bluuebunny/crossref_metadata_2025_split huggingface dataset:
MicrogliaST: a web server for microglia spatiotemportal pattern analysis in normal and disordered brains
Authors: Zhong Xiaoling , Li Feng , Tan Guiyuan , Yi Li , Zhao Jiaxin , Mi Wanqi , Zhang Yu , Hu Congxue , Li Xia , Xu Yingqi , Zhang Chunlong 
Published: January 2022

AbstractBrain is the most complex organ of living organisms, as the celebrated cells in the brain, microglia play an indispensable role in the brain’s immune microenvironment. Microglia have critical roles not only in neural development and homeostasis, but also in neurodegenerative diseases and malignant of the central nervous system. However, little is known about the dynamic characteristics of microglia during development or disease conditions. Recently, the single-cell RNA sequencing technologies have become possible to characterize the heterogeneity of immune system in brain. But it posed computational challenges on integrating and utilizing the massive published datasets to dissect the spatiotemporal characterization of microglia. Here, we present microgliaST (bio-bigdata.hrbmu.edu.cn/MST), a database consisting of single-cell microglia transcriptomes across multiple brain regions and developmental periods. Based on high-quality microglia markers collected from published papers, we annotated and constructed human and mouse transcriptomic profiles of 273,374 microglias, comprising 12 regions, 12 periods and 3 conditions (normal, disease, treatment). In addition, MicrogliaST provides multiple analytical tools to elucidate the landscape of microglia under disorder conditions, conduct personalized difference analysis and spatiotemporal dynamic analysis. More importantly, microgliaST paves an ingenious way to the study of brain environment, and also provides insights into clinical therapy assessments.
Lipid nanoparticles delivering constitutively active STING mRNA as a novel anti-cancer therapeutic approach
Authors: Liu Wei , Alameh Mohamad-Gabriel , Yang June F. , Xu Jonathan R. , Lin Paulo JC , Tam Ying K , Weissman Drew , You Jianxin 
Published: January 2022

AbstractTreating immunosuppressive tumors represents a major challenge in cancer therapies. Activation of STING signaling has shown remarkable potential to invigorate the immunologically ‘cold’ tumor microenvironment (TME). However, we and others have shown that STING is silenced in many cancers, including pancreatic ductal adenocarcinoma (PDAC) and Merkel cell carcinoma (MCC), both of which are associated with an immune-dampened TME. In this study, we applied mRNA lipid nanoparticles (LNP) to deliver a permanently active gain-of-function STINGR284S mutant into PDAC and MCC cells. Expression of STINGR284S induces cytokines and chemokines crucial for promoting intratumoral infiltration of CD8+ T cells and, importantly, also leads to robust cancer cell death while avoiding T cell entry and toxicity. Our studies demonstrated that mRNA-LNP delivery of STINGR284S could be explored as a novel therapeutic tool to reactivate antitumor response in an array of STING-deficient cancers while overcoming the toxicity and limitations of conventional STING agonists.
Real World Evidence of Neutralizing Monoclonal Antibodies for Preventing Hospitalization and Mortality in COVID-19 Outpatients
Authors: Wynia Matthew K. , Beaty Laurel E. , Bennett Tellen D. , Carlson Nichole E. , Davis Christopher B. , Kwan Bethany M. , Mayer David A. , Ong Toan C. , Russell Seth , Steele Jeffrey , Stocker Heather R. , Wogu Adane F. , Zane Richard D. , Sokol Ronald J. , Ginde Adit A. 
Published: January 2022

