bluuebunny/crossref_metadata_2025_split huggingface dataset:
E(Q)AGNN-PPIS: Attention Enhanced Equivariant Graph Neural Network for Protein-Protein Interaction Site Prediction
Authors: Animesh  , Suvvada Rishi , Bhowmick Plaban Kumar , Mitra Pralay 
Published: October 2024

AbstractIdentifying protein binding sites, the specific regions on a protein’s surface where interactions with other molecules occur, is crucial for understanding disease mechanisms and facilitating drug discovery. Although numerous computational techniques have been developed to identify protein binding sites, serving as a valuable screening tool that reduces the time and cost associated with conventional experimental approaches, achieving significant improvements in prediction accuracy remains a formidable challenge. Recent advancements in protein structure prediction, notably through tools like AlphaFold, have made vast numbers of 3-D protein structures available, presenting an opportunity to enhance binding site prediction methods. The availability of detailed 3-D structures has led to the development of Equivariant Graph Neural Networks (GNNs), which can analyze complex spatial relationships in protein structures while maintaining invariance to rotations and translations. However, current equivariant GNN methods still face limitations in fully exploiting the geometric features of protein structures. To address this, we introduce E(Q)AGNN-PPIS1, an Equivariant Attention-Enhanced Graph Neural Network designed for predicting protein binding sites by leveraging 3-D protein structure. Our method augments the Equivariant GNN framework by integrating an attention mechanism. This attention component allows the model to focus on the most relevant structural features for binding site prediction, significantly enhancing its ability to capture complex spatial patterns and interactions within the protein structure. Our experimental findings underscore the enhanced performance of E(Q)AGNN-PPIS compared to current state-of-the-art approaches, exhibiting gains of 8.33% in the Area Under the Precision-Recall Curve (AUPRC) and 10% in the Matthews Correlation Coefficient (MCC) across benchmark datasets. Additionally, our method demonstrates robust generalization across proteins with varying sequence lengths, outperforming baseline methods.
Neuronal plasticity at puberty in hypothalamic neurons controlling fertility in female mice
Authors: Zhang Yuanxin , Pakulat Leonie M. , Galliano Elisa , Colledge William H. , Jones Susan 
Published: October 2024

AbstractPuberty is a critical transition period to achieve fertility and reproductive capacity in all mammalian species. At puberty, the hypothalamic-pituitary-gonadal (HPG) is activated by neuroendocrine changes in the brain. Central to this areKiss1neurons that produce kisspeptin, a neuropeptide which is a potent stimulator of gonadotropin releasing hormone (GnRH) secretion.Kiss1neurons in the arcuate region of the hypothalamus (Kiss1ARC) increase pulsatile secretion of GnRH at puberty. Other developmental maturational changes in the brain are often accompanied by neuronal plasticity changes but this has not been studied inKiss1neurons. Electrophysiological characterisation ofKiss1ARCneurons from female mice shows that these neurons undergo profound intrinsic plasticity at puberty with a critical window between 3 and 4 weeks. ImmatureKiss1ARCneurons cannot sustain depolarisation-evoked firing for even 500 ms and instead fire a brief burst of high frequency spikes before falling silent. This would make them unsuitable for the sustained activity that is needed to activate GnRH neurons and trigger LH secretion in the HPG axis. After puberty, sustained firing can be maintained, which endows post-pubertyKiss1ARCneurons with a mature physiological phenotype that is amenable to neuropeptide modulation for generation of burst firing and pulsatile release of kisspeptin. There is a corresponding decrease in the threshold for action potential initiation, a more hyperpolarised post-spike trough and a larger medium after-hyperpolarisation (mAHP). Gene expression analysis showed a significant decrease inScn2a(Nav1.2 channel),Kcnq2(Kv7.2 channel) andLrrc55(BK channel auxiliary γ3-subunit) expression and an increase inHcn1(hyperpolarization activated cyclic nucleotide-gated potassium channel) expression which may contribute to the observed electrophysiological changes. Ovariectomy and β-estradiol replacement defined a window of estrogen-dependent plasticity of action potential firing at puberty, such that post-pubertyKiss1ARCneurons achieve a mature physiological phenotype for activation of the HPG axis.
Neural correlates differ between crystallized and fluid intelligence in adolescents
Authors: Qiu Bowen , Qian Rui , Gu Baorong , Chen Zhifan , Li Zichao , Li Mingyang , Wu Dan 
Published: October 2024

