan, Kevin; Ohlendieck, Kay

2002-02-01

Unique unaffected skeletal muscle fibres, unlike necrotic torso and limb muscles, may pave the way for a more detailed understanding of the molecular pathogenesis of inherited neuromuscular disorders and help to develop new treatment strategies for muscular dystrophies. The sparing of extraocular muscle in Duchenne muscular dystrophy is mostly attributed to the special protective properties of extremely fast-twitching small-diameter fibres, but here we show that distal muscles also represent a particular phenotype that is more resistant to necrosis. Immunoblot analysis of membranes isolated from the well established dystrophic animal model mdx shows that, in contrast to dystrophic limb muscles, the toe musculature exhibits an up-regulation of the autosomal dystrophin homologue utrophin and a concomitant rescue of dystrophin-associated glycoproteins. Thus distal mdx muscle groups provide a cellular system that naturally avoids myofibre degeneration which might be useful in the search for naturally occurring compensatory mechanisms in inherited skeletal muscle diseases.

Factor concentrates for the treatment of factor XIII deficiency.

Science.gov (United States)

Gootenberg, J E

1998-11-01

Factor XIII deficiency is a severe autosomal recessive bleeding disorder associated with a characteristic pattern of neonatal hemorrhage and a lifelong bleeding diathesis. Even relatively minor trauma can be followed by prolonged and recurrent bleeding. Intracranial hemorrhage is a frequent complication. With the development of safe and effective factor XIII concentrates, reliable prophylactic treatment is possible. Two plasma-derived, virus-inactivated factor XIII concentrates are currently in production. The first, Fibrogammin P, (Centeon LLC, King of Prussia, PA, USA; and Centeon Pharma GmbH, Marburg, Germany) is marketed in Europe, South America, South Africa, and Japan. It is distributed in the United States under a Food and Drug Administration Investigational New Drug Application. A second factor XIII concentrate (Bio Products Laboratory, Elstree, UK) is available for use only on a "named patient" compassionate basis in the United Kingdom. Patients with factor XIII deficiency who receive appropriately timed periodic infusions of such factor XIII concentrates are able to live normal lives, free from catastrophic bleeding episodes.

Sparks, signals and shock absorbers: how dystrophin loss causes muscular dystrophy.

Science.gov (United States)

Batchelor, Clare L; Winder, Steve J

2006-04-01

The dystrophin-glycoprotein complex (DGC) can be considered as a specialized adhesion complex, linking the extracellular matrix to the actin cytoskeleton, primarily in muscle cells. Mutations in several components of the DGC lead to its partial or total loss, resulting in various forms of muscular dystrophy. These typically manifest as progressive wasting diseases with loss of muscle integrity. Debate is ongoing about the precise function of the DGC: initially a strictly mechanical role was proposed but it has been suggested that there is aberrant calcium handling in muscular dystrophy and, more recently, changes in MAP kinase and GTPase signalling have been implicated in the aetiology of the disease. Here, we discuss new and interesting developments in these aspects of DGC function and attempt to rationalize the mechanical, calcium and signalling hypotheses to provide a unifying hypothesis of the underlying process of muscular dystrophy.

Stick balancing, falls and Dragon-Kings

Science.gov (United States)

Cabrera, J. L.; Milton, J. G.

2012-05-01

The extent to which the occurrence of falls, the dominant feature of human attempts to balance a stick at their fingertip, can be predicted is examined in the context of the "Dragon-King" hypothesis. For skilled stick balancers, fluctuations in the controlled variable, namely the vertical displacement angle θ, exhibit power law behaviors. When stick balancing is made less stable by either decreasing the length of the stick or by requiring the subject to balance the stick on the surface of a table tennis racket, systematic departures from the power law behaviors are observed in the range of large θ. This observation raises the possibility that the presence of departures from the power law in the large length scale region, possibly Dragon-Kings, may identify situations in which the occurrence of a fall is more imminent. However, whether or not Dragon-Kings are observed, there is a Weibull-type survival function for stick falling. The possibility that increased risk of falling can, at least to some extent, be predicted from fluctuations in the controlled variable before the event occurs has important implications for the development of preventative strategies for the management of phenomena ranging from earthquakes to epileptic seizures to falls in the elderly.

The anatomy of the king crab Hapalogaster mertensii Brandt, 1850 (Anomura: Paguroidea: Hapalogastridae): new insights into the evolutionary transformation of hermit crabs into king crabs

NARCIS (Netherlands)

Keiler, J.; Richter, S.; Wirkner, C.S.

2015-01-01

The emergence of king crabs from a hermit crab-like ancestor is one of the most curious events in decapod evolution. King crabs comprise two taxa, Lithodidae and Hapalogastridae, and while lithodids have formed the focus of various anatomical studies, the internal anatomy of hapalogastrids has never

The Applicability of Governance at King Saud University in Riyadh

Science.gov (United States)

Kentab, Mohammad Y.

2018-01-01

The problem of the study revolves around the application of the requirements of governance at King Saud University. The study aims to identify the extent of governance requirements at King Saud University as seen by faculty members through transparency, accountability, organizational structure, laws, regulations, and justice. To achieve the…

Toward Inclusive Understandings of Marriage in an Early Childhood Classroom: Negotiating (Un)readiness, Community, and Vulnerability through a Critical Reading of "King and King"

Science.gov (United States)

Bentley, Dana Frantz; Souto-Manning, Mariana

2016-01-01

This collaborative classroom research study examines the ways in which preschoolers made sense of same-sex marriage through a critical reading of the book "King and King" by De Haan and Nijland. Acknowledging the importance of community in doing critical and political work, this article details the ways in which a preschool teacher and a…

Na+-H+ exchanger and proton channel in heart failure associated with Becker and Duchenne muscular dystrophies.

Science.gov (United States)

Bkaily, Ghassan; Jacques, Danielle

2017-10-01

Cardiomyopathy is found in patients with Duchenne (DMD) and Becker (BMD) muscular dystrophies, which are linked muscle diseases caused by mutations in the dystrophin gene. Dystrophin defects are not limited to DMD but are also present in mild BMD. The hereditary cardiomyopathic hamster of the UM-X7.1 strain is a particular experimental model of heart failure (HF) leading to early death in muscular dystrophy (dystrophin deficiency and sarcoglycan mutation) and heart disease (δ-sarcoglycan deficiency and dystrophin mutation) in human DMD. Using this model, our previous work showed a defect in intracellular sodium homeostasis before the appearance of any apparent biochemical and histological defects. This was attributed to the continual presence of the fetal slow sodium channel, which was also found to be active in human DMD. Due to muscular intracellular acidosis, the intracellular sodium overload in DMD and BMD was also due to sodium influx through the sodium-hydrogen exchanger NHE-1. Lifetime treatment with an NHE-1 inhibitor prevented intracellular Na + overload and early death due to HF. Our previous work also showed that another proton transporter, the voltage-gated proton channel (Hv1), exists in many cell types including heart cells and skeletal muscle fibers. The Hv1 could be indirectly implicated in the beneficial effect of blocking NHE-1.

The labour ward analgesic service at King Edward VIII Hospital ...

African Journals Online (AJOL)

The labour ward analgesic service at King Edward VIII. Hospital, Durban. D. A. ROCKE, C. C. ROUT, H. D. RUSSELL, S. SINGH. Abstract The provision of analgesic services to the labour ward at King Edward VIII Hospital was studied during a I-week period. Of249 patients, 113 (45%) received no analgesia whatsoever.

1/13 the establishment of kingdoms and the identification of kings ...

African Journals Online (AJOL)

Dr Tanya du Plessis

disputes, but this article will focus on the newly-created positions of kings and queens. 2 .... (2) The person currently holding office as the King of the Zulu nation .... community (tribe) is no better than the colonial-apartheid recognition of tribes.

Missense mutation Lys18Asn in dystrophin that triggers X-linked dilated cardiomyopathy decreases protein stability, increases protein unfolding, and perturbs protein structure, but does not affect protein function.

Directory of Open Access Journals (Sweden)

Surinder M Singh

Full Text Available Genetic mutations in a vital muscle protein dystrophin trigger X-linked dilated cardiomyopathy (XLDCM. However, disease mechanisms at the fundamental protein level are not understood. Such molecular knowledge is essential for developing therapies for XLDCM. Our main objective is to understand the effect of disease-causing mutations on the structure and function of dystrophin. This study is on a missense mutation K18N. The K18N mutation occurs in the N-terminal actin binding domain (N-ABD. We created and expressed the wild-type (WT N-ABD and its K18N mutant, and purified to homogeneity. Reversible folding experiments demonstrated that both mutant and WT did not aggregate upon refolding. Mutation did not affect the protein's overall secondary structure, as indicated by no changes in circular dichroism of the protein. However, the mutant is thermodynamically less stable than the WT (denaturant melts, and unfolds faster than the WT (stopped-flow kinetics. Despite having global secondary structure similar to that of the WT, mutant showed significant local structural changes at many amino acids when compared with the WT (heteronuclear NMR experiments. These structural changes indicate that the effect of mutation is propagated over long distances in the protein structure. Contrary to these structural and stability changes, the mutant had no significant effect on the actin-binding function as evident from co-sedimentation and depolymerization assays. These results summarize that the K18N mutation decreases thermodynamic stability, accelerates unfolding, perturbs protein structure, but does not affect the function. Therefore, K18N is a stability defect rather than a functional defect. Decrease in stability and increase in unfolding decrease the net population of dystrophin molecules available for function, which might trigger XLDCM. Consistently, XLDCM patients have decreased levels of dystrophin in cardiac muscle.

King and King: Learning to Treat Others Royally Through Diversity Education

OpenAIRE

Dube', Danielle

2009-01-01

Of the hate crimes reported to the FBI in 2007, 16.6% were the result of a sexual orientation bias. In the wake of horrific hate crimes such as the shooting and death of Lawrence King earlier this year, killed because of his sexual orientation, and the murder of Matthew Shepard ten years ago, homophobia and its effects must be addressed. A proposed solution to the problem is mandatory diversity education in public schools, with no parental opt out.

Articulating nurse practitioner practice using King's theory of goal attainment.

Science.gov (United States)

de Leon-Demare, Kathleen; MacDonald, Jane; Gregory, David M; Katz, Alan; Halas, Gayle

2015-11-01

To further understand the interactions between nurse practitioners (NPs) and patients, King's nursing theory of goal attainment was applied as the conceptual framework to describe the interactions between NPs and patients in the primary care setting. Six dyads of NPs and their patients were video- and audio-taped over three consecutive clinic visits. For the purposes of this arm of the study, the audio-taped interactions were transcribed and then coded using King's concepts in her theory of goal attainment. King's theory was applicable to describe NP practice. King's concepts and processes of nurse-patient interactions, such as disturbances, mutual goal setting, and transactions, were observed in NP-patient interactions. Disturbances during clinical encounters were essential in the progression toward goal attainment. Elements, such as social exchange, symptom reporting, role explanation, and information around clinical processes facilitated relationship building. NPs as practitioners need to be reflective of their own practice, embrace disturbances in the clinical encounter, and attend to these as opportunities for mutual goal setting. ©2015 American Association of Nurse Practitioners.

Opportunity Captures 'Lion King' Panorama

Science.gov (United States)

2004-01-01

[figure removed for brevity, see original site] Click on the image for Opportunity Captures 'Lion King' Panorama (QTVR) This approximate true-color panorama, dubbed 'Lion King,' shows 'Eagle Crater' and the surrounding plains of Meridiani Planum. It was obtained by the Mars Exploration Rover Opportunity's panoramic camera on sols 58 and 60 using infrared (750-nanometer), green (530-nanometer) and blue (430-nanometer) filters. This is the largest panorama obtained yet by either rover. It was taken in eight segments using six filters per segment, for a total of 558 images and more than 75 megabytes of data. Additional lower elevation tiers were added to ensure that the entire crater was covered in the mosaic. This panorama depicts a story of exploration including the rover's lander, a thorough examination of the outcrop, a study of the soils at the near-side of the lander, a successful exit from Eagle Crater and finally the rover's next desination, the large crater dubbed 'Endurance'.

His Majesty King Abdullah II of the Hashemite Kingdom of Jordan.

CERN Multimedia

Patrice Loïez

2003-01-01

Photo 03: King of Jordan visited some ATLAS installations. From left to right: Maurice Bourquin, President of the CERN Council, Luciano Maiani, Director-General of CERN, King Abdullah II of Jordan, Herwig Schopper, President of the SESAME Council and Peter Jenni, ATLAS spokesman.

King Harald V and Queen Sonja of Norway visit CERN

CERN Multimedia

Maximilien Brice

2006-01-01

Norway's King Harald V and Queen Sonja take a tour of the ATLAS detector with CERN's Director-General Robert Aymar in April 2006. During their visit the royal party met with members of CERN's Norwegian community. A group of about 40 students greeted the royal motorcade with a belting rendition of 'The King's Song', Norway's royal anthem.

Sensitivity and Frequencies of Dystrophin Gene Mutations in Thai DMD/BMD Patients As Detected by Multiplex PCR

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Thanyachai Sura

2008-01-01

Full Text Available Background: Duchenne muscular dystrophy (DMD, a lethal X-linked disease affecting 1 in 3500 male births, and its more benign variant, Becker muscular dystrophy (BMD, are caused by mutations in the dystrophin gene. Because of its large size, analysing the whole gene is impractical. Methods have been developed to detect the commonest mutations i.e. the deletions of the exons. Although these tests are highly specific, their sensitivity is inherently limited by the prevalence of deletions, which differs among different populations.

Exonization of an Intronic LINE-1 Element Causing Becker Muscular Dystrophy as a Novel Mutational Mechanism in Dystrophin Gene.

Science.gov (United States)

Gonçalves, Ana; Oliveira, Jorge; Coelho, Teresa; Taipa, Ricardo; Melo-Pires, Manuel; Sousa, Mário; Santos, Rosário

2017-10-03

A broad mutational spectrum in the dystrophin ( DMD ) gene, from large deletions/duplications to point mutations, causes Duchenne/Becker muscular dystrophy (D/BMD). Comprehensive genotyping is particularly relevant considering the mutation-centered therapies for dystrophinopathies. We report the genetic characterization of a patient with disease onset at age 13 years, elevated creatine kinase levels and reduced dystrophin labeling, where multiplex-ligation probe amplification (MLPA) and genomic sequencing failed to detect pathogenic variants. Bioinformatic, transcriptomic (real time PCR, RT-PCR), and genomic approaches (Southern blot, long-range PCR, and single molecule real-time sequencing) were used to characterize the mutation. An aberrant transcript was identified, containing a 103-nucleotide insertion between exons 51 and 52, with no similarity with the DMD gene. This corresponded to the partial exonization of a long interspersed nuclear element (LINE-1), disrupting the open reading frame. Further characterization identified a complete LINE-1 (~6 kb with typical hallmarks) deeply inserted in intron 51. Haplotyping and segregation analysis demonstrated that the mutation had a de novo origin. Besides underscoring the importance of mRNA studies in genetically unsolved cases, this is the first report of a disease-causing fully intronic LINE-1 element in DMD , adding to the diversity of mutational events that give rise to D/BMD.

Exonization of an Intronic LINE-1 Element Causing Becker Muscular Dystrophy as a Novel Mutational Mechanism in Dystrophin Gene

Science.gov (United States)

Gonçalves, Ana; Coelho, Teresa; Melo-Pires, Manuel; Sousa, Mário

2017-01-01

A broad mutational spectrum in the dystrophin (DMD) gene, from large deletions/duplications to point mutations, causes Duchenne/Becker muscular dystrophy (D/BMD). Comprehensive genotyping is particularly relevant considering the mutation-centered therapies for dystrophinopathies. We report the genetic characterization of a patient with disease onset at age 13 years, elevated creatine kinase levels and reduced dystrophin labeling, where multiplex-ligation probe amplification (MLPA) and genomic sequencing failed to detect pathogenic variants. Bioinformatic, transcriptomic (real time PCR, RT-PCR), and genomic approaches (Southern blot, long-range PCR, and single molecule real-time sequencing) were used to characterize the mutation. An aberrant transcript was identified, containing a 103-nucleotide insertion between exons 51 and 52, with no similarity with the DMD gene. This corresponded to the partial exonization of a long interspersed nuclear element (LINE-1), disrupting the open reading frame. Further characterization identified a complete LINE-1 (~6 kb with typical hallmarks) deeply inserted in intron 51. Haplotyping and segregation analysis demonstrated that the mutation had a de novo origin. Besides underscoring the importance of mRNA studies in genetically unsolved cases, this is the first report of a disease-causing fully intronic LINE-1 element in DMD, adding to the diversity of mutational events that give rise to D/BMD. PMID:28972564

High Prevalence of Vitamin D Deficiency among Pregnant Saudi Women

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Nora A. Al-Faris

2016-02-01

Full Text Available Vitamin D deficiency has emerged as a public health problem worldwide due to its important role in health and disease. The present work is intended to examine prevalence of vitamin D deficiency among pregnant Saudi women and related risk factors. A cross-sectional study was carried out at King Fahad Medical City in Riyadh, Saudi Arabia. Serum 25-hydroxy vitamin D (25(OHD was measured by enzyme-linked immunosorbent assay in 160 pregnant women during the first trimester of pregnancy. Socio-demographic, lifestyle and maternal characteristics were collected and vitamin D intake was assessed using a 24-h dietary recall. Weight and height were measured using standardized methods. Vitamin D deficiency (25(OHD < 50 nmol/L and insufficiency (25(OHD = 50–74 nmol/L were reported in 50% and 43.8% of the study sample, respectively. Median serum 25(OHD concentration was 49.9 nmol/L. Adequate vitamin D intake (≥600 IU/day was reported among only 8.1% of pregnant women. Age group, educational level, sun exposure frequency and daytime and daily practice of exercise were significantly associated with vitamin D status. Overall, vitamin D deficiency was common among pregnant Saudi women in Riyadh. Steps should be taken to address the current situation, including increased sunlight exposure, consumption of fatty fish, and vitamin D supplements.

High Prevalence of Vitamin D Deficiency among Pregnant Saudi Women.

Science.gov (United States)

Al-Faris, Nora A

2016-02-04

Vitamin D deficiency has emerged as a public health problem worldwide due to its important role in health and disease. The present work is intended to examine prevalence of vitamin D deficiency among pregnant Saudi women and related risk factors. A cross-sectional study was carried out at King Fahad Medical City in Riyadh, Saudi Arabia. Serum 25-hydroxy vitamin D (25(OH)D) was measured by enzyme-linked immunosorbent assay in 160 pregnant women during the first trimester of pregnancy. Socio-demographic, lifestyle and maternal characteristics were collected and vitamin D intake was assessed using a 24-h dietary recall. Weight and height were measured using standardized methods. Vitamin D deficiency (25(OH)D L) and insufficiency (25(OH)D = 50-74 nmol/L) were reported in 50% and 43.8% of the study sample, respectively. Median serum 25(OH)D concentration was 49.9 nmol/L. Adequate vitamin D intake (≥600 IU/day) was reported among only 8.1% of pregnant women. Age group, educational level, sun exposure frequency and daytime and daily practice of exercise were significantly associated with vitamin D status. Overall, vitamin D deficiency was common among pregnant Saudi women in Riyadh. Steps should be taken to address the current situation, including increased sunlight exposure, consumption of fatty fish, and vitamin D supplements.

45 King: A Story of the Southern Home

OpenAIRE

Deluca, Paul Matthew Webb

2014-01-01

The house at 45 King St. in Charleston, South Carolina is more than a home. It is a story of the home. A story told through history, through a vision exhibited in architectural drawings, and through the social heritage closest to my heart. 45 King is a story for the South; the story of its grandeur, its climate, its natural beauty, its hospitality, its comfort, and its veils. It is a story that was told yesterday and one that is still told today. Like an oral history, the telling of it may...

78 FR 39599 - Safety Zone; Independence Day Fireworks, Kings Beach, CA

Science.gov (United States)

2013-07-02

... Zone; Independence Day Fireworks, Kings Beach, CA AGENCY: Coast Guard, DHS. ACTION: Notice of... Fireworks, Kings Beach, CA in the Captain of the Port, San Francisco area of responsibility during the dates... from the hazards associated with the fireworks display. During the enforcement period, unauthorized...

Three Kings and the Bright Star of Fame

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Emalyn J. Bullis

2013-12-01

Full Text Available Many phenomena in music history as well as in American history have helped develop and shape the types of music listened to today, but none have been so fresh as looking back to twentieth-century popular music and the several key individuals that “ruled” in this area. These “rulers” were hailed as “kings” firstly as a media ploy, but the American public did nothing but encourage the titles. This is somewhat confusing considering American’s pride in their democratic political system but history shows that in several key American cultural changes the “Kings” crowned in the music sphere are representative of these changes. While not difficult to determine who these individuals are, as most of them were hailed and recognized as “Kings” to their respective audiences. Benny Goodman, the King of Swing, in the 1920’s and 30’s helped usher in and popularize the Swing movement. Elvis Presley, the King of Rock and Roll, capitalized (intentionally or not on the move towards combining African-American sounds such as blues and jazz with folk, gospel, and soul, thus creating a whole new and extremely popular sound. Michael Jackson, the King of Pop, was practically born into fame with his involvement with the ‘Jackson 5,’ but that did not stop him from rising up the ladder of fame in his solo career to change the face of pop music forever. There were also many artists that surrounded these “kings,” a court, if you will, that allowed their new styles to proliferate throughout American culture, and sometimes even surpassed them musically. However, as icons, these men stand on their own for their achievements in music and their ability to change and adapt to the culture around them. By looking at the three Kings of American pop culture’s past, it is possible to see the direction of America’s culture in general from the 1920’s on and perhaps see the trajectory of music of the USA today

Somatodendritic and excitatory postsynaptic distribution of neuron-type dystrophin isoform, Dp40, in hippocampal neurons

Energy Technology Data Exchange (ETDEWEB)

Fujimoto, Takahiro; Itoh, Kyoko, E-mail: kxi14@koto.kpu-m.ac.jp; Yaoi, Takeshi; Fushiki, Shinji

2014-09-12

Highlights: • Identification of dystrophin (Dp) shortest isoform, Dp40, is a neuron-type Dp. • Dp40 expression is temporally and differentially regulated in comparison to Dp71. • Somatodendritic and nuclear localization of Dp40. • Dp40 is localized to excitatory postsynapses. • Dp40 might play roles in dendritic and synaptic functions. - Abstract: The Duchenne muscular dystrophy (DMD) gene produces multiple dystrophin (Dp) products due to the presence of several promoters. We previously reported the existence of a novel short isoform of Dp, Dp40, in adult mouse brain. However, the exact biochemical expression profile and cytological distribution of the Dp40 protein remain unknown. In this study, we generated a polyclonal antibody against the NH{sub 2}-terminal region of the Dp40 and identified the expression profile of Dp40 in the mouse brain. Through an analysis using embryonic and postnatal mouse cerebrums, we found that Dp40 emerged from the early neonatal stages until adulthood, whereas Dp71, an another Dp short isoform, was highly detected in both prenatal and postnatal cerebrums. Intriguingly, relative expressions of Dp40 and Dp71 were prominent in cultured dissociated neurons and non-neuronal cells derived from mouse hippocampus, respectively. Furthermore, the immunocytological distribution of Dp40 was analyzed in dissociated cultured neurons, revealing that Dp40 is detected in the soma and its dendrites, but not in the axon. It is worthy to note that Dp40 is localized along the subplasmalemmal region of the dendritic shafts, as well as at excitatory postsynaptic sites. Thus, Dp40 was identified as a neuron-type Dp possibly involving dendritic and synaptic functions.

Somatodendritic and excitatory postsynaptic distribution of neuron-type dystrophin isoform, Dp40, in hippocampal neurons

International Nuclear Information System (INIS)

Fujimoto, Takahiro; Itoh, Kyoko; Yaoi, Takeshi; Fushiki, Shinji

2014-01-01

Highlights: • Identification of dystrophin (Dp) shortest isoform, Dp40, is a neuron-type Dp. • Dp40 expression is temporally and differentially regulated in comparison to Dp71. • Somatodendritic and nuclear localization of Dp40. • Dp40 is localized to excitatory postsynapses. • Dp40 might play roles in dendritic and synaptic functions. - Abstract: The Duchenne muscular dystrophy (DMD) gene produces multiple dystrophin (Dp) products due to the presence of several promoters. We previously reported the existence of a novel short isoform of Dp, Dp40, in adult mouse brain. However, the exact biochemical expression profile and cytological distribution of the Dp40 protein remain unknown. In this study, we generated a polyclonal antibody against the NH 2 -terminal region of the Dp40 and identified the expression profile of Dp40 in the mouse brain. Through an analysis using embryonic and postnatal mouse cerebrums, we found that Dp40 emerged from the early neonatal stages until adulthood, whereas Dp71, an another Dp short isoform, was highly detected in both prenatal and postnatal cerebrums. Intriguingly, relative expressions of Dp40 and Dp71 were prominent in cultured dissociated neurons and non-neuronal cells derived from mouse hippocampus, respectively. Furthermore, the immunocytological distribution of Dp40 was analyzed in dissociated cultured neurons, revealing that Dp40 is detected in the soma and its dendrites, but not in the axon. It is worthy to note that Dp40 is localized along the subplasmalemmal region of the dendritic shafts, as well as at excitatory postsynaptic sites. Thus, Dp40 was identified as a neuron-type Dp possibly involving dendritic and synaptic functions

Bone Marrow Transplantation for Leukocyte Adhesion Deficiency-I: Case Report

International Nuclear Information System (INIS)

Al-wahadneh, A.M.; Haddadin, I.; Hamouri, M.; Omari, K.; Ajellat, F.

2006-01-01

Leukocyte Adhesion Deficiency type-I (LAD-I) is a rare autosomal recessive immunodeficiency syndrome leading recurrent bacterial and fungal infections. Bone marrow transplantation offers the only cure. In this report, we describe the course and outcome of bone marrow transplant in a 4-month-old female infant with LAD-I at King Hussein Medical Center, Jordan. A successful matched HLA-I related allogeneic bone marrow transplantation was performed. Engraftment was demonstrated on the 12th day. The patient developed GradeIII grafts versus host disease (GVHD), veno-occlusive disease of the liver and late onset hemorrhagic cystitis. She recovered with appropriate immune reconstitution. (author)

King Chulalongkorn: biography and his activities in medicine and public health.

Science.gov (United States)

Charulukananan, Somrat; Sueblinvong, Tada

2003-06-01

King Rama V, or Chulalongkorn, was the fifth monarch of the Chakri Dynasty. He was one of the most beloved of the Thai kings due to his many activities including abolishing slavery without bloodshed and especially his skillful diplomacy which succeeded in steering Siam out of the grips of the colonial powers. His activities also included reform of the administration of the kingdom according to the European model and in bringing Siam into the modern era with such exquisite skills that he is still vividly remembered today. His reign also saw many developments in medicine and public health. The King's role in these areas, however, were clouded by his more visible activities in politics and diplomacy. The result is that the Thai public learned rather little about his role in these areas. This article aims at collecting this and to show the King's very important role in modernizing medicine and public health in Siam.

Nanopatterned muscle cell patches for enhanced myogenesis and dystrophin expression in a mouse model of muscular dystrophy.

Science.gov (United States)

Yang, Hee Seok; Ieronimakis, Nicholas; Tsui, Jonathan H; Kim, Hong Nam; Suh, Kahp-Yang; Reyes, Morayma; Kim, Deok-Ho

2014-02-01

Skeletal muscle is a highly organized tissue in which the extracellular matrix (ECM) is composed of highly-aligned cables of collagen with nanoscale feature sizes, and provides structural and functional support to muscle fibers. As such, the transplantation of disorganized tissues or the direct injection of cells into muscles for regenerative therapy often results in suboptimal functional improvement due to a failure to integrate with native tissue properly. Here, we present a simple method in which biodegradable, biomimetic substrates with precisely controlled nanotopography were fabricated using solvent-assisted capillary force lithography (CFL) and were able to induce the proper development and differentiation of primary mononucleated cells to form mature muscle patches. Cells cultured on these nanopatterned substrates were highly-aligned and elongated, and formed more mature myotubes as evidenced by up-regulated expression of the myogenic regulatory factors Myf5, MyoD and myogenin (MyoG). When transplanted into mdx mice models for Duchenne muscular dystrophy (DMD), the proposed muscle patches led to the formation of a significantly greater number of dystrophin-positive muscle fibers, indicating that dystrophin replacement and myogenesis is achievable in vivo with this approach. These results demonstrate the feasibility of utilizing biomimetic substrates not only as platforms for studying the influences of the ECM on skeletal muscle function and maturation, but also to create transplantable muscle cell patches for the treatment of chronic and acute muscle diseases or injuries. Copyright © 2013 Elsevier Ltd. All rights reserved.

Identification of new dystroglycan complexes in skeletal muscle.

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Eric K Johnson

Full Text Available The dystroglycan complex contains the transmembrane protein β-dystroglycan and its interacting extracellular mucin-like protein α-dystroglycan. In skeletal muscle fibers, the dystroglycan complex plays an important structural role by linking the cytoskeletal protein dystrophin to laminin in the extracellular matrix. Mutations that affect any of the proteins involved in this structural axis lead to myofiber degeneration and are associated with muscular dystrophies and congenital myopathies. Because loss of dystrophin in Duchenne muscular dystrophy (DMD leads to an almost complete loss of dystroglycan complexes at the myofiber membrane, it is generally assumed that the vast majority of dystroglycan complexes within skeletal muscle fibers interact with dystrophin. The residual dystroglycan present in dystrophin-deficient muscle is thought to be preserved by utrophin, a structural homolog of dystrophin that is up-regulated in dystrophic muscles. However, we found that dystroglycan complexes are still present at the myofiber membrane in the absence of both dystrophin and utrophin. Our data show that only a minority of dystroglycan complexes associate with dystrophin in wild type muscle. Furthermore, we provide evidence for at least three separate pools of dystroglycan complexes within myofibers that differ in composition and are differentially affected by loss of dystrophin. Our findings indicate a more complex role of dystroglycan in muscle than currently recognized and may help explain differences in disease pathology and severity among myopathies linked to mutations in DAPC members.

A translational approach for limb vascular delivery of the micro-dystrophin gene without high volume or high pressure for treatment of Duchenne muscular dystrophy

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Chicoine Louis G

2007-09-01

Full Text Available Abstract Background Duchenne muscular dystrophy (DMD is an X-linked recessive disorder with monogenic mutations setting the stage for successful gene therapy treatment. We have completed a study that directly deals with the following key issues that can be directly adapted to a gene therapy clinical trial using rAAV considering the following criteria: 1 A regional vascular delivery approach that will protect the patient from widespread dissemination of virus; 2 an approach to potentially facilitate safe passage of the virus for efficient skeletal muscle transduction; 3 the use of viral doses to accommodate current limitations imposed by vector production methods; 4 and at the same time, achieve a clinically meaningful outcome by transducing multiple muscles in the lower limb to prolong ambulation. Methods The capacity of AAV1, AAV6 or AAV8 to cross the vascular endothelial barrier carrying a micro-dystrophin cDNA was compared under identical conditions with delivery through a catheter placed in the femoral artery of the mdx mouse. Transduction efficiency was assessed by immuno-staining using an antibody (Manex1a that recognizes the N-terminus of micro-dystrophin. The degree of physiologic correction was assessed by measuring tetanic force and protection from eccentric contraction in the extensor digitorum longus muscle (EDL. The vascular delivery paradigm found successful in the mouse was carried to the non-human primate to test its potential translation to boys with DMD. Results Regional vascular delivery resulted in transduction by rAAV8.micro-dystrophin reaching 94.5 ± 0.9 (1 month, 91.3 ± 3.1 (2 months, and 89.6 ± 1.6% (3 months. rAAV6.micro-dystrophin treated animals demonstrated 87.7 ± 6.8 (1 month, 78.9 ± 7.4 (2 months, and 81.2 ± 6.2% (3 months transduction. In striking contrast, rAAV1 demonstrated very low transduction efficiency [0.9 ± 0.3 (1 month, 2.1 ± 0.8 (2 months, and 2.1 ± 0.7% (3 months] by vascular delivery. Micro-dystrophin

Matthew's Messianic Shepherd-king: In search of “the lost sheep of ...

African Journals Online (AJOL)

p1243322

the Messianic Shepherd-King expectation with its attending expectations for territorial ... Messianic Shepherd-King: In Search of the Lost Sheep of the House of Israel. September. 2007. Berlin: De Gruyter. ...... Exile in the early. Persian Period”.

RT-PCR analysis of dystrophin mRNA in DND/BMD patients

Energy Technology Data Exchange (ETDEWEB)

Ciafaloni, E.; Silva, H.A.R. de; Roses, A.D. [Duke Univ. Medical Center, Durham, NC (United States)

1994-09-01

Duchenne and Becker muscular dystrophies (DMD, BMD) are X-linked recessive disorders caused by mutations in the dystrophin (dys) gene. The majority of these mutations are intragenic deletions of duplications routinely detected by Southern biots and multiplex PCR. The remainder are very likely, smaller mutations, mostly point-mutations. Detection of these mutations is very difficult due to the size and complexity of the dys gene. We applied RT-PCR to analyse the entire dys mRNA of three DMD patients with no detectable genomic defect. In two unrelated patients, a duplication of the 62 bp exon 2 was identified. This causes a frameshift sufficient to explain the DMD phenotype. In the third patient, who had congenital DMD and severe mental retardation, a complex pattern of aberrant splicing at the 3-prime exons 67-79 was observed. Sural nerve biopsy in this patient showed the complete absence of Dp116. PCR-SSCP studies are presently in progress to identify the mutations responsible for the aberrant splicing patterns.

Fat King Penguins Are Less Steady on Their Feet.

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Astrid S T Willener

Full Text Available Returning to the shore after a feeding sojourn at sea, king penguins often undertake a relatively long terrestrial journey to the breeding colony carrying a heavy, mostly frontal, accumulation of fat along with food in the stomach for chick-provisioning. There they must survive a fasting period of up to a month in duration, during which their complete reliance on endogenous energy stores results in a dramatic loss in body mass. Our aim was to determine if the king penguin's walking gait changes with variations in body mass. We investigated this by walking king penguins on a treadmill while instrumented with an acceleration data logger. The stride frequency, dynamic body acceleration (DBA and posture of fat (pre-fasting; 13.2 kg and slim (post fasting; 11 kg king penguins were assessed while they walked at the same speed (1.4 km/h on a treadmill. Paired statistical tests indicated no evidence for a difference in dynamic body acceleration or stride frequency between the two body masses however there was substantially less variability in both leaning angle and the leaning amplitude of the body when the birds were slimmer. Furthermore, there was some evidence that the slimmer birds exhibited a decrease in waddling amplitude. We suggest the increase in variability of both leaning angle and amplitude, as well as a possibly greater variability in the waddling amplitude, is likely to result from the frontal fat accumulation when the birds are heavier, which may move the centre of mass anteriorly, resulting in a less stable upright posture. This study is the first to use accelerometry to better understand the gait of a species within a specific ecological context: the considerable body mass change exhibited by king penguins.

Fat King Penguins Are Less Steady on Their Feet.

