bluuebunny/crossref_metadata_2025_split huggingface dataset:
Social Frailty Index: Development and Validation of an Index of Social Attributes Predictive of Mortality in Older Adults
Authors: Shah Sachin J , Oreper Sandra , Jeon Sun Young , Boscardin W. John , Fang Margaret , Covinsky Kenneth E 
Published: May 2022

ABSTRACTObjectiveTo develop and validate the Social Frailty Index, a summary measure of social risk in older adults, and determine its ability to risk stratify beyond traditional medical risk modelsDesignPrognostic model development and validation using demographics and a comprehensive inventory of social characteristicsSettingThe Health and Retirement Study, a longitudinal, nationally representative survey of U.S. adults >50 years. We developed the model using the 2010 wave and validated it using the 2012 wave; there was no overlap between 2010 and 2012 respondents.Participants8250 adults aged ≥65 years who completed the Psychosocial and Lifestyle Questionnaire (4302 in the 2010 development cohort, 3948 in the 2012 validation cohort).Main exposureDemographic and social characteristicsMain outcome4-year mortalityResultsWithin 4 years of the baseline interview, 22% of study participants in both the development and validation cohort had died. Drawn from 183 possible predictors, the final model included age, gender, and 8 social predictors: lacking neighborhood cleanliness, low perceived control over financial situation, having children and meeting with them less than yearly, not working for pay, less active with children (grandchildren, neighborhood, nieces/nephews), no volunteering or charity work, feeling isolated from others, being treated with less courtesy or respect. In the validation cohort, the model discriminated well (c-statistic 0.73) and was strongly associated with 4-year mortality (7.3% in the lowest decile, 59.9% in the highest decile). Also, the Social Frailty Index meaningfully risk-stratified participants beyond the Charlson score, a commonly used medical comorbidity index, and the Lee Index score, a comorbidity and function model.ConclusionThis prognostic index, which includes age, gender, and 8 social characteristics, accurately risk stratifies older adults and refines the prediction of commonly used comorbidity- and function-based risk models.
Gut Microbes and the Liver Circadian Clock Partition Glucose and Lipid Metabolism
Authors: Frazier Katya , Manzoor Sumeed , Carroll Katherine , DeLeon Orlando , Miyoshi Sawako , Miyoshi Jun , George Marissa St , Tan Alan , Izumo Mariko , Takahashi Joseph S. , Rao Mrinalini C. , Leone Vanessa A. , Chang Eugene B. 
Published: May 2022

SummaryCircadian rhythms govern glucose homeostasis, and their dysregulation leads to complex metabolic diseases. Gut microbes also exhibit diurnal rhythms that influence host circadian networks and metabolic processes, yet underlying mechanisms remain elusive. Here, we show hierarchical, bi-directional communication between the liver circadian clock, gut microbes, and glucose homeostasis in mice. The liver clock, but not the forebrain clock, requires gut microbes to drive glucose clearance and gluconeogenesis. Liver clock dysfunctionality expands proportions and abundances of oscillating microbial features by two-fold relative to controls. The liver clock is the primary driver of differential and rhythmic hepatic expression of glucose and fatty acid metabolic pathways. Absent the liver clock, gut microbes provide secondary cues that dampen these rhythms, resulting in reduced utilization of lipids as fuel relative to carbohydrates. Together, the liver clock transduces signals from gut microbes necessary to regulate glucose and lipid metabolism and meet energy demands over 24 hours.HighlightsThe liver circadian clock is autonomous from the central clock in metabolic regulationLiver clock and gut microbes interact to direct hepatic glucose and lipid metabolismReciprocating host-microbe interactions drive rhythmic hepatic transcriptionPerturbed liverBmal1results in chaotic downstream oscillators and metabolism
Functional analysis of PsbS transmembrane domains through base editing in Physcomitrium patens
Authors: Beraldo Claudia , Guyon-Debast Anouchka , Alboresi Alessandro , Nogué Fabien , Morosinotto Tomas 
Published: May 2022

