bluuebunny/crossref_metadata_2025_split huggingface dataset:
Simplifying species interaction matrices by grouping: optimal groupings differ between effects and responses
Authors: Brown Christopher R. P. , Stouffer Daniel B. 
Published: January 2025

AbstractMost dynamic models of ecological communities require many parameters, making them expensive to fit to experimental or observational data. To reduce the number of parameters, species are often divided into groupsa priori, using phylogenetic or functional groups, and species within a group are assumed to behave identically. Here, we assess the validity of such grouping by deriving the optimal groupingsa posterioribased on the fit of the Beverton–Holt model to experimental data from six species ofDrosophilacompeting in laboratory conditions. We find evidence that grouping can indeed improve the parsimony of species interaction models, but we also observe that there is no single optimal grouping. Further, those groupings that did prove beneficial could not have been easily predicted from available species attributes, calling into question the prevailing method ofa priorispecies grouping. Lastly, we find that species did not group equivalently in their competitive effect and in their response to competition, invalidating a key assumption often made implicitly when defining species groupings. Our study suggests the need for a different, more data-informed, approach to grouping in species interaction models.
The Distribution of Elastin and Collagen Underpinning the Smart Properties of the Interosseous Membrane
Authors: Anastopolous Sotiria , Knothe Tate Melissa L. 
Published: January 2025

AbstractThe interosseous membrane (IOM), a ligament-like structure spanning the radius and ulna, reduces strain in the ulna and structurally stiffens the radio-ulnar complex of the forearm. Using two-photon and second-harmonic-imaging we measured collagen and elastin signal intensity to test the hypothesis that their spatial distributions correspond to predominant loading patterns in the IOM. Distinct spatial gradients in collagen and elastin, as well as cruciate ligament-like architectures, were observed at the submicron and the micron to mesoscopic length scales. Quantitative analysis revealed anisotropies in the elastin-collagen composite comprising the IOM, with elastin 4-6 times higher than collagen concentrations at radius/ulna - IOM interfaces, and organized in the tensile loading direction,i.e. along the major Centroidal Axis, of the IOM. Hence, the IOM exhibits a composite structure comprising elastin and collagen, with spatial distribution of elastin higher than collagen at bone-IOM interfaces and decreasing from the interface with the ulna to that of the radius. These increased concentrations of elastin at interfaces are expected to confer elasticity (spring function). In contrast, peaks in collagen concentrations represent collagens’ organization into fibers, parallel to the length of the IOM, bridging the radius and ulna, and conferring toughness and damping function to the IOM and forearm construct. Mapping the cross-scale elastin and collagen composition of the IOM gives unprecedented insight into its emergent properties and associated mechanical function, an understanding of which may guide future surgical treatments, implant and medical textile design and manufacture, as well as physical therapy protocols to promote healing.
Risk Prediction of RNA Off-Targets of CRISPR Base Editors in Tissue-Specific Transcriptomes Using Language Models
Authors: Nakamae Kazuki , Suzuki Takayuki , Yonezawa Sora , Yamamoto Kentaro , Kakuzaki Taro , Ono Hiromasa , Naito Yuki , Bono Hidemasa 
Published: January 2025

AbstractBase-editing technologies, particularly cytosine base editors (CBEs), allow precise gene modification without introducing double-strand breaks; however, unintended RNA off-target effects remain a critical concern and are under-studied. To address this gap, we developed PiCTURE, a standardized computational pipeline for detecting and quantifying transcriptome-wide CBE-induced RNA off-target events. PiCTURE identifies both canonical ACW (W = A or T/U) motif-dependent and non-canonical RNA off-targets, revealing a broader WCW motif that underlies many unanticipated edits. Additionally, we developed two machine learning models based on the DNABERT-2 language model, termed STL and SNL, which outperformed motif-only approaches in terms of accuracy, precision, recall, and F1 score. To demonstrate the practical application of our predictive model for CBE-induced RNA off-target risk, we integrated PiCTURE outputs with the PROTECTiO pipeline and estimated RNA off-target risk for each transcript showing tissue-specific expression. The analysis revealed differences among tissues: while the brain and ovaries exhibited relatively low off-target burden, the colon and lungs displayed relatively high risks. Our study provides a comprehensive frame-work for RNA off-target profiling, emphasizing the importance of advanced machine learning-based classifiers in CBE safety evaluations and offering valuable insights for the development of safer genome-editing therapies.
Understanding Telomere Biology in Hematopoietic Cell Transplantation: A Dynamical Systems Perspective
Authors: Toor Amir A. , Horton Morgan , Khalid Haniya , Krieger Elizabeth , Lai Tsung-Po , Spellman Stephen R. , Levine John E. , Saber Wael , Aviv Abraham , Stewart Valerie , Gadalla Shahinaz M 
Published: January 2025

