bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impaired Myofibroblast Proliferation is a Central Feature of Pathologic Post-Natal Alveolar Simplification
Authors: Khan Imran S. , Molina Christopher , Ren Xin , Auyeung Vincent C. , Cohen Max , Tsukui Tatsuya , Atakilit Amha , Sheppard Dean 
Published: December 2023

AbstractPremature infants with bronchopulmonary dysplasia (BPD) have impaired alveolar gas exchange due to alveolar simplification and dysmorphic pulmonary vasculature. Advances in clinical care have improved survival for infants with BPD, but the overall incidence of BPD remains unchanged because we lack specific therapies to prevent this disease. Recent work has suggested a role for increased transforming growth factor-beta (TGFβ) signaling and myofibroblast populations in BPD pathogenesis, but the functional significance of each remains unclear. Here, we utilize multiple murine models of alveolar simplification and comparative single-cell RNA sequencing to identify shared mechanisms that could contribute to BPD pathogenesis. Single-cell RNA sequencing reveals a profound loss of myofibroblasts in two models of BPD and identifies gene expression signatures of increased TGFβ signaling, cell cycle arrest, and impaired proliferation in myofibroblasts. Using pharmacologic and genetic approaches, we find no evidence that increased TGFβ signaling in the lung mesenchyme contributes to alveolar simplification. In contrast, this is likely a failed compensatory response, since none of our approaches to inhibit TGFb signaling protect mice from alveolar simplification due to hyperoxia while several make simplification worse. In contrast, we find that impaired myofibroblast proliferation is a central feature in several murine models of BPD, and we show that inhibiting myofibroblast proliferation is sufficient to cause pathologic alveolar simplification. Our results underscore the importance of impaired myofibroblast proliferation as a central feature of alveolar simplification and suggest that efforts to reverse this process could have therapeutic value in BPD.
Neutrophil extracellular traps formation is associated with postoperative complications in neonates and infants undergoing congenital cardiac surgery
Authors: Maisat Wiriya , Hou Lifei , Sandhu Sumiti , Sin Yi-Cheng , Kim Samuel , Pelt Hanna Van , Chen Yue , Emani Sirisha , Kong Sek Won , Emani Sitram , Ibla Juan , Yuki Koichi 
Published: December 2023

AbstractPediatric patients with congenital heart diseases (CHD) often undergo surgical repair on cardiopulmonary bypass (CPB). Despite a significant medical and surgical improvement, the mortality of neonates and infants remains high. Damage-associated molecular patterns (DAMPs) are endogenous molecules released from injured/damaged tissues as danger signals. We examined 101 pediatric patients who underwent congenital cardiac surgery on CPB. The mortality rate was 4.0%, and the complication rate was 31.6%. We found that neonates/infants experienced multiple complications most, consistent with the previous knowledge. Neonates and infants in the complication group had received more transfusion intraoperatively than the non-complication arm with lower maximum amplitude (MA) on rewarming CPB thromboelastography (TEG). Despite TEG profiles were comparable at ICU admission between the two groups, the complication arm had higher postoperative chest tube output, requiring more blood transfusion. The complication group showed greater neutrophil extracellular traps (NETs) formation at the end of CPB and postoperatively. Plasma histones and high mobility group box 1 (HMGB1) levels were significantly higher in the complication arm. Both induced NETsin vitroandin vivo. As histones and HMGB1 target Toll-like receptor (TLR)2 and TLR4, their mRNA expression in neutrophils was upregulated in the complication arm. Taken together, NETs play a major role in postoperative complication in pediatric cardiac surgery and would be considered a target for intervention.Key pointsNeonates and infants showed highest postoperative complications with more upregulation of inflammatory transcriptomes of neutrophils.Neonates and infants with organ dysfunction had more NETs formation with higher plasma histones and HMGB1 levels.
Pre-training with pseudo-labeling compares favorably with large language models for regulatory sequence prediction
Authors: Mourad Raphaël 
Published: December 2023

