bluuebunny/crossref_metadata_2025_split huggingface dataset:
The inactive X chromosome accumulates widespread epigenetic variability with age
Authors: Liu Yunfeng , Sinke Lucy , Jonkman Thomas H. , Slieker Roderick C. ,   BIOS Consortium, van Zwet Erik W. , Daxinger Lucia , Heijmans Bastiaan T. 
Published: March 2023

AbstractBackgroundLoss of epigenetic control is a hallmark of aging. Among the most prominent roles of epigenetic mechanisms is the inactivation of one of two copies of the X chromosome in females through DNA methylation. Hence, age-related disruption of X-chromosome inactivation (XCI) may contribute to the ageing process in women.MethodsWe analyzed 9,777 CpGs on the X chromosome in whole blood samples from 2343 females and 1688 males. We replicated findings in duplicate using one whole blood and one purified monocyte data set (in total, 991/924 females/males). We used double generalized linear models (DGLM) to detect age-related differentially methylated CpGs (aDMCs), whose mean methylation level differs with age, and age-related variable methylated CpGs (aVMCs), whose methylation level becomes more variable with age.ResultsIn females, aDMCs were relatively uncommon (n=33) and preferentially occurred in regions known to escape XCI. In contrast, many CpGs (n=987) were found to display an increased variance with age (aVMCs). Of note, the replication rate of aVMCs was also high in purified monocytes (95%), indicating that their occurrence may be independent of cell composition. aVMCs accumulated in CpG islands and regions subject to XCI. Although few aVMCs were associated with X-linked genes in all females studied, an exploratory analysis suggested that such associations may be more common in old females. In males, aDMCs (n=316) were primarily driven by cell composition, while aVMCs replicated well (94%) but were infrequent (n=37).ConclusionsAge-related DNA methylation differences at the inactive X chromosome are dominated by the accumulation of variability.
Degenerated CRISPRs widely regulate Cas expression to balance immunity and cost
Authors: Liu Chao , Wang Rui , Li Jie , Cheng Feiyue , Shu Xian , Zhao Huiwei , Xue Qiong , Yu Haiying , Wu Aici , Wang Lingyun , Hu Sushu , Zhang Yihan , Yang Jun , Xiang Hua , Li Ming 
Published: March 2023

ABSTRACTCRISPR RNAs (crRNAs) and Cas proteins together provide prokaryotes with adaptive immunity against genetic invaders. How Cas expression is fine-tuned to avoid energy burden while satisfying the dynamic need of crRNAs remains poorly understood. Here we experimentally demonstrated widespread degenerated mini-CRISPRs encode CreR (Cas-regulating)RNAs to mediate autorepression of type I-B, I-E and V-A Cas proteins, based on their partial complementarity tocaspromoters. This autorepression decreases energy burden and autoimmune risks, thus mitigating the fitness cost on host cell, and remarkably, senses and responds to alterations in the volume of canonical crRNAs, which compete with CreR for Cas proteins. Moreover, CreR-guided Cas autorepression can be subverted by diverse anti-CRISPR (Acr) proteins that destruct Cas proteins, which in turn replenishes the weapon depot. Our data unveil a general degenerated crRNA-guided autorepression paradigm for diverse Cas effectors, which highlights the intricate (self-)regulation of CRISPR-Cas and its transcriptional counterstrategy against Acr attack.
Incomplete transcripts dominate theMycobacterium tuberculosistranscriptome
Authors: Ju Xiangwu , Li Shuqi , Froom Ruby , Wang Ling , Lilic Mirjana , Campbell Elizabeth A. , Rock Jeremy M. , Liu Shixin 
Published: March 2023

