bluuebunny/crossref_metadata_2025_split huggingface dataset:
Orai–vascular endothelial-cadherin signaling complex regulates high-glucose exposure-induced increased permeability of mouse aortic endothelial cells
Authors: Wei Yuan , Bai Suwen , Yao YanHeng , Hou Wenxuan , Zhu Junwei , Fang Haoshu , Du Yinan , He Wei , Shen Bing , Du Juan 
Published: April 2021

IntroductionDiabetes-associated endothelial barrier function impairment might be linked to disturbances in Ca2+homeostasis. To study the role and molecular mechanism of Orais–vascular endothelial (VE)-cadherin signaling complex and its downstream signaling pathway in diabetic endothelial injury using mouse aortic endothelial cells (MAECs).Research design and methodsThe activity of store-operated Ca2+entry (SOCE) was detected by calcium imaging after 7 days of high-glucose (HG) or normal-glucose (NG) exposure, the expression levels of Orais after HG treatment was detected by western blot analysis. The effect of HG exposure on the expression of phosphorylated (p)-VE-cadherin and VE-cadherin on cell membrane was observed by immunofluorescence assay. HG-induced transendothelial electrical resistance was examined in vitro after MAECs were cultured in HG medium. FD-20 permeability was tested in monolayer aortic endothelial cells through transwell permeability assay. The interactions between Orais and VE-cadherin were detected by co-immunoprecipitation and immunofluorescence technologies. Immunohistochemical experiment was used to detect the expression changes of Orais, VE-cadherin and p-VE-cadherin in aortic endothelium of mice with diabetes.Results(1) The expression levels of Orais and activity of SOCE were significantly increased in MAECs cultured in HG for 7 days. (2) In MAECs cultured in HG for 7 days, the ratio of p-VE-cadherin to VE-cadherin expressed on the cell membrane and the FD-20 permeability in monolayer endothelial cells increased, indicating that intercellular permeability increased. (3) Orais and VE-cadherin can interact and enhance the interaction ratio through HG stimulation. (4) In MAECs cultured with HG, the SOCE activator ATP enhanced the expression level of p-VE-cadherin, and the SOCE inhibitor BTP2 decreased the expression level of p-VE-cadherin. (5) Significantly increased expression of p-VE-cadherin and Orais in the aortic endothelium of mice with diabetes.ConclusionHG exposure stimulated increased expression of Orais in endothelial cells, and increased VE-cadherin phosphorylation through Orais–VE-cadherin complex and a series of downstream signaling pathways, resulting in disruption of endothelial cell junctions and initiation of atherosclerosis.
Association between variability in body mass index and development of type 2 diabetes: Panasonic cohort study
Authors: Okada Hiroshi , Hamaguchi Masahide , Habu Momoko , Kurogi Kazushiro , Murata Hiroaki , Ito Masato , Fukui Michiaki 
Published: April 2021

IntroductionContrasting results have been reported for the association between the variability in body weight and development of diabetes. In the present study, we evaluated the association between the variability in body mass index (BMI) and development of type 2 diabetes in 19 412 Japanese participants without obesity and without body weight gain or loss during the study period.Research design and methodsWe recorded body weight of the participants consecutively each year in Panasonic Corporation, Osaka, Japan from 2008 to 2014 to evaluate the variability of BMI. The participants with obesity (BMI ≥25 kg/m2) at baseline and body weight gain or loss from 2008 to 2014 (delta BMI ≥±1 kg/m2) were excluded from the study. In total, 416 participants developed type 2 diabetes from 2015 to 2018. We used coefficient of variation (CV) to represent the variability in BMI during 6 years of the study period.ResultsCox regression analyses revealed that the risk of developing type 2 diabetes was higher in the fourth quartile (HR 1.33; 95% CI 1.01 to 1.75) of CV of BMI than that in the first quartile (lowest quartile) of CV of BMI after adjusting for multiple confounding factors. The risk for developing diabetes increased by 11.1% per 1% increase in CV of BMI.ConclusionsIn conclusion, the variability in BMI is a risk factor for the development of diabetes in the Japanese population without obesity and without body weight gain or loss.
Immediate postnatal care following childbirth in Ugandan health facilities: an analysis of Demographic and Health Surveys between 2001 and 2016
Authors: Dey Teesta , Ononge Sam , Weeks Andrew , Benova Lenka 
Published: April 2021

