bluuebunny/crossref_metadata_2025_split huggingface dataset:
Persistent Mullerian duct syndrome in dogs – a new insight into organization ofAMHandAMHR2genes
Authors: Krzeminska Paulina 
Published: December 2024

ABSTRACTPersistent Müllerian Duct Syndrome (PMDS) is a rare congenital disorder in males, characterized by the presence of Müllerian duct derivatives despite normal testes and external genitalia. This condition is typically linked to a dysfunction in the anti-Müllerian hormone (AMH) or its receptor (AMHR2), both of which are critical for the regression of the Müllerian ducts. In dogs, PMDS is particularly frequent in the Miniature Schnauzer breed, although cases have also been reported in other breeds, such as the Yorkshire Terrier. To date, a single causative variant has been identified in theAMHR2gene, but only in Miniature Schnauzers. No deleterious variants have been found in theAMHgene; however, with the exception of one report, most studies have not sequenced the entire exon 5.This study provides novel insights into the genomic organization of canineAMHandAMHR2genes through bioinformatics and in silico analyses of previously reported whole-genome sequencing (WGS) data from a Yorkshire Terrier affected by PMDS. The results indicate that current canine genome assemblies (ROS_Cfam_1.0; CanFam4, and CanFam6) contain a complete reference sequence for theAMHgene, unlike the earlier CanFam3.1 genome. However, next-generation sequencing technologies (WGS and RNA-seq) face challenges due to technical limitations in analyzing GC-rich repetitive elements present in exon 5 of canineAMHgene. In contrast, the genomic structure of theAMHR2gene remains inaccurately represented in the current ROS_Cfam_1.0 genome (eight instead of eleven exons), while both CanFam4 and CanFam6 contain additional and unknown nucleotide/amino acid sequences. The CanFam3.1 genome assembly still provides the most accurate annotation for canineAMHR2gene.Based on these findings, re-sequencing of theAMHgene in previously reported dogs affected by PMDS using the methodology proposed in recent literature is recommended. Further attention should be given to comparative analyses to assess whether the dog’s genome contains accurate information about genes or proteins that correspond to human orthologs.
AlphaPulldown2 – A General Pipeline for High-Throughput Structural Modeling
Authors: Molodenskiy Dmitry , Maurer Valentin J. , Yu Dingquan , Chojnowski Grzegorz , Bienert Stefan , Tauriello Gerardo , Gilep Konstantin , Schwede Torsten , Kosinski Jan 
Published: December 2024

AbstractAlphaPulldown2 streamlines protein structural modeling by automating workflows, improving code adaptability, and optimizing data management for large-scale applications. It introduces an automated Snakemake pipeline, compressed data storage, support for additional modeling backends like UniFold and AlphaLink2, and a range of other improvements. These upgrades make AlphaPulldown2 a versatile platform for predicting both binary interactions and complex multi-unit assemblies.AvailabilityAlphaPulldown2 is freely available athttps://github.com/KosinskiLab/AlphaPulldown.
Large-scale informative priors to better predict the local occurrence rate of a rare tree-related microhabitat
Authors: Cottais Pierre , Courbaud Benoît , Larrieu Laurent , Gouix Nicolas , Laroche Fabien 
Published: December 2024