AbstractPlants exposed to light fluctuations are protected from photodamage by non-photochemical quenching (NPQ), a reversible mechanism that enables dissipation of excess absorbed energy as heat, which is essential for plant fitness and crop productivity. NPQ requires the activity of the membrane protein PsbS that, upon activation, interacts with antenna proteins, inducing their dissipative conformation. Here, we exploited base editing in the moss Physcomitrium patens to introduce in vivo specific amino acid changes and assess their impact on PsbS activity, targeting transmembrane regions to investigate their role in protein–protein interactions. This approach enabled the recognition of residues essential for protein stability and the identification of a hydrophobic cluster of amino acids with a seminal role in PsbS activity. This work provides new information on the PsbS molecular mechanism while also demonstrating the potential of base editing approaches for in planta gene function analysis.
Alcohol reverses the effects ofKCNJ6(GIRK2) noncoding variants on excitability of human glutamatergic neurons
Authors: Popova Dina , Gameiro-Ros Isabel , Youssef Mark M. , Zalamea Petronio , Morris Ayeshia D. , Prytkova Iya , Jadali Azadeh , Kwan Kelvin Y. , Kamarajan Chella , Salvatore Jessica E. , Xuei Xiaoling , Chorlian David B. , Porjesz Bernice , Kuperman Samuel , Dick Danielle M. , Goate Alison , Edenberg Howard J. , Tischfield Jay A. , Pang Zhiping P. , Slesinger Paul A. , Hart Ronald P. 
Published: May 2022

AbstractSynonymous and noncoding single nucleotide polymorphisms (SNPs) in theKCNJ6gene, encoding G protein-gated inwardly rectifying potassium (GIRK2) channel subunit 2, have been linked with increased electroencephalographic frontal theta event-related oscillations (ERO) in subjects diagnosed with alcohol use disorder (AUD). To identify molecular and cellular mechanisms while retaining the appropriate genetic background, we generated induced excitatory glutamatergic neurons (iN) from iPSCs derived from four AUD-diagnosed subjects withKCNJ6variants (‘Affected: AF’) and four control subjects without variants (‘Unaffected: UN’). Neurons were analyzed for changes in gene expression, morphology, excitability and physiological properties. Single cell RNA sequencing suggests thatKCNJ6AF variant neurons have altered patterns of synaptic transmission and cell projection morphogenesis. Results confirm that AF neurons express lower levels of GIRK2, have greater neurite area, and elevated excitability. Interestingly, exposure to intoxicating concentrations of ethanol induces GIRK2 expression and reverses functional effects in AF neurons. Ectopic overexpression of GIRK2 alone mimics the effect of ethanol to normalize induced excitability. We conclude thatKCNJ6variants decrease GIRK2 expression and increase excitability and that this effect can be minimized or reduced with ethanol.
High-fidelity reproduction of visual signals by electrical stimulation in the central primate retina
Authors: Gogliettino Alex R. , Madugula Sasidhar S. , Grosberg Lauren E. , Vilkhu Ramandeep S. , Brown Jeff , Nguyen Huy , Kling Alexandra , Hottowy Paweł , Dąbrowski Władysław , Sher Alexander , Litke Alan M. , Chichilnisky E.J. 
Published: May 2022

AbstractElectrical stimulation of retinal ganglion cells (RGCs) with electronic implants provides rudimentary artificial vision to people blinded by retinal degeneration. However, current devices stimulate indiscriminately and therefore cannot reproduce the intricate neural code of the retina. Recent work has demonstrated more precise activation of RGCs using focal electrical stimulation with multi-electrode arrays in the peripheral macaque retina, but it is unclear how effective this can be in the central retina, which is required for high-resolution vision. This work probes the neural code and effectiveness of focal epiretinal stimulation in the central macaque retina, using large-scale electrical recording and stimulationex vivo. The functional organization, light response properties, and electrical properties of the major RGC types in the central retina were mostly similar to the peripheral retina, with some notable differences in density, kinetics, linearity, spiking statistics and correlations. The major RGC types could be distinguished by their intrinsic electrical properties. Electrical stimulation targeting parasol cells revealed similar activation thresholds and reduced axon bundle activation in the central retina, but lower stimulation selectivity. Quantitative evaluation of the potential for image reconstruction from electrically-evoked parasol cell signals revealed higher overall expected image quality in the central retina. An exploration of inadvertent midget cell activation suggested that it could contribute high spatial frequency noise to the visual signal carried by parasol cells. These results support the possibility of reproducing high-acuity visual signals in the central retina with an epiretinal implant.Significance StatementArtificial restoration of vision with retinal implants is a major treatment for blindness. However, present-day implants do not provide high-resolution visual perception, in part because they do not reproduce the natural neural code of the retina. Here we demonstrate the level of visual signal reproduction that is possible with a future implant by examining how accurately responses to electrical stimulation of parasol retinal ganglion cells (RGCs) can convey visual signals. Although the precision of electrical stimulation in the central retina was diminished relative to the peripheral retina, the quality of expected visual signal reconstruction in parasol cells was greater. These findings suggest that visual signals could be restored with high fidelity in the central retina using a future retinal implant.
Hemin shows antiviral activity in vitro, possibly through suppression of viral entry mediators
Authors: Unal Mehmet Altay , Bitirim Ceylan Verda , Somers Julia , Summak Gokce Yagmur , Besbinar Omur , Kocakaya Ebru , Gurcan Cansu , Nazir Hasan , Aksoy Ozer Zeynep Busra , Ozkan Sibel Aysil , Bereketoglu Sidar , Ozkul Aykut , Demir Emek , Akcali Kamil Can , Yilmazer Acelya 
Published: May 2022