AbstractMycobacterium tuberculosis(Mtb) is a bacterial pathogen that causes tuberculosis, an infectious disease that inflicts major health and economic costs around the world1. Mtb encounters a diversity of environments during its lifecycle, and responds to these changing environments by reprogramming its transcriptional output2. However, the transcriptomic features of Mtb remain poorly characterized. In this work, we comprehensively profile the Mtb transcriptome using the SEnd-seq method that simultaneously captures the 5’ and 3’ ends of RNA3. Surprisingly, we find that the RNA coverage for most of the Mtb transcription units display a gradual drop-off within a 200-500 nucleotide window downstream of the transcription start site, yielding a massive number of incomplete transcripts with heterogeneous 3’ ends. We further show that the accumulation of these short RNAs is mainly due to the intrinsically low processivity of the Mtb transcription machinery rather than trans-acting factors such as Rho. Finally, we demonstrate that transcription-translation coupling plays a critical role in generating full-length protein-coding transcripts in Mtb. In sum, our results depict a mycobacterial transcriptome that is dominated by incomplete RNA products, suggesting a distinctive set of transcriptional regulatory mechanisms that could be exploited for new therapeutics.
Disease Modifying Osteoarthritis Drug Discovery Using A Temporal Phenotypic Reporter In 3D Aggregates of Primary Human Chondrocytes
Authors: Cruz Maria A. , Gronowicz Scott , Karimzadeh Makan , Martyniak Kari , Medam Ramapaada , Kean Thomas J. 
Published: March 2023

ABSTRACTOsteoarthritis is a significant and growing problem with no disease modifying drugs in the clinic. Current screening platforms typically use 2D culture, immortalized or non-human cells in a hyperoxic environment. To challenge this paradigm and identify new drugs, we engineered primary human chondrocytes with a secreted luciferase reporter under the control of the articular cartilage marker, type II collagen. We then successfully screened a natural product library using a high throughput model with COL2A1-Gaussia luciferase primary human chondrocyte reporter cells in 3D aggregates under physioxia. We identified several candidate compounds that increased type II collagen over controls, with aromoline being the best candidate. Aromoline is a bisbenzylisoquinoline alkaloid that has been studied for its anti-proliferative, anti-inflammatory, and anti-microbial properties, and we are the first to explore its effects on chondrocytes and chondrogenesis. In silico analysis of predicted targets narrowed by RNA-Seq data on expression provided an unexpected initial candidate target protein: the dopamine receptor D4 (DRD4). The researchers confirmed upregulation in the expression of DRD4 and type II collagen after treatment with aromoline. This novel approach combining in silico and in vitro methods provides a platform for drug discovery in a challenging and under-researched area. In conclusion, a novel drug (aromoline) and target receptor (dopamine receptor D4) were identified as stimulating type II collagen, with the goal to treat or prevent osteoarthritis.
The 1/f-like behavior of neural field spectra are a natural consequence of noise driven brain dynamics
Authors: Kramer Mark A. , Chu Catherine J. 
Published: March 2023

ABSTRACTConsistent observations across recording modalities, experiments, and neural systems find neural field spectra with 1/f-like scaling, eliciting many alternative theories to explain this universal phenomenon. We show that a general dynamical system with stochastic drive and minimal assumptions generates 1/f-like spectra consistent with the range of values observedin vivo, without requiring a specific biological mechanism or collective critical behavior.
Sperm production is negatively associated with muscle and sperm telomere length in a highly polyandrous species
Authors: Morbiato Elisa , Cattelan Silvia , Pilastro Andrea , Grapputo Alessandro 
Published: March 2023

AbstractLife history theory suggests that aging is one of the costs of reproduction. Accordingly, a higher reproductive allocation is expected to increase the deterioration of both the somatic and the germinal lines through enhanced telomere attrition. In most species, males’ reproductive allocation mainly regards traits that increase mating and fertilization success, i.e. sexually selected traits. In the current study, we tested the hypothesis that a higher investment in sexually selected traits is associated with a reduced telomere length in the guppy (Poecilia reticulata), an ectotherm species characterized by strong pre- and postcopulatory sexual selection. We first measured telomere length in both the soma and the sperm over the course of guppy’s lifespan to see if there was any variation in telomere length associated with age. Secondly, we investigated whether a greater expression of pre- and postcopulatory sexually selected traits is linked to shorter telomere length in both the somatic and the sperm germinal lines, and in young and old males. We found that telomeres lengthened with age in the somatic tissue, but there was no age-dependent variation in telomere length in the sperm cells. Telomere length in guppies was significantly and negatively correlated with sperm production in both tissues and life stages considered in this study. Our findings indicate that telomere erosion in male guppies is more strongly associated with their reproductive investment (sperm production) rather than their age, suggesting a trade-off between reproduction and maintenance is occurring at each stage of males’ life in this species.
Heterospecific developmental models highlight the role ofFBXO32in neural crest lineages and the significance of its variant in pediatric melanoma
Authors: Alexandra Vargas , Clémence Guillermain , Tatiana Gorojankina , Sophie Creuzet 
Published: March 2023

