bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of 105 biological, socioeconomic, behavioural, and environmental factors on the risk of SARS-CoV-2 infection and a severe course of Covid-19: A prospective longitudinal study
Authors: Flegr Jaroslav , Flegr Pavel , Příplatová Lenka 
Published: September 2021

AbstractThe confirmed number of SARS-CoV-2 infections up to 30 August 2021 is 217 mil. worldwide but information about factors affecting the probability of infection or of a severe course of Covid-19 remains insufficient and often speculative. Only a small number of factors have been rigorously examined, mostly by retrospective or cross-sectional studies. We ran a preregistered study on 5,164 internet users who shared with us information about their exposure to 105 risk factors and reported being Covid negative before the beginning of the fourth wave of Covid-19 in the Czech Republic. After the fourth wave, in which 709 (13.7%) of participants were infected, we used a partial Kendall test controlled for sex, age, and urbanisation to compare the risk of infection and of a severe course of the disease in subjects who originally did and did not report exposure to particular risk factors. After the correction for multiple tests, we identified 13 factors – including male sex, lower age, blood group B, and the larger household size – that increased the risk of infection and 16 factors – including mask wearing, borreliosis in the past, use of vitamin D supplements, or rooibos drinking – that decreased it. We also identified 23 factors that increased the risk of a severe course of Covid-19 and 12 factors that decreased the risk.
The non-steroidal anti-inflammatory drug nimesulide kills Gyps vultures at concentrations found in the muscle of treated cattle
Authors: Galligan Toby. H. , Green Rhys. E. , Wolter Kerri. , Taggart Mark. A. , Duncan Neil. , Mallord John. W. , Alderson Dawn. , Li Yuan. , Naidoo Vinny. 
Published: September 2021

AbstractThroughout South Asia, cattle are regularly treated with non-steroidal anti-inflammatory drugs (NSAIDs) and their carcasses are left for scavengers to consume. Residues of the NSAID diclofenac in cattle carcasses caused widespread mortality and catastrophic population declines in three species of Gyps vulture during the 1990s and 2000s. Diclofenac is now banned, but other NSAIDs are used in its place. Different lines of evidence, including safety testing in Gyps vultures, have shown that some of these other NSAIDs are toxic, or probably toxic, to vultures. The NSAID nimesulide is widely available and commonly used, and has been found in dead vultures with signs of renal failure (i.e. visceral gout) and without the presence of diclofenac and/or other vulture-toxic NSAIDs. Nimesulide is therefore probably toxic to vultures. Here, we report safety testing of nimesulide in Gyps vultures. In a controlled toxicity experiment, we gave two vultures the maximum likely exposure of nimesulide calculated from initial pharmacokinetic and residue experiments in cattle. Two other control birds were given an oral dose of water. Both vultures dosed with nimesulide died within 30 h, after showing outward signs of toxicity and increases in biochemical indicators of renal failure. Post-mortem examinations found extensive visceral gout in both vultures. Both control vultures survived without biochemical indicators of renal failure. With this evidence, we call for an immediate and comprehensive ban of nimesulide throughout South Asia to ensure the survival of the region’s Critically Endangered vultures. More generally, testing the impacts of drugs on non-target species should be the responsibility of the pharmaceutical industry, before their veterinary use is licensed.
Closed-loop optimization of transcranial magnetic stimulation with electroencephalography feedback
Authors: Tervo Aino E. , Nieminen Jaakko O. , Lioumis Pantelis , Metsomaa Johanna , Souza Victor H. , Sinisalo Heikki , Stenroos Matti , Sarvas Jukka , Ilmoniemi Risto J. 
Published: September 2021

