bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural insights into the distinct protective mechanisms of human antibodies targeting ZIKV NS1
Authors: Pan Qi , Xing Xiaomin , Yu Jianhai , Chen Qiang , Jiao Haizhan , Zhang Wanqin , Wen Yingfen , Gao Ming , Zhao Wei , Yu Lei , Hu Hongli 
Published: October 2023

AbstractZika virus (ZIKV) Non-structural protein 1 (NS1) plays an essential role in viral replication and immune evasion. Our understanding of the differential protective mechanism of NS1-targeting antibodies is limited. Here, we determined the cryoEM structures of ZIKV NS1 in complex with two group antibodies at 2.6-2.9Å. Group I antibodies (3G2 and 4B8) potently recognize cell surface form of NS1 and multiple oligomeric forms of NS1 by occupy the epitopes on outer surface of dimeric NS1. IgG and Fab from group I antibodies completely abrogate sNS1-mediated endothelial dysfunction in vitro. Group II antibodies (4F10, 2E11, and 14G5) recognize the previously reported epitopes in distal end of theβ-ladder domain of monomeric NS1, and their blockade efficiency depends on the affinity with NS1 protein. These findings elucidate the correlation between the epitope recognition and the protective efficacy of anti-NS1 antibodies and highlight the distinct mechanisms of therapeutic potential of 3G2 and 4B8.
Computational Modeling of Hyperpolarizing Astrocytic Influence on Cortical Up-Down State Transitions
Authors: Verma Jay , Garg Pranjal 
Published: October 2023

AbstractThe Up-Down dynamics seen in cortical structures during non-rapid-eye-movement (NREM) sleep, anesthetized states, and quiet wakefulness is the spontaneous alternation between phases of heightened firing activity (referred to as the Up state) and periods of neuronal inactivity (termed the Down state) within neural networks. By leveraging bistable dynamics imposed by a depolarising astrocyte population, in the current paper, we introduced a hyperpolarising astrocyte population to an existing model of Up-Down dynamics to account for biological relevance. We created a computational rate model that includes populations of depolarizing and hyperpolarizing astrocytes and neurons. To optimize model parameters, we used the Elementary Effects (EE) test. It was followed by linear stability analysis to locate bistable regimes in the parameter hyperspace. The addition of hyperpolarizing gliotransmission perturbed model dynamics, indicating its sensitivity to qualitatively differing architectures. We then identified a bistable regime within the dynamics spectrum. According to the EE test, the strength of cell population coupling is a low-sensitivity parameter, possibly due to neuroplastic changes. We also found that the threshold of excitatory cell populations and the strength of adaptation are high-sensitivity parameters, whereas the threshold of inhibitory cell populations is low-sensitivity. Our model enables the possibility of testing biologically relevant theories of hyperpolarizing gliotransmission, where data remains scant.
CaBP1 and 2 enable sustained CaV1.3 calcium currents and synaptic transmission in inner hair cells
Authors: Oestreicher David , Chepurwar Shashank , Kusch Kathrin , Rankovic Vladan , Jung Sangyong , Strenzke Nicola , Pangrsic Tina 
Published: October 2023

AbstractTo encode continuous sound stimuli, the inner hair cell (IHC) ribbon synapses utilize calcium-binding proteins (CaBPs), which reduce the inactivation of their CaV1.3 calcium channels. Mutations in theCABP2gene underlie non-syndromic autosomal recessive hearing loss DFNB93. Besides CaBP2, the structurally related CaBP1 is highly abundant in the IHCs. Here, we investigated how the two CaBPs cooperatively regulate IHC synaptic function. InCabp1/2double-knockout mice, we find strongly enhanced CaV1.3 inactivation, slowed recovery from inactivation and impaired sustained exocytosis. Already mild IHC activation further reduces the availability of channels to trigger synaptic transmission and may effectively silence synapses. Spontaneous and sound-evoked responses of spiral ganglion neuronsin vivoare strikingly reduced and strongly depend on stimulation rates. Transgenic expression of CaBP2 leads to substantial recovery of IHC synaptic function and hearing sensitivity. We conclude that CaBP1 and 2 act together to suppress voltage and calcium-dependent inactivation of IHC CaV1.3 channels in order to support sufficient rate of exocytosis and enable fast, temporally precise and indefatigable sound encoding.
Plasmid partitioning driven by collective migration of ParA between nucleoid lobes
Authors: Köhler Robin , Murray Seán M. 
Published: October 2023