AbstractBackground.T cell proliferation and repertoire reconstitution is a hallmark of successful hematopoietic cell transplantation (HCT). This process may be modeled as a dynamical system and in such a system, precise telomere length (TL) measurement may reflect the proliferative capacity of donor T cells. TL for different chromosomes span a few orders of magnitude, and different T cell clones will display variable TL; these differences across the population are not represented when examining average TL. This study aims to develop a method that integrates the entire spectrum of TL observed within a sample to better understand the influence on clinical outcomes following HCT.Methods.To better reflect the entire span of TL , we used data generated using the TeLSA PCR technique that provided discrete measurments of individual telomeres for each DNA sample for 72 stem cell transplant (SCT) donor-recipient pairs. Donor and recipient TeSLA TL measurements was performed on samples taken before and 90 days post HCT, respectively. Set correspondence mathematical techniques and area under the curve (AUC) calculations were used to measured donor-recipient TL differences (delta-TL) incorporating the full distribution of measured TL from each sample.Results.Telomere band lengths ranged from 350 basepairs (BP) to 16.7 kilobases with a logarithmically declining distribution in all samples when arrayed in a descending order. Set correspondence methods yielded TL averages which were highly correlated with AUC calculations (r >0.9, p<0.001 for all) TheAUC delta-TLmethod predicted patient overall survival (P-log rank <0.0001). HCT recipients with intermediate degrees of telomere attrition (25th-75thpercentile) post-HCT experienced the best outcomes (2 years overall survival; OS=92%), whilst donors with the least (<25thpercentile; 2 years OS=33%; adjusted HRvs.intermediate shortening=9.3, p=0.001) and the greatest (>75thpercentile; 2 years OS=59%; adjusted HR=6.0, p=0.01) shortening had worse outcomes. By contrast, using the traditional method based on donor-recipient difference in TeSLA mean telomere length did not demonstrate survival association in this small sample set (p log-rank=0.95).Conclusion.The findings described herein suggest that the degree of donor telomere attrition may reflect T cell proliferation and alloreactivity following transplant. Accounting for the entire span of telomere lengths, could better identify post-transplant risk groups.
CAR T cell engineering impacts antigen-independent activation and co-inhibition
Authors: Stücheli Simon , Schultheiß Christoph , Schmidt-Barbo Paul , Zingg Andreas , Franz Natascha , Adamo Sarah , Fischer Claudia , Läubli Heinz , Binder Mascha 
Published: January 2025

AbstractViral vectors have successfully modified T cells to express chimeric antigen receptors (CAR), leading to clinical approvals. However, their high cost and regulatory challenges hinder rapid and broad clinical translation. Here, we demonstrate that our lentivirally (LV) manufactured R110-CAR T cells, targeting a leukemia neoepitope, can also be engineered using non-viral Sleeping Beauty (SB) transposition with minimal-sized DNA vectors. Flow cytometry and single-cell sequencing was used to compare the two production modes using healthy donor and CLL patient-derived T cells and a CD19-CAR T cell control. SB products were shifted towards CD8+subsets with expression of activation/co-inhibition markers (CD69, LAG-3, TIM-3) despite their naïve-like phenotype and lack of antigenic challenge. The CAR binding moiety modulated these patterns with R110-CAR T cells showing more aberrant phenotypes. Moreover, SB engineering resulted in inflammatory signatures along with RIG-I-like and TOLL-like nucleotide sensing potentially resulting from the transfection procedure. Patient-derived products showed significantly fewer CAR-expressing cells, reduced proliferation clusters, and lower T cell diversity, particularly with SB manufacturing, pointing at potential challenges with this method when engineering CLL T cells. Together, our data suggest that the engineering mode may substantially influence T cell properties and that these are further modulated by the CAR binding moiety and the type of T cell donor.
Bulk segregant analysis reveals genomic regions associated with imidacloprid resistance in the Colorado potato beetle
Authors: Edison Alitha , Narimanov Nijat , Duchen Pablo , Xu Shuqing 
Published: January 2025

