bluuebunny/crossref_metadata_2025_split huggingface dataset:
JUND plays a genome-wide role in the quiescent to contractile switch in the pregnant human myometrium
Authors: Khader Nawrah , Dorogin Anna , Shynlova Oksana , Mitchell Jennifer A. 
Published: April 2024

AbstractThe myometrium, the muscular layer of the uterus, undergoes crucial transitions during pregnancy, maintaining quiescence throughout gestation, and generating coordinated contractions during labor. Dysregulation of this transition can lead to premature labor with serious complications for the infant. Despite extensive gene expression data available for varying myometrial states, the molecular mechanisms governing the increase in contraction- associated gene expression at labor onset remain unclear. Transcription factors, such as JUND and progesterone receptor (PR), play essential roles in regulating transcription of select myometrial contraction-associated genes, however, a broader understanding of their involvement in transcriptional regulation at a genome-wide scale is lacking. This study examines changes in transcription and JUND binding within human myometrial tissue during the transition from quiescence (term-not-in labor/TNIL) to contractility (term labor/TL). Total RNA- sequencing reveals a global increase in primary transcript levels at TL, with AP-1/JUND binding motifs overrepresented in the promoters of upregulated transcripts. Interestingly, ChIP-seq analysis demonstrates higher JUND enrichment in TNIL compared to TL tissues, suggesting its role in preparing the myometrium for labor onset. Integration of JUND and PR ChIP-seq data identifies over 10,000 gene promoters bound by both factors at TNIL and TL, including genes involved in labor-driving processes. Additionally, the study uncovers elevated levels of enhancer RNAs (eRNAs) at intergenic JUND peaks in laboring myometrial tissues, and implicates additional transcription factors, such as NFKB and ETS, in the regulatory switch from quiescence to contractility. In summary, this research enhances our understanding of the myometrial molecular regulatory network during pregnancy and labor, shedding light on the roles of JUND and PR in gene expression regulation genome-wide. These findings open avenues for further exploration, potentially leading to improved interventions for preventing premature labor and the associated complications.
Evaluation of multi-peptide sequences identifiedin silicofor the serological identification of antibodies against Vector-Borne Diseases
Authors: Peña-Bates Carlos A. , Lugo-Caballero Cesar I. , Pavía-Ruz Norma , Noh-Pech Henry R. , Omodior Oghenekaro , Puerto-Manzano Fernando I. , Dzul-Rosado Karla R. 
Published: April 2024

ABSTRACTThe socio-ecological conditions of Mexican regions are conducive to the spread of vector-borne diseases. Although there are established treatment guidelines for dengue and rickettsiosis, diagnosis is complicated. The objective of this work was to identify epitopes ofRickettsiaand Dengue virus that could be used in serology screening against vector-borne diseases. For this, epitopes with high HLA-II binding efficiency of OmpB protein ofRickettsia rickettsiiand NS2B protein of dengue virus were identifiedin silicothrough a reverse vaccinology strategy. The selected epitopes were grouped into multi-peptide sequences that were synthesized and immobilized in a nitrocellulose membrane to evaluate the reactivity sera from patients previously infected with dengue orRickettsia. The evaluation of the sequences of the NS2B and OmpB proteins was performed with 60 sera previously diagnosed as positive or negative by the respective gold standard techniques. Thedot blottechnique was used for the antigenic evaluation of the peptides against these serum samples.Dot blotanalysis correctly identified 85% of sera positive for rickettsiosis and 75% of sera positive for dengue. Reverse vaccinology reduces the time and cost of antigen discovery. Experimental evidence from multi-peptide sequences suggests their potential use in the development of diagnostic tests for dengue and rickettsiosis.Abstract Figure
WITHDRAWN: Proteonano™ coupled with Orbitrap Astral™: A robust and standardized workflow for large-cohort clinical plasma proteomics studies
Authors: Fan Chaoyang , Wang Yi , Huang Min , Cao Jianming , Li Xiangjun , Ouyang Xiehua , Wu Hao 
Published: April 2024