AbstractThe ParABS system is crucial for the faithful segregation and inheritance of many bacterial chromosomes and low-copy number plasmids. However, despite extensive research, the spatio-temporal dynamics of the ATPase ParA and its connection to the dynamics and positioning of the ParB-coated cargo has remained unclear. In this study, we utilise high-throughput imaging, quantitative data analysis, and computational modelling to explore thein vivodynamics of ParA and its interaction with ParB-coated plasmids and the nucleoid. As previously observed, we find that F-plasmid ParA undergoes collective migrations (‘flips’) between cell halves multiple times per cell cycle. We reveal that a constricting nucleoid is required for these migrations and that they are triggered by a plasmid crossing into the cell half with greater ParA. Using simulations, we show that these dynamics can be explained by the combination of nucleoid constriction and cooperative ParA binding to the DNA, in line with the behaviour of other ParA proteins. We further show that these ParA flips act to equally partition plasmids between the two lobes of the constricted nucleoid and are therefore important for plasmid stability, especially in fast growth conditions for which the nucleoid constricts early in the cell cycle. Overall our work identifies a second mode of action of the ParABS system and deepens our understanding of how this important segregation system functions.
Data-driven motif discovery in biological neural networks
Authors: Matelsky Jordan K. , Robinette Michael S. , Wester Brock , Gray-Roncal William R. , Johnson Erik C. , Reilly Elizabeth P. 
Published: October 2023

AbstractData from a variety of domains are represented as graphs, including social networks, transportation networks, computer networks, and biological networks. A key question spans these domains: are there meaningful repeated subgraphs, or motifs, within the structure of these larger networks? This is a particularly relevant problem when searching for repeated neural circuits in networks of biological neurons, as the field now regularly produces large brain connectivity maps of neurons and synapses, or connectomes. Given acquisition costs, however, these neuron-synapse connectivity maps are mostly one-of-a-kind. With current graph analysis techniques, it is very challenging to discover new “interesting” subgraphsa priorigiven small sample sizes of host graphs. Another challenge is that for even relatively modest graph sizes, an exhaustive search of all possible subgraphs is computationally intractable. For these reasons, motif discovery in biological graphs remains an unsolved challenge in the field. In this work, we present a motif discovery approach that can derive a list of undirected or directed motifs, with occurrence counts which are statistically significant compared to randomized graphs, from a single graph example. We first address common pitfalls in the current most common approaches when testing for motif statistical significance, and outline a strategy to ameliorate this problem with improved graph randomization techniques. We then propose a progressive-refinement approach for motif discovery, which addresses issues of computational cost. We demonstrate that our sampling correction technique allows for significance testing of target motifs while highlighting misleading conclusions from standard random graph models. Finally, we share our reference implementation, which is available as an open-source Python package, and demonstrate real-world preliminary results on theC. elegansconnectome and the ellipsoid body of theDrosophila melanogasterfruit fly connectome.
Diurnal fluctuations in steroid hormones tied to variation in intrinsic functional connectivity in a densely sampled male
Authors: Grotzinger Hannah , Pritschet Laura , Shapturenka Pavel , Santander Tyler , Murata Elle , Jacobs Emily G. 
Published: October 2023