AbstractBackgroundTranscranial magnetic stimulation (TMS) is widely used in brain research and treatment of various brain dysfunctions. However, the optimal way to target stimulation and administer TMS therapies, for example, where and in which electric field direction the stimuli should be given, is yet to be determined.ObjectiveTo develop an automated closed-loop system for adjusting TMS parameters (in this work, the stimulus orientation) online based on TMS-evoked brain activity measured with electroencephalography (EEG).MethodsWe developed an automated closed-loop TMS–EEG set-up. In this set-up, the stimulus parameters are electronically adjusted with multi-locus TMS. As a proof of concept, we developed an algorithm that automatically optimizes the stimulation orientation based on single-trial EEG responses. We applied the algorithm to determine the electric field orientation that maximizes the amplitude of the TMS– EEG responses. The validation of the algorithm was performed with six healthy volunteers, repeating the search twenty times for each subject.ResultsThe validation demonstrated that the closed-loop control worked as desired despite the large variation in the single-trial EEG responses. We were often able to get close to the orientation that maximizes the EEG amplitude with only a few tens of pulses.ConclusionOptimizing stimulation with EEG feedback in a closed-loop manner is feasible and enables effective coupling to brain activity.
Preproteins couple the intrinsic dynamics of SecA to its ATPase cycle to translocate via a catch and release mechanism
Authors: Krishnamurthy Srinath , Sardis Marios-Frantzeskos , Eleftheriadis Nikolaos , Chatzi Katerina E. , Smit Jochem H. , Karathanou Konstantina , Gouridis Giorgos , Portaliou Athina G. , Bondar Ana-Nicoleta , Karamanou Spyridoula , Economou Anastassios 
Published: September 2021

SummaryProtein machines undergo conformational motions to interact with and manipulate polymeric substrates. The Sec translocase promiscuously recognizes, becomes activated and secretes >500 non-folded preprotein clients across bacterial cytoplasmic membranes. Here, we reveal that the intrinsic dynamics of the translocase ATPase, SecA, and of preproteins combine to achieve translocation. SecA possesses an intrinsically dynamic preprotein clamp attached to an equally dynamic ATPase motor. Alternating motor conformations are finely controlled by the γ-phosphate of ATP, while ADP causes motor stalling, independently of clamp motions. Functional preproteins physically bridge these independent dynamics. Their signal peptide promotes clamp closing; their mature domain overcomes the rate limiting ADP release. While repeated ATP cycles shift the motor between unique states, multiple conformationally frustrated prongs in the clamp repeatedly ‘catch and release’ trapped preprotein segments until translocation completion. This universal mechanism allows any preprotein to promiscuously recognize the translocase, usurp its intrinsic dynamics and become secreted.
Molecular mechanisms of the CdnG-Cap5 antiphage defense system employing 3’,2’-cGAMP as the second messenger
Authors: Fatma Shirin , Chakravarti Arpita , Zeng Xuankun , Huang Raven H. 
Published: September 2021

AbstractCyclic-oligonucleotide-based antiphage signaling systems (CBASS) are diverse and abundant in bacteria. Here, we present biochemical and structural characterization of two CBASS systems, composed of CdnG and Cap5, from Asticcacaulis sp. and Lactococcus lactis. We show that CdnG from Asticcacaulis sp. synthesizes 3’,2’-cGAMP in vitro, and 3’,2’-cGAMP is the biological signaling molecule that activates Cap5 for DNA degradation. Crystal structures of Cap5, together with the SAVED domain in complex with 3’,2’-cGAMP, provide insight into the architecture of Cap5 as well as molecular recognition of 3’,2’-cGAMP by the SAVED domain of Cap5. Amino acid conservation of the SAVED domain of Cap5, together with mutational studies, led us to propose a novel mechanism of Back-to-Front stacking of two SAVED domains, mediated by 3’,2’-cGAMP, to activate HNH nuclease domain for DNA degradation. Our study of the most abundant CBASS system provides new insight into mechanisms employed by bacteria in their conflicts against phage.
The evolutionary origin of host association in an ancient bacterial clade
Authors: Schön Max E. , Martijn Joran , Vosseberg Julian , Köstlbacher Stephan , Ettema Thijs J. G. 
Published: September 2021

AbstractThe evolution of obligate host-association of bacterial symbionts and pathogens remains poorly understood. The Rickettsiales represent an order of obligate alphaproteobacterial endosymbionts and parasites that infect a wide variety of eukaryotic hosts, including humans, livestock, insects and protists. Induced by their host-associated lifestyle, Rickettsiales genomes have undergone reductive evolution, leading to small, AT-rich genomes with limited metabolic capacities. We describe several genomes of deep-branching, environmental alphaproteobacteria that branch basal to previously sampled Rickettsiales, and whose genome content are reminiscent of free-living and biofilm-associated lifestyles. Ancestral genome content reconstruction across the Rickettsiales tree revealed that the free-living to host-association transition of this group occurred more recently than previously anticipated, and likely involved the repurposing of a type IV secretion system.One-Sentence SummaryDeep-branching Rickettsiales provide insights into the evolution of obligate host-associated lifestyle
Multimodal characterization of the murine neurovascular niche using a novel microvascular isolation protocol
Authors: Bjørnholm Katrine Dahl , Vanlandewijck Michael , Del Gaudio Francesca , Lendahl Urban , Nilsson Per , Karlström Helena , Betsholtz Christer 
Published: September 2021

