bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of circRNAs linked to Alzheimer’s disease and related dementias
Authors: Puri Sambhavi , Hu Junming , Sun Zhuorui , Lin Mintao , Stein Thor , Farrer Lindsay , Wolozin Benjamin , Zhang Xiaoling 
Published: July 2022

ABSTRACTWe conducted a circular-transcriptome-wide analysis and examined circRNA expression patterns associated with AD and clinical and neuropathological AD severity measures in human hippocampus and cortex brain regions. We validated prior studies of circRNA in AD cortex, and demonstrate novel patterns of expression in the AD hippocampus. We also examined circRNA expression across multiple types of dementia and show that circRNA expression differs by dementia subtype. We demonstrate robust circRNA expression in human neuronal precursor cells (NPCs). Then, using NPCs to study qPCR validated circRNA, we show that exposure to oligomeric tau elicits downregulation of circRNA similar to that observed in AD brain. These data identify circRNA that are changed with AD, and suggest that treating neuronal cells with oligomeric tau can recapitulate some of these changes.
Multiscale cosimulation design template for neuroscience applications
Authors: Kusch Lionel , Diaz Sandra , Klijn Wouter , Sontheimer Kim , Bernard Christophe , Morrison Abigail , Jirsa Viktor 
Published: July 2022

AbstractIntegration of information across heterogeneous sources creates added scientific value. It is, however, a challenge to progress, often a barrier, to interoperate data, tools and models across spatial and temporal scales. Here we present a design template for coupling simulators operating at different scales and enabling co-simulation. We illustrate its functioning along a neuroscience example, in which individual regions of interest are simulated on the cellular level to address mechanistic questions, while the remaining network is efficiently simulated on the population level. A workflow is illustrated for the use case of The Virtual Brain and NEST, in which the cellular-level hippocampus of the mouse is embedded into a full brain network involving micro and macro electrode recordings. This new tool allows integrating knowledge across scales in the same simulation framework and validate them against multiscale experiments, thereby largely widening the explanatory power of computational models.
Combinatorial microRNA loading into extracellular vesicles for anti-inflammatory therapy
Authors: Pottash Alex Eli , Levy Daniel , Jeyaram Anjana , Kuo Leo , Kronstadt Stephanie M. , Chao Wei , Jay Steven M. 
Published: July 2022

AbstractExtracellular vesicles (EVs) have emerged as promising therapeutic entities in part due to their potential to regulate multiple signaling pathways in target cells. This potential is derived from the broad array of constituent and/or cargo molecules associated with EVs. Among these, microRNAs (miRNAs) are commonly implicated as important and have been associated with a wide variety of EV-induced biological phenomena. While controlled loading of single miRNAs is a well-documented approach for enhancing EV bioactivity, loading of multiple miRNAs has not been fully leveraged to maximize the potential of EV-based therapies. Here, an established approach to extrinsic nucleic acid loading of EVs, sonication, was utilized to enable controlled loading of multiple miRNAs in HEK293T EVs. Combinations of carefully chosen miRNAs were compared to single miRNAs with respect to anti-inflammatory outcomes in assays of increasing stringency, with the combination of miR-146a, miR-155, and miR-223 found to have the most potential amongst tested groups.
A minimal role for synonymous variation in human disease
Authors: Dhindsa Ryan S. , Wang Quanli , Vitsios Dimitrios , Burren Oliver S. , Hu Fengyuan , DiCarlo James E. , Kruglyak Leonid , MacArthur Daniel G. , Hurles Matthew E. , Petrovski Slavé 
Published: July 2022