Science.gov (United States)

Willener, Astrid S T; Handrich, Yves; Halsey, Lewis G; Strike, Siobhán

2016-01-01

Returning to the shore after a feeding sojourn at sea, king penguins often undertake a relatively long terrestrial journey to the breeding colony carrying a heavy, mostly frontal, accumulation of fat along with food in the stomach for chick-provisioning. There they must survive a fasting period of up to a month in duration, during which their complete reliance on endogenous energy stores results in a dramatic loss in body mass. Our aim was to determine if the king penguin's walking gait changes with variations in body mass. We investigated this by walking king penguins on a treadmill while instrumented with an acceleration data logger. The stride frequency, dynamic body acceleration (DBA) and posture of fat (pre-fasting; 13.2 kg) and slim (post fasting; 11 kg) king penguins were assessed while they walked at the same speed (1.4 km/h) on a treadmill. Paired statistical tests indicated no evidence for a difference in dynamic body acceleration or stride frequency between the two body masses however there was substantially less variability in both leaning angle and the leaning amplitude of the body when the birds were slimmer. Furthermore, there was some evidence that the slimmer birds exhibited a decrease in waddling amplitude. We suggest the increase in variability of both leaning angle and amplitude, as well as a possibly greater variability in the waddling amplitude, is likely to result from the frontal fat accumulation when the birds are heavier, which may move the centre of mass anteriorly, resulting in a less stable upright posture. This study is the first to use accelerometry to better understand the gait of a species within a specific ecological context: the considerable body mass change exhibited by king penguins.

The Words of Martin Luther King, Jr.

Science.gov (United States)

Today's Education, 1979

1979-01-01

Excerpts from speeches by Dr. Martin Luther King, Jr., are reprinted. Topics discussed include discrimination, the South, education, nonviolent resistance, poverty, economic opportunity, and world peace. (LH)

Duchenne and Becker muscular dystrophy: a molecular and immunohistochemical approach Distrofia muscular de Duchenne e Becker: abordagem molecular e imuno-histoquímica

Directory of Open Access Journals (Sweden)

Aline Andrade Freund

2007-03-01

Full Text Available Duchenne muscular dystrophy (DMD and Becker muscular dystrophy (BMD are caused by mutations in the dystrophin gene. We studied 106 patients with a diagnosis of probable DMD/BMD by analyzing 20 exons of the dystrophin gene in their blood and, in some of the cases, by immunohistochemical assays for dystrophin in muscle biopsies. In 71.7% of the patients, deletions were found in at least one of the exons; 68% of these deletions were in the hot-spot 3' region. Deletions were found in 81.5% of the DMD cases and in all the BMD cases. The cases without deletions, which included the only woman in the study with DMD, had dystrophin deficiency. The symptomatic female carriers had no deletions but had abnormal dystrophin distribution in the sarcolemma (discontinuous immunostains. The following diagnoses were made for the remaining cases without deletions with the aid of a muscle biopsy: spinal muscular atrophy, congenital myopathy; sarcoglycan deficiency and unclassified limb-girdle muscular dystrophy. Dystrophin analysis by immunohistochemistry continues to be the most specific method for diagnosis of DMD/BMD and should be used when no exon deletions are found in the dystrophin gene in the blood.As distrofias musculares de Duchenne (DMD e de Becker (DMB são doenças causadas por mutação no gene da distrofina. Foram estudados 106 casos com a suspeita diagnóstica de DMD/BMD com a analise de 20 exons do gene da distrofina no sangue e biópsia muscular com imuno-histoquímica para distrofina em alguns casos. Em 71,7% dos casos foi encontrada deleção em pelo menos um dos exons, sendo que 68% das deleções localizam-se na região 3' hot spot. Foram encontradas deleções em 81,5% dos DMD e em todos os BMD, sendo que os sem deleção tinham deficiência de distrofina, incluindo a mulher com DMD. As portadoras sintomáticas não tinham deleções mas anormalidades na distribuição da distrofina no sarcolema. Os outros casos sem deleção, com auxilio da

Feeding performance of king Mackerel, Scomberomorus cavalla.

Science.gov (United States)

Ferguson, Amber R; Huber, Daniel R; Lajeunesse, Marc J; Motta, Philip J

2015-08-01

Feeding performance is an organism's ability to capture and handle prey. Although bite force is a commonly used metric of feeding performance, other factors such as bite pressure and strike speed are also likely to affect prey capture. Therefore, this study investigated static bite force, dynamic speeds, and predator and prey forces resulting from ram strikes, as well as bite pressure of the king mackerel, Scomberomorus cavalla, in order to examine their relative contributions to overall feeding performance. Theoretical posterior bite force ranged from 14.0-318.7 N. Ram speed, recorded with a rod and reel incorporated with a line counter and video camera, ranged from 3.3-15.8B L/s. Impact forces on the prey ranged from 0.1-1.9 N. Bite pressure, estimated using theoretical bite forces at three gape angles and tooth cross-sectional areas, ranged from 1.7-56.9 MPa. Mass-specific bite force for king mackerel is relatively low in comparison with other bony fishes and sharks, with relatively little impact force applied to the prey during the strike. This suggests that king mackerel rely on high velocity chases and high bite pressure generated via sharp, laterally compressed teeth to maximize feeding performance. © 2015 Wiley Periodicals, Inc.

A New Reading of Shakespeare's King John.

Science.gov (United States)

Usher, Peter D.

1995-12-01

Shakespeare wrote King John c.1594, six years after the defeat of the Spanish Armada, and ~ 50 years after publication of the Copernican heliocentric hypothesis. It is said to be the most unhistorical of the History Plays, ``anomalous'', ``puzzling'', and ``odd'', and as such it has engendered far more than the customary range of interpretive opinion. I suggest that the play alerts Elizabethans not just to military and political threats, but to a changing cosmic world view, all especially threatening as they arise in Catholic countries. (a) Personification characterizes the play. John personifies the old order, while Arthur and the Dauphin's armies personify the new. I suggest that Shakespeare decenters King John just as Copernicus decentered the world. (b) Hubert menaces Arthur's eyes for a whole scene (4.1), but the need for such cruelty is not explained and is especially odd as Arthur is already under sentence of death (3.3.65-66). This hitherto unexplained anomaly suggests that the old order fears what the new might see. (c) Eleanor's confession is made only to Heaven and to her son the King (1.1.42-43), yet by echoing and word play the Messenger from France later reveals to John that he is privy to it (4.2.119-124). This circumstance has not been questioned heretofore. I suggest that the Messenger is like the wily Hermes (Mercury), chief communicator of the gods and patron of the sciences; by revealing that he moves in the highest circles, he tells John that he speaks with an authority that transcends even that of a king. The message from on high presages more than political change; it warns of a new cosmic and religious world order (d) Most agree that John is a weak king, so Shakespeare must have suspected flaws in the old ways. He would have known that Tycho Brahe's new star of 1572, the comet of 1577, and the 1576 model of his compatriot Thomas Digges, were shattering old ideas. (e) The tensions of the play are not resolved because in 1594 the new order was

Moessbauer Study of Sedimentary Rocks from King George Island, Antarctica

International Nuclear Information System (INIS)

Kuzmann, E.; Souza, P. A. de; Schuch, L. A.; Oliveira, A. C. de; Garg, R.; Garg, V. K.

2002-01-01

The separation of continents at the periphery of Antarctica occurred about 180 ma ago due to volcanic activity. Geological faults can be very important in the study of geological occurrences. Such geological faults occur across the Admiralty Bay, King George Island, and have been studied in detail previously. Controversial statements were given in earlier works, based on conventional geological investigations, as to whether altered 'Jurassic' and unaltered Tertiary rocks were separated by a major fault which goes across the Admiralty Bay, or whether there is no difference in the alteration of the rocks located at either side of the fault. The aim of our work is to investigate rock samples from the Admiralty Bay of King George Island, Antarctica, from different locations on both sides of the geological fault. For these investigations 57 Fe Moessbauer spectroscopy and X-ray diffractometry were used. We have found that the phase composition, and the iron distribution among the crystallographic sites of iron-bearing minerals, are characteristic of the location of the rock samples from the Admiralty Bay of King George Island. There is a much higher amount of iron oxides in the rocks from the south part of the geological fault than in the north part. The differences in the mineral composition and iron distribution showed that the rocks in the southern part of the geological fault of King George Island are significantly altered compared to the rocks in the northern part. Our present results support and complement well the results obtained earlier on soils from King George Island.

Generation of induced pluripotent stem cells from a Becker muscular dystrophy patient carrying a deletion of exons 45-55 of the dystrophin gene (CCMi002BMD-A-9 ∆45-55

Directory of Open Access Journals (Sweden)

Aoife Gowran

2018-04-01

Full Text Available Becker muscular dystrophy (BMD is a dystrophinopathy caused by mutations in the dystrophin gene on chromosome Xp21. BMD mutations result in truncated semi-functional dystrophin isoforms. Consequently, less severe clinical symptoms become apparent later in life compared to Duchenne muscular dystrophy. Dermal fibroblasts from a BMD patient were electroporated with episomal plasmids containing reprogramming factors to create the induced pluripotent stem cell line: CCMi002BMD-A-9 that showed pluripotent markers, were karyotypically normal and capable of trilineage differentiation. MLPA analyses performed on DNA extracted from CCMi002BMD-A-9 showed an in-frame deletion of exons 45 to 55 (CCMi002BMD-A-9 Δ45-55.

Reading Stephen King: Issues of Censorship, Student Choice, and Popular Literature.

Science.gov (United States)

Power, Brenda Miller, Ed.; Wilhelm, Jeffrey D., Ed.; Chandler, Kelly, Ed.

This collection of essays grew out of the "Reading Stephen King Conference" held at the University of Maine in 1996. Stephen King's books have become a lightning rod for the tensions around issues of including "mass market" popular literature in middle and high school English classes and of who chooses what students read.…

Characterization of a novel Dp71 dystrophin-associated protein complex (DAPC) present in the nucleus of HeLa cells: Members of the nuclear DAPC associate with the nuclear matrix

International Nuclear Information System (INIS)

Fuentes-Mera, Lizeth; Rodriguez-Munoz, Rafael; Gonzalez-Ramirez, Ricardo; Garcia-Sierra, Francisco; Gonzalez, Everardo; Mornet, Dominique; Cisneros, Bulmaro

2006-01-01

Dystrophin is an essential component in the assembly and maintenance of the dystrophin-associated protein complex (DAPC), which includes members of the dystroglycan, syntrophin, sarcoglycan and dystrobrevin protein families. Distinctive complexes have been described in the cell membrane of different tissues and cultured cells. In this work, we report the identification and characterization of a novel DAPC present in the nuclei of HeLa cells, which contains dystrophin Dp71 as a key component. Using confocal microscopy and cell fractionation analyses, we found the presence of Dp71, β-sarcoglycan, β-dystroglycan, α- and β-syntrophin, α1- and β-dystrobrevin and nNOS in the nuclei of HeLa cells. Furthermore, we demonstrated by co-immunoprecipitation experiments that most of these proteins form a complex in the nuclear compartment. Next, we analyze the possible association of the nuclear DAPC with the nuclear matrix. We found the presence of Dp71, β-dystroglycan, nNOS, β-sarcoglycan, α/β syntrophin, α1-dystrobrevin and β-dystrobrevin in the nuclear matrix protein fractions and in situ nuclear matrix preparations from HeLa cells. Moreover, we found that Dp71, β-dystroglycan and β-dystrobrevin co-immunoprecipitated with the nuclear matrix proteins lamin B1 and actin. The association of members of the nuclear DAPC with the nuclear matrix indicates that they may work as scaffolding proteins involved in nuclear architecture

Local seismic activity monitored at King Sejong Station, Antarctica

OpenAIRE

Lee,Duk Kee; Kim,Yea Dong; Nam,Sang Heon; Jin,Young Keun

1998-01-01

Source location estimation from single station earthquake data collected at King Sejong Station (62°13'3l"N, 58°47'07"W) from 1995 to 1996 provides seismic activity around King Sejong Station. Analysis of local events, less than 1.5°in angular epicentral distance, finds epicenters located near the Shackleton Fracture Zone, the South Shetland Platform, Deception Island, and North Bransfield Basin. Estimated magnitudes range from 2.2 to 4.5 on the Richter scale, averaging 4.0 in North Bransfiel...

Emerging genetic therapies to treat Duchenne muscular dystrophy

Science.gov (United States)

Nelson, Stanley F.; Crosbie, Rachelle H.; Miceli, M. Carrie; Spencer, Melissa J.

2010-01-01

Purpose of review Duchenne muscular dystrophy is a progressive muscle degenerative disease caused by dystrophin mutations. The purpose of this review is to highlight two emerging therapies designed to repair the primary genetic defect, called `exon skipping' and `nonsense codon suppression'. Recent findings A drug, PTC124, was identified that suppresses nonsense codon translation termination. PTC124 can lead to restoration of some dystrophin expression in human Duchenne muscular dystrophy muscles with mutations resulting in premature stops. Two drugs developed for exon skipping, PRO051 and AVI-4658, result in the exclusion of exon 51 from mature mRNA. They can restore the translational reading frame to dystrophin transcripts from patients with a particular subset of dystrophin gene deletions and lead to some restoration of dystrophin expression in affected boys' muscle in vivo. Both approaches have concluded phase I trials with no serious adverse events. Summary These novel therapies that act to correct the primary genetic defect of dystrophin deficiency are among the first generation of therapies tailored to correct specific mutations in humans. Thus, they represent paradigm forming approaches to personalized medicine with the potential to lead to life changing treatment for those affected by Duchenne muscular dystrophy. PMID:19745732

Pessoa’s myth of the King Sebastian reinterpreted

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Monika Świda

2013-01-01

Full Text Available The present paper depicts alterations undergone by the sleeping king motif (sebastianism in the writings of Fernando Pessoa. The data to conduct the study were collected in thematic anthologies and several unpublished pieces. The myth of the King Sebastian was given a congregational dimension by Pessoa, thus conveying his cultural and identity project subsumed under the metaphor of the spiritual empire. Pessoa introduces some readjustments in the way the historical king is to be conceived of. In his theory, Sebastian becomes the figure of the individual effort on the way towards the national renewal. The messianic character of D. Sebastião is defeated in this theory despite having been associated with the figures of either Jesus or the Antichrist. The messiah of the Portuguese foundation myth is replaced with the idea of great man and the task to be carried out in this field, included the metaphor of the Fifth Empire, gains a cultural character. That is why Pessoa’s theories must no longer be interpreted in messianic terms. The Pessoa’s transformations of the sebastianism analyzed in this article are the starting point for the new national narration in the poetic cycle of "Mensagem".

More deletions in the 5{prime} region than in the central region of the dystrophin gene were identified among Filipino Duchenne and Becker muscular dystrophy patients

Energy Technology Data Exchange (ETDEWEB)

NONE

1995-11-06

This report describes mutations in the dystrophin gene and the frequency of these mutations in Filipino pedigrees with Duchenne and Becker muscular dystrophy (DMD/BMD). The findings suggest the presence of genetic variability among DMD/BMD patients in different populations. 13 refs., 1 tab.

Mandatory menu labeling in one fast-food chain in King County, Washington.

Science.gov (United States)

Finkelstein, Eric A; Strombotne, Kiersten L; Chan, Nadine L; Krieger, James

2011-02-01

As part of a comprehensive effort to stem the rise in obesity, King County, Washington, enforced a mandatory menu-labeling regulation requiring all restaurant chains with 15 or more locations to disclose calorie information at the point of purchase beginning in January 2009. The purpose of this study is to quantify the impact of the King County regulation on transactions and purchasing behavior at one Mexican fast-food chain with locations within and adjacent to King County. To examine the effect of the King County regulation, a difference-in-difference approach was used to compare total transactions and average calories per transaction between seven King County restaurants and seven control locations focusing on two time periods: one period immediately following the law until the posting of drive-through menu boards (January 2009 to July 2009) and a second period following the drive-through postings (August 2009 through January 2010). Analyses were conducted in 2010. No impact of the regulation on purchasing behavior was found. Trends in transactions and calories per transaction did not vary between control and intervention locations after the law was enacted. In this setting, mandatory menu labeling did not promote healthier food-purchasing behavior. Copyright © 2011 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

Distribution and habitat use of king rails in the Illinois and Upper Mississippi River valleys

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Darrah, Abigail J.; Krementz, David G.

2009-01-01

The migratory population of the king rail (Rallus elegans) has declined dramatically during the past 40 years, emphasizing the need to identify habitat requirements of this species to help guide conservation efforts. To assess distribution and habitat use of king rails along the Illinois and Upper Mississippi valleys, USA, we conducted repeated call-broadcast surveys at 83 locations in 2006 and 114 locations in 2007 distributed among 21 study sites. We detected king rails at 12 survey locations in 2006 and 14 locations in 2007, illustrating the limited distribution of king rails in this region. We found king rails concentrated at Clarence Cannon National Wildlife Refuge, an adjacent private Wetlands Reserve program site, and B. K. Leach Conservation Area, which were located in the Mississippi River floodplain in northeast Missouri. Using Program PRESENCE, we estimated detection probabilities and built models to identify habitat covariates that were important in king rail site occupancy. Habitat covariates included percentage of cover by tall (> 1 m) and short (wetlands that were characterized by high water-vegetation interspersion and little or no cover by woody vegetation. Our results suggest that biologists can improve king rail habitat by implementing management techniques that reduce woody cover and increase vegetation-water interspersion in wetlands.

King's theory of goal attainment: exploring functional status.

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Caceres, Billy A

2015-04-01

Imogene King's Theory of Goal Attainment provides a schema for nurses interested in functional status. However, the lack of a uniform definition for functional status has hindered development of a concise understanding of this phenomenon. Functional status is particularly important to nurses who are concerned with the safety and wellbeing of clients. With healthcare's increased focus on client-family-centered care it is important to develop innovative approaches for evaluating functional status that incorporate the client-family perspective. King's focus on mutual decision-making is an underutilized resource that can provide great insight into the study and understanding of functional status. © The Author(s) 2015.

Martin Luther King Jr. contest winning posters to be displayed in downtown Blacksburg

OpenAIRE

Shannon, Kelly Baker

2010-01-01

Each year as part of the Martin Luther King Jr. celebration at Virginia Tech area kindergarten through 12th grade students are invited to participate in the annual Martin Luther King Jr. poster contest.

Baking hot. Burger King is testing a restaurant with solar power supply; Unter der Sonne braten. Der Fastfood-Riese Burger King testet ein Restaurantkonzept mit Solaranlage

Energy Technology Data Exchange (ETDEWEB)

Kaizl, Mira

2010-07-15

At Waghaeusel in the German state of Baden-Wuerttemberg, the local solar provider Wirsol Solar AG constructed a restaurant building for the Burger King GmbH. The building consumes comparably little energy and has a solar roof for photovoltaic power generation. Burger King hopes for good money and a clean image, while Wirsol Solar is hoping for new projects in Europe and in the USA. (orig.)

When the King Becomes your Personal Enemy: W. T. Stead, King Leopold II, and the Congo Free State

Directory of Open Access Journals (Sweden)

Marysa Demoor

2013-04-01

mso-fareast-language:JA;} This paper will highlight an unknown but important episode in the life of the journalist W. T. Stead, which, intriguingly, remained unmentioned in Belgian, British, and colonial historiography. It concerns a face-to-face meeting between Stead and Leopold II, King of the Belgians, which certainly did not leave Stead the ‘friend of all Kings’, as the posthumous article published by the 'Daily Mirror' contended. Based on Stead’s own Character Sketches in the 'Review of Reviews', the paper will show how Stead’s perceptions of the scandalous government of the Congo Free State result to a large extent from his own meeting (probably towards the end of 1884 with King Leopold II, and the King’s refusal to cooperate with Britain in an improvised rescue of General Gordon in Sudan.

and Antioxidant Activity of Endophytic Fungi from Mahogoni Plant (Swietenia macrophylla King

Directory of Open Access Journals (Sweden)

Edward J Dompeipen

2015-06-01

Full Text Available Diabetes mellitus is a degenerative disease characterized by hyperglycemia due to insulin insulin deficiency either absoluteor relative. This study was conducted to isolate endophytic fungi from plant twigs mahogany (Swietenia macrophylla King which active as antidiabetic and antioxidant. Antidiabetic activity conducted by using the α-glucosidase inhibitory and antioxidant activity using free radical reduction method with reagent 2.2-diphenyl-1-picrylhydrazyl (DPPH. Isolation of microbes conducted in the media Corn Meal Malt Agar (CMMA and Potato Dextrose Agar (PDA which 7 isolates of fungus in total. Inhibitory activity against α-glucosidase to extract the filtrate and biomass of the isolates A.Sm.2F (72.59 and 92.22%, A.Sm.3F (81.87 and 79.37%, B.Sm.1F (63.40 and 98.84%, B.Sm.2F (65.60 and 62.72%, B.Sm.3F (93.91 and 51.48%, B.Sm.4F (87.48 and 74.64% thus has potential as an antidiabetic activity. B.Sm.1F was the only isolates active as antioxidants with IC50 of 84.41.

Responses by king snakes (Lampropeltis getulus) to chemicals from colubrid and crotaline snakes.

Science.gov (United States)

Weldon, P J; Schell, F M

1984-10-01

Four litters of king snakes (Lampropeltis getulus), a snake-eating species, were tested for responses to chemicals from colubrid and crotaline snakes. King snakes presented with swabs rubbed against the dorsal skin of living snakes and with swabs treated with methylene chloride extracts of shed snake skins tongue-flicked more to swabs from a northern copperhead (Agkistrodon contortrix), a crotaline, than to swabs from some colubrid snakes or to blank swabs. Six out of 10 king snakes in one litter attacked and attempted to ingest swabs treated with snake skin chemicals, implicating these chemicals as feeding stimuli for these ophiophagous snakes. Ingestively naive king snakes presented with plain air and snake odors in an olfactometer tongue-flicked more to snake odors. This study and others suggest that crotaline and colubrid snakes can be distinguished by chemical cues.

Generation of induced pluripotent stem cells from a Becker muscular dystrophy patient carrying a deletion of exons 45-55 of the dystrophin gene (CCMi002BMD-A-9 ∆45-55).

Science.gov (United States)

Gowran, Aoife; Spaltro, Gabriella; Casalnuovo, Federica; Vigorelli, Vera; Spinelli, Pietro; Castiglioni, Elisa; Rovina, Davide; Paganini, Stefania; Di Segni, Marina; Gervasini, Cristina; Nigro, Patrizia; Pompilio, Giulio

2018-04-01

Becker muscular dystrophy (BMD) is a dystrophinopathy caused by mutations in the dystrophin gene on chromosome Xp21. BMD mutations result in truncated semi-functional dystrophin isoforms. Consequently, less severe clinical symptoms become apparent later in life compared to Duchenne muscular dystrophy. Dermal fibroblasts from a BMD patient were electroporated with episomal plasmids containing reprogramming factors to create the induced pluripotent stem cell line: CCMi002BMD-A-9 that showed pluripotent markers, were karyotypically normal and capable of trilineage differentiation. MLPA analyses performed on DNA extracted from CCMi002BMD-A-9 showed an in-frame deletion of exons 45 to 55 (CCMi002BMD-A-9 Δ45-55). Copyright © 2018 The Author(s). Published by Elsevier B.V. All rights reserved.

Re-shaping King Lear: Space, Place, Costume, and Genre

Directory of Open Access Journals (Sweden)

Hattaway Michael

2017-06-01

Full Text Available Performance studies must enjoy parity of esteem with critical studies because they remind us of the plurality of “readings” that are generated by a Shakespearean text. Shakespeare seems to have apprehended this when, in Othello, he used a nonce-word, “denotement”, which applies to Othello’s reading of his wife in his mind’s eye. I examine other sequences in which we watch a character “reading” on-stage or imagined action, in Hamlet, Titus Andronicus, Cymbeline, Richard II, and Troilus and Cressida. In Hamlet this involves re-reading as well as generic displacement, which, I argue, is a way of rendering inwardness. As I test case, I analyse a production of King Lear by Shakespeare’s Globe, on a fairground stage, in which the king reshaped himself, became a folkloric figure, like a figure in Nashe’s Summer’s Last Will and Testament. The play itself was thus, indecorously, reshaped as “The Tale of King Lear”. “Dramatic truth”, therefore, in no way depends upon theatrical “realism”.

Ultraviolet reflecting photonic microstructures in the King Penguin beak.

Science.gov (United States)

Dresp, Birgitta; Jouventin, Pierre; Langley, Keith

2005-09-22

King and emperor penguins (Aptenodytes patagonicus and Aptenodytes forsteri) are the only species of marine birds so far known to reflect ultraviolet (UV) light from their beaks. Unlike humans, most birds perceive UV light and several species communicate using the near UV spectrum. Indeed, UV reflectance in addition to the colour of songbird feathers has been recognized as an important signal when choosing a mate. The king penguin is endowed with several highly coloured ornaments, notably its beak horn and breast and auricular plumage, but only its beak reflects UV, a property considered to influence its sexual attraction. Because no avian UV-reflecting pigments have yet been identified, the origin of such reflections is probably structural. In an attempt to identify the structures that give rise to UV reflectance, we combined reflectance spectrophotometry and morphological analysis by both light and electron microscopy, after experimental removal of surface layers of the beak horn. Here, we characterize for the first time a multilayer reflector photonic microstructure that produces the UV reflections in the king penguin beak.

Cloning of human basic A1, a distinct 59-kDa dystrophin-associated protein encoded on chromosome 8q23-24

Energy Technology Data Exchange (ETDEWEB)

Ahn, A.H. [Harvard Medical School, Boston, MA (United States); Yoshida, Mikiharu; Hagiwara, Yasuko; Ozawa, Eijiro [National Institute of Neuroscience, Ogawa Higashi, Kodaira (Japan); Anderson, M.S.; Feener, C.A.; Selig, S. [Howard Hughes Medical Institute at Children`s Hospital, Boston, MA (United States); Kunkel, L.M. [Harvard Medical School, Boston, MA (United States)]|[Howard Hughes Medical Institute at Children`s Hosptial, Boston, MA (United States)

1994-05-10

Duchenne and Becker muscular dystrophies are caused by defects of dystrophin, which forms a part of the membrane cytoskeleton of specialized cells such as muscle. It has been previously shown that the dystrophin-associated protein A1 (59-kDa DAP) is actually a heterogeneous group of phosphorylated proteins consisting of an acidic ({alpha}-A1) and a distinct basic ({beta}-A1) component. Partial peptide sequence of the A1 complex purified from rabbit muscle permitted the design of oligonucleotide probes that were used to isolate a cDNA for one human isoform of A1. This cDNA encodes a basic A1 isoform that is distinct from the recently described syntrophins in Torpedo and mouse and is expressed in many tissues with at least five distinct mRNA species of 5.9, 4.8, 4.3, 3.1, and 1.5 kb. A comparison of the human cDNA sequence with the GenBank expressed sequence tag (EST) data base has identified a relative from human skeletal muscle, EST25263, which is probably a human homologue of the published mouse syntrophin 2. The authors have mapped the human basic component of A1 and EST25263 genes to chromosomes 8q23-24 and 16, respectively.

Behavioral and physiological significance of minimum resting metabolic rate in king penguins.

Science.gov (United States)

Halsey, L G; Butler, P J; Fahlman, A; Woakes, A J; Handrich, Y

2008-01-01

Because fasting king penguins (Aptenodytes patagonicus) need to conserve energy, it is possible that they exhibit particularly low metabolic rates during periods of rest. We investigated the behavioral and physiological aspects of periods of minimum metabolic rate in king penguins under different circumstances. Heart rate (f(H)) measurements were recorded to estimate rate of oxygen consumption during periods of rest. Furthermore, apparent respiratory sinus arrhythmia (RSA) was calculated from the f(H) data to determine probable breathing frequency in resting penguins. The most pertinent results were that minimum f(H) achieved (over 5 min) was higher during respirometry experiments in air than during periods ashore in the field; that minimum f(H) during respirometry experiments on water was similar to that while at sea; and that RSA was apparent in many of the f(H) traces during periods of minimum f(H) and provides accurate estimates of breathing rates of king penguins resting in specific situations in the field. Inferences made from the results include that king penguins do not have the capacity to reduce their metabolism to a particularly low level on land; that they can, however, achieve surprisingly low metabolic rates at sea while resting in cold water; and that during respirometry experiments king penguins are stressed to some degree, exhibiting an elevated metabolism even when resting.

The Institute of Epileptology of King's College, University of London.

Science.gov (United States)

Reynolds, E H

1995-01-01

The Institute of Epileptology of King's College, London has arisen from need and from opportunity. The need is due to the relative neglect nationally and internationally of the most common serious brain disorder with important physical, psychological, and social complications. The relative neglect is reflected in services, research, charitable donations, public profile, and stigma and in a serious lack of professional education. The opportunity arose because of the existence in several medical institutions at Denmark Hill, London, of a group of medical and related colleagues with a special interest covering almost every aspect of this multidisciplinary disorder who agreed to combine their expertise in this initiative. The idea was born and developed in 1991-1992 and was supported by all the parent institutions: The Maudsley and King's College Hospitals, St. Piers Lingfield, The Institute of Psychiatry, King's College School of Medicine and Dentistry, and the School of Life, Basic Medical and Health Sciences, all under the umbrella of King's College, University of London. Further stimulus and help came from a group of dedicated supporters in private and public life. There are three strands to this initiative: (a) a charity, The Fund for Epilepsy; (b) the clinical Centre for Epilepsy, which was formally opened at the Maudsley Hospital in July 1994; and (c) the academic Institute of Epileptology for research and teaching, which was launched on November 15, 1994.

Taurine deficiency, synthesis and transport in the mdx mouse model for Duchenne Muscular Dystrophy.

Science.gov (United States)

Terrill, Jessica R; Grounds, Miranda D; Arthur, Peter G

2015-09-01

The amino acid taurine is essential for the function of skeletal muscle and administration is proposed as a treatment for Duchenne Muscular Dystrophy (DMD). Taurine homeostasis is dependent on multiple processes including absorption of taurine from food, endogenous synthesis from cysteine and reabsorption in the kidney. This study investigates the cause of reported taurine deficiency in the dystrophic mdx mouse model of DMD. Levels of metabolites (taurine, cysteine, cysteine sulfinate and hypotaurine) and proteins (taurine transporter [TauT], cysteine deoxygenase and cysteine sulfinate dehydrogenase) were quantified in juvenile control C57 and dystrophic mdx mice aged 18 days, 4 and 6 weeks. In C57 mice, taurine content was much higher in both liver and plasma at 18 days, and both cysteine and cysteine deoxygenase were increased. As taurine levels decreased in maturing C57 mice, there was increased transport (reabsorption) of taurine in the kidney and muscle. In mdx mice, taurine and cysteine levels were much lower in liver and plasma at 18 days, and in muscle cysteine was low at 18 days, whereas taurine was lower at 4: these changes were associated with perturbations in taurine transport in liver, kidney and muscle and altered metabolism in liver and kidney. These data suggest that the maintenance of adequate body taurine relies on sufficient dietary intake of taurine and cysteine availability and metabolism, as well as retention of taurine by the kidney. This research indicates dystrophin deficiency not only perturbs taurine metabolism in the muscle but also affects taurine metabolism in the liver and kidney, and supports targeting cysteine and taurine deficiency as a potential therapy for DMD. Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.

Briti publik armastab King Kongi / Andris Feldmanis

Index Scriptorium Estoniae

Feldmanis, Andris, 1982-

2006-01-01

Briti filmiajakiri Empire lugejate filmiauhinnad : parim film "King Kong" (Peter Jackson), parim režii Steve Box, Nick Park "Wallace & Gromit - libaküüliku needus", parim meesnäitleja Johnny Depp, parim naisnäitleja Thandie Newton

From Typology to Topography in Clarence King's "Mountaineering in the Sierra Nevada."

Science.gov (United States)

Hoekzema, Loren

The book "Mountaineering in the Sierra Nevada" by Clarence King, a late-ninteenth-century American geologist, writer, art critic, and romantic, is discussed in this paper. In the writing and revision of this book, King was attempting a metamorphosis of landscape description into popular reading as he moved from being a symbolic writer to…

AFSC/RACE/SAP/Long: Data from: Embryo development in golden king crab, Lithodes aequispina.

Data.gov (United States)

National Oceanic and Atmospheric Administration, Department of Commerce — The data from this study, describes embryo development in Golden king crab, Lithodes aequispinus. Six female multiparous golden king crab were captured from the...

The King under the Car Park

Science.gov (United States)

Mirza, Ather

2015-01-01

In February 2013, the University of Leicester staged what The Guardian described as "The most extraordinary press conference ever held at any UK university." This was part of a media and communications campaign that brought worldwide attention to the discovery of King Richard III by the University's archaeologists. How do you manage a…

3 CFR 8340 - Proclamation 8340 of January 15, 2009. Martin Luther King, Jr., Federal Holiday, 2009

Science.gov (United States)

2010-01-01

... Proclamation 8340 of January 15, 2009 Proc. 8340 Martin Luther King, Jr., Federal Holiday, 2009By the President of the United States of America A Proclamation On the Martin Luther King, Jr., Federal Holiday, we... Constitution and laws of the United States, do hereby proclaim January 19, 2009, as the Martin Luther King, Jr...

Sediment sources and transport in Kings Bay and vicinity, Georgia and Florida, July 8-16, 1982

Science.gov (United States)

Radtke, D.B.

1985-01-01

Water quality, bottom-material, suspended-sediment, and current velocity data were collected during July 1982 in Kings Bay and vicinity to provide information on the source and transport of estuarine sediments. Kings Bay and Cumberland Sound, the site of the Poseidon Submarine Base in southeast Georgia, are experiencing high rates of sediment deposition and accumulation, which are causing serious navigational and operational problems. Velocity, bathymetry, turbidity, and bottom-material data suggest sediment transported from lower Kings Bay is accumulating deposits of suspended sediment transported from Cumberland Sound on the floodtide and from upper Kings Bay and the tidal march drained by Marianna Creek on the ebbtide. Suspended-sediment discharges computed for consecutive 13-hr ebbtides and floodtides showed that a net quantity of suspended sediment was transported seaward from upper Kings Bay and Marianna Creek. A net landward transport of suspended sediment computed at the St. Marys Entrance indicated areas seaward of St. Marys Entrance may be supplying sediment to the shoaling areas of the estuary, including lower Kings Bay. (USGS)

A preliminary appraisal of sediment sources and transport in Kings Bay and vicinity, Georgia and Florida

Science.gov (United States)

McConnell, J.B.; Radtke, D.B.; Hale, T.W.; Buell, G.R.

1983-01-01

Water-quality, bottom-material, suspended-sediment, and current-velocity data were collected during November 1981 in Kings Bay and vicinity to provide information on the sources and transport of estuarine sediments. Kings Bay and Cumberland Sound , the site of the Poseidon Submarine Base in southeast Georgia, are experiencing high rates of sediment deposition and accumulation, which are causing serious navigational and operational problems. Velocity, bathymetry, turbidity, and bottom-material data suggest that the area in the vicinity of lower Kings Bay is accumulating deposits of suspended sediment transported from Cumberland Sound on the floodtide and from upper Kings Bay and the tidal marsh drained by Marianna Creek on the ebbtide. Suspended-sediment discharges computed for consecutive 13-hour ebbtides and floodtides showed that a net quantity of suspended sediment was transported seaward from upper Kings Bay and Marianna Creek. A net landward transport of suspended sediment computed at the St. Marys Entrance indicated areas seaward of St. Marys Entrance may be supplying sediment to the shoaling areas of the estuary, including lower Kings Bay. (USGS)

In vivo myomaker-mediated heterologous fusion and nuclear reprogramming.

