bluuebunny/crossref_metadata_2025_split huggingface dataset:
HGNNPIP: A Hybrid Graph Neural Network framework for Protein-protein Interaction Prediction
Authors: Chi Lutong , Ma Jinbiao , Wan Yingqiao , Deng Yang , Wu Yufeng , Cen Xiaochen , Zhou Xiaobo , Zhao Xin , Wang Yiming , Ji Zhiwei 
Published: December 2023

AbstractA deep understanding of Protein-protein interactions (PPIs) can provide comprehensive insights into many biological functions, thereby facilitating drug target identification and novel therapeutic design. Recent developments in artificial intelligence (AI)-driven computational methods have enabled the discovery of previously uncharacterized PPIs from large-scale interactome datasets. Almost all existing machine learning methods rely on Subcellular Localization (SL) to construct balanced datasets based on positive interactions to achieve predictions. Despite high fitting accuracy, the generalization ability of these models is questionable. To solve this problem, we analyzed existing methods and found that the high false positives in these methods are due to the bias in data distribution caused by SL. Therefore, we proposed a new strategy for negative instance sampling in PPI prediction and developed a Hybrid Graph Neural Network framework for Protein-protein Interaction Prediction (HGNNPIP). The experimental results showed that HGNNPIP works well on six benchmark datasets. Comparison analysis demonstrated that our model outperformed the other four existing methods. We also used HGNNPIP to explore the molecular contacts involved in the rice-pathogen interaction system.In vivoexperiments confirmed multiple regulations related to disease resistance in rice. In summary, this study provides new insights into establishing a computational framework for PPI prediction with high reliability.
Low blood concentration of alcohol enhances activity related to stopping failure in the right inferior frontal cortex
Authors: Shinozaki Jun , Matsumoto Hiroshi , Saito Hidekazu , Murahara Takashi , Nagahama Hiroshi , Sakurai Yuuki , Nagamine Takashi 
Published: December 2023

ABSTRACTThis study investigated the effects of low doses of alcohol, which are acceptable for driving a car, on inhibitory control and neural processing using the stop-signal task (SST) in 17 healthy right-handed social drinkers. The study employed simultaneous functional magnetic resonance imaging and electromyography (EMG) recordings to assess behavioural and neural responses under conditions of low-dose alcohol (breath-alcohol concentration of 0.15 mg/L) and placebo. The results demonstrated that even a small amount of alcohol consumption prolonged Go reaction times in the SST and modified stopping behaviour, as evidenced by a decrease in the frequency and magnitude of partial response EMG that did not result in button pressing during successful inhibitory control. Furthermore, alcohol intake enhanced neural activity during failed inhibitory responses in the right inferior frontal cortex, suggesting its potential role in behavioural adaptation following stop-signal failure. These findings suggest that even low levels of alcohol consumption within legal driving limits can greatly impact both the cognitive performance and brain activity involved in inhibiting responses. This research provides important evidence on the neurobehavioural effects of low-dose alcohol consumption, with implications for understanding the biological basis of impaired motor control and decision-making and potentially informing legal guidelines on alcohol consumption.
STN-PFC circuit related to attentional fluctuations during non-movement decision-making
Authors: Ai Shengnan 
Published: December 2023

AbstractDecision-making is a cognitive process, in which participants need to attend to relevant information and ignore the irrelevant information. Previous studies have described a set of cortical areas important for attention. It is unclear whether subcortical areas also serve a role. The subthalamic nucleus (STN), a part of basal ganglia, is traditionally considered a critical node in the cortico-basal ganglia-thalamus-cortico network. Given the location of the STN and its widespread connections with cortical and subcortical brain regions, the STN plays an important role in motor and non-motor cognitive processing. We would like to know if STN is also related to fluctuations in attentional task performance, and how the STN interacts with prefrontal cortical regions during the process. We examined neural activities within STN covaried with lapses of attention (defined as behavior error). We found that decreased neural activities in STN were associated with sustained attention. By examining connectivity across STN and various sub-regions of the prefrontal cortex (PFC), we found that decreased connectivity across areas was associated with sustained attention. Our results indicated that decreased STN activities were associated with sustained attention, and the STN-PFC circuit supported this process.Significance StatementAttention is a core internal state variable that governs the allocation of limited resources depending on the task demands in various cognitive processes. If the subcortical area, subthalamic nucleus (STN), related to attentional fluctuations, and how the STN interacted with cortical regions during the process remains unclear. In this study, we examined neural activities within STN, and connectivity between STN and various prefrontal sub-regions during sustained attention and lapses of attention. We found both neural activities within STN and connectivity between STN-PFC circuit decreased during sustained attention. These findings indicated that decreased STN activities were associated with sustained attention, and the STN-PFC circuit supported this process.
Mapping the shared and unique structural asymmetry abnormalities of young children with autism and developmental delay/intellectual disability with normative models and their multimodal cascade
Authors: Geng Shujie , Dai Yuan , Rolls Edmund T. , Liu Yuqi , Zhang Yue , Deng Lin , Chen Zilin , Feng Jianfeng , Li Fei , Cao Miao 
Published: December 2023