AbstractEcological processes associated to rare events are hard to estimate from individual empirical studies. A typical example in forest ecology is the formation of tree-related microhabitats (TreMs) on trees. TreMs are key features for forest biodiversity, and their accumulation rate is a key information to design integrative management strategies. Many types of TreMs are associated to large old trees and show slow ontogenical processes. The rarity of such TreMs (particularly in intensively managed forests) hinder the estimation of their occurrence rate along tree growth. Several meta-analyses accumulated data on TreMs at continental (e.g. european) scale. However, using data accumulated at these large, heterogeneous scales to orientate management wihtin a specific site remains challenging. Here, we used a large-scale meta-analysis on TreMs occurrence rate along tree growth to build informative priors for a model of basal rot-hole occurrence on oaks within the Grésigne forest, France. We found that calibrating a model without the prior information (i.e. using only Grésigne oak trees) did not reveal any increase of occurrence with tree diameter. Estimation was hindered by confounding effects of plot and tree diameter induced by the local plot-based sampling strategy. Informative priors overcame this confounding effect, restored a positive relationship between diameter and basal rot-hole occurrence but raised the question of whether it introduced biases. A separate validation experiment suggested that it did not. The model with informative priors revealed that the high recruitment of basal rot-holes in Grésigne may be a temporary management effect in stands undergoing conversion from coppice-with-standards to high forest through sprout thinning, which will lead to conservation issues for cavicolous saproxylic species when all conversions are complete. Because using informative priors was simple and beneficial in our study, it should be further explored in other local applied contexts to orientate forest management.
A novelPGRL1paralog refined the control of photoprotection in grasses and facilitated cell specialisation in C4photosynthesis
Authors: Nix Samuel J. , Morton Craig J. , Furbank Robert T. , Ermakova Maria 
Published: December 2024

AbstractOne of the major events in plant history is the emergence of grasses (Poaceae), which colonised previously uninhabitable open land areas. Some grasses later evolved C4photosynthesis—operating between mesophyll and bundle sheath cells—becoming the most productive and resilient plants on Earth. We investigated whether a key regulator of photoprotection PGR5-LIKE PHOTOSYNTHETIC PHENOTYPE 1 (PGRL1), essential for survival of plants under fluctuating light, facilitated the adaptation of grasses to the open environments. We found that, in addition toPGRL1αpresent in all photosynthetic organisms, grasses evolved a new paralog,PGRL1β. AlphaFold3 modelling of predicted PGRL1 dimers suggests that the lumenal regions of PGRL1α monomers are linked by specific hydrogen bonds whereas PGRL1β’s lumenal regions show primarily hydrophobic interactions. These differences likely result in distinct modes of regulation of photoprotection offered by the two paralogs which is supported by predominant expression ofPGRL1αin mesophyll cells andPGRL1βin bundle sheath cells of NADP-ME C4grasses maize, sorghum, andSetaria viridis.We propose that the mixed PGRL1α/β system enabled a better balancing between Photosystem I protection and Photosystem II activity depending on environmental conditions. Therefore, the emergence of PGRL1β contributed to the ecological dominance of grasses and the superior efficiency of NADP-ME C4photosynthesis.
Optimized Protein–Excipient Interactions in the Martini 3 Force Field
Authors: Prass Tobias M. , Lindorff-Larsen Kresten , Garidel Patrick , Blech Michaela , Schäfer Lars V. 
Published: December 2024

AbstractThe high doses of drugs required for biotherapeutics, such as monoclonal antibodies (mAbs), and the small volumes that can be administered to patients by subcutaneous injections pose challenges due to high concentration formulations. The addition of excipients, such as arginine and glutamate, to high concentration protein formulations can increase solubility and reduce the tendency of protein particle formation. Molecular dynamics (MD) simulations can provide microscopic insights into the mode of action of excipients in mAb formulations but require large system sizes and long time scales that are currently beyond reach at the fully atomistic level. Computationally efficient coarse-grained models such as the Martini 3 force field can tackle this challenge but require careful parametrization, testing, and validation. This study extends the popular Martini 3 force field towards realistic protein–excipient interactions of arginine and glutamate excipients, using the Fab domains of the therapeutic mAbs trastuzumab and omalizumab as model systems. A novel all-atom to coarse-grained mapping of the amino acid excipients is introduced, which explicitly captures the zwitterionic character of the backbone. The Fab–excipient interactions of arginine and glutamate are characterized concerning molecular contacts with the Fabs at the single-residue level. The Martini 3 simulations are compared with results from all-atom simulations as a reference. Our findings reveal an overestimation of Fab–excipient contacts with the default interaction parameters of Martini 3, suggesting a too strong attraction between protein residues and excipients. Therefore, we reparametrized the protein–excipient interaction parameters in Martini 3 against all-atom simulations. The excipient interactions obtained with the new Martini 3 mapping and Lennard-Jones (LJ) interaction parameters, coined Martini 3-exc, agree closely with the all-atom reference data. This work presents an improved parameter set for mAb-arginine and mAb-glutamate interactions in the Martini 3 coarse-grained force field, a key step towards large-scale coarse-grained MD simulations of high-concentration mAb formulations and the stabilizing effects of excipients.
Effect of MisMatch Repair Deficiency on metastasis occurrence modelized in a syngeneic mouse model
Authors: Laplante Pierre , Rosa Reginaldo , Nebot-Bral Laetitia , Goulas Jordane , Nikolaev Sergey , Silvin Aymeric , Kannouche Patricia L 
Published: December 2024