ABSTRACTMelanoma is a rare sporadic pediatric cancer caused byde novogenetic accidents. To analyze the involvement ofFBXO32of unknown biological significance, we set up original developmental invivo,ex vivo, andin vitromodels to unmask the biological role ofFBXO32in cephalic and trunk neural crest lineages. We show thatFBXO32silencing impairs melanocyte proliferation, differentiation, and vascularization. In rescue experiments, co-electroporation with the human wild-type gene compensates for the silencing of the endogenous gene and restores normal melanocyte phenotypes. By contrast, co-electroporation with the human variant,FBXO32G139S, alters melanocyte differentiation, pigment synthesis, triggers migration to the dermis, and favors angiotropism. Transcriptomic analysis reveals targets associated with melanocyte transformation, cytoskeleton remodeling, and focal adhesion. We show thatFBXO32orchestrates unexpected interactions withASIPfor melanogenesis andBAP1for the post-translational ubiquitination system. We proposeFBXO32as a tumor suppressor gene capable of preventing the onset of pediatric melanoma.
Influence of visual perception on movement decisions by an ungulate prey species
Authors: Newman Blaise A. , Dyal Jordan R. , Miller Karl V. , Cherry Michael J. , D’Angelo Gino J. 
Published: March 2023

ABSTRACTVisual perception is dynamic and depends on physiological properties of a species’ visual system and physical characteristics of the environment. White-tailed deer (Odocoileus virginianus) are most sensitive to short- and mid-wavelength light (e.g., blue and green). Wavelength enrichment varies spatially and temporally across the landscape. We assessed how the visual perception of deer influences their movement decisions. From August-September 2019, we recorded 10-min locations from 15 GPS collared adult male deer in Central Florida. We used Hidden-Markov models to identify periods of movement by deer and subset these data into three time periods based on temporal changes in light environments. We modeled resource selection during movement using path-selection functions and simulated 10 available paths for every used path. We developed five a priori models and used 10-fold cross validation to assess our top model’s performance for each time period. During the day, deer selected to move through woodland shade, avoided forest shade, and neither selected nor avoided small gaps. At twilight, deer avoided wetlands as cloud cover increased but neither selected nor avoided other cover types. Visual cues and signals are likely more conspicuous to deer in short-wavelength-enriched woodland shade during the day, while at twilight in long-wavelength-enriched wetlands during cloud cover, visual cues are likely less conspicuous. The nocturnal light environment did not influence resource selection and likely has little effect on deer movements because it’s relatively homogenous. Our findings suggest visual perception relative to light environments is likely an underappreciated driver of behaviors and decision-making by an ungulate prey species.Summary StatementWe assessed how visual perception of white-tailed deer influences movement decisions. Our findings suggest visual perception relative to light environments represents an underappreciated driver of decision-making by ungulate prey species.
Altered cell wall hydroxycinnamate composition impacts leaf and canopy-level CO2-uptake and water-use in rice
Authors: Pathare Varsha S. , Panahabadi Rahele , Sonawane Balasaheb V. , Apalla Anthony Jude , Koteyeva Nouria , Bartley Laura E. , Cousins Asaph B. 
Published: March 2023