AbstractFluid and crystallized intelligence are acknowledged as distinct facets of cognitive ability during brain development, but the specific neural substrates and molecular mechanisms underlying them remain unclear. This study used a sample comprising 7471 young adolescents (mean age 9.87 ± 0.62 years) from the ABCD cohort to elucidate the differential neural correlates of fluid and crystallized intelligence. Our findings indicated that micro-level brain MRI phenotypes such as water diffusivity were closely associated with fluid intelligence, whereas macro-level brain MRI phenotypes such as gray matter cortical thickness were indicative of crystallized intelligence. We further investigated the molecular mechanisms underlying fluid and crystallized intelligence by correlating the characteristic MRI markers with spatial transcriptome profiles and PET imaging. Results showed that fluid intelligence had significant associations with serotonin and glutamate system, while crystallized intelligence was related to serotonin, dopamine and acetylcholine system. Furthermore, we examined the impacts of lifestyle factors on these two forms of intelligence and how the molecular pathways mediated these impacts. Our investigation suggested that physical activities, screen use and sleep duration influenced fluid intelligence mainly through mGlu5 receptors and crystallized intelligence through 5HT1a and D2 receptors. In conclusion, these findings illustrated a distinct neural basis between fluid and crystallized intelligence from the perspectives of neuroimaging, neurotransmitters, and lifestyles in young adolescents.
After-effects of Parieto-occipital Gamma Transcranial Alternating Current Stimulation on Behavioral Performance and Neural Activity in Visuo-spatial Attention Task
Authors: Zheng Tianyi , Huang Yunshan , Sugino Masato , Shimba Kenta , Jimbo Yasuhiko , Kotani Kiyoshi 
Published: October 2024

ABSTRACTVisuo-spatial attention enables selective focus on spatial locations while ignoring irrelevant stimuli which involves both endogenous and exogenous attention. Recent advancements in transcranial alternating current stimulation (tACS) have shown promise in modulating these attentional processes by targeting electrical oscillations in specific brain areas. Despite evidence of the online effects of tACS on the task performance of visuo-spatial attention, whether tACS can produce lasting after-effects on behavioral performance and neural activity during the visuo-spatial attention task remains unknown. This study aims to explore these after-effects on visuo-spatial attention by implementing a single-blind, sham-controlled, between-group experiment design. Twenty young and healthy participants were equally divided into two groups receiving either sham or active gamma tACS at 40 Hz targeted at the right parieto-occipital region. Each participant engaged in a version of the Posner cueing task, conducted with EEG recording before and after the tACS intervention. The results revealed that the active tACS group exhibited significant reductions in reaction time compared to the sham group. These changes were not uniform across different attention types, suggesting specific enhancements in cognitive processing. Additionally, EEG analysis showed that gamma tACS influenced various aspects of neural activity, including event-related potentials to the target, as well as the oscillatory power and long-range temporal correlations of EEG signal during the cue-target interval. The amplitude and latency of N1 and P3 components were modulated by gamma tACS. Notably, there was a decrease in alpha power and an increase in gamma power during the cue-target interval, alongside a decrease in long-range temporal correlations. These findings revealed the after-effect of gamma tACS on modulating the behavioral performance and neural activity in the visuo-spatial attention task, paving the way for future applications in cognitive enhancement and therapeutic interventions.
Unsupervised feature extraction using deep learning empowers discovery of genetic determinants of the electrocardiogram
Authors: Sieliwonczyk Ewa , Sau Arunashis , Patlatzoglou Konstantinos , McGurk Kathryn A. , Pastika Libor , Thami Prisca K , Mangino Massimo , Zheng Sean L , Powell George , Curran Lara , Buchan Rachel J , Theotokis Pantazis , Peters Nicholas S , Loeys Bart , Kramer Daniel B. , Waks Jonathan W , Ng Fu Siong , Ware James S 
Published: October 2024