ABSTRACTBackgroundNeutralizing monoclonal antibodies (mAbs) are authorized for early symptomatic COVID-19 patients. Whether mAbs are effective against the SARS-CoV-2 Delta variant, among vaccinated patients, or for prevention of mortality remains unknown.ObjectiveTo evaluate the effectiveness of mAb treatment in preventing progression to severe disease during the Delta phase of the pandemic and based on key baseline risk factors.Design, Setting, and PatientsObservational cohort study of non-hospitalized adult patients with SARS-CoV-2 infection from November 2020-October 2021, using electronic health records from a statewide health system plus state-level vaccine and mortality data. Using propensity matching, we selected approximately 2.5 patients not receiving mAbs for each patient who received mAbs.ExposureNeutralizing mAb treatment under emergency use authorizationMain OutcomesThe primary outcome was 28-day hospitalization; secondary outcomes included mortality and severity of hospitalization.ResultsOf 36,077 patients with SARS-CoV-2 infection, 2,675 receiving mAbs were matched to 6,677 not receiving mAbs. Compared to mAb-untreated patients, mAb-treated patients had lower all-cause hospitalization (4.0% vs 7.7%; adjusted OR 0.48, 95%CI 0.38-0.60) and all-cause mortality (0.1% vs. 0.9%; adjusted OR 0.11, 95%CI 0.03-0.29) to day 28; differences persisted to day 90. Among hospitalized patients, mAb-treated patients had shorter hospital length of stay (5.8 vs. 8.5 days) and lower risk of mechanical ventilation (4.6% vs. 16.6%). Relative effectiveness was similar in preventing hospitalizations during the Delta variant phase (adjusted OR 0.35, 95%CI 0.25-0.50) and across subgroups. Lower number-needed-to-treat (NNT) to prevent hospitalization were observed for subgroups with higher baseline risk of hospitalization (e.g., multiple comorbidities (NNT=17) and not fully vaccinated (NNT=24) vs. no comorbidities (NNT=88) and fully vaccinated (NNT=81).ConclusionReal-world evidence demonstrated mAb effectiveness in reducing hospitalization among COVID-19 outpatients, including during the Delta variant phase, and conferred an overall 89% reduction in 28-day mortality. Early outpatient treatment with mAbs should be prioritized, especially for individuals with highest risk for hospitalization.
Genetic Impairment of Succinate Metabolism Disrupts Bioenergetic Sensing in Adrenal Neuroendocrine Cancer
Authors: Gupta Priyanka , Strange Keehn , Telange Rahul , Guo Ailan , Hatch Heather , Sobh Amin , Elie Jonathan , Carter Angela M. , Totenhagen John , Tan Chunfeng , Sonawane Yogesh A. , Neuzil Jiri , Natarajan Amarnath , Ovens Ashley J. , Oakhill Jonathan S. , Wiederhold Thorsten , Pacak Karel , Ghayee Hans K. , Meijer Laurent , Reddy Sushanth , Bibb James A. 
Published: January 2022

SUMMARYMetabolic dysfunction mutations can impair energy sensing and cause cancer. Loss of function of mitochondrial TCA cycle enzyme, succinate dehydrogenase B (SDHB) results in various forms of cancer typified by pheochromocytoma (PC). Here we delineate a signaling cascade where the loss ofSDHBinduces the Warburg effect in PC tumors, triggers dysregulation of Ca2+homeostasis, and aberrantly activates calpain and the protein kinase Cdk5, through conversion of its cofactor from p35 to p25. Consequently, aberrant Cdk5 initiates a cascade of phospho- signaling where GSK3 inhibition inactivates energy sensing by AMP-kinase through dephosphorylation of the AMP-kinase γ subunit, PRKAG2. Overexpression of p25-GFP in mouse adrenal chromaffin cells also elicits this phosphorylation signaling and causes PC tumor formation. A novel Cdk5 inhibitor, MRT3-007, reversed this phospho-cascade, invoking an anti- Warburg effect, cell cycle arrest, and senescence-like phenotype. This therapeutic approach halted tumor progressionin vivo. Thus, we reveal an important novel mechanistic feature of metabolic sensing and demonstrate that its dysregulation underlies tumor progression in PC and likely other cancers.HighlightsLoss of SDHB function in pheochromocytoma causes Ca2+dysregulation, calpain activation, and aberrant activation of the protein kinase Cdk5.Hyperactive Cdk5 deregulates a GSK3/PRKAG2/AMPKα signaling cascade.p25 overexpression and consequent aberrant Cdk5 activity in chromaffin cells causes pheochromocytoma.Inhibition of Cdk5 activates the PRKAG2/AMPK/p53 signaling to rescue cell senescence and block PC tumor progression.Graphical Abstract
Oil Red O based method for Exosome Labelling and detection
Authors: Bharati Shikha , Anjaly Km , Thoidingjam Shivani , Tiku Ashu Bhan 
Published: January 2022

