bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prostaglandin D2 pathway in a transgenic rat model of Alzheimer’s disease: therapeutic potential of timapiprant a DP2 antagonist
Authors: Wallace Charles H. , Oliveros Giovanni , Serrano Peter A , Rockwell Patricia , Xie Lei , Figueiredo-Pereira Maria 
Published: April 2022

AbstractThe cyclooxygenase pathway, a key mediator of inflammation, is implicated in Alzheimer’s disease (AD). A deeper investigation is required into the contributions of this pathway to the neuropathology of AD. Cyclooxygenases produce prostaglandins, which have multiple receptors and functions including inflammation, nociception, sleep, cardiovascular maintenance and reproduction. In the brain, prostaglandin D2 (PGD2) is the most abundant prostaglandin, increases the most under pathological conditions, and plays roles in sleep, stroke and inflammation. PGD2 signals through its DP1 and DP2 receptors and their activation can be protective or detrimental. We address the relationship between the PGD2 pathway and AD neuropathology with F344-AD transgenic (Tg-AD) rats that exhibit age-dependent and progressive pathology similar to AD patients. We analyzed the PGD2 pathway in the hippocampus of wild type (WT) rats and their Tg-AD littermates, at the age of 11 months, when Tg-AD rats exhibit plaques and perform significantly worse in hippocampal-dependent cognitive tasks than WT rats. Using mass spectrometry, we determined that PGD2 levels were at least 14.5-fold higher than PGE2, independently of genotype. Immunohistochemistry established that microglial DP1 receptors were more abundant and neuronal DP2 receptors were fewer in Tg-AD than in WT rats. RNA sequencing profiling of 33 genes involved in the PGD2 and PGE2 pathways revealed that mRNA levels were the highest for L-PGDS, the major PGD2 synthase in the brain. To evaluate the pathophysiological significance of our findings on the PGD2 pathway, we treated a subset of rats (WT and Tg-AD males) with timapiprant, a potent and highly selective oral DP2 antagonist being developed as a once-daily oral treatment in patients with allergic inflammation. We conclusively show that timapiprant significantly mitigated some of the AD pathology exhibited by the Tg-AD male rats. More comprehensive studies are necessary to support the therapeutic potential of timapiprant and that of other PGD2-related compounds in the treatment of AD.
Ultra-deep Sequencing of Hadza Hunter-Gatherers Recovers Vanishing Gut Microbes
Authors: Merrill Bryan D. , Carter Matthew M. , Olm Matthew R. , Dahan Dylan , Tripathi Surya , Spencer Sean P. , Yu Brian , Jain Sunit , Neff Norma , Jha Aashish R. , Sonnenburg Erica D. , Sonnenburg Justin L. 
Published: April 2022

SummaryThe gut microbiome is a key modulator of immune and metabolic health. Human microbiome data is biased towards industrialized populations, providing limited understanding of the distinct and diverse non-industrialized microbiomes. Here, we performed ultra-deep metagenomic sequencing and strain cultivation on 351 fecal samples from the Hadza, hunter-gatherers in Tanzania, and comparative populations in Nepal and California. We recover 94,971 total genomes of bacteria, archaea, bacteriophages, and eukaryotes, 43% of which are absent from existing unified datasets. Analysis of in situ growth rates, genetic pN/pS signatures, high-resolution strain tracking, and 124 gut-resident species vanishing in industrialized populations reveals differentiating dynamics of the Hadza gut microbiome. Industrialized gut microbes are enriched in genes associated with oxidative stress, possibly a result of microbiome adaptation to inflammatory processes. This unparalleled view of the Hadza gut microbiome provides a valuable resource that expands our understanding of microbes capable of colonizing the human gut and clarifies the extensive perturbation brought on by the industrialized lifestyle.
CRISPR activation rescues abnormalities in SCN2A haploinsufficiency-associated autism spectrum disorder
Authors: Tamura Serena , Nelson Andrew D. , Spratt Perry W.E. , Kyoung Henry , Zhou Xujia , Li Zizheng , Zhao Jingjing , Holden Stephanie S. , Sahagun Atehsa , Keeshen Caroline M. , Lu Congyi , Hamada Elizabeth C. , Ben-Shalom Roy , Pan Jen Q. , Paz Jeanne T. , Sanders Stephan J. , Matharu Navneet , Ahituv Nadav , Bender Kevin J. 
Published: April 2022

