Skeletal muscle has an extraordinary regenerative capacity due to the activity of tissue-specific muscle stem cells. Consequently, these cells have received the most attention in studies ...investigating the cellular processes of skeletal muscle regeneration. However, efficient capacity to rebuild this tissue also depends on additional cells in the local milieu, as disrupting their normal contributions often leads to incomplete regeneration. Here, we review these additional cells that contribute to the regenerative process. Understanding the complex interactions between and among these cell populations has the potential to lead to therapies that will help promote normal skeletal muscle regeneration under conditions in which this process is suboptimal.
Wosczyna and Rando present a Review of the complex cellular milieu surrounding regenerating muscle. They describe the cell types themselves, as well as how they contribute to the regulation of muscle stem cells in the regeneration process.
Persistent and ramping neural activity in the frontal cortex anticipates specific movements
. Preparatory activity is distributed across several brain regions
, but it is unclear which brain areas ...are involved and how this activity is mediated by multi-regional interactions. The cerebellum is thought to be primarily involved in the short-timescale control of movement
; however, roles for this structure in cognitive processes have also been proposed
. In humans, cerebellar damage can cause defects in planning and working memory
. Here we show that persistent representation of information in the frontal cortex during motor planning is dependent on the cerebellum. Mice performed a sensory discrimination task in which they used short-term memory to plan a future directional movement. A transient perturbation in the medial deep cerebellar nucleus (fastigial nucleus) disrupted subsequent correct responses without hampering movement execution. Preparatory activity was observed in both the frontal cortex and the cerebellar nuclei, seconds before the onset of movement. The silencing of frontal cortex activity abolished preparatory activity in the cerebellar nuclei, and fastigial activity was necessary to maintain cortical preparatory activity. Fastigial output selectively targeted the behaviourally relevant part of the frontal cortex through the thalamus, thus closing a cortico-cerebellar loop. Our results support the view that persistent neural dynamics during motor planning is maintained by neural circuits that span multiple brain regions
, and that cerebellar computations extend beyond online motor control
.
Identifying copy number variants (CNVs) can provide diagnoses to patients and provide important biological insights into human health and disease. Current exome and targeted sequencing approaches ...cannot detect clinically and biologically-relevant CNVs outside their target area. We present SavvyCNV, a tool which uses off-target read data from exome and targeted sequencing data to call germline CNVs genome-wide. Up to 70% of sequencing reads from exome and targeted sequencing fall outside the targeted regions. We have developed a new tool, SavvyCNV, to exploit this 'free data' to call CNVs across the genome. We benchmarked SavvyCNV against five state-of-the-art CNV callers using truth sets generated from genome sequencing data and Multiplex Ligation-dependent Probe Amplification assays. SavvyCNV called CNVs with high precision and recall, outperforming the five other tools at calling CNVs genome-wide, using off-target or on-target reads from targeted panel and exome sequencing. We then applied SavvyCNV to clinical samples sequenced using a targeted panel and were able to call previously undetected clinically-relevant CNVs, highlighting the utility of this tool within the diagnostic setting. SavvyCNV outperforms existing tools for calling CNVs from off-target reads. It can call CNVs genome-wide from targeted panel and exome data, increasing the utility and diagnostic yield of these tests. SavvyCNV is freely available at https://github.com/rdemolgen/SavvySuite.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Adult T-cell leukemia (ATL) develops in individuals infected with human T-cell lymphotropic virus-1 (HTLV-1). Presently there is no curative therapy for ATL. HTLV-1–encoded protein Tax ...(transactivator from the X-gene region) up-regulates Bcl-xL (B-cell lymphoma-extra large) expression and activates interleukin-2 (IL-2), IL-9, and IL-15 autocrine/paracrine systems, resulting in amplified JAK/STAT signaling. Inhibition of JAK signaling reduces cytokine-dependent ex vivo proliferation of peripheral blood mononuclear cells (PBMCs) from ATL patients in smoldering/chronic stages. Currently, two JAK inhibitors are approved for human use. In this study, we examined activity of multiple JAK inhibitors in ATL cell lines. The selective JAK inhibitor ruxolitinib was examined in a high-throughput matrix screen combined with >450 potential therapeutic agents, and Bcl-2/Bcl-xL inhibitor navitoclax was identified as a strong candidate for multicomponent therapy. The combination was noted to strongly activate BAX (Bcl-2-associated X protein), effect mitochondrial depolarization, and increase caspase 3/7 activities that lead to cleavage of PARP (poly ADP ribose polymerase) and Mcl-1 (myeloid cell leukemia 1). Ruxolitinib and navitoclax independently demonstrated modest antitumor efficacy, whereas the combination dramatically lowered tumor burden and prolonged survival in an ATL murine model. This combination strongly blocked ex vivo proliferation of five ATL patients’ PBMCs. These studies provide support for a therapeutic trial in patients with smoldering/chronic ATL using a drug combination that inhibits JAK signaling and antiapoptotic protein Bcl-xL.