AbstractGiven the increased accessibility of genomic techniques, the speed of evolution of resistance, and the large number of genes involved in resistance, investigations into the genetic basis of resistance in more species are pertinent. Despite being an important agricultural pest, only a limited number of genetic mapping studies based on crossed populations have been performed to identify genes involved in resistance in the Colorado potato beetle (Leptinotarsa decemlineata, CPB). Here, we performed bulk segregant analysis on a mapping population generated by creating advanced intercross lines from five European strains of CPB. We identified eight peaks across chromosomes 1,8,10, and 16 involved in resistance against the neonicotinoid, imidacloprid. We identified 337 genes within these peaks and shortlisted three candidates based on gene expression and functional annotation. Among the three candidates thus identified, we found that an ABC transporter and a galactosyl transferase are expressed in relatively higher amounts in a relatively more susceptible strain than in a resistant strain. We attempted to validate the role of these two genes in insecticide resistance by knocking them down in a resistant strain using RNA interference (RNAi) and performing toxicity experiments. Surprisingly, our results showed that the activation of RNAi machinery reduced imidacloprid resistance and the effect is not specific to the tested candidate genes, which raised a concern on the suitability of using RNAi for validating insecticide resistance mechanisms in CPB.
STAT3 phosphorylation in the rheumatoid arthritis immunological synapse
Authors: Kotzer Hila Novak , Capera Jesusa , Jainarayanan Ashwin , Mayya Viveka , Zanin-Zhorov Alexandra , Valvo Salvatore , Macdonald Joanne , Taylor Peter C. , Dustin Michael L 
Published: January 2025

ABSTRACTTargeting the JAK/STAT pathway has emerged as a key therapeutic strategy for managing Rheumatoid Arthritis (RA). JAK inhibitors suppress cytokine-mediated signaling, including the critical IL-6/STAT3 axis, thereby effectively targeting different aspects of the pathological process. However, despite their clinical efficacy, a subset of RA patients remains refractory to JAK inhibition, underscoring the need for alternative approaches. Here, we identify a novel JAK-independent mechanism of STAT3 activation, which is triggered by the formation of the immunological synapse (IS) in naïve CD4+ T cells. Our data demonstrates that Lck mediates the TCR-dependent phosphorylation of STAT3 at the IS, highlighting this pathway as a previously unrecognized hallmark of early T cell activation. Furthermore, we show that the synaptic Lck/TCR-STAT3 pathway is compromised in RA. This discovery highlights a new therapeutic target for RA beyond JAK inhibitors, offering potential avenues for treating patients resistant to current therapies.
A Scoping Review of Artificial Intelligence Applications in Clinical Trial Risk Assessment
Authors: Teodoro Douglas , Naderi Nona , Yazdani Anthony , Zhang Boya , Bornet Alban 
Published: January 2025

AbstractArtificial intelligence (AI) is increasingly applied to clinical trial risk assessment, aiming to improve safety and efficiency. This scoping review analyzes 142 studies published between 2013 and 2024, focusing on safety (n=55), efficacy (n=46), and operational (n=45) risk prediction. AI techniques, including traditional machine learning, deep learning (e.g., graph neural networks, transformers), and causal machine learning, are used for tasks like adverse drug event prediction, treatment effect estimation, and phase transition prediction. These methods utilize diverse data sources, from molecular structures and clinical trial protocols to patient data and scientific publications. Recently, large language models (LLMs) have seen a surge in applications, representing over 20% of studies in 2023. While some models achieve high performance (AUROC up to 96%), challenges remain, including selection bias, limited prospective studies, and data quality issues. Despite these limitations, AI-based risk assessment holds substantial promise for transforming clinical trials, particularly through improved risk-based monitoring frameworks.
Optimizing stress in breaking bad news: a randomized controlled trial on the psychophysiological effects of stress arousal reappraisal and worked-example interventions among medical students
Authors: Bosshard Michel , Guttormsen Sissel , Nater Urs Markus , Schmitz Felix , Gomez Patrick , Berendonk Christoph 
Published: January 2025