AbstractMismatch repair deficiency leads to high mutation rates and microsatellite instability (MSI-H), associated with immune infiltration and responsiveness to immunotherapies. In early stages, MSI-H tumors generally have a better prognosis and lower metastatic potential than microsatellite-stable (MSS) tumors, especially in colorectal cancer. However, in advanced stages, MSI-H tumors lose this survival advantage for reasons that remain unclear. We developed a syngeneic mouse model of MSI cancer by knocking out the MMR geneMsh2in the metastatic 4T1 breast cancer cell line. This model mirrored genomic features of MSI-H cancers and showed reduction in metastatic incidence compared to their MSS counterparts. In MSI-H tumors, we observed an enrichment of immune gene-signatures that negatively correlated with metastasis incidence. Importantly, a hybrid epithelial-mesenchymal signature, related to aggressiveness was detected only in metastatic MSI-H tumors which may explain the worse outcomes after recurrence of MSI tumors compared to MSS. Interestingly, we identified immature myeloid cells at primary and metastatic sites in MSI-H tumor-bearing mice, suggesting that MMR deficiency elicits specific immune responses beyond T-cell activation.SignificanceA novel syngeneic mouse model of MSI cancer demonstrates that the immune system regulates MSI cancer cell dissemination, offering an important tool to model advanced stages of human MSI-driven disease.
Mavacamten facilitates myosin head ON-to-OFF transitions and shortens thin filament length in relaxed skeletal muscle
Authors: Kuehn Michel N. , Engels Nichlas M. , Nissen Devin L. , Freundt Johanna K. , Ma Weikang , Irving Thomas C. , Linke Wolfgang A. , Hessel Anthony L. 
Published: December 2024

AbstractThe first-in-its-class cardiac drug mavacamten reduces the proportion of so-called ON-state myosin heads in relaxed sarcomeres, altering contraction performance. However, mavacamten is not completely specific to cardiac myosin and can also affect skeletal muscle myosin, an important consideration since mavacamten is administered orally and so will also be present in skeletal tissue. Here, we studied the effect of mavacamten on skeletal muscle structure using small-angle X-ray diffraction. Mavacamten treatment reduced the proportion of ON myosin heads but did not eliminate the molecular underpinnings of length-dependent activation, demonstrating similar effects to those observed in cardiac muscle. These findings provide valuable insights for the potential use of mavacamten as a tool to study muscle contraction across striated muscle.
The relationship between sexual dimorphism and intersex correlation: do models support intuition?
Authors: Puixeu Gemma , Hayward Laura Katharine 
Published: December 2024