AbstractHeme oxygenase-1 (HO-1) is a stress-induced enzyme that catalyzes the breakdown of heme into biliverdin, carbon monoxide, and iron. Targeting HO-1 to treat severe COVID-19 has been suggested by several groups, yet the role of HO-1 in SARS-CoV-2 infection remains unclear. Based on this, we aimed to investigate the antiviral activity of Hemin, an activator of HO-1. Infectivity of SARS-CoV-2 was decreased in Vero E6 cells treated with Hemin. Hemin also decreased TMPRSS2 and ACE2 mRNA levels in non-infected cells, possibly explaining the observed decrease in infectivity. TMPRSS2 protein expression and proteolytic activity were decreased in Vero E6 cells treated with Hemin. Besides that, experimental studies supported with in silico calculations. Overall, our study supports further exploration of Hemin as a potential antiviral and inflammatory drug for the treatment of COVID-19.
SPIRAL: Significant Process InfeRence ALgorithm for single cell RNA-sequencing and spatial transcriptomics
Authors: Biran Hadas , Hashimshony Tamar , Mandel-Gutfreund Yael , Yakhini Zohar 
Published: May 2022

1AbstractGene expression data is complex and may hold information regarding multiple biological processes at once. We present SPIRAL, an algorithm that uses a Gaussian statistical model to produce a comprehensive overview of a plurality of significant processes detected in single cell RNA-seq or spatial transcriptomics data. SPIRAL identifies biological processes by finding sub-matrices that consist of the subset of genes involved and the subset of cells or spots. We describe the algorithmic method, the analysis pipeline and several example results. SPIRAL is available athttps://spiral.technion.ac.il/.
Chemical effects on ecological interactions within a model-experiment loop
Authors: Lamonica Dominique , Charles Sandrine , Clément Bernard , Lopes Christelle 
Published: May 2022

AbstractWe propose in this paper a method to assess the effects of a contaminant on a micro-ecosystem, integrating the population dynamics and the interactions between species. For that, we developed a dynamic model to describe the functioning of a microcosm exposed to a contaminant and to discriminate direct and indirect effects. Then, we get back from modelling to experimentation in order to identify which of the collected data have really been necessary and sufficient to estimate model parameters in order to propose a more efficient experimental design for further investigations. We illustrated our approach using a 2-L laboratory microcosm involving three species (the duckweedLemna minor, the microalgaePseudokirchneriella subcapitataand the daphnidsDaphnia magna) exposed to cadmium contamination. We modelled the dynamics of the three species and their interactions using a mechanistic model based on coupled ordinary differential equations. The main processes occurring in this three-species microcosm were thus formalized, including growth and settling of algae, growth of duckweeds, interspecific competition between algae and duckweeds, growth, survival and grazing of daphnids, as well as cadmium effects. We estimated model parameters by Bayesian inference, using simultaneously all the data issued from multiple laboratory experiments specifically conducted for this study. Cadmium concentrations ranged between 0 and 50μg.L-1. For all parameters of our model, we obtained biologically realistic values and reasonable uncertainties. The cascade of cadmium effects, both direct and indirect, was identified. Critical effect concentrations were provided for the life history traits of each species. An example of experimental design adapted to this kind a microcosm was also proposed. This approach appears promising when studying contaminant effects on ecosystem functioning.
HyperVR–A hybrid prediction framework for virulence factors and antibiotic resistance genes in microbial data
Authors: Ji Boya , Pi Wending , Zhang Xianglilan , Peng Shaoliang 
Published: May 2022