Withdrawal StatementThe authors have withdrawn their manuscript owing to [INCOMPLETE DATA ANALYSIS]. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Zebrafish as a model to study PERK function in developmental diseases: implications for Wolcott-Rallison syndrome
Authors: Almeida Liliana M. , Lima Leonor Pereira , Oliveira Nuno A. S. , Silva Rui F. O. , Sousa Bruno , Bessa José , Pinho Brígida R. , Oliveira Jorge M. A. 
Published: April 2024

AbstractDevelopmental diseases are challenging to investigate due to their clinical heterogeneity and relatively low prevalence. The Wolcott-Rallison Syndrome (WRS) is a rare developmental disease characterized by skeletal dysplasia and permanent neonatal diabetes due to loss-of-function mutations in the endoplasmic reticulum stress kinase PERK (EIF2AK3). The lack of efficient and less invasive therapies for WRS highlights the need for new animal models that replicate the complex pathological phenotypes, while preserving scalability for drug screening. Zebrafish exhibits high fecundity and rapid development that facilitate efficient and scalablein vivodrug testing. Here, we aimed to assess the potential of zebrafish to study PERK function and its pharmacological modulation, and as model organism of developmental diseases such as the WRS. Using bioinformatic analyses, we showed high similarity between human and zebrafish PERK. We used the pharmacological PERK inhibitor GSK2606414, which was bioactive in zebrafish, to modulate PERK function. Using transgenic zebrafish expressing fluorescent pancreatic markers and a fluorescent glucose probe, we observed that PERK inhibition decreasedβcell mass and disrupted glucose homeostasis. By combining behavioural and functional assays, we show that PERK-inhibited zebrafish present marked skeletal defects and defective growth, as well as neuromuscular and cardiac deficiencies, which are clinically relevant in WRS patients, while sparing parameters like otolith area and eye/body ratio which are not associated with WRS. These results show that zebrafish holds potential to study PERK function and its pharmacological modulation in developmental disorders like WRS, assisting research on their pathophysiology and experimental treatments.
Protein language models are performant in structure-free virtual screening
Authors: Lam Hilbert Yuen In , Guan Jia Sheng , Ong Xing Er , Pincket Robbe , Mu Yuguang 
Published: April 2024

1.1AbstractHitherto virtual screening has been typically performed using a structure-based drug design paradigm. Such methods typically require the use of molecular docking on high-resolution three-dimensional structures of a target protein - a computationally-intensive and time-consuming exercise. This work demonstrates that by employing protein language models and molecular graphs as inputs to a novel graph-to-transformer cross-attention mechanism, a screening power comparable to state-of-the-art structure-based models can be achieved. The implications thereof include highly expedited virtual screening due to the greatly reduced compute required to run this model, and the ability to perform early stages of computer-aided drug design in the complete absence of 3D protein structure.
MedImg: a database for public medical image integration
Authors: Zhong Bitao , Fan Rui , Ji Xiangwen , Cui Qinghua , Cui Chunmei 
Published: April 2024

AbstractThe advancements of deep learning algorithms in medical image analysis has garnered tremendous attention in recent years. Several studies have reported that the models have achieved and even surpassed human performance, whereas the translation of these models into clinical practice is still accompanied by various challenges. A major challenge is the large-scale and well characterized dataset to validate the generalization of models. Therefore, we collected diverse medical image datasets from multiple public sources containing 103 datasets, 1,622,956 images. These images are derived from 14 modalities like XR, CT, MRI, OCT, ultrasound, and endoscopy, and from 9 organs such as lung, brain, eye, and heart. Subsequently, we constructed an online database, MedImg, which incorporates and hierarchically organizes medical images to facilitate data access. MedImg serves as an intuitive and open-access platform for contributing to deep learning-based medical image analysis, accessible athttps://www.cuilab.cn/medimg/.
Cytosolic Ribosomal Protein Haploinsufficiency affects Mitochondrial Morphology and Respiration
Authors: Surya Agustian , Bolton Blythe Marie , Rothe Reed , Mejia-Trujillo Raquel , Zhao Qiuxia , Leonita Amanda , Liu Yue , Rangan Rekha , Gorusu Yasash , Nguyen Pamela , Cenik Can , Cenik Elif Sarinay 
Published: April 2024

