bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evolution of the Jawed Vertebrate (Gnathostomata) Stomach through Gene Repertoire Loss: Findings from Agastric Species
Authors: Dann Jackson , Grützner Frank 
Published: December 2024

AbstractIndependent and convergent gene loss, such as the loss of gastric enzymes (Pga,Pgc) and proton pump subunits (Atp4a,Atp4b) in monotremes and polyphyletic teleost species have been associated with the agastric phenotype – stomachs lacking gross morphology, gastric glands and acid secretion. The loss of the key gastric hormone gastrin (Gast) has been observed in monotremes, but not corroborated in agastric teleosts. Furthermore, it is unclear how this loss affects the evolution and selection of the native receptor (Cckbr), gastrin releasing peptide (Grp) and receptor (Grpr), or if there are further gene losses associated with the agastric phenotype. We investigated the evolution, selection and conservation of the gastrin physiological pathway and novel gastric genes in a broad range of gastric and agastric vertebrates. Our analyses showed no correlation between the losses ofGastandGrprwith the agastric phenotype in vertebrate lineages. We identified genes implicated in gastric mucosal maintenance and development (Gkn1,Gkn2,Tff1,Tff2,Vsig1,Anxa10) that are lost in agastric species except the echidna, which retained some of them (Gkn1,Tff2,Vsig1). Our findings demonstrate a convergent repertoire of gastric genes lost in agastric species, partial retention of gastric functionality in the echidna, and the diversified roles of gastrin pathway constituents in vertebrate lineages.
Voltage Gated Calcium Channel Dysregulation May Contribute to Neurological Symptoms in Calmodulinopathies
Authors: Hussey John W. , DeMarco Emily , DiSilvestre Deborah , Brohus Malene , Busuioc Ana-Octavia , Iversen Emil D. , Jensen Helene H. , Nyegaard Mette , Overgaard Michael T. , Ben-Johny Manu , Dick Ivy E. 
Published: December 2024

AbstractCalmodulinopathies are caused by mutations in calmodulin (CaM), and result in debilitating cardiac arrythmias such as long-QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). In addition, many patients exhibit neurological comorbidities, including developmental delay and autism spectrum disorder. Until now, most work into these mutations has focused on cardiac effects, identifying impairment of Ca2+/CaM-dependent inactivation (CDI) of CaV1.2 channels as a major pathogenic mechanism. However, the impact of these mutations on neurological function has yet to be fully explored. CaM regulation of voltage-gated calcium channels (VGCCs) is a critical element of neuronal function, implicating multiple VGCC subtypes in the neurological pathogenesis of calmodulinopathies. Here, we explore the potential for pathological CaM variants to impair the Ca2+/CaM-dependent regulation of CaV1.3 and CaV2.1, both essential for neuronal function. We find that mutations in CaM can impair the CDI of CaV1.3 and reduce the Ca2+-dependent facilitation (CDF) of CaV2.1 channels. We find that mutations associated with significant neurological symptoms exhibit marked effects on CaV1.3 CDI, with overlapping but distinct impacts on CaV2.1 CDF. Moreover, while the majority of CaM variants demonstrated the ability to bind the IQ region of each channel, distinct differences were noted between CaV1.3 and CaV2.1, demonstrating distinct CaM interactions across the two channel subtypes. Further, C-domain CaM variants display a reduced ability to sense Ca2+when in complex with the CaVIQ domains, explaining the Ca2+/CaM regulation deficits. Overall, these results support the possibility that disrupted Ca2+/CaM regulation of VGCCs may contribute to neurological pathogenesis of calmodulinopathies.
Retrieval Augmented Protein Language Models for Protein Structure Prediction
Authors: Li Pan , Cheng Xingyi , Song Le , Xing Eric 
Published: December 2024

