bluuebunny/crossref_metadata_2025_split huggingface dataset:
Homeostatic model assessment of insulin resistance closely related to lobular inflammation in nonalcoholic fatty liver disease
Authors: Ye Fang-Zhou , Liu Wen-Yue , Zheng Kenneth I. , Pan Xiao-Yan , Ma Hong-Lei , Wang Xiao-Dong , Chen Yong-Ping , Zheng Ming-Hua 
Published: October 2019

Objective
Insulin resistance (IR) has been established as a major risk factor for nonalcoholic fatty liver disease (NAFLD) where it exerts effects on plasma glucose homeostasis, cellular anabolism, and organ glucose uptake. Owing to paucity of studies focused on peripheral IR in relation to pathological outcome, we aim to investigate homeostatic model assessment of insulin resistance (HOMA-IR) by histological characteristics of NAFLD.

Methods
Liver biopsy of 588 patients was screened. After excluding etiologies other than NAFLD and factors contributing to IR, serum HOMA-IR was compared with patients’ histologic features. Univariate and multivariate analyses were conducted to assess their relationship. Area under the receiver operating characteristic (AUROC) was calculated to assess the discriminatory ability of homeostatic model assessment of IR for advanced lobular inflammation (LI).

Results
We observed higher serum level of alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and low-density lipoprotein as HOMA-IR increased. HOMA-IR is significantly associated with severity of LI (odds ratio = 1.222, 95% confidence interval = 1.135–1.315, P < 0.001), similar association remained after adjusting for age, BMI, hemoglobin A1c, alanine aminotransferase, aspartate aminotransferase, low-density lipoprotein, high-density lipoprotein, and triglycerides (odds ratio = 1.205, 95% confidence interval = 1.102–1.317, P < 0.001). HOMA-IR is discriminant of LI with AUROC = 0.832 and cutoff = 2.995 (sensitivity = 0.938, specificity = 0.569).

Conclusion
This study demonstrated a strong and independent association of HOMA-IR with the severity of liver inflammation by histological evaluation in NAFLD patients without diabetes or metabolic syndrome, and its possible role in diagnosis of LI could be translated into clinical assessment of NAFLD patients with uncertainty of nonalcoholic steatohepatitis progression.
Hemophagocytic Lymphohistiocytosis in Critically Ill Patients
Authors: Knaak Cornelia , Schuster Friederike S. , Spies Claudia , Vorderwülbecke Gerald , Nyvlt Peter , Schenk Thomas , Balzer Felix , La Rosée Paul , Janka Gritta , Brunkhorst Frank M. , Keh Didier , Lachmann Gunnar 
Published: October 2019

ABSTRACT

Background:
Hemophagocytic lymphohistiocytosis (HLH), an uncontrolled overactivation of the immune system, is well characterized in pediatric patients, yet, much less is known about this life-threatening condition in adult patients. As HLH is often complicated by organ failure, patients will require admission to the intensive care unit for organ support therapy. However, recognition of HLH patients in the intensive care unit (ICU) is challenged by the clinical overlap with sepsis. Here, we analyze HLH patients to better understand its clinical presentation, diagnosis, and treatment.

Methods:
For the purpose of this retrospective observational study, we searched for suspected and diagnosed adult HLH of all patients admitted to at least one adult surgical, anesthesiological or medical ICU between January 2006 and August 2018 at the university hospital Charité — Universitätsmedizin Berlin. All cases were reviewed by two HLH experts, who confirmed or declined the diagnosis.

Results:
Of 6,340 ICU patients with ferritin measurement, 40 suffered from HLH (0.63%). Of these, in-hospital mortality was 60.0% over all cases, which was highest in malignancy-associated HLH (71.4%). Infections were identified as most common triggers (42.5%). A variety of 19 different treatment strategies were applied. Non-survivors showed higher ferritin at diagnosis compared with survivors (
P
= 0.021), which was also seen in multivariable analyses. A minimum ferritin of 4083 μg/L after diagnosis was most predictive for 30-day mortality (AUC 0.888, 95% CI 0.771–1.000; sensitivity 93.8%, specificity 78.9%).

