bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulatory B cells (Bregs) inhibit osteoclastogenesis and prevent bone loss in osteoporotic mice model
Authors: Sapra Leena , Bhardwaj Asha , Mishra Pradyumna K. , Verma Bhupendra K. , Srivastava Rupesh K. 
Published: March 2021

AbstractIncreasing evidences in recent years have suggested that regulatory B cells (Bregs) are crucial modulator in various inflammatory disease conditions. However, the role of Bregs in case of postmenopausal osteoporosis remains unknown. Also, no study till date have ever investigated the significance of Bregs in modulating osteoclastogenesis. In the present study, we for the first time examined the anti-osteoclastogenic potential of Bregs underin vitroconditions and we observed that Bregs suppressed RANKL mediated osteoclastogenesis in bone marrow cells in a dose dependent manner. We further elucidated the mechanism behind the suppression of osteoclasts differentiation by Bregs and found that Bregs inhibit osteoclastogenesis via IL-10 production. To further confirm the bone health modulating potential of Bregs we employed post-menopausal osteoporotic mice model. Remarkably, ourin vivodata clearly suggest a significant reduction (p < 0.01) in both CD19+IL-10+and CD19+CD1dhiCD5+IL-10+B10 Bregs in case of osteoporotic mice model. Moreover, our serum cytokine data further confirms the significant reduction of IL-10 levels in osteoporotic mice. Taken together, the present study for the first time unravels and establish the unexplored role of regulatory B cells in case of osteoporosis and provide new insight into Bregs biology in the context of post-menopausal osteoporosis.
A rapid and efficient learning rule for biological neural circuits
Authors: Sezener Eren , Grabska-Barwińska Agnieszka , Kostadinov Dimitar , Beau Maxime , Krishnagopal Sanjukta , Budden David , Hutter Marcus , Veness Joel , Botvinick Matthew , Clopath Claudia , Häusser Michael , Latham Peter E. 
Published: March 2021

AbstractThe dominant view in neuroscience is that changes in synaptic weights underlie learning. It is unclear, however, how the brain is able to determine which synapses should change, and by how much. This uncertainty stands in sharp contrast to deep learning, where changes in weights are explicitly engineered to optimize performance. However, the main tool for that, backpropagation, has two problems. One is neuro-science related: it is not biologically plausible. The other is inherent: networks trained with this rule tend to forget old tasks when learning new ones. Here we introduce the Dendritic Gated Network (DGN), a variant of the Gated Linear Network, which offers a biologically plausible alternative to backpropagation. DGNs combine dendritic ‘gating’ (whereby interneurons target dendrites to shape neuronal responses) with local learning rules to yield provably efficient performance. They are significantly more data efficient than conventional artificial networks, and are highly resistant to forgetting. Consequently, they perform well on a variety of tasks, in some cases better than backpropagation. Importantly, DGNs have structural and functional similarities to the cerebellum, a link that we strengthen by usingin vivotwo-photon calcium imaging to show that single interneurons suppress activity in individual dendritic branches of Purkinje cells, a key feature of the model. Thus, DGNs leverage targeted dendritic inhibition and local learning – two features ubiquitous in the brain – to achieve fast and efficient learning.
Paradoxical relationship between speed and accuracy in olfactory figure-background segregation
Authors: Lebovich Lior , Yunerman Michael , Scaiewicz Viviana , Loewenstein Yonatan , Rokni Dan 
Published: March 2021

AbstractIn natural settings, many stimuli impinge on our sensory organs simultaneously. Parsing these sensory stimuli into perceptual objects is a fundamental task faced by all sensory systems. Similar to other sensory modalities, increased odor backgrounds decrease the detectability of target odors by the olfactory system. The mechanisms by which background odors interfere with the detection and identification of target odors are unknown. Here we utilized the framework of the Drift Diffusion Model (DDM) to consider possible interference mechanisms in an odor detection task. We consider effects of background odors on both signal and noise in the decision-making dynamics, and show that these produce different predictions about decision accuracy and speed. To test these predictions, we trained mice to detect target odors that are embedded in random background mixtures in a two-alternative choice task. Trial duration was independent of behavioral reaction times to avoid motivating rapid responses. We found that the behavioral data is most consistent with background odors acting by adding noise to the decision-making dynamics. The added noise decreases the correct rate, but also decreases decision times, thereby creating a paradoxical relationship between speed and accuracy of target detection, where mice make faster and less accurate decisions in the presence of background odors.
Divergence in Population Coding for Space between Dorsal and Ventral CA1
Authors: Chockanathan Udaysankar , Padmanabhan Krishnan 
Published: March 2021