AbstractPredicting molecular processes using deep learning is a promising approach to provide biological insights for non-coding SNPs identified in genome-wide association studies. However, most deep learning methods rely on supervised learning, which requires DNA sequences associated with functional data, and whose amount is severely limited by the finite size of the human genome. Conversely, the amount of mammalian DNA sequences is growing exponentially due to ongoing large-scale sequencing projects, but in most cases without functional data. To alleviate the limitations of supervised learning, we propose a novel semi-supervised learning based on pseudo-labeling, which allows to exploit unlabeled DNA sequences from numerous genomes during model pre-training. The approach is very flexible and can be used to train any neural architecture including state-of-the-art models, and shows in certain situations strong predictive performance improvements compared to standard supervised learning in most cases. Moreover, small models trained by SSL showed similar or better performance than large language model DNABERT2.
Structural dynamics and functional cooperativity of human NQO1 by ambient temperature serial crystallography and simulations
Authors: Grieco Alice , Boneta Sergio , Gavira José A. , Pey Angel L. , Basu Shibom , Orlans Julien , de Sanctis Daniele , Medina Milagros , Martin-Garcia Jose Manuel 
Published: December 2023

ABSTRACTThe human NQO1 (hNQO1) is a FAD-dependent oxidoreductase that catalyzes the two-electron reduction of quinones to hydroquinones, being essential for the antioxidant defense system, stabilization of tumor suppressors, and activation of quinone-based chemotherapeutics, and it is over-expressed in several tumors, which makes it an attractive cancer drug target. To decipher new structural insights into the flavin reductive half-reaction of the catalytic mechanism of hNQO1, we have carried serial crystallography experiments at new ID29 beamline of the ESRF to determine, to the best of our knowledge, the first structure of the hNQO1 in complex with NADH. The use of room temperature serial crystallography with microcrystals has been key to study this mechanism. We have also performed molecular dynamics simulations of free hNQO1 and in complex with NADH. Both structural results and MD simulations have supported that the binding of NADH significantly decreases protein dynamics and stabilizes hNQO1 especially at the dimer core and interface. This is the first structural evidence that the hNQO1 functional cooperativity is driven by structural communication between the active sites through long-range propagation of cooperative effects across the hNQO1 structure. Altogether, these results pave the way for future time-resolved studies, both at XFELs and synchrotrons, of the dynamics of hNQO1 upon binding to NADH as well as during the FAD cofactor reductive half-reaction. This knowledge will allow us to reveal unprecedented structural information of the relevance of the dynamics during the catalytic function of hNQO1.
Assessing cross-contamination in spike-sorted electrophysiology data
Authors: Vincent Jack P. , Economo Michael N. 
Published: December 2023

ABSTRACTRecent advances in extracellular electrophysiology now facilitate the recording of spikes from hundreds or thousands of neurons simultaneously. This has necessitated both the development of new computational methods for spike sorting and better methods to determine spike sorting accuracy. One longstanding method of assessing the false discovery rate (FDR) of spike sorting – the rate at which spikes are misassigned to the wrong cluster – has been the rate of inter-spike-interval (ISI) violations. Despite their near ubiquitous usage in spike sorting, our understanding of how exactly ISI violations relate to FDR, as well as best practices for using ISI violations as a quality metric, remain limited. Here, we describe an analytical solution that can be used to predict FDR from ISI violation rate. We test this model in silico through Monte Carlo simulation, and apply it to publicly available spike-sorted electrophysiology datasets. We find that the relationship between ISI violation rate and FDR is highly nonlinear, with additional dependencies on firing rate, the correlation in activity between neurons, and contaminant neuron count. Predicted median FDRs in public datasets were found to range from 3.1% to 50.0%. We find that stochasticity in the occurrence of ISI violations as well as uncertainty in cluster-specific parameters make it difficult to predict FDR for single clusters with high confidence, but that FDR can be estimated accurately across a population of clusters. Our findings will help the growing community of researchers using extracellular electrophysiology assess spike sorting accuracy in a principled manner.SIGNIFICANCE STATEMENTHigh-density silicon probes are widely used to record the activity of large populations of neurons while animals are engaged in complex behavior. In this approach, each electrode records spikes from many neurons, and “spike sorting” algorithms are used to group the spikes originating from each neuron together. This process is error-prone, however, and so the ability to assess spike sorting accuracy is essential for properly interpreting neural activity. The rate of inter-spike-interval (ISI) violations is commonly used to assess spike sorting accuracy, but the relationship between ISI violation rate and sorting accuracy is complex and poorly understood. Here, we describe this relationship in detail and provide guidelines for how to properly use ISI violation rate to assess spike sorting accuracy.
The Treatment of diarrheal mice with Tenebrio Molitor meal
Authors: Liu Tingting , Wang Qiaoli , Wang Zhengli , Yan Jiaxu , Zhu Jianjun , Shen Hong , Wang Jungang 
Published: December 2023

