bluuebunny/crossref_metadata_2025_split huggingface dataset:
Treatment and Outcome of Supracondylar Humeral Fractures in Children Over 10 Years of Age at the Time of Injury: A Review of 60 Cases
Authors: Li YiQiang , Wei Sheng , Canavese Federico , Liu YuanZhong , Li JingChun , Liu YanHan , Xu HongWen 
Published: April 2024

Objectives:
To assess the treatment and outcomes of supracondylar humeral fractures (SHFs) in children older than 10 years of age at the time of injury.

Methods:
The study analyzed clinical data from 60 patients who sustained SHF, all over the age of 10 years, were analyzed. The patients included 49 males and 11 females with a mean age of 10.9 ± 0.9 years (range, 10 to 14.5). All patients underwent surgical treatment under general anesthesia. Closed reduction (CR) and percutaneous fixation were the primary treatment, with open reduction and internal fixation being employed only in cases CR was unsuccessful. The study assessed the healing of fractures by measuring the radiographic angles, including the carrying angle (RCA), Baumann’s angle (BA), and metaphyseal–diaphyseal angle (MDA) on anteroposterior radiographs of the elbow joint. In addition, the study evaluated whether the anterior humeral line (AHL) appropriately passed through the middle third of the capitellum. The final follow-up visit used the Mayo Elbow Performance Index score (MEPI) and Flynn’s criteria to analyze the recovery of elbow function.

Results:
There were 15 (25%) SHF type II, 17 (28.3%) type III and 28 (46.7%) type IV. Of the 60 patients, 56 (93.3%) underwent successful CR, whereas 4 (6.7%) required open reduction and internal fixation because of an unsuccessful CR. The final follow-up showed the average BA as 72° ± 5.3°, the average MDA as 88.3° ± 2.8°, and the average RCA as 9.6° ± 3.9°. The AHL bisected accurately the capitellum in 59 cases (98.3%). The average range of elbow flexion-extension was 146.6° ± 8.6°, whereas the average MEPI score was 99.9 ± 0.6; 98.3% (n=59) were rated as excellent and 1.7% (n=1) were rated as good. According to Flynn’s criteria, 86.7% had an excellent outcome (n=52), 10% had a good outcome (n=6), and 3.3% had a poor outcome (n=2). Only 1 patient (1.7%) experienced redisplacement. Eight cases of nerve injury were reported, with 7 involving the radial nerve and 1 involving the ulnar nerve; all resolved spontaneously.

Conclusions:
CR and percutaneous fixation have been shown to be effective in treating SHF in 93.3% of children aged 10 years old and older at the time of injury, with favorable radiographic and functional outcomes and a low risk of secondary displacement. Open reduction should only be considered when CR is ineffective.
In silicodesign of stable single-domain antibodies with high affinity
Authors: Zhang Zhongyao , van der Kant Rob , Marković Iva , Vizarraga David , Garcia Teresa , Maragkou Katerina , Delgado Blanco Javier , Cianferoni Damiano , Orlando Gabriele , Cia Gabriel , Geukens Nick , Carolis Carlo , Volkov Alexander N. , Savvides Savvas N. , Dewilde Maarten , Schymkowitz Joost , Serrano Pubul Luis , Rousseau Frederic 
Published: April 2024

AbstractAntibody-based therapeutics have become indispensable in modern medicine, but traditional methods of antibody discovery often present with limitations in developability, cross-reactivity, and ethical concerns. While deep learning and generative approaches have shown promise in the design of high affinity protein binders,de novoantibody design remains challenging. Here, we present EvolveX, a structure-based computational pipeline for designing antibody fragments. EvolveX utilizes ModelX and empirical force field FoldX to optimize complementarity- determining regions (CDRs) and TANGO for aggregation analysis. We demonstrate the ability of EvolveX to redesign a single-domain VHH antibody fragment targeting mouse Vsig4 to address two challenges: enhancing stability and affinity for the original target and redesigning it for high affinity to the human ortholog. The redesigned variants of VHH fragments specific to mouse Vsig4 showed improved physicochemical properties, while retaining binding affinities comparable to the original version. Notably, EvolveX improved the binding affinity of VHHs to human Vsig4 by over 1000-fold, transforming low-affinity binders into nanomolar-affinity molecules. Structural analyses by X-ray crystallography and NMR confirmed the accuracy of the designs, which display optimized interactions with the antigen. NGS and re-modelling analysis further demonstrated the efficiency of FoldX-based design pipeline. Collectively, our study highlights EvolveX’s potential to overcome current limitations in antibody design, offering a powerful tool for the development of next-generation therapeutics with enhanced specificity, stability, and efficacy.
Microglial MyD88-dependent pathways are regulated in a sex-specific manner in the context of HMGB1-induced anxiety
Authors: Rawls Ashleigh , Nyugen Dang , Dziabis Julia , Anbarci Dilara , Clark Madeline , Dzirasa Kafui , Bilbo Staci D. 
Published: April 2024