AbstractThat a high genetic correlation between the sexes (rfm) constrains the evolution of sexual dimorphism and that they should negatively correlate with one another, are assumptions commonly made in the field of sex-specific adaptation. While some empirical observations support a general negative relationship, the mechanisms underlying this pattern and the conditions under which it arises are poorly understood. Concretely, two primary hypotheses are often invoked: first, that traits with ancestrally lowrfmare less constrained in their ability to respond to sex-specific selection and thus evolve to be more dimorphic; second, that sex-specific selection acts to reducerfm. However, no model to date has formalized these hypotheses and tested the conditions in which they hold. Here, we develop models of sex-specific stabilizing selection, mutation and drift to explore various scenarios potentially generating a negative correlation between intersex correlation and sexual dimorphism, with a focus on testing the common hypotheses. We recover the classical result that, with an infinite population size,rfmand sexual dimorphism are independent at equilibrium. Further, we show that this independence is maintained with a finite population; and this is in spite of the fact that, as we demonstrate, genetic drift generates nonzero sexual dimorphism even when selection between the two sexes is identical. Moreover, we demonstrate that the two common hypotheses only imply a negative association if additional assumptions are made. Specifically, that 1) some traits are sex-specifically adapting under directional selection, and 2) this sex-specific adaptation favours increased dimorphism more often than decreased dimorphism. These results provide, to our knowledge, the first mechanistic framework for understanding the conditions under which a negative correlation between intersex correlation and sexual dimorphism may arise. They also offer a compelling explanation for the inconsistent empirical evidence observed in nature, highlighting the importance of context-specific factors in shaping this relationship.
Translocation of effector proteins into plant cells by the flax rust pathogenMelampsora lini
Authors: Zhang Xiaoxiao , Catanzariti Ann-Maree , Lawrence Gregory J. , Gan Pamela H. P. , Jones David A. , Dodds Peter N. , Rathjen John P. 
Published: December 2024

AbstractDuring infection, rust fungi secrete effector proteins into host plant cells from haustoria to aid their colonisation. How rust effectors are secreted from the haustorium and delivered into the cytoplasm of host cells remains poorly understood. We used anAgrobacterium-mediated transformation procedure to generate stable transgenic flax rust strains expressing the effectors AvrM and AvrP123 fused to yellow fluorescent protein (YFP). We showed that both AvrM-YFP and AvrP123-YFP fusion proteins were secreted by the fungus into the extrahaustorial matrix (EHMx); however only AvrM-YFP was delivered into host cells, triggering a typical resistance phenotype in plants carrying the corresponding resistance (R)geneM. The signal peptide of AvrM was sufficient to direct YFP secretion into the EHMx; however, delivery into the host cell required a larger 105 amino acid N-terminal fragment of AvrM. These results indicate that translocation of this protein into the host cell from the EHMx is a separate process from secretion into the EHMx and requires a signal present in AvrM between amino acids 34 and 105. This is in contrast to previous observations of AvrM localisation after transient expression in plants, highlighting the necessity for analysis in the natural infection system.
ARBEL: A Machine Learning Tool with Light-Based Image Analysis for Automatic Classification of 3D Pain Behaviors
Authors: Barkai Omer , Zhang Biyao , Lenfers Turnes Bruna , Arab Maryam , Yarmolinsky David A , Zhang Zihe , Barrett Lee B , Woolf Clifford J 
Published: December 2024

AbstractA detailed analysis of pain-related behaviors in rodents is essential for exploring both the mechanisms of pain and evaluating analgesic efficacy. With the advancement of pose-estimation tools, automatic single-camera video animal behavior pipelines are growing and integrating rapidly into quantitative behavioral research. However, current existing algorithms do not consider an animal’s body-part contact intensity with- and distance from- the surface, a critical nuance for measuring certain pain-related responses like paw withdrawals (‘flinching’) with high accuracy and interpretability. Quantifying these bouts demands a high degree of attention to body part movement and currently relies on laborious and subjective human visual assessment. Here, we introduce a supervised machine learning algorithm, ARBEL: Automated Recognition of Behavior Enhanced with Light, that utilizes a combination of pose estimation together with a novel light-based analysis of body part pressure and distance from the surface, to automatically score pain-related behaviors in freely moving mice in three dimensions. We show the utility and accuracy of this algorithm for capturing a range of pain-related behavioral bouts using a bottom-up animal behavior platform, and its application for robust drug-screening. It allows for rapid objective pain behavior scoring over extended periods with high precision. This open-source algorithm is adaptable for detecting diverse behaviors across species and experimental platforms.
Quantitative analysis of gas chromatography-coupled electroantennographic detection (GC-EAD) of plant volatiles by insects
Authors: Byers Kelsey J.R.P. , Jacobs Robert N. 
Published: December 2024