AbstractMost of mammalian physiology is under the control of biological rhythms, including the endocrine system with time-varying hormone secretion. Precision neuroimaging studies provide unique insights into the means through which our endocrine system regulates dynamic properties of the human brain. Recently, we established estrogen’s ability to drive widespread patterns of connectivity and enhance the functional efficiency of large-scale brain networks in a woman sampled every 24h across 30 consecutive days, capturing a complete menstrual cycle. Steroid hormone production also follows a pronounced sinusoidal pattern, with a peak in testosterone between 6-7am and nadir between 7-8pm. To capture the brain’s response to diurnal changes in hormone production, we carried out a companion precision imaging study of a healthy adult man who completed MRI and venipuncture every 12-24 hours across 30 consecutive days. Results confirmed robust diurnal fluctuations in testosterone, cortisol, and estradiol. Standardized regression analyses revealed predominantly positive associations between testosterone, cortisol, and estradiol concentrations and whole-brain patterns of coherence. In particular, functional connectivity in Dorsal Attention and Salience/Ventral Attention Networks were coupled with diurnally fluctuating hormones. Further, comparing dense-sampling datasets between a man and naturally-cycling woman revealed that fluctuations in sex hormones are tied to patterns of whole-brain coherence to a comparable degree in both sexes. Together, these findings enhance our understanding of steroid hormones as rapid neuromodulators and provide evidence that diurnal changes in steroid hormones are tied to patterns of whole-brain functional connectivity.Significance StatementDiurnal variation is an essential biorhythm, yet the relationship between diurnal fluctuations in steroid hormones and the functional architecture of the human brain is virtually unknown. This precision neuroimaging study suggests that endogenous fluctuations in testosterone, estradiol, and cortisol concentrations are tied to rhythmic changes in coherence across the brain. Precision imaging studies that track individuals across major endocrine transitions (e.g. the diurnal cycle and menstrual cycle) demonstrate steroid hormones’ ability to modulate the functional architecture of the brain in both sexes, and provide a starting point for future studies to probe the functional significance of these rhythms for behavior.
Complete genome sequence of thermophilic cellulolytic actinobacteriumThermobifida fuscastrain UPMC 901 producing thermostable cellulases
Authors: Zainudin Mohd Huzairi Mohd , Gan Han Ming , Tokura Mitsunori 
Published: October 2023

AbstractThermophilic cellulolytic bacteria producing thermostable cellulase have multiple potential industrial and biotechnological applications. In this study, we reported the complete genome sequence of the speciesThermobifida fuscaUPMC 901 by using nano-pore sequencing technology. The represented genome is 3.76 Mb with a G + C content of 67.4%. The genome is composed of 1 scaffold with 3,193 protein-coding genes. The results indicated that the genome of theThermobifida fuscagene encodes at least 109 genes for carbohydrate-active enzymes. Of these genes, 38 glycoside hydrolases (GHs), 36 glycosylTransferases (GTs), 21 carbohydrate-binding modules (CBMs), 9 carbohydrate esterases (CEs), and 3 polysaccharide lyases (PL) were identified. In addition, two genes encoding for lytic polysaccharide monooxygenase (LPMO), the copper-dependent enzymes that catalyse oxidative cleavage of recalcitrant crystalline cellulose, that is auxiliary activity (AAs) were also detected in theT. fuscagenome. This study represented the ninth genome of the speciesT. fusca, and the cellulase genes identified will facilitate the exploration of potential sources fromT. fuscafor industrial and agricultural applications.
Forecasting regional-level COVID-19 hospitalisation in England as an ordinal variable using the machine learning method
Authors: Wang Haowei , Kwok Kin On , Li Ruiyun , Riley Steven 
Published: October 2023

AbstractBackgroundCOVID-19 causes substantial pressure on healthcare, with many healthcare systems now needing to prepare for and mitigate the consequences of surges in demand caused by multiple overlapping waves of infections. Therefore, public health agencies and health system managers also now benefit from short-term forecasts for respiratory infections that allow them to manage services better. However, the availability of easily implemented effective tools for generating precise forecasts at the individual regional level still needs to be improved.MethodsWe extended prior work on influenza to forecast regional COVID-19 hospitalisations in England for the period from 19th March 2020 to 31st December 2022, treating the number of hospital admissions in each region as an ordinal variable. We further developed the XGBoost model used previously to forecast influenza to enable it to exploit the ordering information in ordinal hospital admission levels. We incorporated different types of data as predictors: epidemiological data including weekly region COVID-19 cases and hospital admissions, weather conditions and mobility data for multiple categories of locations (e.g., parks, workplaces, etc). The impact of different discretisation methods and the number of ordinal levels was also considered.ResultsWe find that the inclusion of weather data consistently increases the accuracy of our forecasts compared with models that rely only on the intrinsic epidemiological data, but only by a small amount. Mobility data brings about a more substantial increase in our forecasts. When both weather and mobility data are used in addition to the epidemiological data, the results are very similar to the model with only epidemiological data and mobility data.ConclusionAccurate ordinal forecasts of COVID-19 hospitalisations can be obtained using XGBoost and mobility data. While uniform ordinal levels show higher apparent accuracy, we recommend N-tile ordinal levels which contain far richer information.Author SummaryAt the regional level, we address the pressing need for precise short-term forecasts of respiratory infections, particularly COVID-19. We focus on the specific context of England and cover the period from January 1 to December 31, 2022. We introduced an enhanced XGBoost model that leverages the ordinal nature of hospital admission data, utilising a combination of predictors, including epidemiological data, weather conditions, and mobility data across various location categories. Our findings indicate that the inclusion of weather data marginally improves forecasting accuracy, while mobility data yields more significant enhancements. This research contributes valuable insights for public health agencies and healthcare system managers in their ongoing efforts to manage and respond to the complexities of the COVID-19 pandemic.
Expert panel identified health-related social needs and methodological considerations for a polysocial risk score
Authors: Vest Joshua R , McNamee Cassidy , Musey Paul I 
Published: October 2023