AbstractThe blood-brain barrier (BBB) is central to separate blood from the extracellular fluids of the brain. To understand disease-related changes in the BBB is pivotal and such changes can increasingly be studied by single-cell RNA sequencing (scRNAseq), which provides high-resolution insight into gene expression changes related to the pathophysiological response of the vasculature. However, analysis of the vascular cells in the brain is challenging due to the low abundance of these cells relative to neuronal and glial cells, and improved techniques for enrichment of the vascular component is therefore warranted. The present study describes a method whereby panning with CD31-coated magnetic beads allows isolation of brain vasculature without the need for transgenic reporter lines or FACS sorting. The protocol was tested in three modalities: isolation of cells for scRNAseq, western blot (WB) analysis, and primary cell culture. For scRNAseq, a total of 22,515 single-cell transcriptomes were generated from 12-months old mice and separated into 23 clusters corresponding to all known vascular and perivascular cell types. The most abundant cell type was endothelial cells (EC) (Pecam1- and Cdh5-positive), which dispersed into clusters of arterial, capillary, and venous EC according to previously established BBB arterio-venous zonation markers. Furthermore, we identified clusters of microglia (Aif1-positive), one cluster of fenestrated endothelial cells (Plvap-positive; Cldn5-negative), a cluster of pericytes (Kcnj8- and Abcc9-positive) and a cluster of vascular smooth muscle cells (VSMC) (Acta2- and Tagln-positive). WB analysis using established markers for the different cell types (CD31 (EC), SM22 (VSMC), PDGFRB (pericytes), GFAP (astrocytes), and IBA1 (microglia) confirmed their presence in the isolated vascular component and suggests that the protocol is suitable for future proteomic analysis. Finally, we adapted the isolation protocol to accommodate primary culture of brain vascular cells. In conclusion, we have successfully established a simple and fast method for isolating microvasculature from the murine brain independent of cell sorting and alleviating the need to use reporter mouse lines. The protocol is suitable for a multitude of testing modalities, including single-cell analyses, WB and primary cell culture.
Simultaneous Detection of Dopamine and Serotonin with Carbon-based Electrodes
Authors: Khot Gaurang , Shirtcliffe Neil , Celikel Tansu 
Published: September 2021

AbstractGraphite-based materials, like pyrolyzed carbon electrodes, are widely used as implantable electrochemical sensors, for the detection of neurotransmitters, neuromodulators, and gaseous species, thanks to their strong mechanical properties, superior electron-transfer kinetics, and in-vivo stability. Electrochemical properties of graphite can be improved by coating them with carbon nanotubes (CNTs) which improves sensitivity, selectivity, and resistance to biofouling. Although several types of electrodes have been developed to detect biologically relevant targets like monoamines, multiplexed sensing of dopamine and serotonin is not yet widely available. Herein we introduce pyrolyzed carbon electrodes coated with CNTs for fast scan cyclic voltammetry for simultaneous detection of dopamine and serotonin with a sensitivity of 52±8nA/μM and 5±17nA/μM, respectively. Serotonin shows a broad oxidation peak at 0.68V±0.12V. When dopamine and serotonin are probed simultaneously at 10 Hz, dopamine oxidizes at 0.1V± 0.1 and serotonin oxidizes at 0.78V±0.12 and dopamine reduces at −0.35V±0.1 and serotonin at 0.1V±0.2 V. Thus the sensors shows discrimination between dopamine and serotonin and are suitable for simultaneous detection of these monoamines.
A comprehensive neural simulation of slow-wave sleep and highly responsive wakefulness dynamics
Authors: Goldman Jennifer S. , Kusch Lionel , Yalçinkaya Bahar Hazal , Depannemaecker Damien , Nghiem Trang-Anh E. , Jirsa Viktor , Destexhe Alain 
Published: September 2021