AbstractThe advent of advanced artificial intelligence technology has significantly accelerated progress in protein structure prediction. AlphaFold2, a pioneering method in this field, has set a new benchmark for prediction accuracy by leveraging the Evoformer module to automatically extract co-evolutionary information from multiple sequence alignments (MSA). However, the efficacy of structure prediction methods like AlphaFold2 is heavily dependent on the depth and quality of the MSA. To address this limitation, we propose two novel models, AIDO.RAGPLM and AIDO.RAGFold, which are pretrained modules forRetrieval-AuGmented protein language model and structure prediction in an AI-driven Digital Organism [1]. AIDO.RAGPLM integrates pre-trained protein language models with retrieved MSA, allowing for the incorporation of co-evolutionary information in structure prediction while compensating for insufficient MSA information through large-scale pretraining. Our method surpasses single-sequence protein language models in perplexity, contact prediction, and fitness prediction. We utilized AIDO.RAGPLM as the feature extractor for protein structure prediction, resulting in the development of AIDO.RAGFold. When sufficient MSA is available, AIDO.RAGFold achieves TM-scores comparable to AlphaFold2 and operates up to eight times faster. In scenarios where MSA is insufficient, our method significantly outperforms AlphaFold2 (ΔTM-score=0.379, 0.116 and 0.059 for 0, 5 and 10 MSA sequences as input). Additionally, we developed an MSA retriever for MSA searching from the UniClust30 database using hierarchical ID generation, which is 45 to 90 times faster than traditional methods, and is used to expand the MSA training set for AIDO.RAGPLM by 32%. Our findings suggest that AIDO.RAGPLM provides an efficient and accurate solution for protein structure prediction.
Peritraumatic C-reactive protein levels predict pain outcomes following traumatic stress exposure in a sex-dependent manner
Authors: McKibben Lauren A. , Layne Miranda N. , Albertorio-Sáez Liz Marie , Zhao Ying , Branham Erica M. , House Stacey L. , Beaudoin Francesca L. , An Xinming , Stevens Jennifer S. , Neylan Thomas C. , Clifford Gari D. , Germine Laura T. , Bollen Kenneth A. , Rauch Scott L. , Haran John P. , Storrow Alan B. , Lewandowski Christopher , Musey Paul I. , Hendry Phyllis L. , Sheikh Sophia , Jones Christopher W. , Punches Brittany E. , Swor Robert A. , Hudak Lauren A. , Pascual Jose L. , Seamon Mark J. , Datner Elizabeth M. , Peak David A. , Merchant Roland C. , Domeier Robert M. , Rathlev Niels K. , O’Neil Brian J. , Sanchez Leon D. , Bruce Steven E. , Sheridan John F. , Harte Steven E. , Kessler Ronald C. , Koenen Karestan C. , Ressler Kerry J. , McLean Samuel A. , Linnstaedt Sarah D. 
Published: December 2024

ABSTRACTBackgroundChronic pain following traumatic stress exposure (TSE) is common. Increasing evidence suggests inflammatory/immune mechanisms are induced by TSE, play a key role in the recovery process versus development of post-TSE chronic pain, and are sex specific. In this study, we tested the hypothesis that the inflammatory marker C-reactive protein (CRP) is associated with chronic pain after TSE in a sex-specific manner.MethodsWe utilized blood-plasma samples and pain questionnaire data from men (n=99) and (n=223) women enrolled inAURORA, a multi-site emergency department (ED)-based longitudinal study of TSE survivors. We measured CRP using Ella/ELISA from plasma samples collected in the ED (‘peritraumatic CRP’, n=322) and six months following TSE (n=322). Repeated measures mixed-effects models were used to assess the relationship between peritraumatic CRP and post-TSE chronic pain.ResultsPeritraumatic CRP levels significantly predicted post-TSE chronic pain, such that higher levels of CRP were associated with lower levels of pain over time following TSE, but only in men (men:β=-0.24,p=0.037; women:β=0.05,p=0.470). By six months, circulating CRP levels had decreased by more than half in men, but maintained similar levels in women (t(290)=1.926,p=0.055). More men with a decrease in CRP levels had decreasing pain over time versus women (men:83% women:65%; Z=2.21,p=0.027).ConclusionsIn men but not women, we found circulating peritraumatic CRP levels predict chronic pain outcomes following TSE and resolution of CRP levels in men over time might be associated with increased pain recovery. Further studies are needed to validate these results.SummaryPeritraumatic circulating CRP levels predicted pain recovery in men following TSE and decreases in CRP levels over time were greater in men compared to women.
Does the habitual dietary intake of adults in Bavaria, Germany, match dietary intake recommendations? – Results of the 3rdBavarian Food Consumption Survey (BVS III)
Authors: Rohm Florian , Wawro Nina , Gimpfl Sebastian , Ohlhaut Nadine , Senger Melanie , Röger Christine , Kussmann Martin , Gedrich Kurt , Linseisen Jakob 
Published: December 2024