Science.gov (United States)

Mitani, Yasuyuki; Vagnozzi, Ronald J; Millay, Douglas P

2017-01-01

Knowledge regarding cellular fusion and nuclear reprogramming may aid in cell therapy strategies for skeletal muscle diseases. An issue with cell therapy approaches to restore dystrophin expression in muscular dystrophy is obtaining a sufficient quantity of cells that normally fuse with muscle. Here we conferred fusogenic activity without transdifferentiation to multiple non-muscle cell types and tested dystrophin restoration in mouse models of muscular dystrophy. We previously demonstrated that myomaker, a skeletal muscle-specific transmembrane protein necessary for myoblast fusion, is sufficient to fuse 10T 1/2 fibroblasts to myoblasts in vitro. Whether myomaker-mediated heterologous fusion is functional in vivo and whether the newly introduced nonmuscle nuclei undergoes nuclear reprogramming has not been investigated. We showed that mesenchymal stromal cells, cortical bone stem cells, and tail-tip fibroblasts fuse to skeletal muscle when they express myomaker. These cells restored dystrophin expression in a fraction of dystrophin-deficient myotubes after fusion in vitro. However, dystrophin restoration was not detected in vivo although nuclear reprogramming of the muscle-specific myosin light chain promoter did occur. Despite the lack of detectable dystrophin reprogramming by immunostaining, this study indicated that myomaker could be used in nonmuscle cells to induce fusion with muscle in vivo, thereby providing a platform to deliver therapeutic material.-Mitani, Y., Vagnozzi, R. J., Millay, D. P. In vivo myomaker-mediated heterologous fusion and nuclear reprogramming. © FASEB.

AHP 47: THE GREEDY KING AND TRICKY MAN

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Lcags so lhun 'grub ལྕགས་སོ་ལྷུན་འགྲུབ། (Klu sgrub ཀླུ་སྒྲུབ།

2017-04-01

Full Text Available Rgya mo skyid (b. 1992 of Mdo ba Town, Reb gong (Thun rin, Tongren County, Rma lho (Huangnan Tibetan Autonomous Prefecture, Mtsho sngon (Qinghai Province, China told me this story in an apartment in Xi'an City, Shaanxi Province on 21 August, 2016. She said, "When I was about five years old, my grandfather (Kun bzang, b. 1939 told me many stories such as this before we went to bed every night. I forgot many stories, but this story is still very clear." There was once a greedy local king who collected taxes monthly. There was also a very poor man known as Tricky Tsag thul. The local king came to Tricky's home to punish him for not paying his taxes for several months. ...

An ideal for leadership - Psalm 72: The (wise king - Royal mediation of God�s universal reign

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D. J. Human

2002-08-01

Full Text Available Psalm 72 propounds illuminating theological perspectives on leadership. The central figure in the psalm is the king. Throughout the Ancient Near East the king played a distinctive role, not only in contemporary politics, but also in religious life. Despite several differences from the other nations, kingship in Israel was rooted in the worldview of the ancient East. Yahweh, like other gods, commissioned the king for his tasks. The wise king in Israel, who alludes in Psalm 72 to the figure of Solomon, is obliged to rule with justice in order to maintain peace and prosperity in society.

Treatment with the anti-IL-6 receptor antibody attenuates muscular dystrophy via promoting skeletal muscle regeneration in dystrophin-/utrophin-deficient mice.

Science.gov (United States)

Wada, Eiji; Tanihata, Jun; Iwamura, Akira; Takeda, Shin'ichi; Hayashi, Yukiko K; Matsuda, Ryoichi

2017-10-27

Chronic increases in the levels of the inflammatory cytokine interleukin-6 (IL-6) in serum and skeletal muscle are thought to contribute to the progression of muscular dystrophy. Dystrophin/utrophin double-knockout (dKO) mice develop a more severe and progressive muscular dystrophy than the mdx mice, the most common murine model of Duchenne muscular dystrophy (DMD). In particular, dKO mice have smaller body sizes and muscle diameters, and develop progressive kyphosis and fibrosis in skeletal and cardiac muscles. As mdx mice and DMD patients, we found that IL-6 levels in the skeletal muscle were significantly increased in dKO mice. Thus, in this study, we aimed to analyze the effects of IL-6 receptor (IL-6R) blockade on the muscle pathology of dKO mice. Male dKO mice were administered an initial injection (200 mg/kg intraperitoneally (i.p.)) of either the anti-IL-6R antibody MR16-1 or an isotype-matched control rat IgG at the age of 14 days, and were then given weekly injections (25 mg/kg i.p.) until 90 days of age. Treatment of dKO mice with the MR16-1 antibody successfully inhibited the IL-6 pathway in the skeletal muscle and resulted in a significant reduction in the expression levels of phosphorylated signal transducer and activator of transcription 3 in the skeletal muscle. Pathologically, a significant increase in the area of embryonic myosin heavy chain-positive myofibers and muscle diameter, and reduced fibrosis in the quadriceps muscle were observed. These results demonstrated the therapeutic effects of IL-6R blockade on promoting muscle regeneration. Consistently, serum creatine kinase levels were decreased. Despite these improvements observed in the limb muscles, degeneration of the diaphragm and cardiac muscles was not ameliorated by the treatment of mice with the MR16-1 antibody. As no adverse effects of treatment with the MR16-1 antibody were observed, our results indicate that the anti-IL-6R antibody is a potential therapy for muscular dystrophy

Religión y Paz en Martin Luther King Jr.

OpenAIRE

Mussio, Ria Stacy

2016-01-01

Esta tesis pretende mostrar el rol integral que la religión desempeñaba en la obtención de los derechos civiles para los afroamericanos y, también en el logro de la paz positiva. Martin Luther King Jr. y la mayoría de los manifestantes del movimiento eran cristianos, poniendo su fe en Dios, para el pleno disfrute de sus derechos humanos. King Jr., anclado en su fe, impulsó el avance de los derechos civiles, mediante la resistencia no violenta. El primer capítulo tiene como finalidad orientar ...

An Uncommon Complication with a Supraglottic Airway: The King LT.

Science.gov (United States)

Brown, Sara; Cherian, Verghese T; Greco, Katherine; Mets, Elbert; Budde, Arne

2016-02-15

General anesthesia was administered in an 18-year-old man for removal of hardware from his right knee using a King Laryngeal Tube supraglottic airway. An hour after extubation, he reported inability to swallow with no respiratory distress. Examination showed an edematous uvula, which took 3 days to subside with anti-inflammatory medication. During the positioning of the King Laryngeal Tube, it was pulled back to ensure adequate ventilation. The inflated cuff could have dragged the uvula and folded it on itself, leading to venous congestion and edema.

Synchronization and an application of a novel fractional order King Cobra chaotic system

Energy Technology Data Exchange (ETDEWEB)

Muthukumar, P., E-mail: muthukumardgl@gmail.com; Balasubramaniam, P., E-mail: balugru@gmail.com [Department of Mathematics, Gandhigram Rural Institute‐Deemed University, Gandhigram 624 302, Tamilnadu (India); Ratnavelu, K., E-mail: kuru052001@gmail.com [Faculty of Science, Institute of Mathematical Sciences, University of Malaya, 50603 Kuala Lumpur (Malaysia)

2014-09-01

In this paper, we design a new three dimensional King Cobra face shaped fractional order chaotic system. The multi-scale synchronization scheme of two fractional order chaotic systems is described. The necessary conditions for the multi-scale synchronization of two identical fractional order King Cobra chaotic systems are derived through feedback control. A new cryptosystem is proposed for an image encryption and decryption by using synchronized fractional order King Cobra chaotic systems with the supports of multiple cryptographic assumptions. The security of the proposed cryptosystem is analyzed by the well known algebraic attacks. Numerical simulations are given to show the effectiveness of the proposed theoretical results.

Archeology in Medicine: Digging up into the tophi of Popes, Dukes and Kings

Directory of Open Access Journals (Sweden)

G. Ceccarelli

2011-09-01

Full Text Available According to an Anglo-Saxon pun, “gout is the king of diseases and the disease of Kings”. In fact, it is well-known that in past times a quantity of famous persons, including Kings and Popes, were affected with this rheumatic disorder. In this paper biographical anecdotes on several Popes (Pius III, Julius II, Julius III, Clement VIII, Innocent XI, Clement XII and Pius VIII, King George IV and Queen Anne of England, as well as on some members of the Lorraine lineage, all suffering from gout, are sketched out. These historical data are briefly discussed in relation to the celebrated Hippocrates’s aphorisms on gout.

Thermal characteristics of soil and water during summer at King Sejong Station, King George Island, Antarctica

Science.gov (United States)

Lim, H. S.; Lee, J. Y.; Yoon, H.

2016-12-01

Soil temperatures, water temperatures, and weather parameters were monitored at a variety of locations in the vicinity of King Sejong station, King George Island, Antarctica, during summer 2010-2011. Thermal characteristics of soil and water were analysed using time-series analyses, apparent thermal diffusivity (ATD), and active layer thickness. The temperatures of pond water and nearby seawater showed the distinctive diurnal variations and correlated strongly with solar radiation (r = 0.411-0.797). Soil temperature (0.1-0.3 m depth) also showed diurnal fluctuations that decreased with depth and were directly linked to air temperature (r = 0.513-0.783) rather than to solar radiation; correlation decreased with depth and the time lag in the response increased by 2-3 hours per 0.1 m of soil depth. Owing to the lack of snow cover, summertime soil temperature was not decoupled from air temperature. Estimated ATD was between 0.022 and 29.209 mm2/sec, showed temporal and spatial variations, and correlated strongly with soil moisture content. The maximum estimated active layer thickness in the study area was a 41-70 cm, which is consistent with values reported in the previous work.

Arctic observers: Richard King, monogenism and the historicisation of Inuit through travel narratives.

Science.gov (United States)

Sera-Shriar, Efram

2015-06-01

In 1848 the ethnologist, surgeon and Arctic explorer Richard King (1810-1876) published a three-part series on Inuit in the Journal of the Ethnological Society of London. This series provided a detailed history of Inuit from the eleventh century to the early nineteenth century. It incorporated a mixture of King's personal observations from his experience travelling to the Arctic as a member of George Back's expedition (1833-1835), and the testimonies of other contemporary and historical actors who had written on the subject. The aim was to historicise Inuit through the use of travel reports and show persistent features among the race. King was a monogenist and his sensitive recasting of Inuit was influenced by his participation in a research community actively engaged in humanitarian and abolitionist causes. The physician and ethnologist Thomas Hodgkin (1798-1866) argued that King's research on Inuit was one of the best ethnological approaches to emulate and that it set the standard for the nascent discipline. If we are to take seriously Hodgkin's claim, we should look at how King constructed his depiction of Inuit. There is much to be gained by investigating the practices of nineteenth-century ethnologists because it strengthens our knowledge of the discipline's past and shows how modern understandings of races were formed. Copyright © 2015 Elsevier Ltd. All rights reserved.

Five analogies between a King's Speech treatment and contemporary play therapies.

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Terr, Lenore C

2012-01-01

Psychiatric patients frequently respond positively to play therapy, which may rely on psychoanalytic, Jungian, cognitive-behavioral, familial, school-based, or other theories. I wished to determine if there were unifying principles that tie together these various types of play treatments. The fact-based film, The King's Speech, vividly illustrates play utilized by Lionel Logue in his speech treatment (1926-1939) of the future King of England. In the film I found five analogies to the play therapy I employ in office practice. The play scenes in The King's Speech point to five unifying principles among contemporary play therapies: (1) the crucial nature of the relationship, (2) the centrality of having fun, (3) the occasional reliance on others, (4) the interjection of pithy talk, and (5) the usefulness of a little drama. No matter what theory a play therapist ascribes to, these five unifying principles should be kept in mind during treatment.

Pairing Behavior of the Monogamous King Quail, Coturnix chinensis.

Directory of Open Access Journals (Sweden)

Elizabeth Adkins-Regan

Full Text Available Animals with socially monogamous mating systems are valuable for discovering proximate mechanisms of prosocial behavior and close social relationships. Especially powerful are comparisons between related species that differ in monogamous tendency. Birds are the most socially monogamous vertebrates. Thus far most research on mechanisms of pairing has used zebra finches, which do not have a relative with a different mating system, however. The goal of the experiments reported here was to develop a new comparative avian system by studying the pairing behavior of a reportedly strongly monogamous quail, the king quail (Coturnix chinensis, a species in the same clade as the less monogamous Japanese quail (Coturnix japonica, the subject of much prior research. In Experiment 1 male-female pairs of king quail housed together were initially avoidant or aggressive but most rapidly progressed to allopreening and huddling. A separation-reunion paradigm reliably elicited both of these behaviors in males that had cohabited for one week. In Experiment 2 the allopreening and huddling behavior of males in cohabiting pairs was highly selective, and a majority of the males were aggressive toward a familiar female that was not the cohabitation partner. In Experiment 3 males were separated from their female cohabitation partners for 9-10 weeks and then given two-choice tests. All but one male spent more time near an unfamiliar female, which may have reflected aggression and shows recognition of and memory for the past pairing experience. Thus king quail show robust, selective and easy to measure pairing behavior that can be reliably elicited with simple separation-reunion testing procedures. Copulation is rarely seen during tests. The behavior of king quail is a striking contrast to that of Japanese quail, providing a new comparative system for discovering mechanisms of behavior related to close social relationships and monogamy.

Pairing Behavior of the Monogamous King Quail, Coturnix chinensis.

Science.gov (United States)

Adkins-Regan, Elizabeth

2016-01-01

Animals with socially monogamous mating systems are valuable for discovering proximate mechanisms of prosocial behavior and close social relationships. Especially powerful are comparisons between related species that differ in monogamous tendency. Birds are the most socially monogamous vertebrates. Thus far most research on mechanisms of pairing has used zebra finches, which do not have a relative with a different mating system, however. The goal of the experiments reported here was to develop a new comparative avian system by studying the pairing behavior of a reportedly strongly monogamous quail, the king quail (Coturnix chinensis), a species in the same clade as the less monogamous Japanese quail (Coturnix japonica), the subject of much prior research. In Experiment 1 male-female pairs of king quail housed together were initially avoidant or aggressive but most rapidly progressed to allopreening and huddling. A separation-reunion paradigm reliably elicited both of these behaviors in males that had cohabited for one week. In Experiment 2 the allopreening and huddling behavior of males in cohabiting pairs was highly selective, and a majority of the males were aggressive toward a familiar female that was not the cohabitation partner. In Experiment 3 males were separated from their female cohabitation partners for 9-10 weeks and then given two-choice tests. All but one male spent more time near an unfamiliar female, which may have reflected aggression and shows recognition of and memory for the past pairing experience. Thus king quail show robust, selective and easy to measure pairing behavior that can be reliably elicited with simple separation-reunion testing procedures. Copulation is rarely seen during tests. The behavior of king quail is a striking contrast to that of Japanese quail, providing a new comparative system for discovering mechanisms of behavior related to close social relationships and monogamy.

Neuronal differentiation modulates the dystrophin Dp71d binding to the nuclear matrix

International Nuclear Information System (INIS)

Rodriguez-Munoz, Rafael; Villarreal-Silva, Marcela; Gonzalez-Ramirez, Ricardo; Garcia-Sierra, Francisco; Mondragon, Monica; Mondragon, Ricardo; Cerna, Joel; Cisneros, Bulmaro

2008-01-01

The function of dystrophin Dp71 in neuronal cells remains unknown. To approach this issue, we have selected the PC12 neuronal cell line. These cells express both a Dp71f cytoplasmic variant and a Dp71d nuclear isoform. In this study, we demonstrated by electron and confocal microscopy analyses of in situ nuclear matrices and Western blotting evaluation of cell extracts that Dp71d associates with the nuclear matrix. Interestingly, this binding is modulated during NGF-induced neuronal differentiation of PC12 cells with a twofold increment in the differentiated cells, compared to control cells. Also, distribution of Dp71d along the periphery of the nuclear matrix observed in the undifferentiated cells is replaced by intense fluorescent foci localized in Center of the nucleoskeletal structure. In summary, we revealed that Dp71d is a dynamic component of nuclear matrix that might participate in the nuclear modeling occurring during neuronal differentiation

"King Corn": Teaching the Food Crisis

Science.gov (United States)

Swinehart, Tim

2012-01-01

"King Corn" is in so many ways the story of how government food policy has entirely remade the food landscape in the United States over the last 40 years. From the massive expansion of the number of acres of corn grown across the country, to the ever-increasing ways that corn is incorporated into the food production process, to the…

AFSC/RACE/SAP/Urban: Golden King Crab tagging

Data.gov (United States)

National Oceanic and Atmospheric Administration, Department of Commerce — The data is comprised of the records of individual male golden king crab (GKC) tagged at the Kodiak Laboratory. Initial size, shell condition and missing limbs was...

Lenke and King classification systems for adolescent idiopathic scoliosis: interobserver agreement and postoperative results.

Science.gov (United States)

Hosseinpour-Feizi, Hojjat; Soleimanpour, Jafar; Sales, Jafar Ganjpour; Arzroumchilar, Ali

2011-01-01

The aim of this study was to investigate the interobserver agreement of the Lenke and King classifications for adolescent idiopathic scoliosis, and to compare the results of surgery performed based on classification of the scoliosis according to each of these classification systems. The study was conducted in Shohada Hospital in Tabriz, Iran, between 2009 and 2010. First, a reliability assessment was undertaken to assess interobserver agreement of the Lenke and King classifications for adolescent idiopathic scoliosis. Second, postoperative efficacy and safety of surgery performed based on the Lenke and King classifications were compared. Kappa coefficients of agreement were calculated to assess the agreement. Outcomes were compared using bivariate tests and repeated measures analysis of variance. A low to moderate interobserver agreement was observed for the King classification; the Lenke classification yielded mostly high agreement coefficients. The outcome of surgery was not found to be substantially different between the two systems. Based on the results, the Lenke classification method seems advantageous. This takes into consideration the Lenke classification's priority in providing details of curvatures in different anatomical surfaces to explain precise intensity of scoliosis, that it has higher interobserver agreement scores, and also that it leads to noninferior postoperative results compared with the King classification method.

Wol man's disease: The King Faisal Specialist Hospital and Research Centre Experience

International Nuclear Information System (INIS)

Al-Essa, M.; Sakati, N.; Joshi, S.; Ozand, P.T.; Nounou, R.; Le Quesne, G.; Archibald, A.

1998-01-01

Wolman's disease is a rare autosomal recessive lysosomal storage disease. A recent review indicates that approximately 50 patients have reported in the world. Reports of patients from the Arabian Peninsula are rare due to lack of awareness among pediatricians. We retrospectively reviewed the clinical, radiological, biochemical and histopathological findings of four Saudi patients diagnosed with Wolman's disease at King Faisal Hospital and Research Centre. The diagnosis was confirmed by deficient acid lipase activity in the leukocytes and fibroblasts, which was measured using 4-methylumbelliferyl palmitate. All patients were failing to thrive with progressive heptasplenomegaly. Abdominal x-ray revealed calcifications which were confirmed on abdominal CT scan. Peripheral blood film showed foamy histiocytes. Liver biopsy in one patient showed marked steatosis and elliptical empty clefs predominantly in the Kupffer cells, indicating cholesterol storage in the reticulo-endothelial cells. The acid lipase activity was less than 6% in all patients. In all suspected cases of Wolman's disease, a plane abdominal x-ray should be obtained to check for the typical pattern of adrenal calcification characteristic of the disease, especially ant young infant with failure to thrive and progressive hepatosplenomegaly. (author)

The King-Denborough syndrome in the paediatric patient.

African Journals Online (AJOL)

We describe the management of two children with a diagnosis of King Denborough syndrome. ... the anaesthetic management of two cases of KDS presenting for sur- .... al suggest that the syndrome represents a phenotype that is common to.

Additional calcium carbonate into concentrate diet for sheep fed ensiled king grass as a based-diet

Directory of Open Access Journals (Sweden)

I-W Mathius

1997-10-01

Full Text Available In order to ascertain the effect of additional calcium carbonate into concentrate diet, on the performance of sheep fed ensiled king grass as a basal diet, a trial was conducted using 28 growing sheep ( average body weight 17 _+ 1 .4 kg. Based on body weight, the animals were grouped and randomized into four dietary treatments in block randomized design . Dietary treatments were (i chopped king grass + 400 g of concentrate, (ii ensiled king grass + 400 g concentrate + 0 % of calcium carbonate, (iii ensiled king grass + 400 g concentrate + 5 % calcium carbonate and (iv ensiled king grass + 400 g concentrate + 10 % calcium carbonate . Results showed that offering 5 % of calcium carbonate into concentrate diet increased (P 0 .05 for all groups . No differences in the apparent digestibility of the nutrient components were observed, but crude protein decreased significantly (P < 0 .05 . A significant relationship ( P < 0 .01 was found between nitrogen intake (NI and nitrogen retention (NR, and the equation was NR = - 0.1848 + 0.3788 NI ( r = 0.9 . Based on data found that feeding only ensiled king grass as a single diet could not meet the maintenance requirement of energy and protein, therefore, additional energy and crude protein sources is needed .

When physics became king

CERN Document Server

Morus, Iwan Rhys

2005-01-01

As recently as two hundred years ago, physics as we know it today did not exist. Born in the early nineteenth century during the second scientific revolution, physics struggled at first to achieve legitimacy in the scientific community and culture at large. In fact, the term "physicist" did not appear in English until the 1830s.When Physics Became King traces the emergence of this revolutionary science, demonstrating how a discipline that barely existed in 1800 came to be regarded a century later as the ultimate key to unlocking nature's secrets. A cultural history designed to provid

Phreatic explosions during basaltic fissure eruptions: Kings Bowl lava field, Snake River Plain, USA

Science.gov (United States)

Hughes, Scott S.; Kobs Nawotniak, Shannon E.; Sears, Derek W. G.; Borg, Christian; Garry, William Brent; Christiansen, Eric H.; Haberle, Christopher W.; Lim, Darlene S. S.; Heldmann, Jennifer L.

2018-02-01

Physical and compositional measurements are made at the 7 km-long ( 2200 years B.P.) Kings Bowl basaltic fissure system and surrounding lava field in order to further understand the interaction of fissure-fed lavas with phreatic explosive events. These assessments are intended to elucidate the cause and potential for hazards associated with phreatic phases that occur during basaltic fissure eruptions. In the present paper we focus on a general understanding of the geological history of the site. We utilize geospatial analysis of lava surfaces, lithologic and geochemical signatures of lava flows and explosively ejected blocks, and surveys via ground observation and remote sensing. Lithologic and geochemical signatures readily distinguish between Kings Bowl and underlying pre-Kings Bowl lava flows, both of which comprise phreatic ejecta from the Kings Bowl fissure. These basalt types, as well as neighboring lava flows from the contemporaneous Wapi lava field and the older Inferno Chasm vent and outflow channel, fall compositionally within the framework of eastern Snake River Plain olivine tholeiites. Total volume of lava in the Kings Bowl field is estimated to be 0.0125 km3, compared to a previous estimate of 0.005 km3. The main (central) lava lake lost a total of 0.0018 km3 of magma by either drain-back into the fissure system or breakout flows from breached levees. Phreatic explosions along the Kings Bowl fissure system occurred after magma supply was cut off, leading to fissure evacuation, and were triggered by magma withdrawal. The fissure system produced multiple phreatic explosions and the main pit is accompanied by others that occur as subordinate pits and linear blast corridors along the fissure. The drop in magma supply and the concomitant influx of groundwater were necessary processes that led to the formation of Kings Bowl and other pits along the fissure. A conceptual model is presented that has relevance to the broader range of low-volume, monogenetic

76 FR 5326 - Fisheries of the Caribbean, Gulf of Mexico, and South Atlantic; King and Spanish Mackerel Coastal...

Science.gov (United States)

2011-01-31

... Spanish Mackerel Coastal Migratory Pelagic Fishery Off the Southern Atlantic States; Control Date AGENCY... that it is establishing a new control date to control future access to the king and Spanish mackerel... September 17, 2010, for king and Spanish mackerel. The Council requested a new control date for the king and...

Dual AAV therapy ameliorates exercise-induced muscle injury and functional ischemia in murine models of Duchenne muscular dystrophy.

Science.gov (United States)

Zhang, Yadong; Yue, Yongping; Li, Liang; Hakim, Chady H; Zhang, Keqing; Thomas, Gail D; Duan, Dongsheng

2013-09-15

Neuronal nitric oxide synthase (nNOS) membrane delocalization contributes to the pathogenesis of Duchenne muscular dystrophy (DMD) by promoting functional muscle ischemia and exacerbating muscle injury during exercise. We have previously shown that supra-physiological expression of nNOS-binding mini-dystrophin restores normal blood flow regulation and prevents functional ischemia in transgenic mdx mice, a DMD model. A critical next issue is whether systemic dual adeno-associated virus (AAV) gene therapy can restore nNOS-binding mini-dystrophin expression and mitigate muscle activity-related functional ischemia and injury. Here, we performed systemic gene transfer in mdx and mdx4cv mice using a pair of dual AAV vectors that expressed a 6 kb nNOS-binding mini-dystrophin gene. Vectors were packaged in tyrosine mutant AAV-9 and co-injected (5 × 10(12) viral genome particles/vector/mouse) via the tail vein to 1-month-old dystrophin-null mice. Four months later, we observed 30-50% mini-dystrophin positive myofibers in limb muscles. Treatment ameliorated histopathology, increased muscle force and protected against eccentric contraction-induced injury. Importantly, dual AAV therapy successfully prevented chronic exercise-induced muscle force drop. Doppler hemodynamic assay further showed that therapy attenuated adrenergic vasoconstriction in contracting muscle. Our results suggest that partial transduction can still ameliorate nNOS delocalization-associated functional deficiency. Further evaluation of nNOS binding mini-dystrophin dual AAV vectors is warranted in dystrophic dogs and eventually in human patients.

The Influence of Martin Luther King on Education

Science.gov (United States)

Harper, Frederick D.

1973-01-01

In a sense, Martin Luther King was an educator whose students composed citizens of the United States, whose classroom encompassed the entire country, and whose course contents and lesson plans included civil rights, race relations, human rights, and love. (Author)

Thermal strategies of king penguins during prolonged fasting in water.

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Lewden, Agnès; Enstipp, Manfred R; Bonnet, Batshéva; Bost, Caroline; Georges, Jean-Yves; Handrich, Yves

2017-12-15

Most animals experience periods of unfavourable conditions, challenging their daily energy balance. During breeding, king penguins fast voluntarily for up to 1.5 months in the colony, after which they replenish their energy stores at sea. However, at sea, birds might encounter periods of low foraging profitability, forcing them to draw from previously stored energy (e.g. subcutaneous fat). Accessing peripheral fat stores requires perfusion, increasing heat loss and thermoregulatory costs. Hence, how these birds balance the conflicting demands of nutritional needs and thermoregulation is unclear. We investigated the physiological responses of king penguins to fasting in cold water by: (1) monitoring tissue temperatures, as a proxy of tissue perfusion, at four distinct sites (deep and peripheral); and (2) recording their oxygen consumption rate while birds floated inside a water tank. Despite frequent oscillations, temperatures of all tissues often reached near-normothermic levels, indicating that birds maintained perfusion to peripheral tissues throughout their fasting period in water. The oxygen consumption rate of birds increased with fasting duration in water, while it was also higher when the flank tissue was warmer, indicating greater perfusion. Hence, fasting king penguins in water maintained peripheral perfusion, despite the associated greater heat loss and, therefore, thermoregulatory costs, probably to access subcutaneous fat stores. Hence, the observed normothermia in peripheral tissues of king penguins at sea, upon completion of a foraging bout, is likely explained by their nutritional needs: depositing free fatty acids (FFA) in subcutaneous tissues after profitable foraging or mobilizing FFA to fuel metabolism when foraging success was insufficient. © 2017. Published by The Company of Biologists Ltd.

Anogeissus sericea var. nummalaria King ex Duthie

Indian Academy of Sciences (India)

Home; Journals; Resonance – Journal of Science Education; Volume 8; Issue 4. Anogeissus sericea var. nummalaria King ex Duthie. Flowering Trees Volume 8 Issue 4 April 2003 pp 89-89. Fulltext. Click here to view fulltext PDF. Permanent link: https://www.ias.ac.in/article/fulltext/reso/008/04/0089-0089. Resonance ...

Vitamin D Deficiency in Patients with Systemic Lupus Erythematosus

Directory of Open Access Journals (Sweden)

Suzan M. Attar

2013-01-01

Full Text Available Objectives: Hypovitaminosis D is common in the general population. Many studies that have been conducted to show the association between vitamin D deficiency and systemic lupus erythematosus (SLE reveal that deficiencies in vitamin D are common in this group of patients. Our aim was to study the relationship between 25(OHD and disease activity in patients with SLE.Methods: Retrospective cohort study of patients with SLE who were followed up at King Abdulaziz University Hospital, Jeddah, from January 2007 to November 2010. Demographic and clinical data were recorded and the 25(OHD levels of the patients were measured. Chi square tests, Student’s t-test, ANOVA and Pearson tests were used for data analysis. ANOVA test was followed by Bonferroni correction. A p-value <0.05 was considered significant.Results: Ninety-five patients with SLE were enrolled in the study. The levels of 25(OHD were significantly lower in patients with active SLE (n=41; 43% than in those with inactive disease (n=54; 57%; p=0.04. The mean (SD levels were 22.3 (14 nmol/L for patients with active disease against 25.0 (14 nmol/L for patients with inactive SLE. No correlation was detected between 25(OH D levels and disease activity score evaluated by SLEDAI-2K. By Pearson correlation, a significant negative correlation existed between 25(OH D and anti ds-DNA (r=-0.38; p<0.001; a positive correlation existed between 25(OHD levels and C4 (r=0.25; p=0.25. By chi square testing, azathioprine treatment (OR=3.5, low C4 (OR= 2.23, low C3 (OR=1.92, and active disease (OR=1.6 were associated with 25(OHD deficiency in SLE patients.Conclusion: Vitamin D deficiency is frequent in patients with SLE. Patients with SLE have a higher risk of developing 25(OHD deficiency in the presence of low serum C3 and C4 levels, and high anti-dsDNA levels.

Duchenne Muscular Dystrophy Gene Therapy in the Canine Model

Science.gov (United States)

2015-01-01

Abstract Duchenne muscular dystrophy (DMD) is an X-linked lethal muscle disease caused by dystrophin deficiency. Gene therapy has significantly improved the outcome of dystrophin-deficient mice. Yet, clinical translation has not resulted in the expected benefits in human patients. This translational gap is largely because of the insufficient modeling of DMD in mice. Specifically, mice lacking dystrophin show minimum dystrophic symptoms, and they do not respond to the gene therapy vector in the same way as human patients do. Further, the size of a mouse is hundredfolds smaller than a boy, making it impossible to scale-up gene therapy in a mouse model. None of these limitations exist in the canine DMD (cDMD) model. For this reason, cDMD dogs have been considered a highly valuable platform to test experimental DMD gene therapy. Over the last three decades, a variety of gene therapy approaches have been evaluated in cDMD dogs using a number of nonviral and viral vectors. These studies have provided critical insight for the development of an effective gene therapy protocol in human patients. This review discusses the history, current status, and future directions of the DMD gene therapy in the canine model. PMID:25710459

The Relationship between Body Image Satisfaction and Bulimia Nervosa among King Saud University Students

Science.gov (United States)

Aljomaa, Suliman Saleh

2018-01-01

The study aimed at examining the relationship between body image satisfaction and bulimia nervosa among the students of education faculty at king said university students. The author used the tests of bulimia nervosa and body image test. The researcher verified tests reliability. Students from King Saud University randomly selected (No. 337)…

Lichen flora around the Korean Antarctic Scientific Station, King George Island, Antarctic.

Science.gov (United States)

Kim, Ji Hee; Ahn, In-Young; Hong, Soon Gyu; Andreev, Mikhail; Lim, Kwang-Mi; Oh, Mi Jin; Koh, Young Jin; Hur, Jae-Seoun

2006-10-01

As part of the long-term monitoring projects on Antarctic terrestrial vegetation in relation to global climate change, a lichen floristical survey was conducted around the Korean Antarctic Station (King Sejong Station), which is located on Barton Peninsula, King George Island, in January and February of 2006. Two hundred and twenty-five lichen specimens were collected and sixty-two lichen species in 38 genera were identified by morphological characteristics, chemical constituents, TLC analysis and ITS nucleotide sequence analysis.

Ornamental colors reveal age in the king penguin

NARCIS (Netherlands)

Nicolaus, Marion; Le Bohec, Celine; Nolan, Paul M.; Gauthier-Clerc, Michel; Le Maho, Yvon; Komdeur, Jan; Jouventin, Pierre

2007-01-01

We investigated whether delayed plumage maturation occurred in king penguins (Aptenodytes patagonicus). Therefore we examined the relationships between age and sex on spectral properties and size of two colored plumage patches and a UV-reflective beak spot, using known-age cohorts. Unlike the

HIV intertest interval among MSM in King County, Washington.

Science.gov (United States)

Katz, David A; Dombrowski, Julia C; Swanson, Fred; Buskin, Susan E; Golden, Matthew R; Stekler, Joanne D

2013-02-01

The authors examined temporal trends and correlates of HIV testing frequency among men who have sex with men (MSM) in King County, Washington. The authors evaluated data from MSM testing for HIV at the Public Health-Seattle & King County (PHSKC) STD Clinic and Gay City Health Project (GCHP) and testing history data from MSM in PHSKC HIV surveillance. The intertest interval (ITI) was defined as the number of days between the last negative HIV test and the current testing visit or first positive test. Correlates of the log(10)-transformed ITI were determined using generalised estimating equations linear regression. Between 2003 and 2010, the median ITI among MSM seeking HIV testing at the STD Clinic and GCHP were 215 (IQR: 124-409) and 257 (IQR: 148-503) days, respectively. In multivariate analyses, younger age, having only male partners and reporting ≥10 male sex partners in the last year were associated with shorter ITIs at both testing sites (pGCHP attendees, having a regular healthcare provider, seeking a test as part of a regular schedule and inhaled nitrite use in the last year were also associated with shorter ITIs (pGCHP (median 359 vs 255 days, p=0.02). Although MSM in King County appear to be testing at frequent intervals, further efforts are needed to reduce the time that HIV-infected persons are unaware of their status.

Prevalence of glucose-6-phosphate dehydrogenase deficiency and sickle cell trait among blood donors in Riyadh

Directory of Open Access Journals (Sweden)

Alabdulaali Mohammed

2010-01-01

Full Text Available Background and Aims: Blood donation from glucose-6-phosphate dehydrogenase (G6PD-deficient and sickle cell trait (SCT donors might alter the quality of the donated blood during processing, storage or in the recipient′s circulatory system. The aim of this study was to determine the prevalence of G6PD deficiency and SCT among blood donors coming to King Khalid University Hospital (KKUH in Riyadh. It was also reviewed the benefits and risks of transfusing blood from these blood donors. Materials and Methods: This cross-sectional study was conducted on 1150 blood samples obtained from blood donors that presented to KKUH blood bank during the period April 2006 to May 2006. All samples were tested for Hb-S by solubility test, alkaline gel electrophoresis; and for G6PD deficiency, by fluorescent spot test. Results: Out of the 1150 donors, 23 (2% were diagnosed for SCT, 9 (0.78% for G6PD deficiency and 4 (0.35% for both conditions. Our prevalence of SCT and G6PD deficiency is higher than that of the general population of Riyadh. Conclusion: We recommend to screen all units for G6PD deficiency and sickle cell trait and to defer donations from donors with either of these conditions, unless if needed for special blood group compatibility, platelet apheresis or if these are likely to affect the blood bank inventory. If such blood is to be used, special precautions need to be undertaken to avoid complications in high-risk recipients.