ABSTRACTThe interplay between ribosomal protein composition and mitochondrial function is essential for sustaining energy homeostasis. Precise stoichiometric production of ribosomal proteins is crucial to maximize protein synthesis efficiency while reducing the energy costs to the cell. However, the impact of this balance on mitochondrial ATP generation, morphology and function remains unclear. Particularly, the loss of a single copy ribosomal protein gene is observed in Mendelian disorders like Diamond Blackfan Anemia and is common in somatic tumors, yet the implications of this imbalance on mitochondrial function and energy dynamics are still unclear. In this study, we investigated the impact of haploinsufficiency for four ribosomal protein genes implicated in ribosomopathy disorders (rps-10, rpl-5, rpl-33, rps-23) inCaenorhabditis elegansand corresponding reductions in human lymphoblast cells. Our findings uncover significant, albeit variably penetrant, mitochondrial morphological differences across these mutants, alongside an upregulation of glutathione transferases, and SKN-1 dependent increase in oxidative stress resistance, indicative of increased ROS production. Specifically, loss of a single copy ofrps-10inC. elegansled to decreased mitochondrial activity, characterized by lower energy levels and reduced oxygen consumption. A similar reduction in mitochondrial activity and energy levels was observed in human leukemia cells with a 50% reduction inRPS10transcript levels. Importantly, we also observed alterations in the translation efficiency of nuclear and mitochondrial electron transport chain components in response to reductions in ribosomal protein genes’ expression in bothC. elegansand human cells. This suggests a conserved mechanism whereby the synthesis of components vital for mitochondrial function are adjusted in the face of compromised ribosomal machinery. Finally, mitochondrial membrane and cytosolic ribosomal components exhibited significant covariation at the RNA and translation efficiency level in lymphoblastoid cells across a diverse group of individuals, emphasizing the interplay between the protein synthesis machinery and mitochondrial energy production. By uncovering the impact of ribosomal protein haploinsufficiency on the translation efficiency of electron transport chain components, mitochondrial physiology, and the adaptive stress responses, we provide evidence for an evolutionarily conserved strategy to safeguard cellular functionality under genetic stress.
Dynamic spatiotemporal activation of a pervasive neurogenic competence in striatal astrocytes supports continuous neurogenesis following injury
Authors: Fogli Marco , Nato Giulia , Greulich Philip , Pinto Jacopo , Peretto Paolo , Buffo Annalisa , Luzzati Federico 
Published: April 2024

SUMMARYAdult brain neural stem cells (NSCs) are conventionally regarded as rare cells restricted to two niches: the subventricular zone (SVZ) and the subgranular zone. Parenchymal astrocytes can also contribute to neurogenesis after injury, however the prevalence, distribution, and behaviour of these latent NSCs remained elusive. To tackle these issues, we reconstructed the spatiotemporal pattern of striatal astrocytes neurogenic activation after excitotoxic lesion in mice. Our results indicate that a neurogenic potential is broadly distributed throughout the striatum but is focally activated at the lesion border. In this region, similarly to canonical niches, steady state neurogenesis is ensured by the continuous stochastic activation of local astrocytes. Activated astrocytes quickly return to quiescence, while their progeny locally proliferate for about 10 days following a stochastic behaviour that features an acceleration in differentiation propensity. Notably, striatal astrocytes activation rate matches that of SVZ astrocytes indicating a comparable prevalence of NSC potential.
Common viral infections inhibit egg laying in honey bee queens and are linked to premature supersedure
Authors: Chapman Abigail , McAfee Alison , Tarpy David R. , Fine Julia , Rempel Zoe , Peters Kira , Currie Rob , Foster Leonard J. 
Published: April 2024