AbstractWith the realization of the role of exosomes in diseases especially cancer, exosome research is gaining popularity in biomedical sciences. To understand exosome biology, their labelling and tracking studies are important. New and improved methods of exosome labelling for detection and tracking of exosomes need to be developed to harness their therapeutic and diagnostic potential. In this paper, we report a novel, simple and effective method of labelling and detecting exosomes using Oil red O (ORO) which is a dye commonly used for lipid staining. Using ORO is a cost effective and easy approach with intense red colouration of stained exosomes. Further, the issues faced with commonly used lipophilic dyes for exosomes labelling such as long term persistence of dyes, aggregation and micelle formation of dyes, difficulty to distinguish dye particles from labelled exosomes and detection of large aggregates of dye or dye-exosome are not seen with ORO dye. This method shows good labelling efficiency of exosomes with very sensitive detection and real-time tracking of the cellular uptake of exosomes.Abstract Figure
Robust and Brain-Like Working Memory through Short-Term Synaptic Plasticity
Authors: Kozachkov Leo , Tauber John , Lundqvist Mikael , Brincat Scott L. , Slotine Jean-Jacques , Miller Earl K. 
Published: January 2022

AbstractWorking memory has long been thought to arise from sustained spiking/attractor dynamics. However, recent work has suggested that short-term synaptic plasticity (STSP) may help maintain attractor states over gaps in time with little or no spiking. To determine if STSP endows additional functional advantages, we trained artificial recurrent neural networks (RNNs) with and without STSP to perform an object working memory task. We found that RNNs with and without STSP were able to maintain memories over distractors presented in the middle of the memory delay. However, RNNs with STSP showed activity that was similar to that seen in the cortex of a non-human primate (NHP) performing the same task. By contrast, RNNs without STSP showed activity that was less brain-like. Further, RNNs with STSP were more robust to noise and network degradation than RNNs without STSP. These results show that STSP can not only help maintain working memories, it also makes neural networks more robust and brain-like.
Membrane tension propagation couples axon growth and collateral branching
Authors: Shi Zheng , Innes-Gold Sarah , Cohen Adam E. 
Published: January 2022

AbstractNeuronal axons must navigate a mechanically heterogeneous environment to reach their targets, but the biophysical mechanisms coupling mechanosensation, growth, and branching are not fully understood. Here, we show that local changes in membrane tension propagate along axons at approximately 20 µm/s, more than 1000-fold faster than in other non-motile cells. This rapid and long-range mechanical signaling mediates bidirectional competition between axonal branch initiation and growth cone extension. Our data suggest a mechanism by which mechanical cues at one part of a growing axon can affect growth dynamics remotely.
Cohort-specific serological recognition of SARS-CoV-2 variant RBD antigens
Authors: Fraser Douglas D. , Miller Michael R. , Martin Claudio M. , Slessarev Marat , Hahn Paul , Higgins Ian , Melo Christopher , Pest Michael A. , Rothery Nate , Wang Xiaoqin , Zeidler Johannes , Cruz-Aguado Jorge A. 
Published: January 2022

AbstractBackgroundEstimating the response of different cohorts (e.g. vaccinated or critically ill) to new SARS-CoV-2 variants is important to customize measures of control. Thus, our goal was to evaluate binding of antibodies from sera of infected and vaccinated people to different antigens expressed by SARS-CoV-2 variants.MethodsWe compared sera from vaccinated donors with sera from four patient/donor cohorts: critically ill patients admitted to an intensive care unit (split in sera collected between 2 and 7 days after admission and more than ten days later), a NIBSC/WHO reference panel of SARS-CoV-2 positive individuals, and ambulatory or hospitalized (but not critically ill) positive donors. Samples were tested with an anti-SARS-CoV-2 IgG serological assay designed with microplates coated with a SARS-CoV-2 RBD recombinant antigen. The same sample sets were also tested with microplates coated with antigens harbouring RBD mutations present in eleven of the most widespread variants.ResultsSera from vaccinated individuals exhibited higher antibody binding (P<0.001) than sera from infected (but not critically ill) individuals when tested against the WT and each of 11 variants’ RBD.The optical density generated by sera from non-critically ill convalescence individuals upon binding to variant’s antigens was different (P<0.05) from that of the WT in some variants—noteworthy, Beta, Gamma, Delta, and Delta Plus variants.ConclusionsUnderstanding differences in binding and neutralizing antibody titers against WT vs variant RBD antigens from different donor cohorts can help design variant-specific immunoassays and complement other diagnostic and clinical data to evaluate the epidemiology of new variants.
Genomic Machine Learning Meta-regression: Insights on Associations of Study Features with Reported Model Performance
Authors: Barnett Eric , Onete Daniel , Salekin Asif , Faraone Stephen V 
Published: January 2022