Biohistorical materials and contemporary privacy concerns-the forensic case of King Albert I.

Science.gov (United States)

Larmuseau, Maarten H D; Bekaert, Bram; Baumers, Maarten; Wenseleers, Tom; Deforce, Dieter; Borry, Pascal; Decorte, Ronny

2016-09-01

The rapid advancement of technology in genomic analysis increasingly allows researchers to study human biohistorical materials. Nevertheless, little attention has been paid to the privacy of the donor's living relatives and the negative impact they might experience from the (public) availability of genetic results, even in cases of scientific, forensic or historical relevance. This issue has become clear during a cold case investigation of a relic attributed to Belgian King and World War I-hero Albert I who died, according to the official version, in a solo climbing accident in 1934. Authentication of the relic with blood stains assigned to the King and collected on the place where his body was discovered is recognised as one of the final opportunities to test the plausibility of various conspiracy theories on the King's demise. While the historical value and current technological developments allow the genomic analysis of this relic, publication of genetic data would immediately lead to privacy concerns for living descendants and relatives of the King, including the Belgian and British royal families, even after more than 80 years. Therefore, the authentication study of the relic of King Albert I has been a difficult exercise towards balancing public research interests and privacy interests. The identification of the relic was realised by using a strict genetic genealogical approach including Y-chromosome and mitochondrial genome comparison with living relatives, thereby limiting the analysis to genomic regions relevant for identification. The genetic results combined with all available historical elements concerning the relic, provide strong evidence that King Albert I was indeed the donor of the blood stains, which is in line with the official climbing accident hypothesis and contradicts widespread 'mise-en-scène' scenarios. Since publication of the haploid data of the blood stains has the potential to violate the privacy of living relatives, we opted for

A local equation for differential diagnosis of β-thalassemia trait and iron deficiency anemia by logistic regression analysis in Southeast Iran.

Science.gov (United States)

Sargolzaie, Narjes; Miri-Moghaddam, Ebrahim

2014-01-01

The most common differential diagnosis of β-thalassemia (β-thal) trait is iron deficiency anemia. Several red blood cell equations were introduced during different studies for differential diagnosis between β-thal trait and iron deficiency anemia. Due to genetic variations in different regions, these equations cannot be useful in all population. The aim of this study was to determine a native equation with high accuracy for differential diagnosis of β-thal trait and iron deficiency anemia for the Sistan and Baluchestan population by logistic regression analysis. We selected 77 iron deficiency anemia and 100 β-thal trait cases. We used binary logistic regression analysis and determined best equations for probability prediction of β-thal trait against iron deficiency anemia in our population. We compared diagnostic values and receiver operative characteristic (ROC) curve related to this equation and another 10 published equations in discriminating β-thal trait and iron deficiency anemia. The binary logistic regression analysis determined the best equation for best probability prediction of β-thal trait against iron deficiency anemia with area under curve (AUC) 0.998. Based on ROC curves and AUC, Green & King, England & Frazer, and then Sirdah indices, respectively, had the most accuracy after our equation. We suggest that to get the best equation and cut-off in each region, one needs to evaluate specific information of each region, specifically in areas where populations are homogeneous, to provide a specific formula for differentiating between β-thal trait and iron deficiency anemia.

The last Viking King

DEFF Research Database (Denmark)

Dissing, J.; Binladen, J.; Hansen, Anders J.

2007-01-01

of King Sven Estridsen to haplogroup H; Estrid's sequence differed from that of Sven at two positions in HVR-1, 16093T -> C and 16304T -> C, indicating that she belongs to subgroup H5a. Given the maternal inheritance of mtDNA, offspring will have the same mtDNA sequence as their mother with the exception......, there have been doubts among historians whether the woman entombed was indeed Estrid. To shed light on this problem, we have extracted and analysed mitochondrial DNA (mtDNA) from pulp of teeth from each of the two royals. Four overlapping DNA-fragments covering about 400 bp of hypervariable region 1 (HVR-1...

King penguin population threatened by Southern Ocean warming.

Science.gov (United States)

Le Bohec, Céline; Durant, Joël M; Gauthier-Clerc, Michel; Stenseth, Nils C; Park, Young-Hyang; Pradel, Roger; Grémillet, David; Gendner, Jean-Paul; Le Maho, Yvon

2008-02-19

Seabirds are sensitive indicators of changes in marine ecosystems and might integrate and/or amplify the effects of climate forcing on lower levels in food chains. Current knowledge on the impact of climate changes on penguins is primarily based on Antarctic birds identified by using flipper bands. Although flipper bands have helped to answer many questions about penguin biology, they were shown in some penguin species to have a detrimental effect. Here, we present for a Subantarctic species, king penguin (Aptenodytes patagonicus), reliable results on the effect of climate on survival and breeding based on unbanded birds but instead marked by subcutaneous electronic tags. We show that warm events negatively affect both breeding success and adult survival of this seabird. However, the observed effect is complex because it affects penguins at several spatio/temporal levels. Breeding reveals an immediate response to forcing during warm phases of El Niño Southern Oscillation affecting food availability close to the colony. Conversely, adult survival decreases with a remote sea-surface temperature forcing (i.e., a 2-year lag warming taking place at the northern boundary of pack ice, their winter foraging place). We suggest that this time lag may be explained by the delay between the recruitment and abundance of their prey, adjusted to the particular 1-year breeding cycle of the king penguin. The derived population dynamic model suggests a 9% decline in adult survival for a 0.26 degrees C warming. Our findings suggest that king penguin populations are at heavy extinction risk under the current global warming predictions.

Evaluation of multiplex ligation-dependent probe amplification analysis versus multiplex polymerase chain reaction assays in the detection of dystrophin gene rearrangements in an Iranian population subset

Directory of Open Access Journals (Sweden)

Nayereh Nouri

2014-01-01

Full Text Available Background: The Duchenne muscular dystrophy (DMD gene is located in the short arm of the X chromosome (Xp21. It spans 2.4 Mb of the human genomic DNA and is composed of 79 exons. Mutations in the Dystrophin gene result in DMD and Becker muscular dystrophy. In this study, the efficiency of multiplex ligation-dependent probe amplification (MLPA over multiplex polymerase chain reaction (PCR assays in an Iranian population was investigated. Materials and Methods: Multiplex PCR assays and MLPA analysis were carried out in 74 patients affected with DMD. Results: Multiplex PCR detected deletions in 51% of the patients with DMD. MLPA analysis could determine all the deletions detected by the multiplex PCR. Additionally, MLPA was able to identify one more deletion and duplication in patients without detectable mutations by multiplex PCR. Moreover, MLPA precisely determined the exact size of the deletions. Conclusion: Although MLPA analysis is more sensitive for detection of deletions and duplications in the dystrophin gene, multiplex PCR might be used for the initial analysis of the boys affected with DMD in the Iranian population as it was able to detect 95% of the rearrangements in patients with DMD.

Dystrophin Hot-Spot Mutants Leading to Becker Muscular Dystrophy Insert More Deeply into Membrane Models than the Native Protein.

Science.gov (United States)

Ameziane-Le Hir, Sarah; Paboeuf, Gilles; Tascon, Christophe; Hubert, Jean-François; Le Rumeur, Elisabeth; Vié, Véronique; Raguénès-Nicol, Céline

2016-07-26

Dystrophin (DYS) is a membrane skeleton protein whose mutations lead to lethal Duchenne muscular dystrophy or to the milder Becker muscular dystrophy (BMD). One third of BMD "in-frame" exon deletions are located in the region that codes for spectrin-like repeats R16 to R21. We focused on four prevalent mutated proteins deleted in this area (called RΔ45-47, RΔ45-48, RΔ45-49, and RΔ45-51 according to the deleted exon numbers), analyzing protein/membrane interactions. Two of the mutants, RΔ45-48 and RΔ45-51, led to mild pathologies and displayed a similar triple coiled-coil structure as the full-length DYS R16-21, whereas the two others, RΔ45-47 and RΔ45-49, induced more severe pathologies and showed "fractional" structures unrelated to the normal one. To explore lipid packing, small unilamellar liposomes (SUVs) and planar monolayers were used at various initial surface pressures. The dissociation constants determined by microscale thermophoresis (MST) were much higher for the full-length DYS R161-21 than for the mutants; thus the wild type protein has weaker SUV binding. Comparing surface pressures after protein adsorption and analysis of atomic force microscopy images of mixed protein/lipid monolayers revealed that the mutants insert more into the lipid monolayer than the wild type does. In fact, in both models every deletion mutant showed more interactions with membranes than the full-length protein did. This means that mutations in the R16-21 part of dystrophin disturb the protein's molecular behavior as it relates to membranes, regardless of whether the accompanying pathology is mild or severe.

Tribute to Julie Taymor's Lion King Costumes

Science.gov (United States)

Carter, Mary C.; Beaty, Ben

2011-01-01

Julie Taymor's costumes and masks for the stage version of "The Lion King" were stunning in the way they combined the dual images of human and animal forms. Taymor visually incorporated the human form of a dancer into the simplified form of the animal character so both are equally visible. This visible duality of human form and animal…

Effects of Sildenafil on Cerebrovascular Reactivity in Patients with Becker Muscular Dystrophy

DEFF Research Database (Denmark)

Lindberg, Ulrich; Witting, Nanna; Jørgensen, Stine Lundgaard

2017-01-01

Patients suffering from Becker muscular dystrophy (BMD) have dysfunctional dystrophin proteins and are deficient in neuronal nitric oxide synthase (nNOS) in muscles. This causes functional ischemia and contributes to muscle wasting. Similar functional ischemia may be present in brains of patients...

Whatsapp for Educational Purposes for Female Students at College of Education--King Saud University

Science.gov (United States)

Aljaad, Nawal Hamad Mohmad

2017-01-01

This research aims at finding out the educational usages of "Whatsapp" by the Saudi female students who are involved in the College of Education at King Saud University. To achieve the goal of this study, the researcher uses a simple sample of (122) female students from the Education College of King Saud University, which is chosen…

King eider foraging effort during the pre-breeding period in Alaska

Science.gov (United States)

Oppel, Steffen; Powell, Abby N.; Butler, Malcolm G.

2011-01-01

For reproduction, many arctic-nesting migratory birds rely on nutrients obtained on the breeding grounds, so they devote sufficient time to foraging immediately prior to nesting. However, little is known about the increase in foraging effort necessary to meet the energetic requirements of reproduction. In early June 2006 and 2008, we quantified the proportion of time spent foraging before breeding by a large sea duck, the King Eider (Somateria spectabilis), on its breeding grounds in northern Alaska. During >235 hours of behavioral observations, both male and female King Eiders spent >50% of the day loafing (resting, sleeping, comfort behavior, or being alert). Females foraged on average 30% of the time (mean 7.2 hr day-1,95% CI 6.0-8.4 hr day-1), three times as much as males (9%; 2.3 hr day-1, 95% CI 1.5–2.8 hr day-1). The most common prey in ponds where the eiders foraged were chironomid larvae and worms ranging in length from 1 to 30 mm. If the King Eider's daily energy expenditure on its breeding grounds is similar to values published for related species, it would need to ingest only 0.2–0.6 g dry mass of invertebrates per minute of foraging to meet its energetic requirements. Males did not lose body mass before breeding, and we assume that their foraging effort was sufficient for energy balance. Therefore, female King Eiders appear to triple their foraging effort over maintenance requirements to meet the energetic challenges of egg formation.

Deletion of exon 26 of the dystrophin gene is associated with a mild Becker muscular dystrophy phenotype

DEFF Research Database (Denmark)

Witting, Nanna; Duno, Morten; Vissing, John

2011-01-01

With the possible introduction of exon skipping therapy in Duchenne muscular dystrophy, it has become increasingly important to know the role of each exon of the dystrophin gene to protein expression, and thus the phenotype. In this report, we present two related men with an unusually mild BMD...... skipping therapy for Duchenne muscular dystrophy. This report also shows that BMD may present with a normal CK....... associated with an exon 26 deletion. The proband, a 23-year-old man, had slightly delayed motor milestones, walking 1 1/2 years old. He had no complaints of muscle weakness, but had muscle pain. Clinical examination revealed no muscle wasting or loss of power, but his CK was 1500-7000 U/l. Muscle biopsy...

Musculoskeletal simulation can help explain selective muscle degeneration in Duchenne muscular dystrophy.

Science.gov (United States)

Hu, Xiao; Blemker, Silvia S

2015-08-01

Duchenne muscular dystrophy (DMD) is a genetic disease that occurs due to the deficiency of the dystrophin protein. Although dystrophin is deficient in all muscles, it is unclear why degeneration progresses differently across muscles in DMD. We hypothesized that each muscle undergoes a different degree of eccentric contraction during gait, which could contribute to the selective degeneration in lower limb muscle, as indicated by various amounts of fatty infiltration. By comparing eccentric contractions quantified from a previous multibody dynamic musculoskeletal gait simulation and fat fractions quantified in a recent imaging study, our preliminary analyses show a strong correlation between eccentric contractions during gait and lower limb muscle fat fractions, supporting our hypothesis. This knowledge is critical for developing safe exercise regimens for the DMD population. This study also provides supportive evidence for using multiscale modeling and simulation of the musculoskeletal system in future DMD research. © 2015 Wiley Periodicals, Inc.

Lenke and King classification systems for adolescent idiopathic scoliosis: interobserver agreement and postoperative results

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Hosseinpour-Feizi H

2011-12-01

Full Text Available Hojjat Hosseinpour-Feizi, Jafar Soleimanpour, Jafar Ganjpour Sales, Ali ArzroumchilarDepartment of Orthopedics, Shohada Hospital, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, IranPurpose: The aim of this study was to investigate the interobserver agreement of the Lenke and King classifications for adolescent idiopathic scoliosis, and to compare the results of surgery performed based on classification of the scoliosis according to each of these classification systems.Methods: The study was conducted in Shohada Hospital in Tabriz, Iran, between 2009 and 2010. First, a reliability assessment was undertaken to assess interobserver agreement of the Lenke and King classifications for adolescent idiopathic scoliosis. Second, postoperative efficacy and safety of surgery performed based on the Lenke and King classifications were compared. Kappa coefficients of agreement were calculated to assess the agreement. Outcomes were compared using bivariate tests and repeated measures analysis of variance.Results: A low to moderate interobserver agreement was observed for the King classification; the Lenke classification yielded mostly high agreement coefficients. The outcome of surgery was not found to be substantially different between the two systems.Conclusion: Based on the results, the Lenke classification method seems advantageous. This takes into consideration the Lenke classification’s priority in providing details of curvatures in different anatomical surfaces to explain precise intensity of scoliosis, that it has higher interobserver agreement scores, and also that it leads to noninferior postoperative results compared with the King classification method.Keywords: test reliability, scoliosis classification, postoperative efficacy, adolescents

Platelet function in dogs

DEFF Research Database (Denmark)

Nielsen, Line A.; Zois, Nora Elisabeth; Pedersen, Henrik D.

2007-01-01

Background: Clinical studies investigating platelet function in dogs have had conflicting results that may be caused by normal physiologic variation in platelet response to agonists. Objectives: The objective of this study was to investigate platelet function in clinically healthy dogs of 4...... different breeds by whole-blood aggregometry and with a point-of-care platelet function analyzer (PFA-100), and to evaluate the effect of acetylsalicylic acid (ASA) administration on the results from both methods. Methods: Forty-five clinically healthy dogs (12 Cavalier King Charles Spaniels [CKCS], 12...... applied. However, the importance of these breed differences remains to be investigated. The PFA-100 method with Col + Epi as agonists, and ADP-induced platelet aggregation appear to be sensitive to ASA in dogs....

Review of records and notes on King Penguin (Aptenodytes patagonicus) and Rockhopper Penguin (Eudyptes chrysocome) in Brazil

OpenAIRE

Barquete, Viviane; Bugoni, Leandro; Silva-Filho, Rodolfo P.; Adornes, Andréa C.

2006-01-01

A review of previous findings and new records of King Penguin (Aptenodytes patagonicus) and Rockhopper Penguin (Eudyptes chrysocome) on the Brazilian coast is presented. In total there are six records of the King Penguin and ten records of the Rockhopper Penguin. Juvenile and adults of both species were found stranded mostly on Rio Grande do Sul coast, southern Brazil. Records of King Penguins are restricted to the summer season, while records of Rockhopper Penguins are mostly during winter. ...

Loss of nNOS inhibits compensatory muscle hypertrophy and exacerbates inflammation and eccentric contraction-induced damage in mdx mice

Science.gov (United States)

Froehner, Stanley C.; Reed, Sarah M.; Anderson, Kendra N.; Huang, Paul L.; Percival, Justin M.

2015-01-01

Approaches targeting nitric oxide (NO) signaling show promise as therapies for Duchenne and Becker muscular dystrophies. However, the mechanisms by which NO benefits dystrophin-deficient muscle remain unclear, but may involve nNOSβ, a newly discovered enzymatic source of NO in skeletal muscle. Here we investigate the impact of dystrophin deficiency on nNOSβ and use mdx mice engineered to lack nNOSμ and nNOSβ to discern how the loss of nNOS impacts dystrophic skeletal muscle pathology. In mdx muscle, nNOSβ was mislocalized and its association with the Golgi complex was reduced. nNOS depletion from mdx mice prevented compensatory skeletal muscle cell hypertrophy, decreased myofiber central nucleation and increased focal macrophage cell infiltration, indicating exacerbated dystrophic muscle damage. Reductions in muscle integrity in nNOS-null mdx mice were accompanied by decreases in specific force and increased susceptibility to eccentric contraction-induced muscle damage compared with mdx controls. Unexpectedly, muscle fatigue was unaffected by nNOS depletion, revealing a novel latent compensatory mechanism for the loss of nNOS in mdx mice. Together with previous studies, these data suggest that localization of both nNOSμ and nNOSβ is disrupted by dystrophin deficiency. They also indicate that nNOS has a more complex role as a modifier of dystrophic pathology and broader therapeutic potential than previously recognized. Importantly, these findings also suggest nNOSβ as a new drug target and provide a new conceptual framework for understanding nNOS signaling and the benefits of NO therapies in dystrophinopathies. PMID:25214536

Connect the Book. Martin's Big Words: The Life of Dr. Martin Luther King, Jr.

Science.gov (United States)

Brodie, Carolyn S.

2005-01-01

In honor of Martin Luther King, Jr. Day, this month's featured book is "Martin's Big Words: The Life of Dr. Martin Luther King, Jr." The book was written by Doreen Rappaport and illustrated by Bryan Collier (Jump at the Sun, 2001. 40p. ISBN 0786807148). This pictorial biography of the world-renowned civil rights leader has one of the most striking…

Were king Stefan the First-Crowned and his son Radoslav co-rulers?

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Bubalo Đorđe

2009-01-01

Full Text Available The Serbian historiography considers the issue of the co-ruling of King Stefan the First-Crowned and his son Radoslav as the one finally resolved. The suggested solution on the co-rule of Stefan and Radoslav may be most succinctly expressed as following: as early as in the year of 1220, due to the frail health of Stefan the First-Crowned and Radoslav's marriage to Anne the Epirus princess, Radoslav was crowned to be the king and positioned to co-rule with his father after the Byzantine model of governing. Nevertheless this point of view has some loose ends. The notion of co-ruling and the very term of 'co-ruler' are quite freely used in the scholarly works. A general consensus on the precise meaning has not been reached yet. At the point where one author perceives a co-rule, the other categorically denies it. Basically the approach equalizing the heir to the throne and the co-ruler is wrong. Although the co-rulers in most cases were the throne heirs, they cannot be called the co-rulers because of the right to inherit the throne, but for the ruling attributes that formally established that right. The conviction of the co-rule of King Stefan and his son Radoslav is founded on the interpretation of the facts coming from the following sources: entitling charters for the monastery of Žiča, produced by Stefan and Radoslav around 1220; some segments from St. Sava's biographies by Domentian and Theodosius describing the circumstances of Stefan's death-bed leaving the throne to Radoslav; the three acts of the town of Kotor from 1221 and 1227 dated by the rule of king Radoslav, the portraits of Stefan and Radoslav next to the entrance to the Church of the Ascension in the monastery of Žiča and in the nartex of the Mileševa monastery church. In the first Žiča charter, Stefan calls Radoslav his heir, while in the second Žiča charter Stefan points out Radoslav as his first-born son blessed by him to be the king of the whole state. (jegože i

Immunohistochemical alterations of dystrophin in congenital muscular dystrophy Alterações imuno-hístoquímicas da distrofina na distrofia muscular congênita

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Lineu Cesar Werneck

1995-09-01

Full Text Available The dystrophin distribution in the plasma muscle membrane using immunohystochemistry was studied in 22 children with congenital muscular dystrophy. The dystrophin was detected by immunofluorescence in muscle biopsy through a polyclonal antibody. All the cases had patchy interruptions of the fluorescence in the plasma membrane. A large patchy interruption of the sarcolemma was found in 17 cases, small interruption in 12, and a combination of large and small patchy discontinuity in 7. Small gaps around the fiber like a rosary were found in 15 cases. The frequency of these abnormalities ranged cases from: all fibers in 5 cases, frequent in 8, occasional in 5, and rare in 4. Five cases had total absence of immunofluorescence. These results suggest that the dystrophin expression is abnormal in this group of children and that this type of abnormalities can not be differentiated from early Becker muscular dystrophy nor childhood autosomal recessive muscular dystrophy through immunohystochemistry alone.Foi estudada a distribuição da distrofina na membrana plasmática das fibras musculares em 22 crianças com distrofia muscular congênita, através de técnicas de imuno-histoquímica. A distrofina foi identificada nas biópsias musculares processadas a fresco, por técnicas de imunofluorescência utilizando anticorpos policlonais. Todos os casos tinham interrupções da imunofluorescência na membrana plasmática. Em 17 elas eram grandes, em 12 eram pequenas e em 7 eram de ambos os tipos. Fibras com interrupções pequenas e constantes, como um rosário, foram vistas em 15 casos. Essas anormalidades estavam presentes em todas as fibras em 5 casos, eram frequentes em 8, ocasionais em 5 e raras em 4. Cinco casos mostraram fibras sem distrofina. Esses dados sugerem que a expressão da distrofina é anormal nesse grupo de crianças. Essas anormalidades podem também ser encontradas em casos precoces de distrofia muscular de Becker e distrofia autoss

Outliers and Extremes: Dragon-Kings or Dragon-Fools?

Science.gov (United States)

Schertzer, D. J.; Tchiguirinskaia, I.; Lovejoy, S.

2012-12-01

Geophysics seems full of monsters like Victor Hugo's Court of Miracles and monstrous extremes have been statistically considered as outliers with respect to more normal events. However, a characteristic magnitude separating abnormal events from normal ones would be at odd with the generic scaling behaviour of nonlinear systems, contrary to "fat tailed" probability distributions and self-organized criticality. More precisely, it can be shown [1] how the apparent monsters could be mere manifestations of a singular measure mishandled as a regular measure. Monstrous fluctuations are the rule, not outliers and they are more frequent than usually thought up to the point that (theoretical) statistical moments can easily be infinite. The empirical estimates of the latter are erratic and diverge with sample size. The corresponding physics is that intense small scale events cannot be smoothed out by upscaling. However, based on a few examples, it has also been argued [2] that one should consider "genuine" outliers of fat tailed distributions so monstrous that they can be called "dragon-kings". We critically analyse these arguments, e.g. finite sample size and statistical estimates of the largest events, multifractal phase transition vs. more classical phase transition. We emphasize the fact that dragon-kings are not needed in order that the largest events become predictable. This is rather reminiscent of the Feast of Fools picturesquely described by Victor Hugo. [1] D. Schertzer, I. Tchiguirinskaia, S. Lovejoy et P. Hubert (2010): No monsters, no miracles: in nonlinear sciences hydrology is not an outlier! Hydrological Sciences Journal, 55 (6) 965 - 979. [2] D. Sornette (2009): Dragon-Kings, Black Swans and the Prediction of Crises. International Journal of Terraspace Science and Engineering 1(3), 1-17.

Overvåking av jordboende sopp i Røsskleiva NR, Bamble 2016

OpenAIRE

Brandrud, Tor Erik; Dima, Bàlint

2017-01-01

Brandrud, T.E. & Dima, B. 2017. Overvåking av jordboende sopp i Røsskleiva NR, Bamble 2016. – NINA Kortrapport 80. 15 s. Kartlegging (start av overvåking) av habitat-spesifikke, jordboende kalksopper i nordre del av Røsskleiva NR ble gjennomført i 2016, før oppstart av skjøtselstiltak med storfébeiting. Tilsammen 27 habitat-spesifikke arter, inkludert 18 rødlistede arter ble registrert i løpet av to registreringsrunder i 2016. Funnene fordelte seg på 10 kalkbarskogsopper, 5 kalklinde-skogs...

Neuronal nitric oxide synthase-rescue of dystrophin/utrophin double knockout mice does not require nNOS localization to the cell membrane.

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Michelle Wehling-Henricks

Full Text Available Survival of dystrophin/utrophin double-knockout (dko mice was increased by muscle-specific expression of a neuronal nitric oxide synthase (nNOS transgene. Dko mice expressing the transgene (nNOS TG+/dko experienced delayed onset of mortality and increased life-span. The nNOS TG+/dko mice demonstrated a significant decrease in the concentration of CD163+, M2c macrophages that can express arginase and promote fibrosis. The decrease in M2c macrophages was associated with a significant reduction in fibrosis of heart, diaphragm and hindlimb muscles of nNOS TG+/dko mice. The nNOS transgene had no effect on the concentration of cytolytic, CD68+, M1 macrophages. Accordingly, we did not observe any change in the extent of muscle fiber lysis in the nNOS TG+/dko mice. These findings show that nNOS/NO (nitric oxide-mediated decreases in M2c macrophages lead to a reduction in the muscle fibrosis that is associated with increased mortality in mice lacking dystrophin and utrophin. Interestingly, the dramatic and beneficial effects of the nNOS transgene were not attributable to localization of nNOS protein at the cell membrane. We did not detect any nNOS protein at the sarcolemma in nNOS TG+/dko muscles. This important observation shows that sarcolemmal localization is not necessary for nNOS to have beneficial effects in dystrophic tissue and the presence of nNOS in the cytosol of dystrophic muscle fibers can ameliorate the pathology and most importantly, significantly increase life-span.

Fish for peasants and kings - a Danish perspective

DEFF Research Database (Denmark)

Kristiansen, Mette Svart

2011-01-01

Fish played an important role in medieval Europe. It formed the basis of a food culture influenced by Catholicism and was a central commodity in the national and international network of trade. Fish of all sorts held a prominent position on the dining tables of peasants as well as kings. Househol...

Anogeissus sericea var. nummalaria King ex Duthie (Combretaceae ...

Indian Academy of Sciences (India)

Anogeissus sericea var. nummalaria King ex Duthie (Combretaceae) is moderate sized multipurpose hard wood tree of dry deciduous forests with drooping branches and yellow to brownish-yellow flowers. it is endemic to Rajasthan and is considered to be a threatened tree of the region due to over exploitation for timber ...

Guillem IV de Cervera, cavalier i monjo de Poblet

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Gonzalvo i Bou, Gener

1998-12-01

Full Text Available Guillem IV of Cervera could be the prototype of the noble closely linked to all spheres of power. This article studies his connections as a councillor to the royal court of Pere I and during the early decades of that of Jaume I, at a time of crisis for this royal institution. Guillem of Cervera was also a key player in the difficult relations between the crown and the earldom of Urgell in the context of the absortion of the earldom into the House of Barcelona. On a spiritual level, the close ties between a lineage like the House of Cervera and the monastery of Poblet will be shown, these perhaps being in the image and reflections of the kings.[fr] Guillem IV de Cervera pourrait être le prototype de chevalier lié étroitement à toutes les spheres du pouvoir. Dans cet article, nous étudions ses relations en tant que conseiller de la cour royale de Pere I et ses relations dans la première époque du règne de Jaume I, à une époque de crise de l'institution royale. Guillem de Cervera fut aussi un personnage clé dans les rapports difficiles entre la Couronne et le Comté d'Urgell, dans un contexte d'absorption du Comté à la Maison de Barcelone. Au niveau spirituel, nous montrons les liens étroits d'une lignée comme celle des Cervera avec le monastère de Poblet, à l'image de ses rois.

Comparative proteomic profiling of soleus, extensor digitorum longus, flexor digitorum brevis and interosseus muscles from the mdx mouse model of Duchenne muscular dystrophy.

Science.gov (United States)

Carberry, Steven; Brinkmeier, Heinrich; Zhang, Yaxin; Winkler, Claudia K; Ohlendieck, Kay

2013-09-01

Duchenne muscular dystrophy is due to genetic abnormalities in the dystrophin gene and represents one of the most frequent genetic childhood diseases. In the X-linked muscular dystrophy (mdx) mouse model of dystrophinopathy, different subtypes of skeletal muscles are affected to a varying degree albeit the same single base substitution within exon 23 of the dystrophin gene. Thus, to determine potential muscle subtype-specific differences in secondary alterations due to a deficiency in dystrophin, in this study, we carried out a comparative histological and proteomic survey of mdx muscles. We intentionally included the skeletal muscles that are often used for studying the pathomechanism of muscular dystrophy. Histological examinations revealed a significantly higher degree of central nucleation in the soleus and extensor digitorum longus muscles compared with the flexor digitorum brevis and interosseus muscles. Muscular hypertrophy of 20-25% was likewise only observed in the soleus and extensor digitorum longus muscles from mdx mice, but not in the flexor digitorum brevis and interosseus muscles. For proteomic analysis, muscle protein extracts were separated by fluorescence two-dimensional (2D) gel electrophoresis. Proteins with a significant change in their expression were identified by mass spectrometry. Proteomic profiling established an altered abundance of 24, 17, 19 and 5 protein species in the dystrophin-deficient soleus, extensor digitorum longus, flexor digitorum brevis and interosseus muscle, respectively. The key proteomic findings were verified by immunoblot analysis. The identified proteins are involved in the contraction-relaxation cycle, metabolite transport, muscle metabolism and the cellular stress response. Thus, histological and proteomic profiling of muscle subtypes from mdx mice indicated that distinct skeletal muscles are differentially affected by the loss of the membrane cytoskeletal protein, dystrophin. Varying degrees of perturbed protein

Fisher research and the Kings River Sustainable Forest Ecosystem Project: current results and future efforts

Science.gov (United States)

Brian B. Boroski; Richard T. Golightly; Amie K. Mazzoni; Kimberly A. Sager

2002-01-01

The Kings River Sustainable Forest Ecosystems Project was initiated on the Kings River Ranger District of the Sierra National Forest, California, in 1993, with fieldwork beginning in 1994. Knowledge of the ecology of the fisher (Martes pennanti) in the Project area, and in the Sierra Nevada of California in general, is insufficient to develop...

The King James Bible and the Politics of Religious Education: Secular State and Sacred Scripture

Science.gov (United States)

Gearon, Liam

2013-01-01

This article provides an outline historical-educational analysis of the King James Bible from its 1611 publication through to its four-hundredth anniversary commemoration in 2011. With particular focus on England, the article traces the educational impact of the King James Bible and charts, in the country of its origin, its progressive decline in…

Purification and antibacterial activities of an L-amino acid oxidase from king cobra (Ophiophagus hannah venom

Directory of Open Access Journals (Sweden)

CS Phua

2012-01-01

Full Text Available Some constituents of snake venom have been found to display a variety of biological activities. The antibacterial property of snake venom, in particular, has gathered increasing scientific interest due to antibiotic resistance. In the present study, king cobra venom was screened against three strains of Staphylococcus aureus [including methicillin-resistant Staphylococcus aureus (MRSA], three other species of gram-positive bacteria and six gram-negative bacteria. King cobra venom was active against all the 12 bacteria tested, and was most effective against Staphylococcus spp. (S. aureus and S. epidermidis. Subsequently, an antibacterial protein from king cobra venom was purified by gel filtration, anion exchange and heparin chromatography. Mass spectrometry analysis confirmed that the protein was king cobra L-amino acid oxidase (Oh-LAAO. SDS-PAGE showed that the protein has an estimated molecular weight of 68 kDa and 70 kDa under reducing and non-reducing conditions, respectively. The minimum inhibitory concentrations (MIC of Oh-LAAO for all the 12 bacteria were obtained using radial diffusion assay method. Oh-LAAO had the lowest MIC value of 7.5 µg/mL against S. aureus ATCC 25923 and ATCC 29213, MRSA ATCC 43300, and S. epidermidis ATCC 12228. Therefore, the LAAO enzyme from king cobra venom may be useful as an antimicrobial agent.

Interactions between surface waters in King George Island, Antarctica - a stable isotope perspective

Science.gov (United States)

Perşoiu, Aurel; Bădăluşă, Carmen

2017-04-01

In this paper we present a first study of the isotopic composition of surface waters in the southern peninsulas (Barton, Fildes, Weaver and Potter) of King George Island, Antarctica. We have collected > 200 samples of snow and snowmelt, water (lake, river and spring), ice (glacier ice and permafrost) from the four peninsulas in February 2016 and analyzed them for their oxygen and hydrogen stable isotopic composition. Samples from lake water (50+) indicate a clear west-east depletion trend, suggesting a rain-out process as air masses are moving westward (and are progressively depleted in heavy isotopes) from their origin in the Drake Passage. In both Fildes and Barton Peninsulas, permafrost samples have the heaviest isotopic composition, most probably due to preferential incorporation of heavy isotopes in the ice during freezing (and no fractionation during melting). As permafrost melts, the resulting water mixes with isotopically lighter infiltrated snowmelt, and thus the groundwater has a lower isotopic composition. Further, lake and river (the later fed by lakes) water has the lightest isotopic composition, being derived mostly from the melting of light snow and glacier ice. It seems feasible to separate isotopically water in lakes/rivers (largely fed by melting multi-year glaciers and snow) and water from melting of snow/ground ice This preliminary study suggests that it is possible to separate various water sources in the southern peninsulas of King George Island, and this separation could be used to study permafrost degradation, as well as feeding and migration patterns in the bird fauna, with implications for protection purposes. Acknowledgments. The National Institute of Research and Development for Biological Sciences (Bucharest, Romania) and the Korean polar institute financially supported fieldwork in King George Island. We thank the personal at King Sejong (South Korea), Belingshaussen (Russia) and Carlini (Argentina) stations in King George Island for

78 FR 59414 - Environmental Impact Statement; King County, Washington

Science.gov (United States)

2013-09-26

... DEPARTMENT OF TRANSPORTATION Federal Highway Administration Environmental Impact Statement; King... prepare an environmental impact statement. SUMMARY: The Federal Highway Administration is issuing this notice to advise the public that an Environmental Impact Statement (EIS) will be prepared for a proposed...

Multivariate characterization of elements accumulated in King Bolete Boletus edulis mushroom at lowland and high mountain regions.

