184 research outputs found

    Single-cell analysis reveals regional reprogramming during adaptation to massive small bowel resection in mice

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    BACKGROUND & AIMS: The small intestine (SI) displays regionality in nutrient and immunological function. Following SI tissue loss (as occurs in short gut syndrome, or SGS), remaining SI must compensate, or adapt ; the capacity of SI epithelium to reprogram its regional identity has not been described. Here, we apply single-cell resolution analyses to characterize molecular changes underpinning adaptation to SGS. METHODS: Single-cell RNA sequencing was performed on epithelial cells isolated from distal SI of mice following 50% proximal small bowel resection (SBR) vs sham surgery. Single-cell profiles were clustered based on transcriptional similarity, reconstructing differentiation events from intestinal stem cells (ISCs) through to mature enterocytes. An unsupervised computational approach to score cell identity was used to quantify changes in regional (proximal vs distal) SI identity, validated using immunofluorescence, immunohistochemistry, qPCR, western blotting, and RNA-FISH. RESULTS: Uniform Manifold Approximation and Projection-based clustering and visualization revealed differentiation trajectories from ISCs to mature enterocytes in sham and SBR. Cell identity scoring demonstrated segregation of enterocytes by regional SI identity: SBR enterocytes assumed more mature proximal identities. This was associated with significant upregulation of lipid metabolism and oxidative stress gene expression, which was validated via orthogonal analyses. Observed upstream transcriptional changes suggest retinoid metabolism and proximal transcription factor Creb3l3 drive proximalization of cell identity in response to SBR. CONCLUSIONS: Adaptation to proximal SBR involves regional reprogramming of ileal enterocytes toward a proximal identity. Interventions bolstering the endogenous reprogramming capacity of SI enterocytes-conceivably by engaging the retinoid metabolism pathway-merit further investigation, as they may increase enteral feeding tolerance, and obviate intestinal failure, in SGS

    A review of sample analysis at mars-evolved gas analysis laboratory analog work supporting the presence of perchlorates and chlorates in gale crater, mars

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    Funding Information: The research reviewed in this paper was funded by the Mars Science Laboratory (MSL) project office. M.-P.Z. acknowledges funding from the Ministerio de Ciencia e Innovacion (ref. PID2019-104205GB-C21). The authors are grateful to the engineers and scientists of the MSL Curiosity team, who have made the mission possible and the reported data available. The authors would also like to thank the two anonymous reviewers who provided careful reviews that increased the quality of this manuscript. The authors would like to remember and recognize the contributions of Rafael Navarro-Gonzalez, a dedicated SAM and HABIT team member who passed away on 28 January 2021. Navarro-Gonzalez, who was a distinguished researcher, conducted laboratory experiments that demonstrated that chloromethanes could form through a reaction between perchlorates and organics during sample heating, which greatly advanced our understanding of perchlorates and organic detection on Mars. Data Availability Statement: SAM data are publicly available through the NASA Planetary Data System at: http://pds-geosciences.wustl.edu/missions/msl/sam.htm, which was updated in March 2021. See references for the original research articles that contain the data reviewed in this paper.Peer reviewedPublisher PD

    Effect of population stratification analysis on false-positive rates for common and rare variants

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    Principal components analysis (PCA) has been successfully used to correct for population stratification in genome-wide association studies of common variants. However, rare variants also have a role in common disease etiology. Whether PCA successfully controls population stratification for rare variants has not been addressed. Thus we evaluate the effect of population stratification analysis on false-positive rates for common and rare variants at the single-nucleotide polymorphism (SNP) and gene level. We use the simulation data from Genetic Analysis Workshop 17 and compare false-positive rates with and without PCA at the SNP and gene level. We found that SNPs’ minor allele frequency (MAF) influenced the ability of PCA to effectively control false discovery. Specifically, PCA reduced false-positive rates more effectively in common SNPs (MAF > 0.05) than in rare SNPs (MAF < 0.01). Furthermore, at the gene level, although false-positive rates were reduced, power to detect true associations was also reduced using PCA. Taken together, these results suggest that sequence-level data should be interpreted with caution, because extremely rare SNPs may exhibit sporadic association that is not controlled using PCA

    Sulfur-bearing phases detected by evolved gas analysis of the Rocknest aeolian deposit, Gale Crater, Mars