AbstractBackgroundMany studies have been conducted with the goal of correctly predicting diagnostic status of a disorder using the combination of genetic data and machine learning. The methods of these studies often differ drastically. It is often hard to judge which components of a study led to better results and whether better reported results represent a true improvement or an uncorrected bias inflating performance.MethodsIn this systematic review, we extracted information about the methods used and other differentiating features in genomic machine learning models. We used the extracted features in mixed-effects linear regression models predicting model performance. We tested for univariate and multivariate associations as well as interactions between features.ResultsIn univariate models the number of hyperparameter optimizations reported and data leakage due to feature selection were significantly associated with an increase in reported model performance. In our multivariate model, the number of hyperparameter optimizations, data leakage due to feature selection, and training size were significantly associated with an increase in reported model performance. The interaction between number of hyperparameter optimizations and training size as well as the interaction between data leakage due to optimization and training size were significantly associated reported model performance.ConclusionsOur results suggest that methods susceptible to data leakage are prevalent among genomic machine learning research, which may result in inflated reported performance. The interactions of these features with training size suggest that if data leakage susceptible methods continue to be used, modelling efforts using larger data sets may result in unexpectedly lower results compared to smaller data sets. Best practice guidelines that promote the avoidance and recognition of data leakage may help the field advance and avoid biased results.
Changes in foot progression angle during gait reduce the knee adduction moment and do not increase hip moments in individuals with knee osteoarthritis
Authors: Seagers Kirsten , Uhlrich Scott D. , Kolesar Julie A. , Berkson Madeleine , Kaneda Janelle M. , Beaupre Gary S. , Delp Scott L. 
Published: January 2022

AbstractPeople with knee osteoarthritis who adopt a modified foot progression angle (FPA) during gait often benefit from a reduction in the knee adduction moment. It is unknown, however, whether changes in the FPA increase hip moments, a surrogate measure of hip loading, which will increase the mechanical demand on the joint. This study examined how altering the FPA affects hip moments. Individuals with knee osteoarthritis walked on an instrumented treadmill with their baseline gait, 10° toe-in gait, and 10° toe-out gait. A musculoskeletal modeling package was used to compute joint moments from the experimental data. Fifty participants were selected from a larger study who reduced their peak knee adduction moment with a modified FPA. In this group, participants reduced the first peak of the knee adduction moment by 7.6% with 10° toe-in gait and reduced the second peak by 11.0% with 10° toe-out gait. Modifying the FPA reduced the early-stance hip abduction moment, at the time of peak hip contact force, by 4.3% ± 1.3% for 10° toe-in gait (p=0.005, d=0.49) and by 4.6% ± 1.1% for 10° toe-out gait (p<0.001, d=0.59) without increasing the flexion and internal rotation moments (p>0.15). Additionally, 74% of individuals reduced their total hip moment at time of peak hip contact force with a modified FPA. In summary, when adopting a FPA modification that reduced the knee adduction moment, participants, on average, did not increase surrogate measures of hip loading.
EFFECT OF FULL VACCINATION AND POST-COVID OLFACTORY DYSFUNCTION IN RECOVERED COVID-19 PATIENT. A RETROSPECTIVE LONGITUDINAL STUDY WITH PROPENSITY MATCHING
Authors: Herman Bumi , Viwattanakulvanid Pramon , Dzulhadj Azhar , Oo Aye Chan , Patricia Karina , Pongpanich Sathirakorn 
Published: January 2022