This article explores the extent to which insights gleaned from detailed studies of molecular photodissociations in the gas phase (i.e. under isolated molecule conditions) can inform our ...understanding of the corresponding photofragmentation processes in solution. Systems selected for comparison include a thiophenol (p-methylthiophenol), a thioanisole (p-methylthioanisole) and phenol, in vacuum and in cyclohexane solution. UV excitation in the gas phase results in RX-Y (X = O, S; Y = H, CH3) bond fission in all cases, but over timescales that vary by ~4 orders of magnitude - all of which behaviours can be rationalised on the basis of the relevant bound and dissociative excited state potential energy surfaces (PESs) accessed by UV photoexcitation, and of the conical intersections that facilitate radiationless transfer between these PESs. Time-resolved UV pump-broadband UV/visible probe and/or UV pump-broadband IR probe studies of the corresponding systems in cyclohexane solution reveal additional processes that are unique to the condensed phase. Thus, for example, the data clearly reveal evidence of (i) vibrational relaxation of the photoexcited molecules prior to their dissociation and of the radical fragments formed upon X-Y bond fission, and (ii) geminate recombination of the RX and Y products (leading to reformation of the ground state parent and/or isomeric adducts). Nonetheless, the data also show that, in each case, the characteristics (and the timescale) of the initial bond fission process that occurs under isolated molecule conditions are barely changed by the presence of a weakly interacting solvent like cyclohexane. These condensed phase studies are then extended to an ether analogue of phenol (allyl phenyl ether), wherein UV photo-induced RO-allyl bond fission constitutes the first step of a photo-Claisen rearrangement.
The necessity of mesenchymal stromal cells, called fibroadipogenic progenitors (FAPs), in skeletal muscle regeneration and maintenance remains unestablished. We report the generation of a PDGFRαCreER ...knockin mouse model that provides a specific means of labeling and targeting FAPs. Depletion of FAPs using Cre-dependent diphtheria toxin expression results in loss of expansion of muscle stem cells (MuSCs) and CD45+ hematopoietic cells after injury and impaired skeletal muscle regeneration. Furthermore, FAP-depleted mice under homeostatic conditions exhibit muscle atrophy and loss of MuSCs, revealing that FAPs are required for the maintenance of both skeletal muscle and the MuSC pool. We also report that local tamoxifen metabolite delivery to target CreER activity in a single muscle, removing potentially confounding systemic effects of ablating PDGFRα+ cells distantly, also causes muscle atrophy. These data establish a critical role of FAPs in skeletal muscle regeneration and maintenance.
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•A method to target or deplete FAPs locally in skeletal muscle is described•Depletion of FAPs results in a regenerative deficit in skeletal muscle•Depletion of FAPs results in skeletal muscle atrophy•MuSC number declines in muscles in which FAPs have been depleted
Wosczyna et al. develop genetic models to target and deplete fibroadipogenic progenitors (FAPs) in skeletal muscle (SkM). Following injury of FAP-depleted SkM, muscle stem cell (MuSC) expansion is impaired, leading to a regenerative deficit. Under homeostatic conditions, FAP-depleted SkM undergoes muscle fiber atrophy, and MuSC numbers decline.