ABSTRACTObjectivesA polysocial risk score, which summaries multiple different health-related social needs (HRSNs) into a single likelihood of risk, could support more effective patient and population health management. Nevertheless, developing a polysocial risk score faces uncertainties and challenges due the HRSNs’ differing etiologies and interventions, cooccurrence, and variation in information availability.MethodsA 3-round Delphi technique to elicit expert opinion and develop a preliminary polysocial risk score approach. Expert panel members included physicians (n=8), social service professionals & staff (n=9), and patients (n=6). For physicians, the primary qualification was direct patient care experience in screening or asking about patients’ health-related social needs. Social service professionals & staff had titles of: nurse, patient care assistant, patient advocate, community health worker, director of community services. Round 1 obtained an initial importance of HRSNs on general health & well-being and total healthcare cost. Panelists also suggested additional HRSNs Responses served as discussion points for Round 2. Five focus groups explored how HRSNs should be ranked; additional HRSNs to include; timing of measurements; management of non-response and missing data; and concerns about bias and equity. We analyzed the transcripts using a consensus coding approach. Panelists then completed a follow-up survey.ResultsPanelists identified 17 HRSNs relevant to health and well-being for inclusion in a polysocial risk score. Methodology concerns ranging from the sources and quality of data, non-random missing information, data timeliness, and the need for different risk scores by population. Panelist also raised concerns about potential bias and missaplication of a polysocial risk score.ConclusionA polysocial risk score is a potentially useful addition to the growing methodologies to better understand and address HRSNs. Nevertheless, development is potentially complicated and fraught with challenges.
iSCORED: nanopore-based random genomic sampling for intraoperative molecular diagnosis
Authors: Emiliani Francesco E. , Ould Ismail Abdol Aziz , Hughes Edward G. , Tsongalis Gregory J. , Zanazzi George J , Lin Chun-Chieh 
Published: October 2023

AbstractCopy number variations (CNVs) are almost ubiquitous in cancer. In many cases, somatic CNV analysis has led to the identification of oncogenic pathways and suggested molecular-defined therapeutic targets. Here, we develop iSCORED, a one-step random genomic DNA reconstruction method that enables efficient, unbiased quantification of CNVs using a real-time Nanopore sequencer. By leveraging the long concatenated reads, we generate approximately 1-2 million genomic fragments within one hour of MinION sequencing, allowing for high-resolution genomic dosage comparisons. In our cohort of 26 malignant brain tumors, we demonstrated 100% concordance in CNV detections, including chromosomal alterations and oncogene amplifications when compared to clinically validated next generation sequencing and chromosomal microarray results. In addition, iSCORED allows concurrent brain tumor methylation classification without additional tissue preparation. The integrated methylation information revealed promoter hypomethylation in all detected amplified oncogenes. The entire workflow, including the automatic generation of CNV and methylation reports, can be accomplished within 120-140 minutes. Ultrafast molecular analysis can enhance clinical decision-making, optimize surgical planning and identify potential molecular therapies within surgical timeframes.
Short-term Functional Outcomes of Patients with acute intracerebral hemorrhage in the Native and Expatriate Population
Authors: Akhtar Naveed , Kate Mahesh , Kamran Saadat , Joseph Sujatha , Morgan Deborah , Uy Ryan , Babu Blessy , Shanti Shobhna , Shuaib Ashfaq 
Published: October 2023