AbstractTo understand the neural mechanism of autism spectrum disorder (ASD) concurrent with developmental delay/intellectual disability (DD/ID), it is essential to comprehensively take genetic, brain, and behavioural measurements as a whole and focus on subjects at early age. However, such research is still lacking.Here, using the sMRI data of 1030 children under 8 years old, we employed developmental normative models to explore the atypical development of gray matter volume (GMV) asymmetry in individuals with ASD without DD/ID, ASD with DD/ID and DD/ID, and their associations with neurophysiological measures and transcription profiles.By computing the individual deviations from typical controls, we observed an ASD-specific abnormal GMV laterality pattern that was more rightwards in the inferior parietal cortex and precentral cortex and noted abnormal within-group heterogeneity in the temporal pole. Specifically, ASD with DD/ID children exhibited more regional abnormalities; ASD without DD/ID children showed higher within-group variability; while children with DD/ID showed no significant abnormalities. However, there were no significant differences among the three groups. The GMV laterality of ASD without DD/ID children was associated with ASD symptoms, whereas that of ASD with DD/ID children was associated with both ASD symptoms and verbal IQ. Last, the GMV laterality of the ASD with DD/ID, ASD without DD/ID, and DD/ID groups was associated with shared and unique gene expression profiles, but the associations of the latter two groups with intellectual genes showed opposite effects.Our findings illustrated the atypical development of regional structural lateralization in autistic children, which is associated with upstream genes and downstream behavioural performance. The differences and similarity between ASD and DD/ID additionally improve our standing to the neural mechanism of neurodevelopmental disorders comorbidity.
Molecular and micro-architectural mapping of gray matter alterations in psychosis
Authors: García-San-Martín Natalia , Bethlehem Richard AI , Mihalik Agoston , Seidlitz Jakob , Sebenius Isaac , Alemán-Morillo Claudio , Dorfschmidt Lena , Shafiei Golia , Ortiz-García de la Foz Víctor , Merritt Kate , David Anthony , Morgan Sarah E. , Ruiz-Veguilla Miguel , Ayesa-Arriola Rosa , Vázquez-Bourgon Javier , Alexander-Bloch Aaron , Misic Bratislav , Bullmore Edward T. , Suckling John , Crespo-Facorro Benedicto ,   Lifespan Brain Chart Consortium, Romero-García Rafael 
Published: December 2023