AbstractFeeding Tenebrio Molitor meal has an important effect on promoting the growth, absorption, reproduction, and disease resistance of animals. In this study, 3×108cfu/ml Escherichia coli was used to establish a mouse diarrhea model. Different doses (8%, 5%, 2.5%) of tenebrio molitor meal were added to the basic diet, respectively. The feed intake, water intake, body weight, loose stool rate, diarrhea rate, intestinal flora number, immune organ index, intestinal enzyme, and serum enzyme activities of the diarrhea mice were detected. The results showed that compared with the model group, the feed intake, water intake, and body weight of mice with diarrhea were improved by adding tenebrio molitor meal, and the dosage was proportional to that of tenebrio molitor meal. The rate of loose stool and diarrhea decreased with the increase of tenebrio molitor meal. The total bacterial count and Escherichia coli count in the intestinal tract of mice with diarrhea were negatively correlated with the dosage of tenebrio molitor meal. The immune organ index of the diarrhea mice in the three tenebrio molitor meal supplementation groups was higher than that in the model group and was proportional to the dosage. The liver index of the 8% tenebrio molitor meal supplementation group was 11.79mg/g higher than that in the blank group. Compared with the blank group, diarrhea significantly decreased the activities of various enzymes in the intestinal tract and serum of mice (P<0.05). Compared with the model group, the activities of intestinal and serum protective enzymes (superoxide dismutase, peroxidase, catalase), detoxification enzymes (glutathione-S transferase, acetylcholinesterase, acid phosphatase) and digestive enzymes (serum amylase, serum lipase, lactate dehydrogenase) in diarrhea mice were increased by adding tenebrio molitor meal (P<0.05). The results showed that tenebrio molitor meal had a positive effect on the treatment of diarrhea in mice.
The Effects of Multi-Colour Light Filtering Glasses on Human Brain Wave Activity
Authors: Boere Katherine , Krigolson Olave E. 
Published: December 2023

AbstractThe prevalence of electronic screens in modern society has significantly increased our exposure to high-energy blue and violet light wavelengths. Accumulating evidence links this exposure to adverse visual and cognitive effects and sleep disturbances. To mitigate these effects, the optical industry has introduced a variety of filtering glasses. However, the scientific validation of these glasses has often been based on subjective reports and a narrow range of objective measures, casting doubt on their true efficacy. In this study, we used electroencephalography (EEG) to record brain wave activity to evaluate the effects of glasses that filter multiple wavelengths (blue, violet, indigo, and green) on human brain function. Our results demonstrate that wearing these multi-colour light filtering glasses significantly reduces beta wave power (13-30 Hz) compared to control or no glasses. Prior research has associated a reduction in beta power with the calming of heightened mental states, such as anxiety. As such, our results suggest that wearing glasses such as the ones used in this study may also positively change mental states, for instance, by promoting relaxation. This investigation is innovative in applying neuroimaging techniques to confirm that light-filtering glasses can induce measurable changes in brain activity.
RELEVANCE OF SHAM CONTROL GROUP IN PRECLINICAL ANIMAL STUDIES OF CEREBRAL ISCHEMIA
Authors: Candamo-Lourido María , López-Arias Esteban , López-Amoedo Sonia , Correa-Paz Clara , Bravo Susana B. , Bugallo-Casal Ana , del Pozo-Filíu Lucía , Pérez-Gayol Lara , Palomar-Alonso Nuria , Chantada-Vázquez María Pilar , Campos Francisco , Pérez-Mato María 
Published: December 2023

