Interstitial Cell Remodeling Promotes Aberrant Adipogenesis in Dystrophic Muscles.

Fibrosis and fat replacement in skeletal muscle are major complications that lead to a loss of mobility in chronic muscle disorders, such as muscular dystrophy. However, the in vivo properties of adipogenic stem and precursor cells remain unclear, mainly due to the high cell heterogeneity in skeletal muscles. Here, we use single-cell RNA sequencing to decomplexify interstitial cell populations in healthy and dystrophic skeletal muscles. We identify an interstitial CD142-positive cell population in mice and humans that is responsible for the inhibition of adipogenesis through GDF10 secretion. Furthermore, we show that the interstitial cell composition is completely altered in muscular dystrophy, with a near absence of CD142-positive cells. The identification of these adipo-regulatory cells in the skeletal muscle aids our understanding of the aberrant fat deposition in muscular dystrophy, paving the way for treatments that could counteract degeneration in patients with muscular dystrophy

A simplified microwave-based motion detector for home cage activity monitoring in mice

Background: Locomotor activity of rodents is an important readout to assess well-being and physical health, and is pivotal for behavioral phenotyping. Measuring homecage-activity with standard and cost-effective optical methods in mice has become difficult, as modern housing conditions (e.g. individually ventilated cages, cage enrichment) do not allow constant, unobstructed, visual access. Resolving this issue either makes greater investments necessary, especially if several experiments will be run in parallel, or is at the animals' expense. The purpose of this study is to provide an easy, yet satisfying solution for the behavioral biologist at novice makers level. Results: We show the design, construction and validation of a simplified, low-cost, radar-based motion detector for home cage activity monitoring in mice. In addition we demonstrate that mice which have been selectively bred for low levels of anxiety-related behavior (LAB) have deficits in circadian photoentrainment compared to CD1 control animals. Conclusion: In this study we have demonstrated that our proposed low-cost microwave-based motion detector is well-suited for the study of circadian rhythms in mice

Model-based prediction of portal dose images during patient treatment

Purpose: Dosimetric verification of radiation therapy is crucial when delivering complex treatments like intensity modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT. Pretreatment verification, characterized by methods applied without the patient present and before the treatment start date, is typically carried out at most centers.In vivo dosimetric verification, characterized by methods applied with the patient present, is not commonly carried out in the clinic. This work presents a novel, model-based EPID dosimetry method that could be used for routine clinical in vivo patient treatment verification. Methods: The authors integrated a detailed fluence model with a patient scatter prediction model that uses a superposition of scatter energy fluence kernels, generated via Monte Carlo techniques, to determine patient scatter fluence delivered to the EPID. The total dose to the EPID was calculated using the sum of convolutions of the calculated energy fluence distribution entering the EPID with monoenergetic dose kernels, specific to the a-Si EPID. Measured images with simple, square fields delivered to slab phantoms were validated against predicted images. Measured and predicted images acquired during the delivery of IMRT fields to slabs and an anthropomorphic phantom were compared using theχ-comparison for 3% dose difference and 3 mm distance-to-agreement criteria. Results: Predicted and measured images of the square fields with slabs in the field agreed within 2.5%. Predicted portal dose images of clinical IMRT fields delivered to slabs and an anthropomorphic phantom agreed with measured images within 3% and 3 mm for an average of at least 97% of the infield pixels (defined as >10% maximum field dose) for each case, over all fields. Conclusions: This work presents the first validation of the integration of a comprehensive fluence model with a patient and EPID radiation transport model that accounts for patient transmission, including complex factors such as patient scatter and the energy response of the a-Si detector. The portal dose image prediction model satisfies the 3% and 3 mm criteria for IMRT fields delivered to slab phantoms and could be used for patient treatment verification

Tau promotes oxidative stress-associated cycling neurons in S phase as a pro-survival mechanism: possible implication for Alzheimer's disease.

Multiple lines of evidence have linked oxidative stress, tau pathology and neuronal cell cycle re-activation to Alzheimer's disease (AD). While a prevailing idea is that oxidative stress-induced neuronal cell cycle reactivation acts as an upstream trigger for pathological tau phosphorylation, others have identified tau as an inducer of cell cycle abnormalities in both mitotic and postmitotic conditions. In addition, nuclear hypophosphorylated tau has been identified as a key player in the DNA damage response to oxidative stress. Whether and to what extent these observations are causally linked remains unclear. Using immunofluorescence, fluorescence-activated nucleus sorting and single-nucleus sequencing, we report an oxidative stress-associated accumulation of nuclear hypophosphorylated tau in a subpopulation of cycling neurons confined in S phase in AD brains, near amyloid plaques. Tau downregulation in murine neurons revealed an essential role for tau to promote cell cycle progression to S phase and prevent apoptosis in response to oxidative stress. Our results suggest that tau holds oxidative stress-associated cycling neurons in S phase to escape cell death. Together, this study proposes a tau-dependent protective effect of neuronal cell cycle reactivation in AD brains and challenges the current view that the neuronal cell cycle is an early mediator of tau pathology

Common clonal origin of conventional T cells and induced regulatory T cells in breast cancer patients

Regulatory CD4+ T cells (Treg) prevent tumor clearance by conventional T cells (Tconv) comprising a major obstacle of cancer immune-surveillance. Hitherto, the mechanisms of Treg repertoire formation in human cancers remain largely unclear. Here, we analyze Treg clonal origin in breast cancer patients using T-Cell Receptor and single-cell transcriptome sequencing. While Treg in peripheral blood and breast tumors are clonally distinct, Tconv clones, including tumor-antigen reactive effectors (Teff), are detected in both compartments. Tumor-infiltrating CD4+ cells accumulate into distinct transcriptome clusters, including early activated Tconv, uncommitted Teff, Th1 Teff, suppressive Treg and pro-tumorigenic Treg. Trajectory analysis suggests early activated Tconv differentiation either into Th1 Teff or into suppressive and pro-tumorigenic Treg. Importantly, Tconv, activated Tconv and Treg share highly-expanded clones contributing up to 65% of intratumoral Treg. Here we show that Treg in human breast cancer may considerably stem from antigen-experienced Tconv converting into secondary induced Treg through intratumoral activation