Conclusions:
Mortality in adult HLH patients in the ICU is high, particularly in malignancy-associated HLH. Infections are the most frequent HLH triggers in critically ill patients. At present, there is no standardized treatment for HLH in adult patients available. Assessment of ferritin is valuable for diagnosis, prognosis, and treatment monitoring.

Trial registration: The study was registered with www.ClinicalTrials.gov (NCT02854943) on August 1, 2016.
Overexpression of BCL-2 in the Intestinal Epithelium Prevents Sepsis-Induced Gut Barrier Dysfunction via Altering Tight Junction Protein Expression
Authors: Otani Shunsuke , Oami Takehiko , Yoseph Benyam P. , Klingensmith Nathan J. , Chen Ching-wen , Liang Zhe , Coopersmith Craig M. 
Published: October 2019

ABSTRACT
Sepsis induces both intestinal hyperpermeability and epithelial apoptosis. While each has been implicated in mediating sepsis mortality, the relationship between these two processes is unclear. We hypothesized that preventing intestinal apoptosis would prevent gut barrier dysfunction. To test this hypothesis, transgenic mice that overexpress the anti-apoptotic protein Bcl-2 in the gut epithelium (Fabpl-Bcl-2 mice) and wild-type (WT) mice were subjected to sham laparotomy or cecal ligation and puncture and orally gavaged with fluorescein isothiocyanate conjugated-dextran (FD-4) 5 h before sacrifice. Serum FD-4 concentration was assayed to measure intestinal permeability, and jejunal tight junctions were assayed for mRNA and protein expression. Baseline FD-4 concentration was similar between WT and Fabpl-Bcl-2 mice. Intestinal permeability increased 6, 12, 24, and 48 h following sepsis in WT mice; however, FD-4 concentration was significantly lower at each timepoint in Fabpl-Bcl-2 mice. In addition, there were no statistically significant changes in permeability between septic and sham transgenic mice. Intestinal mRNA expression of claudin 3, claudin 5, and occludin was lower in septic Fabpl-Bcl-2 mice, while claudin 4 mRNA levels were higher in Fabpl-Bcl-2 mice. In contrast, no differences were detected in claudins 2, 7, 15, JAM-A, or ZO-1. Protein levels followed the same trend for all tight junction mediators different between WT and Fabpl-Bcl-2 mice except occludin was significantly higher in transgenic mice. Together these results demonstrate that decreasing intestinal epithelial apoptosis prevents hyperpermeability following sepsis via tight junction alterations which may be at least partially responsible for improved survival conferred by Bcl-2 overexpression.
Genistein Protects Against Burn-Induced Myocardial Injury via Notch1-Mediated Suppression of Oxidative/Nitrative Stress
Authors: Fang Zhuoqun , Wu Gaofeng , Zhang Dongliang , Wang Kejia , Deng Xudong , Liu Mengdong , Han Juntao , Hu Dahai , Yang Xuekang 
Published: October 2019

ABSTRACT
Genistein (Gen) exhibits strong anti-oxidative/antinitrative activity and cardioprotective effects in several models; however, its role in burn-induced myocardial injury is unknown. This study investigated the protective effect of Gen on burn-induced myocardial injury and aimed to elucidate the mechanism of protection. Mice were injected with Gen, intraperitoneally, at different dose immediately after burn injury. The expression levels of Notch-1 intracellular domain (NICD1) and hairy and enhancer of split (Hes-1) were determined by immunoblotting. Conditional Notch-RBP-J knockout mice were used to investigate the mechanisms of Gen-induced cardioprotection. Gen alleviated burn-induced myocardial injury, as shown by improved left ventricle ejection fraction, decreased serum lactate dehydrogenase and creatine kinase levels, and apoptosis. Moreover, Gen decreased expressions of inducible nitric oxide (NO) synthase and gp91phox, reduced NO and superoxide anions production, and ameliorated their cytotoxic reaction product, peroxynitrite. More importantly, Gen significantly up-regulated the expression of NICD1 and Hes1 after burn injury. In addition, genetic knockout of Notch1 not only blocked the cardioprotection of Gen but also markedly attenuated Gen-induced anti-oxidative/antinitrative effect. These results demonstrate, for the first time, that Gen treatment attenuates burn-induced myocardial injury via the Notch1 mediated suppression of oxidative/nitrative stress.
Mad dephosphorylation at the nuclear envelope is essential for asymmetric stem cell division
Authors: Sardi Justin , Bener Muhammed Burak , Simao Taylor , Descoteaux Abigail E. , Slepchenko Boris M. , Inaba Mayu 
Published: October 2019