Science.gov (United States)

Falandysz, J; Kunito, T; Kubota, R; Bielawski, L; Frankowska, A; Falandysz, Justyna J; Tanabe, S

2008-12-01

Based on ICP-MS, ICP-OES, HG-AAS, CV-AAS and elementary instrumental analysis of King Bolete collected from four sites of different soil bedrock geochemistry considered could be as mushroom abundant in certain elements. King's Bolete fruiting bodies are very rich in K (> 20 mg/g dry weight), rich in Ca, Mg, Na, Rb and Zn (> 100 microg/g dw), and relatively also rich in Ag, Cd, Cs, Cu, Fe, Mn and Se (> 10 microg/g dw). The caps of King Bolete when compared to stipes around two-to three-fold more abundant are in Ag, Cd, Cs, Cu, Hg, K, Mg, Mo, N, Rb, Se and Zn. King Bolete collected at the lowland and mountain sites showed Ag, Ba, Co, Cr, Hg, K, Mg, Mn, Mo and Na in caps in comparable concentrations, and specimens from the mountain areas accumulated more Cd and Sb. Elements such as Al, Pb and Rb occurred at relatively elevated concentration in King Bolete picked up at the metal ores-rich region of the Sudety Mountains. Because of high bioconcentration potential King Bolete at the background sites accumulate in fruiting bodies great concentrations of problematic elements such as Cd, Pb and Hg, i.e. up to nearly 20, 3 and 5 microg/g dw, on the average, respectively. The interdependence among determined mineral elements examined were using the principal components analysis (PCA) method. The PCA explained 56% of the total variance. The metals tend to cluster together (Ba, Cd, Cs, Cr, Ga, Rb, Se, Sr and V; K and Mg; Cu and Mo). The results provided useful environmental and nutritional background level information on 26 minerals as the composition of King Bolete from the sites of different bedrock soil geochemistry.

Effect of experience with pine (Pituophis melanoleucus) and king (Lampropeltis getulus) snake odors on Y-maze behavior of pine snake hatchlings.

Science.gov (United States)

Burger, J; Boarman, W; Kurzava, L; Gochfeld, M

1991-01-01

The abilities of hatchling pine snakes (Pituophis melanoleucus) and king snakes (Lampropeltis getulus) to discriminate the chemical trails of pine and king snakes was investigated inY-maze experiments. Pine snakes were housed for 17 days either with shavings impregnated with pine snake odor, king snake odor, or no odor to test for the effect of experience on choice. Both pine and king snake hatchlings entered the arm with the pine snake odor and did not enter the arm with the king snake odor. The data support the hypothesis that hatchlings of both species can distinguish conspecific odors from other odors and that our manipulation of previous experience was without effect for pine snake hatchlings.

Beat characteristics and beat maps of the King Seong-deok Divine Bell

Science.gov (United States)

Kim, Seock-Hyun; Lee, Chi-Wook; Lee, Jang-Moo

2005-03-01

King Seong-deok Divine Bell is the second oldest bell in Korea. The bell is considered to have the best sound quality among Korean bells. The beat phenomenon is one of the most important characteristics for the sound of the King Seong-deok Divine Bell. In this study, the relationships between the modal parameters and the peculiar beat phenomena of the bell are investigated. It is theoretically proved from the beat characteristics that the sound might indeed be heard differently depending on the listening positions. The beat map method is introduced to visualize the beat distribution properties. It is shown that the beat maps can be drawn with a theoretical model based on the modal data of the bell. Using the beat maps of the King Seong-deok Divine Bell, it is investigated why clear and unclear beats, large and small amplitudes of the vibrations are repeated periodically along the circumference of the bell. Furthermore, the effect of the striking position on the beat distribution property is examined systematically.

Ontogeny of thermoregulatory mechanisms in king penguin chicks (Aptenodytes patagonicus).

Science.gov (United States)

Duchamp, Claude; Rouanet, Jean Louis; Barré, Hervé

2002-04-01

The rapid maturation of thermoregulatory mechanisms may be of critical importance for optimising chick growth and survival and parental energy investment under harsh climatic conditions. The ontogeny of thermoregulatory mechanisms was studied in growing king penguin chicks from hatching to the full emancipation observed at 1 month of age in the sub-Antarctic area (Crozet Archipelago). Newly hatched chicks showed small, but significant regulatory thermogenesis (21% rise in heat production assessed by indirect calorimetry), but rapidly became hypothermic. Within a few days, both resting (+32%) and peak (+52%) metabolic rates increased. The first week of life was characterised by a two-fold rise in thermogenic capacity in the cold, while thermal insulation was not improved. During the second and third weeks of age, thermal insulation markedly rose (two-fold drop in thermal conductance) in relation to down growth, while resting heat production was slightly reduced (-13%). Shivering (assessed by electromyography) was visible right after hatching, although its efficiency was limited. Thermogenic efficiency of shivering increased five-fold with age during the first weeks of life, but there was no sign of non-shivering thermogenesis. We conclude that thermal emancipation of king penguin chicks may be primarily determined by improvement of thermal insulation after thermogenic processes have become sufficiently matured. Both insulative and metabolic adaptations are required for the rapid ontogeny of thermoregulation and thermal emancipation in growing king penguin chicks.

An analysis of Cobit 5 as a framework for the implementation of it governance with reference to King III

Directory of Open Access Journals (Sweden)

Maseko, L.

2016-02-01

Full Text Available Owing to the complexity and general lack of understanding of information technology (“IT”, the management of IT is often treated as a separately managed value-providing asset. This has resulted in IT rarely receiving the necessary attention of the board, thus creating a disconnect between the board and IT. The King Code of Governance for South Africa 2009 (hereafter referred to as “King III” provides principles and recommended practices for effective IT governance in order to create a greater awareness at board level. King III, however, provides no detailed guidance with regard to the practical implementation of these principles and practices. It is worth noting that numerous international guidelines are recommended within King III that can be adopted as frameworks to assist in the effective implementation of IT governance. COBIT 5 provides, as part of its governance process practices, related guidance activities linking it to the seven IT governance principles of King III, thus making it a practical framework for the implementation of King III recommendations. This study sought to establish the extent to which the governance processes, practices and activities of COBIT 5 are mapped to the recommended practices of IT governance as highlighted in King III in order to resolve COBIT 5 as the de facto framework for IT governance in terms of King III. The study found that though King III principles and practices may be interpreted as vague with regard to how to implement IT governance principles, COBIT 5 succeeds in bridging the gap between control requirements, technical issues, information systems and business risk, which consequently results in a better facilitation of IT governance. The study also revealed that COBIT 5 contains additional activities to assist the board in more transparent reporting of IT performance and conformance management to stakeholders as well activities which enable the connection of resource management with human

The origins of dragon-kings and their occurrence in society

Science.gov (United States)

Malkov, Artemy; Zinkina, Julia; Korotayev, Andrey

2012-11-01

A society is a medium with a complex structure of one-to-one relations between people. Those could be relations between friends, wife-husband relationships, relations between business partners, and so on. At a certain level of analysis, a society can be regarded as a gigantic maze constituted of one-to-one relationships between people. From a physical standpoint it can be considered as a highly porous medium. Such media are widely known for their outstanding properties and effects like self-organized criticality, percolation, power-law distribution of network cluster sizes, etc. In these media supercritical events, referred to as dragon-kings, may occur in two cases: when increasing stress is applied to a system (self-organized criticality scenario) or when increasing conductivity of a system is observed (percolation scenario). In social applications the first scenario is typical for negative effects: crises, wars, revolutions, financial breakdowns, state collapses, etc. The second scenario is more typical for positive effects like emergence of cities, growth of firms, population blow-ups, economic miracles, technology diffusion, social network formation, etc. If both conditions (increasing stress and increasing conductivity) are observed together, then absolutely miraculous dragon-king effects can occur that involve most human society. Historical examples of this effect are the emergence of the Mongol Empire, world religions, World War II, and the explosive proliferation of global internet services. This article describes these two scenarios in detail beginning with an overview of historical dragon-king events and phenomena starting from the early human history till the last decades and concluding with an analysis of their possible near future consequences on our global society. Thus we demonstrate that in social systems dragon-king is not a random outlier unexplainable by power-law statistics, but a natural effect. It is a very large cluster in a porous

Extreme Precipitation, Stormwater, and Flooding in King County: Co-producing Research to Support Adaptation

Science.gov (United States)

Mauger, G. S.; Lorente-Plazas, R.; Salathe, E. P., Jr.; Mitchell, T. P.; Simmonds, J.; Lee, S. Y.; Hegewisch, K.; Warner, M.; Won, J.

2017-12-01

King County has experienced 12 federally declared flood disasters since 1990, and tens of thousands of county residents commute through, live, and work in floodplains. In addition to flooding, stormwater is a critical management challenge, exacerbated by aging infrastructure, combined sewer and drainage systems, and continued development. Even absent the effects of climate change these are challenging management issues. Recent studies clearly point to an increase in precipitation extremes for the Pacific Northwest (e.g., Warner et al. 2015). Yet very little information is available on the magnitude and spatial distribution of this change. Others clearly show that local-scale changes in extreme precipitation can only be accurately quantified with dynamical downscaling, i.e.: using a regional climate model. This talk will describe a suite of research and adaptation efforts developed in a close collaboration between King County and the UW Climate Impacts Group. Building on past collaborations, research efforts were defined in collaboration with King County managers, addressing three key science questions: (1) How are the mesoscale variations in extreme precipitation modulated by changes in large-scale weather conditions? (2) How will precipitation extremes change? This was assessed via two new high-resolution regional model projections using the Weather Research and Forecasting (WRF) mesoscale model (Skamarock et al. 2005). (3) What are the implications for stormwater and flooding in King County? This was assessed by both exploring the statistics of hourly precipitation extremes in the new projections, as well as new hydrologic modeling to assess the implications for river flooding. The talk will present results from these efforts, review the implications for King County planning and infrastructure, and synthesize lessons learned and opportunities for additional work.

Structural organisation and dynamics in king penguin colonies

Science.gov (United States)

Gerum, Richard; Richter, Sebastian; Fabry, Ben; Le Bohec, Céline; Bonadonna, Francesco; Nesterova, Anna; Zitterbart, Daniel P.

2018-04-01

During breeding, king penguins do not build nests, however they show strong territorial behaviour and keep a pecking distance to neighbouring penguins. Penguin positions in breeding colonies are highly stable over weeks and appear regularly spaced, but thus far no quantitative analysis of the structural order inside a colony has been performed. In this study, we use the radial distribution function to analyse the spatial coordinates of penguin positions. Coordinates are obtained from aerial images of two colonies that were observed for several years. Our data demonstrate that the structural order in king penguin colonies resembles a 2D liquid of particles with a Lennard-Jones-type interaction potential. We verify this using a molecular dynamics simulation with thermally driven particles, whereby temperature corresponds to penguin movements, the energy well depth ɛ of the attractive potential corresponds to the strength of the colony-forming behaviour, and the repulsive zone corresponds to the pecking radius. We can recapitulate the liquid disorder of the colony, as measured by the radial distribution function, when the particles have a temperature of several (1.4–10) \

Are dragon-king neuronal avalanches dungeons for self-organized brain activity?

Science.gov (United States)

de Arcangelis, L.

2012-05-01

Recent experiments have detected a novel form of spontaneous neuronal activity both in vitro and in vivo: neuronal avalanches. The statistical properties of this activity are typical of critical phenomena, with power laws characterizing the distributions of avalanche size and duration. A critical behaviour for the spontaneous brain activity has important consequences on stimulated activity and learning. Very interestingly, these statistical properties can be altered in significant ways in epilepsy and by pharmacological manipulations. In particular, there can be an increase in the number of large events anticipated by the power law, referred to herein as dragon-king avalanches. This behaviour, as verified by numerical models, can originate from a number of different mechanisms. For instance, it is observed experimentally that the emergence of a critical behaviour depends on the subtle balance between excitatory and inhibitory mechanisms acting in the system. Perturbing this balance, by increasing either synaptic excitation or the incidence of depolarized neuronal up-states causes frequent dragon-king avalanches. Conversely, an unbalanced GABAergic inhibition or long periods of low activity in the network give rise to sub-critical behaviour. Moreover, the existence of power laws, common to other stochastic processes, like earthquakes or solar flares, suggests that correlations are relevant in these phenomena. The dragon-king avalanches may then also be the expression of pathological correlations leading to frequent avalanches encompassing all neurons. We will review the statistics of neuronal avalanches in experimental systems. We then present numerical simulations of a neuronal network model introducing within the self-organized criticality framework ingredients from the physiology of real neurons, as the refractory period, synaptic plasticity and inhibitory synapses. The avalanche critical behaviour and the role of dragon-king avalanches will be discussed in

Why short stature is beneficial in Duchenne muscular dystrophy.

Science.gov (United States)

Bodor, Marko; McDonald, Craig M

2013-09-01

Duchenne muscular dystrophy (DMD) is caused by a genetic defect resulting in absent dystrophin, yet children are able to walk when small and young but lose this ability as they grow. The mdx mouse has absent dystrophin yet does not exhibit significant disability. Allometric modeling of linearly increasing load per muscle fiber and stress on the sarcolemma with growth and exponential decline associated with loss of muscle fibers correlated with case studies and animal models of DMD. Smaller species or breeds are predictably less affected than large as follows: mdx mice muscular dystrophy (GRMD) dogs < large GRMD dogs < humans. Case reports of combined growth hormone and dystrophin deficiency show a relatively benign course of disease. Future therapeutic trials in DMD might include specific growth inhibitors in combination with standard of care treatments to delay the clinical onset and reduce the severity of disease and disability. Copyright © 2013 Wiley Periodicals, Inc.

The artificial gene Jazz, a transcriptional regulator of utrophin, corrects the dystrophic pathology in mdx mice.

Science.gov (United States)

Di Certo, Maria Grazia; Corbi, Nicoletta; Strimpakos, Georgios; Onori, Annalisa; Luvisetto, Siro; Severini, Cinzia; Guglielmotti, Angelo; Batassa, Enrico Maria; Pisani, Cinzia; Floridi, Aristide; Benassi, Barbara; Fanciulli, Maurizio; Magrelli, Armando; Mattei, Elisabetta; Passananti, Claudio

2010-03-01

The absence of the cytoskeletal protein dystrophin results in Duchenne muscular dystrophy (DMD). The utrophin protein is the best candidate for dystrophin replacement in DMD patients. To obtain therapeutic levels of utrophin expression in dystrophic muscle, we developed an alternative strategy based on the use of artificial zinc finger transcription factors (ZF ATFs). The ZF ATF 'Jazz' was recently engineered and tested in vivo by generating a transgenic mouse specifically expressing Jazz at the muscular level. To validate the ZF ATF technology for DMD treatment we generated a second mouse model by crossing Jazz-transgenic mice with dystrophin-deficient mdx mice. Here, we show that the artificial Jazz protein restores sarcolemmal integrity and prevents the development of the dystrophic disease in mdx mice. This exclusive animal model establishes the notion that utrophin-based therapy for DMD can be efficiently developed using ZF ATF technology and candidates Jazz as a novel therapeutic molecule for DMD therapy.

Utilidade e significância social da teoria do alcance de metas de king

Directory of Open Access Journals (Sweden)

Inácia Sátiro Xavier de França

2002-02-01

Full Text Available Esta pesquisa enfocou o modelo de análise de teorias de Meleis, a Teoria do Alcance de Objetivos (King, 1981 e um estudo realizado por Silveira, objetivando analisar a utilidade e significância social da Teoria de King. Realizamos uma leitura compreensiva da Teoria de King e do modelo proposto por Meleis. Recortamos, desse modelo, o segmento "Crítica de teoria" para servir de suporte analítico. Selecionamos o estudo "Estar despido na unidade de terapia intensiva: duas percepções e um encontro" (Silveira, 1996, cujo marco teórico é a teoria supracitada. Da análise crítica, apoiada na inter-relação desses construtos, concluímos que: a teoria de King é útil à pesquisa por possibilitar a percepção e a interpretação dos dados objetivo-subjetivos da realidade concreta. Sua significância social tem relação com a aplicação da teoria por representantes dos vários segmentos sociais, viabilizando a re-socialização de pessoas e grupos em prol de um mundo mais humano, solidário, cidadão.

77 FR 39174 - Safety Zone, Temporary Change for Recurring Fifth Coast Guard District Fireworks Displays...

Science.gov (United States)

2012-07-02

..., Cavalier Golf & Yacht Club Independence Day Fireworks Display, Broad Bay; Virginia Beach, VA AGENCY: Coast... the Cavalier Golf & Yacht Club Independence Day Fireworks Display. This action is intended to restrict..., 2012, we published a notice of proposed rulemaking (NPRM) entitled Cavalier Golf & Yacht Club...

International education, the internet, and the Three Kings experiment

NARCIS (Netherlands)

Kooijman, J.; Davies, J.; Berg-Cross, L.; Copier, L.; Asby, A.

2004-01-01

The current project linked students in three universities in a guided discussion of the movie, Three Kings. The goals were to assess the viability of having students from three different courses, in three different universities, in three different countries find common ground to have intellectual

Mutual mate choice for olorful traits in King Penguins

NARCIS (Netherlands)

Nolan, Paul M.; Dobson, F. Stephen; Nicolaus, Marion; Karels, Tim J.; McGraw, Kevin J.; Jouventin, Pierre

While studies of mate choice based on male color pattern are ubiquitous, studies of mate choice based on ornamental color traits in sexually monomorphic species are less common. We conducted manipulative field experiments on two color ornaments of king penguins (Aptenodytes patagonicus), the size of

Growth, chemical components and ensiling characteristics of king ...

African Journals Online (AJOL)

user

2012-08-09

Aug 9, 2012 ... Wilting had different effects on the 1st cutting and 3rd cutting silages in pH value and NH3-N content, ... On February 16, 2008, king grass was planted with seed stem on ... Home Electrical Appliance Company Limited, Hongkong, China). ... The plant height and the yield from the first cutting to fourth cutting.

Blindness and Insight in King Lear

Institute of Scientific and Technical Information of China (English)

岳元玉

2008-01-01

This paper intends to explore how William Shakespeare illustrates the theme of blindness and insight in his great tragedy "King Lear".Four characters’ deeds and their fate are used as a case study to examine what blindness is,what insight is,and the relationship between the two.The writer finds that by depicting the characters’ deeds and their fate in a double plot,Shakespeare renders the folly of blindness,the transition from blindness to insight,and the use of reason and thought to understand the truth.

The acute mania of King George III: A computational linguistic analysis.

Directory of Open Access Journals (Sweden)

Vassiliki Rentoumi

Full Text Available We used a computational linguistic approach, exploiting machine learning techniques, to examine the letters written by King George III during mentally healthy and apparently mentally ill periods of his life. The aims of the study were: first, to establish the existence of alterations in the King's written language at the onset of his first manic episode; and secondly to identify salient sources of variation contributing to the changes. Effects on language were sought in two control conditions (politically stressful vs. politically tranquil periods and seasonal variation. We found clear differences in the letter corpus, across a range of different features, in association with the onset of mental derangement, which were driven by a combination of linguistic and information theory features that appeared to be specific to the contrast between acute mania and mental stability. The paucity of existing data relevant to changes in written language in the presence of acute mania suggests that lexical, syntactic and stylometric descriptions of written discourse produced by a cohort of patients with a diagnosis of acute mania will be necessary to support the diagnosis independently and to look for other periods of mental illness of the course of the King's life, and in other historically significant figures with similarly large archives of handwritten documents.

Oxalate Content of the Herb Good-King-Henry, Blitum Bonus-Henricus

Directory of Open Access Journals (Sweden)

Wanying Li

2015-05-01

Full Text Available The total, soluble and insoluble oxalate contents of the leaves, stems and buds of Good-King-Henry (Blitum Bonus-Henricus were extracted and measured using HPLC chromatography. The large, mature leaves contained 42% more total oxalate than in the small leaves and the soluble oxalate content of the large leaves was 33% higher than the smaller leaves. Cooking the mixed leaves, stems and buds in boiling water for two minutes significantly (p < 0.05 reduced the total oxalate when compared to the raw plant parts. Pesto sauce made from mixed leaves contained 257 mg total oxalate/100 g fresh weight; this was largely made up of insoluble oxalates (85% of the total oxalate content. Soup made from mixed leaves contained lower levels of total oxalates (44.26 ± 0.49 mg total oxalate/100 g fresh weight and insoluble oxalate made up 49% of the oxalate contents. The levels of oxalates in the Good-King-Henry leaves were high, suggesting that the leaves should be consumed occasionally as a delicacy because of their unique taste rather than as a significant part of the diet. However, the products made from Good-King-Henry leaves indicated that larger amounts could be consumed as the oxalate levels were reduced by dilution and processing.

Arterial roads and area socioeconomic status are predictors of fast food restaurant density in King County, WA

Directory of Open Access Journals (Sweden)

Streichert Laura C

2009-07-01

Full Text Available Abstract Background Fast food restaurants reportedly target specific populations by locating in lower-income and in minority neighborhoods. Physical proximity to fast food restaurants has been associated with higher obesity rates. Objective To examine possible associations, at the census tract level, between area demographics, arterial road density, and fast food restaurant density in King County, WA, USA. Methods Data on median household incomes, property values, and race/ethnicity were obtained from King County and from US Census data. Fast food restaurant addresses were obtained from Public Health-Seattle & King County and were geocoded. Fast food density was expressed per tract unit area and per capita. Arterial road density was a measure of vehicular and pedestrian access. Multivariate logistic regression models containing both socioeconomic status and road density were used in data analyses. Results Over one half (53.1% of King County census tracts had at least one fast food restaurant. Mean network distance from dwelling units to a fast food restaurant countywide was 1.40 km, and 1.07 km for census tracts containing at least one fast food restaurant. Fast food restaurant density was significantly associated in regression models with low median household income (p Conclusion No significant association was observed between census tract minority status and fast food density in King County. Although restaurant density was linked to low household incomes, that effect was attenuated by arterial road density. Fast food restaurants in King County are more likely to be located in lower income neighborhoods and higher traffic areas.

77 FR 27156 - Safety Zone, Temporary Change for Recurring Fifth Coast Guard District Fireworks Displays...

Science.gov (United States)

2012-05-09

..., Cavalier Golf & Yacht Club Independence Day Fireworks Display, Broad Bay Virginia Beach, VA AGENCY: Coast... the safety of life on navigable waters during the Cavalier Golf & Yacht Club Independence Day..., 2012 Cavalier Golf & Yacht Club will host a fireworks display on the shoreline of the navigable waters...

Yukon River King Salmon - Ichthyophonus Pilot Study

Science.gov (United States)

Kocan, R.M.; Hershberger, P.K.

2001-01-01

When king salmon enter the Yukon River on their spawning migration in mid June, over 25% of the population are infected with Ichthyophonus. The percent of infected fish remains relatively constant until the fish pass river mile 1,319 at Dawson, Y.T., then it drops to 13% when they reach river mile 1,745 at Whitehorse, Y.T. When the sexes are examined separately, slightly more females are infected than males (29% vs 22%). The percent of fish exhibiting clinical signs (diseased) is 2-3% when they enter the river, but increases to over 20% at river mile 715 near Tanana, AK. Disease prevalence within the population remains constant at >20% until fish pass Dawson, then the percent of diseased fish drops to <9% at Whitehorse. When the sexes are examined separately, male disease prevalence is highest at Tanana (22.6%) then gradually drops to just 12.9% at Whitehorse. Females however, continue to show an increase in disease prevalence peaking at river mile 1,081 near Circle, AK, at 36.4%, then dropping to just 5.3% at Whitehorse. Data on infection and disease collected from kings at Nenana on the Tanana River more closely resembles that seen at Whitehorse than the lower and middle Yukon River.

AFSC/RACE/SAP/Long: Data from: Habitat, predation, growth, and coexistence: Could interactions between juvenile red and blue king crabs limit blue king crab productivity?

Data.gov (United States)

National Oceanic and Atmospheric Administration, Department of Commerce — This data set is from a series of laboratory experiments examining the interactions between red and blue king crabs and habitat. We examined how density and predator...

The Role of Authors in the “Uruk List of Kings and Sages”: Canonization and Cultural Contact

DEFF Research Database (Denmark)

Helle, Sophus

2018-01-01

The so-called "Uruk List of Kings and Sages" includes a selection of (pseudo-)historical figures known from other sources as the authors of literary and scholarly works. These authors are placed alongside famous kings and mythical sages, in a synoptic and schematic overview of cuneiform culture...

Reflections on Cambridge: John Maynard Keynes at King's College Cambridge

OpenAIRE

Macfarlane, Alan

2012-01-01

.mp4 video file The economist John Maynard Keynes spent much of his life in Cambridge, connected to King's College. Alan Macfarlane reflects on a few aspects of his life and work. Filmed by Xu Bei in 2010

Metabolic response to lipid infusion in fasting winter-acclimatized king penguin chicks (Aptenodytes patagonicus).

Science.gov (United States)

Teulier, Loïc; Tornos, Jérémy; Rouanet, Jean-Louis; Rey, Benjamin; Roussel, Damien

2013-05-01

During the cold austral winter, king penguin chicks are infrequently fed by their parents and thus experience severe nutritional deprivation under harsh environmental conditions. These energetic constraints lead to a range of energy sparing mechanisms balanced by the maintenance of efficient thermogenic processes. The present work investigated whether the high thermogenic capacities exhibited by winter-acclimatized king penguin chicks could be related to an increase in lipid substrate supply and oxidation in skeletal muscle, the main site of thermogenesis in birds. To test this hypothesis, we examined i) the effect of an experimental rise in plasma triglyceride on the whole metabolic rate in winter-acclimatized (WA) and de-acclimatized king penguin chicks kept at thermoneutrality (TN), and ii) investigated the fuel preference of muscle mitochondria. In vivo, a perfusion of a lipid emulsion induced a small 10% increase of metabolic rate in WA chicks but not in TN group. In vitro, the oxidation rate of muscle mitochondria respiring on lipid-derived substrate was +40% higher in WA chicks than in TN, while no differences were found between groups when mitochondria oxidized carbohydrate-derived substrate or succinate. Despite an enhanced fuel selection towards lipid oxidation in skeletal muscle, a rise of circulating lipids per se was not sufficient to fully unravel the thermogenic capacity of winter-acclimatized king penguin chicks. Copyright © 2013 Elsevier Inc. All rights reserved.

Correlating In Vitro Splice Switching Activity With Systemic In Vivo Delivery Using Novel ZEN-modified Oligonucleotides

Directory of Open Access Journals (Sweden)

Suzan M Hammond

2014-01-01

Full Text Available Splice switching oligonucleotides (SSOs induce alternative splicing of pre-mRNA and typically employ chemical modifications to increase nuclease resistance and binding affinity to target pre-mRNA. Here we describe a new SSO non-base modifier (a naphthyl-azo group, “ZEN™” to direct exon exclusion in mutant dystrophin pre-mRNA to generate functional dystrophin protein. The ZEN modifier is placed near the ends of a 2′-O-methyl (2′OMe oligonucleotide, increasing melting temperature and potency over unmodified 2′OMe oligonucleotides. In cultured H2K cells, a ZEN-modified 2′OMe phosphorothioate (PS oligonucleotide delivered by lipid transfection greatly enhanced dystrophin exon skipping over the same 2′OMePS SSO lacking ZEN. However, when tested using free gymnotic uptake in vitro and following systemic delivery in vivo in dystrophin deficient mdx mice, the same ZEN-modified SSO failed to enhance potency. Importantly, we show for the first time that in vivo activity of anionic SSOs is modelled in vitro only when using gymnotic delivery. ZEN is thus a novel modifier that enhances activity of SSOs in vitro but will require improved delivery methods before its in vivo clinical potential can be realized.

RISK MANAGEMENT DISCLOSURE PRACTICESIN ACCORDANCEWITH KING II AND III: THE CASE OF SELECTED JSE LISTEDCOMPANIES

Directory of Open Access Journals (Sweden)

Heleen Janse van Vuuren

2016-07-01

Full Text Available The ongoing collapse of large international companies could have been partiallyprevented if good corporate governance principles and,more specifically,effectiverisk management practices had been implemented and adhered to.Research reveals that the majority offinancial institutions in Europe do notmanage risk effectively and the global financial crisis proved that excessive risk-taking can result in corporate failure. Similar trends are prevalent in South Africa.The aim of this research was to investigate the compliance of Johannesburg StockExchange (JSE listed companies with recommended risk management practicesand disclosure requirements after the introduction of King II and III. To achievethis the annual reports ofselectedJSElisted companies were evaluated toestablish the quality of their reporting on risk management practices asrecommended in King II andIII. The results of the study indicated that theminority of the companies investigated, fully complied with all the recommendedrequirements. This study contributed to literature by showing that althoughdisclosure on risk management practicesimproved significantly since King IIbecame operational in 2002, companies still did not adhere to all the requirementsas stipulated even after King III became effectivein 2010. The finding, therefore,supports the notion that full compliance is an evolutionary process, rather than arevolutionary process and will therefore only be achieved over time.

Automated purification of Borrelia burgdorferi s.l. PCR products with KingFisherTM magnetic particle processor prior to genome sequencing

International Nuclear Information System (INIS)

Maekinen, Johanna; Marttila, Harri; Viljanen, Matti K.

2001-01-01

Borrelia burgdorferi sensu lato genospecies were differentiated by PCR-based sequencing of the borrelial flagellin gene. To evaluate the usefulness of KingFisher TM magnetic particle processor in PCR product purification, borrelia PCR products were purified with KingFisher TM magnetic particle processor prior to cycle sequencing and the quality of the sequence data received was analyzed. KingFisher was found to offer a rapid and reliable alternative for borrelial PCR product purification

Shame, recognition and love in Shakespeare’s 'King Lear'

DEFF Research Database (Denmark)

Montes Sanchez, Alba

2014-01-01

In this paper, I explore the experience of shame and its connections to recognition and love as manifested in Shakespeare’s King Lear. My main focus in this paper is the ethical relevance of shame. I start from Sartre’s account of shame in Being and Nothingness, and I consider Webber’s attempt...

Sequence characterisation of deletion breakpoints in the dystrophin gene by PCR

Energy Technology Data Exchange (ETDEWEB)

Abbs, S.; Sandhu, S.; Bobrow, M. [Guy`s Hospital, London (United Kingdom)

1994-09-01

Partial deletions of the dystrophin gene account for 65% of cases of Duchenne muscular dystrophy. A high proportion of these structural changes are generated by new mutational events, and lie predominantly within two `hotspot` regions, yet the underlying reasons for this are not known. We are characterizing and sequencing the regions surrounding deletion breakpoints in order to: (i) investigate the mechanisms of deletion mutation, and (ii) enable the design of PCR assays to specifically amplify mutant and normal sequences, allowing us to search for the presence of somatic mosaicism in appropriate family members. Using this approach we have been able to demonstrate the presence of somatic mosaicism in a maternal grandfather of a DMD-affected male, deleted for exons 49-50. Three deletions, namely of exons 48-49, 49-50, and 50, have been characterized using a PCR approach that avoids any cloning procedures. Breakpoints were initially localized to within regions of a few kilobases using Southern blot restriction analyses with exon-specific probes and PCR amplification of exonic and intronic loci. Sequencing was performed directly on PCR products: (i) mutant sequences were obtained from long-range or inverse-PCR across the deletion junction fragments, and (ii) normal sequences were obtained from the products of standard PCR, vectorette PCR, or inverse-PCR performed on YACs. Further characterization of intronic sequences will allow us to amplify and sequence across other deletion breakpoints and increase our knowledge of the mechanisms of mutation in the dystophin gene.

Using King's interacting systems theory to link emotional intelligence and nursing practice.

Science.gov (United States)

Shanta, Linda L; Connolly, Maria

2013-01-01

King's theory is a broad theory designed to provide a framework for nursing (I.M. King, 1981), whereas emotional intelligence (EI; J.D. Mayer & P. Salovey, 2004) is a theory that is specific for addressing potential competency in dealing with emotions and emotional information. J.D. Mayer, P. Salovey, D.R. Caruso, and G. Sitarenios (2001) defined EI as the "ability to recognize the meaning of emotions and their relationships and to use them as a basis for reasoning and problem solving" (p. 234). These researchers believed that EI is related to cognitive intellect through the ability to use reasoning by way of information to find meaning. J.D. Mayer and P. Salovey (2004) argued that the skills that comprise EI were likely enhanced through obtaining a liberal education infused with values exploration. J.D. Mayer, P. Salovey, D.R. Caruso, and G. Sitarenios (2001) contended that there are 4 branches of abilities that create EI: (a) the skill of perceiving emotion within oneself and others, (b) assimilation of an emotion to facilitate thinking, (c) understanding and knowledge of emotion, and (d) conscious regulation of emotion. Each level or branch builds upon the previous one, and awareness of what each branch offers the individual in enhancing relationships with others is a key component of healthy emotional interactions. This article will provide a theoretic foundation based upon King's interacting systems theory (IST; 1981) that embraces EI as a crucial component in the nurse's ability to provide holistic care for patients, peers, and themselves. King's IST underscores the necessity of nurses possessing abilities of EI as they care for others but does not fully describe a mechanism to understand and incorporate emotions within the complex nurse-patient interactions and communications that are part of the nursing process. Copyright © 2013 Elsevier Inc. All rights reserved.

Dr Julia King CBE FREng, Chief Executive Designate, Institute of Physics (United Kingdom), visiting the NA48 experiment.

CERN Multimedia

Patrice Loïez

2002-01-01

Photo 02: Visiting the NA48 experiment, Dr Julia King, Chief Executive Designate, Institute of Physics (Britain and Ireland) (right) with A. Ceccucci and K. Peach. Photo 05: Visiting the NA48 experiment, Dr Julia King, Chief Executive Designate, Institute of Physics (Britain and Ireland) (centre) with A. Ceccucci and C. Lazzeroni. Photo 08: Visiting the NA48 experiment, Dr Julia King, Chief Executive Designate, Institute of Physics (Britain and Ireland) (second from left) with (left to right) R. Barlow, J. Wood, N. McCubbin, K. Peach, A. Ceccucci, C. Lazzeroni, M. Patel and D. Munday.

Profile and bioconcentration of minerals by King Bolete (Boletus edulis) from the Płocka Dale in Poland.

Science.gov (United States)

Frankowska, Aneta; Ziółkowska, Joanna; Bielawski, Leszek; Falandysz, Jerzy

2010-01-01

This study aimed to provide basic data on the composition of metallic elements, including toxicologically important Cd and Hg, in popular and prized wild King Bolete mushrooms. We investigated the importance of soil substratum as a source of these metals. ICP-OES and CV-AAS were applied to determine the profile of Al, Ba, Ca, Cd, Cu, Fe, Hg, K, Mg, Mn, Na, Sr and Zn in caps and stipes of King Bolete mushroom and in the surface layer of soil (0-10 cm) from the Płocka Dale area of Poland. Hg, Cu, Cd, Zn, Mg and K exhibited bioconcentration factors (BCF) > 1. Specifically, Hg, Cu and Cd (mean BCFs for caps were 110, 19 and 16, respectively) were efficiently bioconcentrated by King Bolete, while other elements were bioexcluded (BCF < 1). Cadmium was present in the caps at mean levels of 5.5 ± 2.4 mg kg(-1) dry weight (dw) and mercury at levels of 4.9 ± 1.4 mg kg(-1) dw, both occurring at elevated concentrations in those King Bolete mushrooms surveyed.

Geochemical interpretation of Kings Mountain, North Carolina, orientation area

International Nuclear Information System (INIS)

Price, V.; Ferguson, R.B.