AbstractBreaking bad news (BBN) is among the most distressing communication tasks in the medical field, wherein physicians disclose serious diagnoses to their patients. Under stress, physicians may resort to maladaptive communication behaviors, potentially affecting patient’s health in the long-term. Therefore, it is essential to support medical professionals in effectively managing their stress responses early in their careers. Using the biopsychosocial model of challenge and threat as theoretical framework, we employed a 2 x 2 study design to examine the effects of stress arousal reappraisal (SAR; i.e., reinterpretation of bodily changes as functional coping resources) and worked example (WE; i.e., step-by-step demonstration of how to BBN) interventions on demand and resource appraisals and cardiovascular responses of 229 medical students engaged in simulated BBN encounters. Participants who prepared with WE reported more coping resources relative to demands after the BBN encounter than participants not preparing with WE. Participants receiving SAR instructions exhibited improved cardiovascular responses during the BBN task, indicated by increased cardiac output and decreased total peripheral resistance, than participants not receiving SAR instructions. These findings align with the notion that both interventions facilitate a shift from a threat to a challenge state, supporting their potential for integration into BBN training.
Evaluation of Physico-chemical parameters of selected Clotrimazole pessaries from pharmaceutical importers and Accredited Drug Dispensing Outlets in Dar es Salaam, Tanzania
Authors: Brashi Benedict , Mlugu Eulambius M. , Kaale Eliangiringa A. 
Published: January 2025

AbstractIntroductionQuality assured medicines make an important contribution to a global reduction in morbidity and mortality. Tanzania depends on approximately 70% of imported medicines, some are manufactured in countries with different climatic zones for stabilities. The prevalence of vaginal candidiasis amongst women seeking primary health care for genital infections in Dar es Salaam is 45%. Clotrimazole pessaries is the first-line drug for the treatment vaginal candidiasis (VC). However, their reports show the existence of poor quality clotrimazole in the market as well as microbial resistance.Study objectivesThis study aimed to assess the quality of clotrimazole pessaries among pharmaceutical importers and Accredited Drug Dispensing Outlets (ADDOs) outlets in Dar es Salaam.MethodsThe experimental study laboratory-based was conducted between October 2021 to July 2022. A total of 72 samples, 5 from pharmaceutical importers and 67 from ADDO outlets, were collected by mystery clients through the convenient method. Assay for the content of active ingredients and disintegration time were performed as described in the British Pharmacopoeia (BP).ResultsAll samples passed the physical inspection and disintegration test. Among the collected samples, two of 72(2.78%) failed the assay test. The assay for an active pharmaceutical ingredient for samples from importers was significantly greater than that from ADDO outlets.ConclusionStorage conditions may affect the drug content of clotrimazole pessaries. A few samples from ADDO without fan failed to meet the assay test as per British Pharmacopeia specification.RecommendationsThe Pharmacy Regulation 2019, for Accredited Drugs, Dispensing Outlets, Standards, and Ethics for Dispensation of Medicines to be revitalized to include a specification on ADDO outlets regarding the storage conditions to align with the pharmaceutical manufacturer’s recommendations. Also, regulatory inspections should be emphasized by the Regulatory Authority including Pharmacy Council and TMDA so as ensure the registered pharmaceutical outlets continue complying with standards required like the presence of air conditions so that the medicines continue to be of desired quality throughout their shelf life.
Isolation and characterization of synaptic structures from human neural organoids
Authors: Øhlenschlæger Marie S. , Criscuolo Lucrezia , Jensen Pia , Sánchez Daniel J. Lloyd-Davies , Sutcliffe Magdalena , Bhosale Santosh , Bogetofte Helle , Tahir Muhammad , Jakobsen Lene A. , Pihl Maria , Brewer Jonathan , Schwämmle Veit , Poulsen Frantz R. , Freude Kristine , Lancaster Madeline A. , Robinson Phillip J. , Larsen Martin R. 
Published: January 2025