AbstractChronic stress is a significant risk factor for the development and recurrence of anxiety disorders. Chronic stress impacts the immune system, causing microglial functional alterations in the medial prefrontal cortex (mPFC), a brain region involved in the pathogenesis of anxiety. High mobility group box 1 protein (HMGB1) is an established modulator of neuronal firing and a potent pro-inflammatory stimulus released from neuronal and non-neuronal cells following stress. HMGB1, in the context of stress, acts as a danger-associated molecular pattern (DAMP), instigating robust proinflammatory responses throughout the brain, so much so that localized drug delivery of HMGB1 alters behavior in the absence of any other forms of stress, i.e., social isolation, or behavioral stress models. Few studies have investigated the molecular mechanisms that underlie HMGB1-associated behavioral effects in a cell-specific manner. The aim of this study is to investigate cellular and molecular mechanisms underlying HMGB1-induced behavioral dysfunction with regard to cell-type specificity and potential sex differences. Here, we report that both male and female mice exhibited anxiety-like behavior following increased HMGB1 in the mPFC as well as changes in microglial morphology. Interestingly, our results demonstrate that HMGB1-induced anxiety may be mediated by distinct microglial MyD88-dependent mechanisms in females compared to males. This study supports the hypothesis that MyD88 signaling in microglia may be a crucial mediator of the stress response in adult female mice.
Self-supervised Vision Transformers for image-to-image labeling: a BiaPy solution to the LightMyCells Challenge
Authors: Franco-Barranco Daniel , González-Marfil Aitor , Arganda-Carreras Ignacio 
Published: April 2024

ABSTRACTFluorescence microscopy plays a crucial role in cellular analysis but is often hindered by phototoxicity and limited spectral channels. Label-free transmitted light microscopy presents an attractive alternative, yet recovering fluorescence images from such inputs remains difficult. In this work, we address the Cell Painting problem within the LightMyCells challenge at the International Symposium on Biomedical Imaging (ISBI) 2024, aiming to predict optimally focused fluorescence images from label-free transmitted light inputs. Leveraging advancements self-supervised Vision Transformers, our method overcomes the constraints of scarce annotated biomedical data and fluorescence microscopy’s drawbacks. Four specialized models, each targeting a different organelle, are pretrained in a self-supervised manner to enhance model generalization. Our method, integrated within the open-source BiaPy library, contributes to the advancement of image-to-image deep-learning techniques in cellular analysis, offering a promising solution for robust and accurate fluorescence image prediction from label-free transmitted light inputs. Code and documentation can be found athttps://github.com/danifranco/BiaPyand a custom tutorial to reproduce all results is available athttps://biapy.readthedocs.io/en/latest/tutorials/image-to-image/lightmycells.html.
Action Potential Threshold Variability for Different Electrostimulation Models and the Impact on Occupational Exposure Limit Values
Authors: Soyka Florian , Tarnaud Thomas , Alteköster Carsten , Schoeters Ruben , Plovie Tom , Joseph Wout , Tanghe Emmeric 
Published: April 2024