1AbstractObjectiveMonitoring dietary habits is crucial for identifying shortcomings and delineating countermeasures. About 20 years after the last population-based surveys in Bavaria and Germany, dietary habits were assessed to describe the intake distributions and compare these with recommendations at food and nutrient level.MethodsThe 3rdBavarian Food Consumption Survey (BVS III) was designed as a diet survey representative of adults in Bavaria; from 2021 to 2023, repeated 24-hour diet recalls were collected by telephone using the software GloboDiet©. Food (sub-)group and nutrient intake data were modeled with the so-called NCI method, weighted for the deviation from the underlying population. Intake distributions in men and women were described as percentiles. These data were used to estimate the proportion of persons meeting dietary intake recommendations. In addition, food consumption data were compared with the results reported 20 years ago collected by the same methodology (2ndBavarian Food Consumption Survey, BVS II).ResultsUsing 24-hour diet recalls of 550 male and 698 female participants, we estimated intake distributions for food (sub-)groups and nutrients. A major proportion of the adult population does not meet the food-based dietary guidelines; this refers to a series of food groups, including fruit and vegetables, legumes, nuts, cereal products, and especially whole grain products, as well as fresh and processed meat. Regarding selected essential nutrients, a considerable proportion of the population was at higher risk of insufficiency from iron (women), zinc (men), and folic acid (both men and women), as already described in previous studies.ConclusionA major proportion of the adult Bavarian population does not meet the current food-based dietary guidelines. Compared to BVS II data, favorable changes refer to lower consumption of total meat (especially processed meat) and soft drinks, and an increased intake of vegetables. The conclusions based on the intake of selected essential nutrients hardly changed over time. From a public health perspective, the still low intake of vegetables, fruit, nuts, cereal products, and particularly of whole grain products, and associated higher risks of insufficient supply of several vitamins and minerals call for action for improvement.
Self-Assessment of amyotrophic lateral sclerosis functional rating scale on the patient’s smartphone proves to be non-inferior to clinic data capture
Authors: Steinfurth Laura , Grehl Torsten , Weyen Ute , Kettemann Dagmar , Steinbach Robert , Rödiger Annekathrin , Großkreutz Julian , Petri Susanne , Boentert Matthias , Weydt Patrick , Bernsen Sarah , Walter Bertram , Günther René , Lingor Paul , Koch Jan Christoph , Baum Petra , Weishaupt Jochen H. , Dorst Johannes , Koc Yasemin , Cordts Isabell , Vidovic Maximilian , Norden Jenny , Schumann Peggy , Körtvélyessy Péter , Spittel Susanne , Münch Christoph , Maier André , Meyer Thomas 
Published: December 2024

AbstractObjectiveTo investigate self-assessment of the amyotrophic lateral sclerosis functional rating scale–revised (ALSFRS-R) using the patient’s smartphone and to analyze non-inferiority to clinic assessment.MethodsIn an observational study, ALSFRS-R data being remotely collected on a mobile application (App-ALSFRS-R) were compared to ALSFRS-R captured during clinic visits (clinic-ALSFRS-R). ALS progression rate (ALSPR) – as calculated by the monthly decline of ALSFRS-R – and its intrasubject variability (ALSPR-ISV) between ratings were used to compare both cohorts. To investigate non-inferiority of App-ALSFRS-R data, a non-inferiority margin was determined.Results691 ALS patients using the ALS-App, and 1895 patients with clinic assessments were included. Clinical characteristics for the App-ALSFRS-R and clinic-ALSFRS-R cohorts were as follows: Mean age 60.45 (SD 10.43) and 63.69 (SD 11.30) years (p<0.001), disease duration 38.7 (SD 37.68) and 56.75 (SD 54.34) months (p<0.001) and ALSPR 0.72 and 0.59 (p<0.001), respectively. A paired sample analysis of ALSPR-ISV was applicable for 398 patients with clinic as well as app assessments and did not show a significant difference (IQR 0.12 [CI 0.11, 0.14] vs 0.12 [CI 0.11, 0.14], p=0.24; Coheńs d =0.06). CI of IQR for App-ALSFRS-R was below the predefined non-inferiority margin of 0.15 IQR, demonstrating non-inferiority.ConclusionsPatients using a mobile application for remote digital self-assessment of the ALSFRS-R revealed younger age, earlier disease course and faster ALS progression. The finding of non-inferiority of App-ALSFRS-R assessments underscores, that data collection using the ALS-App on the patient’s smartphone can serve as additional source of ALSFRS-R in ALS research and clinical practice.
Application of a general LLM-based classification system to retrieve information about oncological trials
Authors: Dennstädt Fabio , Windisch Paul , Filchenko Irina , Zink Johannes , Putora Paul Martin , Shaheen Ahmed , Gaio Roberto , Cihoric Nikola , Wosny Marie , Aeppli Stefanie , Schmerder Max , Shelan Mohamed , Hastings Janna 
Published: December 2024