SummarySynonymous mutations change the DNA sequence of a gene without affecting the amino acid sequence of the encoded protein. Although emerging evidence suggests that synonymous mutations can impact RNA splicing, translational efficiency, and mRNA stability1, studies in human genetics, mutagenesis screens, and other experiments and evolutionary analyses have repeatedly shown that most synonymous variants are neutral or only weakly deleterious, with some notable exceptions. In their recent article, Shen et al. claim to have disproved these well-established findings. They perform mutagenesis experiments in yeast and conclude that synonymous mutations frequently reduce fitness to the same extent as nonsynonymous mutations2. Based on their findings, the authors state that their results “imply that synonymous mutations are nearly as important as nonsynonymous mutations in causing disease.” An accompanying News and Views argues that “revising our expectations about synonymous mutations should expand our view of the genetic underpinnings of human health”3. Considering potential technical concerns with these experiments4 and a large, coherent body of knowledge establishing the predominant neutrality of synonymous variants, we caution against interpreting this study in the context of human disease.
SARS-CoV-2 booster vaccination rescues attenuated IgG1 memory B cell response in primary antibody deficiency patients
Authors: Lin Frank J. , Altman Doss Alexa Michelle , Davis-Adams Hannah G. , Adams Lucas J. , Hanson Christopher H. , VanBlargan Laura A. , Liang Chieh-Yu , Chen Rita. E. , Monroy Jennifer Marie , Wedner H. James , Kulczycki Anthony , Mantia Tarisa L. , O’Shaughnessy Caitlin C. , Raju Saravanan , Zhao Fang R. , Rizzi Elise , Rigell Christopher J. , Dy Tiffany Biason , Kau Andrew L. , Ren Zhen , Turner Jackson , O’Halloran Jane A. , Presti Rachel M. , Fremont Daved H. , Kendall Peggy L. , Ellebedy Ali H. , Mudd Philip A. , Diamond Michael S. , Zimmerman Ofer , Laidlaw Brian J. 
Published: July 2022

ABSTRACTSARS-CoV-2 vaccines have proven effective in eliciting an immune response capable of providing protective immunity in healthy individuals. However, whether SARS-CoV-2 vaccination induces a long-lived immune response in immunocompromised individuals is poorly understood. Primary antibody deficiency (PAD) syndromes are among the most common immunodeficiency disorders in adults and are characterized by an impaired ability to mount robust antibody responses following infection or vaccination. Here, we present data from a prospective study in which we analyzed the B and T cell response in PAD patients following SARS-COV-2 vaccination. Unexpectedly, individuals with PAD syndromes mounted a SARS-CoV-2 specific B and CD4+ T cell response that was comparable in magnitude to healthy individuals. Many individuals with PAD syndromes displayed reduced IgG1+ and CD11c+ memory B cell responses following the primary vaccination series. However, the IgG1 class-switching defect was largely rescued following mRNA booster vaccination. Boosting also elicited an increase in the SARS-CoV-2-specific B and T cell response and the development of Omicron-specific memory B cells in COVID-19-naïve PAD patients. Together, these data indicate that SARS-CoV-2 vaccines elicit memory B and T cells in PAD patients that may contribute to long-term protective immunity.
Application of Carleman approximants for the estimation of epidemic parameters from incidence data time-series
Authors: Muñoz-Sánchez Juan C. , Elena Santiago F. , Oteo José–Angel 
Published: July 2022

AbstractWe have analyzed the possibility of estimating epidemiological parameters from daily infection incidence data. In particular, we have focused on the determination of the instantaneous reproduction number, the contagion period and the duration of the infectious period using only the reported incidence time-series information. We have developed a data-driven method based on the instantaneous mapping of the infection incidence data on the simplest (two parameter) SIR model, along the progression of an epidemy. The mapping is carried out via Carleman linearization of the non-linear model equations. We concluded that the daily infection incidence series on its own does not carry enough information to provide estimates for the above time scales and hence additional measurements and/or hypotheses must be considered. In contrast, the prevalence time-series does allow for accurate estimates. For the case in which the characteristic infectious period is available, a new algebraic formula for the instantaneous reproduction number has been derived.
Practical application of CO2 as an indicator regarding the risk of infection
Authors: Hartmann Anne , Cetin Yunus Emre , Gastmeier Petra , Kriegel Martin 
Published: July 2022

