Mechanochemical Control of Stem Cell Biology in Development and Disease: Experimental and Theoretical Models

Whether a stem cell remains or egresses away from its physiological niche is a function of mechanical and soluble factors in a time-dependent manner, which implicates a `memory\u27 of prior mechanochemical conditioning. Virtually every organ in the body contains resident stem or progenitor cells that contribute to organ homeostasis or repair. The wound healing process in higher vertebrate animals is spatiotemporally complex and usually leads to scarring. Limitations for the use of stem cells as regenerative therapy include the lack of expansion capabilities in vitro as well as materials issues that complicate traditional biochemical protocols. A minimal `scar in a dish\u27 model is developed to clarify the kinetics of tension-sensitive proteins in mesenchymal stem cells (MSCs), which possess plasticity to mechanochemical changes of the microenvironment that are typical of scars. The organization and expression of such proteins implicates transcription factors that ultimately steer cell fate. In contrast to classic mechano-transducers of matrix mechanics such as actin assembly-dependent serum response factor (SRF) signaling, a novel mechano-repressive role of NKX2.5 is implicated in maintaining intracellular tension in long-term stem cell cultures on stiff matrices via nucleo-cytoplasmic shuttling — ultimately setting up a \u27mechanical memory\u27. Core gene circuits with known roles in stem cell mechanobiology are modeled based on the \u27use it or lose it\u27 concept: tension inhibits turnover of structural proteins such as extracellular collagens, cytoskeletal myosins and nucleoskeletal lamins. This theoretical approach is tested in a variety of processes in vitro and in vivo that involve forces including cardiac development, osteogenic commitment of MSCs, and fibrosis therapy. With the sophistication of the science and technology of biomaterials relevant to stem cell biology and medicine, matrix mechanics can thus be rigorously combined with biochemical instructions in order to maximize therapeutic utility of stem cells

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Management of mild traumatic brain injury

Mild traumatic brain injury (TBI) is common and associated with a range of diffuse, non-specific symptoms including headache, nausea, dizziness, fatigue, hypersomnolence, attentional difficulties, photosensitivity and phonosensitivity, irritability and depersonalisation. Although these symptoms usually resolve within 3 months, 5%-15% of patients are left with chronic symptoms. We argue that simply labelling such symptoms as ' postconcussional' is of little benefit to patients. Instead, we suggest that detailed assessment, including investigation, both of the severity of the ' mild' injury and of the individual symptom syndromes, should be used to tailor a rehabilitative approach to symptoms. To complement such an approach, we have developed a self-help website for patients with mild TBI, based on neurorehabilitative and cognitive behavioural therapy principles, offering information, tips and tools to guide recovery: www.headinjurysymptoms.org.</p

How to implement live video recording in the clinical environment: A practical guide for clinical services

Background: The use of video in healthcare is becoming more common, particularly in simulation and educational settings. However, video recording live episodes of clinical care is far less routine. Aim To provide a practical guide for clinical services to embed live video recording.Materials and Methods: Using Kotter's 8-step process for leading change, we provide a ?how to? guide to navigate the challenges required to implement a continuous video-audit system based on our experience of video recording in our emergency department resuscitation rooms.Results: The most significant hurdles in installing continuous video audit in a busy clinical area involve change management rather than equipment. Clinicians are faced with considerable ethical, legal and data protection challenges which are the primary barriers for services that pursue video recording of patient care.Discussion: Existing accounts of video use rarely acknowledge the organisational and cultural dimensions that are key to the success of establishing a video system. This article outlines core implementation issues that need to be addressed if video is to become part of routine care delivery.Conclusion: By focussing on issues such as staff acceptability, departmental culture and organisational readiness, we provide a roadmap that can be pragmatically adapted by all clinical environments, locally and internationally, that seek to utilise video recording as an approach to improving clinical care

The first joint observation by KAGRA with GEO 600

KAGRA conducted its first joint observation with GEO 600 for two weeks in April, 2020. We performed two types of all-sky searches and two searches dedicated to gravitational wave signals associated with gamma-ray burst events observed during the run. We did not detect any gravitational wave signals, which was expected given the sensitivity of both detectors at that time. However, we did confirm that several search pipelines used in the LIGO-Virgo-KAGRA collaborations worked effectively on the KAGRA data. In this proceeding, we will summarize the data quality of detectors and the search results. The contents and figures are based on [1]

GWTC-2: Compact Binary Coalescences Observed by LIGO and Virgo during the First Half of the Third Observing Run

We report on gravitational-wave discoveries from compact binary coalescences detected by Advanced LIGO and Advanced Virgo in the first half of the third observing run (O3a) between 1 April 2019 15∶00 UTC and 1 October 2019 15∶00 UTC. By imposing a false-alarm-rate threshold of two per year in each of the four search pipelines that constitute our search, we present 39 candidate gravitational-wave events. At this threshold, we expect a contamination fraction of less than 10%. Of these, 26 candidate events were reported previously in near-real time through gamma-ray coordinates network notices and circulars; 13 are reported here for the first time. The catalog contains events whose sources are black hole binary mergers up to a redshift of approximately 0.8, as well as events whose components cannot be unambiguously identified as black holes or neutron stars. For the latter group, we are unable to determine the nature based on estimates of the component masses and spins from gravitational-wave data alone. The range of candidate event masses which are unambiguously identified as binary black holes (both objects ≥ 3 M⊙) is increased compared to GWTC-1, with total masses from approximately 14 M⊙ for GW190924_021846 to approximately 150 M⊙ for GW190521. For the first time, this catalog includes binary systems with significantly asymmetric mass ratios, which had not been observed in data taken before April 2019. We also find that 11 of the 39 events detected since April 2019 have positive effective inspiral spins under our default prior (at 90% credibility), while none exhibit negative effective inspiral spin. Given the increased sensitivity of Advanced LIGO and Advanced Virgo, the detection of 39 candidate events in approximately 26 weeks of data (approximately 1.5 per week) is consistent with GWTC-1