bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interpretable antibody-antigen interaction prediction by introducing route and priors guidance
Authors: Liu Yutian , Nie Zhiwei , Chen Jie , Zheng Xinhao , Fu Jie , Liu Zhihong , Liu Xudong , Xu Fan , Huang Xiansong , Zhang Wen-Bin , Ma Siwei , Gao Wen , Tian Yonghong 
Published: March 2024

AbstractWith the application of personalized and precision medicine, more precise and efficient antibody drug development technology is urgently needed. Identification of antibody-antigen interactions is crucial to antibody engineering. The time-consuming and expensive nature of wet-lab experiments calls for efficient computational methods. Taking into account the non-overlapping advantage of current structure-dependent and sequence-only computational methods, we propose an interpretable antibody-antigen interaction prediction method, S3AI. The introduction of structural knowledge, combined with explicit modeling of chemical rules, establishes a ‘sequence-to-function’ route in S3AI, thereby facilitating its perception of intricate molecular interactions through providing route and priors guidance. S3AI significantly and comprehensively outperforms the state-of-the-art models and exhibits excellent generalization when predicting unknown antibody-antigen pairs, surpassing specialized prediction methods designed for out-of-distribution generalization in fair comparisons. More importantly, S3AI captures the universal pattern of antibody-antigen interactions, which not only identifies the CDRs responsible for specific binding to the antigen but also unearths the importance of CDR-H3 for the interaction. Structure-free design and superior performance make S3AI ideal for large-scale, parallelized antibody optimization and screening, enabling the rapid and precise identification of promising candidates within the extensive antibody space.
PIGOME: An Integrated and Comprehensive Multi-omics Database for Pig Functional Genomics Studies
Authors: Han Guohao , Yang Peng , Zhang Yongjin , Li Qiaowei , Fan Xinhao , Chen Ruipu , Yan Chao , Zeng Mu , Yang Yalan , Tang Zhonglin 
Published: March 2024

AbstractIn addition to being a major source of animal protein, pigs are important model for the study of development and diseases in humans. During the past two decades, thousands of high-throughput sequencing studies in pigs have been performed using a variety of tissues from different breeds and developmental stages. However, the multi-omics database specifically used for pig functional genomic research is still limited. Here, we present a user-friendly database of pig multi-omics named PIGOME. PIGOME contains seven types of pig omics datasets, including whole-genome sequencing, RNA-seq, miRNA-seq, ChIP-seq, ATAC-seq, bisulfite-seq, and MeRIP-seq, from 6,901 samples and 392 projects with manually curated metadata, integrated gene annotation, and quantitative trait locus information. Furthermore, various ‘explore and browse’ functions have been established for user-friendly access to omics information. PIGOME implemented several tools to visualize genomic variants, gene expression, and epigenetic signals of a given gene in the pig genome, enabling efficient exploration of spatial-temporal expression/epigenetic pattern, function, regulatory mechanism, and associated economic traits. Collectively, PIGOME provides valuable resources for pig breeding and is helpful for human biomedical research. PIGOME is available athttps://pigome.com.
Dissociable representations of decision variables within subdivisions of macaque orbitofrontal and ventrolateral frontal cortex
Authors: Stoll Frederic M. , Rudebeck Peter H. 
Published: March 2024