AbstractBackgroundIn experimental animal studies, control sham groups are essential to reduce the influence of the surgical intervention on the analysis. The intraluminal filament procedure is one of the most common models of middle cerebral artery occlusion (MCAO) used in the study of cerebral ischemia. However, in these studies, the sham group has not usually been included in the experimental design because of the assumption that the surgical procedure required to access the middle cerebral artery does not affect brain tissue, or that the results obtained from this group are not relevant.ObjectivesIn this study, we aimed to evaluate the relevance of the sham group by analyzing and comparing the brain protein profile of a sham and an ischemic group subjected to the surgical intraluminal filament occlusion of the middle cerebral artery.Material and MethodsThree randomized experimental groups were tested: control group (healthy animals), sham group, and ischemic group. Twenty-four hours after the interventional procedure, the brain tissue was evaluated by magnetic resonance imaging (MRI). After animal perfusion, the brain is removed for proteomic analysis by liquid chromatography-mass spectrometry (LC-MS/MS) using both a qualitative analysis by data-dependent acquisition (DDA) mode and a quantitative analysis, using a sequential window acquisition of all theoretical mass spectra (SWATH-MS) method on a hybrid quadrupole time-of-flight mass spectrometer.ResultsMRI results showed that only animals subjected to cerebral ischemia had ischemic injury. In the sham group 137 dysregulated proteins were detected compared to the 65 in the ischemic group. Moreover, a comparative study of both protein profiles showed the existence of a pool of 17 that appeared dysregulated in both sham and ischemic animals. These results indicate that the surgical procedure required for intraluminal occlusion of the MCA induce changes on brain protein expression that are not associated with the ischemic lesion.ConclusionThis study highlights the importance of including a sham group in the experimental model design to guarantee that the therapeutic target under study is not affected by the surgical intervention.
Dynamics of single-cell protein covariation during epithelial–mesenchymal transition
Authors: Khan Saad , Conover Rachel , Asthagiri Anand R. , Slavov Nikolai 
Published: December 2023

AbstractPhysiological processes, such as epithelial–mesenchymal transition (EMT), are mediated by changes in protein interactions. These changes may be better reflected in protein covariation within cellular cluster than in the temporal dynamics of cluster-average protein abundance. To explore this possibility, we quantified proteins in single human cells undergoing EMT. Covariation analysis of the data revealed that functionally coherent protein clusters dynamically changed their protein-protein correlations without concomitant changes in cluster-average protein abundance. These dynamics of protein-protein correlations were monotonic in time and delineated protein modules functioning in actin cytoskeleton organization, energy metabolism and protein transport. These protein modules are defined by protein covariation within the same time point and cluster and thus reflect biological regulation masked by the cluster-average protein dynamics. Thus, protein correlation dynamics across single cells offer a window into protein regulation during physiological transitions.
Molecular dynamics of outer membrane-embedded polysaccharide secretion porins reveals closed resting-state surface gates targetable by virtual fragment screening for drug hotspot identification
Authors: França Tanos C. C. , Saïdi Fares , Ajamian Alain , Islam Salim T. , LaPlante Steven R. 
Published: December 2023