SummaryMolecular, anatomic, and behavioral studies show that the hippocampus is structurally and functionally heterogeneous, with dorsal hippocampus implicated in mnemonic processes and spatial navigation and ventral hippocampus involved in affective processes. By performing electrophysiological recordings of large neuronal populations in dorsal and ventral CA1 in head-fixed mice navigating a virtual environment, we found that this diversity resulted in different strategies for population coding of space. We found that the populations of neurons in dorsal CA1 had a higher dimensionality and showed more complex patterns of activity, translating to more information being encoded, as compared ensembles in vCA1. Furthermore, a pairwise maximum entropy model was better at predicting the structure of global patterns of activity in ventral CA1 as compared to dorsal CA1. Taken together, we uncovered different coding strategies that likely emerge from anatomical and physiological differences along the longitudinal axis of hippocampus and that may, in turn, underpin the divergent ethological roles of dorsal and ventral CA1.HighlightsNo differences in dCA1 and vCA1 place field size in recordings of neuronal populations in mice navigating a virtual environmentdCA1 has higher single-neuron and population-level spatial information compared to vCA1 due to differences in the sparsity of firing.Population activity of dCA1 has higher entropy and is higher dimensional than vCA1Pairwise maximum entropy models are better at predicting population activity in vCA1 compared to dCA1
how_are_we_stranded_here: Quick determination of RNA-Seq strandedness
Authors: Signal Beth , Kahlke Tim 
Published: March 2021

ABSTRACTQuality control checks are the first step in RNA-Sequencing analysis, which enable the identification of common issues that occur in the sequenced reads. Checks for sequence quality, contamination, and complexity are commonplace, and allow users to implement steps downstream which can account for these issues. Strand-specificity of reads is frequently overlooked and is often unavailable even in published data, yet when unknown or incorrectly specified can have detrimental effects on the reproducibility and accuracy of downstream analyses. We present how_are_we_stranded_here, a Python library that helps to quickly infer strandedness of paired-end RNA-Sequencing data.
Pre-existing health conditions and severe COVID-19 infection: Analysis of commercial health insurance data from 690,000 infected patients
Authors: Wineinger Nathan E. , Li Victoria , Waalen Jill , Topol Eric J. 
Published: March 2021

AbstractThe development and distribution of new vaccines promises an end to the COVID-19 pandemic. With the elderly and front line workers first in line, the vaccination strategy for the general population remains unclear. In this study we identified 690,000 patients infected with COVID-19 with commercial health insurance coverage across the country between April 1, 2020 and September 30, 2020. From prior health care claims, we determined each person’s pre-existing diseases among 26 common chronic diseases. Across age-sex strata we determined the relationships between these conditions and severe COVID-19 infections: ICU admission and extended in-patient stay. We classify disease according to risk, develop multivariable models to predict infection outcomes, and created an online risk assessment tool to estimate risk of ICU admission based on pre-existing health conditions. Our results could be used to help guide risk, vaccination health policy, and personal decision-making as these become available to the general population.
Seroprevalence of SARS-CoV-2 Infection in Cincinnati Ohio USA from August to December 2020
Authors: Davis Greg , York Allen J. , Bacon Willis Clark , Suh-Chin Lin , McNeal Monica Malone , Yarawsky Alexander E. , Maciag Joseph J. , Miller Jeanette L. C. , Locker Kathryn C. S. , Bailey Michelle , Stone Rebecca , Hall Michael , Gonzalez Judith , Sproles Alyssa , Woodle E. Steve , Safier Kristen , Justus Kristine A. , Spearman Paul , Ware Russell E. , Cancelas Jose A. , Jordan Michael B. , Herr Andrew B. , Hildeman David A. , Molkentin Jeffery D. 
Published: March 2021