AbstractAdvanced data-driven methods can outperform conventional features in electrocardiogram (ECG) analysis, but often lack interpretability. The variational autoencoder (VAE), a form of unsupervised machine learning, can address this shortcoming by extracting comprehensive and interpretable new ECG features. Our novel VAE model, trained on a dataset comprising over one million secondary care median beat ECGs, and validated using the UK Biobank, reveals 20 independent features that capture ECG information content with high reconstruction accuracy. Through phenome- and genome-wide association studies, we illustrate the increased power of the VAE approach for gene discovery, compared with conventional ECG traits, and identify previously unrecognised common and rare variant determinants of ECG morphology. Additionally, to highlight the interpretability of the model, we provide detailed visualisation of the associated ECG alterations. Our study shows that the VAE provides a valuable tool for advancing our understanding of cardiac function and its genetic underpinnings.
Applications of Artificial Intelligence in Vasculitides: A Systematic Review
Authors: Omar Mahmud , Agbareia Reem , Naffaa Mohammad E. , Watad Abdulla , Glicksberg Benjamin S , Nadkarni Girish N , Klang Eyal 
Published: October 2024

AbstractBackground and AimVasculitides are rare inflammatory disorders that sometimes can be difficult to diagnose due to their diverse presentations. This review examines the use of Artificial Intelligence (AI) to improve diagnosis and outcome prediction in vasculitis.MethodsA systematic search of PubMed, Embase, Web of Science, IEEE Xplore, and Scopus identified relevant studies from 2000 to 2024. AI applications were categorized by data type (clinical, imaging, textual) and by task (diagnosis or prediction). Studies were assessed for risk of bias using PROBAST and QUADAS-2 tools.ResultsForty-six studies were included. AI models achieved high diagnostic performance in Kawasaki Disease, with sensitivities up to 92.5% and specificities up to 97.3%. Predictive models for complications, such as IVIG resistance in Kawasaki Disease, showed AUCs between 0.716 and 0.834. Other vasculitis types, especially those using imaging data, were less studied and often limited by small datasets.ConclusionThe current literature shows that AI algorithms can enhance vasculitis diagnosis and prediction, with deep and machine learning models showing promise in Kawasaki Disease. However, broader datasets, more external validation, and the integration of newer models like LLMs are needed to advance their clinical applicability across different vasculitis types.
Early changes in the gut microbiome among HIV-infected Individuals in Uganda initiating daily TMP/SMX
Authors: Atugonza Carolyne , Muwonge Adrian , Najjuka Christine F. , Kateete David P. , Katagirya Eric , Mwesigwa Savannah , Asiimwe Benon 
Published: October 2024

AbstractDaily cotrimoxazole (TMP/SXT) prophylaxis is part of the HIV treatment package for all new HIV-infected individuals in Uganda. Although this treatment has shown reduced morbidity and mortality in HIV, it remains controversial due to its contribution to developing antibiotic-resistant bacteria. Moreover, the effects of daily use of a broad-spectrum antibiotic on the gut microbiome remain unknown.To study the early effects, we analysed shotgun metagenome sequence data from stool samples of five newly HIV-infected individuals initiating TMP/SXT prophylaxis longitudinally for the first 30 days of treatment. Using shotgun metagenomics sequencing, we generated both taxonomic and functional profiles from each patient and compared gut microbial changes Pre-TMP/SXT and post-TMP/SXT on Day 5, Day 14, and Day 30.Daily TMP/SXT prophylaxis resulted in a shift characterised by an enrichment ofPrevetolleaandRuminococcusgenera members and the depletion ofLactococcusandBacteroidesgenera members. Furthermore, these microbial shifts were associated with changes in the functional profile revealed by a differential abundance of pathways of amino acid metabolism, carbohydrate metabolism, and nucleotide biosynthesis linked to members of the Bacteroidaceae and Enterobacteriaceae families.TMP/SXT daily prophylaxis in HIV-infected individuals is associated with dramatic changes in microbial composition and functional profiles; however, other factors such as Age, Gender, HIV clinical stage, and ART regiment are at play. Further investigation is needed to examine the implication of these shifts on clinical management and outcomes among HIV patients.
HIV-1 budding requires cortical actin disassembly by the oxidoreductase MICAL1
Authors: Serrano Thomas , Casartelli Nicoletta , Ghasemi Foad , Wioland Hugo , Cuvelier Frédérique , Salles Audrey , Moya-Nilges Maryse , Welker Lisa , Bernacchi Serena , Ruff Marc , Jégou Antoine , Romet-Lemonne Guillaume , Schwartz Olivier , Frémont Stéphane , Echard Arnaud 
Published: October 2024