ABSTRACTHallmarks of neural dynamics during healthy human brain states span spatial scales from neuromodulators acting on microscopic ion channels to macroscopic changes in communication between brain regions. Developing a scale-integrated understanding of neural dynamics has therefore remained challenging. Here, we perform the integration across scales using mean-field modeling of Adaptive Exponential (AdEx) neurons, explicitly incorporating intrinsic properties of excitatory and inhibitory neurons. We report that when AdEx mean-field neural populations are connected via structural tracts defined by the human connectome, macroscopic dynamics resembling human brain activity emerge. Importantly, the model can qualitatively and quantitatively account for properties of empirical spontaneous and stimulus-evoked dynamics in the space, time, phase, and frequency domains. Remarkably, the model also reproduces brain-wide enhanced responsiveness and capacity to encode information particularly during wake-like states, as quantified using the perturbational complexity index. The model was run using The Virtual Brain (TVB) simulator, and is open-access in EBRAINS. This approach not only provides a scale-integrated understanding of brain states and their underlying mechanisms, but also open access tools to investigate brain responsiveness, toward producing a more unified, formal understanding of experimental data from conscious and unconscious states, as well as their associated pathologies.
Sequential Transmission of Task-Relevant Information in Cortical Neuronal Networks
Authors: Francis Nikolas A. , Mukherjee Shoutik , Koçillari Loren , Panzeri Stefano , Babadi Behtash , Kanold Patrick O. 
Published: September 2021

ABSTRACTDuring auditory task performance, cortical processing of task-relevant information enables mammals to recognize sensory input and flexibly select behavioral responses. In mouse auditory cortex, small neuronal networks encode behavioral choice during a pure-tone detection task, but it is poorly understood how neuronal networks encode behavioral choice during a pure-tone discrimination task where tones have to be categorized into targets and non-targets. While the interactions between networked neurons are thought to encode behavioral choice, it remains unclear how patterns of neuronal network activity indicate the transmission of task-relevant information within the network. To this end, we trained mice to behaviorally discriminate target vs. non-target pure-tones while we used in vivo 2-photon imaging to record neuronal population activity in primary auditory cortex layer 2/3. We found that during task performance, a specialized subset of neurons transiently encoded intersection information, i.e., sensory information that was used to inform behavioral choice. Granger causality analysis showed that these neurons formed functional networks in which task-relevant information was transmitted sequentially between neurons. Differences in network structure between target and non-target sounds encoded behavioral choice. Correct behavioral choices were associated with shorter timescale communication between neurons. In summary, we find that specialized neuronal populations in auditory cortex form functional networks during auditory task performance whose structures depend on both sensory input and behavioral choice.
An Arabidopsis root phloem pole cell atlas reveals PINEAPPLE genes as transitioners to autotrophy
Authors: Otero Sofia , Sevilem Iris , Roszak Pawel , Lu Yipeng , Vittori Valerio Di , Bourdon Matthieu , Kalmbach Lothar , Blob Bernhard , Heo Jung-ok , Peruzzo Federico , Laux Thomas , Fernie Alisdair R. , Tavares Hugo , Helariutta Yka 
Published: September 2021

AbstractSingle cell sequencing has recently allowed the generation of exhaustive root cell atlases. However, some cell types are elusive and remain underrepresented. Here, we use a second- generation single cell approach, where we zoom in on the root transcriptome sorting with specific markers to profile the phloem poles at an unprecedented resolution. Our data highlight the similarities among the developmental trajectories and gene regulatory networks communal to protophloem sieve element (PSE) adjacent lineages in relation to PSE enucleation, a key event in phloem biology.As a signature for early PSE-adjacent lineages, we have identified a set of DNA-binding with one finger (DOF) transcription factors, the PINEAPPLEs (PAPL), that act downstream of PHLOEM EARLY DOF (PEAR) genes, and are important to guarantee a proper root nutrition in the transition to autotrophy.Our data provide a holistic view of the phloem poles that act as a functional unit in root development.
Accounting for 16S rRNA copy number prediction uncertainty and its implications in bacterial diversity analyses
Authors: Gao Yingnan , Wu Martin 
Published: September 2021