AbstractThe world is currently in a pandemic of COVID-19 (Coronavirus disease-2019) caused by a novel positive-sense, single-stranded RNA β-coronavirus referred to as SARS-CoV-2. Fortunately, most infected individuals recover and are then resistant to re-infection for a period, indicating that a vaccination approach can be successful. Elucidation of rates of past SARS-CoV-2 infection within select regions across the United States of America (USA) will help direct vaccination efforts and together will inform our approach towards achieving herd immunity. Here we investigated rates of SARS-CoV-2 infection in the greater Cincinnati, Ohio, USA metropolitan area from August to December 2020, just prior to initiation of the national vaccination program. Examination of 9,550 adult blood donor volunteers for serum IgG antibody positivity against the SARS-CoV-2 Spike protein showed an overall prevalence of 8.40%, measured as 7.56% in the first 58 days of this time frame, versus a significant increase to 9.24% in the last 58 days, and a final rate of 12.86% in December 2020. Approximately 56% of Spike seropositive individuals also had immunoreactivity against the receptor binding domain (RBD) within the Spike protein, which is associated with viral neutralization. Males and females in the Cincinnati area showed nearly identical rates of past infection, and rates among Hispanics, African Americans and Caucasians were not significantly different. Interestingly, donors under 30 years of age had the highest rates of past infection, while those over 60 had the lowest. Geographic analysis showed that the West side of Cincinnati had a rate of 9.63% versus 8.13% on the East side (demarcated by Interstate-75), while the adjoining area of Kentucky was 7.04% (as demarcated by the Ohio River). These results among healthy blood donors will be critical in calculating the time needed to achieve regional herd immunity in conjunction with the national vaccination campaign.
BMI is positively associated with accelerated epigenetic aging in twin pairs discordant for BMI
Authors: Lundgren Sara , Kuitunen Sara , Pietiläinen Kirsi H. , Hurme Mikko , Kähönen Mika , Männistö Satu , Perola Markus , Lehtimäki Terho , Raitakari Olli , Kaprio Jaakko , Ollikainen Miina 
Published: March 2021

ABSTRACTBackgroundObesity is a heritable complex phenotype which can increase the risk of age-related outcomes. Biological age can be estimated from DNA methylation (DNAm) using various “epigenetic clocks.” Previous work suggests individuals with elevated weight also display accelerated aging, but results vary by epigenetic clock and population. Here, we utilize the new epigenetic clock GrimAge, which closely relates with mortality.ObjectivesWe aimed to assess the cross-sectional association of BMI with age acceleration in twins to limit confounding by genetics and shared environment.Methods and ResultsParticipants were from the Finnish Twin Cohort (FTC; n = 1424), including monozygotic (MZ) and dizygotic (DZ) twins, and DNAm was measured using the Illumina 450k array. Multivariate linear mixed effects models including MZ and DZ twins showed an accelerated epigenetic age of 1.02 months (p-value = 6.1 × 10−12) per 1-unit BMI increase. Additionally, heavier twins in a BMI-discordant MZ twin pair (ΔBMI > 3 kg/m2) had an epigenetic age 5.2 months older than their lighter co-twin (p-value = 0.0074). We also found a positive association between log(HOMA-IR) and age acceleration, confirmed by a meta-analysis of the FTC and two other Finnish cohorts (overall effect = 0.45 years, p-value = 0.0025) from adjusted models.ConclusionWe identified significant associations of BMI and insulin resistance with age acceleration based on GrimAge, which were not due to genetic effects on BMI and aging. Overall, these results support a role of BMI in aging, potentially in part due to the effects of insulin resistance.
Day Camp in the Time of COVID-19: What Went Right?
Authors: Nachman Sharon , Brauner Gabrielle , Beleck Aviva , Handel Andrew S. 
Published: March 2021