AbstractCell wall properties can play a major role in determining photosynthetic carbon-uptake and water-use through impacts on mesophyll conductance (CO2diffusion from substomatal cavities into photosynthetic mesophyll cells) and leaf hydraulic conductance (water movement from xylem, through leaf tissue to stomata). Consequently, modification of cell wall properties is proposed as a major path for improving photosynthesis and crop water-use efficiency. We tested this using two independent transgenic rice lines that overexpress the riceOsAT10gene (a “BAHD” CoA acyltransferase) which altered cell wall hydroxycinnamic acid content (greaterpara-coumaric acid and lower ferulic acid). Plants were grown under high and low water-levels and traits related to leaf anatomy, cell wall composition, gas exchange and hydraulics, plant biomass, and canopy-level water-use were measured. Alteration of hydroxycinnamic acid content led to significant decreases in mesophyll cell wall thickness (−14%), and increased mesophyll conductance (+120%) and photosynthesis (+22%). However, concomitant increases in stomatal conductance negated increased photosynthesis, resulting in no change in intrinsic water-use efficiency (ratio of photosynthesis/stomatal conductance). The leaf hydraulic conductance was also unchanged; however, the transgenics showed small, but significant increase in above-ground biomass (+12.5%), and canopy-level water-use efficiency (+8.8%; ratio of above-ground biomass/ water-used) and performed better under low water-level. Our results demonstrate that changes in cell wall composition, specifically hydroxycinnamic acid content, can increase mesophyll conductance and photosynthesis in C3cereal crops like rice. However, attempts to improve photosynthetic water-use efficiency will need to enhance mesophyll conductance and photosynthesis whilst maintaining or decreasing stomatal conductance.
Differential contribution of nitrifying prokaryotes to groundwater nitrification
Authors: Krüger Markus , Chaudhari Narendrakumar , Thamdrup Bo , Overholt Will , Bristow Laura , Taubert Martin , Küsel Kirsten , Jehmlich Nico , von Bergen Martin , Herrmann Martina 
Published: March 2023

AbstractThe ecophysiology of complete ammonia-oxidizing bacteria (CMX) of the genusNitrospiraand their widespread occurrence in groundwater suggests that CMX bacteria have a competitive advantage over ammonia-oxidizing bacteria (AOB) and archaea (AOA) in these environments. However, the specific contribution of their activity to nitrification processes has remained unclear. We aimed to disentangle the contribution of CMX, AOA and AOB to nitrification and to identify the environmental drivers of their niche differentiation at different levels of ammonium and oxygen in oligotrophic carbonate rock aquifers. CMXamoAgenes accounted on average for 16 to 75% of the total groundwateramoAgenes detected. Nitrification rates were positively correlated to CMX clade A associated phylotypes and AOB affiliated withNitrosomonas ureae. Short-term incubations amended with the nitrification inhibitors allylthiourea and chlorate suggested that AOB contributed a large fraction to overall ammonia oxidation, while metaproteomics analysis confirmed an active role of CMX in both ammonia and nitrite oxidation. Ecophysiological niche differentiation of CMX clades A and B, AOB and AOA was linked to their requirements for ammonium, oxygen tolerance, and metabolic versatility. Our results demonstrate that despite numerical predominance of CMX, the first step of nitrification in oligotrophic groundwater appears to be primarily governed by AOB. Higher growth yields at lower ammonia turnover rates and energy derived from nitrite oxidation most likely enable CMX to maintain consistently high populations.
Self-supervised deep learning of gene-gene interactions for improved gene expression recovery
Authors: Wei Qingyue , Islam Md Tauhidul , Zhou Yuyin , Xing Lei 
Published: March 2023

ABSTRACTSingle-cell RNA sequencing (scRNA-seq) has emerged as a powerful tool to gain biological insights at the cellular level. However, due to technical limitations of the existing sequencing technologies, low gene expression values are often omitted, leading to inaccurate gene counts. The available methods, including state-of-the-art deep learning techniques, are incapable of imputing the gene expressions reliably because of the lack of a mechanism to explicitly consider the underlying biological knowledge of the system. Here we tackle the problem in two steps to exploit the gene-gene interactions of the system: (i) we reposition the genes in such a way that their spatial configuration reflects their interactive relationships; and (ii) we use a self-supervised 2D convolutional neural network to extract the contextual features of the interactions from the spatially configured genes and impute the omitted values. Extensive experiments with both simulated and experimental scRNA-seq datasets are carried out to demonstrate the superior performance of the proposed strategy against the existing imputation methods.
La-related protein 4 is enriched in vaccinia virus factories and is required for efficient viral replication in primary human fibroblasts
Authors: Dhungel Pragyesh , Belhaouari Djamal Brahim , Yang Zhilong 
Published: March 2023

