bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuroinvasive and neurovirulent potential of SARS-CoV-2 in the acute and post-acute phase of intranasally inoculated ferrets
Authors: Benavides Feline F. W. , Kroeze Edwin J. B. Veldhuis , Leijten Lonneke , Schmitz Katharina S. , van Run Peter , Kuiken Thijs , de Vries Rory D. , Bauer Lisa , van Riel Debby 
Published: September 2024

AbstractSevere acute respiratory syndrome corona virus 2 (SARS-CoV-2) can cause systemic disease, including neurological complications, even after mild respiratory disease. Previous studies have shown that SARS-CoV-2 infection can induce neurovirulence through microglial activation in the brains of patients and experimentally inoculated animals, which are models representative for moderate to severe respiratory disease. Here, we aimed to investigate the neuroinvasive and neurovirulent potential of SARS-CoV-2 in intranasally inoculated ferrets, a model for subclinical to mild respiratory disease. The presence of viral RNA, histological lesions, virus-infected cells, and the number and surface area of microglia and astrocytes were investigated. Viral RNA was detected in various respiratory tissue samples by qPCR at 7 days post inoculation (dpi). Virus antigen was detected in the nasal turbinates of ferrets sacrificed at 7 dpi and was associated with inflammation. Viral RNA was detected in the brains of ferrets sacrificed 7 dpi, butin situhybridization nor immunohistochemistry did not verify evidence of infection. Histopathological analysis of the brains showed no evidence for an influx of inflammatory cells. Despite this, we observed an increased number of Alzheimer type II astrocytes in the hindbrains of SARS-CoV-2 inoculated ferrets. Additionally, we detected an increased microglial activation in the olfactory bulb and hippocampus, and a decrease in the astrocytic activation status in the white matter and hippocampus of SARS-CoV-2 inoculated ferrets. In conclusion, although showed that SARS-CoV-2 has limited neuroinvasive potential in this model for subclinical to mild respiratory disease, there is evidence for neurovirulent potential. This study highlights the value of this ferret model to study the neuropathogenecity of SARS-CoV-2 and reveals that a mild SARS-CoV-2 infection can affect both microglia and astrocytes in different parts of the brain.
Postmortem findings of free-ranging North American beavers (Castor canadensis) reveal potential threats to California freshwater ecosystems
Authors: Gonzales-Viera Omar A. , Woods Leslie W. , Mete Aslı , Fritz Heather , Armien Anibal G. , Lantz Emma , Gomez-Puerta Luis A. , Famini Daniel , Sherman Jaime , Rudd Jaime L. , Camp Lauren E. , Shapiro Karen , Clifford Deana L. 
Published: September 2024

AbstractNorth American beavers (Castor canadensis) are semi-aquatic rodents recognized as keystone species that increase the diversity of freshwater ecosystems. This study aimed to characterize the mortality and pathological findings of free-ranging beavers in California and, based on these results, establish the potential threats to freshwater ecosystems. This study included eighteen beavers submitted for postmortem examination between 2008 and 2024 at the California Animal Health and Food Safety Laboratory, UC Davis. Gross and microscopic examination, bacteriological, parasitological, immunohistochemical, and molecular techniques were used as tools to diagnose the cause of death/reason for euthanasia and comorbidities in the beavers. Encephalitis caused by the larva migrans ofBaylisascarisspp. was the most prevalent (9/18) cause of mortality/reason for euthanasia followed by bacterial infections in 6 individuals. In these 6 animals, bacterial bronchopneumonia was diagnosed in two (Staphylococcus aureusand a mix of gram-negative and -positive bacterial infection) andListeria monocytogenesencephalitis, bacterial myofascitis (Aeromonas bestiarumandPasteurella multocida), bacterial encephalitis (Acinetobacter towneri), and tularemia (Francisella tularensis) were diagnosed in one beaver each. Three animals died or were euthanized due to non-infectious causes including motor vehicle trauma, squamous cell carcinoma, and capture cardiomyopathy. Endoparasitism was the main comorbidity including granulomatous hepatitis by a suspected capillarid species, cerebral toxoplasmosis, Giardia infection, gastric nematodiasis, and cecal trematodiasis. In California, beavers are exposed to various pathogens that represent threats to humans, domestic animals, and wildlife. Since the interspecies transmission of these pathogens occurs in rivers, streams, lakes, and ponds, we suggest that studying beaver health can reflect freshwater ecosystem health. This study also indicates that the translocation of beavers into new areas without consideration and/or mitigation represents a potential risk for pathogen introduction.
Sequestration of dead-end undecaprenyl phosphate-linked oligosaccharide intermediate
Authors: Hong Yaoqin , Reeves Peter R. 
Published: September 2024