ABSTRACTVentral frontal cortex (VFC) in macaques is involved in many affective and cognitive processes and has a key role in flexibly guiding reward-based decision-making. VFC is composed of a set of anatomically distinct subdivisions that are within the orbitofrontal cortex, ventrolateral prefrontal cortex, and anterior insula. In part, because prior studies have lacked the resolution to test for differences, it is unclear if neural representations related to decision-making are dissociable across these subdivisions. Here we recorded the activity of thousands of neurons within eight anatomically defined subregions of VFC in macaque monkeys performing a two-choice probabilistic task for different fruit juices outcomes. We found substantial variation in the encoding of decision variables across these eight subdivisions. Notably, ventrolateral subdivision 12l was unique relative to the other areas that we recorded from as the activity of single neurons integrated multiple attributes when monkeys evaluated the different choice options. Activity within 12o, by contrast, more closely represented reward probability and whether reward was received on a given trial. Orbitofrontal area 11m/l contained more specific representations of the quality of the outcome that could be earned later on. We also found that reward delivery encoding was highly distributed across all VFC subregions, while the properties of the reward, such as its flavor, were more strongly represented in areas 11m/l and 13m. Taken together, our work reveals the diversity of encoding within the various anatomically distinct subdivisions of VFC in primates.SIGNIFICANCE STATEMENTVentral frontal cortex (VFC) is essential for flexible decision-making and is composed of many anatomically defined subdivisions. How neural representations related to decision-making vary or not between these subdivisions is unclear. Here we recorded single neuron activity from eight anatomically distinct subdivisions of VFC while macaques made choices between stimuli based on the probability of receiving different flavored fruit juices. We report that neural representations across these subdivisions were dissociable. Area 12l exhibiting the most integrated representations of decision variables at the level of single neurons. By contrast, activity in area 12o was closely related to reward probability whereas activity in area 11m/l and 13m represented juice flavor. Thus, neural representations are distinct across anatomically separable parts of VFC.
Regenerative clustering of Enteroblasts in theDrosophilamidgut revealed by a morphometric analysis
Authors: Zhu Fionna , Murray Michael J. 
Published: March 2024

AbstractEnteroblasts (EBs) are the cells responsible for the maintenance of the epithelium that lines the adult midgut inDrosophila. In response to cell death and damage, EBs undergo a Mesenchymal-Epithelial-Transition (MET) as they incorporate into the epithelium and differentiate into enterocytes (ECs). The morphogenetic mechanisms driving this MET process are not well understood. To improve phenotypic analysis of EBs, we established an analysis pipeline that uses machine learning segmentation to produce a reliable and automated quantification of cellular morphology and spatial distributions. EB morphology and fate is visualised using the Repressible Dual Differential stability cell Marker (ReDDM) approach. We show that wildtype EB cells exhibit a bimodal distribution pattern in which midguts fall into two categories: “quiescent” guts, in which EBs are evenly spaced out and newly formed ECs are uncommon, and “regenerative” guts, in which EBs are clustered and new ECs are prevalent. Using this system we first show that RNAi knockdown of Septate Junction proteins disrupts normal EB morphology and spatial distribution. With time-lapse imaging, we have also established that EBs are motile in nature, and when artificial tissue damage was introduced, exhibited increased cytoplasmic movements, and formed distinct clusters. We then demonstrate the utility of our pipeline in a small candidate screen for genes that might mediate EB clustering. Based on our results, we propose a working model that links the dynamic behaviour of EBs with midgut regeneration.
Monensin as potential drug for treatment of SLeX-positive tumors
Authors: Costa Ana F. , Senra Emanuel , Campos Diana , Faria-Ramos Isabel , Santos-Ferreira Liliana , Lamas Sofia , Gomes Joana , Pinto Filipe , Teixeira Andreia , Abrantes Rafaela , Duarte Henrique O. , Pacheco Mariana , Pinto Marta T. , Maia André F. , Pombinho António , Barros Rita , Fernandes Verónica , Casanova-Gonçalves Frederica , Sousa Fabiana , Barbosa José , Pereira Luísa , Carneiro Fátima , Reis Celso A. , Gomes Catarina 
Published: March 2024

