The ability to maintain quiescence is critical for the long-term maintenance of a functional stem cell pool. To date, the epigenetic and transcriptional characteristics of quiescent stem cells and ...how they change with age remain largely unknown. In this study, we explore the chromatin features of adult skeletal muscle stem cells, or satellite cells (SCs), which reside predominantly in a quiescent state in fully developed limb muscles of both young and aged mice. Using a ChIP-seq approach to obtain global epigenetic profiles of quiescent SCs (QSCs), we show that QSCs possess a permissive chromatin state in which few genes are epigenetically repressed by Polycomb group (PcG)-mediated histone 3 lysine 27 trimethylation (H3K27me3), and a large number of genes encoding regulators that specify nonmyogenic lineages are demarcated by bivalent domains at their transcription start sites (TSSs). By comparing epigenetic profiles of QSCs from young and old mice, we also provide direct evidence that, with age, epigenetic changes accumulate and may lead to a functional decline in quiescent stem cells. These findings highlight the importance of chromatin mapping in understanding unique features of stem cell identity and stem cell aging.
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•Chromatin modification pattern on myogenic regulatory factor genes in QSCs•Chromatin modification pattern on myogenic regulatory factor genes in QSCs•Increase in H3K27me3 across the genome in adult QSCs with age•Decrease of histone expression in adult QSCs with age
The comprehensive transcriptional and chromatin modification profile of an adult quiescent stem cell population, skeletal muscle satellite cells, is now examined by Rando and colleagues. The authors characterize changes associated with satellite cell activation and aging, providing direct evidence for global changes in histone modifications in adult stem cells with age.
The role of multiple antennas for secure communication is investigated within the framework of Wyner's wiretap channel. We characterize the secrecy capacity in terms of generalized eigenvalues when ...the sender and eavesdropper have multiple antennas, the intended receiver has a single antenna, and the channel matrices are fixed and known to all the terminals, and show that a beamforming strategy is capacity-achieving. In addition, we study a masked beamforming scheme that radiates power isotropically in all directions and show that it attains near-optimal performance in the high SNR regime. Insights into the scaling behavior of the capacity in the large antenna regime as well as extensions to ergodic fading channels are also provided.
Components of neural circuits are often repurposed so that the same biological hardware can be used for distinct computations. This flexibility in circuit operation is required to account for the ...changes in sensory computations that accompany changes in input signals. Yet we know little about how such changes in circuit operation are implemented. Here we show that a single retinal ganglion cell performs a different computation in dim light—averaging contrast within its receptive field—than in brighter light, when the cell becomes sensitive to fine spatial detail. This computational change depends on interactions between two parallel circuits that control the ganglion cell’s excitatory synaptic inputs. Specifically, steady-state interactions through dendro-axonal gap junctions control rectification of the synapses providing excitatory input to the ganglion cell. These findings provide a clear example of how a simple synaptic mechanism can repurpose a neural circuit to perform diverse computations.
•Repurposing of retinal circuits provides luminance-dependent computation•Dendro-axonal gap junctions control rectification of cone bipolar synapse•Spatial integration by retinal ganglion cells changes with luminance•Interactions between parallel circuits control spatial integration
Interactions between parallel circuits controlling the responses of On alpha retinal ganglion cells cause spatial integration to shift from linear to nonlinear with increasing luminance. Grimes et al. show that this shift causes a fundamental change in ganglion cell sensitivity to fine spatial information.
Background
Management algorithms for adult severe traumatic brain injury (sTBI) were omitted in later editions of the Brain Trauma Foundation’s sTBI Management Guidelines, as they were not ...evidence-based.
Methods
We used a Delphi-method-based consensus approach to address management of sTBI patients undergoing intracranial pressure (ICP) monitoring. Forty-two experienced, clinically active sTBI specialists from six continents comprised the panel. Eight surveys iterated queries and comments. An in-person meeting included whole- and small-group discussions and blinded voting. Consensus required 80% agreement. We developed heatmaps based on a traffic-light model where panelists’ decision tendencies were the focus of recommendations.