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    The Sample Analysis at Mars (SAM) instrument suite detected SO_2, H_(2)S, OCS, and CS_2 from ~450 to 800°C during evolved gas analysis (EGA) of materials from the Rocknest aeolian deposit in Gale Crater, Mars. This was the first detection of evolved sulfur species from a Martian surface sample during in situ EGA. SO_2 (~3–22 ”mol) is consistent with the thermal decomposition of Fe sulfates or Ca sulfites, or evolution/desorption from sulfur-bearing amorphous phases. Reactions between reduced sulfur phases such as sulfides and evolved O_2 or H_(2)O in the SAM oven are another candidate SO_2 source. H_(2)S (~41–109 nmol) is consistent with interactions of H_(2)O, H_2 and/or HCl with reduced sulfur phases and/or SO2 in the SAM oven. OCS (~1–5 nmol) and CS2 (~0.2–1 nmol) are likely derived from reactions between carbon-bearing compounds and reduced sulfur. Sulfates and sulfites indicate some aqueous interactions, although not necessarily at the Rocknest site; Fe sulfates imply interaction with acid solutions whereas Ca sulfites can form from acidic to near-neutral solutions. Sulfides in the Rocknest materials suggest input from materials originally deposited in a reducing environment or from detrital sulfides from an igneous source. The presence of sulfides also suggests that the materials have not been extensively altered by oxidative aqueous weathering. The possibility of both reduced and oxidized sulfur compounds in the deposit indicates a nonequilibrium assemblage. Understanding the sulfur mineralogy in Rocknest materials, which exhibit chemical similarities to basaltic fines analyzed elsewhere on Mars, can provide insight in to the origin and alteration history of Martian surface materials

    Every Large Point Set contains Many Collinear Points or an Empty Pentagon

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    We prove the following generalised empty pentagon theorem: for every integer ℓ≄2\ell \geq 2, every sufficiently large set of points in the plane contains ℓ\ell collinear points or an empty pentagon. As an application, we settle the next open case of the "big line or big clique" conjecture of K\'ara, P\'or, and Wood [\emph{Discrete Comput. Geom.} 34(3):497--506, 2005]

    BurstCube: A CubeSat for gravitational wave counterparts

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    BurstCube aims to expand sky coverage in order to detect, localize, and rapidly disseminate information about gamma-ray bursts (GRBs). BurstCube is a\u276U\u27 CubeSat with an instrument comprised of 4 Cesium Iodide (CsI) scintillators coupled to arrays of Silicon photo-multipliers (SiPMs) and will be sensitive to gamma-rays between 50 keV and 1 MeV. BurstCube will assist current observatories, such as Swift and Fermi, in the detection of GRBs as well as provide astronomical context to gravitational wave (GW) events detected by LIGO, Virgo, and KAGRA. BurstCube is currently in its development phase with a launch readiness date in early 2022

    Use of Novel Strategies to Develop Guidelines for Management of Pyogenic Osteomyelitis in Adults: A WikiGuidelines Group Consensus Statement.

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    Importance Traditional approaches to practice guidelines frequently result in dissociation between strength of recommendation and quality of evidence. Objective To construct a clinical guideline for pyogenic osteomyelitis management, with a new standard of evidence to resolve the gap between strength of recommendation and quality of evidence, through the use of a novel open access approach utilizing social media tools. Evidence Review This consensus statement and systematic review study used a novel approach from the WikiGuidelines Group, an open access collaborative research project, to construct clinical guidelines for pyogenic osteomyelitis. In June 2021 and February 2022, authors recruited via social media conducted multiple PubMed literature searches, including all years and languages, regarding osteomyelitis management; criteria for article quality and inclusion were specified in the group's charter. The GRADE system for evaluating evidence was not used based on previously published concerns regarding the potential dissociation between strength of recommendation and quality of evidence. Instead, the charter required that clear recommendations be made only when reproducible, prospective, controlled studies provided hypothesis-confirming evidence. In the absence of such data, clinical reviews were drafted to discuss pros and cons of care choices. Both clear recommendations and clinical reviews were planned with the intention to be regularly updated as new data become available. Findings Sixty-three participants with diverse expertise from 8 countries developed the group's charter and its first guideline on pyogenic osteomyelitis. These participants included both nonacademic and academic physicians and pharmacists specializing in general internal medicine or hospital medicine, infectious diseases, orthopedic surgery, pharmacology, and medical microbiology. Of the 7 questions addressed in the guideline, 2 clear recommendations were offered for the use of oral antibiotic therapy and the duration of therapy. In addition, 5 clinical reviews were authored addressing diagnosis, approaches to osteomyelitis underlying a pressure ulcer, timing for the administration of empirical therapy, specific antimicrobial options (including empirical regimens, use of antimicrobials targeting resistant pathogens, the role of bone penetration, and the use of rifampin as adjunctive therapy), and the role of biomarkers and imaging to assess responses to therapy. Conclusions and Relevance The WikiGuidelines approach offers a novel methodology for clinical guideline development that precludes recommendations based on low-quality data or opinion. The primary limitation is the need for more rigorous clinical investigations, enabling additional clear recommendations for clinical questions currently unresolved by high-quality data
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