BackgroundSymptoms after COVID-19 infection affect the quality of life of its survivor especially to the special senses including olfactory function. It is important to prevent the disability at an earlier stage. Vaccination as key prevention has been proven to be effective in reducing symptomatic disease and severity. However, the effects of vaccination on post COVID symptoms have not been evaluated. This study aimed to evaluate the possible protection of full vaccination and the occurrence of post-COVID olfactory dysfunction, specifically anosmia and hyposmia in patients who were diagnosed with COVID19.MethodA longitudinal analysis using the retrospective cohort of the Indonesian patient-based Post-COVID survey collected from July 2021 until December 2021, involving COVID-19 Patients confirmed by RT-PCR and/or Antigen test. Variables including demography, comorbidities, health behavior, type of vaccine, symptoms, and treatment were collected through an online questionnaire based on the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS). Participants were matched (1:1) using propensity matching score into two exposure statuses, infected 1)>14 days of full vaccination and 2)<14 days or incomplete or unvaccinated. The olfactory dysfunction was assessed two weeks and four weeks after negative conversion with PCR using a self-measured olfactory questionnaire (MOQ). The Generalized Estimating Equation (GEE) was performed to assess the effect of full vaccination on post-COVID olfactory dysfunction. The Receiver Operating Characteristic determined the sensitivity and specificity of the cutoff value of the days from fully vaccinated to diagnosis and the olfactory dysfunction.ResultsA total of 442 participants were extracted from the cohort and inoculated with the inactivated viral vaccine (99.5%). The prevalence of olfactory dysfunction in two weeks was 9.95% and 5.43% after four weeks. Adjusted by other variables, people who were infected >14 days after being fully vaccinated had a 69% (adjusted OR 0.31 95% CI 0.102-0.941) probability of developing olfactory dysfunction. Longer days of fully vaccinated to infection associated with increased risk (adjusted OR 1.012 95% CI 1.002-1.022 p-value 0.015). A cut-off of 88 days of full vaccination-to-diagnosis duration has Area Under Curve (AUC) of 0.693 (p=0.002), the sensitivity of 73.9%, and specificity of 63.3% in differentiating the olfactory dysfunction event in two weeks after COVID with a crude odds ratio of 4.852 (95% CI 1.831-12.855 p=0.001)ConclusionAfter 14 days of full vaccination, the protective effect could reduce the chance of post-COVID olfactory dysfunction although a longer full vaccination-to-diagnosis duration increases the risk. It is important to consider a booster shot starting from 89 days after the last dose in those who received the inactivated viral regimen.
Environmental risk factors associated with the presence ofMycobacterium ulceransin Victoria, Australia
Authors: Blasdell Kim R. , McNamara Bridgette , O’Brien Daniel P. , Tachedjian Mary , Boyd Victoria , Dunn Michael , Mee Peter T. , Clayton Simone , Gaburro Julie , Smith Ina , Gibney Katherine B. , Tay Ee Laine , Hobbs Emma C , Waidyatillake Nilakshi , Lynch Stacey E. , Stinear Timothy P. , Athan Eugene 
Published: January 2022

AbstractIn recent years reported cases of Buruli ulcer (BU), caused byMycobacterium ulcerans(MU), have increased substantially in Victoria, Australia, with the epidemic also expanding geographically. To develop an understanding of how MU circulates in the environment and transmits to humans we analyzed environmental samples collected from 115 properties of recent BU cases and from 115 postcode-matched control properties, for the presence of MU. Environmental factors associated with increased odds of MU presence at a property included certain native plant species and native vegetation in general, more alkaline soil, lower altitude, the presence of common ringtail possums (Pseudocheirus peregrinus) and overhead powerlines. However, only powerlines and the absence of the native plantMelaleuca lanceolatawere associated with BU case properties. Samples positive for MU were more likely to be found at case properties and were associated with detections of MU in ringtail possum feces, supporting the hypothesis that MU is zoonotic, with ringtail possums the strongest reservoir host candidate. However, the disparity in environmental risk factors associated with MU positive properties versus case properties indicates a strong human behavioral component or the influence of other environmental factors in disease acquisition that requires further study.Article Summary LinePossums, powerlines, and native vegetation are associated with the presence ofMycobacterium ulceransin residential properties in Victoria, Australia.
Analytic sensitivity of the Abbott BinaxNOW™ lateral flow immunochromatographic assay for the SARS-CoV-2 Omicron variant
Authors: Kanjilal Sanjat , Chalise Sujata , Shah Adnan Shami , Cheng Chi-An , Senussi Yasmeen , Springer Michael , Walt David R. 
Published: January 2022

AbstractThe emergence of the SARS-CoV-2 Omicron variant has motivated a re-evaluation of the test characteristics for lateral flow immunochromatographic assays (LFIAs), commonly referred to as rapid antigen tests. To address this need, we evaluated the analytic sensitivity of one of the most widely used LFIAs in the US market, the Abbott BinaxNOW™ COVID-19 Ag At-Home Card using 32 samples of Omicron and 30 samples of the Delta variant. Samples were chosen to intentionally over-represent the range of viral loads where differences are most likely to appear. We found no changes in the analytic sensitivity of the BinaxNOW™ assay by variant even after controlling for variation in cycle threshold values in the two populations. Similar to prior studies, the sensitivity of the assay is highly dependent on the amount of virus present in the sample. While the analytic sensitivity of the BinaxNOW™ LFIA remains intact versus the Omicron variant, its clinical sensitivity is influenced by the interaction between viral replication, the dynamics of tissue tropism and the timing of sampling. Further research is necessary to optimally adapt current testing strategies to robustly detect early infection by the Omicron variant to prevent transmission.