ABSTRACTThe majority of autism spectrum disorder (ASD) risk genes are associated with ASD due to haploinsufficiency, where only one gene copy is functional. Here, using SCN2A haploinsufficiency, a major risk factor for ASD, we show that increasing the expression of the existing functional SCN2A allele with CRISPR activation (CRISPRa) can provide a viable therapeutic approach. We first demonstrate therapeutic potential by showing that restoring Scn2a expression in adolescent heterozygous Scn2a conditional knock-in mice rescues electrophysiological deficits associated with Scn2a haploinsufficiency. Next, using an rAAV-CRISPRa based treatment, we restore electrophysiological deficits in both Scn2a heterozygous mice and human stem-cell-derived neurons. Our results provide a novel therapeutic approach for numerous ASD-associated genes and demonstrate that rescue of Scn2a haploinsufficiency, even at adolescent stages, can ameliorate neurodevelopmental phenotypes.
Impact of spatiotemporal heterogeneity in COVID-19 disease surveillance on epidemiological parameters and case growth rates
Authors: Inward Rhys P.D. , Jackson Felix , Dasgupta Abhishek , Lee Graham , Battle Anya Lindström ,   Global.health consortium, Parag Kris V. , Kraemer Moritz U.G. 
Published: April 2022

AbstractSARS-CoV-2 case data are primary sources for estimating epidemiological parameters and for modelling the dynamics of outbreaks. Understanding biases within case based data sources used in epidemiological analyses are important as they can detract from the value of these rich datasets. This raises questions of how variations in surveillance can affect the estimation of epidemiological parameters such as the case growth rates. We use standardised line list data of COVID-19 from Argentina, Brazil, Mexico and Colombia to estimate delay distributions of symptom-onset-to-confirmation, -hospitalisation and -death as well as hospitalisation-to-death at high spatial resolutions and throughout time. Using these estimates, we model the biases introduced by the delay from symptom-onset-to-confirmation on national and state level case growth rates (rt) using an adaptation of the Richardson-Lucy deconvolution algorithm. We find significant heterogeneities in the estimation of delay distributions through time and space with delay difference of up to 19 days between epochs at the state level. Further, we find that by changing the spatial scale, estimates of case growth rate can vary by up to 0.13 d-1. Lastly, we find that states with a high variance and/or mean delay in symptom-onset-to-diagnosis also have the largest difference between the rt estimated from raw and deconvolved case counts at the state level. We highlight the importance of high-resolution case based data in understanding biases in disease reporting and how these biases can be avoided by adjusting case numbers based on empirical delay distributions. Code and openly accessible data to reproduce analyses presented here are available.
Endo-lysosomal assembly variations among Human Leukocyte Antigen class I (HLA-I) allotypes
Authors: Olson Eli , Ceccarelli Theadora , Raghavan Malini 
Published: April 2022

AbstractThe extreme polymorphisms of HLA-I proteins enable the presentation of diverse peptides to cytotoxic T lymphocytes (CTL). The canonical endoplasmic reticulum (ER) HLA-I assembly pathway enables presentation of cytosolic peptides, but effective intracellular surveillance requires multi-compartmental antigen sampling. Endo-lysosomes are generally sites of HLA class II assembly, but human monocytes and monocyte-derived dendritic cells (moDCs) also contain significant reserves of endo-lysosomal HLA-I molecules. We hypothesized variable influences of HLA-I polymorphisms upon outcomes of endo-lysosomal trafficking, as the stabilities and peptide occupancies of cell surface HLA-I are variable. For example, in moDCs, compared with HLA-B*08:01, HLA-B*35:01 displays reduced cell-surface stability and greater receptivity to exogenous peptide. Perturbations of endo-lysosomal pH negatively affect the surface expression of moDC HLA-B*35:01 but not HLA-B*08:01, causing HLA-B*35:01 accumulation in LAMP1+ compartments. These findings reveal the intersection of the vacuolar cross-presentation pathway with a constitutive assembly pathway for HLA-B*35:01. Notably, cross-presentation of epitopes derived from two soluble antigens was also more efficient for B*35:01 compared to B*08:01, even when matched for T cell response sensitivity, and more affected by cathepsin inhibition. Thus, HLA-I polymorphisms dictate the degree of endo-lysosomal assembly, which can supplement ER assembly for constitutive HLA-I expression and increase the efficiency of cross-presentation.
Normative sleep spindle database and findings from 772 healthy children from birth through 18 years
Authors: Kwon Hunki , Walsh Katherine G. , Berja Erin D. , Manoach Dara S. , Eden Uri T. , Kramer Mark A. , Chu Catherine J. 
Published: April 2022

