A screen for proteins that interact with beta 2-syntrophin led to the isolation of MAST205 (microtubule-associated serine/threonine kinase-205 kD) and a newly identified homologue, SAST ...(syntrophin-associated serine/threonine kinase). Binding studies showed that beta 2-syntrophin and MAST205/SAST associated via a PDZ-PDZ domain interaction. MAST205 colocalized with beta 2-syntrophin and utrophin at neuromuscular junctions. SAST colocalized with syntrophin in cerebral vasculature, spermatic acrosomes and neuronal processes. SAST and syntrophin were highly associated with purified microtubules and microtubule-associated proteins, whereas utrophin and dystrophin were only partially associated with microtubules. Our data suggest that MAST205 and SAST link the dystrophin/utrophin network with microtubule filaments via the syntrophins.
Major depressive disorder is a clinically heterogeneous psychiatric disorder with a polygenic architecture. Genome-wide association studies have identified a number of risk-associated variants across ...the genome and have reported growing evidence of NETRIN1 pathway involvement. Stratifying disease risk by genetic variation within the NETRIN1 pathway may provide important routes for identification of disease mechanisms by focusing on a specific process, excluding heterogeneous risk-associated variation in other pathways. Here, we sought to investigate whether major depressive disorder polygenic risk scores derived from the NETRIN1 signaling pathway (NETRIN1-PRSs) and the whole genome, excluding NETRIN1 pathway genes (genomic-PRSs), were associated with white matter microstructure.
We used two diffusion tensor imaging measures, fractional anisotropy (FA) and mean diffusivity (MD), in the most up-to-date UK Biobank neuroimaging data release (FA: n = 6401; MD: n = 6390).
We found significantly lower FA in the superior longitudinal fasciculus (β = −.035, pcorrected = .029) and significantly higher MD in a global measure of thalamic radiations (β = .029, pcorrected = .021), as well as higher MD in the superior (β = .034, pcorrected = .039) and inferior (β = .029, pcorrected = .043) longitudinal fasciculus and in the anterior (β = .025, pcorrected = .046) and superior (β = .027, pcorrected = .043) thalamic radiation associated with NETRIN1-PRS. Genomic-PRS was also associated with lower FA and higher MD in several tracts.
Our findings indicate that variation in the NETRIN1 signaling pathway may confer risk for major depressive disorder through effects on a number of white matter tracts.
The incidence of heparin-induced thrombocytopenia in human immunodeficiency virus (HIV)–infected inpatients was compared with that in a control group that was not known to be infected with HIV in a ...retrospective cohort study. HIV-infected patients receiving heparin therapy, especially unfractionated heparin therapy, were at increased risk of developing heparin-induced thrombocytopenia, compared with HIV-uninfected patients.
Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while ...here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (
~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.
We developed a computational model to explore the hypothesis that regulatory instructions are context dependent and conveyed through specific ‘codes’ in human genomic DNA. We provide examples of ...correlation of computational predictions to reported mapped DNase I hypersensitive segments in the HOXA locus in human chromosome 7. The examples show that statistically significant 9-mers from promoter regions may occur in sequences near and upstream of transcription initiation sites, in intronic regions, and within intergenic regions. Additionally, a subset of 9-mers from coding sequences appears frequently, as clusters, in regulatory regions dispersed in noncoding regions in genomic DNA. The results suggest that the computational model has the potential of decoding regulatory instructions to discover candidate transcription factor binding sites and to discover candidate epigenetic signals that appear in both coding and regulatory regions of genes.
Abstract Pneumorachis has previously been described only after spread from a contiguous site or after a traumatic event. Our patient experienced sepsis due to multiple enteric organisms, and gas was ...identified within the spinal canal on computed tomographic imaging. We present the 1st case of pneumorachis caused by disseminated infection.
Duchenne muscular dystrophy (DMD) is characterized by progressive muscle degeneration that results from the absence of dystrophin. Despite null mutations in the dystrophin gene, many DMD patients ...display a low percentage of dystrophin-positive fibers. These "revertant fibers" are also present in the dystrophin-deficient mdx mouse and are believed to result from alternative splicing or second mutation events that bypass the mutation and restore an open reading frame. However, it is unclear what role dystrophin and the dystrophic pathology might play in revertant fiber formation and accumulation. We have analyzed the role of dystrophin expression and the dystrophic pathology in this process by monitoring revertant fibers in transgenic mdx mice that express truncated dystrophins. We found that newborn transgenic mice displayed approximately the same number of revertant fibers as newborn mdx mice, indicating that expression of a functional dystrophin does not suppress the initiation of revertant fiber formation. Surprisingly, when the transgene encoded a functional dystrophin, revertant fibers were not detected in adult or old mdx mice. In contrast, adult transgenic mice expressing a non-functional dystrophin accumulated increasing numbers of revertant fibers, similar to mdx mice, suggesting that positive selection is required for the persistence of revertant fibers. Finally, we provide evidence that the loss of revertant dystrophin in transgenic mdx muscle fibers overexpressing a functional dystrophin results from displacement of the revertant protein by the transgene-encoded dystrophin.
Candida krusei is an opportunistic pathogen commonly implicated in urinary tract infections in immunocompromised patients. We present the first case of C. krusei renal cyst infection, occurring in a ...post-liver and kidney transplant patient with autosomal dominant polycystic kidney disease. Her persistent candiduria and fevers were refractory to prolonged therapy with AmBisome (Fujisawa Pharmaceuticals Co. Ltd., Osaka, Japan). She eventually required bilateral nephrectomies of her native kidneys. Cystic fluid was aspirated from six hemorrhagic and six nonhemorrhagic cysts. Cystic fluid cultures yielded C. krusei. Fluid from the nonhemorrhagic cysts was also analyzed for amphotericin B levels, measured using a bioassay. Free amphotericin B levels in the cysts were lower than the minimal inhibitory concentration for amphotericin B for this organism. We provide the first description of amphotericin B levels in cystic fluid obtained during bilateral nephrectomies.
Candida krusei is an opportunistic pathogen commonly implicated in urinary tract infections in immunocompromised patients. We present the first case of C. krusei renal cyst infection, occurring in a ...post-liver and kidney transplant patient with autosomal dominant polycystic kidney disease. Her persistent candiduria and fevers were refractory to prolonged therapy with AmBisome registered (Fujisawa Pharmaceuticals Co. Ltd., Osaka, Japan). She eventually required bilateral nephrectomies of her native kidneys. Cystic fluid was aspirated from six hemorrhagic and six nonhemorrhagic cysts. Cystic fluid cultures yielded C. krusei. Fluid from the nonhemorrhagic cysts was also analyzed for amphotericin B levels, measured using a bioassay. Free amphotericin B levels in the cysts were lower than the minimal inhibitory concentration for amphotericin B for this organism. We provide the first description of amphotericin B levels in cystic fluid obtained during bilateral nephrectomies.
Photon correlation spectroscopy has been used to study capillary waves on black lipid membranes of glycerol monooleate at temperatures above the lipid transition. For the first time the tension and ...viscosity of solvent-free bilayers have been observed to display a frequency dependence. The variations of both parameters can be accounted for by a Maxwell viscoelastic fluid model having a relaxation time of 37 microseconds. The equilibrium (omega = 0) tension is compatible with literature values. The present results do not suffice to precisely define the specific molecular processes involved, but relaxation times similar to the present are associated with certain phenomena in phospholipid vesicles. Bilayers containing hydrocarbon solvent do not show such relaxation, presumably due to their weaker intermolecular interactions.
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