AbstractSynapses are essential for neuronal function and are central to numerous neurological disorders including developmental and neurodegenerative diseases. Synapses structurally constitute a very small proportion of a neuron, and their protein content is difficult to study using whole tissue preparations. Especially studying synapses on the functional level is challenging. To overcome this limitation, synapses can be captured as synaptosomes generated through enrichment of isolated nerve terminals. Such synaptosomes have a re-sealed plasma membrane and can regenerate their membrane potential and perform physiological function, for example neurotransmitter release.Synaptosomes are traditionally enriched from rodent or postmortem human brain tissue, but rodent models lack human-specific synaptic features, and the functionality of synaptosomes from postmortem tissues is limited by the postmortem interval and often only show disease endpoints. Furthermore, due to ethical issues and availability, only a few studies have been conducted on human samples. However, neural organoids (NOs) have emerged as a possible new source for isolation of intact and live human nerve terminals to study human-specific aspects of synaptic transmission. Further, the enrichment of synaptosomes is usually performed using density gradient centrifugation, which requires a lot of starting material. In the present study we developed a method for the enrichment of synaptic structures from human NOs applying a differential centrifugation protocol. We then used mass spectrometry-based quantitative proteomics to document the enrichment of synapse and growth cone specific proteins, and quantitative phosphoproteomics upon KCl stimulation to demonstrate viability and physiological function of the derived synaptic structures.
Mapping brain function underlying naturalistic motor observation and imitation using high-density diffuse optical tomography
Authors: Yang Dalin , George Tessa G. , Sobolewski Chloe M. , McMorrow Sophia R. , Pacheco Carolina , King Kelsey T. , Rochowiak Rebecca , Daniels-Day Evan , Park Sungmin , Speh Emma , Lidstone Daniel , Santra Romila , Crocetti Deana , Nebel Mary Beth , Tuncgenc Bahar , Vidal Rene , Marrus Natasha M. , Mostofsky Stewart H. , Eggebrecht Adam T. 
Published: January 2025

AbstractBackgroundWhile autism spectrum disorder (ASD) is defined by deficits in social communication with restricted interests and repetitive behaviors, autistic individuals often show early impairments in motor imitation that persist through childhood and into adulthood. High-density diffuse optical tomography (HD-DOT) overcomes logistical challenges of functional magnetic resonance imaging (fMRI) to provide an open scanning environment conducive to neuroimaging during naturalistic motor imitation. Additionally, the mirror neuron system (MNS) is crucial for understanding and imitating actions, and its dysfunction is hypothesized to underlie key ASD features.ObjectiveWe aim to investigate brain function underlying motor observation and motor imitation in adult autistic and non-autistic individuals (NAI). We hypothesize that HD-DOT will reveal greater MNS activity during motor imitation than motor observation, and that MNS activity will exhibit a negative correlation with autistic traits.MethodsWe imaged brain function using HD-DOT in N=100 participants as they passively observed videos of an actor completing sequences of meaningless arm movements. Additionally, while being simultaneously recorded with both HD-DOT and Kinect 3D cameras for computer-vision-based assessment of motor imitation (CAMI), participants imitated different videos of an actor completing similar arm movements. Responses to the tasks were estimated using general linear models, and multiple regression was used to investigate brain-behavior associations with autistic traits, using the Social Responsiveness Scale, and imitation fidelity as measured with CAMI.ResultsBoth motor observation and imitation tasks elicited significant activations in visual, temporal, and MNS areas, with imitation showing stronger activation in motor regions. Notably, MNS regions exhibited greater activation during observation than imitation. Additionally, activity during observation in the right parietal lobe correlated with autistic traits assessed with the SRS.ConclusionsOur findings provide robust evidence of shared and task-specific neural mechanisms underlying motor observation and imitation, emphasizing the differential engagement of MNS regions during motor observation and imitation.