AbstractPremisePlant-interacting insects receive plant volatile signals through their antennae, and voltage changes across an antenna exposed to volatile stimuli can be measured to determine if insects can perceive them, often by coupling gas chromatography to electroantennographic detection (GC-EAD). Current methods for analysing GC-EAD data rely onqualitativeobservation, rather than usingquantitativeanalysis, and are thus prone to bias.Methods and ResultsWe developed a novelquantitativemethodology for analysis of GC-EAD data using a signal processing technique on EAD data to compare responses of hawkmoths and bumble bees to a library of common floral volatiles. Responses varied between species and sexes and these responses were in some cases affected by compound type or modification.ConclusionsOur novel GC-EAD analysis technique is robust to baseline drift and low signal:noise ratios commonly found in GC-EAD data, and provides a way forward for quantitative studies of plant volatile-mediated plant-insect interactions.
An exploratory study of urinary proteome in trigeminal neuralgia
Authors: Wei Lilong , Wang Haitong , Zhou Yun , Wu Jianqiang , Zhan Yuliang , Cao Yongtong , Gao Youhe 
Published: December 2024

AbstractTrigeminal neuralgia (TN) is a neurological disorder characterized by severe pain, with a complex pathogenesis that seriously affects the quality of life of patients. Urinary proteomics has shown great potential in disease research. The aim of this study is to explore the diagnostic and therapeutic value of urine proteomics in TN. The urine of 10 cases of TN and 11 healthy individuals were studied using liquid chromatography-mass spectrometry (LC-MS) proteomics technology. Group analysis and one to many individual analysis strategies were used in quantitative analysis. A total of 2620 proteins were identified in group analysis, of which 1865 were quantifiable proteins. The majority of specimens in each group could be distinguished by unsupervised clustering analysis of urine proteome. The biological processes of immune response regulation signal pathway, immune response, natural killer cell activation, fatty acid transport, and natural killer cell inhibition signal pathway, as well as the KEGG pathway of antigen processing and presentation and natural killer cell-mediated cytotoxicity, were significantly enriched in the comparison between the two populations. An individual analysis revealed that there were more significantly different proteins among individuals, with 15 proteins identified in at least 9 different patients. The urinary proteome provided molecular characteristics of urinary proteins for patients with TN, describing the changes that occur in the patient’s body. The strong enrichment of its immune response might be related to the onset of the disease, providing new directions for immune related treatment of the disease; the significant differential proteins could become potential disease markers for disease diagnosis and treatment evaluation.
Next Generation Evidence: High-Precision Information Retrieval for Rapid Clinical Guideline Updates
Authors: Borchert Florian , Wullenweber Paul , Oeser Annika , Kreuzberger Nina , Karge Torsten , Langer Thomas , Skoetz Nicole , Wieler Lothar H. , Schapranow Matthieu-P. , Arnrich Bert 
Published: December 2024

AbstractDelays in translating new medical evidence into clinical practice hinder patient access to the best available treatments. Our data reveals an average delay of nine years from the initiation of human research to its adoption in clinical guidelines, with 1.7–3.0 years lost between trial publication and guideline updates. A substantial part of these delays stems from slow, manual processes in updating clinical guidelines, which rely on time-intensive evidence synthesis workflows. The Next Generation Evidence (NGE) system addresses this challenge by harnessing state-of-the-art biomedical Natural Language Processing (NLP) methods. This novel system integrates diverse evidence sources, such as clinical trial reports and digital guidelines, enabling automated, data-driven analyses of the time it takes for research findings to inform clinical practice. The NGE system accelerates guideline updates by employing precision-focused literature search filters tailored specifically for guideline maintenance. In benchmarking against two German oncology guidelines, these filters demonstrate exceptional precision in identifying pivotal publications for guideline updates. By streamlining evidence synthesis, NGE has the potential to deliver faster updates, improve guideline responsiveness, and enhance patient access to state-of-the-art treatments.