AbstractObjectiveTo evaluate whether a successful camp experience can be achieved with implementation of COVID-19 education, screening and hygiene protocols, and designated cohorts during the summer of 2020.Study DesignA survey study of summer day camp directors in the metro-New York area was conducted in September, 2020. The survey inquired about camper demographics, COVID-10 related policies, and the number of COVID-19 cases and exposures at each camp.ResultsResponses were received from 77% (23/30) of camp directors at the completion of the 2020 summer. There were 8,480 camper children and 3,698 staff across the 23 camps surveyed. A variety of precautions were taken to limit COVID-19 incidence among campers and staff, most often including COVID-19 screening at entry, cohorting campers, maximizing outdoor activities, mandating mask use when indoors, and frequent hand sanitizing. Six staff and one camper tested positive for COVID-19. There was no secondary spread within the staff or campers in any of the camps.ConclusionCamps successfully stayed open in the summer of 2020. The low level of COVID-19 in the community was critical to the initial success of camp opening. Policies that were consistent and maintained among the camps helped prevent further spread.
Genome-wide association study identifies two new loci associated with anti-NMDAR encephalitis
Authors: Tietz Anja K , Angstwurm Klemens , Baumgartner Tobias , Doppler Kathrin , Eisenhut Katharina , Elišák Martin , Franke Andre , Golombeck Kristin S , Handreka Robert , Kaufmann Max , Kraemer Markus , Kraft Andrea , Lewerenz Jan , Lieb Wolfgang , Madlener Marie , Melzer Nico , Mojzisova Hana , Möller Peter , Pfefferkorn Thomas , Prüss Harald , Rostásy Kevin , Schnegelsberg Margret , Schröder Ina , Siebenbrodt Kai , Sühs Kurt-Wolfram , Wandinger Klaus-Peter , Wickel Jonathan , Leypoldt Frank , Kuhlenbäumer Gregor 
Published: March 2021

AbstractObjectiveTo investigate the genetic determinants of the most common type of antibody-mediated autoimmune encephalitis, anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis.MethodsWe performed a genome-wide association study in 178 patients with anti-NMDAR encephalitis and 590 healthy controls followed by a colocalization analysis to identify putatively causal genes.ResultsWe identified two independent risk loci harboring genome-wide significant variants (P < 5 × 10−8, OR ≤ 2.2), one on chromosome 15, harboring only the LRRK1 gene, and one on chromosome 11 centered on the ACP2 and NR1H3 genes in a larger region of high linkage-disequilibrium. Colocalization signals with expression quantitative trait loci (eQTL) for different brain regions and immune cell types suggested ACP2, NR1H3, MADD, DDB2, and C11orf49 as putatively causal genes. The best candidate genes in each region are LRRK1, encoding Leucine-Rich Repeat Kinase 1, a protein involved in B-cell development, and NR1H3 liver x receptor alpha, a transcription factor whose activation inhibits inflammatory processes.ConclusionThis study provides evidence for relevant genetic determinants of antibody-mediated autoimmune encephalitides outside the HLA-region. The results suggest that future studies with larger sample sizes will successfully identify additional genetic determinants and contribute to the elucidation of the pathomechanism.
A target HbA1c between 7 – 7.7% reduces macrovascular events in T2D regardless of duration of diabetes – a meta-analysis of randomized controlled trials
Authors: Sinha Binayak , Ghosal Samit 
Published: March 2021

ABSTRACTIntroductionThe target glycosylated haemoglobin (HbA1c) at which macrovascular benefits may be derived in type 2 diabetes (T2D) has never been clearly outlined. This meta-analysis was conducted on fifteen randomized controlled trials to highlight the association of HbA1c range with macrovascular events.MethodsThe association of different HbA1c clusters (intention to treat (ITT) and end-of-study [EOS]) range (less or equal than 6.5%, 6.6%–7.0%, 7.1%–7.7%) with macrovascular complications and also the combined effect of duration of T2D (< 10 years or ≥ 10 years) and HbA1c levels was assessed.ResultsIntensive glucose-lowering strategy resulted in a significant 13% reduction in non-fatal myocardial infarction (NFMI) (P=0.006). Based on HbA1c achieved, a significant 36% reduction in non-fatal stroke (P=0.008) and a 22% reduction in all-cause mortality (P=0.02) were observed in the group with HbA1c between 7.1% – 7.7% irrespective of diabetes duration. In the cohort, with diabetes duration <10 years, reduction of HbA1c in the range7.1% - 7.7% resulted in a significant 36% reduction in non-fatal stroke (NFS) (P<0.001).ConclusionThis is probably the first meta-analysis highlighting the importance of treating patients with T2D to a target HbA1C of 7 – 7.7%, as this target is associated with reduction in macrovascular events.
Early mechanisms of whisker development: Prdm1 and its regulation in whisker development and evolutionary loss
Authors: Manti Pierluigi Giuseppe , Darbellay Fabrice , Leleu Marion , Moret Bernard , Cuennet Julien , Droux Frederic , Stoudmann Magali , Mancini Gian-Filippo , Hautier Agnès , Barrandon Yann 
Published: March 2021