AbstractThe psychosis spectrum encompasses a heterogeneous range of clinical conditions associated with abnormal brain development. Detecting patterns of atypical neuroanatomical maturation across psychiatric disorders requires an interpretable metric standardized by age-, sex- and site-effect. The molecular and micro-architectural attributes that account for these deviations in brain structure from typical neurodevelopment are still unknown. Here, we aggregate structural magnetic resonance imaging data from 38,696 healthy controls (HC) and 1,256 psychosis-related conditions, including first-degree relatives of schizophrenia (SCZ) and schizoaffective disorder (SAD) patients (n= 160), individuals who had psychotic experiences (n= 157), patients who experienced a first episode of psychosis (FEP,n= 352), and individuals with chronic SCZ or SAD (n= 587). Using a normative modeling approach, we generated centile scores for cortical gray matter (GM) phenotypes, identifying deviations in regional volumes below the expected trajectory for all conditions, with a greater impact on the clinically diagnosed ones, FEP and chronic. Additionally, we mapped 46 neurobiological features from healthy individuals (including neurotransmitters, cell types, layer thickness, microstructure, cortical expansion, and metabolism) to these abnormal centiles using a multivariate approach. Results revealed that neurobiological features were highly co-localized with centile deviations, where metabolism (e.g., cerebral metabolic rate of oxygen (CMRGlu) and cerebral blood flow (CBF)) and neurotransmitter concentrations (e.g., serotonin (5-HT) and acetylcholine (α4β2) receptors) showed the most consistent spatial overlap with abnormal GM trajectories. Taken together these findings shed light on the vulnerability factors that may underlie atypical brain maturation during different stages of psychosis.
Comparison of semaglutide in combined with empagliflozin versus semaglutide and empagliflozin monotherapy in non-alcoholic fatty liver disease with type 2 diabetes: study protocol for a randomised controlled clinical trial
Authors: Lin Yu-Hao , Zhang Zhi-Jun , Zhong Jin-Qing , Wang Zhi-Yi , Peng Yi-Ting , Lin Yan-Mei , Zhang Huo-Ping , Tian Jian-Qing 
Published: December 2023

ABSTRACTBackgroundNonalcoholic fatty liver disease (NAFLD) is strongly associated with type 2 diabetes (T2DM). Lifestyle intervention remains a preferred treatment modality for NAFLD. As the glucose-lowering agents, glucagon-like peptide (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors have been demonstrated to improve liver fat content and glycaemic control in patients with NAFLD and T2DM. However, studies exploring the efficacy of GLP-1 receptor agonists combined with SGLT-2 inhibitors in patients with NAFLD and T2DM are scanty. Thus, the present randomised controlled trial aims at comparing the efficacy and safety of semaglutide plus empagliflozin with each treatment alone in patients with NAFLD and T2DM.MethodsThis 52-week double-blinded, randomised, parallel-group, active-controlled trial evaluates the effects of semaglutide, empagliflozin and semaglutide + empagliflozin in 105 eligible overweight/obese subjects with NAFLD and T2DM. The primary outcome will be a change from baseline to week 52 in the controlled attenuation parameter, free fatty acid and glucagon. Secondary endpoints include changes in liver stiffness measurement, liver enzymes, blood glucose, lipid levels, renal function, electrolyte balances, minerals and bone metabolism, cytokines, high-sensitivity C-reactive protein, ferritin, anthropometric indicators, nonalcoholic fatty liver fibrosis score, fibrosis 4 score and homeostatic model assessment for insulin resistance. In addition, intention-to-treat, interim analysis and safety analysis will be performed.DiscussionThis double-blinded, randomised, clinical trial involves a multi-disciplinary approach and aims to explore the synergistic effects of the combination of semaglutide and empagliflozin. The results can provide important insights into mechanisms of GLP-1 receptor agonists and/or SGLT-2 inhibitors in patients with NAFLD and T2DM.Trial registrationThis study has been registered with Chinese Clinical Trial Registry (ChiCTR2300070674).
Infection Inspection: Using the power of citizen science to help with image-based prediction of antibiotic resistance inEscherichia coli
Authors: Farrar Alison , Feehily Conor , Turner Piers , Zagajewski Aleksander , Chatzimichail Stelios , Crook Derrick , Andersson Monique , Oakley Sarah , Barrett Lucinda , Sayyed Hafez El , Fowler Philip W. , Nellåker Christoffer , Kapanidis Achillefs N. , Stoesser Nicole 
Published: December 2023