ABSTRACTPurposeThe automated classification of clinical trials and medical literature is increasingly relevant, particularly in oncology, as the volume of publications and trial reports continues to expand. Large Language Models (LLMs) may provide new opportunities for automated diverse classification tasks. In this study, we developed a general-purpose text classification framework using LLMs and evaluated its performance on oncological trial classification tasks.Methods and MaterialsA general text classification framework with adaptable prompt, model and categories for the classification was developed. The framework was tested with four datasets comprising nine binary classification questions related to oncological trials. Evaluation was conducted using a locally hosted version of Mixtral-8x7B-Instruct v0.1 and three cloud-based LLMs: Mixtral-8x7B-Instruct v0.1, Llama3.1-70B-Instruct, and Qwen-2.5-72B.ResultsThe system consistently produced valid responses with the local Mixtral-8x7B-Instruct model and the Llama3.1-70B-Instruct model. It achieved a response validity rate of 99.70% and 99.88% for the cloud-based Mixtral and Qwen models, respectively. Across all models, the framework achieved an overall accuracy of >94%, precision of >92%, recall of >90%, and an F1-score of >92%. Question-specific accuracy ranged from 86.33% to 99.83% for the local Mixtral model, 85.49% to 99.83% for the cloud-based Mixtral model, 90.50% to 99.83% for the Llama3.1 model, and 77.13% to 99.83% for the Qwen model.ConclusionsThe LLM-based classification framework exhibits robust accuracy and adaptability across various oncological trial classification tasks. The findings highlight the potential of automated, LLM- driven trial classification systems, which may become increasingly used in oncology.
Integrating Clustering and Semantic Similarity for MAUDE Database Dimensionality Reduction
Authors: Hua Lei 
Published: December 2024

AbstractObjectiveTo develop and evaluate an automated methodology for dimensionality reduction of the FDA’s MAUDE database through schema matching and merging.MethodsWe conducted 96 trails integrating clustering algorithms with semantic similarity evaluations using the DeepSeek V2.5 API. This approach identified and merged semantically similar tables. Feature extraction was performed using Term Frequency-Inverse Document Frequency (TF-IDF) vectorization and Sentence Transformer embeddings. The methodology was assessed against manual groupings provided by domain experts using metrics such as Adjusted Rand Index (ARI), Normalized Mutual Information (NMI), precision, recall, and F1 score. Different similarity thresholds (0.7, 0.8, 0.9) were applied to evaluate their impact on table merging performance.ResultsThe integration of clustering with semantic similarity evaluations enhanced the F1 score from 0.51 (clustering alone) to 1.00, utilizing fewer than 1,425 API similarity evaluations. Consequently, the number of tables was compressed from 113 to 13–16 table groups, a reduction of 86% to 89%. In addition, the application of clustering algorithms decreased the number of table pair comparisons by 77% to 83%. Sentence Transformer embeddings outperformed TF-IDF vectorization in clustering performance, with F1 scores increasing from a range of approximately 0.51–0.87 to 0.51–0.95 in clustering-only scenarios. DeepSeek V2.5 demonstrated the potential to match and quantify subtle semantic differences across various similarity thresholds, maintaining high merging accuracy with F1 scores reaching up to 1.00.ConclusionThe proposed automated dimensionality reduction methodology effectively enhances data quality and analysis efficiency within the MAUDE database. By reducing the number of tables to manageable groups, optimizing context lengths, and leveraging DeepSeek V2.5’s semantic matching capabilities, the framework streamlines data processing and ensures compatibility with advanced analytical tools such as Large Language Models (LLMs). This makes the methodology applicable across various industries, facilitating more efficient and accurate data analysis workflows
Conserved interhemispheric morphogenesis in amniotes preceded the evolution of the corpus callosum
Authors: Noji Ryota , Kaneko Mari , Abe Takaya , Kiyonari Hiroshi , Nishikawa Yukihiro , Kumamoto Takuma , Gotoh Hitoshi , Ohtaka-Maruyama Chiaki , Ono Katsuhiko , Yoshizawa Tatsuya , Nomura Tadashi 
Published: December 2024