AbstractInfectious diseases, particularly bacterial infections, are emerging at an unprecedented rate, posing a serious challenge to public health and the global economy. Different virulence factors (VFs) work in concert to enable pathogenic bacteria to successfully adhere, reproduce and cause damage to host cells, and antibiotic resistance genes (ARGs) allow pathogens to evade otherwise curable treatments. To understand the causal relationship between microbiome composition, function and disease, both VFs and ARGs in microbial data must be identified. Most existing computational models cannot simultaneously identify VFs or ARGs, hindering the related research. The best hit approaches are currently the main tools to identify VFs and ARGs concurrently; yet they usually have high false-negative rates and are very sensitive to the cut-off thresholds. In this work, we proposed a hybrid computational framework called HyperVR to predict VFs and ARGs at the same time. Specifically, HyperVR integrates key genetic features and then stacks classical ensemble learning methods and deep learning for training and prediction. HyperVR accurately predicts VFs, ARGs and negative genes (neither VFs nor ARGs) simultaneously, with both high precision (>0.91) and recall (>0.91) rates. Also, HyperVR keeps the flexibility to predict VFs or ARGs individually. Regarding novel VFs and ARGs, the VFs and ARGs in metagenomic data, and pseudo VFs and ARGs (gene fragments), HyperVR has shown good prediction, outperforming the current state-of-the-art predition tools and best hit approaches in terms of precision and recall. HyperVR is a powerful tool for predicting VFs and ARGs simultaneously by using only gene sequences and without strict cut-off thresholds, hence making prediction straightforward and accurate.
Robust genome editing via modRNA-based Cas9 or base editor in human pluripotent stem cells
Authors: Haideri Tahir , Howells Alessandro , Jiang Yuqian , Yang Jian , Bao Xiaoping , Lian Xiaojun Lance 
Published: May 2022

SummaryCRISPR systems have revolutionized biomedical research because they offer an unprecedented opportunity to explore the application of genome editing in human pluripotent stem cells (hPSCs). Due to the inherent simplicity of CRISPR systems, requiring a Cas protein and its corresponding single guide RNA (sgRNA), they are more widely adopted and used for diverse biomedical research than their predecessors (zinc finger nucleases and TALENs). However, a bottleneck of applying CRISPR systems in hPSCs is how to deliver CRISPR effectors easily and efficiently into hPSCs. Herein, we developed modified mRNA (modRNA) based CRIPSR systems that utilized Cas9 or base editor (ABE8e) modRNA for genome editing of hPSCs via simple lipid-based transfection. We have achieved 71.09% ± 9.13% and 68.53% ± 3.81% gene knockout (KO) efficiency with Cas9 modRNA and ABE8e modRNA, respectively, which is significantly higher than plasmid-based systems. In summary, we demonstrate that our non-integrating modRNA based CRISPR methods hold great promise as the more efficient and accessible techniques for genome editing of hPSCs.
Bi-phasic patterns of age-related differences in dopamine D1 receptors across the adult lifespan
Authors: Johansson Jarkko , Nordin Kristin , Pedersen Robin , Karalija Nina , Papenberg Goran , Andersson Micael , Korkki Saana M. , Riklund Katrine , Guitart-Masip Marc , Rieckmann Anna , Bäckman Lars , Nyberg Lars , Salami Alireza 
Published: May 2022

ABSTRACTThe dopamine (DA) system, particularly D1-like DA receptors (D1DR), declines across the adult life. The functional consequences of reduced D1DR has been hypothesized to vary across life periods, but the precise timing of these periods is unknown. To examine distinct phases in age-related D1DR reductions, we studied 180 healthy adults (90 females, 20-80 years), who underwent D1DR PET assessment using [11C]SCH23390. A bi-phasic pattern of age-related D1DR differences was revealed, with an inflection point at approximately 40 years of age. Notably, D1DR levels before and after the inflection showed opposing relations to neurocognitive functions, in concordance with distinct consequences of D1DR differences during development and in old age. Furthermore, D1DR reductions in later life were linked to age-related cerebrovascular consequences. These results support a distinction between D1DR reductions in early adulthood from those later in life, and suggest less dramatic and more malleable DA losses in aging than previously suggested.
Reproducible patterns of neural activity without attractors in cortical networks
Authors: Guarino Domenico , Filipchuk Anton , Destexhe Alain 
Published: May 2022