SummaryStem cell niche signals act over a short range so that only stem cells but not the differentiating daughter cells receive the self-renewal signals.Drosophilafemale germline stem cells (GSCs) are maintained by short range BMP signaling; BMP ligands Dpp/Gbb activate receptor Tkv to phosphorylate Mad (phosphor-Mad or pMad) which accumulates in the GSC nucleus and activates the stem cell transcription program. pMad is highly concentrated in the nucleus of the GSC, but is immediately downregulated in the nucleus of the pre-cystoblast (preCB), a differentiating daughter cell, that is displaced away from the niche. Here we show that this asymmetry in the intensity of pMad is formed even before the completion of cytokinesis. A delay in establishing the pMad asymmetry leads to germline tumors through conversion of differentiating cells into a stem cell-like state. We show that a Mad phosphatase Dullard (Dd) interacts with Mad at the nuclear pore, where it may dephosphorylate Mad. A mathematical model explains how an asymmetry can be established in a common cytoplasm. It also demonstrates that the ratio of pMad concentrations in GSC/preCB is highly sensitive to Mad dephosphorylation rate. Our study reveals a previously unappreciated mechanism for breaking symmetry between daughter cells during asymmetric stem cell division.
The microevolutionary response to male-limited X-chromosome evolution inDrosophila melanogasterreflects macroevolutionary patterns
Authors: Abbott Jessica K. , Chippindale Adam K. , Morrow Edward H. 
Published: October 2019

AbstractDue to its hemizygous inheritance and role in sex determination, the X chromosome is expected to play an important role in the evolution of sexual dimorphism, and to be enriched for sexually antagonistic genetic variation. By forcing the X chromosome to only be expressed in males over >40 generations, we changed the selection pressures on the X to become similar to those experienced by the Y. This releases the X from any constraints arising from selection in females, and should lead to specialization for male fitness, which could occur either via direct effects of X-linked loci or trans-regulation of autosomal loci by the X. We found evidence of masculinization via upregulation of male-benefit sexually antagonistic genes, and downregulation of X-linked female benefit genes. Interestingly, we could detect evidence of microevolutionary changes consistent with previously documented macroevolutionary patterns, such as changes in expression consistent with previously established patterns of sexual dimorphism, an increase in the expression of metabolic genes related to mitonuclear conflict, and evidence that dosage compensation effects can be rapidly altered. These results confirm the importance of the X in the evolution of sexual dimorphism and as a source for sexually antagonistic genetic variation, and demonstrate that experimental evolution can be a fruitful method for testing theories of sex chromosome evolution.
Combining Crowdsourcing and Deep Learning to Assess Public Opinion on CRISPR-Cas9
Authors: Müller Martin , Schneider Manuel , Salathé Marcel , Vayena Effy 
Published: October 2019

AbstractThe discovery of the CRISPR-Cas9-based gene editing method has opened un-precedented new potential for biological and medical engineering, sparking a growing public debate on both the potential and dangers of CRISPR applications. Given the speed of technology development, and the almost instantaneous global spread of news, it’s important to follow evolving debates without much delay and in sufficient detail, as certain events may have a major long-term impact on public opinion and later influence policy decisions. Social media networks such as Twitter have shown to be major drivers of news dissemination and public discourse. They provide a vast amount of semi-structured data in almost real-time and give direct access to the content of the conversations. Such data can now be mined and analyzed quickly because of recent developments in machine learning and natural language processing. Here, we used BERT, an attention-based transformer model, in combination with statistical methods to analyse the entirety of all tweets ever published on CRISPR since the publication of the first gene editing application in 2013. We show that the mean sentiment of tweets was initially very positive, but began to decrease over time, and that this decline was driven by rare peaks of strong negative sentiments. Due to the high temporal resolution of the data, we were able to associate these peaks with specific events, and to observe how trending topics changed over time. Overall, this type of analysis can provide valuable and complementary insights into ongoing public debates, extending the traditional empirical bioethics toolset.
Traditional functional groups capture limited variation in the trait space of macroalgae
Authors: Mauffrey Alizée R. L. , Cappelatti Laura , Griffin John N. 
Published: October 2019