Results
We provide comprehensive algorithms for ICP-monitor-based adult sTBI management. Consensus established 18 interventions as fundamental and ten treatments not to be used. We provide a three-tier algorithm for treating elevated ICP. Treatments within a tier are considered empirically equivalent. Higher tiers involve higher risk therapies. Tiers 1, 2, and 3 include 10, 4, and 3 interventions, respectively. We include inter-tier considerations, and recommendations for critical neuroworsening to assist the recognition and treatment of declining patients. Novel elements include guidance for autoregulation-based ICP treatment based on MAP Challenge results, and two heatmaps to guide (1) ICP-monitor removal and (2) consideration of sedation holidays for neurological examination.
Conclusions
Our modern and comprehensive sTBI-management protocol is designed to assist clinicians managing sTBI patients monitored with ICP-monitors alone. Consensus-based (class III evidence), it provides management recommendations based on combined expert opinion. It reflects neither a standard-of-care nor a substitute for thoughtful individualized management.
Prognostics and health management (PHM) technologies reduce time and costs for maintenance of products or processes through efficient and cost-effective diagnostic and prognostic activities. PHM ...systems use real-time and historical state information of subsystems and components to provide actionable information, enabling intelligent decision-making for improved performance, safety, reliability, and maintainability. However, PHM is still an emerging field, and much of the published work has been either too exploratory or too limited in scope. Future smart manufacturing systems will require PHM capabilities that overcome current challenges, while meeting future needs based on best practices, for implementation of diagnostics and prognostics. This paper reviews the challenges, needs, methods, and best practices for PHM within manufacturing systems. This includes PHM system development of numerous areas highlighted by diagnostics, prognostics, dependability analysis, data management, and business. Based on current capabilities, PHM systems are shown to benefit from open-system architectures, cost-benefit analyses, method verification and validation, and standards.
Commensal bacteria impact host health and immunity through various mechanisms, including the production of immunomodulatory molecules. Bacteroides fragilis produces a capsular polysaccharide (PSA), ...which induces regulatory T cells and mucosal tolerance. However, unlike pathogens, which employ secretion systems, the mechanisms by which commensal bacteria deliver molecules to the host remain unknown. We reveal that Bacteroides fragilis releases PSA in outer membrane vesicles (OMVs) that induce immunomodulatory effects and prevent experimental colitis. Dendritic cells (DCs) sense OMV-associated PSA through TLR2, resulting in enhanced regulatory T cells and anti-inflammatory cytokine production. OMV-induced signaling in DCs requires growth arrest and DNA-damage-inducible protein (Gadd45α). DCs treated with PSA-containing OMVs prevent experimental colitis, whereas Gadd45α−/− DCs are unable to promote regulatory T cell responses or suppress proinflammatory cytokine production and host pathology. These findings demonstrate that OMV-mediated delivery of a commensal molecule prevents disease, uncovering a mechanism of interkingdom communication between the microbiota and mammals.
► Bacteroides fragilis packages PSA into outer membrane vesicles ► OMV-mediated delivery of PSA to dendritic cells promotes regulatory T cells ► Toll-like receptor 2 on DCs is required to sense OMV-associated PSA ► Gadd45α expression in DCs is required for PSA-containing OMV activity
Background
Acute treatment of cerebral edema and elevated intracranial pressure is a common issue in patients with neurological injury. Practical recommendations regarding selection and monitoring of ...therapies for initial management of cerebral edema for optimal efficacy and safety are generally lacking. This guideline evaluates the role of hyperosmolar agents (mannitol, HTS), corticosteroids, and selected non-pharmacologic therapies in the acute treatment of cerebral edema. Clinicians must be able to select appropriate therapies for initial cerebral edema management based on available evidence while balancing efficacy and safety.