1977-01-01

An orientation study has been made of uranium occurrences in the area of Kings Mountain, North Carolina. This is one of the orientation studies of known uranium occurrences that are being conducted in several geologic provinces and under various climatic (weathering) conditions to provide the technical basis for design and interpretation of NURE geochemical reconnaissance programs. The Kings Mountain area was chosen for study primarily because of the reported presence of high-uranium monazite. This 750-mi 2 area is in the deeply weathered southern Appalachian Piedmont and spans portions of the Inner Piedmont, Kings Mountain, and Charlotte geologic belts. Uranium concentration maps for ground and surface water samples clearly outline the outcrop area of the Cherryville Quartz Monzonite with highs up to 10 ppb uranium near the reported uraninite. Several surface water samples appear to be anomalous because of trace industrial contamination. Uranium concentration maps for -100 to +200 mesh stream sediments indicate the area of monazite abundance. Several samples with >100 ppM uranium content appear to be high in uranium-rich resistate minerals. When the uranium content of sediment samples is ratioed to the sum of Hf, Dy, and Th, the anomaly pattern shifts to coincide with uranium highs in ground and surface water samples. False anomalies from concentrations of monazite (Ce,ThPO 4 ), xenotime (Y,DyPO 4 ), and zircon (Zr,HfSiO 4 ) in stream sediment samples can thus be eliminated. Residual anomalies should be related to unusual uranium enrichment of these common minerals or to the presence of an uncommon uranium-rich mineral. Tantalum, beryllium, and tin in stream sediments correspond to high concentrations of uranium in stream and ground water but not to uranium in sediments. In an initial reconnaissance, several media should be sampled, and it is essential to correct uranium in sediments for the sample mineralogy

Distribution of Anaerobic Hydrocarbon-Degrading Bacteria in Soils from King George Island, Maritime Antarctica.

Science.gov (United States)

Sampaio, Dayanna Souza; Almeida, Juliana Rodrigues Barboza; de Jesus, Hugo E; Rosado, Alexandre S; Seldin, Lucy; Jurelevicius, Diogo

2017-11-01

Anaerobic diesel fuel Arctic (DFA) degradation has already been demonstrated in Antarctic soils. However, studies comparing the distribution of anaerobic bacterial groups and of anaerobic hydrocarbon-degrading bacteria in Antarctic soils containing different concentrations of DFA are scarce. In this study, functional genes were used to study the diversity and distribution of anaerobic hydrocarbon-degrading bacteria (bamA, assA, and bssA) and of sulfate-reducing bacteria (SRB-apsR) in highly, intermediate, and non-DFA-contaminated soils collected during the summers of 2009, 2010, and 2011 from King George Island, Antarctica. Signatures of bamA genes were detected in all soils analyzed, whereas bssA and assA were found in only 4 of 10 soils. The concentration of DFA was the main factor influencing the distribution of bamA-containing bacteria and of SRB in the analyzed soils, as shown by PCR-DGGE results. bamA sequences related to genes previously described in Desulfuromonas, Lautropia, Magnetospirillum, Sulfuritalea, Rhodovolum, Rhodomicrobium, Azoarcus, Geobacter, Ramlibacter, and Gemmatimonas genera were dominant in King George Island soils. Although DFA modulated the distribution of bamA-hosting bacteria, DFA concentration was not related to bamA abundance in the soils studied here. This result suggests that King George Island soils show functional redundancy for aromatic hydrocarbon degradation. The results obtained in this study support the hypothesis that specialized anaerobic hydrocarbon-degrading bacteria have been selected by hydrocarbon concentrations present in King George Island soils.

On-farm flood capture could reduce groundwater overdraft in Kings River Basin

Directory of Open Access Journals (Sweden)

Philip A.M. Bachand

2016-11-01

Full Text Available Chronic groundwater overdraft threatens agricultural sustainability in California's Central Valley. Diverting flood flows onto farmland for groundwater recharge offers an opportunity to help address this challenge. We studied the infiltration rate of floodwater diverted from the Kings River at a turnout upstream of the James Weir onto adjoining cropland; and calculated how much land would be necessary to capture the available floodwater, how much recharge of groundwater might be achieved, and the costs. The 1,000-acre pilot study included fields growing tomatoes, wine grapes, alfalfa and pistachios. Flood flows diverted onto vineyards infiltrated at an average rate of 2.5 inches per day under sustained flooding. At that relatively high infiltration rate, 10 acres are needed to capture one CFS of diverted flood flow. We considered these findings in the context of regional expansion. Based upon a 30-year record of Kings Basin surplus flood flows, we estimate 30,000 acres operated for on-farm flood recharge would have had the capacity to capture 80% of available flood flows and potentially offset overdraft rates in the Kings Basin. Costs of on-farm flood capture for this study were estimated at $36 per acre-foot, less than the cost for surface water storage and dedicated recharge basins.

King penguins can detect two odours associated with conspecifics.

Science.gov (United States)

Cunningham, Gregory B; Bonadonna, Francesco

2015-11-01

Recent studies on olfaction in penguins have focused on their use of odours while foraging. It has been proposed for some seabirds that an olfactory landscape shaped by odours coming from feeding areas exists. Islands and colonies, however, may also contribute to the olfactory landscape and may act as an orienting map. To test sensitivities to a colony scent we studied whether King penguins (Aptenodytes patagonicus) could detect the smell of sand, feathers or feces by holding presentations beneath their beaks while they naturally slept on the beach. Penguins had a significantly greater response to the feathers and feces presentations than to sand. Although only a first step in exploring a broader role of olfaction in this species, our results raise the possibility of olfaction being used by King penguins in three potential ways: (1) locating the colony from the water or the shore, (2) finding the rendezvous zone within the colony where a chick or partner may be found, or (3) recognizing individuals by scent, as in Humboldt penguins (Spheniscus demersus). © 2015. Published by The Company of Biologists Ltd.

The Greek charter of the Hungarian King Stephen I

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Stojkovski Boris

2016-01-01

Full Text Available The first Hungarian Christian ruler, King Stephen I (997-1038 issued several charters that have survived to this day. One of them is the charter issued on behalf of the nuns from the Monastery of the Holy Theotokos in Veszprémvölgy. The charter was written in the Greek language, and has been the subject of many studies. The original has not been preserved; what remains is a copy from the time of King Coloman, dated to 1109. The charter has not been published in a critical edition in any language other than Hungarian and even though it has been examined by numerous Hungarian scholars, many questions remain open. The aim of the author is to provide a critical edition and an English translation of the charter, but also to clarify some remaining doubts about the charter and its contents. Furthermore, some comparisons will be made with the Byzantine charters issued at the beginning of the 11th and during the 12th century.

Iron deficiency anaemia in reproductive age women attending obstetrics and gynecology outpatient of university health centre in Al-Ahsa, Saudi Arabia.

Science.gov (United States)

Taha, Asia; Azhar, Saira; Lone, Talib; Murtaza, Ghulam; Khan, Shujaat Ali; Mumtaz, Amara; Asad, Muhammad Hassham Hassan Bin; Kousar, Rozina; Karim, Sabiha; Tariq, Imran; Ul Hassan, Syed Saeed; Hussain, Izhar

2014-01-01

Iron deficiency is the most common nutritional disorder in the world. The aim of this questionnaire based survey study was to determine the prevalence of iron deficiency anemia in reproductive age women, and their relation to variables such as age, marital status, education with those attending obstetrics and gynecology outpatient of King Faisal University Health Centre in Al-Ahsa in eastern region of Kingdom of Saudi Arabia. This study was conducted for the period of 6 month staring from September 2012 to February 2013. The questionnaire had three sections on personal information: their educational indicators, gynecological clinical history, and hematological indices. The average age was 25.97±7.17 years. According to the gynecological clinical history of the respondents, 15 (48.4%) respondents were pregnant while 16 (51.6%) were not pregnant. There was significant effect of pregnancy status on Hb level. Majority of the anemic respondents 15/17 were married. Moreover 14/17 anemic women were experiencing severe menstrual bleeding, 11/17 respondents were pregnant. 54.8% of respondents were hemoglobin deficient while 77.4% were found to have low Hct. In 87.1 % of the respondents, transferrin saturation was found to be abnormal. In this study iron deficiency anemia is quite prevalent in the university community especially among pregnant women. The fetus's and newborn infant's iron status depends on the iron status of the pregnant woman and therefore, iron deficiency in the mother-to-be means that growing fetus probably will be iron deficient as well. Thus iron deficiency anemia during pregnancy in well-educated set up needs more attention by the concerned authorities.

Salmon Supplementation Studies in Idaho Rivers; Field Activities Conducted on Clear and Pete King Creeks, 2002 Annual Report.

Energy Technology Data Exchange (ETDEWEB)

Bretz, Justin K.; Olson, Jill M. (US Fish and Wildlife Service, Idaho Fishery Resource Office, Ahsahka, ID)

2003-03-01

In 2002 the Idaho Fisheries Resource Office continued working as a cooperator on the Salmon Supplementation Studies in Idaho Rivers (ISS) project on Pete King and Clear creeks. Data relating to supplementation treatment releases, juvenile sampling, juvenile PIT tagging, broodstock spawning and rearing, spawning ground surveys, and snorkel surveys were used to evaluate the project data points and augment past data. Supplementation treatments included the release of 51,329 left ventral-clipped smolts into Clear Creek (750 were PIT tagged), and 12,000 unmarked coded-wire tagged parr into Pete King Creek (998 were PIT tagged). Using juvenile collection methods, Idaho Fisheries Resource Office staff PIT tagged and released 579 naturally produced spring chinook juveniles in Clear Creek, and 54 on Pete King Creek, for minimum survival estimates to Lower Granite Dam. For Clear Creek, minimum survival estimates to Lower Granite Dam of hatchery produced supplementation and naturally produced PIT tagged smolts, were 36.0%, and 53.1%, respectively. For Pete King Creek, minimum survival estimates to Lower Granite Dam, of hatchery produced supplementation smolts and naturally produced smolts PIT tagged as parr and presmolts, were 18.8%, and 8.3%, respectively. Adults collected for broodstock in 2002 represented the final adult broodstock group collected for the ISS project. Twenty-six ventral clipped, and 28 natural adult spring chinook were transported above the weir. Monitoring and evaluation of spawning success was continued on Clear and Pete King creeks. A total of 69 redds were counted and 79 carcasses were recovered on Clear Creek. Two redds were observed and no carcasses were collected on Pete King Creek.

Contrapuntal Significations in Wole Soyinka's Death and the King's ...

African Journals Online (AJOL)

Wole Soyinka's Death and the King's Horseman has been widely acclaimed as a great example of African tragedy. It is, in fact, the dramatic aggregation of Soyinka's treatise in Myth, Literature and the African World. Hence, the play is most often 'read' in the lights of its 'difference' from western notions of the tragic, the place ...

The King-Denborough syndrome in the paediatric patient. | Maharaj ...

African Journals Online (AJOL)

We describe the management of two children with a diagnosis of King Denborough syndrome. The first case is that of a 23-month-old term male infant requiring repair of a cleft palate. After flushing the anaesthetic machine, infusions of remifentanil at 0.25 μ/kg/min and propofol at 12 mg/kg/hr were commenced. These were ...

Evaluation of medical consultation letters at King Fahd Hospital, Al ...

African Journals Online (AJOL)

Evaluation of medical consultation letters at King Fahd Hospital, Al Hufuf, Saudi Arabia. Hamed Abd Allah Al Wadaani, Magdy Hassan Balaha. Abstract. Background: In surgical wards, it is of paramount importance to communicate with other health care providers, mostly physicians, referring patients to them for their ...

Validation of the King's Health Questionnaire for South Africa in ...

African Journals Online (AJOL)

Objective. To validate the King's Health Questionnaire for urinary incontinence in the local South African English, Afrikaans and isiXhosa female community. Design. A cohort analytical study. Setting and subjects. The study utilised a sample of convenience. Women with urinary incontinence attending the gynaecology clinic ...

Endotracheal Intubation Using the Macintosh Laryngoscope or KingVision Video Laryngoscope during Uninterrupted Chest Compression

Directory of Open Access Journals (Sweden)

Ewelina Gaszynska

2014-01-01

Full Text Available Objective. Advanced airway management, endotracheal intubation (ETI, during CPR is more difficult than, for example, during anesthesia. However, new devices such as video laryngoscopes should help in such circumstances. The aim of this study was to assess the performance of the KingVision video laryngoscopes in a manikin cardiopulmonary resuscitation (CPR scenario. Methods. Thirty students enrolled in the third year of paramedic school took part in the study. The simulated CPR scenario was ETI using the standard laryngoscope with a Macintosh blade (MCL and ETI using the KingVision video laryngoscope performed during uninterrupted chest compressions. The primary endpoints were the time needed for ETI and the success ratio. Results. The mean time required for intubation was similar for both laryngoscopes: 16.6 (SD 5.11, median 15.64, range 7.9–27.9 seconds versus 17.91 (SD 5.6, median 16.28, range 10.6–28.6 seconds for the MCL and KingVision, respectively (P=0.1888. On the first attempt at ETI, the success rate during CPR was comparable between the evaluated laryngoscopes: P=0.9032. Conclusion. The KingVision video laryngoscope proves to be less superior when used for endotracheal intubation during CPR compared to the standard laryngoscope with a Mackintosh blade. This proves true in terms of shortening the time needed for ETI and increasing the success ratio.

King County Metro Battery Electric Bus Demonstration: Preliminary Project Results

Energy Technology Data Exchange (ETDEWEB)

2017-05-22

The U.S. Federal Transit Administration (FTA) funds a variety of research projects that support the commercialization of zero-emission bus technology. To evaluate projects funded through these programs, FTA has enlisted the help of the National Renewable Energy Laboratory (NREL) to conduct third-party evaluations of the technologies deployed under the FTA programs. NREL works with the selected agencies to evaluate the performance of the zero-emission buses compared to baseline conventional buses in similar service. The evaluation effort will advance the knowledge base of zero-emission technologies in transit bus applications and provide 'lessons learned' to aid other fleets in incrementally introducing next generation zero-emission buses into their operations. This report provides preliminary performance evaluation results from a demonstration of three zero-emission battery electric buses at King County Metro in King County, Washington. NREL developed this preliminary results report to quickly disseminate evaluation results to stakeholders. Detailed evaluation results will be published in future reports.

"I Just Want to Do God's Will:" Teaching Martin Luther King, Jr. as a Religious Leader

Science.gov (United States)

Neumann, David

2018-01-01

Teachers often respond to the perils of teaching about religion by simply avoiding the subject. An investigation of secondary lesson plans on three prominent Martin Luther King, Jr. websites reveals little attention to the ideology of the civil rights movement, especially those touching on religious ideas. Ignoring King's religious views risks…

Mitral Regurgitation Severity and Left Ventricular Systolic Dimension Predict Survival in Young Cavalier King Charles Spaniels

DEFF Research Database (Denmark)

Reimann, M. J.; Moller, J. E.; Haggstrom, J.

2017-01-01

Background Development and progression of myxomatous mitral valve disease (MMVD) in dogs are difficult to predict. Identification at a young age of dogs at high risk of adverse outcome in the future is desirable. Hypothesis/Objectives To study the predictive value of selected clinical.......016) mortality increased with increasing left ventricular end-systolic internal dimension normalized for body weight (LVIDSN). Conclusions and clinical importance Moderate to severe MR, even if intermittent, and increased LVIDSN in dogs

Advanced electrocardiography can predict mitral regurgitation in cavalier king charles spaniels with myxomatous mitral valve disease

DEFF Research Database (Denmark)

Spiljak, Maja; Petric, Alexandra; Olsen, Lisbeth Høier

2011-01-01

(HRV), QT variability (QTV), T-wave complexity, wave morphology and 3-D ECG. One-way ANOVA determined 21 ECG parameters, which were significantly different (P .... Clinic for Surgery and Small Animal Medicine, Veterinary Faculty, University of Ljubljana, Slovenia. 3. Department of Basic Animal and Veterinary Sciences, Faculty of Life Sciences, University of Copenhagen, Denmark. 4. Quality Control Department, Metallurgical and Chemical Industry Cinkarna Celje, INC...

24-HOUR ELECTROCARDIOGRAPHY IN CLINICAL HEALTHY CAVALIER KING CHARLES SPANIELS, WIRE-HAIRED DACHSHUNDS AND CAIRN TERRIERS

DEFF Research Database (Denmark)

Rasmussen, Caroline Elisabeth; Vesterholm, Stina; Ludvigsen, Trine Pagh

2010-01-01

analysis were analyzed for influence by breed, age, gender, relevant heart rate (HR) parameters and bodyweight. CKCS had a significantly higher HRex (mean 121 ± SD 12 bpm) compared to wD (94±18 bpm) (P>0.0001) and CT (102±16bpm) (P=0.0009). The minimum HR (HRmin) measured during Holter recording...... was significantly higher in CKCS (51±10 bpm) compared to wD (42±7 bpm) (P=0.001) and CT (45±7 bpm) (P=0.05). In addition, CKCS had a higher mean HR (HRmean) during Holter recording (83±13 bpm) compared to wD (68±8 bpm) (P>0.0001) and CT (75±10 bpm) (P=0.04). Both HRmean (P>0.0001) and HRmin (P=0.001) were...

Storage Pool Deficiencies

Science.gov (United States)

... Deficiency Factor V Deficiency Combined FV & FVIII Deficiencies Factor VII Deficiency Factor X Deficiency Factor XI Deficiency Factor ... Deficiency Factor V Deficiency Combined FV & FVIII Deficiencies Factor VII Deficiency Factor X Deficiency Factor XI Deficiency Factor ...

Muscle function recovery in golden retriever muscular dystrophy after AAV1-U7 exon skipping.

Science.gov (United States)

Vulin, Adeline; Barthélémy, Inès; Goyenvalle, Aurélie; Thibaud, Jean-Laurent; Beley, Cyriaque; Griffith, Graziella; Benchaouir, Rachid; le Hir, Maëva; Unterfinger, Yves; Lorain, Stéphanie; Dreyfus, Patrick; Voit, Thomas; Carlier, Pierre; Blot, Stéphane; Garcia, Luis

2012-11-01

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder resulting from lesions of the gene encoding dystrophin. These usually consist of large genomic deletions, the extents of which are not correlated with the severity of the phenotype. Out-of-frame deletions give rise to dystrophin deficiency and severe DMD phenotypes, while internal deletions that produce in-frame mRNAs encoding truncated proteins can lead to a milder myopathy known as Becker muscular dystrophy (BMD). Widespread restoration of dystrophin expression via adeno-associated virus (AAV)-mediated exon skipping has been successfully demonstrated in the mdx mouse model and in cardiac muscle after percutaneous transendocardial delivery in the golden retriever muscular dystrophy dog (GRMD) model. Here, a set of optimized U7snRNAs carrying antisense sequences designed to rescue dystrophin were delivered into GRMD skeletal muscles by AAV1 gene transfer using intramuscular injection or forelimb perfusion. We show sustained correction of the dystrophic phenotype in extended muscle areas and partial recovery of muscle strength. Muscle architecture was improved and fibers displayed the hallmarks of mature and functional units. A 5-year follow-up ruled out immune rejection drawbacks but showed a progressive decline in the number of corrected muscle fibers, likely due to the persistence of a mild dystrophic process such as occurs in BMD phenotypes. Although AAV-mediated exon skipping was shown safe and efficient to rescue a truncated dystrophin, it appears that recurrent treatments would be required to maintain therapeutic benefit ahead of the progression of the disease.

Inter-annual dynamics of the Barents Sea red king crab (Paralithodes camtschaticus) stock indices in relation to environmental factors

Science.gov (United States)

Dvoretsky, Alexander G.; Dvoretsky, Vladimir G.

2016-12-01

Knowledge of relationships between environmental variables and biological processes can greatly improve fisheries assessment and management in commercially important species. We analyzed the effects of environmental factors (climatic indices and water temperature) on the stock characteristics (total population number, number of pre-recruits and number of legal males) of the red king crab (Paralithodes camtschaticus), an introduced species in the Barents Sea. Stock trends in red king crab appear to be related to decadal climate shifts. Abundances were negatively related to the North Atlantic Oscillation index (NAO) in August and positively related to water temperature in late winter-early summer. Total and commercial stock abundance were negatively correlated with the lag-1 Arctic Oscillation index (AO) in August and the lag-2 winter NAO index. The total number of P. camtschaticus was most strongly associated with water temperature in spring and summer and NAO/AO indices in April and May. Lagged NAO indices in February and August (9 or 10 yr) had a positive relationship to the commercial stock of P. camtschaticus. These findings suggest that temperature conditions of current and previous year affect natural mortality of larvae and juvenile red king crabs. Warmer temperature conditions lead to increased biomass of red king crab food items. Negative correlations between climatic indices and the red king crab stocks may be associated with predator pressure on juvenile red king crabs or higher mortality because of predator or parasite pressure and diseases. The associations between stock indices and environmental variables could help better predict recruitment patterns of P. camtschaticus.

Implications of using On-Farm Flood Flow Capture to recharge groundwater and mitigate flood risks along the Kings River, CA

OpenAIRE

Bachand, P.A.M.; Horwath, W.R.; Roy, S.; Choperena, J.; Cameron, D.

2012-01-01

Two large hydrologic issues face the Kings Basin, severe and chronic overdraft of about 0.16M ac-ft annually, and flood risks along the Kings River and the downstream San Joaquin River. Since 1983, these floods have caused over $1B in damage in today’s dollars. Capturing flood flows of sufficient volume could help address these two pressing issues which are relevant to many regions of the Central Valley and will only be exacerbated with climate change. However, the Kings River has high vari...

75 FR 3839 - Martin Luther King, Jr., Federal Holiday, 2010

Science.gov (United States)

2010-01-22

... Part III The President Proclamation 8473--Martin Luther King, Jr., Federal Holiday, 2010 Proclamation 8474--Religious Freedom Day, 2010 Notice of January 20, 2010--Continuation of the National... only by the power of his words, which still call on us to perfect those sacred ideals enshrined in our...

Littoral Encounters : The Shore as Cultural Interface in King Horn

NARCIS (Netherlands)

Sobecki, Sebastian

2006-01-01

1. III * Later Medieval: Excluding Chaucer -- Brown et al., 10.1093 ... ... between the Saracens and the londisse men allied to the protagonist (' Littoral Encounters: the Shore as Cultural Interface in King Horn', Al-Mas a ... www.ywes.oxfordjournals.org/cgi/content/full/man0092 2.Murray, Alan V.

His Majesty King Abdullah II of the Hashemite Kingdom of Jordan

CERN Multimedia

Patrice Loïez

2003-01-01

Left to right : King Abdullah II of Jordan visiting CERN with Luciano Maiani, Director-General of CERN, Maurice Bourquin (behind), President of the CERN Council, and Herwig Schopper, President of the SESAME Council and former Director-General of CERN.

King penguin population on Macquarie Island recovers ancient DNA diversity after heavy exploitation in historic times.

Science.gov (United States)

Heupink, Tim H; van den Hoff, John; Lambert, David M

2012-08-23

Historically, king penguin populations on Macquarie Island have suffered greatly from human exploitation. Two large colonies on the island were drastically reduced to a single small colony as a result of harvesting for the blubber oil industry. However, recent conservation efforts have resulted in the king penguin population expanding in numbers and range to recolonize previous as well as new sites. Ancient DNA methods were used to estimate past genetic diversity and combined with studies of modern populations, we are now able to compare past levels of variation with extant populations on northern Macquarie Island. The ancient and modern populations are closely related and show a similar level of genetic diversity. These results suggest that the king penguin population has recovered past genetic diversity in just 80 years owing to conservation efforts, despite having seen the brink of extinction.

The chondrogenic response to exercise in the proximal femur of normal and mdx mice

Directory of Open Access Journals (Sweden)

Nye David J

2010-09-01

Full Text Available Abstract Background Submaximal exercise is used in the management of muscular dystrophy. The effects of mechanical stimulation on skeletal development are well understood, although its effects on cartilage growth have yet to be investigated in the dystrophic condition. The objective of this study was to investigate the chondrogenic response to voluntary exercise in dystrophin-deficient mice. Methods Control and dystrophin-deficient (mdx mice were divided into sedentary and exercise-treated groups and tested for chondral histomorphometric differences at the proximal femur. Results Control mice ran 7 km/week further than mdx mice on average, but this difference was not statistically significant (P > 0.05. However, exercised control mice exhibited significantly enlarged femur head diameter, articular cartilage thickness, articular cartilage tissue area, and area of calcified cartilage relative to sedentary controls and exercised mdx mice (P Conclusions Mdx mice exhibit a reduced chondrogenic response to increased mechanical stimulation relative to controls. However, no significant reduction in articular dimensions was found, indicating loss of chondral tissue may not be a clinical concern with dystrophinopathy.

Reconciling PM10 analyses by different sampling methods for Iron King Mine tailings dust.

Science.gov (United States)

Li, Xu; Félix, Omar I; Gonzales, Patricia; Sáez, Avelino Eduardo; Ela, Wendell P

2016-03-01

The overall project objective at the Iron King Mine Superfund site is to determine the level and potential risk associated with heavy metal exposure of the proximate population emanating from the site's tailings pile. To provide sufficient size-fractioned dust for multi-discipline research studies, a dust generator was built and is now being used to generate size-fractioned dust samples for toxicity investigations using in vitro cell culture and animal exposure experiments as well as studies on geochemical characterization and bioassay solubilization with simulated lung and gastric fluid extractants. The objective of this study is to provide a robust method for source identification by comparing the tailing sample produced by dust generator and that collected by MOUDI sampler. As and Pb concentrations of the PM10 fraction in the MOUDI sample were much lower than in tailing samples produced by the dust generator, indicating a dilution of Iron King tailing dust by dust from other sources. For source apportionment purposes, single element concentration method was used based on the assumption that the PM10 fraction comes from a background source plus the Iron King tailing source. The method's conclusion that nearly all arsenic and lead in the PM10 dust fraction originated from the tailings substantiates our previous Pb and Sr isotope study conclusion. As and Pb showed a similar mass fraction from Iron King for all sites suggesting that As and Pb have the same major emission source. Further validation of this simple source apportionment method is needed based on other elements and sites.

JEWISH IDEA: FROM KING TEMPLE TO KING STATE YAHUDİ İDEASI: KRAL MABEDİNDEN KRAL DEVLETE

Directory of Open Access Journals (Sweden)

Mustafa YİĞİTOĞLU

2012-06-01

Full Text Available The study focuses on a process that has become the main problem of Judaism. As the subject, this article is reflectiton the world and the beyond world of the point of view of Judaism. This actually means that the analysis in general terms the history of Jewish thought. Although concentrated in the research issue is not exactly a history of thought. But this article examines the structure of Judaism directly. Firstly in this research discusses King Solomon’s temple which was built as an indicator of Judaism is institutionalized and the idea of Jewish towards to King State. Bu çalışma Yahudiliğin temel sorunu haline gelen bir süreci ele almaktadır. Konu itibari ile Yahudiliğin dünyaya ve dünya ötesine bakış açısını yansıtmaktadır. Bu, aslında Yahudi düşünce tarihinin genel anlamda analizi demektir. Gerçi araştırmanın yoğunlaştığı husus tam anlamıyla bir düşünce tarihi değildir. Ancak alan itibariyle Yahudiliğin doğrudan yapısını inceleyen bir duruma haizdir.Araştırmada ilk olarak Yahudiliğin kurumsallaştığının bir göstergesi olan Kral Süleyman’ın inşa ettirdiği mabed; önemi, konumu ve etkisi gibi hususiyetleriyle tarihsel bir çerçevede ele alınmış, nihayetinde Kral Devlete doğru giden bir Yahudi düşüncesine yer verilmiştir.

Monarchical Activities of the Yoruba Kings of South Western Nigeria: A Cultural Heritage in Printmaking Visual Documentary.

Directory of Open Access Journals (Sweden)

Emmanuel Bankole Oladumiye

2014-10-01

Full Text Available Printmaking is a visual documentary media of art which was used as a medium of expression in analyzing myth and mythology monarchical activities of the Yorubas in South Western Nigeria in this study. The  monarchical activities of the Yoruba Kings, is  the cultural heritage and legacy that people do guide jealously and considered to be of high cultural value. The Yoruba Kings of South Western Nigeria are traditional entity which passed through the rites of installing kings for the throne fore fathers as a leader with symbol of authority between the people and the spirit world. The kings in Yoruba kingdom is so much respected that they are seen as divine and representative of God on earth and they are exalted into the position of deity because of his monarchical duties to his subjects at large. The funfairs that accompany the monarch roles  are worth documenting using printmaking as vehicle of visual and historical expression of myths and mythologies demonstrating African culture which stands out as sacred. The discourse also relies on oral testimonies written and archival documents. The materials used for the execution of the prints are rubber, wood, plate, offset printing inks and glass which records the events as an alternative to the use of photographic documentation. The research examine the philosophy behind the monarchical roles of the Yoruba Kings in print visuals based on the cultural heritage of the Yoruba people it employs an exploratory qualitative methods rely on literature review.

Examples of Mechanism Design : From King Solomon to eBay

NARCIS (Netherlands)

De Weerdt, M.M.

2007-01-01

The judgment of king Solomon is an early example of mechanism design. Mechanism design attempts to achieve desired outcomes in situations with self-interested players by setting the rules of the game in a specific way. We will see that the game Solomon proposed would not have worked if the women

Investigation of hypereosinophilia and potential treatments.

Science.gov (United States)

Lilliehöök, Inger; Tvedten, Harold

2003-11-01

Hypereosinophilia is excessive eosinophilia and has been defined in dogs and cats as eosinophils greater than 5 x 10(9)/L (> 5000/microL). Canine breeds with a predisposition to higher eosinophil counts or certain eosinophilic diseases include the Rottweiler, German Shepard, Siberian Husky, Alaskan Malamute, and Cavalier King Charles Spaniel. Two of the more common causes of canine hypereosinophilia are pulmonary infiltrates with eosinophils (PIE) and gastrointestinal disease. The highest eosinophil counts are expected in dogs with pneumonia or PIE. The most common cause of eosinophilia in cats is flea allergy. The greatest eosinophilia occurs in cats with flea allergy, feline asthma, and eosinophilic granuloma. Innovative recent treatments for human patients with asthma have been successful in reducing eosinophil numbers but have had a confusing and disappointing lack of reducing symptoms. The role of eosinophils in many eosinophilic diseases remains a mystery.

R-R interval variations influence the degree of mitral regurgitation in dogs with myxomatous mitral valve disease

DEFF Research Database (Denmark)

Reimann, M. J.; Moller, J. E.; Haggstrom, J.

2014-01-01

of congestive heart failure due to MMVD. The severity of MR was evaluated in apical four-chamber view using colour Doppler flow mapping (maximum % of the left atrium area) and colour Doppler M-mode (duration in ms). The influence of the ratio between present and preceding R-R interval on MR severity......Mitral regurgitation (MR) due to myxomatous mitral valve disease (MMVD) is a frequent finding in Cavalier King Charles Spaniels (CKCSs). Sinus arrhythmia and atrial premature complexes leading to R-R interval variations occur in dogs. The aim of the study was to evaluate whether the duration...... of the RR interval immediately influences the degree of MR assessed by echocardiography in dogs. Clinical examination including echocardiography was performed in 103 privately-owned dogs: 16 control Beagles, 70 CKCSs with different degree of MR and 17 dogs of different breeds with clinical signs...

Effects of breed, gender, exercise and white-coat effect on markers of endothelial function in dogs

DEFF Research Database (Denmark)

Moesgaard, Sophia Gry; Holte, A.V.; Mogensen, T.

2007-01-01

This study examines how systemic biomarkers of endothelial function and nitric oxide metabolism are affected by exercise in dogs. Furthermore, breed variation and white-coat effect have been tested by sampling three different dog breeds both in their home and in a clinical setting. Short......-term exercise increased plasma nitrate and nitrite (NOx) and von Willebrand factor (vWf). There was significant difference between Pointers and the small dog breeds Cairn Terriers and Cavalier King Charles Spaniels in the general plasma levels of vWf and asymmetric dimethylarginine (ADMA9. NOx and vWf were...... significantly higher when the sample was taken in the laboratory cf. at home, whereas ADMA and L-arginine were significantly lower. In conclusion, both short-term exercise and white-coat effect influence several plasma markers of endothelial function depending also on the breed and gender of the dogs...

King customer forever: Customer satisfaction and beyond

Directory of Open Access Journals (Sweden)

Myuers James

2004-01-01

Full Text Available "King Customer!" So proclaimed the front cover of Business Week in a 1989 issue. At about the same time, "Rediscovering the Customer" was the title of a series of company vignettes in Fortune magazine. And a Wall Street Journal article asked, "For Customers, More Than Lip Service?" Combined, these three prestigious business publications reflected a new era in business firms perceptions of their customers and the role they should play in the formulation of company strategies and priorities. Had the "Era of the Customer" finally arrived in American business? .

Distinct characteristics of NPP HRD and establishment of KINGS in Korea

International Nuclear Information System (INIS)

Namgung, Ihn

2013-01-01

Full text:Korean government set-up nuclear energy department within the ministry of education in 1956 and joined IAEA in 1957 and set up nuclear energy agency in 1959, and installed the first research reactor in 1962. The Korean Government started constructing NPP in 1971 that had started commercial operation in 1978. The first oil shock in 1973 had devastated Korean economy and that made Korean Government to accelerate the construction of NPPs. Since then Korea steadily constructed NPP as well as invested in the development of indigenized NPP technology. During 1990s, Korea developed KSNP PWR 600 MWe NPP and in the last decade Korea developed APR1400 MWe NPP. Through the time, the engineers and operators involved in every field of nuclear industry is getting old and started to retire. Someone freshly out from the university with bachelor or post graduate degree will take many years to be able to understand how things running and operating in nuclear industry. Even in many years of job assignment, one cannot experience and understand all aspect of nuclear industry. It is this reason to establish a special educational system to teach people already in the field and to be able to see the whole picture by systematically teaching most of the related subject. In order to prevent any influence from existing university system, it was determined to establish KINGS (KEPCO International Nuclear Graduate School) as separate and independent institution and as a post-graduate institution. The curriculum of KINGS was set up along this philosophy, and has only one academic department, for example NPP Engineering Department, to make more interactions among faculty and students. Also the curriculum is set up to teach practical experience; hence the graduates can bridge between industry and academia as well as fill in the large gap of technical experience of older generation. Also another aim is to make KINGS international institution to share experience of Korean NPP development

Development of a real-time PCR assay for detection of planktonic red king crab (Paralithodes camtschaticus (Tilesius 1815)) larvae

Science.gov (United States)

Jensen, Pamela C.; Purcell, Maureen K.; Morado, J. Frank; Eckert, Ginny L.

2012-01-01

The Alaskan red king crab (Paralithodes camtschaticus) fishery was once one of the most economically important single-species fisheries in the world, but is currently depressed. This fishery would benefit from improved stock assessment capabilities. Larval crab distribution is patchy temporally and spatially, requiring extensive sampling efforts to locate and track larval dispersal. Large-scale plankton surveys are generally cost prohibitive because of the effort required for collection and the time and taxonomic expertise required to sort samples to identify plankton individually via light microscopy. Here, we report the development of primers and a dual-labeled probe for use in a DNA-based real-time polymerase chain reaction assay targeting the red king crab, mitochondrial gene cytochrome oxidase I for the detection of red king crab larvae DNA in plankton samples. The assay allows identification of plankton samples containing crab larvae DNA and provides an estimate of DNA copy number present in a sample without sorting the plankton sample visually. The assay was tested on DNA extracted from whole red king crab larvae and plankton samples seeded with whole larvae, and it detected DNA copies equivalent to 1/10,000th of a larva and 1 crab larva/5mL sieved plankton, respectively. The real-time polymerase chain reaction assay can be used to screen plankton samples for larvae in a fraction of the time required for traditional microscopial methods, which offers advantages for stock assessment methodologies for red king crab as well as a rapid and reliable method to assess abundance of red king crab larvae as needed to improve the understanding of life history and population processes, including larval population dynamics.