AbstractIn addition to the 3’-poly(A) tail, vaccinia virus mRNAs synthesized after viral DNA replication (post-replicative mRNAs) possess a 5’-poly(A) leader that confers a translational advantage in virally infected cells. These mRNAs are synthesized in viral factories, the cytoplasmic compartment where vaccinia virus DNA replication, mRNA synthesis, and translation occur. However, a previous study indicates that the poly(A)-binding protein (PABPC1)-which has a well-established role in RNA stability and translation-is not present in the viral factories. This prompts the question of whether another poly(A)-binding protein engages vaccinia virus post-replicative mRNA in viral factories. In this study, we found that La-related protein 4 (LARP4), a poly(A) binding protein, was enriched in viral factories in multiple types of cells during vaccinia virus infection. Further studies showed that LARP4 enrichment in the viral factories required viral post-replicative gene expression and functional decapping enzymes encoded by vaccinia virus. We further showed that knockdown of LARP4 expression in human foreskin fibroblasts (HFFs) significantly reduced vaccinia virus post-replicative gene expression and viral replication. Interestingly, the knockdown of LARP4 expression also reduced 5’-poly(A) leader-mediated mRNA translation in vaccinia virus-infected and uninfected HFFs. Together, our results identified a poly(A)-binding protein, LARP4, enriched in the vaccinia virus viral factories and facilitates viral replication and mRNA translation.ImportancePoxviruses are a family of large DNA viruses comprising members infecting a broad range of hosts, including many animals and humans. Poxvirus infections can cause deadly diseases in humans and animals. Vaccinia virus, the prototype poxvirus, encodes over 200 open reading frames (ORFs). Over 90 of vaccinia virus ORFs are transcribed post-viral DNA replication. All these mRNAs contain a 5’-poly(A) leader, as well as a 3’-poly(A) tail. They are synthesized in viral factories, where vaccinia virus DNA replication, mRNA synthesis and translation occur. However, surprisingly, the poly(A) binding protein (PABPC1) that is important for mRNA metabolism and translation is not present in the viral factories, suggesting other poly(A) binding protein(s) may be present in viral factories. Here we found another poly(A)-binding protein, La-related protein 4 (LARP4), is enriched in viral factories during vaccinia virus infection. We also showed that LARP4 enrichment in the viral factories depends on viral post-replicative gene expression and functional viral decapping enzymes. The knockdown of LARP4 expression in human foreskin fibroblasts (HFFs) significantly reduced vaccinia virus post-replicative gene expression and viral replication. Overall, this study identified a poly(A)-binding protein that plays an important role in vaccinia virus replication.
Spatial Transcriptomics Arena (STAr): an Integrated Platform for Spatial Transcriptomics Methodology Research
Authors: Jiang Xi , Luo Danni , Fernández Esteban , Yang Jie , Li Huimin , Jin Kevin W. , Zhan Yuanchun , Yao Bo , Bedi Suhana , Xiao Guanghua , Zhan Xiaowei , Li Qiwei , Xie Yang 
Published: March 2023

AbstractThe emerging field of spatially resolved transcriptomics (SRT) has revolutionized biomedical research. SRT quantifies expression levels at different spatial locations, providing a new and powerful tool to interrogate novel biological insights. An essential question in the analysis of SRT data is to identify spatially variable (SV) genes; the expression levels of such genes have spatial variation across different tissues. SV genes usually play an important role in underlying biological mechanisms and tissue heterogeneity. Currently, several computational methods have been developed to detect such genes; however, there is a lack of unbiased assessment of these approaches to guide researchers in selecting the appropriate methods for their specific biomedical applications. In addition, it is difficult for researchers to implement different existing methods for either biological study or methodology development.Furthermore, currently available public SRT datasets are scattered across different websites and preprocessed in different ways, posing additional obstacles for quantitative researchers developing computational methods for SRT data analysis. To address these challenges, we designed Spatial Transcriptomics Arena (STAr), an open platform comprising 193 curated datasets from seven technologies, seven statistical methods, and analysis results. This resource allows users to retrieve high-quality datasets, apply or develop spatial gene detection methods, as well as browse and compare spatial gene analysis results. It also enables researchers to comprehensively evaluate SRT methodology research in both simulated and real datasets. Altogether, STAr is an integrated research resource intended to promote reproducible research and accelerate rigorous methodology development, which can eventually lead to an improved understanding of biological processes and diseases. STAr can be accessed athttps://lce.biohpc.swmed.edu/star/.