IntroductionProgress in reducing maternal and neonatal mortality, particularly in sub-Saharan Africa, is insufficient to achieve the Sustainable Developmental Goals by 2030. The first 24 hours following childbirth (immediate postnatal period), where the majority of morbidity and mortality occurs, is critical for mothers and babies. In Uganda,<50% of women reported receiving such care. This paper describes the coverage, changes over time and determinants of immediate postnatal care in Uganda after facility births between 2001 and 2016.MethodsWe analysed the 2006, 2011 and 2016 Ugandan Demographic and Health Surveys, including women 15–49 years with most recent live birth in a healthcare facility during the survey 5-year recall period. Immediate postnatal care coverage and changes over time were presented descriptively. Multivariable logistic regression was used to examine determinants of immediate postnatal care.ResultsData from 12 872 mothers were analysed. Between 2006 and 2016, births in healthcare facilities increased from 44.6% (95% CI: 41.9% to 47.3%) to 75.2% (95% CI: 73.4% to 77.0%) and coverage of immediate maternal postnatal care from 35.7% (95% CI 33.4% to 38.1%) to 65.0% (95% CI: 63.2% to 66.7%). The majority of first checks occurred between 1 and 4 hours post partum; the median time reduced from 4 hours to 1 hour. The most important factor associated with receipt of immediate postnatal care was women having a caesarean section birth adjusted OR (aOR) 2.93 (95% CI: 2.28 to 3.75). Other significant factors included exposure to mass media aOR 1.38 (95% CI: 1.15 to 1.65), baby being weighed at birth aOR 1.84 (95% CI: 1.58 to 2.14) and receipt of antenatal care with 4+Antenatal visits aOR 2.34 (95% CI: 1.50 to 3.64).ConclusionIn Uganda, a large gap in coverage remains and universal immediate postnatal care has not materialised through increasing facility-based births or longer length of stay. To ensure universal coverage of high-quality care during this critical time, we recommend that maternal and newborn services should be integrated and actively involve mothers and their partners.
Blount disease and familial inheritance in Ghana, area cross-sectional study
Authors: Jansen Niels , Hollman Freek , Bovendeert Frans , Moh Prosper , Stegmann Alexander , Staal Heleen M 
Published: April 2021

ObjectiveThe objective of this study is to study familial inheritance for Blount disease to create better understanding of the aetiology of Blount disease.MethodsAfter reviewing patient files and conventional roentgenologic imaging, 139 patients with Blount disease were included in this cross-sectional study, of which 102 patients were interviewed. During the interviews, patient characteristics and family history were collected. Blood samples were taken from five patients and three families and a whole exome sequencing was performed.ResultsAlthough patients came from all over the country, 90% of the patients belonged to the Akan tribe. A positive family history was found in 63 families (62%), of which, almost two-third had a positive family history in a first-degree family member. In most of the cases (64%), the varus legs resolved over time. In 9%, severe bowing remained ‘just like the patient’. The results of the whole exome sequencing did not show a genetic predisposition.ConclusionThis study describes a large group of Blount patients. Because of the high numbers of positive family history and the centralisation of patients in the Akan region, a familial predisposition is suggested. Further genetic research is essential for better understanding of the possible multifactorial aetiology in Blount disease.
Haploinsufficiency in non-homologous end joining factor 1 induces ovarian dysfunction in humans and mice
Authors: Li Guoqing , Yang Xi , Wang Lingbo , Pan Yuncheng , Chen Siyuan , Shang Lingyue , Zhang Yicheng , Wu Yucheng , Zhou Zixue , Chen Qing , Zhang Xue , Zhang Ling , Wang Yingchen , Li Jinsong , Jin Li , Wu Yanhua , Zhang Xiaojin , Zhang Feng 
Published: April 2021