Taxonomic Study of Suborder Calcaxonia (Alcyonacea: Octocorallia: Anthozoa from King Sejong Station, Antarctic

Directory of Open Access Journals (Sweden)

Jun-Im Song

2012-04-01

Full Text Available Some gorgonians in the families, Primnoidae and Isididae within the suborder Calcaxonia were collected from subtidal zones between depths of 10 and 45 m in the coastal regions of King Sejong Station (62??13′S, 058?? 47′W, Korea Polar Research Institute of Korea Ocean Research and Development Institute (KORDI by SCUBA diving from 2009 to 2011. Three species in the Primnoidae, Arntzia gracilis (Molander, 1929, Thouarella (Thouarella antarctica (Valenciennes, 1846 and Onogorgia nodosa (Molander, 1929, and also one species in the family Isididae, Tenuisis microspiculata (Molander, 1929 are newly recorded to octocorallian fauna in Marian Cove and Potter Cove of King George Island. These four species have been described in detail.

Evaluation of point mutations in dystrophin gene in Iranian Duchenne and Becker muscular dystrophy patients: introducing three novel variants.

Science.gov (United States)

Haghshenas, Maryam; Akbari, Mohammad Taghi; Karizi, Shohreh Zare; Deilamani, Faravareh Khordadpoor; Nafissi, Shahriar; Salehi, Zivar

2016-06-01

Duchenne and Becker muscular dystrophies (DMD and BMD) are X-linked neuromuscular diseases characterized by progressive muscular weakness and degeneration of skeletal muscles. Approximately two-thirds of the patients have large deletions or duplications in the dystrophin gene and the remaining one-third have point mutations. This study was performed to evaluate point mutations in Iranian DMD/BMD male patients. A total of 29 DNA samples from patients who did not show any large deletion/duplication mutations following multiplex polymerase chain reaction (PCR) and multiplex ligation-dependent probe amplification (MLPA) screening were sequenced for detection of point mutations in exons 50-79. Also exon 44 was sequenced in one sample in which a false positive deletion was detected by MLPA method. Cycle sequencing revealed four nonsense, one frameshift and two splice site mutations as well as two missense variants.

One Voice Too Many: Echoes of Irony and Trauma in Oedipus the King

Directory of Open Access Journals (Sweden)

Joshua Waggoner

2017-11-01

Full Text Available Sophocles’ Oedipus the King has often inspired concurrent interpretations examining the tragic irony of the play and the traumatic neurosis of its protagonist. The Theban king epitomizes a man who knows everything but himself, and Sophocles’ use of irony allows Oedipus to discover the truth in a manner that Freud viewed in The Interpretation of Dreams as “comparable to the work of a psychoanalysis.” Psychoanalytical readings of Oedipus at times depend greatly on his role as a doubled figure, but this article specifically investigates his doubled voice in order to demonstrate the interrelated, chiasmic relationship between Oedipus’ trauma and the trope of irony. It argues, in fact, that irony serves as the language, so to speak, of the traumatic experiences haunting the king and his city, but it also posits that this doubled voice compounds the irony of the play and its hero. In other words, in addition to the Sophoclean irony that dominates the work, the doubling of the king’s voice reveals a modified form of Socratic irony that contributes to the tragedy’s power. Consequently, even after the king’s recognition of the truth ultimately resolves the work’s tragic irony, Oedipus remains divided by a state of simultaneous knowledge and ignorance.

God our king

Directory of Open Access Journals (Sweden)

Jan Muis

2008-01-01

Full Text Available This article discusses whether the metaphor of “king” can still be used in Christian God-talk. Firstly, it is argued that the “king” metaphor for God is an indispensable key metaphor in both the Old and the New Testament. “King” has become a root metaphor in the canonical text of the Old Testament and Jesus’ proclamation of the coming kingdom of God presupposes that God is king. Secondly, the Biblical meanings of the metaphor are explored. God’s kingship implies his authority and power to fight the forces of evil, to liberate and lead his people and to control the events of history. Modified by Jesus Christ, God’s kingship is universal, non-violent and in accordance with his love. Then, the use of the metaphor in contemporary God-talk is considered. Because “king” is the only metaphor that can give expression to God’s ultimate highness and authority, it cannot be replaced by others. In the concluding section the “king” metaphor for God is conceptually explained in terms of the relationship, the agency and the power of God it implies.

How accurately can we estimate energetic costs in a marine top predator, the king penguin?

Science.gov (United States)

Halsey, Lewis G; Fahlman, Andreas; Handrich, Yves; Schmidt, Alexander; Woakes, Anthony J; Butler, Patrick J

2007-01-01

King penguins (Aptenodytes patagonicus) are one of the greatest consumers of marine resources. However, while their influence on the marine ecosystem is likely to be significant, only an accurate knowledge of their energy demands will indicate their true food requirements. Energy consumption has been estimated for many marine species using the heart rate-rate of oxygen consumption (f(H) - V(O2)) technique, and the technique has been applied successfully to answer eco-physiological questions. However, previous studies on the energetics of king penguins, based on developing or applying this technique, have raised a number of issues about the degree of validity of the technique for this species. These include the predictive validity of the present f(H) - V(O2) equations across different seasons and individuals and during different modes of locomotion. In many cases, these issues also apply to other species for which the f(H) - V(O2) technique has been applied. In the present study, the accuracy of three prediction equations for king penguins was investigated based on validity studies and on estimates of V(O2) from published, field f(H) data. The major conclusions from the present study are: (1) in contrast to that for walking, the f(H) - V(O2) relationship for swimming king penguins is not affected by body mass; (2) prediction equation (1), log(V(O2) = -0.279 + 1.24log(f(H) + 0.0237t - 0.0157log(f(H)t, derived in a previous study, is the most suitable equation presently available for estimating V(O2) in king penguins for all locomotory and nutritional states. A number of possible problems associated with producing an f(H) - V(O2) relationship are discussed in the present study. Finally, a statistical method to include easy-to-measure morphometric characteristics, which may improve the accuracy of f(H) - V(O2) prediction equations, is explained.

Modeling the marine resources consumed in raising a king penguin chick: an energetics approach.

Science.gov (United States)

Halsey, L G; Butler, P J; Fahlman, A; Bost, C-A; Woakes, A J; Handrich, Y

2008-01-01

Accurate estimates of penguin energetics would represent an important contribution to our understanding of the trophodynamics of the Southern Ocean ecosystem and our ability to predict effects of environmental change on these species. We used the heart rate-rate of oxygen consumption technique to estimate rate of energy expenditure in adult king penguins raising a chick, in combination with data from the literature on changes in adult mass, chick energy requirements, and prey energy density. Our model estimated a variety of energetic costs and quantities of prey consumption related to raising a king penguin chick during the austral summer. The total energy requirements of a king penguin chick at the Crozet Archipelago from hatching until reaching a mass of 8 kg 90 d later is 271 MJ, representing the consumption of 38.4 kg of myctophid fish. A successfully breeding male requires 0.78 kg d(-1) of fish during the entirety of the incubation period and 1.14 kg d(-1) during the subsequent 90 d of chick rearing. Assuming the same energy requirements for females, the estimated 580,000 pairs of king penguins that breed successfully at Crozet each year, together with their chicks, consume a total of around 190,000 tons of fish during the incubation and summer rearing periods combined. If, due to depletion of fish stocks, the diet of breeders and chicks during the summer becomes identical to the typical diet of adults during the austral winter, the mass of prey required by both adults and chicks combined (where the chick still reaches 8 kg after 90 d) would increase by more than 25%.

[The advantage of a modern operational approach to the diagnosis of mental disorders. The case of the Bavarian King Ludwig II--an example from biographical research].

Science.gov (United States)

von Zerssen, D

2013-05-01

Worldwide discrepancies in the classification, terminology and diagnosis of mental disorders have induced efforts for unification after World War II. This led to the introduction of an operational diagnostic approach according to strict criteria, at the same time taking into account the comorbidity of disorders. However, this approach is still not routinely used. The consequences of this deficiency are demonstrated here by an example from biographical research referring to the Bavarian King Ludwig II. The study is based on an extensive search of the relevant literature. Although the pathography of this Bavarian king is well documented, the diagnoses published between 1910 and 2010 by altogether 21 specialists, are distributed rather chaotically over 24 diagnostic categories of the ICD-10. Merely in the (probably wrong) diagnosis of a schizophrenic psychosis is there agreement among half of the authors. This is concordant with the expert diagnosis of paranoia by von Gudden and his colleagues (1886) when considering the then contemporary concept of the disorder. According to modern diagnostic principles almost half of the 24 diagnoses can be confirmed. The others have to be regarded as false diagnoses. The conclusion is that modern principles of the diagnosis of mental disorders should be applied according to internationally accepted diagnostic manuals. This approach should be used in, but is not exclusive to, biographical research. Precondition is, of course, the exact knowledge and careful application of these principles.

FitzPatrick Lecture: King George III and the porphyria myth - causes, consequences and re-evaluation of his mental illness with computer diagnostics.

Science.gov (United States)

Peters, Timothy

2015-04-01

Recent studies have shown that the claim that King George III suffered from acute porphyria is seriously at fault. This article explores some of the causes of this misdiagnosis and the consequences of the misleading claims, also reporting on the nature of the king's recurrent mental illness according to computer diagnostics. In addition, techniques of cognitive archaeology are used to investigate the nature of the king's final decade of mental illness, which resulted in the appointment of the Prince of Wales as Prince Regent. The results of this analysis confirm that the king suffered from bipolar disorder type I, with a final decade of dementia, due, in part, to the neurotoxicity of his recurrent episodes of acute mania. © 2015 Royal College of Physicians.

AFSC/RACE/SAP/Cummiskey: Red king crab sonic tagging and dive database

Data.gov (United States)

National Oceanic and Atmospheric Administration, Department of Commerce — This is data from a long-term monitoring project which utilized sonic tags to follow aggregations of red king crab in Womens Bay near Kodiak Alaska. The database...

Dragon kings of the deep sea: marine particles deviate markedly from the common number-size spectrum.

Science.gov (United States)

Bochdansky, Alexander B; Clouse, Melissa A; Herndl, Gerhard J

2016-03-04

Particles are the major vector for the transfer of carbon from the upper ocean to the deep sea. However, little is known about their abundance, composition and role at depths greater than 2000 m. We present the first number-size spectrum of bathy- and abyssopelagic particles to a depth of 5500 m based on surveys performed with a custom-made holographic microscope. The particle spectrum was unusual in that particles of several millimetres in length were almost 100 times more abundant than expected from the number spectrum of smaller particles, thereby meeting the definition of "dragon kings." Marine snow particles overwhelmingly contributed to the total particle volume (95-98%). Approximately 1/3 of the particles in the dragon-king size domain contained large amounts of transparent exopolymers with little ballast, which likely either make them neutrally buoyant or cause them to sink slowly. Dragon-king particles thus provide large volumes of unique microenvironments that may help to explain discrepancies in deep-sea biogeochemical budgets.

The Role of Continuous Education Programs Organized by Saudi Universities in Literacy--A Case Study of King Saud University

Science.gov (United States)

Al Rawaf, Haya Saad Abdulla; Fattah, Azza Khalil Abdel; Megeid, Fadia Yousif Abdel; Nazmy, Rania Mohammed Aziz; Alarifi, Sarah Nasser; Al Sulaihm, Hind Sulaiman

2017-01-01

This study aims at highlighting the role of Continuous Education Programs at the Saudi Universities in Religious, Social, and Health Literacy; King Saud University was taken as an example. To achieve the goals of the study two questionnaires were distributed among two samples from King Saud University; (101) of students, and (9) of continuous…

Aspects of the biology of three benthic-feeding teleosts from King's ...

African Journals Online (AJOL)

Aspects of the biology of three benthic-feeding teleosts from King's Beach, Algoa Bay. Theresa A. Lasiak. Department of Zoology, University of Port Elizabeth, Port Elizabeth. The lengths, abundance pattems and feeding habits of three species of benthic·feeding teleosts, Lithognathus mormyrus,. Lithognathus lithognathus ...

AFSC/RACE/SAP/Swiney: Red king crab fecundity and embryo and larval quality

Data.gov (United States)

National Oceanic and Atmospheric Administration, Department of Commerce — Stock assessment of Alaskan red king crab, Paralithodes camtschaticus (Tilesius, 1815), can be improved by incorporating reproductive output, which requires an...

A CLINICAL ASSESSMENT OF MACINTOSH BLADE, MILLER BLADE AND KING VISIONTM VIDEOLARYNGOSCOPE FOR LARYNGEAL EXPOSURE AND DIFFICULTY IN ENDOTRACHEAL INTUBATION

Directory of Open Access Journals (Sweden)

Apoorva Mahendera

2016-03-01

Full Text Available CONTEXT Previous studies suggest glottic view is better achieved with straight blades while tracheal intubation is easier with curved blades and videolaryngoscope is better than conventional laryngoscope. AIMS Comparison of conventional laryngoscope (Macintosh blade and Miller blade with channelled videolaryngoscope (King Vision TM with respect to laryngeal visualisation and difficulty in endotracheal intubation. SETTINGS AND DESIGN This prospective randomised comparative study was conducted at a tertiary care hospital (in ASA I and ASA II patients after approval from the Institutional Ethics Committee. METHODS We compared Macintosh, Miller, and the King VisionTM videolaryngoscope for glottic visualisation and ease of tracheal intubation. Patients undergoing elective surgeries under general anaesthesia requiring endotracheal intubation were randomly divided into three groups (N=180. After induction of anaesthesia, laryngoscopy was performed and trachea intubated. We recorded visualisation of glottis (Cormack-Lehane grade-CL, ease of intubation, number of attempts, need to change blade, and need for external laryngeal manipulation. STATISTICAL ANALYSIS Demographic data, Mandibular length, Mallampati classification were compared using ANOVA, Chi-square test, Kruskal-Wallis Test, where P value <0.005 is statically significant. RESULTS CL grade 1 was most often observed in King Vision -TM VL group (90% which is followed by Miller (28.33%, and Macintosh group (15%. We found intubation was to be easier (grade 1 with King Vision -TM VL group (73.33%, followed by Macintosh (38.33%, and Miller group (1.67%. External manipulation (BURP was needed more frequently in patients in Miller group (71.67%, followed by Macintosh (28.33% and in King Vision -TM VL group (6.67%. All (100% patients were intubated in the 1 st attempt with King Vision -TM VL group, followed by Macintosh group (90% and Miller group (58.33%. CONCLUSIONS In patients with normal airway

Just how literal is the King James Version?

OpenAIRE

Jan (JH) Kroeze; Manie (CM) van den Heever; Bertus (AJ) van Rooy

2010-01-01

Many scholars have the perception that the King James Version (KJV) is a literal translation. However, it is not so easy to define the concept of "literal translation". The simplest definition may be to regard it as word-for-word translation. However, when one compares the KJV carefully with the original Hebrew Bible, there are numerous instances where lexical items are changed to adapt the idiom to that of the target language. In this article, a measuring instrument will be proposed and u...

Survey on composition and bioconcentration potential of 12 metallic elements in King Bolete (Boletus edulis) mushroom that emerged at 11 spatially distant sites.

Science.gov (United States)

Falandysz, Jerzy; Frankowska, Aneta; Jarzynska, Grazyna; Dryzałowska, Anna; Kojta, Anna K; Zhang, Dan

2011-01-01

This paper provides data on baseline concentrations, interrelationships and bioconcentration potential of 12 metallic elements by King Bolete collected from 11 spatially distant sites across Poland. There are significant differences in concentrations of metals (Al, Ba, Ca, Cd, Cu, Fe, K, Mg, Mn, Na, Sr, Zn) and their bioconcentration potential in King Bolete Boletus edulis at 11 spatially distant sites surveyed across Poland. These have resulted from significant geographical differences in trace metal concentrations in a layer (0-10 cm) of organic and mineral soil underneath to fruiting bodies and possible local bioavailabilities of macro- (Ca, K, Mg, Na) and trace metals (Al, Ba, Cd, Cu, Fe, Mn, Sr, Zn) to King Bolete. The use of highly appreciated wild-grown edible King Bolete mushroom has established a baseline measure of regional minerals status, heavy metals pollution and assessment of intake rates for wild mushroom dish fanciers against which future changes can be compared. Data on Cd, Cu and Zn from this study and from literature search can be useful to set the maximum limit of these metals in King Bolete collected from uncontaminated (background) areas. In this report also reviewed are data on Al, Ba, Ca, Cd, Cu, Fe, K, Mg, Mn, Na, Sr and Zn accumulation in King Bolete.

Cellulolytic Protist Numbers Rise and Fall Dramatically in Termite Queens and Kings during Colony Foundation

Science.gov (United States)

Shimada, Keisuke; Lo, Nathan; Kitade, Osamu; Wakui, Akane

2013-01-01

Among the best-known examples of mutualistic symbioses is that between lower termites and the cellulolytic flagellate protists in their hindguts. Although the symbiosis in worker termites has attracted much attention, there have been only a few studies of protists in other castes. We have performed the first examination of protist population dynamics in queens and kings during termite colony foundation. Protist numbers, as well as measurements of hindgut and reproductive tissue sizes, were undertaken at five time points over 400 days in incipient colonies of Reticulitermes speratus, as well as in other castes of mature colonies of this species. We found that protist numbers increased dramatically in both queens and kings during the first 50 days of colony foundation but began to decrease by day 100, eventually disappearing by day 400. Hindgut width followed a pattern similar to that of protist numbers, while ovary and testis widths increased significantly only at day 400. Kings were found to contain higher numbers of protists than queens in incipient colonies, which may be linked to higher levels of nutrient transfer from kings to queens than vice versa, as is known in some other termite species. Protists were found to be abundant in soldiers from mature colonies but absent in neotenics. This probably reflects feeding of soldiers by workers via proctodeal trophallaxis and of reproductives via stomodeal trophallaxis. The results reveal the dynamic nature of protist numbers during colony foundation and highlight the trade-offs that exist between reproduction and parental care during this critical phase of the termite life cycle. PMID:23376945

Riflessioni su diritto e religione a margine del Martin Luther King Day

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Giancarlo Anello

2018-04-01

ABSTRACT: April 4, 2018 commemorates the fiftieth anniversary of the death of Martin Luther King jr., in Memphis-Tennessee. The importance of Martin Luther King’s personality goes far beyond the borders of United States and spreads on the global scale. The present paper concerns the universality and the present impact of Martin Luther King’s legacy, considering also the European context. The paper analyses in brief the history of Martin Luther King, taking into account both his activism in the US and his international criticism against global issues such as post-colonialism and third-worldism; a second part is dedicated to the so called religious “global left” of the 50s and 70s. Conclusions show how and why the global religions have still to be considered a critical background for the rule of law, its inequalities and its injustices.

Genetic diagnosis of Duchenne and Becker muscular dystrophy using next-generation sequencing technology: comprehensive mutational search in a single platform.

Science.gov (United States)

Lim, Byung Chan; Lee, Seungbok; Shin, Jong-Yeon; Kim, Jong-Il; Hwang, Hee; Kim, Ki Joong; Hwang, Yong Seung; Seo, Jeong-Sun; Chae, Jong Hee

2011-11-01

Duchenne muscular dystrophy or Becker muscular dystrophy might be a suitable candidate disease for application of next-generation sequencing in the genetic diagnosis because the complex mutational spectrum and the large size of the dystrophin gene require two or more analytical methods and have a high cost. The authors tested whether large deletions/duplications or small mutations, such as point mutations or short insertions/deletions of the dystrophin gene, could be predicted accurately in a single platform using next-generation sequencing technology. A custom solution-based target enrichment kit was designed to capture whole genomic regions of the dystrophin gene and other muscular-dystrophy-related genes. A multiplexing strategy, wherein four differently bar-coded samples were captured and sequenced together in a single lane of the Illumina Genome Analyser, was applied. The study subjects were 25 16 with deficient dystrophin expression without a large deletion/duplication and 9 with a known large deletion/duplication. Nearly 100% of the exonic region of the dystrophin gene was covered by at least eight reads with a mean read depth of 107. Pathogenic small mutations were identified in 15 of the 16 patients without a large deletion/duplication. Using these 16 patients as the standard, the authors' method accurately predicted the deleted or duplicated exons in the 9 patients with known mutations. Inclusion of non-coding regions and paired-end sequence analysis enabled accurate identification by increasing the read depth and providing information about the breakpoint junction. The current method has an advantage for the genetic diagnosis of Duchenne muscular dystrophy and Becker muscular dystrophy wherein a comprehensive mutational search may be feasible using a single platform.

Caspase-12 ablation preserves muscle function in the mdx mouse

Science.gov (United States)

Moorwood, Catherine; Barton, Elisabeth R.

2014-01-01

Duchenne muscular dystrophy (DMD) is a devastating muscle wasting disease caused by mutations in dystrophin. Several downstream consequences of dystrophin deficiency are triggers of endoplasmic reticulum (ER) stress, including loss of calcium homeostasis, hypoxia and oxidative stress. During ER stress, misfolded proteins accumulate in the ER lumen and the unfolded protein response (UPR) is triggered, leading to adaptation or apoptosis. We hypothesized that ER stress is heightened in dystrophic muscles and contributes to the pathology of DMD. We observed increases in the ER stress markers BiP and cleaved caspase-4 in DMD patient biopsies, compared with controls, and an increase in multiple UPR pathways in muscles of the dystrophin-deficient mdx mouse. We then crossed mdx mice with mice null for caspase-12, the murine equivalent of human caspase-4, which are resistant to ER stress. We found that deleting caspase-12 preserved mdx muscle function, resulting in a 75% recovery of both specific force generation and resistance to eccentric contractions. The compensatory hypertrophy normally found in mdx muscles was normalized in the absence of caspase-12; this was found to be due to decreased fibre sizes, and not to a fibre type shift or a decrease in fibrosis. Fibre central nucleation was not significantly altered in the absence of caspase-12, but muscle fibre degeneration found in the mdx mouse was reduced almost to wild-type levels. In conclusion, we have identified heightened ER stress and abnormal UPR signalling as novel contributors to the dystrophic phenotype. Caspase-4 is therefore a potential therapeutic target for DMD. PMID:24879640

Iodine Deficiency

Science.gov (United States)

... Fax/Phone Home » Iodine Deficiency Leer en Español Iodine Deficiency Iodine is an element that is needed ... world’s population remains at risk for iodine deficiency. Iodine Deficiency FAQs WHAT IS THE THYROID GLAND? The ...

Species profiles: Life history and environmental requirements of coastal fishes and invertebrates (South Florida): King mackerel and Spanish mackerel. [Scomberomorus cavalla; Scomberomorus maculatus

Energy Technology Data Exchange (ETDEWEB)

Godcharles, M.F.; Murphy, M.D.

1986-06-01

This Species Profile on king and Spanish mackerel summarizes the taxonomy, morphology, distribution, life history, fishery descriptions, ecological role, and environmental requirements of these coastal pelagic fish to assist environmental impact assessment. King and Spanish mackerel support major commercial and sport fisheries in south Florida. In 1974 to 1983, Gulf of Mexico and Atlantic commercial landings of king mackerel declined from 10.4 to 4.3 million lb.; Spanish mackerel have fluctuated between 4.9 to 17.4 million lb. Both inhabit coastal waters, but Spanish mackerel are generally found closer to beaches and in outer estuarine waters. Both species feed principally on estuarine-dependent species. They are highly migratory, exhibiting seasonal migrations to winter feeding grounds off south Florida and summer spawning/feeding grounds in the northern Gulf of Mexico and off the Atlantic coast of the Southeastern US. Spawning occurs from March/April through September/October between the middle and Outer Continental Shelf (35 to 183 mi) for king mackerel and the inner shelf (12 to 34 mi) for Spanish mackerel. King mackerel reach sexual maturity in their 3rd and 4th years and Spanish, between their 2nd and 3rd. Female king mackerel live longer and grow larger and faster than males. Spanish mackerel live to 8 years; females also grow faster than males. King and Spanish mackerel feed principally on schooling fishes. Larvae and juveniles of both species are prey to little tunny and dolphin; adults are prey for sharks and bottlenose dolphin. Temperature and salinity are important factors regulating mackerel distribution.

"The Lion King" and "Hamlet": A Homecoming for the Exiled Child.

Science.gov (United States)

Gavin, Rosemarie

1996-01-01

Explains how the movie "The Lion King" may be used to elucidate Shakespeare's "Hamlet," a play about a prince who does not always seem heroic to modern audiences. Gives specific points of comparison between the two works concerning heroes, characters, conflicts, themes, ending scenes, and archetypal patterns. (TB)

Clinical and molecular characterization of a cohort of patients with novel nucleotide alterations of the Dystrophin gene detected by direct sequencing

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Corti Stefania

2011-03-01

Full Text Available Abstract Background Duchenne and Becker Muscular dystrophies (DMD/BMD are allelic disorders caused by mutations in the dystrophin gene, which encodes a sarcolemmal protein responsible for muscle integrity. Deletions and duplications account for approximately 75% of mutations in DMD and 85% in BMD. The implementation of techniques allowing complete gene sequencing has focused attention on small point mutations and other mechanisms underlying complex rearrangements. Methods We selected 47 patients (41 families; 35 DMD, 6 BMD without deletions and duplications in DMD gene (excluded by multiplex ligation-dependent probe amplification and multiplex polymerase chain reaction analysis. This cohort was investigated by systematic direct sequence analysis to study sequence variation. We focused our attention on rare mutational events which were further studied through transcript analysis. Results We identified 40 different nucleotide alterations in DMD gene and their clinical correlates; altogether, 16 mutations were novel. DMD probands carried 9 microinsertions/microdeletions, 19 nonsense mutations, and 7 splice-site mutations. BMD patients carried 2 nonsense mutations, 2 splice-site mutations, 1 missense substitution, and 1 single base insertion. The most frequent stop codon was TGA (n = 10 patients, followed by TAG (n = 7 and TAA (n = 4. We also analyzed the molecular mechanisms of five rare mutational events. They are two frame-shifting mutations in the DMD gene 3'end in BMD and three novel splicing defects: IVS42: c.6118-3C>A, which causes a leaky splice-site; c.9560A>G, which determines a cryptic splice-site activation and c.9564-426 T>G, which creates pseudoexon retention within IVS65. Conclusion The analysis of our patients' sample, carrying point mutations or complex rearrangements in DMD gene, contributes to the knowledge on phenotypic correlations in dystrophinopatic patients and can provide a better understanding of pre-mRNA maturation defects

Red king crab’s bycatch in demersal fishing in the South-Eeastern part of the Barents Sea

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Stes Aleksej Vladimirovich

2016-03-01

Full Text Available In the paper, the data of the red king crab by-catch in demersal fishing in the South-Eastern part of the Barents Sea, including those in the areas forbidden to trawling are presented. The impact of the catch of demersal fish on the distribution of the king crab is analyzed. It was shown that intensive fishing contributes to the growth of crabs’ density, possibly, they are attracted by the wastes of fish factories.

Environmental conditions of interstadial (MIS 3 and features of the last glacial maximum on the King George island (West Antarctica

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S. R. Verkulich

2013-01-01

Full Text Available The interstadial marine deposits stratum was described in the Fildes Peninsula (King George Island due to field and laboratory investigations during 2008–2011. The stratum fragments occur in the west and north-west parts of peninsula in following forms: sections of soft sediments, containing fossil shells, marine algae, bones of marine animals and rich marine diatom complexes in situ (11 sites; fragments of shells and bones on the surface (25 sites. According to the results of radiocarbon dating, these deposits were accumulated within the period 19–50 ky BP. Geographical and altitude settings of the sites, age characteristics, taxonomy of fossil flora and fauna, and good safety of the soft deposits stratum allow to make following conclusions: during interstadial, sea water covered significant part of King George Island up to the present altitude of 40 m a.s.l., and the King George Island glaciation had smaller size then; environmental conditions for the interstadial deposit stratum accumulation were at least not colder than today; probably, the King George island territory was covered entirely by ice masses of Last glacial maximum not earlier than 19 ky BP; during Last glacial maximum, King George Island was covered by thin, «cold», not mobile glaciers, which contribute to conservation of the soft marine interstadial deposits filled with fossil flora and fauna.

Life-threatening Arrhythmias in a Becker Muscular Dystrophy Family due to the Duplication of Exons 3-4 of the Dystrophin Gene.

Science.gov (United States)

Ishizaki, Masatoshi; Fujimoto, Akiko; Ueyama, Hidetsugu; Nishida, Yasuto; Imamura, Shigehiro; Uchino, Makoto; Ando, Yukio

2015-01-01

We herein present a report of three patients with Becker muscular dystrophy in the same family who developed complete atrioventricular block or ventricular tachycardia with severe cardiomyopathy. Our cases became unable to walk in their teens, and were introduced to mechanical ventilation due to respiratory muscle weakness in their twenties and thirties. In all three cases, a medical device such as a permanent cardiac pacemaker or an implantable cardiac defibrillator was considered to be necessary. The duplication of exons 3-4 in the dystrophin gene was detected in two of the patients. In patients with Becker muscular dystrophy, complete atrioventricular block or ventricular tachycardia within a family has rarely been reported. Thus attention should be paid to the possibility of severe arrhythmias in the severe phenotype of Becker muscular dystrophy.

The Poukai ceremony of the Maori King Movement: An ethnohistorical interpretation

NARCIS (Netherlands)

Meijl, A.H.M. van

2009-01-01

The poukai is a ceremonial gathering held on 28 days a year at different Marae [1] or ceremonial centres supporting the K ngitanga, or Maori King Movement, which is largely based within the Tainui confederation of tribes in the Waikato region of New Zealand's North Island. The K ngitanga was

Wole Soyinka's A Play of Giants and King Baabu : The crises ...

African Journals Online (AJOL)

This paper, using Soyinka's A Play of Giants and King Baabu, re-examines the centrality of ideology to texts of social engagement in the postcolonial space. Within the context of the humanistic values that the playwright esteems, this essay scrutinizes the social conditions in the plays and the dramatist's “vision.

77 FR 38005 - Safety Zone; Independence Day Fireworks, Kings Beach, CA

Science.gov (United States)

2012-06-26

... Zone; Independence Day Fireworks, Kings Beach, CA AGENCY: Coast Guard, DHS. ACTION: Notice of... Independence Day Fireworks display from 7 a.m. until 10 p.m. on July 3, 2012. This action is necessary to protect life and property of the maritime public from the hazards associated with the fireworks display...

Validation of King's transaction process for healthcare provider-patient communication in pharmaceutical context: One cross-sectional study.

Science.gov (United States)

Wang, Dan; Liu, Chenxi; Zhang, Zinan; Ye, Liping; Zhang, Xinping

2018-03-27

With the impressive advantages of patient-pharmacist communication being advocated and poor pharmacist-patient communication in different settings, it is of great significance and urgency to explore the mechanism of the pharmacist-patient communicative relationship. The King's theory of goal attainment is proposed as one of the most promising models to be applied, because it takes into consideration both improving the patient-pharmacist relationship and attaining patients' health outcomes. This study aimed to validate the King's transaction process and build the linkage between the transaction process and patient satisfaction in a pharmaceutical context. A cross-sectional study was conducted in four tertiary hospitals in two provincial cities (Wuhan and Shanghai) in central and east China in July 2017. Patients over 18 were investigated in the pharmacies of the hospitals. The instrument for the transaction process was revised and tested. Path analysis was conducted for the King's transaction process and its relationship with patient satisfaction. Five hundred eighty-nine participants were investigated for main study. Prior to the addition of covariates, the hypothesised model of the King's transaction process was validated, in which all paths of the transaction process were statistically significant (p process had direct effects on patient satisfaction (p process was established as one valid theoretical framework of healthcare provider-patient communication in a pharmaceutical context. Copyright © 2018 Elsevier Inc. All rights reserved.

AFSC/RACE/SAP/Long: Effects of ocean acidification on blue king crab

Data.gov (United States)

National Oceanic and Atmospheric Administration, Department of Commerce — This is data from a laboratory experiment in which blue king crab juveniles were held at three different pHs (ambient, pH 7.8, and pH 7.5) for a year. Growth,...

Iron-Deficiency Anemia

Medline Plus

Full Text Available ... Research Home / < Back To Health Topics / Iron-Deficiency Anemia Iron-Deficiency Anemia Also known as Leer en español Iron-deficiency ... iron-deficiency anemia. Blood tests to screen for iron-deficiency anemia To screen for iron-deficiency anemia, your doctor ...

Quantitative study of fruit flavonoids in citrus hybrids of King (C. nobilis) and Mukaku Kishu (C. kinokuni).

Science.gov (United States)

Kawaii, S; Tomono, Y; Katase, E; Ogawa, K; Nonomura-Nakano, M; Nesumi, H; Yoshida, T; Sugiura, M; Yano, M

2001-08-01

Twenty-four Citrus hybrids of King (C. nobilis) and Mukaku Kishu (C. kinokuni) were examined for their flavonoid profiles of the edible part by reversed-phase HPLC analysis. Two hybrids (G-155 and G-156) contained higher amounts of natsudaidain than their parents, whereas the remainder of the hybrids had a character intermediate between those of King and Mukaku Kishu on the basis of polymethoxylated flavone composition. Principal component analysis revealed the distribution of the hybrids by quantifying 23 flavonoid contents.

Lion King Surveys Homeland

Science.gov (United States)

2004-01-01

This image from the Mars Exploration Rover Opportunity's panoramic camera shows one octant of a larger panoramic image which has not yet been fully processed. The full panorama, dubbed 'Lion King' was obtained on sols 58 and 60 of the mission as the rover was perched at the lip of Eagle Crater, majestically looking down into its former home. It is the largest panorama yet obtained by either rover. The octant, which faces directly into the crater, shows features as small as a few millimeters across in the field near the rover arm, to features a few meters across or larger on the horizon. The full panoramic image was taken in eight segments using six filters per segment, for a total of 558 images and more than 75 megabytes of data. This enhanced color composite was assembled from the infrared (750 nanometer), green (530 nanometer), and violet (430 nanometer) filters. Additional lower elevation tiers were added relative to other panoramas to ensure that the entire crater was covered in the mosaic.

King Lear Reveals the Tragic Pattern of Shakespeare

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Salim Eflih Al-Ibia

2017-04-01

Full Text Available Rather than focusing on the obvious traditions of evaluating Shakespearean tragic heroes, this paper presents a groundbreaking approach to unfold the pattern William Shakespeare follows as he designed his unique characters. This pattern applies to most, if not all, Shakespearean tragic heroes. I argue that Shakespeare himself reveals a great portion of this pattern on the tongue of Lear as the latter disowns Goneril and Regan promising to have “such revenges on [them] both” in King Lear. Lear’s threats bestow four unique aspects that apply not only to his character but they also apply to Shakespearean tragic heroes. Lear’s speech tells us that he is determined to have an awful type of revenge on his daughters. However, the very same speech tells us that he seems uncertain about the method through which he should carry out this revenge. Lear does not express any type of remorse as he pursues his vengeful plans nor should he aim at amnesty. He also admits his own madness as he closes his revealing speech. This research develops these facts about Lear to unfold the unique pattern Shakespeare follows as he portrayed his major tragic figures. This pattern is examined, described and analyzed in King Lear, Othello, and Hamlet. We will find out that the pattern suggested in this study helps us better understand Shakespeare’s tragedies and enables us to provide better explanations for some controversial scenes in the tragedies discussed.