ABSTRACTMacroalgal (seaweed) beds and forests fuel coastal ecosystems and are rapidly reorganising under global change, but quantifying their functional structure still relies on binning species into coarse groups on the assumption that they adequately capture relevant underlying traits.To interrogate this “group gambit”, we first measured 12 traits relating to competitive dominance and resource economics across 95 macroalgal species collected from UK rocky shores. We then assessed trait variation explained by traditional grouping approaches consisting of (i) two highly-cited schemes based on gross morphology and anatomy and (ii) two commonly-used categorisations of vertical space use. To identify the limitations of traditional grouping approaches and to reveal potential alternatives, we also assessed the ability of (iii) emergent groups created from post hoc clustering of our dataset to account for macroalgal trait variation.(i) Traditional groups explained about a third of multivariate trait expression with considerable group overlap. (ii) Classifications of vertical space use accounted for even less multivariate trait expression. Notwithstanding considerable overlap, the canopy vs. turf scheme explained significant differences in most individual traits, with turf species tending to display attributes of opportunistic forms. (iii) Emergent groups were substantially more parsimonious than all existing grouping approaches.Synthesis: Our analysis using a comprehensive dataset of directly measured functional traits failed to strongly support the group gambit in macroalgae. While existing grouping approaches may allow first order approximations, they risk considerable loss of information at the trait and, potentially, ecosystem levels. We call for further development of a trait-based approach to macroalgal functional ecology to capture unfolding community and ecosystem changes with greater accuracy and generality.
The receptor PTPRU is a redox sensitive pseudophosphatase
Authors: Hay Iain M. , Fearnley Gareth W. , Rios Pablo , Köhn Maja , Sharpe Hayley J. , Deane Janet E. 
Published: October 2019

ABSTRACTThe dynamic regulation of protein tyrosine phosphorylation is a critical feature of intercellular communication and is regulated by the actions of kinases and phosphatases. The receptor-linked protein tyrosine phosphatases (RPTPs) are key signaling molecules that possess an extracellular domain and intracellular phosphatase domains. Most human RPTPs have tandem intracellular tyrosine phosphatase domains: a catalytically active membrane proximal (D1) domain; and a membrane distal (D2) inactive “pseudophosphatase” domain. The receptor PTPRU plays a role in development, multiple cancers and has been implicated in the dephosphorylation of cell adhesion proteins. However, PTPRU has a non-canonical D1 domain containing several sequence variations in key catalytic loops that suggest it may function using a mechanism distinct from related RPTPs. Here, we demonstrate through biochemical and structural studies that PTPRU is unique amongst the RPTPs in possessing two pseudophosphatase domains. We show that PTPRU-D1 displays no detectable catalytic activity against a range of phosphorylated substrates and determine that this is due to substantial disorder in the substrate-binding pocket as well as rearrangement of the catalytic loop such that the active site cysteine is occluded. We also show that this cysteine can form an intramolecular disulfide bond with a vicinal “backdoor” cysteine. Further, we demonstrate that the PTPRU D2 domain can recruit substrates of related RPTPs suggesting that this pseudophosphatase functions by competing with active phosphatases for the binding of substrates involved in cell adhesion. Therefore, PTPRU is abona-fidepseudophosphatase and its functional role in cell signaling is via a non-catalytic mechanism.SIGNIFICANCE STATEMENTProtein tyrosine phosphorylation is a key post-translational modification required for cellular communication that is dynamically regulated by the activities of tyrosine kinases and phosphatases. Receptor tyrosine phosphatases (RPTPs) possess an extracellular receptor domain and intracellular phosphatase domains. We show that PTPRU is a non-canonical RPTP devoid of catalytic activity and demonstrate that this is due to multiple structural rearrangements. Despite this, PTPRU retains the capacity to bind the substrates of related phosphatases suggesting that the non-catalytic function of this pseudophosphatase is to compete with active phosphatases for the binding of substrates. Such pseudoenzymes represent an exciting and growing area of research with implications as key regulators of signaling networks.
Natural selection drives population divergence for local adaptation in a wheat pathogen
Authors: Pereira Danilo , Croll Daniel , Brunner Patrick C. , McDonald Bruce A. 
Published: October 2019