AbstractThe air quality of enclosed spaces has attracted great attention due to the ongoing Covid-19 pandemic. The infection risk in these spaces can be estimated for various scenarios with different methods so the important parameters and effective infection prevention measures can be compared. Previous studies showed that indoor CO2 concentration could be considered a surrogate for infection risk. In this regard, a generic relation can be established between the CO2 levels and infection probability. Based on this consideration, some practical evaluations between CO2 concentration and infection risk are conducted in this study. The effect of mask efficiency, viral emission rate, and duration of exposure are also included in the assessments. It is shown that continuous CO2 monitoring can be helpful in the evaluation of possible preventive measures. Findings are expected to contribute to the understanding of the simple parameters related to the infection risk.
Estimating waning vaccine effectiveness from population-level surveillance data in multi-variant epidemics
Authors: Murayama Hiroaki , Endo Akira , Yonekura Shouto 
Published: July 2022

AbstractMonitoring time-varying vaccine effectiveness (e.g., due to waning of immunity and the emergence of novel variants) provides crucial information for outbreak control. Existing studies of time-varying vaccine effectiveness have used individual-level data, most importantly dates of vaccination and variant classification, which are often not available in a timely manner or from a wide range of population groups. We present a novel Bayesian framework for estimating the waning of variant-specific vaccine effectiveness in the presence of multi-variant circulation from population-level surveillance data. Applications to simulated outbreak and COVID-19 epidemic in Japan are also presented. Our results show that variant-specific waning vaccine effectiveness estimated from population-level surveillance data could approximately reproduce the estimates from previous test-negative design studies, allowing for rapid, if crude, assessment of the epidemic situation before fine-scale studies are made available.Author summaryThe emergence of immunity-escaping SARS-CoV-2 variants and the waning of vaccine effectiveness have highlighted the need for near-real-time monitoring of variant-specific protection in the population to guide control efforts. However, standard epidemiological studies to this end typically require access to detailed individual-level dataset, which may not be timely available in an ongoing outbreak. A more convenient and less resource-intensive approach using routinely-collected data could complement such studies by providing tentative estimates of waning vaccine effectiveness until the conclusive evidence becomes available. In this paper, we propose a novel Bayesian framework for estimating waning vaccine effectiveness against multiple co-circulating variants that requires only population-level surveillance data. Using simulated outbreak data of multiple variants,we showed that the proposed method can plausibly recover the ground truth from population-level data. We also applied the proposed method to empirical COVID-19 data in Japan, which yielded estimates that are overall in line with those derived from studies using individual-level data.
Dehydration and infection elicit increased feeding in the western flower thrips,Frankliniella occidentalis, likely triggered by glycogen depletion
Authors: Bailey Samuel T. , Kondragunta Alekhya , Choi Hyojin A. , Han Jinlong , Rotenberg Dorith , Ullman Diane E. , Benoit Joshua B. 
Published: July 2022

AbstractWe examined water balance characteristics and influence of desiccating conditions on adult western flower thrips (Frankliniella occidentalis) physiology and behavior. Western flower thrips are globally invasive and likely to contend with shifts in water availability across their expansive geographic range. Basic water balance characteristics, including water mass and dry mass, were established for adult males and females, revealing a distinct sexual dimorphism wherein females are larger, but males retain a larger percentage of their mass as body water. Males lose relative water mass more quickly and their survival times are shorter when compared to females. RNA-seq analysis identified significant enrichment of factors associated with carbohydrate transport and metabolism in dehydrated males and females. A reduction of glycogen reserves was confirmed during dehydration. The probability of thrips feeding significantly increased when desiccation was a factor. Lastly, infection withTomato spotted wilt orthotospovirus(TSWV), a principal plant-pathogenic virus transmitted byF. occidentalis, did not have a consistent and apparent influence on desiccation tolerance; however, a reduction in glycogen reserves, and an increase in feeding activity in infected thrips, very similar to that observed in dehydrated thrips, was observed. Our results establish the fundamental water balance characteristics of adult thrips, and indicate that dehydration significantly influences the survivorship and feeding behavior of thrips; crucial factors that contribute to their capacity to spread disease.
Structural characterization of human RPA70N association with DNA damage response proteins
Authors: Wu Yeyao , Zang Ning , Fu Wangmi , Zhou Chun 
Published: July 2022