Compreensão do modelo de king sobre o paradigma do Interacionismo Simbólico Entendiendo el modelo de king en el paradigma del Interaccionismo Simbolico Understanding of king's model on the paradigm of Simbolic Interactionism

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Iliana Maria de Almeida Araújo

2005-12-01

Full Text Available Objetivou-se refletir sobre o modelo conceitual de King, segundo a abordagem do Interacionismo Simbólico, dentro do modelo de análises de teoria de Meleis. Para alcançar o objetivo, realizamos uma leitura dos três modelos citados nos trabalho, buscando as congruências e discrepâncias entre os conceitos e correlacionando-os. O estudo permitiu concluir que as teorias concordam ao elucidar o homem como um ser que reage e busca compreender o significado das coisas ao seu redor, planejando e julgando suas ações e a dos outros. É importante a questão dos significados poderem ser modificados e gerarem a elaboração de metas em comum.Se apuntó a reflectir acerca del modelo conceptual de King, según el acercamiento de Interacionismo Simbólico, dentro del modelo de análisis de la teoría de Meleis. Para alcanzar el objetivo, nosotros logramos una lectura de los tres modelos mencionada en el trabajo, mientras buscando las consistencias y diferencias entre los conceptos y poniéndolos en correlación. El estudio permitió concluir que las teorías están de acuerdo al elucidar al hombre como un ser que reacciona e investiga para entender el significado de las cosas en suyo circuito, mientras flotando y juzgando sus acciones y el uno de los otros. Es importante el asunto de los significados podría modificarse y ellos generan la elaboración de metas en común.It was aimed to reflect on King's Theory, according to the approach of Symbolic Interaccionism, and theory analyses model of Meleis. To reach the objective, we proceeded the reading of the three models as mentioned before, looking for the consistencies and discrepancies among the concepts and correlating them. The study allowed to conclude that the theories agree when elucidating the man as a being that reacts and search to understand the meaning of things to his/her circuit, drifting and judging their actions and the one of the other ones. It is important the subject of the meanings

Genetic diversity and molecular evolution of Naga King Chili inferred from internal transcribed spacer sequence of nuclear ribosomal DNA.

Science.gov (United States)

Kehie, Mechuselie; Kumaria, Suman; Devi, Khumuckcham Sangeeta; Tandon, Pramod

2016-02-01

Sequences of the Internal Transcribed Spacer (ITS1-5.8S-ITS2) of nuclear ribosomal DNAs were explored to study the genetic diversity and molecular evolution of Naga King Chili. Our study indicated the occurrence of nucleotide polymorphism and haplotypic diversity in the ITS regions. The present study demonstrated that the variability of ITS1 with respect to nucleotide diversity and sequence polymorphism exceeded that of ITS2. Sequence analysis of 5.8S gene revealed a much conserved region in all the accessions of Naga King Chili. However, strong phylogenetic information of this species is the distinct 13 bp deletion in the 5.8S gene which discriminated Naga King Chili from the rest of the Capsicum sp. Neutrality test results implied a neutral variation, and population seems to be evolving at drift-mutation equilibrium and free from directed selection pressure. Furthermore, mismatch analysis showed multimodal curve indicating a demographic equilibrium. Phylogenetic relationships revealed by Median Joining Network (MJN) analysis denoted a clear discrimination of Naga King Chili from its closest sister species (Capsicum chinense and Capsicum frutescens). The absence of star-like network of haplotypes suggested an ancient population expansion of this chili.

Aerosols in King George Island (Antarctic peninsula) using PIXE and alpha spectrometry

International Nuclear Information System (INIS)

Dias da Cunha, K.; Medeiros, G.; Leal, M.A.; Lima, C.; Dalia, K.C.

2009-01-01

The aim of this study was to characterize the airborne particles and particles deposited in the recent snow samples collected at King George Island (Admiralty Bay) in order to evaluate the possible local sources of airborne particles and the aerosol transport from South America to Antarctic at sea level. Airborne particles samples were collected using a cascade impactor and cyclones at several sampling points at Admiralty Bay. Airborne particles were also collected during the ship travel from Rio de Janeiro to Antarctica. The recent snow samples and aerosols collected at several sampling points at Admiralty Bay were analyzed by PIXE for the determination of the elemental mass concentration. Snow samples were analyzed by alpha spectrometry to determine the 232Th, 228Th, 238U and 234U concentrations in snow. The Mass Median Aerodynamic Diameter of airborne particles was determined. The results suggest that there is a correlation between the aerosol samples and the particles deposited in the snow, but the elemental mass distributions are not equal. The snow elemental concentration can be used as an indicator of the elements present in the aerosols. The local aerosol sources (natural and anthropogenic) have been considered to characterize the aerosol transport to Antarctic, mainly King George Island. The main aerosol sources are the marine spray, weathering of local rocks and anthropogenic sources, as the diesel burning in the island. Besides the local aerosol sources the transport of airborne particles from south Atlantic to Antarctic is an important source of airborne particles at King George Island. (author)

History and hydrologic effects of ground water use in Kings, Queens, and western Nassau counties, Long Island, New York, 1800's through 1997

Science.gov (United States)

Cartwright, Richard A.

2002-01-01

Ground-water withdrawals from the aquifers underlying Kings and Queens Counties varied temporally and spatially during the 20th century and caused extreme changes in water levels. The resultant lowering of water levels during periods of heavy pumping caused saltwater intrusion in nearshore areas and the migration of contaminants from land surface into deep aquifers. The recovery of water levels in response to countywide curtailment of pumping has resulted in the flooding of underground structures. Combined withdrawals for public and industrial supply in Kings and Queens Counties were greatest during the 1930's--about 130 million gallons per day. During this period, a large cone of depression developed in the water table in Kings County; within this depression, water levels were about 45 feet lower than in 1903. All pumping for public supply was halted in Kings County in 1947, and in Jamaica (in Queens County) in 1974. Water levels in Kings County had recovered by 1974 and have remained similar to those of 1903 since then, except for minor localized drawdowns due to industrial-supply or dewatering withdrawals. A large cone of depression that had formed in southeastern Queens County before 1974 has now (1997) disappeared. The estimated combined withdrawal for public supply and industrial supply in Kings and Queens Counties in 1996 was only about 50 million gallons per day.The water-level recoveries in the water-table and confined aquifers generally have resulted in the dilution and dispersion of residual salty and nitrate-contaminated ground water. The majority of recently sampled wells indicate stable or decreasing chloride and nitrate concentrations in all aquifers since 1983. Organic contaminants remain in ground water in Kings, Queens, and Nassau Counties, however; the most commonly detected compounds in 1992-96 were tetrachloroethene, trichloroethene, chloroform, and total trihalomethanes. Water samples from monitoring wells in Kings County indicate a greater

Kings, Nobles, and Frontier: Violence and Kinship around the Galician-Portuguese border (12th-13th centuries

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Inés Calderón Medina

2017-09-01

Full Text Available The birth of the frontier between Galicia and Portugal was an arduous process. The control over this area relied, to a great extent, on the success of the kings of Leon and Portugal in assuring the local nobles’ loyalty and service. The role played by the local nobility in the creation and military defense of this border can be analysed throughout chronicles and diplomas. These sources cast light on the nobility’s key military role in southern Galicia and the political consequences derived from these nobles’ loyalty or infidelity. The kings of Portugal and Leon actively seek the local nobility’s support; however they also relied on royal marriages in order to solve border conflicts. In that regard, disputed landholdings and castles were given to the Portuguese monarchs as part of the Leonese queens’ dowry. Some nobles were chosen as executors of these marriages agreements, so they acted as intermediaries between both kings.

Predictive value of natriuretic peptides in dogs with mitral valve disease

DEFF Research Database (Denmark)

Tarnow, Inge; Olsen, Lisbeth Høier; Kvart, Clarence

2009-01-01

Natriuretic peptides are useful in diagnosing heart failure in dogs. However, their usefulness in detecting early stages of myxomatous mitral valve disease (MMVD) has been debated. This study evaluated N-terminal (NT) fragment pro-atrial natriuretic peptide (NT-proANP) and NT-pro-brain natriuretic...... peptide (NT-proBNP) in 39 Cavalier King Charles Spaniels (CKCS) with pre-clinical mitral valve regurgitation (MR), sixteen dogs with clinical signs of heart failure (HF) and thirteen healthy control dogs. Twenty seven CKCS and ten control dogs were re-examined 4 years after the initial examination...... and the status of the dogs 5 years after the initial examination was determined by telephone calls to the owner. All dogs were evaluated by clinical examination and echocardiography. CKCS with severe MR had higher NT-proANP and NT-proBNP compared to controls and CKCS with less severe MR. Dogs with clinical signs...

Biopterin status in dogs with myxomatous mitral valve disease is associated with disease severity and cardiovascular risk factors

DEFF Research Database (Denmark)

Reimann, Maria Josefine; Häggström, J.; Mortensen, Alan

2014-01-01

BACKGROUND: Endothelial dysfunction (ED) has been suggested to be associated with myxomatous mitral valve disease (MMVD) in dogs. Tetrahydrobiopterin (BH4) is an important cofactor for production of the endothelium-derived vasodilator nitric oxide (NO). Under conditions of oxidative stress, BH4...... is oxidized to the biologically inactive form dihydrobiopterin (BH2). Thus, plasma concentrations of BH2 and BH4 may reflect ED and oxidative stress. OBJECTIVE: To determine plasma concentrations of BH2 and BH4 in dogs with different degrees of MMVD. ANIMALS: Eighty-four privately owned dogs grouped according...... to ACVIM guidelines (37 healthy control dogs including 13 Beagles and 24 Cavalier King Charles Spaniels [CKCSs], 33 CKCSs with MMVD of differing severity including 18 CKCSs [group B1] and 15 CKCSs [group B2], and 14 dogs of different breeds with clinical signs of congestive heart failure [CHF] because...

El cuerpo entre la resistencia y la asimilación: Estrategias incorporadas e itinerario corporal de un latin King

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Porzio, Laura

2012-06-01

Full Text Available This article focuses on the biographical account of King Manaba, who for many years was the Inca, the supreme leader of the latin King tribes in Catalonia and Spain. Referring to his biography, I will focus on the social presentation of the bodies of Manaba and the latin King, through their dress, adornments and tattoos. From a theoretical and analytical point of view, the body represents one of the main elements for the creation and diffusion of the imaginary of the so called “Latin gangs”. The body can be a stigma and create inequalities and, at the same time, a place of experiences, reflexion and resistance as an emblem. At the end, the article reflects on the tension and paradoxical relationship between resistance and assimilation practices in youth culture.El artículo se centra en el relato biográfico de King Manaba, que durante muchos años fue el Inca, es decir, el líder supremo de una de las tribus de los latin King en Cataluña y en España. Mediante el recurso de su biografía, nos centraremos en la presentación social del cuerpo de Manaba y de los latin King, a través de sus vestidos, adornos y tatuajes. Desde un punto de vista teórico y analítico, el cuerpo representa uno de los elementos centrales para la creación y difusión del imaginario de las llamadas “bandas latinas”. El cuerpo puede ser un estigma y crear desigualdades y, al mismo tiempo, un espacio de vivencias, reflexión y resistencia en cuanto emblema. Finalmente, el artículo reflexiona sobre la tensión y paradójica relación entre prácticas de resistencias y de asimilación en las culturas juveniles.

Advanced electrocardiographic parameters change with severity of mitral regurgitation in Cavalier King Charles Spaniels in sinus rhythm

DEFF Research Database (Denmark)

Pakkanen, M. Spiljak; Petric, A. Domanjko; Olsen, Lisbeth Høier

2012-01-01

Multiple advanced resting ECG (A-ECG) techniques have improved the diagnostic or prognostic value of ECG in detecting human cardiac diseases even before onset of clinical signs or changes in conventional ECG....

Identification of 2 loci associated with development of myxomatous mitral valve disease in Cavalier King Charles Spaniels

DEFF Research Database (Denmark)

Madsen, Majbritt Busk; Olsen, Lisbeth Høier; Häggström, Jens

2011-01-01

of MMVD as cases and old dogs with no or mild signs of MMVD as controls, we conducted a genome-wide association study (GWAS) to identify loci associated with development of MMVD. We have identified a 1.58 Mb region on CFA13 (P(genome) = 4.0 × 10(-5)) and a 1.68 Mb region on CFA14 (P(genome) = 7.9 × 10...

Iron-Deficiency Anemia

Science.gov (United States)

... To Health Topics / Iron-Deficiency Anemia Iron-Deficiency Anemia Also known as Leer en español Iron-deficiency ... anemia. Blood tests to screen for iron-deficiency anemia To screen for iron-deficiency anemia, your doctor ...

The Kings River Sustainable Forest Ecosystems Project: inception, objectives, and progress

Science.gov (United States)

Jared Verner; Mark T. Smith

2002-01-01

The Kings River Sustainable Forest Ecosystems Project, a formal administrative study involving extensive and intensive collaboration between Forest Service managers and researchers, is a response to changes in the agency’s orientation in favor of ecosystem approaches and to recent concern over issues associated with maintenance of late successional forest attributes...

Observations of Upper Thermospheric Temperatures Using a Ground-Based Optical Instrument at the King Sejong Station, Antarctic

OpenAIRE

Jong-Kyun Chung; Young-In Won; Bang Yong Lee; Jhoon Kim

1998-01-01

We measured the terrestrial nightglow of OI 6300A in the thermosphere(~250km) using a ground-based Fabry-Perot interferometer at the King Sejong Station, Antarctic from March through September, 1997. The King Sejong Station is located at high latitude geographically (62.22 deg S, 301.25 deg E) but at mid-latitude geomagnetically (50.65 deg S, 7.51 deg E). It is therefore the strategic location to measure the temperatures of the thermosphere in the Southern Hemisphere associated with both sola...

Isolation and identification of lactid acid bacteria originated from king grass (Pennisetum purpureophoides as candidate of probiotic for livestock

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Santoso B

2013-06-01

Full Text Available A study was conducted to isolate and identify strain of lactic acid bacteria (LAB isolated from king grass, and to determine their potential as candidate of probiotic for livestock. The LAB was isolated by culturing king grass extract in De Man, Rogosa and Sharpe (MRS medium. The pure culture LAB was used to identify strain of bacteria using Analytical Profile Index (API 50 CH kit. The result showed that the strain bacteria was identified as Lactobacillus plantarum. L. plantarum was able to survive in extreme condition at pH 2 and 0.3% bile salt. L. plantarum also survived against pathogenic bacteria i.e. Staphylococcus aureus, Escherechia coli and Salmonella thypi. It is concluded that L. plantarum isolated from king grass could potentially to be used as probiotic for livestock.

Iron-Deficiency Anemia

Medline Plus

Full Text Available ... To Health Topics / Iron-Deficiency Anemia Iron-Deficiency Anemia Also known as Leer en español Iron-deficiency ... anemia. Blood tests to screen for iron-deficiency anemia To screen for iron-deficiency anemia, your doctor ...

Use of cycle stacking patterns to define third-order depositional sequences: Middle to Late Cambrian Bonanza King Formation, southern Great basin

Energy Technology Data Exchange (ETDEWEB)

Montanez, I.P.; Droser, M.L. (Univ. of California, Riverside (United States))

1991-03-01

The Middle to Late Cambrian Bonanza King Formation (CA, NV) is characterized by superimposed scales of cyclicity. Small-scale cycles (0.5 to 10m) occur as shallowing-upward peritidal and subtidal cycles that repeat at high frequencies (10{sup 4} to 10{sup 5}). Systematic changes in stacking patterns of meter-scale cycles define several large-scale (50-250 m) third-order depositional sequences in the Bonanza King Formation. Third-order depositional sequences can be traced within ranges and correlated regionally across the platform. Peritidal cycles in the Bonanza King Formation are both subtidal- and tidal flat-dominated. Tidal flat-dominated cycles consist of muddy bases grading upward into thrombolites or columnar stromatolites all capped by planar stromatolites. Subtidal cycles in the Bonanza King Formation consist of grainstone bases that commonly fine upward and contain stacked hardgrounds. These are overlain by digitate-algal bioherms with grainstone channel fills and/or bioturbated ribbon carbonates with grainstone lenses. Transgressive depositional facies of third-order depositional sequences consist primarily of stacks of subtidal-dominated pertidial cycles and subtidal cycles, whereas regressive depositional facies are dominated by stacks of tidal flat-dominated peritidal cycles and regoliths developed over laminite cycle caps. The use of high frequency cycles in the Bonanza King Formation to delineate regionally developed third-order depositional sequences thus provides a link between cycle stratigraphy and sequence stratigraphy.

Superoxide activates a GDP-sensitive proton conductance in skeletal muscle mitochondria from king penguin (Aptenodytes patagonicus).

Science.gov (United States)

Talbot, Darren A; Hanuise, Nicolas; Rey, Benjamin; Rouanet, Jean-Louis; Duchamp, Claude; Brand, Martin D

2003-12-26

We present the partial nucleotide sequence of the avian uncoupling protein (avUCP) gene from king penguin (Aptenodytes patagonicus), showing that the protein is 88-92% identical to chicken (Gallus gallus), turkey (Meleagris gallopavo), and hummingbird (Eupetomena macroura). We show that superoxide activates the proton conductance of mitochondria isolated from king penguin skeletal muscle. GDP abolishes the superoxide-activated proton conductance, indicating that it is mediated via avUCP. In the absence of superoxide there is no GDP-sensitive component of the proton conductance from penguin muscle mitochondria demonstrating that avUCP plays no role in the basal proton leak.

A transcriptome-based assessment of the astrocytic dystrophin-associated complex in the developing human brain.

Science.gov (United States)

Simon, Matthew J; Murchison, Charles; Iliff, Jeffrey J

2018-02-01

Astrocytes play a critical role in regulating the interface between the cerebral vasculature and the central nervous system. Contributing to this is the astrocytic endfoot domain, a specialized structure that ensheathes the entirety of the vasculature and mediates signaling between endothelial cells, pericytes, and neurons. The astrocytic endfoot has been implicated as a critical element of the glymphatic pathway, and changes in protein expression profiles in this cellular domain are linked to Alzheimer's disease pathology. Despite this, basic physiological properties of this structure remain poorly understood including the developmental timing of its formation, and the protein components that localize there to mediate its functions. Here we use human transcriptome data from male and female subjects across several developmental stages and brain regions to characterize the gene expression profile of the dystrophin-associated complex (DAC), a known structural component of the astrocytic endfoot that supports perivascular localization of the astroglial water channel aquaporin-4. Transcriptomic profiling is also used to define genes exhibiting parallel expression profiles to DAC elements, generating a pool of candidate genes that encode gene products that may contribute to the physiological function of the perivascular astrocytic endfoot domain. We found that several genes encoding transporter proteins are transcriptionally associated with DAC genes. © 2017 Wiley Periodicals, Inc.

Recombinase-mediated reprogramming and dystrophin gene addition in mdx mouse induced pluripotent stem cells.

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Chunli Zhao

Full Text Available A cell therapy strategy utilizing genetically-corrected induced pluripotent stem cells (iPSC may be an attractive approach for genetic disorders such as muscular dystrophies. Methods for genetic engineering of iPSC that emphasize precision and minimize random integration would be beneficial. We demonstrate here an approach in the mdx mouse model of Duchenne muscular dystrophy that focuses on the use of site-specific recombinases to achieve genetic engineering. We employed non-viral, plasmid-mediated methods to reprogram mdx fibroblasts, using phiC31 integrase to insert a single copy of the reprogramming genes at a safe location in the genome. We next used Bxb1 integrase to add the therapeutic full-length dystrophin cDNA to the iPSC in a site-specific manner. Unwanted DNA sequences, including the reprogramming genes, were then precisely deleted with Cre resolvase. Pluripotency of the iPSC was analyzed before and after gene addition, and ability of the genetically corrected iPSC to differentiate into myogenic precursors was evaluated by morphology, immunohistochemistry, qRT-PCR, FACS analysis, and intramuscular engraftment. These data demonstrate a non-viral, reprogramming-plus-gene addition genetic engineering strategy utilizing site-specific recombinases that can be applied easily to mouse cells. This work introduces a significant level of precision in the genetic engineering of iPSC that can be built upon in future studies.

Seasonal variation of seismic ambient noise level at King Sejong Station, Antarctica

Science.gov (United States)

Lee, W.; Sheen, D.; Seo, K.; Yun, S.

2009-12-01

The generation of the secondary- or double-frequency (DF) microseisms with dominant frequencies between 0.1 and 0.5 Hz has been explained by nonlinear second-order pressure perturbations on the ocean bottom due to the interference of two ocean waves of equal wavelengths traveling in opposite directions. Korea Polar Research Institute (KOPRI) has been operating a broadband seismic station (KSJ1) at King George Island (KGI), Antarctica, since 2001. Examining the ambient seismic noise level for the period from 2006 to 2008 at KSJ1, we found a significant seasonal variation in the frequency range 0.1-0.5 Hz. Correlation of the DF peaks with significant ocean wave height and peak wave period models indicates that the oceanic infragravity waves in the Drake Passage is a possible source to excite the DF microseisms at KGI. Location of King Sejong Station, Antarctica Seasonal variations of DF peak, significant wave height, and peak wave period

Salmon Supplementation Studies in Idaho Rivers; Field Activities Conducted on Clear and Pete King Creeks, 2001 Annual Report.

Energy Technology Data Exchange (ETDEWEB)

Gass, Carrie; Olson, Jim M. (US Fish and Wildlife Service, idaho Fishery Resource Office, Ahsahka, ID)

2004-11-01

In 2001 the Idaho Fisheries Resource Office continued as a cooperator on the Salmon Supplementation Studies in Idaho Rivers (ISS) project on Pete King and Clear creeks. Data relating to supplementation treatment releases, juvenile sampling, juvenile PIT tagging, brood stock spawning and rearing, spawning ground surveys, and snorkel surveys were used to evaluate project data points and augment past data. Due to low adult spring Chinook returns to Kooskia National Fish Hatchery (KNFH) in brood year 1999 there was no smolt supplementation treatment release into Clear Creek in 2001. A 17,014 spring Chinook parr supplementation treatment (containing 1000 PIT tags) was released into Pete King Creek on July 24, 2001. On Clear Creek, there were 412 naturally produced spring Chinook parr PIT tagged and released. Using juvenile collection methods, Idaho Fisheries Resource Office staff PIT tagged and released 320 naturally produced spring Chinook pre-smolts on Clear Creek, and 16 natural pre-smolts on Pete King Creek, for minimum survival estimates to Lower Granite Dam. There were no PIT tag detections of brood year 1999 smolts from Clear or Pete King creeks. A total of 2261 adult spring Chinook were collected at KNFH. Forty-three females were used for supplementation brood stock, and 45 supplementation (ventral fin-clip), and 45 natural (unmarked) adults were released upstream of KNFH to spawn naturally. Spatial and temporal distribution of 37 adults released above the KNFH weir was determined through the use of radio telemetry. On Clear Creek, a total of 166 redds (8.2 redds/km) were observed and data was collected from 195 carcasses. Seventeen completed redds (2.1 redds/km) were found, and data was collected data from six carcasses on Pete King Creek.

King Cotton's Lasting Legacy of Poverty and Southern Region Contemporary Conditions

Science.gov (United States)

Guthrie, James W.; Peevely, Gary

2010-01-01

One hundred fifty years ago, cotton was considered as the king of all United States' agricultural exports. Cotton's dollar value far exceeded that of any other mid-19th-century United States trade item, much more than tobacco, fish, forest products, raw materials for manufacturing, or manufactured items. Indeed, in the mid-19th century, cotton was…

Prescribed burning in the Kings River Ecosystem Project Area: lessons learned

Science.gov (United States)

David S. McCandliss

2002-01-01

The prescribed fire program on the Sierra National Forest is in its infancy. Prescription burning was initiated in 1994 in two 32,000-acre watersheds in the Kings River District of the Sierra National Forest. Primary objectives are to return fire to a more historical role in forest ecosystems and to provide opportunities for scientists from the Pacific Southwest...

GPM GROUND VALIDATION DUAL POLARIZED C-BAND DOPPLER RADAR KING CITY GCPEX V1

Data.gov (United States)

National Aeronautics and Space Administration — The GPM Ground Validation Dual Polarized C-Band Doppler Radar King City GCPEx dataset has special Range Height Indicator (RHI) and sector scans of several dual...

Unknown Fragment of King Sigismundus III’s Diary about Campaign to Russia, 1609–1611

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Igor O. Tyumentsev

2017-09-01

Full Text Available Events of the Time of Troubles of the early 17th century played a great role in the history of Russia. In the year of 1609, the Polish royal army under high command of hetman Stanislav Zholkevsky and the King Sigismundus III himself invaded Russia and resiged Smolensk. At this time, a massive offensive to Western, South-Western and North-Western regions of Russia was launched by some detachments under Aleksander Korvinus Gosievsky, some of Polish colonels who were at the head of their regiments and the Cossacks of Zaporozhye. The role of this invasion was very important. The Polish authorities viewed the Russians as a potentially oppositional force, though actual economic collapse and repressions from the state authorities of Vasily Shuiski and the false Dimitry II considerably undermined their enthusiasm and brought social apathy among the Russians. Nevertheless, a garrison of Smolensk refused to surrender and decided to fight against the enemy. History of this siege was described by the King’s secretaries in King Sigismundus III’s Diary about Campaign to Russia. It belongs to the main sources about Russia’s Time of Troubles and about these events, as well as other documents of foreign observers. Using the procedures developed by R.G. Skrynnikov and I.O. Tyumentsev, the authors found and analysed unknown fragment of the “King Sigismundus‘ journal”, which are edited in this publication for the first time. Comparison of this document with the another data of King Sigismundus III’s Diary about Campaign to Russia and other Polish-Luthuanian sources from the beginning of the 17th century enables them to carry out a complex examination of the materials and to cross-verify their data. Experience shows that this technique works effectively.

The Spanish King Alfonso XIII on pages of Russian Press in 1902–1917

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Ariadna A. Petrova

2016-06-01

Full Text Available The article examines the approaches of the Russian press (“Moskovskie Vedomosti”, “Russkie Vedomosti”, “Novoe Vremia” to the evaluation of the Spanish King Alfonso XIII (1886–1941 at the first stage of his government. During this time he, acting within the powers granted to him by the Spanish constitution of the Restoration era, tried to stabilize the political situation in Spain and raise the prestige of the royal power, is also actively involved in social and political life of the country. Alfonso XIII also sought to raise the country's prestige in the international arena, seriously shaken after the “disaster in 1898”. The special attention is paid to the problem of formation of public opinion by the Russian press, on the example of newspaper coverage of humanitarian and intermediate activity of the Spanish king during the First World War. The activity of Alfonso XIII, aimed at protecting the interests of the citizens of the Russian Empire and the Slavic population of Austria-Hungary, in particular, his personal involvement in the rescue of the Austrian authorities was sentenced to death by a correspondent of the newspaper "New time" in Vienna D.G. Yanchevetskiy, forced the Russian public during the war to change the attitude towards Spain, its king and Spanish neutrality.

Siim Nestor soovitab : Goldie. Kevin Saunderson. Nicole Willis. King Britt / Siim Nestor

Index Scriptorium Estoniae

Nestor, Siim, 1974-

2005-01-01

Popmuusikaüritustest: briti muusik Goldie esineb jungle-muusikaga Tallinnas 21. apr. klubis Privé, DJ Kevin Saunderson 22. apr. klubis Privé, laulja Nicole Willis 27. apr. BonBon Jazz Lounge'il klubis BonBon, Philadelphia muusik King Britt ja Eesti ansambel Broken Time Orchestra esitlevad oma heliplaate

Hazardous Waste Cleanup: Thermo King de Puerto Rico Incorporated in Arecibo, Puerto Rico

Science.gov (United States)

Thermo King de Puerto Rico, Inc. facility is located in the Zeno Gandia Industrial Area in Arecibo, Puerto Rico. Major features of the facility include six buildings used for manufacturing and storage, a wastewater treatment plant, a hazardous waste and no

Accumulation factors of mercury by King Bolete Boletus edulis

Science.gov (United States)

Falandysz, J.; Frankowska, A.

2003-05-01

To understand pollution picture with mercury and to examine suitability of King Bolete Boletits edulis Bull.: Fr. as possible bioindicator the total mercurv concentrations were determined both in the fruiting bodies and underlying soil substrate collected from various regions of Poland. There were quite large spatial variations of mercury concentration and some seasonal also were noted. Mercury content of the caps exceeded that of stalks (p<0.05), Nvhile Hg BCF values varied between 9 and 40, and 4 and 40, respectively.

Micro-gravity studies in archeo-prospecting of the Valley of the Kings, Luxor, Egypt

Czech Academy of Sciences Publication Activity Database

Issawy, E. A.; Tealeb, A. A.; Mrlina, Jan; Radwan, A. H.; Hassan, G. S.; Sakr, K. O.

- (2001), s. 201-212 ISSN 1110-6417 Institutional research plan: CEZ:AV0Z3012916 Keywords : micro-gravity investigations * archaeo-prospecting * Valley of the Kings * Egypt Subject RIV: DE - Earth Magnetism, Geodesy, Geography

Heterothermy in growing king penguins.

Science.gov (United States)

Eichhorn, Götz; Groscolas, René; Le Glaunec, Gaële; Parisel, Camille; Arnold, Laurent; Medina, Patrice; Handrich, Yves

2011-08-16

A drop in body temperature allows significant energy savings in endotherms, but facultative heterothermy is usually restricted to small animals. Here we report that king penguin chicks (Aptenodytes patagonicus), which are able to fast for up to 5 months in winter, undergo marked seasonal heterothermy during this period of general food scarcity and slow-down of growth. They also experience short-term heterothermy below 20 °C in the lower abdomen during the intense (re)feeding period in spring, induced by cold meals and adverse weather. The heterothermic response involves reductions in peripheral temperature, reductions in thermal core volume and temporal abandonment of high core temperature. Among climate variables, air temperature and wind speed show the strongest effect on body temperature, but their effect size depends on physiological state. The observed heterothermy is remarkable for such a large bird (10 kg before fasting), which may account for its unrivalled fasting capacity among birds.

Does winter region affect spring arrival time and body mass of king eiders in northern Alaska?

Science.gov (United States)

Powell, Abby N.; Oppel, Steffen

2009-01-01

Events during the non-breeding season may affect the body condition of migratory birds and influence performance during the following breeding season. Migratory birds nesting in the Arctic often rely on endogenous nutrients for reproductive efforts, and are thus potentially subject to such carry-over effects. We tested whether king eider (Somateria spectabilis) arrival time and body mass upon arrival at breeding grounds in northern Alaska were affected by their choice of a winter region in the Bering Sea. We captured birds shortly after arrival on breeding grounds in early June 2002–2006 at two sites in northern Alaska and determined the region in which individuals wintered using satellite telemetry or stable isotope ratios of head feathers. We used generalized linear models to assess whether winter region explained variation in arrival body mass among individuals by accounting for sex, site, annual variation, and the date a bird was captured. We found no support for our hypothesis that either arrival time or arrival body mass of king eiders differed among winter regions. We conclude that wintering in different regions in the Bering Sea is unlikely to have reproductive consequences for king eiders in our study areas.

[Neurological evaluation of the leper king Baldwin IV of Jerusalem].

Science.gov (United States)

Guerrero-Peral, A L

In the medieval period, physicians became more aware of leprosy symptoms and differentiated it from other similar diseases. Baldwin, the leper king of Jerusalem (1161-1185), probably contributed to an increasing interest and tolerance to this disease in medieval Christian states. We review historical descriptions of the neurological manifestations he developed. William of Tyre gives us a description of first symptoms experienced by the prince when aged nine. He notices that half of his right arm and hand were partially numb. No skin or nervous lesions are described. By his early twenties, muscle weakness makes him unable to walk. He gets blinded, probably due to keratopathy related to facial nerves involvement. Repeated attacks of fever lead to progressive worsening of his disease. He finally dies in Jerusalem, aged twenty-five, probably due to a septicaemia from infected sores. The earliest sign of Baldwin's disease is anaesthesia. Though skin lesions are not described, it is likely that at this point he had a tuberculoid form of leprosy. As his disease finally takes a lepromatous form, we suspect that it began as a borderline, immunologically unstable form. Leper king Baldwin biography gives us interesting descriptions of neurological clinical features of leprosy. Besides, it helps us to discover twelfth century medicine knowledge about this disease.

The Role of W.L. Mackenzie King in the Development of the Canadian Political Culture (Dedicated to His 140th Anniversary

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Sokov Ilya Anatolyevich

2015-04-01

Full Text Available The author of the article analyses the role of Canada’s Prime Minister W.L. Mackenzie King in the creation of the unique Canadian political culture. The basis for this political culture was represented not only by the British political system, the adopted ideology of English classical liberalism, but also the national historical and cultural traditions connected with one and a half century existence of two nations on the North American continent. The author confirms that the Liberal Party and Mackenzie King as its leader decided upon the wide modernization of the Canadian society in the conditions of the post-war reconstruction in 1920s. This process would have been impossible without the reorganization of the political culture. The change of political practice allowed the autonomy to obtain more rights and the sovereignty. That is why M. King held two posts during almost the whole period – as Prime Minister and as Minister of Foreign Affairs. This approach helped him to have significant influence on the external political aspect in the development of the Canadian political culture. The author of the article points the main seven directions in the political activity of Mackenzie King which contributed to the creation of the unique Canadian political culture. The author concludes that the influence of Mackenzie King on the creation of the Canadian political culture was crucial in the second half of the 20th Century.

King James II in Foreign Historiography: the Main Scientifi c Trends and Approaches .

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Stankov Kirill

2016-07-01

Full Text Available The fate of the tragic figure of the British king James II Stuart is considered in the article. In this paper the author pays speсial attention to the history of investigation of the character and politics of this person by the British historians, as well as by the leading European and American specialists on the Early Modern Time. The estimates of James II are of vast variety in the British historiography but at the same time diff erent authors have some similar features in their attitude. Except the apologists the British historians on the whole criticized this king and explain that the majority of the problems connected with him are based on the religious factor that is not really right. On the other hand there are some differences in this negative approaches among various scientifi c schools of British historiography. The Whigs stated that James II tried to limit the personal rights of the Englishmen which was the main result of the English revolution of the middle of the 17th century. The Tories proved that the king neglected the gentry’s property rights and tried to transform the dualistic monarchy into absolutism. The Positivists thought that James II supported the Catholic Counterreformation and fought against the Enlightenment. The revisionists and postrevisionists tried to revalue the person of James II based on the true scientific foundations. A special view on James II’ policy is produced by Non-British authors: German, French and American historians.

Burger King in Portugal : to lead or to follow?

OpenAIRE

Patrone, Sara Saraiva

2012-01-01

In 2001, the Burger King (BK) brand, managed by Ibersol group entered the growing fast food Portuguese market. Marginally higher prices along with the fact of having entered the market 10 years after its most direct competitor (McDonald´s), led BK to a sub leader position. Although being recognized as offering superior quality products when compared to McDonald´s, BK´s growth margins in the Portuguese market have been decreasing since 2007. The company´s uncertainty situation, offers the p...

Iron-Deficiency Anemia

Medline Plus

Full Text Available ... Iron-Deficiency Anemia Iron-Deficiency Anemia Also known as Leer en español Iron-deficiency anemia is a ... address the cause of your iron deficiency, such as any underlying bleeding. If undiagnosed or untreated, iron- ...