AbstractColorectal (CRC) and gastric (GC) cancers remain the top lethal cancers and targeted therapies in this setting are still very limited. Sialyl Lewis X (SLeX), a cancer-associated glycan highly expressed in both CRC and GC, plays a crucial role in cancer cell dissemination and metastasis. Thus, presenting a promising but still underexplored therapeutic target. In this work, we performed a high-throughput screening (HTS) approach to identify potential inhibitors of SLeX expression on cancer cells. Two libraries including a total of 7836 compounds were screened and monensin emerged as a promising SLeX inhibitor. Monensin promoted structural alterations in the secretory pathway, particularly at the Golgi apparatus, impacting proteinO-glycosylation and secretion. RNAseq transcriptomic analysis uncovered significant alterations in Gene Ontology (GO) terms associated with protein misfolding, target to the membrane, as well as, epithelial cell-cell adhesion protein.In vitrostudies showed that, upon treatment with monensin, SLeX-positive cancer cells showed reduced viability, concomitant with decreased motility and invasive capacities. Usingin vivoxenograft models of chick embryo chorioallantoic membrane (CAM) and nude mice, revealed that monensin reduced tumor formation and invasion. Pre-clinical validation using gastric cancer patient-derived organoids (PDOs) and organoid xenotransplants in mice further underscored the clinical potential of monensin in suppressing the growth of SLeX- positive tumors. Overall, our findings set the ground for further evaluation of monensin as a novel therapeutic agent in GC and CRC in the clinical setting.
The PRIME-NL study: evaluating a complex healthcare intervention for people with Parkinson’s disease in a dynamic environment
Authors: Maas Bart R. , van den Bergh Robin , van den Berg Sanne W. , Hulstein Eveline , Stadhouders Niek , Jeurissen Patrick P.T. , de Vries Nienke M. , Bloem Bastiaan R. , Munneke Marten , Ben-Shlomo Yoav , Darweesh Sirwan K.L. 
Published: March 2024

AbstractBackgroundAn innovative, integrative care model for people with Parkinson (PRIME Parkinson) has gradually been implemented in a selected region of the Netherlands since 2021. A prospective evaluation of this model (PRIME-NL study) was initiated in parallel, spanning the year prior to implementation (baseline) and the implementation period. Following publication of the original study protocol, the COVID-19 crisis delayed implementation of the full PRIME Parkinson care model by two years and hampered the recruitment of study participants.ObjectiveTo describe which methodological adjustments were made to the study protocol because of these developments.MethodsWe compare various outcomes between a region where PRIME Parkinson care was implemented (innovation region) versus the rest of the Netherlands (usual care region). We use healthcare claims data of virtually all people with Parkinson in the Netherlands and annual questionnaires in a representative subsample of 984 people with Parkinson, 566 caregivers and 192 healthcare professionals. Four major methodological adjustments had to be made since publication of the original protocol. First, we extended the evaluation period by two years. Second, we incorporated annual process measures of the stage of implementation of the new care model. Third, we introduced a real-time iterative feedback loop of interim results to relevant stakeholders. Fourth, we updated the statistical analysis plan.DiscussionThis manuscript provides transparency in how the design and analyses of the evaluation study had to be adapted to control for external influences in a dynamic environment, including eruption of the COVID-19 crisis. Our solutions could serve as a template for evaluating other complex healthcare interventions in a dynamic environment.
Effects of silver diamine fluoride on oral bacteriome and mycobiome: a randomized clinical trial
Authors: Manerkar Mayura , Cruz de Jesus Vivianne , Mittermuller Betty-Anne , Lee Victor H. K. , Singh Sarbjeet , Bertone Mary , Chelikani Prashen , Schroth Robert J. 
Published: March 2024