AbstractWith their long lives and extreme reproductive output, social insect queens have escaped the classic trade-off between fecundity and lifespan but evidence for a trade-off between fecundity and immunity has been inconclusive. This is in part because pathogenic effects are seldom decoupled from effects of immune induction. We conducted parallel, blind virus infection experiments in the laboratory and in the field to interrogate the idea of a reproductive immunity trade-off and better understand how these ubiquitous honey bee stressors affect queen health. We found that queens injected with infectious virus had smaller ovaries and were less likely to recommence egg-laying than controls, while queens injected with UV-inactivated virus displayed an intermediate phenotype. In the field, heavily infected queens had smaller ovaries and infection was a meaningful predictor of whether supersedure cells were observed in the colony. Immune responses in queens receiving live virus were similar to queens receiving inactivated virus, and several of the same immune proteins were negatively associated with ovary mass in the field. This work solidifies the relationship between virus infection and symptoms associated with queen failure and suggests that a reproductive-immunity trade-off is partially, but not wholly responsible for these effects.
Organelle-targeted Laurdans measure heterogeneity in subcellular membranes and their responses to saturated lipid stress
Authors: Wong Adrian M. , Budin Itay 
Published: April 2024

AbstractCell organelles feature characteristic lipid compositions that lead to differences in membrane properties. In living cells, membrane ordering and fluidity are commonly measured using the solvatochromic dye Laurdan, whose fluorescence is sensitive to membrane packing. As a general lipophilic dye, Laurdan stains all hydrophobic environments in cells, so it is challenging to characterize membrane properties in specific organelles or assess their responses to pharmacological treatments in intact cells. Here, we describe the synthesis and application of Laurdan-derived probes that read out membrane packing of individual cellular organelles. The set of Organelle-targeted Laurdans (OTL) localizes to the ER, mitochondria, lysosomes and Golgi compartments with high specificity, while retaining the spectral resolution needed to detect biological changes in membrane packing. We show that ratiometric imaging with OTL can resolve membrane heterogeneity within organelles, as well as changes in membrane packing resulting from inhibition of lipid trafficking or bioenergetic processes. We apply these probes to characterize organelle-specific responses to saturated lipid stress. While ER and lysosomal membrane fluidity is sensitive to exogenous saturated fatty acids, that of mitochondrial membranes is protected. We then use differences in ER membrane fluidity to sort populations of cells based on their fatty acid diet, highlighting the ability of organelle-localized solvatochromic probes to distinguish between cells based on their metabolic state. These results expand the repertoire of targeted membrane probes and demonstrate their application to interrogating lipid dysregulation.
Neurophysiological and Autonomic Dynamics of Threat Processing During Sustained Social Fear Generalization
Authors: Pouliot Jourdan J. , Ward Richard T. , Traiser Caitlin M. , Chiasson Payton , Gilbert Faith E. , Keil Andreas 
Published: April 2024

AbstractSurvival in dynamic environments requires that organisms learn to predict danger from situational cues. One key facet of threat prediction is generalization from a predictive cue to similar cues, ensuring that a cue-outcome contingency is applied beyond the original learning environment. Generalization has been observed in laboratory studies of aversive conditioning: behavioral and physiological processes generalize responses from a stimulus paired with threat (the CS+) to unpaired stimuli, with response magnitudes varying with CS+ similarity. In contrast, work focusing on sensory responses in visual cortex has found a sharpening pattern, in which responses to stimuli closely resembling the CS+ are maximally suppressed, potentially reflecting lateral inhibitory interactions with the CS+ representation. Originally demonstrated with simple visual cues, changes in visuocortical tuning have also been observed in threat generalization learning across facial identities. It is unclear to what extent these visuocortical changes represent transient or sustained effects and if generalization learning requires prior conditioning to the CS+. The present study addressed these questions using EEG and pupillometry in an aversive generalization paradigm involving hundreds of trials using a gradient of facial identities. Visuocortical ssVEP sharpening occurred after dozens of trials of generalization learning without prior differential conditioning, but diminished as learning continued. By contrast, generalization of alpha power suppression, pupil dilation, and self-reported valence and arousal was seen throughout the experiment. Findings are consistent with threat processing models emphasizing the role of changing visucocortical and attentional dynamics when forming, curating, and shaping fear memories as observers continue learning about stimulus-outcome contingencies.
Depletion of Protein Phosphatase 1 Results in Persistent Activation of the Integrated Stress Response and Age-Associated Exacerbation of Pulmonary Veno-Occlusive Disease
Authors: Prabhakar Amit , Wadhwa Meetu , Ghatpande Prajakta , Kumar Rahul , Graham Brian B. , Lagna Giorgio , Hata Akiko 
Published: April 2024

