Duchenne muscular dystrophy (DMD) is the most common single-gene lethal disorder. Substantial patient-patient variability in disease onset and progression and response to glucocorticoids is seen, ...suggesting genetic or environmental modifiers.
Two DMD cohorts were used as test and validation groups to define genetic modifiers: a Padova longitudinal cohort (n = 106) and the Cooperative International Neuromuscular Research Group (CINRG) cross-sectional natural history cohort (n = 156). Single nucleotide polymorphisms to be genotyped were selected from mRNA profiling in patients with severe vs mild DMD, and genome-wide association studies in metabolism and polymorphisms influencing muscle phenotypes in normal volunteers were studied.
Effects on both disease progression and response to glucocorticoids were observed with polymorphism rs28357094 in the gene promoter of SPP1 (osteopontin). The G allele (dominant model; 35% of subjects) was associated with more rapid progression (Padova cohort log rank p = 0.003), and 12%-19% less grip strength (CINRG cohort p = 0.0003).
Osteopontin genotype is a genetic modifier of disease severity in Duchenne dystrophy. Inclusion of genotype data as a covariate or in inclusion criteria in DMD clinical trials would reduce intersubject variance, and increase sensitivity of the trials, particularly in older subjects.
The molecular mechanisms underlying the sex differences in human muscle morphology and function remain to be elucidated. The sex differences in the skeletal muscle transcriptome in both the resting ...state and following anabolic stimuli, such as resistance exercise (RE), might provide insight to the contributors of sexual dimorphism of muscle phenotypes. We used microarrays to profile the transcriptome of the biceps brachii of young men and women who underwent an acute unilateral RE session following 12 weeks of progressive training. Bilateral muscle biopsies were obtained either at an early (4 h post-exercise) or late recovery (24 h post-exercise) time point. Muscle transcription profiles were compared in the resting state between men (n = 6) and women (n = 8), and in response to acute RE in trained exercised vs. untrained non-exercised control muscle for each sex and time point separately (4 h post-exercise, n = 3 males, n = 4 females; 24 h post-exercise, n = 3 males, n = 4 females). A logistic regression-based method (LRpath), following Bayesian moderated t-statistic (IMBT), was used to test gene functional groups and biological pathways enriched with differentially expressed genes.
This investigation identified extensive sex differences present in the muscle transcriptome at baseline and following acute RE. In the resting state, female muscle had a greater transcript abundance of genes involved in fatty acid oxidation and gene transcription/translation processes. After strenuous RE at the same relative intensity, the time course of the transcriptional modulation was sex-dependent. Males experienced prolonged changes while females exhibited a rapid restoration. Most of the biological processes involved in the RE-induced transcriptional regulation were observed in both males and females, but sex specificity was suggested for several signaling pathways including activation of notch signaling and TGF-beta signaling in females. Sex differences in skeletal muscle transcriptional regulation might implicate a mechanism behind disproportional muscle growth in males as compared with female counterparts after RE training at the same relative intensity.
Sex differences exist in skeletal muscle gene transcription both at rest and following acute RE, suggesting that sex is a significant modifier of the transcriptional regulation in skeletal muscle. The findings from the present study provide insight into the molecular mechanisms for sex differences in muscle phenotypes and for muscle transcriptional regulation associated with training adaptations to resistance exercise.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary A systematic search and quality assessment of published literature was conducted to establish current knowledge on the role of healthcare workers uniforms’ as vehicles for the transfer of ...healthcare-associated infections. This review comprised a systematic search of national and international guidance, published literature and data on recent advances in laundry technology and processes. We found only a small number of relevant studies that provided limited evidence directly related to the decontamination of uniforms. Studies concerning domestic laundry processes are small scale and largely observational. Current practice and guidance for laundering uniforms is extrapolated from studies of industrial hospital linen processing. Healthcare workers' uniforms, including white coats, become progressively contaminated in use with bacteria of low pathogenicity from the wearer and of mixed pathogenicity from the clinical environment and patients. The hypothesis that uniforms/clothing could be a vehicle for the transmission of infections is not supported by existing evidence. All components of the laundering process contribute to the removal or killing of micro-organisms on fabric. There is no robust evidence of a difference in efficacy of decontamination of uniforms/clothing between industrial and domestic laundry processes, or that the home laundering of uniforms provides inadequate decontamination.
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.
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•miRNAs in muscle microenvironments cause variable dystrophin in muscular dystrophy•miRNAs are elevated in dystrophic myofibers and increase with disease severity•Inflammatory cytokines induce miRNAs, and anti-inflammatories block their expression•miRNAs provide a precision medicine target in dystrophy and exon skipping
Fiorillo et al. find that miRNAs in muscle promote variable dystrophin levels in muscular dystrophies. Dystrophin-targeting miRNAs reduce dystrophin and increase with disease severity. Innate inflammatory pathways induce miRNAs, whereas NFκB inhibition dampens induction. These events initiate a self-sustaining feedback loop, exacerbating disease progression. Thus, miRNA inhibition in dystrophic muscle could provide therapeutic targets.
In 1887, Canada was in a fervour over so-called “combines,” a term used to cover price-fixing schemes, pool agreements, trusts, and other cartel arrangements. The public debate led to the passage in ...1889 of the Anti-Combines Act, the world’s first modern competition statute, enacted a year prior to the United States’ Sherman Antitrust Act. But while Canada acted before its neighbour to the south, the United States was omnipresent in the Canadian debates in four ways: as a benchmark against which the Canadian economy and the combines problem should be judged; as a model for potential legal action; as a potential economic liberator; and as the very source and propagator of the combines problem. Canadians thus alternately presented the United States as saviour or devil, as paragon or antithesis. The result was a paradox of a sort: Canadians borrowed American ideas in order to avoid becoming American.