AbstractIntroductionSilver diamine fluoride (SDF) is a simple and non-invasive agent used to arrest early childhood caries (ECC). This study aimed to investigate potential changes to the oral microbiome in children with ECC who were treated with SDF at three different frequency regimens.MethodsForty-five children (n=15 per group) with ECC were recruited into a randomized clinical trial testing three different treatment frequency regimens of SDF. A total of 195 carious lesions were treated with two applications of 38% SDF and 5% sodium fluoride varnish (NaFV) and assessed over three study visits (one month (Regimen 1M), four months (Regimen 4M), or six months (Regimen 6M) apart). Dental plaque samples were collected at each visit. Sequencing of the V4-16S rRNAandITS1 rRNAgenes were used to study the supragingival plaque microbiome.ResultsThe overall arrest rates for treated carious lesions were 75.9% at Visit 2 and 92.8% at Visit 3. Arrest rates were higher for all lesions after two applications of SDF with NaFV, and applications one month and four months apart had higher arrest rates (95.9% and 98.5%) than six months (81.1%) apart. The microbial diversity analyses showed no significant differences in the overall microbiome after SDF treatment. However, significant changes in the abundance of specific bacteria and fungi, particularlyLactobacillus spp.,Bifidobacterium spp., and Candida spp.were observed after treatment. Furthermore, overabundance ofStreptococcus mutansandCandida dubliniensisat baseline was observed in children who had at least one caries lesion not arrested after one SDF application, compared to those who had 100% arrest rates.ConclusionSDF with NaFV applications were an effective modality for arresting ECC, with higher arrest rates after two SDF applications. No loss of diversity but significant changes in the abundance of specific bacteria and fungi were consequences of SDF treatment.
Symmetry breaking and fate divergence during lateral inhibition inDrosophila
Authors: Phan Minh-Son , Kim Jang-mi , Picciotto Cara , Couturier Lydie , Veits Nisha , Mazouni Khallil , Schweisguth François 
Published: March 2024

AbstractLateral inhibition by Notch mediates the adoption of alternative cell fates amongst groups of initially equipotent cells, leading to the formation of regular patterns of cell fates in many tissues across species. Genetic and molecular studies have established a model whereby an intercellular negative feedback loop serves to amplify small stochastic differences in Notch activity, thereby generating ordered salt-and-pepper patterns. InDrosophila, lateral inhibition selects Sensory Organ Precursor cells (SOPs) from clusters of proneural cells that are competent to become neural through the expression of proneural transcription factors. When and how symmetry breaking occurs during lateral inhibition remains, however, to be addressed. Here, we have used the pupal abdomen as an experimental model to study the dynamics of lateral inhibition inDrosophila. Using quantitative live imaging, we monitored the accumulation of the transcription factor Scute (Sc), used as a surrogate for proneural competence and adoption of the SOP fate. We found that fate symmetry breaking occurred at low Sc levels and that fate divergence was not preceded by a prolonged phase of low or intermediate level of Sc accumulation. The relative size of the apical area did not appear to bias this fate choice. Unexpectedly, we observed at low frequency (10%) pairs of cells that are in direct contact at the time of SB and that adopt the SOP fate. These lateral inhibition defects were corrected via cellular rearrangements. Analysis of Sc dynamics in wild-type and genetically mosaic pupae further revealed that cell-to-cell variations in Sc levels promoted fate divergence, thereby providing experimental support for the intercellular negative feedback loop model.
Mutational Profiling of SARS-CoV-2 PLpro in human cells reveals requirements for function, structure, and drug escape
Authors: Wu Xinyu , Go Margareta , Nguyen Julie V. , Kuchel Nathan W. , Lu Bernadine G.C. , Lowes Kym N. , Calleja Dale J. , Mitchell Jeffrey P. , Lessene Guillaume , Komander David , Call Matthew E. , Call Melissa J. 
Published: March 2024

AbstractSARS-CoV-2, the causative agent of COVID-19, is responsible for the recent global pandemic and remains a major source of mortality. Papain-like protease (PLpro) is a target for SARS-CoV-2 inhibitor development, as it is not only essential for viral replication through cleavage of the viral poly-proteins pp1a and pp1ab, but also has de-ubiquitylation and de-ISGylation activities, which can affect innate immune responses. To understand the features of PLpro that dictate activity and anticipate how emerging PLpro variants will affect function, we employed Deep Mutational Scanning to evaluate the mutational effects on enzymatic activity and protein stability in mammalian cells. We confirm features of the active site and identify all mutations in neighboring residues that support or ablate activity. We characterize residues responsible for substrate binding and demonstrate that although the blocking loop is remarkably tolerant to nearly all mutations, its flexibility is important for enzymatic function. We additionally find a connected network of mutations affecting function but not structure that extends far from the active site. Using our DMS libraries we were able to identify drug-escape variants to a common PLpro inhibitor scaffold and predict that plasticity in both the S4 pocket and blocking loop sequence should be considered during the drug design process.
Neuroprotective role of Hippo signaling by microtubule stability control inC. elegans
Authors: Lee Hanee , Kang Junsu , Lee Sang-Hee , Lee Dowoon , Chung Christine H. , Lee Junho 
Published: March 2024