ABSTRACTIn the predominant Wzx/Wzy-dependent bacterial surface polysaccharide biosynthetic pathway, synthesis is divided between the cytoplasmic and periplasmic faces of the membrane. Initially, an oligosaccharide composed of 3-8 sugars is synthesized on a membrane-embedded lipid carrier, Und-P, within the cytoplasmic face of the membrane. This Und-P-linked oligosaccharide is then translocated to the periplasmic face by the Wzx flippase, where it is polymerized into a repeat-unit polysaccharide. Structural alterations to the repeating oligosaccharide significantly reduce polysaccharide yield and lead to cell death or morphological abnormalities. These effects are attributed to the substrate recognition function of the Wzx flippase, which we postulated to act as a gatekeeper to ensure only complete substrates are translocated to the periplasmic face. Here, we labelledSalmonella entericaserovar Typhimurium Group B1 with [14C] D-galactose. Our results showed that strains unable to synthesize the full O-antigen repeat unit accumulate significantly higher levels of Und-P-linked material (∼10-fold). Importantly, this sequestration is alleviated by mild membrane disruption which opens the cytosolic face Und-PP-linked material to O-antigen ligation that supports the accumulation to occur at the cytosolic face of the membrane.
Importance of higher-order epistasis in large protein sequence-function relationships
Authors: Sethi Palash , Zhou Juannan 
Published: September 2024

AbstractEpistasis complicates our understanding of protein sequence-function relationships and impedes our ability to build accurate predictive models for novel genotypes. Although pairwise epistasis has been extensively studied in proteins, the significance of higher-order epistasis for protein sequence-function relationships remains contentious, largely due to challenges in fitting higher-order epistatatic interactions for full-length proteins. Here, we introduce a novel transformer-based approach. The key feature of our method is that we can adjust the order of interactions fit by the model by changing the number of attention layers while also accounting for any global nonlinearity induced by the experimental conditions. This allows us to test if inclusion of higher-order interactions leads to enhanced model performance. Applying our method to 10 large protein sequence-function datasets, we found that the importance of higher-order epistasis differs substantially between proteins, accounting for up to 60% of the total variance attributed to epistasis. We also found that including higher-order epistasis is particularly important for generalizing locally sampled fitness data to distant regions of sequence space and for modeling an additional multipeak fitness landscape derived from combining mutagenesis data from 4 orthologous green fluorescencent proteins. Our findings suggest that higher-order epistasis often does play an important role in protein sequence-function relationships, and thus should be properly incorporated during protein engineering and evolutionary data analysis.
Beyond Static Brain Atlases: AI-Powered Open Databasing and Dynamic Mining of Brain-Wide Neuron Morphometry
Authors: Jiang Shengdian , Wang Lijun , Yun Zhixi , Chen Hanbo , Yao Jianhua , Peng Hanchuan 
Published: September 2024