AbstractWork in the last two decades has identified sleep spindles, discrete “sigma band” oscillations during stage 2 sleep, as a key oscillatory mechanism required for off-line memory consolidation. Although, sleep spindles are known to evolve concomitant with brain maturation and reflect cognitive function across the lifespan, the details of this developmental trajectory are unknown. To address this, we curated a database of sleep electroencephalograms from 772 developmentally normal children to characterize spindles from birth through 18 years. After validating an automated spindle detector against ~20,000 hand-marked spindles across ages, we demonstrate that sleep spindle features follow distinct age-specific patterns in distribution, rate, duration, frequency, estimated refractory period, and inter-hemispheric spindle lag. These data expand our current knowledge of normal physiological brain development and provide a large normative database to detect deviations in sleep spindles to aid discovery, biomarker development, and diagnosis in pediatric neurodevelopmental disorders.
The impact of sparsity in low-rank recurrent neural networks
Authors: Herbert Elizabeth , Ostojic Srdjan 
Published: April 2022

AbstractNeural population dynamics are often highly coordinated, allowing task-related computations to be understood as neural trajectories through low-dimensional subspaces. How the network connectivity and input structure give rise to such activity can be investigated with the aid of low-rank recurrent neural networks, a recently-developed class of computational models which offer a rich theoretical framework linking the underlying connectivity structure to emergent low-dimensional dynamics. This framework has so far relied on the assumption of all-to-all connectivity, yet cortical networks are known to be highly sparse. Here we investigate the dynamics of low-rank recurrent networks in which the connections are randomly sparsified, which makes the network connectivity formally full-rank. We first analyse the impact of sparsity on the eigenvalue spectrum of low-rank connectivity matrices, and use this to examine the implications for the dynamics. We find that in the presence of sparsity, the eigenspectra in the complex plane consist of a continuous bulk and isolated outliers, a form analogous to the eigenspectra of connectivity matrices composed of a low-rank and a full-rank random component. This analogy allows us to characterise distinct dynamical regimes of the sparsified low-rank network as a function of key network parameters. Altogether, we find that the low-dimensional dynamics induced by low-rank connectivity structure are preserved even at high levels of sparsity, and can therefore support rich and robust computations even in networks sparsified to a biologically-realistic extent.Author summaryIn large networks of neurons, the activity displayed by the population depends on the strength of the connections between each neuron. In cortical regions engaged in cognitive tasks, this population activity is often seen to be highly coordinated and low-dimensional. A recent line of theoretical work explores how such coordinated activity can arise in a network of neurons in which the matrix defining the connections is constrained to be mathematically low-rank. Until now, this connectivity structure has only been explored in fully-connected networks, in which every neuron is connected to every other. However, in the brain, network connections are often highly sparse, in the sense that most neurons do not share direct connections. Here, we test the robustness of the theoretical framework of low-rank networks to the reality of sparsity present in biological networks. By mathematically analysing the impact of removing connections, we find that the low-dimensional dynamics previously found in dense low-rank networks can in fact persist even at very high levels of sparsity. This has promising implications for the proposal that complex cortical computations which appear to rely on low-dimensional dynamics may be underpinned by a network which has a fundamentally low-rank structure, albeit with only a small fraction of possible connections present.
Structural interplay between DNA-shape protein recognition and supercoiling: the case of IHF
Authors: Watson George D. , Chan Elliot W. , Leake Mark C. , Noy Agnes 
Published: April 2022