AbstractThe evolutionarily conserved Hippo (Hpo) pathway has been shown to impact early development and tumorigenesis by governing cell proliferation and apoptosis. However, its post-developmental roles are relatively unexplored. Here, we demonstrate its roles in post-mitotic cells by showing that defective Hpo signaling accelerates age-associated structural and functional decline of neurons inC. elegans. Loss ofwts-1/LATS resulted in premature deformation of touch neurons and impaired touch responses in ayap-1/YAP-dependent manner. Decreased movement as well as microtubule destabilization by treatment with colchicine or disruption of microtubule stabilizing genes alleviated the neuronal deformation ofwts-1mutants. Colchicine exerted neuroprotective effects even during normal aging. In addition, the deficiency of a microtubule-severing enzymespas-1also led to precocious structural deformation. These results consistently suggest that hyper-stabilized microtubules in bothwts-1-deficient neurons and normally aged neurons are detrimental to the maintenance of neuronal structural integrity. In summary, Hpo pathway governs the structural and functional maintenance of differentiated neurons by modulating microtubule stability, raising the possibility that the microtubule stability of fully developed neurons could be a promising target to delay neuronal aging. Our study provides potential therapeutic approaches to combat age- or disease-related neurodegeneration.
Construction of invariant features for time-domain EEG/MEG signals using Grassmann manifolds
Authors: Hindriks Rikkert , Rot Thomas O. , van Putten Michel J.A.M. , Tewarie Prejaas 
Published: March 2024

AbstractA challenge in interpreting features derived from source-space electroencephalography (EEG) and magnetoencephalography (MEG) signals is residual mixing of the true source signals. A common approach is to use features that are invariant under linear and instantaneous mixing. In the context of this approach, it is of interest to know which invariant features can be constructed from a given set of source-projected EEG/MEG signals. We address this question by exploiting the fact that invariant features can be viewed as functions on the Grassmann manifold. By embedding the Grassmann manifold in a vector space, coordinates are obtained that serve as building blocks for invariant features, in the sense that all invariant features can be constructed from them. We illustrate this approach by constructing several new bivariate, higher-order, and multidimensional functional connectivity measures for static and time-resolved analysis of time-domain EEG/MEG signals. Lastly, we apply such an invariant feature derived from the Grassmann manifold to EEG data from comatose survivors of cardiac arrest and show its superior sensitivity to identify changes in functional connectivity.Author SummaryElectroencephalography (EEG) and magnetoencephalography (MEG) are techniques to non-invasively measure brain activity in human subjects. This works by measuring the electric potentials on the scalp (EEG) or the magnetic fluxes surrounding the head (MEG) that are induced by currents flowing in the brains’ grey matter (the ”brain activity”). However, reconstruction of brain activity from EEG/MEG sensor signals is an ill-posed inverse problem and, consequently, the reconstructed brain signals are linear superpositions of the true brain signals. This fact complicates the interpretation of the reconstructed brain activity. A common approach is to only use features of the reconstructed activity that are invariant under linear superpositions. In this study we show that all invariant features of reconstructed brain signals can be obtained by taking combinations of a finite set of fundamental features. The fundamental features are parametrized by a high-dimensional space known as the Grass-mann manifold, which has a rich geometric structure that can be exploited to construct new invariant features. Our study advances the systematic study of invariant properties of EEG/MEG data and can be used as a framework to systematize and interrelate existing results. We use the theory to construct a new invariant connectivity measure and apply it to EEG data from comatose survivors of cardiac arrest. We find that this measure enables superior identification of affected brain regions.