AbstractWe introduce NeuroXiv (neuroxiv.org), a large-scale, AI-powered database that provides detailed 3D morphologies of individual neurons mapped to a standard brain atlas, designed to support a wide array of dynamic, interactive neuroscience applications. NeuroXiv offers a comprehensive collection of 175,149 atlas-oriented reconstructed morphologies of individual neurons derived from more than 518 mouse brains, classified into 292 distinct types and mapped into the Common Coordinate Framework Version 3 (CCFv3). Different from conventional static brain atlases that are often limited to data-browsing, NeuroXiv allows interactive analyses as well as uploading and databasing custom neuron morphologies, which are mapped to the brain atlas for objective comparisons. Powered by a cutting-edge AI engine (AIPOM), NeuroXiv enables dynamic, user-specific analysis and data mining. We specifically developed a mixture-of-experts algorithm to harness the capabilities of multiple large language models. We also developed a client program to achieve more than 10 times better performance compared to a typical server-side setup. We demonstrate NeuroXiv’s scalability, efficiency, flexibility, openness, and robustness through various applications.
Joint Modeling of Cellular Heterogeneity and Condition Effects with scPCA in Single-Cell RNA-Seq
Authors: Vöhringer Harald , Dietrich Sascha 
Published: September 2024

AbstractSingle-cell RNA sequencing (scRNA-seq) in multi-condition experiments enables the systematic assessment of treatment effects. Analyzing scRNA-seq data relies on linear dimensionality reduction (DR) methods like principal component analysis (PCA). These methods decompose high-dimensional gene expression profiles into tractable factor representations and prototypical gene expression patterns (components), facilitating the study of cell type variation. However, integrating study covariates within linear DR frameworks remains a challenging task. We present scPCA, a flexible DR framework that jointly models cellular heterogeneity and conditioning variables, allowing it to recover an integrated factor representation and reveal transcriptional changes across conditions and components of the decomposition. We show that scPCA extracts an interpretable latent representation by analyzing unstimulated and IFN-beta-treated PBMCs, and showcase that the model may be employed to effectively address batch effects. We examine age-related changes in rodent lung cell populations, uncovering a previously unreported surge inCcl5expression in T cells. We illustrate how scPCA may be employed to identify coordinated transcriptional changes across multiple time-points in depolarized visual cortex neurons. Finally, we show that scPCA elucidates transcriptional shifts in CRISPR-Cas9 chordin knockout zebrafish fish single-cell data despite large difference cell abundance across conditions. Since scPCA introduces a general approach to account for conditioning variables in high-dimensional data, it may also be applicable to datasets other than scRNA-seq.
Constructing a Mouse Brain Atlas of Dendritic Microenvironments Helps Discover Hidden Associations Between Anatomical Layout, Projection Targets and Transcriptomic Profiles of Neurons
Authors: Liu Yufeng , Zhao Sujun , Yun Zhixi , Xiong Feng , Peng Hanchuan 
Published: September 2024

AbstractDigital brain atlases have become essential anatomical references for understanding the spatial and functional organization of brains. For mice, typical resources include the Allen Reference Atlas, the Allen Common Coordinate Framework (CCF), and their variants, like CCFv3. However, previous whole-brain atlases were constructed based on limited neuronal features, such as cell body (soma) density or average maps from collections of registered brain images, without considering the spatial organization of neuronal arbors. This study introduces a microenvironment representation that incorporates the morphological features of neighboring neurons to better quantify brain modularity. We generated a large dataset containing dendrites from 101,136 neurons across 111 mouse brains, covering 91% of non-ventricular, non-fiber-tract CCF regions, and constructed a multidimensional microenvironment feature map of the whole brain. Our findings reveal that the spatial organization of these microenvironments outperforms the CCFv3 and a state-of-the-art spatial transcriptomic cell atlas by providing complementary subregions within established regions, nearly doubling the total number of brain regions compared to CCFv3. In this way, our atlas enables the identification of previously unobserved neuron groupings or “subtypes”. Our results also demonstrate that this microenvironment atlas enhances local spatial homogeneity while maintaining spatial differentiation within established CCF brain regions. For example, we found that the microenvironments of hippocampal neurons are correlated with axonal projection targets and improve the specificity of projection mapping, which implies the potential characterization of long-range axonal projections of mammalian neurons based on only local dendritic organization. The sub-parcellation of the caudoputamen (CP) aligns well with previous studies on projections, connectivity, and transcriptomics, revealing diverse input and output wiring patterns among CP subregions.
Population dynamics of fruit flies (Diptera: Tephritidae) in a semirural area under subtropical monsoon climate of Bangladesh
Authors: Momen Mahfuza , Hossain Md. Aftab , Seheli Kajla , Hossain Md. Forhad , Bari Md. Abdul 
Published: September 2024