ABSTRACTMany enveloped viruses bud from the plasma membrane that is tightly associated with a dense and thick actin cortex. This actin network represents a significant challenge for membrane deformation and scission, and how it is remodeled during the late steps of the viral cycle is largely unknown. Using super-resolution microscopy, we show that HIV-1 buds in areas of the plasma membrane with low cortical F-actin levels. We find that the cellular oxidoreductase MICAL1 locally depolymerizes actin at budding sites to promote HIV-1 budding and release. In the absence of MICAL1, F-actin abnormally remains at viral budding sites, incompletely budded viruses accumulate at the plasma membrane and viral release is impaired. Remarkably, normal viral release can be restored in MICAL1-depleted cells by inhibiting Arp2/3-dependent branched actin networks. Mechanistically, we find that MICAL1 directly disassembles branched-actin networks and controls the timely recruitment of the ESCRT scission machinery during viral budding. In addition, the MICAL1 activator Rab35 is recruited at budding sites, functions in the same pathway as MICAL1 and is also required for viral release. This work reveals a role for oxidoreduction in triggering local actin depolymerization to control HIV-1 budding, a mechanism that may be widely used by other viruses. The debranching activity of MICAL1 could be involved beyond viral budding in various other cellular functions requiring local plasma membrane deformation.
Reconcile sensory attenuation and enhancement: The temporal dynamics of self-generated sensory feedback
Authors: Suzuishi Yosuke , Chang Acer Yu-Chan , Wen Wen 
Published: October 2024

AbstractSelf-generated touches are often perceived as weaker than externally generated ones, a phenomenon known as sensory attenuation. However, recent studies have challenged this view by providing evidences that actions could also enhance predicted touch. To investigate this paradox, we examined the temporal dynamics of perceptual processing using steady-state somatosensory evoked potentials (SSSEP) and sliding time window analysis. Results showed that SSSEP in the very early window was smaller in the no-delay and active conditions compared to the delayed and passive condition, respectively, consistent with sensory attenuation. However, this attenuation soon disappeared and reversed in the later windows and onward, indicating an early attenuation followed by a later enhancement. This study resolves the paradox of sensory attenuation and enhancement in self-generated sensory signals by demonstrating that these processes occur at different phases of sensory processing. The findings reveal a sophisticated dynamic balance in sensory processing, facilitating optimal interaction with the environment.
Effective Polarization in Potassium Channel Simulations: Ion Conductance, Occupancy, Voltage Response, and Selectivity
Authors: Hui Chenggong , de Vries Reinier , Kopec Wojciech , de Groot Bert L. 
Published: October 2024