AbstractEvolution favors the emergence of locally-adapted optimum phenotypes that are likely to differ across a wide array of environmental conditions. The emergence of favorable adaptive characteristics is accelerated in agricultural pathogens due to the unique properties of agro-ecosystems. We performed a QST- FSTcomparison using 164 strains ofParastagonospora nodorumsampled from eight global field populations to disentangle the predominant evolutionary forces driving population divergence in a wheat pathogen. We used digital image analysis to obtain quantitative measurements of growth rate and melanization at different temperatures and under different fungicide concentrations in a common garden experiment. FSTmeasures were based on complete genome sequences obtained for all 164 isolates. Our analyses indicated that all measured traits were under selection. Growth rates at 18°C and 24°C were under stabilizing selection (QST< FST), while diversifying selection (QST> FST) was the predominant evolutionary force affecting growth under fungicide and high temperature stress. Stabilizing selection (QST< FST) was the predominant force affecting melanization across the different environments. Melanin production increased at 30°C but was negatively correlated with higher growth rates, consistent with a trade-off under heat stress. Our results demonstrate that global populations ofP. nodorumpossess significant evolutionary potential to adapt to changing local conditions, including warmer temperatures and applications of fungicides.
Vector Trace cells in the Subiculum of the Hippocampal formation
Authors: Poulter Steven , Lee Sang Ah , Dachtler James , Wills Thomas J. , Lever Colin 
Published: October 2019

AbstractSuccessfully navigating in physical or semantic space requires a neural representation of allocentric (map-based) vectors to boundaries, objects, and goals. Cognitive processes such as path-planning and imagination entail recall of vector representations, but evidence of neuron-level memory for allocentric vectors has been lacking. Here we describe a novel neuron type (Vector Trace cell, VTC) whose firing generates a new vector field when a cue is encountered, and also a ‘trace’ version of that field for hours after cue removal. VTCs are concentrated in subiculum distal to CA1. Compared to non-trace cells, VTCs fire at further distances from cues, and exhibit earlier-going shifts in preferred theta phase in response to newly introduced cues, demonstrating a theta-linked neural substrate for memory encoding. VTCs suggest a vector-based model of computing spatial relationships between an agent and multiple spatial objects, or between different objects, freed from the constraints of direct perception of those objects.
Rare species perform worse than common species under changed climate
Authors: Vincent Hugo , Bornand Christophe N. , Kempel Anne , Fischer Markus 
Published: October 2019

AbstractPredicting how species, particularly rare and endangered ones, will react to climate change is a major current challenge in ecology. Rare species are expected to have a narrower niche width than common species. However, we know little whether they are also less able to cope with new climatic conditions. To simulate climate change, we transplanted 35 plant species varying in rarity to five botanical gardens in Switzerland, differing in altitude. For each species we calculated the difference in climate between their natural habitats and the novel climate of the respective botanical garden. We found that rare species had generally lower survival and biomass production than common species. Moreover, rare plant species survived less when the amount of precipitation differed more from the one in their natural range, indicating a higher susceptibility to climate change. Common species, in contrast, survived equally well under all climates and even increased their biomass under wetter or drier conditions. Our study shows that rarer species are less able to cope with changes in climate compared to more widespread ones, which might even benefit from these changes. This indicates that already rare and endangered plant species might suffer strongly from future climate change.