AbstractFruit flies belonging to Tephritidae family are highly destructive agricultural pests, posing a significant threat to various fruits and vegetables grown in Bangladesh. A comprehensive year-round survey was conducted at Atomic Energy Research Establishment (AERE) campus located in the central region of Bangladesh. Three types of male lures (methyl eugenol, cue-lure and zingerone) were used to detect and assess the diversity of pest fruit fly species. A total of seventeen species of Tephritidae fruit flies were detected in this survey. TheBactrocera carambolaefruit fly has been discovered for the first time in our survey area, indicating spread of its range towards the north-west region from its previous detection sites (Chattogram and Sylhet Divisions) in Bangladesh. Among the detected pest species, we identified six abundant species:Bactrocera dorsalis, Zeugodacus cucurbitae, Zeugodacus tau, Bactrocera rubigina, Bactrocera zonata, andDacus longicornis. The most abundant species was the polyphagous fruit pestB. dorsalis, comprising 76.83% of all captured flies. The speciesZ. cucurbitaewas the second most abundant, representing 13.82% of the total trapped flies. The fitted curve to survey data using Gaussian mixture model revealed the existence of overlapped subgroups in the population ofB. dorsalisandZ. cucurbitae. In addition, our statistical analysis of the six abundant Tephritidae fruit fly species revealed correlation of population dynamics with several factors including temperature, rainfall, humidity, photoperiod, and fruiting time of host plant species in the selected area.
An initial genome editing toolset forCaldimonasthermodepolymerans, the first model of thermophilic polyhydroxyalkanoates producer
Authors: Grybchuk-Ieremenko Anastasiia , Lipovská Kristýna , Kouřilová Xenie , Obruča Stanislav , Dvořák Pavel 
Published: September 2024

AbstractThe limited number of well-characterized model bacteria cannot address all the challenges in a circular bioeconomy. Therefore, there is a growing demand for new production strains with enhanced resistance to extreme conditions, versatile metabolic capabilities, and the ability to utilize cost-effective renewable resources while efficiently generating attractive biobased products. Particular thermophilic microorganisms fulfill these requirements. Non-virulent Gram-negativeCaldimonas thermodepolymeransDSM15344 is one such attractive thermophile that efficiently converts a spectrum of plant biomass sugars into high quantities of polyhydroxyalkanoates (PHA) - a fully biodegradable substitutes for synthetic plastics. However, to enhance its biotechnological potential, the bacterium needs to be “domesticated”. In this study we established effective homologous recombination and transposon-based genome editing systems forC. thermodepolymerans. By optimizing the electroporation protocol and refining counterselection methods, we achieved significant improvements in genetic manipulation and constructed the AI01 chassis strain with improved transformation efficiency and a ΔphaCmutant that will be used to study the importance of PHA synthesis inCaldimonas. The advances described herein highlight the need for tailored approaches when working with thermophilic bacteria and provide a springboard for further genetic and metabolic engineering ofC. thermodepolymerans, which can be considered the first model of thermophilic PHA producer.
TDRD3 functions as a selective autophagy receptor with dual roles in autophagy and modulation of stress granule stability
Authors: Deater Matthew , Lloyd Richard E. 
Published: September 2024