AbstractObjectivesFunctional outcomes in patients with intracerebral hemorrhage (ICH) have not been well characterized in the Middle East and North Africa Region. We report the 30 and 90-day clinical outcomes in the native and expatriate of Qatar with ICH.MethodsWe evaluated the Glasgow Coma Scale (GCS), NIHSS, and imaging in the Qatar Stroke Registry (2013–22). The outcome measures were a modified Rankin Scale (mRS) at 90 days and mortality at 30 and 90 days. Unfavourable outcome was defined as mRS of 4-6. We performed non-parametric ROC analyses to measure the concordance index (C-index) to assess the goodness-of-fit of ICH score for predicting 30 day and 90-day mortality and functional outcome.Results1660 patients (median age of 49 (41.5-58) years; male 83.1%, expatriates 77.5%) with ICH, including supratentorial deep in 65.2%, cortical in 16.2%, infratentorial 16% and primary intraventricular in 2.5% were studied. The median baseline ICH volume was 7.5 (3.2-15.8) ml. An unfavorable outcome was seen in 673 (40.5%) patients at 90 days. Mortality at 30 days and 90 days was 10.4% and 15.1%. Increasing age (OR (95% CI), 1.02 (1.00-1.03)), lower GCS (0.77 (0.73-0.80)), prior use of antiplatelet medications (1.82 (1.19-2.08)), higher ICH volume (1.03 (1.02-1.04)), and presence of any intraventricular hemorrhage (1.57(1.19-2.08)), were associated with unfavorable outcome.ConclusionsIn this relatively younger ICH cohort more than 75% were expatriates, had smaller ICH volume and had better functional outcomes. Prognostic scoring systems may have to be modified in this population to avoid early withdrawal of care.
Non-evoked frequencies: Retinotopic position modulation induces SSVEP signals without intrinsic neural signal processing
Authors: Duymaz İlker , Kogo Naoki , Alp Nihan 
Published: October 2023

AbstractSteady-state visually evoked potentials (SSVEPs) are defined as periodic EEG responses elicited by periodic modulations in visual stimuli. These periodic responses can be extracted as narrowband frequency components by employing frequency domain analyses. Frequency components extracted this way are traditionally attributed to modulations in neuronal activity, particularly of neurons sensitive to a modulated stimulus property. Here, we demonstrate a scenario in which frequency components arise solely due to retinotopic variations in signal strength without representing the activity of any specific neural mechanism. Specifically, we present evidence from two EEG experiments for the existence of signal fluctuations that depend solely on retinotopic stimulus position, which are also able to yield identifiable frequency components in the face of a position-modulated stimulus. Given the large extent of positional variation in our stimulus, these position-dependent fluctuations likely reflect the factors that impact the strength of the measured responses from different retinotopic areas. These results offer a counterexample to the conventional approach of associating frequency components with neuronal activity, and underscore potentially confounding interactions between stimuli and the brain’s architecture.
Global regulation via modulation of ribosome pausing by the ABC-F protein EttA
Authors: Ousalem Farès , Ngo Saravuth , Oïffer Thomas , Omairi-Nasser Amin , Hamon Marion , Monlezun Laura , Boël Grégory 
Published: October 2023

AbstractHaving multiple rounds of translation of the same mRNA creates dynamic complexities along with opportunities for regulation related to ribosome pausing and stalling at specific sequences. Yet, mechanisms controlling these critical processes and the principles guiding their evolution remain poorly understood. Through genetic, genomic, physiological, and biochemical approaches, we demonstrate that regulating ribosome pausing at specific amino acid sequences can produce ∼2-fold changes in protein expression levels which strongly influence cell growth and therefore evolutionary fitness. We demonstrate, bothin vivoandin vitro,that the ABC-F protein EttA directly controls the translation of mRNAs coding for a subset of enzymes in the tricarboxylic acid (TCA) cycle and its glyoxylate shunt, which modulates growth in some chemical environments. EttA also modulates expression of specific proteins involved in metabolically related physiological and stress-response pathways. These regulatory activities are mediated by EttA rescuing ribosomes paused at specific patterns of negatively charged residues within the first 30 amino acids of nascent proteins. We thus establish a unique global regulatory paradigm based on sequence-specific modulation of translational pausing.