AbstractWhiskers (vibrissae) are miniaturized organs that are designed for tactile sensing. Extremely conserved among mammals, they underwent a reduction in primates and disappeared in the human lineage. Furthermore, whiskers are highly innervated and their mechanoceptors signal to the primary somatosensory cortex, where a column of neurons called “barrel” represents each of them. This structure, known as barrel cortex, occupies a large portion of the somatosensory cortex of the rodent brain. Strikingly,Prdm1conditional knockout mice are one of the rare transgenic strains that do not develop whisker hair follicles while still displaying a pelage (Robertson et al. 2007). Here we show thatPrdm1is expressed early on during whisker development, more precisely in clusters of mesenchymal cells before placode formation. Its conditional knockout leads to the loss of expression ofBmp2, Shh, Bmp4, Krt17, Edar, Gli1though leaving the β-catenin driven first dermal signal intact. Furthermore, we prove thatPrdm1expressing cells not only act as a signaling center but also as a multipotent progenitor population contributing to the formation of the dermal papilla, dermal sheath and pericytes of the vascular sinuses of vibrissae. We confirm by genetic ablation experiments that the absence of motile vibrissae (macro vibrissae) formation reverberates on the organization of nerve wiring in the mystacial pads and organization of the barrel cortex. We prove thatLef1acts upstream ofPrdm1and identify a potential enhancer (named Leaf) that might be involved in the evolutionary process that led to the progressive reduction of snout size and vibrissae in primates.
Systems-level network modeling deciphers the master regulators of phenotypic plasticity and heterogeneity in melanoma
Authors: Pillai Maalavika , Jolly Mohit Kumar 
Published: March 2021

AbstractPhenotypic (i.e. non-genetic) heterogeneity in melanoma drives dedifferentiation, recalcitrance to targeted therapy and immunotherapy, and consequent tumor relapse and metastasis. Various markers or regulators associated with distinct phenotypes in melanoma have been identified, but, how does a network of interactions among these regulators give rise to multiple “attractor” states and phenotypic switching remains elusive. Here, we inferred a network of transcription factors (TFs) that act as master regulators for gene signatures of diverse cell-states in melanoma. Dynamical simulations of this network predicted how this network can settle into different “attractors” (TF expression patterns), suggesting that TF network dynamics drives the emergence of phenotypic heterogeneity. These simulations can recapitulate major phenotypes observed in melanoma and explain de-differentiation trajectory observed upon BRAF inhibition. Our systems-level modeling framework offers a platform to understand trajectories of phenotypic transitions in the landscape of a regulatory TF network and identify novel therapeutic strategies targeting melanoma plasticity.
Protocol-dependence of middle cerebral artery dilation to modest hypercapnia
Authors: Al-Khazraji Baraa K. , Buch Sagar , Kadem Mason , Matushewski Brad J. , Norozi Kambiz , Menon Ravi S. , Shoemaker J. Kevin 
Published: March 2021

AbstractThere is a need for improved understanding of how different cerebrovascular reactivity (CVR) protocols affect vascular cross-sectional area (CSA) when measures of vascular CSA are not feasible. In human participants, we delivered ~±4mmHg end-tidal partial pressure of CO2(PETCO2) relative to baseline through controlled delivery, and measured changes in middle cerebral artery (MCA) cross-sectional area (CSA; magnetic resonance imaging (7 Tesla MRI)), blood velocity (transcranial Doppler and Phase contrast MRI), and calculated CVR based on steady-state versus a ramp protocol during two protocols: a 3-minute steady-state (+4mmHg PETCO2) and a ramp (delta of −3 to +4mmHg of PETCO2). We observed that 1) the MCA did not dilate during the ramp protocol, but did dilate during steady-state hypercapnia, and 2) MCA blood velocity CVR was similar between ramp and steady-state hypercapnia protocols, although calculated MCA blood flow CVR was greater during steady-state hypercapnia than during ramp, the discrepancy due to MCA CSA changes during steady-state hypercapnia. Due to the ability to achieve similar levels of MCA blood velocity CVR as steady-state hypercapnia, the lack of change in MCA cross-sectional area, and the minimal expected change in blood pressure, we propose that a ramp model, across a delta of ~−3 to +4mmHg PETCO2, may provide one alternative approach to collecting CVR measures in young adults with TCD when CSA measures are not feasible.