AbstractTudor Domain Containing 3 (TDRD3) is a methylarginine-reader protein that functions as a scaffold in the nucleus facilitating transcription, however TDRD3 is also recruited to stress granules (SGs) during the Integrated Stress Response (ISR) although its function therein remains largely unknown. We previously showed that TDRD3 is a novel antiviral restriction factor that is cleaved by virus 2A protease, and plays complex modulatory roles in both interferon and inflammatory signaling during stress and enterovirus infections. Here we have found that TDRD3 contains structural motifs similar to known selective autophagy receptors such as p62/SQSTM1, sharing ubiquitin associated domains (UBA) and LC3 interacting regions (LIR) that anchor cargo destined for autophagosomes to activated LC3 protein coating autophagosome membranes. This is of interest since enteroviruses hijack autophagy machinery to facilitate formation of viral replication factories, virus assembly and egress from the infected cell. Here we explored possible roles of TDRD3 in autophagy, hypothesizing that TDRD3 may function as a specialized selective autophagy receptor. We found that KO of TDRD3 in HeLa cells significantly reduces starvation induced autophagy, while its reintroduction restores it in a dose-dependent manner. Autophagy receptors are degraded during autophagy and expression levels decrease during this time. We found that TDRD3 levels decrease to the same extent as the autophagy receptor p62/SQSTM1 during autophagy, indicating autophagy-targeted turnover in that role. Knockout of TDRD3 or G3BP1 did not make significant changes in overall cell localization of LC3B or p62/SQSTM1, but did result in greater concentration of Lamp2 phagosome marker for phagosomes and phagolysosomes. To test the potential roles of TDRD3 in autophagic processes, we created a series of deletion mutants of TDRD3 lacking either UBA domain or the various LIR motifs that are predicted to interact with LC3B. Microscopic examination of starved cells expressing these variants of TDRD3 showed ΔLIR-TDRD3 had defects in colocalization with LC3B or Lamp2. Further, super resolution microscopy revealed ring structures with TDRD3 interfacing with p62/SQSTM1. In examination of arsenite induced stress granules we found recruitment of TDRD3 variants disrupted normally tight SG condensation, altered the decay rate of SGs upon release from stress and the kinetics of SG formation. We found evidence that the LIR3 motif on TDRD3 is involved in TDRD3 interaction with LC3B in coIP experiments, colocalization studies, and that this motif plays a key role in TDRD3 recruitment to SGs and SG resolution. Overall, these data support a functional role of TDRD3 in selective autophagy in a mode similar to p62/SQSTM1, with specific roles in SG stability and turnover. Enterovirus cleavage of TDRD3 likely affects both antiviral and autophagic responses that the virus controls for replication.
Distinct Neural Representations of Hunger and Thirst in Neonatal Mice before the Emergence of Food- and Water-seeking Behaviors
Authors: Wang David C. , Wu Yunming , Mehaffy Conor , Espinoza-Campomanes Leslie A. , Santos-Valencia Fernando , Franks Kevin M. , Luo Liqun 
Published: September 2024

SUMMARYHunger and thirst are two fundamental drives for maintaining homeostasis and elicit distinct food- and water-seeking behaviors essential for survival. For neonatal mammals, however, both hunger and thirst are sated by consuming milk from their mother. While distinct neural circuits underlying hunger and thirst drives in the adult brain have been characterized, it is unclear when these distinctions emerge in neonates and what processes may affect their development. Here we show that hypothalamic hunger and thirst regions already exhibit specific responses to starvation and dehydration well before a neonatal mouse can seek food and water separately. At this early age, hunger neurons drive feeding behaviors more than do thirst neurons.In vivoNeuropixels recordings in dehydrated and starved neonatal mice revealed that maternal presentation leads to a relative increase in activity which is suppressed by feeding on short timescales, particularly in hypothalamic and thalamic neurons. Changes in activity become more heterogeneous on longer timescales. Lastly, within neonatal regions that respond to both hunger and thirst, subpopulations of neurons respond distinctly to one or the other need. Combining food and water into a liquid diet throughout the animal’s life does not alter the distinct representations of hunger and thirst in the adult brain. Thus, neural representations of hunger and thirst in mice become distinct before food- and water-seeking behaviors mature and are robust to environmental changes in food and water sources.