ABSTRACTOccupational exposure limit values (ELVs) for body internal electric fields can be derived from thresholds for action potential generation. These thresholds can be calculated with electrostimulation models. The spatially extended nonlinear node model (SENN) is often used to determine such thresholds. An important part of these models are the membrane channel dynamics describing the ionic transmembrane currents. This work shows how ELVs change significantly with different ion channel dynamics (up to a factor of 22). Furthermore, two more detailed double-cable models by Gaines et al. (MRG-Sensory and MRG-Motor) are also considered in this work. Thresholds calculated with the SENN model (with Frankenhaeuser-Huxley membrane channel dynamics) and the MRG models are compared for frequencies between 1 Hz and 100 kHz and temperatures between 22 °C and 37 °C. Results show that MRG thresholds are lower than SENN thresholds. In the context of occupational ELVs, using the double cable model would lead to approximately ten times lower limit values. Therefore, future exposure guidelines should take the influence of different electrostimulation models into account when deriving ELVs.HighlightsDifferent membrane channel dynamics change derived exposure limit values by more than one order of magnitude.Double-cable models result in a reduction of derived exposure limit values by one order of magnitude.Lower temperatures reduce the action potential thresholds at frequencies below 300 Hz.
Pharmaco-resistant temporal lobe epilepsy gradually perturbs the cortex-wide excitation-inhibition balance
Authors: Xie Ke , Royer Jessica , Rodriguez-Cruces Raul , Horwood Linda , Ngo Alexander , Arafat Thaera , Auer Hans , Sahlas Ella , Chen Judy , Zhou Yigu , Valk Sofie L. , Hong Seok-Jun , Frauscher Birgit , Pana Raluca , Bernasconi Andrea , Bernasconi Neda , Concha Luis , Bernhardt Boris 
Published: April 2024

AbstractExcitation-inhibition (E/I) imbalance is theorized as a key mechanism in the pathophysiology of epilepsy, with a mounting body of previous research focusing on elucidating its cellular manifestations. However, there are limited studies into E/I imbalance at macroscale and its microcircuit-level mechanisms and clinical associations. In our current work, we computed the Hurst exponent—a previously validated index of the E/I ratio—from resting-state fMRI time series, and simulated microcircuit parameters using biophysical computational models. We found a broad reduction in the Hurst exponent in pharmaco-resistant temporal lobe epilepsy (TLE), indicative of a shift towards more excitable network dynamics. Connectome decoders pointed to temporolimbic and frontocentral areas as plausible network epicenters of E/I imbalance. Computational simulations further revealed that enhancing cortical excitability in patients likely reflected atypical increases in recurrent connection strength of local neuronal ensembles. Moreover, mixed cross-sectional and longitudinal analyses revealed heightened E/I elevation in patients with longer disease duration, more frequent electroclinical seizures and inter-ictal epileptic spikes, and worse cognitive functioning. Replicated in an independent dataset, our work provides compellingin-vivoevidence of a macroscale shift in E/I balance in TLE patients that undergoes progressive changes and underpins cognitive impairments, potentially informing treatment strategies targeting E/I mechanisms.
Unified somatic calling and machine learning-based classification enhance the discovery of clonal hematopoiesis of indeterminate potential
Authors: Tian Shulan , Jenkinson Garrett , Ferrer Alejandro , Yan Huihuang , Morales-Rosado Joel A. , Wang Kevin L. , Lasho Terra L. , Yan Benjamin B. , Baheti Saurabh , Olson Janet E. , Baughn Linda B. , Ding Wei , Slager Susan L. , Patnaik Mrinal S. , Lazaridis Konstantinos N. , Klee Eric W. 
Published: April 2024

ABSTRACTClonal hematopoiesis (CH) of indeterminate potential (CHIP), driven by somatic mutations in leukemia-associated genes, confers increased risk of hematologic malignancies, cardiovascular disease and all-cause mortality. In blood of healthy individuals, small CH clones can expand over time to reach 2% variant allele frequency (VAF), the current threshold for CHIP. Nevertheless, reliable detection of low-VAF CHIP mutations is challenging, often relying on deep targeted sequencing. Here, we present UNISOM, a streamlined workflow for CHIP detection from whole-genome and whole-exome sequencing data that are underpowered, especially for low VAFs. UNISOM utilizes a meta-caller for variant detection, in couple with machine learning models which classify variants into CHIP, germline and artifact. In whole-exome data, UNISOM recovered nearly 80% of the CHIP mutations identified via deep targeted sequencing in the same cohort. Applied to whole-genome data from Mayo Clinic Biobank, it recapitulated the patterns previously established in much larger cohorts, including the most frequently mutated CHIP genes, predominant mutation types and signatures, as well as strong associations of CHIP with age and smoking status. Notably, 30% of the identified CHIP mutations had <5% VAFs, demonstrating its high sensitivity toward small mutant clones. This workflow is applicable to CHIP screening in population genomic studies.
Multi-scale drivers of daily flow intermittency in a regulated desert river
Authors: Gilbert Eliza. I. , Turner Thomas F. , Moses Melanie E. , Webster Alex J. 
Published: April 2024