AbstractPulmonary veno-occlusive disease (PVOD) is a form of pulmonary hypertension that affects individuals across the age spectrum. PVOD is characterized by the obstruction of small pulmonary vessels, causing increased pulmonary artery (PA) pressure and leading to right ventricular heart (RV) failure. Previous research showed that the administration of Mitomycin-C (MMC) in rats mediates PVOD through the activation of the eukaryotic initiation factor 2 (eIF2) kinase PKR and the integrated stress response (ISR), resulting in the impairment of vascular endothelial junctional structure and barrier function. In this study, we reveal that older rats experience more severe pulmonary vascular remodeling and RV hypertrophy than younger rats after MMC treatment due to lower levels of protein phosphatase 1, leading to prolonged eIF2 phosphorylation and ISR activation. We demonstrate that pharmacological blocking of the PKR-ISR pathway mitigates PVOD symptoms in both age groups, suggesting targeting the PKR-ISR axis as a potential PVOD therapeutic strategy.
Classification and Regression Trees to predict Transcription Factor Combinatorial Interaction in scRNA-seq data
Authors: Carluer Jean Baptiste , Steinmann Laura , Carré Clément , Mas André , Krouk Gabriel 
Published: April 2024

AbstractUnderstanding the regulatory mechanisms that govern gene expression is crucial for deciphering cellular functions. Transcription factors (TFs) play a key role in regulating gene expression. In particular TF combinatorial interactions (TFCI) are now thought to largely shape genomic transcriptional responses, but predicting TFCIper seis still a difficult task. Single-cell RNA sequencing (scRNA-seq) has emerged as a powerful tool providing a whole new readout of gene regulatory effects. In this study, we propose a machine learning approach utilizing Classification and Regression Trees (CART) for predicting TFCI in >110k scRNA-seq data points yielded fromArabidopsis thalianaroot. The proposed methodology provides a valuable tool for pointing to new TFCI mechanisms and could advance our understanding of Gene Regulatory Networks’ functioning.
Prolonged signaling of backbone-modified glucagon-like peptide-1 analogues with diverse receptor trafficking
Authors: Cary Brian P. , Hager Marlies V. , Morris Rylie K. , Belousoff Matthew J. , Sexton Patrick M. , Wootten Denise , Gellman Samuel H. 
Published: April 2024

AbstractSignal duration and subcellular location are emerging as important facets of G protein-coupled receptor (GPCR) function. The glucagon-like peptide-1 receptor (GLP-1R), a clinically relevant class B1 GPCR, stimulates production of the second messenger cAMP upon activation by the native hormone, GLP-1. cAMP production continues after the hormone-receptor complex has been internalized via endocytosis. Here, we report GLP-1 analogues that induce prolonged signaling relative to GLP-1. A single β-amino acid substitution at position 18, with the residue derived from (S,S)-trans-2-aminocyclopentanecarboxylic acid (ACPC), enhances signaling duration with retention of receptor endocytosis. Pairing ACPC at position 18 with a second substitution, α-aminoisobutyric acid (Aib) at position 16, abrogates endocytosis, but prolonged signaling is maintained. Prolonged signaling is sensitive to the structure of the β residue at position 18. Cryo-electron microscopy (cryo-EM) structures of two GLP-1 analogues bound to the GLP- 1R:Gs complex suggest substantial alterations to bound peptide structure and dynamics compared to the GLP-1:GLP-1R complex. These structural findings strengthen an emerging view that agonist dynamics in the receptor-bound state influence signaling profile. Our results advance understanding of the structural underpinnings of receptor activation and introduce new tools for exploring the impact of spatiotemporal signaling profiles following GLP-1R activation.