Type 1 diabetes is typically considered a disease of children and young adults. Genetic susceptibility to young-onset type 1 diabetes is well defined and does not predispose to type 2 diabetes. It is ...not known how frequently genetic susceptibility to type 1 diabetes leads to a diagnosis of diabetes after age 30 years. We aimed to investigate the frequency and phenotype of type 1 diabetes resulting from high genetic susceptibility in the first six decades of life.
In this cross-sectional analysis, we used a type 1 diabetes genetic risk score based on 29 common variants to identify individuals of white European descent in UK Biobank in the half of the population with high or low genetic susceptibility to type 1 diabetes. We used Kaplan-Meier analysis to evaluate the number of cases of diabetes in both groups in the first six decades of life. We genetically defined type 1 diabetes as the additional cases of diabetes that occurred in the high genetic susceptibility group compared with the low genetic susceptibility group. All remaining cases were defined as type 2 diabetes. We assessed the clinical characteristics of the groups with genetically defined type 1 or type 2 diabetes.
13 250 (3·5%) of 379 511 white European individuals in UK Biobank had developed diabetes in the first six decades of life. 1286 more cases of diabetes were in the half of the population with high genetic susceptibility to type 1 diabetes than in the half of the population with low genetic susceptibility. These genetically defined cases of type 1 diabetes were distributed across all ages of diagnosis; 537 (42%) were in individuals diagnosed when aged 31–60 years, representing 4% (537/12 233) of all diabetes cases diagnosed after age 30 years. The clinical characteristics of the group diagnosed with type 1 diabetes when aged 31–60 years were similar to the clinical characteristics of the group diagnosed with type 1 diabetes when aged 30 years or younger. For individuals diagnosed with diabetes when aged 31–60 years, the clinical characteristics of type 1 diabetes differed from those of type 2 diabetes: they had a lower BMI (27·4 kg/m2 95% CI 26·7–28·0 vs 32·4 kg/m2 32·2–32·5; p<0·0001), were more likely to use insulin in the first year after diagnosis (89% 476/537 vs 6% 648/11 696; p<0·0001), and were more likely to have diabetic ketoacidosis (11% 61/537 vs 0·3% 30/11 696; p<0·0001).
Genetic susceptibility to type 1 diabetes results in non-obesity-related, insulin-dependent diabetes, which presents throughout the first six decades of life. Our results highlight the difficulty of identifying type 1 diabetes after age 30 years because of the increasing background prevalence of type 2 diabetes. Failure to diagnose late-onset type 1 diabetes can have serious consequences because these patients rapidly develop insulin dependency.
Wellcome Trust and Diabetes UK.
Abstract Objective Malnutrition is known to independently affect patient outcomes. The aim of this study was to investigate the prevalence of patients at risk for malnutrition in an elective surgery ...patient cohort and to analyze the effects of malnutrition on morbidity, mortality, and hospital length of hospital (LOS). Furthermore, we aimed to evaluate the economic effect of a diligent coding of malnutrition, as a side diagnosis, in a simulation of the German Diagnosis-Related Group system. Methods The nutritional status of 1244 patients undergoing elective surgery was standardized on the day of admission by the Nutritional Risk Screening (NRS) 2002. To quantify the influence of malnutrition on revenue, the real DRGs of all patients were grouped. In simulation, an appropriate International Classification of Diseases code was used as a secondary diagnosis for all malnourished patients based on the NRS rating. A multivariate logistic regression analysis and a Cox regression were performed to identify potential confounders and to determine the adjusted effect of nutritional status on the occurrence of complications and hospital LOS. Results The prevalence of patients at risk for malnutrition (NRS ≥3) was 24.1% (300 of 1244). These patients showed a significant increase in hospital LOS (13 versus 7 d). Additionally, postoperative complications were significantly higher in this group (7.23% versus 6.91%). Including malnutrition in the Diagnosis-Related Group coding system resulted in a reimbursement of €1979.67 per patient at risk for malnutrition and a total reimbursement of €79,186.73 for all patients at risk for malnutrition in the present study. Conclusion Establishment of a structured, comprehensive assessment of the nutritional status of hospitalized patients can repetitiously identify patients at risk for malnutrition. Additionally, the diligent codification of malnutrition can lead to cost compensation in the German Diagnosis-Related Group system.
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