AbstractThe heterotrimeric Replication protein A (RPA) is the ubiquitous eukaryotic single-stranded DNA (ssDNA) binding protein and participates in nearly all aspects of DNA metabolism, especially DNA damage response. The N-terminal OB domain of the RPA70 subunit (RPA70N) is a major protein-protein interaction element for RPA. Previous crystallography studies of RPA70N with p53, DNA2 and PrimPol fragments revealed that RPA70N binds to amphipathic peptides that mimics ssDNA. NMR chemical-shift studies also provided valuable information of RPA70N residues interacting with target sequences. However, it is still not clear how RPA70N recognizes and distinguishes such a diverse group of proteins. Here we present high resolution crystal structures of RPA70N in complex with peptides from HelB, ATRIP, RMI1, WRN and BLM. The structures showed that in addition to the ssDNA mimicry mode of interaction, RPA70N employs multiple ways to bind its partners, some of which may serve to increase the avidity of RPA70N binding.
Adera: A drug repurposing workflow for neuro-immunological investigations using neural networks
Authors: lazarczyk Marzena , Duda Kamila , Mickael Michel-Edwar , Kowalczyk Agnieszka , Sacharczuk Mariusz 
Published: July 2022

AbstractDrug repurposing in the context of neuro-immunological (NI) investigations is still in its primary stages. Drug repurposing is an important method that bypasses lengthy drug discovery procedures and rather focuses on discovering new usage for known medications. Neuro-immunological diseases such as Alzheimer’s, Parkinson, multiple sclerosis and depression include various pathologies that resulted from the interaction between the central nervous system and the immune system. However, repurposing of medications is hindered by the vast amount of information that needs mining. To challenge the need for repurposing known medications for neuro-immunological diseases, we built a deep neural network named Adera to perform drug repurposing. The model uses two deep learning networks. The first network is an encoder and its main task is to embed text into matrices. The second network we explored the usage of two different loss function, binary cross entropy and means square error (MSE). Furthermore, we investigated the effect of ten different network architecture with each loss function. Our results show that for the binary cross entropy loss function, the best architecture consists of a two layers of convolution neural network and it achieves a loss of less than 0.001. In the case of MSE loss function a shallow network using aRelu activation achieved an accuracy of over 98 % and loss of 0.001. Additionally, Adera was able to predict various drug repurposing targets in agreement with DRUG Repurposing Hub. These results establish the ability of Adera to repurpose with high accuracy drug candidates that can shorten the development of the drug cycle. The software could be downloaded from https://github.com/michel-phylo/ADERA1.
Cryo-EM structure of a RAS/RAF recruitment complex
Authors: Park Eunyoung , Rawson Shaun , Schmoker Anna , Kim Byeong-Won , Oh Sehee , Song KangKang , Jeon Hyesung , Eck Michael 
Published: July 2022

AbstractCryo-EM structures of a KRAS/BRAF/MEK1/14-3-3 complex reveal KRAS bound to the flexible Ras-binding domain of BRAF, captured in two orientations. Autoinhibitory interactions are unperturbed by binding of KRAS and in vitro activation studies confirm that KRAS binding is insufficient to activate BRAF, absent membrane recruitment. These structures illustrate the separability of binding and activation of BRAF by Ras and suggest stabilization of this pre-activation intermediate as an alternative to blocking binding of KRAS.
Visual and motor signatures of locomotion dynamically shape a population code for feature detection in Drosophila
Authors: Turner Maxwell H. , Krieger Avery , Pang Michelle M. , Clandinin Thomas R. 
Published: July 2022

