Studies on the Cobalt Deficiency in Ruminants (III) : Effects of Thiamine, Glucose and Cobalamin Injection on the Metabolism of Cobalt-deficient Sheep

International audienceN-terminal acetylation is a common protein modification in eukaryotes associated with numerous cellular processes. Inherited mutations in NAA10, encoding the catalytic subunit of the major N-terminal acetylation complex NatA have been associated with diverse, syndromic X-linked recessive disorders, whereas de novo missense mutations have been reported in one male and one female individual with severe intellectual disability but otherwise unspecific phenotypes. Thus, the full genetic and clinical spectrum of NAA10 deficiency is yet to be delineated. We identified three different novel and one known missense mutation in NAA10, de novo in 11 females, and due to maternal germ line mosaicism in another girl and her more severely affected and deceased brother. In vitro enzymatic assays for the novel, recurrent mutations p.(Arg83Cys) and p.(Phe128Leu) revealed reduced catalytic activity. X-inactivation was random in five females. The core phenotype of X-linked NAA10-related N-terminal-acetyltransferase deficiency in both males and females includes developmental delay, severe intellectual disability, postnatal growth failure with severe microcephaly, and skeletal or cardiac anomalies. Genotype–phenotype correlations within and between both genders are complex and may include various factors such as location and nature of mutations, enzymatic stability and activity, and X-inactivation in females

Mixed and multi-precision SpMV for GPUs with row-wise precision selection

Sparse Matrix-Vector Multiplication (SpMV) is one of the key memory-bound kernels commonly used in industrial and scientific applications. To improve its data movement and benefit from higher compute rates, there are several efforts to utilize mixed precision on SpMV. Most of the prior-art focus on performing the entire SpMV in single-precision within a bigger context of an iterative solver (e.g., CG, GMRES). In this work, we are interested in a more fine-grained mixed-precision SpMV, where the level of precision is decided for each element in the matrix to be used in a single operation. We extend an existing entry-wise precision based approach by deciding precisions per row, motivated by the granularity of parallelism on a GPU where groups of threads process rows in CSR-based matrices. We propose mixed-precision CSR storage methods with row permutations and describe their greater efficiency and load-balancing compared to the existing method. We also consider a multi-precision case where single and double precision copies of the matrix are stored priorly and further extend our mixed-precision SpMV approach to comply with it. As such, we leverage a mixed-precision SpMV to obtain a multi-precision Jacobi method which is faster than yet almost as accurate as double-precision Jacobi implementation, and further evaluate a multi-precision Cardiac modeling algorithm. We demonstrate the effectiveness of the proposed SpMV methods on an extensive dataset of real-valued large sparse matrices from the SuiteSparse Matrix Collection using an NVIDIA V100 GPU

Androphenotypic features in patients with coronary artery disease

Objective: It has been a debate whether phenotypic features are associated with increased risk of coronary heart disease. Proposed explanations for this relation include biological aging, individual susceptibilities, and androgens which contribute to both the atherosclerotic process and dermatological signs. The results of the studies are inconsistent and most are not based on cardiovascular imaging techniques. Here, association between androphenotypic features and the risk and severity of coronary artery disease (CAD) in men is evaluated. Methods: This case-control study consists of 166 male patients with angiography-proven CAD and 160 age-gender-matched controls. Gensini score of angiograms (for severity of CAD) and phenotypic characteristics including androgenetic alopecia (AGA), thoracic hairiness (TH), hair graying a diagonal earlobe crease (DEC), and hairy ear (HE) were recorded. Men with well-established cardiovascular risk factors were excluded. Results: AGA, DEC, and HE were significantly more frequent in patients with CAD than controls (98.2% and 83.1% [P < 0.001], 61.4% and 23.8% [P < 0.001], 69.3% and 50.6% [P = 0.001], respectively). As the severity of AGA increased, the incidence of heart disease was increasing in patients. The presence of TH and AGA was found to be related to higher Gensini scores. Conclusion: The exact mechanism between these phenotypic features and CAD still remains to be elucidated. However, observation of visible aging signs is easy and inexpensive. AGA, HE, and DEC may be used as early screening tools for CAD

Adult Intracranial Ependymal Tumors: Results of TROD Neurooncology Group 07-009 Study

[No Abstract Available

Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling.

BackgroundThe X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative.MethodsWe used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology.ResultsTwelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor β signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocampal-dependent learning and memory.ConclusionsOur data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor β signaling and hippocampal function

Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling

The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative. We used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology. Twelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor β signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocampal-dependent learning and memory. Our data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor β signaling and hippocampal function