BackgroundPremature ovarian insufficiency (POI) is a common disease in women that leads to a reduced reproductive lifespan. The aetiology of POI is genetically heterogeneous, with certain double-strand break (DSB) repair genes being implicated in POI. Although non-homologous end joining (NHEJ) is an efficient DSB repair pathway, the functional relationship between this pathway and POI remains unknown.Methods and resultsWe conducted whole-exome sequencing in a Chinese family and identified a rare heterozygous loss-of-function variant in non-homologous end joining factor 1 (NHEJ1): c.532C>T (p.R178*), which co-segregated with POI and irregular menstruation. The amount of NHEJ1 protein in the proband was half of the normal level, indicating a link between NHEJ1 haploinsufficiency and POI. Furthermore, another rare heterozygous NHEJ1 variant c.500A>G (p.Y167C) was identified in one of 100 sporadic POI cases. Both variants were predicted to be deleterious by multiple in silico tools. In vitro assays showed that knock-down of NHEJ1 in human KGN ovarian cells impaired DNA repair capacity. We also generated a knock-in mouse model with a heterozygous Nhej1 variant equivalent to NHEJ1 p.R178* in familial patients. Compared with wild-type mice, heterozygous Nhej1-mutated female mice required a longer time to first birth, and displayed reduced numbers of primordial and growing follicles. Moreover, these mice exhibited higher sensitivity to DSB-inducing drugs. All these phenotypes are analogous to the progressive loss of ovarian function observed in POI.ConclusionsOur observations in both humans and mice suggest that NHEJ1 haploinsufficiency is associated with non-syndromic POI, providing novel insights into genetic counselling and clinical prevention of POI.
Artificial Intelligence–Assisted Amphiregulin and Epiregulin IHC Predicts Panitumumab Benefit in RAS Wild-Type Metastatic Colorectal Cancer
Authors: Williams Christopher J.M. , Seligmann Jenny F. , Elliott Faye , Shires Michael , Richman Susan D. , Brown Sarah , Zhang Liping , Singh Shalini , Pugh Judith , Xu Xiao-Meng , Muranyi Andrea , Guetter Christoph , Lorsakul Auranuch , Kurkure Uday , Zhao Zuo , Martin Jim , Wang Xingwei , Nguyen Kien , Liu Wen-Wei , Yan Dongyao , West Nicholas P. , Barrett Jennifer H. , Barnes Michael , Bai Isaac , Seymour Matthew T. , Quirke Philip , Shanmugam Kandavel 
Published: April 2021

Abstract

Purpose:
High tumor mRNA levels of the EGFR ligands amphiregulin (AREG) and epiregulin (EREG) are associated with anti-EGFR agent response in metastatic colorectal cancer (mCRC). However, ligand RNA assays have not been adopted into routine practice due to issues with analytic precision and practicality. We investigated whether AREG/EREG IHC could predict benefit from the anti-EGFR agent panitumumab.

Experimental Design:
Artificial intelligence algorithms were developed to assess AREG/EREG IHC in 274 patients from the PICCOLO trial of irinotecan with or without panitumumab (Ir vs. IrPan) in RAS wild-type mCRC. The primary endpoint was progression-free survival (PFS). Secondary endpoints were RECIST response rate (RR) and overall survival (OS). Models were repeated adjusting separately for BRAF mutation status and primary tumor location (PTL).

Results:
High ligand expression was associated with significant PFS benefit from IrPan compared with Ir [8.0 vs. 3.2 months; HR, 0.54; 95% confidence interval (CI), 0.37–0.79; P = 0.001]; whereas low ligand expression was not (3.4 vs. 4.4 months; HR, 1.05; 95% CI, 0.74–1.49; P = 0.78). The ligand-treatment interaction was significant (Pinteraction = 0.02) and remained significant after adjustment for BRAF-mutation status and PTL. Likewise, RECIST RR was significantly improved in patients with high ligand expression (IrPan vs. Ir: 48% vs. 6%; P &lt; 0.0001) but not those with low ligand expression (25% vs. 14%; P = 0.10; Pinteraction = 0.01). The effect on OS was similar but not statistically significant.

Conclusions:
AREG/EREG IHC identified patients who benefitted from the addition of panitumumab to irinotecan chemotherapy. IHC is a practicable assay that may be of use in routine practice.
Distinct Biomarker Profiles and TCR Sequence Diversity Characterize the Response to PD-L1 Blockade in a Mouse Melanoma Model
Authors: El Meskini Rajaa , Atkinson Devon , Kulaga Alan , Abdelmaksoud Abdalla , Gumprecht Michelle , Pate Nathan , Hayes Susana , Oberst Michael , Kaplan Ian M. , Raber Patrick , Van Dyke Terry , Sharan Shyam K. , Hollingsworth Robert , Day Chi-Ping , Merlino Glenn , Weaver Ohler Zoë 
Published: April 2021