SUMMARYThe corpus callosum (CC) is the large axon bundle connecting the telencephalic hemispheres. The CC is formed exclusively in placental mammals, and the lack of comparable structures in other amniotes obscures the evolutionary origin of the CC. We here demonstrate that interhemispheric remodeling, a prior developmental step for CC formation, is highly conserved in non-mammalian amniotes, such as reptiles and birds. In these animal groups, the spatiotemporal dynamics of interhemispheric remodeling are tightly connected with distinct commissural formations. We observed a high degree of similarity between the mammalian CC and reptilian rostral pallial commissure, (RPC) and significant modifications in the avian pallial projection. Furthermore, we determined that Satb2 plays crucial roles in interhemispheric remodeling, which is associated with proper formation of both the CC and RPC in mice and geckoes, via the use of CRISPR-mediated gene-targeting. Our findings suggest that developmental mechanisms for midline remodeling were already present in the common ancestor of amniotes, which contributed to the evolution of eutherian-specific CC formation.
Mapping Cryptic Phosphorylation Sites in the Human Proteome
Authors: Gasparotto Dino , Zanon Annarita , Bonaldo Valerio , Marchiori Elisa , Casagranda Massimo , Di Domenico Erika , Copat Laura , Asquini Tommaso Fortunato , Rigoli Marta , Feltrin Sirio Vittorio , Lorenzo Nuria Lopez , Lolli Graziano , Pennuto Maria , Requena Jesùs R. , Stabelli Omar Rota , Minervini Giovanni , Micheletti Cristian , Spagnolli Giovanni , Faccioli Pietro , Biasini Emiliano 
Published: December 2024

AbstractAdvances in computational and experimental methods have revealed the existence of transient, non-native protein folding intermediates that could play roles in disparate biological processes, from regulation of protein expression to disease-relevant misfolding mechanisms. Here, we tested the possibility that specific post-translational modifications may involve residues exposed during the folding process by assessing the solvent accessibility of 87,138 post-translationally modified amino acids in the human proteome. Unexpectedly, we found that one-third of phosphorylated proteins present at least one phosphosite completely buried within the protein’s inner core. Computational and experimental analyses suggest that these cryptic phosphosites may become exposed during the folding process, where their modification could destabilize native structures and trigger protein degradation. Phylogenetic investigation also reveals that cryptic phosphosites are more conserved than surface-exposed phosphorylated residues. Finally, cross-referencing with cancer mutation databases suggests that phosphomimetic mutations in cryptic phosphosites can increase tumor fitness by inactivating specific onco-suppressors. These findings define a novel role for co-translational phosphorylation in shaping protein folding and expression, laying the groundwork for exploring the implications of cryptic phosphosites in health and disease.
DNA tensiometer reveals catch-bond detachment kinetics of kinesin-1, -2 and -3
Authors: Noell Crystal R. , Ma Tzu-Chen , Jiang Rui , McKinley Scott A. , Hancock William O. 
Published: December 2024

AbstractBidirectional cargo transport by kinesin and dynein is essential for cell viability and defects are linked to neurodegenerative diseases. The competition between motors is described as a tug-of-war, and computational modeling suggests that the load-dependent off-rate is the strongest determinant of which motor ‘wins’. Optical tweezer experiments find that the load-dependent detachment sensitivity of transport kinesins is kinesin-3 > kinesin-2 > kinesin-1. However, when kinesin-dynein pairs were analyzed in vitro, all three kinesin families competed nearly equally well against dynein. One possible explanation is that vertical forces inherent to the large trapping beads enhance motor detachment. Because intracellular cargo range from ∼30 nm to > 1000 nm, vertical forces in vivo are expected to range from near zero to larger than the horizontal forces of transport. To investigate detachment rates against loads oriented parallel to the microtubule, we created a DNA tensiometer comprising a DNA entropic spring that is attached to the microtubule on one end and a kinesin motor on the other. Surprisingly, kinesin dissociation rates at stall were slower than detachment rates during unloaded runs, a property termed a catch-bond. A plausible mechanism, supported by stochastic simulations, is that the strong-to-weak transition in the kinesin cycle is slowed with load. We also find evidence that the long run lengths of kinesin-3 (KIF1A) result from the concatenation of multiple short runs connected by diffusive episodes. The finding that kinesins form catch-bonds under horizontal loads necessitates a reevaluation of the role of cargo geometry in kinesin-dynein bidirectional transport.Significance StatementKinesin and dynein motor proteins transport intracellular cargo bidirectionally along microtubule tracks, with the speed and directionality of transport involving a tug-of-war between the motor teams. We created a ‘DNA tensiometer’ that uses DNA as a spring to measure kinesin performance against loads oriented parallel to the microtubule. We find that dissociation rates paradoxically slow down with imposed loads. Dyneins are also thought to possess this ‘catch-bond’ behavior, meaning that both motors will hang on tightly during a tug-of-war. Previous work showed that combined vertical and horizontal loads cause faster detachment rates under load. Hence, we conclude that the effectiveness of kinesins during bidirectional transport depends strongly on the geometry of their cargo.