Methods
The Neurocritical Care Society recruited experts in neurocritical care, nursing, and pharmacy to create a panel in 2017. The group generated 16 clinical questions related to initial management of cerebral edema in various neurological insults using the PICO format. A research librarian executed a comprehensive literature search through July 2018. The panel screened the identified articles for inclusion related to each specific PICO question and abstracted necessary information for pertinent publications. The panel used GRADE methodology to categorize the quality of evidence as high, moderate, low, or very low based on their confidence that the findings of each publication approximate the true effect of the therapy.
Results
The panel generated recommendations regarding initial management of cerebral edema in neurocritical care patients with subarachnoid hemorrhage, traumatic brain injury, acute ischemic stroke, intracerebral hemorrhage, bacterial meningitis, and hepatic encephalopathy.
Conclusion
The available evidence suggests hyperosmolar therapy may be helpful in reducing ICP elevations or cerebral edema in patients with SAH, TBI, AIS, ICH, and HE, although neurological outcomes do not appear to be affected. Corticosteroids appear to be helpful in reducing cerebral edema in patients with bacterial meningitis, but not ICH. Differences in therapeutic response and safety may exist between HTS and mannitol. The use of these agents in these critical clinical situations merits close monitoring for adverse effects. There is a dire need for high-quality research to better inform clinicians of the best options for individualized care of patients with cerebral edema.
Novel approaches toward understanding the evolution of disease can lead to the discovery of biomarkers that will enable better management of disease progression and improve prognostic evaluation. ...Raman spectroscopy is a promising investigative and diagnostic tool that can assist in uncovering the molecular basis of disease and provide objective, quantifiable molecular information for diagnosis and treatment evaluation. This technique probes molecular vibrations/rotations associated with chemical bonds in a sample to obtain information on molecular structure, composition, and intermolecular interactions. Raman scattering occurs when light interacts with a molecular vibration/rotation and a change in polarizability takes place during molecular motion. This results in light being scattered at an optical frequency shifted (up or down) from the incident light. By monitoring the intensity profile of the inelastically scattered light as a function of frequency, the unique spectroscopic fingerprint of a tissue sample is obtained. Since each sample has a unique composition, the spectroscopic profile arising from Raman-active functional groups of nucleic acids, proteins, lipids, and carbohydrates allows for the evaluation, characterization, and discrimination of tissue type. This review provides an overview of the theory of Raman spectroscopy, instrumentation used for measurement, and variation of Raman spectroscopic techniques for clinical applications in cancer, including detection of brain, ovarian, breast, prostate, and pancreatic cancers and circulating tumor cells.
The distributions of neurons in sensory circuits display ordered spatial patterns arranged to enhance or encode specific regions or features of the external environment. Indeed, visual space is not ...sampled uniformly across the vertebrate retina. Retinal ganglion cell (RGC) density increases and dendritic arbor size decreases toward retinal locations with higher sampling frequency, such as the fovea in primates and area centralis in carnivores 1. In these locations, higher acuity at the level of individual cells is obtained because the receptive field center of a RGC corresponds approximately to the spatial extent of its dendritic arbor 2, 3. For most species, structurally and functionally distinct RGC types appear to have similar topographies, collectively scaling their cell densities and arbor sizes toward the same retinal location 4. Thus, visual space is represented across the retina in parallel by multiple distinct circuits 5. In contrast, we find a population of mouse RGCs, known as alpha or alpha-like 6, that displays a nasal-to-temporal gradient in cell density, size, and receptive fields, which facilitates enhanced visual sampling in frontal visual fields. The distribution of alpha-like RGCs contrasts with other known mouse RGC types and suggests that, unlike most mammals, RGC topographies in mice are arranged to sample space differentially.
•A functionally distinct RGC type has a density and size gradient across the retina•Gradient allows for enhanced sampling of frontal visual space•Peak density in temporal retina contrasts with distributions of known RGC types•Diverse topographies of RGC types suggest visual space is sampled differentially
Bleckert et al. demonstrate a nasal-temporal gradient in density and size of a ganglion cell (GC) type across the mouse retina, promoting enhanced sampling of frontal visual space. This gradient contrasts with other mouse GC topographies, suggesting that visual space is sampled differentially by diverse GC types in this species.
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