Abstract

Only a subset of patients responds to immune checkpoint blockade (ICB) in melanoma. A preclinical model recapitulating the clinical activity of ICB would provide a valuable platform for mechanistic studies. We used melanoma tumors arising from an Hgftg;Cdk4R24C/R24C genetically engineered mouse (GEM) model to evaluate the efficacy of an anti–mouse PD-L1 antibody similar to the anti–human PD-L1 antibodies durvalumab and atezolizumab. Consistent with clinical observations for ICB in melanoma, anti–PD-L1 treatment elicited complete and durable response in a subset of melanoma-bearing mice. We also observed tumor growth delay or regression followed by recurrence. For early treatment assessment, we analyzed gene expression profiles, T-cell infiltration, and T-cell receptor (TCR) signatures in regressing tumors compared with tumors exhibiting no response to anti–PD-L1 treatment. We found that CD8+ T-cell tumor infiltration corresponded to response to treatment, and that anti–PD-L1 gene signature response indicated an increase in antigen processing and presentation, cytokine–cytokine receptor interaction, and natural killer cell–mediated cytotoxicity. TCR sequence data suggest that an anti–PD-L1–mediated melanoma regression response requires not only an expansion of the TCR repertoire that is unique to individual mice, but also tumor access to the appropriate TCRs. Thus, this melanoma model recapitulated the variable response to ICB observed in patients and exhibited biomarkers that differentiate between early response and resistance to treatment, providing a valuable platform for prediction of successful immunotherapy.

Implications:
Our melanoma model recapitulates the variable response to anti–PD-L1 observed in patients and exhibits biomarkers that characterize early antibody response, including expansion of the TCR repertoire.
From Univariate to Multivariate Coupling Between Continuous Signals and Point Processes: A Mathematical Framework
Authors: Safavi Shervin , Logothetis Nikos K. , Besserve Michel 
Published: April 2021

AbstractTime series data sets often contain heterogeneous signals, composed of both continuously changing quantities and discretely occurring events. The coupling between these measurements may provide insights into key underlying mechanisms of the systems under study. To better extract this information, we investigate the asymptotic statistical properties of coupling measures between continuous signals and point processes. We first introduce martingale stochastic integration theory as a mathematical model for a family of statistical quantities that include the phase locking value, a classical coupling measure to characterize complex dynamics. Based on the martingale central limit theorem, we can then derive the asymptotic gaussian distribution of estimates of such coupling measure that can be exploited for statistical testing. Second, based on multivariate extensions of this result and random matrix theory, we establish a principled way to analyze the low-rank coupling between a large number of point processes and continuous signals. For a null hypothesis of no coupling, we establish sufficient conditions for the empirical distribution of squared singular values of the matrix to converge, as the number of measured signals increases, to the well-known Marchenko-Pastur (MP) law, and the largest squared singular value converges to the upper end of the MP support. This justifies a simple thresholding approach to assess the significance of multivariate coupling. Finally, we illustrate with simulations the relevance of our univariate and multivariate results in the context of neural time series, addressing how to reliably quantify the interplay between multichannel local field potential signals and the spiking activity of a large population of neurons.
Skip-Connected Self-Recurrent Spiking Neural Networks With Joint Intrinsic Parameter and Synaptic Weight Training
Authors: Zhang Wenrui , Li Peng 
Published: April 2021

AbstractAs an important class of spiking neural networks (SNNs), recurrent spiking neural networks (RSNNs) possess great computational power and have been widely used for processing sequential data like audio and text. However, most RSNNs suffer from two problems. First, due to the lack of architectural guidance, random recurrent connectivity is often adopted, which does not guarantee good performance. Second, training of RSNNs is in general challenging, bottlenecking achievable model accuracy. To address these problems, we propose a new type of RSNN, skip-connected self-recurrent SNNs (ScSr-SNNs). Recurrence in ScSr-SNNs is introduced by adding self-recurrent connections to spiking neurons. The SNNs with self-recurrent connections can realize recurrent behaviors similar to those of more complex RSNNs, while the error gradients can be more straightforwardly calculated due to the mostly feedforward nature of the network. The network dynamics is enriched by skip connections between nonadjacent layers. Moreover, we propose a new backpropagation (BP) method, backpropagated intrinsic plasticity (BIP), to boost the performance of ScSr-SNNs further by training intrinsic model parameters. Unlike standard intrinsic plasticity rules that adjust the neuron's intrinsic parameters according to neuronal activity, the proposed BIP method optimizes intrinsic parameters based on the backpropagated error gradient of a well-defined global loss function in addition to synaptic weight training. Based on challenging speech, neuromorphic speech, and neuromorphic image data sets, the proposed ScSr-SNNs can boost performance by up to 2.85% compared with other types of RSNNs trained by state-of-the-art BP methods.
Nonlinear Decoding of Natural Images From Large-Scale Primate Retinal Ganglion Recordings
Authors: Kim Young Joon , Brackbill Nora , Batty Eleanor , Lee JinHyung , Mitelut Catalin , Tong William , Chichilnisky E. J. , Paninski Liam 
Published: April 2021