AbstractFluvial ecosystems are vital for biodiversity and human welfare but face increasing threats from flow intermittency caused by climate change and other human activities. To better understand drivers of flow intermittency, we analyzed long-term and spatially explicit river drying data from the Rio Grande, a regulated river in the North American desert southwest that was historically perennial but is now persistently intermittent. We examined the spatial structure and influences of precipitation, temperature, in-channel infrastructure, and river discharge on flow intermittency using multivariate autoregressive state space (MARSS) models and 12 years of daily data. Our findings indicate that river diversion rates at dams and irrigation return flows significantly structure the spatial occurrence of flow intermittency, but factors (possibly geologic) at distances ≤ 7 kilometers (km) are more influential as predictors of drying. Controlling influences of temperature and precipitation were not detected at the reach level (∼154 km) but were significant at each of the subreach scales (n = 3) investigated. At all subreach scales, temperature’s effect size exceeds precipitation by 2.5 times and is the strongest predictor of drying. Overall, process variance decreased by 98% between our reach- and all subreach models, suggesting that scale-sensitive models have great potential to accurately inform environmental flow management strategies aimed at mitigating negative effects of climate change and water extraction.
QM/MM Free Energy Calculations of Long-Range Biological Protonation Dynamics by Adaptive and Focused Sampling
Authors: Pöverlein Maximilian C. , Hulm Andreas , Dietschreit Johannes C. B. , Kussmann Jörg , Ochsenfeld Christian , Kaila Ville R. I. 
Published: April 2024

ABSTRACTWater-mediated proton transfer reactions are central for catalytic processes in a wide range of biochemical systems, ranging from biological energy conversion to chemical transformations in the metabolism. Yet, the accurate computational treatment of such complex bio-chemical reactions is highly challenging and requires the application of multiscale methods, in particular hybrid quantum/classical (QM/MM) approaches combined with free energy simulations. Here we combine the unique exploration power of new advanced sampling methods with density functional theory (DFT)-based QM/MM free energy methods for multiscale simulations of long-range protonation dynamics in biological systems. In this regard, we show that combining multiple walkers/well-tempered metadynamics with an extended-system adaptive biasing force method (MWE), provides a powerful approach for exploration of water-mediated proton transfer reactions in complex biochemical systems. We compare and combine the MWE method also with QM/MM-umbrella sampling and explore the sampling of the free energy landscape with both geometric (linear combination of proton transfer distances) and physical (center of excess charge) reaction coordinates, and show how these affect the convergence of the potential of mean force (PMF) and the activation free energy. We find that the QM/MM-MWE method can efficiently explore both direct and water-mediated proton transfer pathways together with forward and reverse hole transfer mechanisms in the highly complex proton channel of respiratory Complex I, while the QM/MM-US approach shows a systematic convergence of selected long-range proton transfer pathways. In this regard, we show that the PMF along multiple proton transfer pathways is recovered by combining the strengths of both approaches in a QM/MM-MWE/focused US (FUS) scheme, and revealing new mechanistic insight into the proton transfer principles of Complex I. Our findings provide a promising basis for the quantitative multi-scale simulations of long-range proton transfer reactions in biological systems.
Benchmarking tools for transcription factor prioritization
Authors: Santana Leonor Schubert , Reyes Alejandro , Hoersch Sebastian , Ferrero Enrico , Kolter Christian , Gaulis Swann , Steinhauser Sebastian 
Published: April 2024