AbstractCortical activity often consists of recurring population events of correlated neuronal firing and highly reproducible firing patterns. Because of their resemblance with attractor dynamics, the attractor model prevails today, although it has not been firmly demonstrated. Here, we used a unique dataset, with co-registered two-photon calcium imaging and electron microscopy of the same cortical tissue, to test the central assumption of attractor networks: recurrently active “core” neurons should be strongly interconnected. We report that, contrary to the attractor paradigm, core neurons have fewer weaker connections compared to other neurons. Instead, core neurons funnel the flow of multiple connectivity pathways. Computational models give a mechanistic account of these features showing that distance-dependent connectivity forms converging-diverging motifs and, at their funneling centers, core neurons are found. Thus, reproducible cortical activity and connectivity can be explained without postulating underlying attractor networks but rather by the existence of overlapping information flows.
Induction of Anxiety-Like Phenotypes by Knockout of Cannabinoid Type-1 Receptor in Amygdala of Marmosets
Authors: Zheng Di , Zhu Lin , Li Rui , Shen Chen-Jie , Cai Ruolan , Sun Hao , Wang Xiaohui , Ding Yu , Xu Bin , Jia Guoqiang , Li Xinjian , Gao Lixia , Li Xiao-Ming 
Published: May 2022

AbstractThe amygdala is an important hub for the regulation of emotions, which is crucial for elucidating cellular and molecular mechanisms of many mental diseases. In the central nervous system, the endocannabinoid system plays a key role in the regulation of emotions and mainly functions through the cannabinoid type-1 receptor (CB1R), which is encoded by theCnr1gene. Although CB1R is highly expressed in the amygdala of non-human primates, little is known about its function. Here, we investigated the function of CB1R by knocking out the CB1R in the amygdala of adult marmosets through regional delivery of AAV-SaCas9-gRNA. We found that CB1R knockout in the amygdala of marmosets induced anxiety-like behaviors, including disrupted night sleep, agitated psychomotor activity in new environments, and reduced social desire, but had no effect on hedonic state and fear response. Moreover, CB1R-knockout marmosets exhibited up-regulated plasma cortisol levels, suggesting increased stress. These results showed that knockout of CB1R in the amygdala induced anxiety-like phenotypes in marmosets and shed new light on the mechanisms underlying the regulation of anxiety by CB1R in the amygdala of non-human primates.
Defining the spatial distribution of extracellular adenosine revealed a myeloid-dependent immunosuppressive microenvironment in pancreatic ductal adenocarcinoma
Authors: Graziano Vincenzo , Dannhorn Andreas , Hulme Heather , Williamson Kate , Buckley Hannah , Karim Saadia A , Lee Sheng Y. , Kaistha Brajesh P. , Islam Sabita , Thaventhiran James E. D. , Richards Frances M. , Goodwin Richard , Brais Rebecca , Morton Jennifer P , Dovedi Simon J. , Schuller Alwin G. , Eyles Jim , Jodrell Duncan I. 
Published: May 2022

AbstractThe prognosis for patients with pancreatic ductal adenocarcinoma (PDAC) remains extremely poor. It has been suggested that the adenosine pathway contributes to the ability of PDAC to evade the immune system and its resistance to immunotherapies (Immuno-Oncology Therapy, IOT), by generating extracellular adenosine (eAdo).Using genetically engineered allograft models of PDAC in syngeneic mice with differential immune infiltration and response to IOT, we showed enrichment of the adenosine pathway in tumour-infiltrating immune cells (in particular, myeloid populations). Using MS-Imaging, we showed that extracellular adenosine distribution is heterogeneous in tumours, with high concentrations in hypoxic margins that surround necrotic areas, associated with a rich myeloid infiltration, demonstrated using Imaging Mass Cytometry (IMC). Pro-tumorigenic M2 macrophages express high levels of the Adora2a receptor; particularly in the IOT resistant model. Blocking thein vivoformation and function of eAdo (Adoi), using a combination of anti-CD73 antibody and an Adora2a inhibitor slowed tumour growth and reduced metastatic burden. In addition, blocking the adenosine pathway improved the efficacy of combinations of cytotoxic agents or immunotherapy. Finally, Adoi remodelled the tumour microenvironment (TME), as evidenced by reduced infiltration of M2 macrophages and Tregs. RNAseq analysis showed that genes related to immune modulation, hypoxia and tumour stroma were downregulated following Adoi and a specific adenosine signature derived from this is associated with a poorer prognosis in patients with PDAC.The formation of eAdo appears to promote the development of the immunosuppressive TME in PDAC, contributing to its resistance to conventional and novel therapies. Therefore, inhibition of the adenosine pathway may represent a strategy to modulate the stroma and improve therapy response in patients with PDAC.