AbstractThe integration host factor (IHF) is a prominent example of indirect readout as it imposes one of the strongest bends on relaxed linear DNA. However, the relation between IHF and torsionally constrained DNA, as occurs physiologically, remains unclear. By using atomistic molecular dynamics simulations on DNA minicircles, we reveal, for the first time, the reciprocal influence between a DNA-bending protein and supercoiling. While the increased curvature of supercoiled DNA enhances wrapping around IHF, the protein pins the position of plectonemes, organizing the topology of the loop in a unique and specific manner. In addition, IHF restrains underor overtwisted DNA depending on whether the complex is formed in negatively or positively supercoiled DNA. This effectively enables IHF to become a ‘supercoiling buffer’ that dampens changes in the surrounding superhelical stress through DNA breathing around the protein or complex dissociation. We finally provide evidence of DNA bridging by IHF and reveal that these bridges divide DNA into independent topological domains. We anticipate that the crosstalk detected here between the ‘active’ DNA and the multifaceted IHF could be common to other DNA-protein complexes relying on the deformation of DNA.
SARS-CoV-2 Omicron is specifically restricted in its replication in human lung tissue, compared to other variants of concern
Authors: Alfi Or , Hamdan Marah , Wald Ori , Yakirevitch Arkadi , Wandel Ori , Oiknine-Djian Esther , Gvili Ben , Knoller Hadas , Rozendorn Noa , Golan Hadar , Adar Sheera , Vorontsov Olesya , Mandelboim Michal , Zakay-Rones Zichria , Oberbaum Menachem , Panet Amos , Wolf Dana G. 
Published: April 2022

ABSTRACTSARS-CoV-2 Omicron variant has been characterized by decreased clinical severity, raising the question of whether early variant-specific interactions within the mucosal surfaces of the respiratory tract could mediate its attenuated pathogenicity. Here, we employed ex vivo infection of native human nasal and lung tissues to investigate the local-mucosal susceptibility and innate immune response to Omicron, compared to Delta and earlier SARS-CoV-2 variants of concern (VOC). We show that the replication of Omicron in lung tissues is highly restricted compared to other VOC, whereas it remains relatively unchanged in nasal tissues. Mechanistically, Omicron induced a much stronger antiviral interferon response in infected tissues compared to Delta and earlier VOC - a difference which was most striking in the lung tissues, where the innate immune response to all other SARS-CoV-2 VOC was blunted. Our data provide new insights to the reduced lung involvement and clinical severity of Omicron.
Understanding the transcriptional response to ER stress in Chinese hamster ovary cells using multiplexed single cell RNA-seq
Authors: Tzani Ioanna , Castro-Rivadeneyra Marina , Boi Stefano , Clarke Colin 
Published: April 2022