Mechanical deflection of the sensory hair bundles of receptor cells in the inner ear causes ion channels located at the tips of the bundle to open, thereby initiating the perception of sound. ...Although some protein constituents of the transduction apparatus are known, the mechanically gated transduction channels have not been identified in higher vertebrates. Here, we investigate TRP (transient receptor potential) ion channels as candidates and find one, TRPA1 (also known as ANKTM1), that meets criteria for the transduction channel. The appearance of TRPA1 messenger RNA expression in hair cell epithelia coincides developmentally with the onset of mechanosensitivity. Antibodies to TRPA1 label hair bundles, especially at their tips, and tip labelling disappears when the transduction apparatus is chemically disrupted. Inhibition of TRPA1 protein expression in zebrafish and mouse inner ears inhibits receptor cell function, as assessed with electrical recording and with accumulation of a channel-permeant fluorescent dye. TRPA1 is probably a component of the transduction channel itself.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Organ formation and regeneration require epithelial progenitor expansion to engineer, maintain, and repair the branched tissue architecture. Identifying the mechanisms that control progenitor ...expansion will inform therapeutic organ (re)generation. Here, we discover that combined KIT and fibroblast growth factor receptor 2b (FGFR2b) signaling specifically increases distal progenitor expansion during salivary gland organogenesis. FGFR2b signaling upregulates the epithelial KIT pathway so that combined KIT/FGFR2b signaling, via separate AKT and mitogen-activated protein kinase (MAPK) pathways, amplifies FGFR2b-dependent transcription. Combined KIT/FGFR2b signaling selectively expands the number of KIT+K14+SOX10+ distal progenitors, and a genetic loss of KIT signaling depletes the distal progenitors but also unexpectedly depletes the K5+ proximal progenitors. This occurs because the distal progenitors produce neurotrophic factors that support gland innervation, which maintains the proximal progenitors. Furthermore, a rare population of KIT+FGFR2b+ cells is present in adult glands, in which KIT signaling also regulates epithelial-neuronal communication during homeostasis. Our findings provide a framework to direct regeneration of branched epithelial organs.
•Combined KIT and FGFR2b signaling amplifies FGFR2b-dependent transcription•KIT/FGFR2b signaling during organogenesis expands distal KIT+ epithelial progenitors•Distal progenitors communicate with proximal progenitors via the neuronal niche•KIT+ progenitors maintain epithelial-neuronal communication during adult homeostasis
Hoffman and colleagues demonstrate that combined KIT and fibroblast growth factor receptor 2b (FGFR2b) signaling expands the distal KIT+FGFR2b+ progenitor population in branching organs. This is important for continued branching morphogenesis because the KIT+FGFR2b+ progenitors produce neurotrophic factors to communicate with the neuronal niche to direct the ductal differentiation of proximal Keratin 5+ progenitors.
The objectives of this study were to determine how feeding diets that differed in dietary neutral detergent fiber (NDF) concentration and in vitro NDF digestibility affects dry matter (DM) intake, ...ruminal fermentation, and milk production in early lactation dairy cows. Twelve rumen-cannulated, multiparous Holstein cows averaging 38±15 d (±standard deviation) in milk, and producing 40±9kg of milk daily, were used in a replicated 4×4 Latin square design with 28-d periods. Treatment diets were arranged in a 2×2 factorial with 28 or 32% dietary NDF (DM basis) and 2 levels of straw NDF digestibility: 1) LD, untreated wheat straw (77% NDF, 41% NDF digestibility) or 2) HD, anhydrous NH3-treated wheat straw (76% NDF, 62% NDF digestibility). All 4 diets consisted of wheat straw, alfalfa silage, corn silage, and a concentrate mix of cracked corn grain, corn gluten meal, 48% soybean meal, and vitamins and minerals. Wheat straw comprised 8.5% DM of the 28% NDF diets and 16% DM of the 32% NDF diets. Cows fed 28% NDF and HD diets produced more milk, fat, and protein than those consuming 32% NDF or LD diets. Dry matter intake was greater for cows consuming 28% NDF diets, but intakes of DM and total NDF were not affected by in vitro NDF digestibility. Intake of digestible NDF was greater for cows consuming HD diets. Ruminal fermentation was not affected by feeding diets that differed in NDF digestibility. Ruminal NDF passage rate was slower for cows fed HD than LD. No interactions of dietary NDF concentration and in vitro NDF digestibility were observed for any parameter measured. Regardless of dietary NDF concentration, increased in vitro NDF digestibility improved intake and production in early lactation dairy cows.
Understanding the dynamic transcriptional landscape throughout organ development will provide a template for regenerative therapies. Here, we generated a single-cell RNA sequencing atlas of murine ...submandibular glands identifying transcriptional profiles that revealed cellular heterogeneity during landmark developmental events: end bud formation, branching morphogenesis, cytodifferentiation, maturation, and homeostasis. Trajectory inference analysis suggests plasticity among acinar and duct populations. We identify transcription factors correlated with acinar differentiation including Spdef, Etv1, and Xbp1, and loss of Ybx1, Eno1, Sox11, and Atf4. Furthermore, we characterize two intercalated duct populations defined by either Gfra3 and Kit, or Gstt1. This atlas can be used to investigate specific cell functions and comparative studies predicting common mechanisms involved in development of branching organs.
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•Generated scRNAseq atlas of E12, E14, E16, P1, P30, and adult SMG•Smgc and Bpifa2 define two proacinar populations in the developing SMG•Loss of Ybx1, Eno1, Sox11, and Atf4 associated with acinar phenotype•Gstt1 defines Kit-negative and sexually dimorphic intercalated duct cells
Biological Sciences; Developmental Biology; Systems Biology; Transcriptomics
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