AbstractAntibiotic resistance is an urgent global health challenge, necessitating rapid diagnostic tools to combat its escalating threat. This study introduces innovative approaches for expedited bacterial antimicrobial resistance profiling, addressing the critical need for swift clinical responses. Between February and April 2023, we conducted the Infection Inspection project, a citizen science initiative in which the public could participate in advancing an antimicrobial susceptibility testing method based on single-cell images of cellular phenotypes in response to ciprofloxacin exposure. A total of 5,273 users participated, classifying 1,045,199 images. Notably, aggregated user accuracy in image classification reached 66.8%, lower than our deep learning model’s performance at 75.3%, but accuracy increased for both users and the model when ciprofloxacin treatment was greater than a strain’s own minimum inhibitory concentration. We used the users’ classifications to elucidate which visual features influence classification decisions, most importantly the degree of DNA compaction and heterogeneity. We paired our classification data with an image feature analysis which showed that most of the incorrect classifications were due to cellular features that varied from the expected response. This understanding informs ongoing efforts to enhance the robustness of our deep learning-based bacterial classifier and diagnostic methodology. Our successful engagement with the public through citizen science is another demonstration of the potential for collaborative efforts in scientific research, specifically increasing public awareness and advocacy on the pressing issue of antibiotic resistance, and empowering individuals to actively contribute to the development of novel diagnostics.Lay summaryAntibiotic resistance is a big health problem worldwide. We need fast ways to find out if bacteria are resistant to antibiotics. In our study, we develop new methods to do this quickly. We ran an online project called Infection Inspection from February to April 2023, in which 5,273 people took part. Together, they classified more than a million pictures of bacterial cells, helping our project use these pictures to detect antibiotic resistance. The volunteers performed well, getting near 67% of the answers right. We also learned which pictures helped or confused them. This will help us make our computer program better. This project didn’t just help science; it also taught people about antibiotic resistance. Partnerships between the public and scientists can make a difference to developing technologies that protect our health.
DPYDgenetic polymorphisms in non-European patients with severe fluoropyrimidine-related toxicity: A systematic review
Authors: Chan Tsun Ho , Zhang J. Eunice , Pirmohamed Munir 
Published: December 2023

AbstractBackgroundPre-treatmentDPYDscreening is mandated in the UK and EU to reduce the risk of severe and potentially fatal fluoropyrimidine-related toxicity. FourDPYDgene variants which are more prominently found in Europeans are tested.MethodsOur systematic review in patients of non-European ancestry followed PRISMA guidelines to identify relevant articles up to April 2023. Publishedin silicofunctional predictions andin vitrofunctional data were also extracted. We also undertookin silicoprediction for allDPYDvariants identified.ResultsIn 32 studies, published between 1998 and 2022, 53DPYDvariants were evaluated in patients from 12 countries encompassing 5 ethnic groups: African American, East Asian, Latin American, Middle Eastern, and South Asian. One of the 4 common EuropeanDPYDvariants, c.1905+1G>A, is also present in South Asian, East Asian and Middle Eastern patients with severe fluoropyrimidine-related toxicity. There seems to be relatively strong evidence for the c.557A>G variant, which is found in individuals of African ancestry, but is not currently included in the UK genotyping panel.ConclusionExtending UK pre-treatmentDPYDscreening to include variants that are present in some non-European ancestry groups will improve patient safety and reduce race and health inequalities in ethnically diverse societies.
Trends in Efficacy, Safety, and Tolerability of Approved Multiple Sclerosis Disease Modifying Treatments
Authors: Valker Kyle , Suh Kangho 
Published: December 2023

AbstractBackgroundDisease-modifying therapies (DMTs) have become the mainstay of treatment for relapsing forms of multiple sclerosis (MS), reducing relapse rates and slowing disease progression.ObjectivesTo determine whether or not available MS DMTs have demonstrated an increase in safety, efficacy, and tolerability over time.MethodsResults from pivotal phase III trials of approved MS DMTs were used to create a dataset of relevant outcomes. Common endpoints analyzed include annualized relapse rates (ARR), rates of serious adverse events (SAE), and rates of discontinuation due to adverse events. Trial comparator, active or placebo, was also documented. Descriptive statistics and Fisher exact tests were performed on outcomes stratified by recency of pivotal trials.ResultsOn visual inspection, there was a trend of decrease in ARR. A significant relationship was seen between recent approvals and trial design with an active comparator (p=0.004), as well as between recent approvals and ARR (p=0.020). No significance was found between recent approvals and SAE (p=0.138), formulation and discontinuation (p=0.559), or recent approvals and formulation (p=0.352).ConclusionDMTs for relapsing forms of MS increased in efficacy over time. Oral therapies offered similar tolerability to other routes of administration. Further research is warranted to identify if these clinical trial findings translate to real world evidence.What was already knownThe number of FDA approved disease-modifying therapies for multiple sclerosis has been steadily increasing. Available routes of administration include injectable, oral, and infusions.These medications are proven to be effective in reducing MS relapse rates and slowing overall disease progression, with varying degrees of safety and tolerability.The comparative efficacy of these therapies varies, with certain medications often deemed high efficacy.What this study addsWe used published phase III trial results for each medication to provide a direct comparison between each medication’s efficacy, safety, and tolerability at time of approval.Our analysis demonstrates a trend in increasing efficacy of available therapies along with the use of active comparators for controls in disease modifying treatments for multiple sclerosis.
Degenerate DropSynth for Simultaneous Assembly of Diverse Gene Libraries and Local Designed Mutants
Authors: Holston Andrew S. , Hinton Samuel R. , Lindley Kyra A. , Kearns Nora C. , Plesa Calin 
Published: December 2023