AbstractRecent advances in iterative neural-network analyses (e.g. AlphaFold2 and RoseTTA fold) have been revolutionary for protein 3D-structure prediction, especially for difficult-to-manipulate α-helical/β-barrel integral membrane proteins. These model structures are calculated based on the co-evolution of amino acids within the protein of interest and similarities to existing protein structures; local effects of the membrane on folding and stability of the calculated model structures are not considered. We recently reported the discovery, 3D modelling, and characterization of 18-β-stranded outer-membrane (OM) WzpX, WzpS, and WzpB β-barrel secretion porins for the exopolysaccharide (EPS), major spore coat polysaccharide (MASC), and biosurfactant polysaccharide (BPS) pathways (respectively) in the Gram-negative social predatory bacteriumMyxococcus xanthusDZ2. However, information was not obtained regarding the dynamic behavior of surface-gating WzpX/S/B loop domains, nor on potential treatments to inactivate these porins. Herein, we developed a molecular dynamics (MD) protocol to study the core stability and loop dynamism of neural network-based integral membrane protein structure models embedded in an asymmetric OM bilayer, using theM. xanthusWzpX, WzpS, and WzpB proteins as test candidates. This was accomplished through integration of the CHARMM-graphical user interface (GUI) and Molecular Operating Environment (MOE) workflows to allow for rapid simulation system setup and facilitate data analysis. In addition to serving as a method of model-structure validation, our molecular dynamics simulations revealed minimal movement of extracellular WzpX/S/B loops in the absence of an external stimulus, as well as druggable cavities between the loops. Virtual screening of a commercial fragment library against these cavities revealed putative fragment-binding hotspots on the cell-surface face of each β-barrel, along with key interacting residues, and identified promising hits for the design of potential binders capable of plugging the β-barrels and inhibiting polysaccharide secretion.
Integrated data models on Receptor-Like Kinases for novel domain discovery and functional inference in the plant kingdom
Authors: Liu Qian , Fu Qiong , Yan Yujie , Jiang Qian , Mao Longfei , Wang Long , Yu Feng , Zheng Heping 
Published: December 2023

ABSTRACTReceptor-like kinases (RLKs) are the largest signal transduction component in plants, determining how different plants adapt to their ecological environment, resulting in plant-specific ecological niches. Current research on RLKs has focused mainly on a small number of typical RLK members of a few model plants. There is an urgent need to study the composition, distribution, and evolution of RLKs at the holistic level to accelerate the understanding of how RLK assists in the ecological adaptation of different plants. In this study, we have collected 528 plant genomes and established an RLK data model, resulting in the discovery and characterization of 524,948 RLK members. Each member is subject to systematic topology classification and coherent gene ID assignment. Using this data model, we discovered two novel families (Xiao and Xiang) of RLKs. Evolutionary analysis of the RLK families indicates that RLCK-XVII and RLCK-XII-2 exist exclusively in dicots, suggesting that the diversification in RLKs between monocots and dicots could cause differences in downstream cytoplasmic responses. We also use interaction proteome to help empower the data mining of inferring new functions of RLK from a global perspective, with the ultimate goal of understanding how RLKs shape the adaptation of different plants to the environment/ecology. The RLK data model compiled herein, together with the annotations and analytic tools, form an integrated data foundation involving multi-omics data and is publicly accessible via the web portal (http://metaRLK.biocloud.top).
Predicting the Structural Impact of Human Alternative Splicing
Authors: Song Yuxuan , Zhang Chengxin , Omenn Gilbert S. , O’Meara Matthew J. , Welch Joshua D. 
Published: December 2023

SummaryProtein structure prediction with neural networks is a powerful new method for linking protein sequence, structure, and function, but structures have generally been predicted for only a single isoform of each gene, neglecting splice variants. To investigate the structural implications of alternative splicing, we used AlphaFold2 to predict the structures of more than 11,000 human isoforms. We employed multiple metrics to identify splicing-induced structural alterations, including template matching score, secondary structure composition, surface charge distribution, radius of gyration, accessibility of post-translational modification sites, and structure-based function prediction. We identified examples of how alternative splicing induced clear changes in each of these properties. Structural similarity between isoforms largely correlated with degree of sequence identity, but we identified a subset of isoforms with low structural similarity despite high sequence similarity. Exon skipping and alternative last exons tended to increase the surface charge and radius of gyration. Splicing also buried or exposed numerous post-translational modification sites, most notably among the isoforms ofBAX. Functional prediction nominated numerous functional differences among isoforms of the same gene, with loss of function compared to the reference predominating. Finally, we used single-cell RNA-seq data from the Tabula Sapiens to determine the cell types in which each structure is expressed. Our work represents an important resource for studying the structure and function of splice isoforms across the cell types of the human body.