SummaryNatural vision is dynamic: as an animal moves, its visual input changes dramatically. How can the visual system reliably extract local features from an input dominated by self-generated signals? In Drosophila, diverse local visual features are represented by a group of projection neurons with distinct tuning properties. Here we describe a connectome-based volumetric imaging strategy to measure visually evoked neural activity across this population. We show that local visual features are jointly represented across the population, and that a shared gain factor improves trial-to-trial coding fidelity. A subset of these neurons, tuned to small objects, is modulated by two independent signals associated with self-movement, a motor-related signal and a visual motion signal. These two inputs adjust the sensitivity of these feature detectors across the locomotor cycle, selectively reducing their gain during saccades and restoring it during intersaccadic intervals. This work reveals a strategy for reliable feature detection during locomotion.
Conformational and Thermodynamic Differences Underlying Wild-type and Mutant ENL YEATS Domain Specificity for Epigenetic Marks
Authors: Baweja Lokesh , Wereszczynski Jeff 
Published: July 2022

AbstractHistone post-translational modifications (PTMs) are interpreted by multiple reader domains and proteins to regulate gene expression. The ENL YEATS domain is a prototypical PTM reader that recognizes multiple lysine acetylation marks on the histone H3 tails as a way of recruiting chromatin remodellers. Two ENL YEATS mutations have been identified which have been linked with leukemia, Wilms tumor, and other forms of cancer and result in either an insertion or deletion of residues in the loop connecting beta sheets distant from the protein active site.In vitroexperiments have shown that these mutations modulate the selectivity of YEATS domains for various lysine acetylation marks, although different experiments have provided contrasting views on the ability of the insertion and deletion mutants to discern specific PTMs. Here, we have performed multiple molecular dynamics simulations of wild-type, insertion, and deletion mutant YEATS domains free from and in complex with two PTM peptides: one that is acetylated at K9 of H3 and the other that is acetylated at residue K27 of H3. Results show that these two peptides have distinct flexibilities and binding energetics when bound to YEATS domains, and that these properties are affected by interactions with residues within and outside of the peptide consensus motif. Furthermore, these properties are modulated by the YEATS insertion and deletion mutants, which results in disparate binding effects in these systems. Together, these results suggest that only the partial exposure of histone tails is sufficient in the context of nucleosomes for YEATS-mediated recognition of acetylation marks on histone tails. They also caution against the over-interpretation of results obtained from experiments on reader domainhistone peptide binding in isolation and not in the full-length nucleosome context.
Versatile mapping-by-sequencing with Easymap v.2
Authors: Lup Samuel Daniel , Navarro-Quiles Carla , Micol José Luis 
Published: July 2022

ABSTRACTMotivationMapping-by-sequencing combines Next Generation Sequencing (NGS) with classical genetic mapping by linkage analysis to establish gene-to-phenotype relationships. Although numerous tools have been developed to analyze NGS datasets, only a few are available for mapping-by-sequencing. One such tool is Easymap, a versatile, easy-to-use package that performs automated mapping of point mutations and small insertion/deletions (InDels), as well as large DNA insertions.ResultsHere, we describe Easymap v.2, which includes additional workflows to perform QTL-seq and variant density mapping analyses. Each mapping workflow can accommodate different experimental designs, including outcrossing and backcrossing, F2, M2, and M3mapping populations, chemically induced mutation and natural variant mapping, input files containing single-end or paired-end reads of genomic or complementary DNA sequences, and alternative control sample files in FASTQ and VCF formats. Easymap v.2 can also be used as a variant analyzer in the absence of a mapping algorithm and includes a multi-threading option.Availability and implementationCode is available athttp://genetics.edu.umh.es/resources/easymap/Contactjlmicol@umh.es