Abstract
Decoding sensory stimuli from neural activity can provide insight into how the nervous system might interpret the physical environment, and facilitates the development of brain-machine interfaces. Nevertheless, the neural decoding problem remains a significant open challenge. Here, we present an efficient nonlinear decoding approach for inferring natural scene stimuli from the spiking activities of retinal ganglion cells (RGCs). Our approach uses neural networks to improve on existing decoders in both accuracy and scalability. Trained and validated on real retinal spike data from more than 1000 simultaneously recorded macaque RGC units, the decoder demonstrates the necessity of nonlinear computations for accurate decoding of the fine structures of visual stimuli. Specifically, high-pass spatial features of natural images can only be decoded using nonlinear techniques, while low-pass features can be extracted equally well by linear and nonlinear methods. Together, these results advance the state of the art in decoding natural stimuli from large populations of neurons.
Collaborative Production in Science: An Empirical Analysis of Coauthorships in Economics
Authors: Anderson Katharine A. , Richards-Shubik Seth 
Published: April 2021

Abstract
This paper studies productivity and preferences in scientific research. Collaboration is increasingly important for innovation in science and other domains, but we have limited understanding of the factors researchers use to choose their collaborators and the projects they work on. Here, we use a model of strategic network formation and a recently developed econometric method to examine this question in the context of economics researchers. We learn that research teams with more collaborators tend to produce papers with higher impact, and without increasing individual costs of communication and coordination. This suggests the trend toward larger research teams in economics will continue.
Beliefs about Racial Discrimination and Support for Pro-Black Policies
Authors: Haaland Ingar , Roth Christopher 
Published: April 2021

Abstract
This paper provides representative evidence on beliefs about racial discrimination and examines whether information causally affects support for pro-black policies. Eliciting quantitative beliefs about the extent of hiring discrimination against blacks, we uncover large disagreement about the extent of racial discrimination with particularly pronounced partisan differences. An information treatment leads to a convergence in beliefs about racial discrimination but does not lead to a similar convergence in support of pro-black policies. The results demonstrate that while providing information can substantially reduce disagreement about the extent of racial discrimination, it is not sufficient to reduce disagreement about pro-black policies.
Paying Outsourced Labor: Direct Evidence from Linked Temp Agency-Worker-Client Data
Authors: Drenik Andres , Jäger Simon , Plotkin Pascuel , Schoefer Benjamin 
Published: April 2021

Abstract
We estimate how much firms differentiate pay premia between regular and outsourced workers in temp agency work arrangements. We leverage unique Argentinian administrative data that feature links between user firms (the workplaces where temp workers perform their labor) and temp agencies (their formal employers). We estimate that a high-wage user firm that pays a regular worker a 10% premium pays a temp worker on average only a 4.9% premium, compared to what these workers would earn in a low-wage user firm in their respective work arrangements. This 49% pass-through constitutes the midpoint between the benchmarks for insiders (one) and the competitive spot-labor market (zero).
Longer-Run Economic Consequences of Pandemics
Authors: Jordà Òscar , Singh Sanjay R. , Taylor Alan M. 
Published: April 2021

Abstract
What are the medium- to long-term effects of pandemics? Do they differ from other economic disasters? We study major pandemics using rates of return on assets stretching back to the fourteenth century. Significant macroeconomic after-effects of pandemics persist for decades, with rates of return substantially depressed. The responses are in stark contrast to what happens after wars. Our findings also accord with wage and output responses, using more limited data, and are consistent with the neoclassical growth model: capital is destroyed in wars but not in pandemics; pandemics instead may induce more labor scarcity or more precautionary savings, or both.