Abstract16S rRNA gene copy number (16S GCN) varies among bacterial species and this variation introduces potential biases to microbial diversity analyses using 16S rRNA read counts. To correct the biases, methods have been developed to predict 16S GCN. A recent study suggests that the prediction uncertainty can be so great that copy number correction is not justified in practice. Here we develop RasperGade16S, a novel method and software to better model and capture the inherent uncertainty in 16S GCN prediction. RasperGade16S implements a maximum likelihood framework of pulsed evolution model and explicitly accounts for intraspecific GCN variation and heterogeneous GCN evolution rates among species. Using cross validation, we show that our method provides robust confidence estimates for the GCN predictions and outperforms other methods in both precision and recall. We have predicted GCN for 592605 OTUs in the SILVA database and tested 113842 bacterial communities that represent an exhaustive and diverse list of engineered and natural environments. We found that the prediction uncertainty is small enough for 99% of the communities that 16S GCN correction should improve their compositional and functional profiles estimated using 16S rRNA reads. On the other hand, we found that GCN variation has limited impacts on beta-diversity analyses such as PCoA, PERMANOVA and random forest test.
Inheritance of Repressed Chromatin Domains during S-phase Requires the Histone Chaperone NPM1
Authors: Escobar Thelma M. , Yu Jia-Ray , Liu Sanxiong , Lucero Kimberly , Vasilyev Nikita , Nudler Evgeny , Reinberg Danny 
Published: September 2021

AbstractThe epigenetic process safeguards cell identity during cell division through the inheritance of appropriate gene expression profiles. We demonstrated previously that parental nucleosomes are inherited by the same chromatin domains during DNA replication only in the case of repressed chromatin. We now show that this specificity is conveyed by NPM1, a histone H3/H4 chaperone. Proteomic analyses of late S-phase chromatin revealed NPM1 in association with both H3K27me3, an integral component of facultative heterochromatin and MCM2, an integral component of the DNA replication machinery; moreover NPM1 interacts directly with PRC2 and with MCM2. Given that NPM1 is essential, the inheritance of repressed chromatin domains was examined anew using mESCs expressing an auxin-degradable version of endogenous NPM1. Upon NPM1 degradation, cells accumulated in S-phase of the cell-cycle and parental nucleosome inheritance from repressed chromatin domains was markedly compromised. Appropriate inheritance required the NPM1 acidic patches that function in chaperone activity, pointing to NPM1 being integral to the epigenetic process.One-Sentence SummaryThe histone H3/H4 chaperone, NPM1, fosters epigenetic inheritance from parental repressed chromatin during DNA replication.
A Useful Guide to Lectin Binding: Machine-Learning Directed Annotation of 57 Unique Lectin Specificities
Authors: Bojar Daniel , Meche Lawrence , Meng Guanmin , Eng William , Smith David F. , Cummings Richard D. , Mahal Lara K. 
Published: September 2021

ABSTRACTGlycans are critical to every facet of biology and medicine, from viral infections to embryogenesis. Tools to study glycans are rapidly evolving, however the majority of our knowledge is deeply dependent on binding by glycan binding proteins (e.g., lectins). The specificities of lectins, which are often naturally isolated proteins, have not been well- defined, making it difficult to leverage their full potential for glycan analysis. Herein, we use glycan microarray analysis of 116 commercially available lectins, including different preparations of the same lectin, to extract the specific glycan features required for lectin binding. Data was obtained using the Consortium for Functional Glycomics microarray (CFG v5.0) containing 611 glycans. We use a combination of machine learning algorithms to define lectin specificity, mapping inputs (glycan sequences) to outputs (lectin-glycan binding) for a large-scale evaluation of lectin-glycan binding behaviours. Our motif analysis was performed by integrating 68 manually defined glycan features with systematic probing of computational rules for significant binding motifs using mono- and disaccharides- and linkages. Using a combination of machine learning and manual annotation of the data, we created a detailed interpretation of glycan-binding specificity for 57 unique lectins, categorized by their major binding motifs: mannose, complex-type N-glycan, O-glycan, fucose, sialic acid and sulfate, GlcNAc and chitin, Gal and LacNAc, and GalNAc. Our work provides fresh insights into the complex binding features of commercially available lectins in current use, providing a critical guide to these important reagents.