AbstractSpatiotemporal regulation of gene expression is controlled by transcription factor (TF) binding to regulatory elements, resulting in a plethora of cell types and cell states from the same genetic information. Due to the importance of regulatory elements, various sequencing methods have been developed to localise them in genomes, for example using ChIP-seq profiling of the histone mark H3K27ac that marks active regulatory regions. Moreover, multiple tools have been developed to predict TF binding to these regulatory elements based on DNA sequence. As altered gene expression is a hallmark of disease phenotypes, identifying TFs driving such gene expression programs is critical for the identification of novel drug targets.In this study, we curated 84 chromatin profiling experiments (H3K27ac ChIP-seq) where TFs were perturbed through e.g., genetic knockout or overexpression. We ran nine published tools to prioritize TFs using these real-world data sets and evaluated the performance of the methods in identifying the perturbed TFs. This allowed the nomination of three frontrunner tools, namely RcisTarget, MEIRLOP and monaLisa. Our analyses revealed opportunities and commonalities of tools that will help to guide further improvements and developments in the field.
Disrupting USP39 deubiquitinase function impairs the survival and migration of multiple myeloma cells through ZEB1 degradation
Authors: Sirera Jessy , Sarlak Saharnaz , Teisseire Manon , Carminati Alexandrine , Savy Coline , Nicolini Victoria J , Brest Patrick , Juel Thierry , Bontoux Christophe , Deckert Marcel , Ohanna Mickael , Giuliano Sandy , Dufies Maeva , Pages Gilles , Luciano Frederic 
Published: April 2024

ABSTRACTRationaleMultiple Myeloma (MM) stands as the second most common hematological malignancy characterized by the accumulation of monoclonal plasmocytes within the bone marrow. Despite the introduction of proteasome inhibitors, immunomodulatory agents and CD38-targeting antibodies which have extended survival rates, the disease remains incurable for most patients due to the emergence of resistant clones and frequent relapses. The efficacy of the proteasome inhibitor bortezomib (BTZ) in MM treatment underscores the critical role of the ubiquitin proteasome system (UPS) in this cancer. Deubiquitinases (DUBs), a class of enzymes governing the stability, interactions or localization of cellular proteins by removing ubiquitin modifications, have emerged as promising therapeutic targets across various cancers, including MM.MethodsThrough an exhaustive loss-of-function approach, we have identified for the first time USP39 DUB as a pivotal survival determinant for MM cells.ResultsOur analysis reveals a direct correlation between heightened USP39 mRNA levels and shorter survival in MM patients. Additionally, robust USP39 protein expression is observed in MM patient plasmocytes compared to healthy counterparts. Knockdown of Usp39 not only impedes clonogenic capabilities, but also induces apoptosis, triggers cell cycle arrest and overcomes BTZ resistance. Complementary gain-of-function assays, further elucidate how USP39, by stabilizing the transcription factor ZEB1, enhances the trans-migratory potential of MM cells.ConclusionsIn summary, our findings underscores the pivotal role of the deubiquitinase USP39, suggesting that targeting the USP39/ZEB1 axis hold promise as a prospective diagnostic marker and therapeutic target in MM.
Microdiversity in marine pelagic ammonia-oxidizing archaeal populations
Authors: Suárez-Moo Pablo , Haro-Moreno Jose M. , Rodriguez-Valera Francisco 
Published: April 2024

ABSTRACTThe knowledge of the different population-level processes operating within a species, and the genetic variability of the individual prokaryotic genomes, is key to understanding the adaptability of microbial populations. Here, we characterized the flexible genome of ammonia-oxidizing archaeal (AOA) populations using a metagenomic recruitment approach and long-read (PacBio HiFi) metagenomic sequencing. In the lower photic zone of the western Mediterranean Sea, the genomesNitrosopelagicus brevisCN25 andNitrosopumilus catalinensisSPOT1 had the highest recruitment values among AOA. These two complete genomes were used to analyze the diversity of flexible genes (variable from strain to strain) by analyzing the long-reads located within the flexible genomic islands (fGIs) identified through their under-recruitment. Both AOA genomes had a large fGI involved in the glycosylation of exposed structures, highly variable and rich in glycosyltransferases.N. brevishad two fGIs related to the transport of phosphorus and ammonium respectively.N. catalinensishad fGIs involved in phosphorus transportation and metal uptake. A flexible genomic island (fGI5) previously reported as “unassigned function” inN. breviscould be associated with defense. These findings demonstrate that the microdiversity of marine microbe populations, including AOA, can be effectively characterized using an approach that incorporates new third-generation sequencing metagenomics.