AbstractSingle cell RNA-seq (scRNA-seq) has recently been shown to provide a powerful method for the analysis of transcriptional heterogeneity in Chinese hamster ovary (CHO) cells. A potential drawback of current scRNA-seq platforms is that the cost can limit the complexity of experimental design and therefore the utility of the approach. In this manuscript, we report the use of oligonucleotide barcoding to perform multiplexed CHO cell scRNA-seq to study the impact of tunicamycin (TM), an inducer of the unfolded protein response (UPR). For this experiment, we treated a CHO-K1 GS cell line with 10μg/ml tunicamycin and acquired samples at 1, 2, 4 and 8 hr post-treatment as well as a non-treated TM-control. We transfected cells with sample-specific polyadenylated ssDNA oligonucleotide barcodes enabling us to pool all cells for scRNA-seq. The sample from which each cell originated was subsequently determined by the oligonucleotide barcode sequence. Visualisation of the transcriptome data in a reduced dimensional space confirmed that cells were not only separable by sample but were also distributed according to time post-treatment. These data were subsequently utilised to perform weighted gene co-expression analysis (WGCNA) and uncovered groups of genes associated with TM treatment. For example, the expression of one group of coexpressed genes was found to increase over the time course and were enriched for biological processes associated with ER stress. The use of multiplexed single cell RNA-seq has the potential to reduce the cost associated with higher sample numbers and avoid batch effects for future studies of CHO cell biology.HighlightsPolyadenylated ssDNA oligonucleotide labelling is a viable strategy for multiplexed CHO cell scRNA-seq analysis.To demonstrate the effectiveness of the method we conducted an experiment to study the CHO cell response to tunicamycin treatment.scRNA-seq was carried out on an untreated control and at 4 time points post tunicamycin treatment. Cells from each sample were transfected with a unique oligonucleotide barcode and pooled for single cell transcriptomics.Each sample was demultiplexed post-sequencing and gene expression profiles of > 5,300 cells were obtained across the experiment. Following dimensionality reduction and visualisation, the cells were distributed according to sample identity.Analysis of the resulting data enabled improved understanding of the transcriptional response to tunicamycin treatment. Three gene coexpression modules were found to be correlated with the tunicamycin time course. Gene set enrichment analysis revealed the over representation of genes related to biological processes associated with ER stress, and protein misfolding in one of these groups of coexpressed genes.Further use of this approach will enable the CHO cell biology community to perform increasingly complex single cell experiments in a cost-effective manner.
Robust inference of expression state in bulk and single-cell RNA-Seq using curated intergenic regions
Authors: Costa Sara S. Fonseca , Rosikiewicz Marta , Roux Julien , Wollbrett Julien , Bastian Frederic B. , Robinson-Rechavi Marc 
Published: April 2022

AbstractRNA-Seq is a powerful technique to provide quantitative information on gene expression. While many applications focus on estimated expression levels, it is also important to determine which genes are actively transcribed, and which are not. The problem can be viewed as simply setting a biologically meaningful threshold for calling a gene expressed. We propose to define this threshold per sample relative to the background level for non-expressed genomic features, inferred by the amount of reads mapped to intergenic regions of the genome. To this aim, we first define a stringent set of reference intergenic regions, based on available bulk RNA-Seq libraries for each species. We provide predefined regions selected for different animal species with varying genome annotation quality through the Bgee database. We then call genes expressed if their level of expression is significantly higher than the background noise. This approach can be applied to bulk as well as single-cell RNA-Seq, on a single library as well as on a combination of libraries over one condition. We show that the estimated proportion of expressed genes is biologically meaningful and stable between libraries originating from the same tissue, in both model and non-model organisms.
Establishment of a social conditioned place preference paradigm for the study of social reward in female mice
Authors: Harda Zofia , Chrószcz Magdalena , Misiołek Klaudia , Klimczak Marta , Szumiec Łukasz , Kaczmarczyk-Jarosz Maria , Parkitna Jan Rodriguez 
Published: April 2022

AbstractSocial interactions can be and often are rewarding. The effect of social contact strongly depends on circumstances, and the reward may be driven by varied motivational processes, ranging from parental or affiliative behaviors to investigation or aggression. Reward associated with nonreproductive interactions in rodents is measured using the social conditioned place preference (sCPP) paradigm, where a change in preference for an initially neutral context confirms reinforcing effects of social contact. Here, we revised the sCPP method and reexamined social reward in adult female mice. Contrary to earlier studies, we found that robust rewarding effects of social contact could be detected in adult (14-week-old) female C57BL/6 mice when the sCPP task was refined to remove confounding factors. Strikingly, the rewarding effects of social interaction were only observed among female siblings who remained together from birth. Contact with same-age nonsiblings was not rewarding even after 8 weeks of cohousing. Other factors critical for the social reward effect in the sCPP paradigm included the number of conditioning sessions and the inherent preference for contextual cues. Thus, we show that social interaction is rewarding in adult female mice, but this effect strictly depends on the familiarity of the interaction partners. Furthermore, by identifying confounding factors, we provide a behavioral model to study the mechanisms underlying the rewarding effects of nonreproductive social interaction in adult mice.