AbstractProtein engineering efforts often involve the creation of hybrid or chimeric proteins, where functionality critically hinges on the precise design of linkers and fusion points. Traditional methods have been constrained by a focus on single genes or the random selection of fusion points. Here we introduce an approach which enables the creation of large gene libraries where each library comprises a multitude of diverse, specifically designed genes, each with a corresponding set of programmatically designed fusion points or linkers. When combined with multiplex functional assays, these libraries facilitate the derivation of generalized engineering principles applicable across whole protein families or domain types. Degenerate DropSynth is a multiplex gene synthesis technique which allows for the assembly of up to eight distinct variants for each of the 1,536 designed parent genes in a single reaction. We assemble chimeric sensor histidine kinases and demonstrate the assembly of genes up to 1 kbp in length with an 8% rate of perfect assemblies per gene. Our findings indicate that incorporating an increased number of variants in droplets containing barcoded beads does not significantly affect the rate of perfect assemblies. However, maintaining a consistent level of degeneracy across the library is important to ensure good coverage and reduce inequality. The results suggest the potential for scaling this process to assemble at least 8,000 distinct variants in a single reaction. Degenerate DropSynth enables the systematic exploration of protein families through large-scale, programmable assembly of chimeric proteins, moving beyond the limitations of individual protein studies.
Protein phosphatases regulate the formation of Müller glia-derived progenitor cells in the chick retina
Authors: Kelly Lisa E. , El-Hodiri Heithem M. , Crider Andrew , Fischer Andy J. 
Published: December 2023

AbstractDifferent kinase-dependent cell signaling pathways are known to play important roles in glia-mediated neuroprotection and reprogramming of Müller glia (MG) into Müller glia-derived progenitor cells (MGPCs) in the retina. However, very little is known about the phosphatases that regulate kinase-dependent signaling in MG. Using single-cell RNA-sequencing (scRNA-seq) databases, we investigated patterns of expression of Dual Specificity Phosphatases (DUSP1/6) and other protein phosphatases in normal and damaged chick retinas. We found thatDUSP1, DUSP6, PPP3CB, PPP3R1andPPPM1A/B/D/E/Gare dynamically expressed by MG and MGPCs in retinas during the process of reprogramming. We find that inhibition of DUSP1/6 and PP2C phosphatases enhances the formation of proliferating MGPCs in damaged retinas and in retinas treated with insulin in FGF2 in the absence of damage. By contrast, inhibition of PP2B phosphatases suppressed the formation of proliferating MGPCs, but increased numbers of proliferating MGPCs in undamaged retinas treated with insulin and FGF2. In damaged retinas, inhibition of DUSP1/6 increased levels of pERK1/2 and cFos in MG whereas inhibition of PP2B’s decreased levels of pStat3 and pS6 in MG. Analyses of scRNA-seq libraries identified numerous differentially activated gene modules in MG in damaged retinas versus MG in retinas treated with insulin+FGF2 suggesting significant differences in kinase-dependent signaling pathways that converge on the formation of MGPCs. Inhibition of phosphatases had no significant effects upon numbers of dying cells in damaged retinas. We conclude that the activity of different protein phosphatases “fine-tune” the cell signaling responses of MG in damaged retinas and during the reprogramming of MG into MGPCs.