AbstractPotassium (K+) channels are widely distributed in many types of organisms. They combine high efficiency (∼100 pS) and K+/Na+selectivity by a conserved selectivity filter (SF). Molecular Dynamics (MD) simulations can provide detailed, atomistic mechanisms of this sophisticated ion permeation. However, currently there are clear inconsistencies between computational predictions and experimental results. Firstly, the ion occupancy of the SF in simulations is lower than expected (∼2.5 in MD compared to ∼4 in X-ray crystallography). Secondly, in many reported MD simulations of K+channels, K+conductance is typically an order of magnitude lower than experimental values. This discrepancy is in part because the force fields used in MD simulations of potassium channels do not account for polarization. One of the proposed solutions is the Electronic Continuum Correction (ECC), a force field modification that scales down formal charges, to introduce the polarization in a mean-field way. When the ECC is used in conjunction with the Charmm36m force field, the simulated K+conductance increases 13-fold. Following the analysis of ion occupancy states using Hamiltonian Replica Exchange (HRE) simulations, we propose a new parameter set for Amber14sb, that also leads to a similar increase in conductance. These two force fields are then used to compute, for the first time, the full current-voltage (I-V) curves from MD simulations, approaching quantitative agreement with experiments at all voltages. In general, the ECC-enabled simulations are in excellent agreement with experiment, in terms of ion occupancy, conductance, current-voltage response, and K+/Na+selectivity.Significance StatementPotassium (K+) channels are essential membrane proteins that facilitate the selective conduction of K+ions while excluding Na+ions. Incorporation of electronic polarization effects through the Electronic Continuum Correction (ECC) method enables molecular dynamics simulations to reproduce rapid K+permeation under physiological voltage conditions. In this study, we demonstrate that employing ECC approximated polarization in molecular dynamics simulations allows for the prediction of multiple channel properties: conductance, ion occupancy, voltage response, and selectivity, with unprecedented accuracy. Furthermore, our simulations provide atomistic insights into the asymmetrical current-voltage (I-V) relationship observed in the MthK channel.
Ketamine reverses chronic stress-induced behavioral changes via the expression of Ca2+-permeable AMPA receptors in mice
Authors: Flowers Joshua C. , Vetter Paige E. , Wiles McKennon J. , Roh Seung Hyun , Black Ellison R. , Bouckova Evelina , Wustrau Madison H. , Lee Rahmi , Lee Sang-Hun , Kim Seonil 
Published: October 2024

AbstractChronic stress affects brain functions leading to the development of mental disorders like anxiety and depression, as well as cognitive decline and social dysfunction. Among many biological changes in chronically stressed brains, disruptions in AMPA Receptor (AMPAR)-mediated synaptic transmission in the hippocampus are associated with stress responses. We have revealed that low-dose ketamine rapidly induces the expression of GluA1-containing, GluA2-lacking Ca2+-Permeable AMPARs (CP-AMPARs), which enhances glutamatergic synaptic strength in hippocampal neurons. Additionally, subanesthetic low-dose ketamine decreases anxiety- and depression-like behaviors in naïve animals. In addition to reducing depression, some research indicates that ketamine may have protective effects against chronic stress in both humans and animals. However, the role of CP-AMPARs in the actions of ketamine’s antistress effects is largely unknown. Here, we use whole-cell patch-clamp recordings from CA1 pyramidal neurons in female and male hippocampal slices to affirm that subanesthetic low-dose ketamine treatment induces CP-AMPAR expression in these cells. Using multiple behavioral assays including reciprocal social interaction, contextual fear conditioning, and tail suspension test, we demonstrate that low-dose ketamine treatment reverses chronic restraint stress (CRS)-induced social dysfunction, hippocampus-dependent fear memory loss, and depression-like behavior in both female and male mice. Furthermore, we show that the ketamine-induced antistress effects on these behaviors are dependent on CP-AMPAR expression. From this, our findings suggest that subanesthetic low-dose ketamine rapidly triggers the expression of CP-AMPARs in the hippocampus, which induces antidepressant and antistress effects.
The arrival of the Near Eastern ancestry in Central Italy predates the onset of the Roman Empire
Authors: Ravasini Francesco , Conati Barbaro Cecilia , Scheib Christiana Lyn , Tambets Kristiina , Metspalu Mait , Cruciani Fulvio , Trombetta Beniamino , D’Atanasio Eugenia 
Published: October 2024

AbstractItalian genetic history was profoundly shaped by Romans. While the Iron Age was comparable to contemporary European regions, the gene pool of Central Italy underwent significant influence from Near Eastern ancestry during the Imperial age. To explain this shift, it has been proposed that during this period people from Eastern Mediterranean regions of the Empire migrated towards its political center. In this study, by analyzing a new individual (1.25x) and published Republican samples, we propose a novel perspective for the presence of Near Eastern ancestry in the Imperial gene pool. In our scenario, the spread of this genetic ancestry took place during the late Republican period, predating the onset of the Empire by ∼200 years. The diffusion of this ancestry may have occurred due to early East-to-West movements, since Eastern Mediterranean regions were already under Roman political influence during the Republic, or even as a result of migration from Southern Italy where Greeks and Phoenicians settled.