bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic value of admission H3.1 nucleosome levels in sepsis-associated acute kidney injury: a secondary analysis of the SISPCT randomised clinical trial
Authors: Neumann Caroline , Bloos Frank , Hla Teddy Tun Win , Bygott Thomas , Bogatsch Holger , Kiehntopf Michael , Börner Friedemann , Press Adrian T , Bauer Michael , Retter Andrew ,   SepNet Critical Care Trials Group
Published: January 2025

AbstractBackgroundNETosis is a key innate immune defence mechanism where neutrophils release extracellular traps (NETs). However, excessive NET formation may damage organs during sepsis. We investigated the association between NETs and sepsis outcomes, including mortality and acute kidney injury (AKI).MethodsWe analysed levels of H3.1 nucleosomes in 971 patients with severe sepsis and septic shock from the SISPCT trial (Effect of Sodium Selenite Administration and Procalcitonin-Guided Therapy on Mortality in Patients With Severe Sepsis or Septic Shock). We evaluated associations between H3.1 levels and mortality and the need for renal replacement therapy using multivariable Cox regression and receiver operating characteristic analyses.ResultsWe analysed 971 critically ill patients with complete data including admission H3.1 levels. 443 patients (45.6%) presented with sepsis, 520 (53.6%) had septic shock, and eight patients had an unknown diagnosis as defined by Sepsis-3. Admission H3.1 levels were higher in patients with septic shock than with sepsis (median 921.84 vs 432.71 ng/mL; p<0.001). Admission H3.1 levels were higher in non-survivors, and in a univariate Cox analysis, each log-10 increase in H3.1 was associated with a hazard ratio of 1.86 (95% confidence interval 1.41–2.47, p<0.05). H3.1 was also higher in patients requiring renal replacement therapy with septic shock vs sepsis (1832 ng/mL vs 801.4 ng/mL, p=0.01) and demonstrated a dose-response relationship with the severity of AKI.ConclusionElevated levels of H3.1 nucleosomes at admission are independently associated with mortality and severe kidney dysfunction requiring renal replacement therapy.Trial registrationClinicaltrials.govIdentifier,NCT00832039.
Cognitive Costs and Gait Parameters During Single- and Dual-Task Conditions: A Comparative Study in Individuals With and Without Non-Specific Neck Pain
Authors: Moustafa Ibrahim M. , Abu-Ghosh Shorouk , Ahbouch Amal , Zadeh Shima Abdollah Mohammad , Kim Meeyoung , Khowailed Iman 
Published: January 2025

AbstractBackgroundThe high incidence of non-specific neck pain (NSNP) among students, commonly associated with prolonged sedentary behavior and extensive use of electronic devices, highlights the need to assess its impact on cognitive and motor functions. This study aims to evaluate the effects of NSNP on dual-task performance by analyzing gait parameters and cognitive performance during both single-task and dual-task conditions.MethodsForty-five participants with NSNP and forty-five age-matched controls were assessed using an optical motion-capture system. Participants underwent gait assessments during both single-task (without cognitive load) and dual-task conditions, in which the cognitive tasks involved simple mathematical computations.ResultsResults revealed that, under single-task conditions, differences in gait parameters between groups were not statistically significant. However, under dual-task conditions, participants with NSNP exhibited significant impairments in gait parameters and higher cognitive costs (p < 0.05). Correlation analysis indicated that pain intensity was significantly associated with cognitive cost and gait parameter alterations during dual-task conditions (p < 0.05).ConclusionsThese findings suggest that NSNP significantly elevates the cognitive effort required during dual tasking. These finding emphasizes on the need for interventions to alleviate neck pain and improve both physical and cognitive health.
A mathematical model of H5N1 influenza transmission in US dairy cattle
Authors: Rawson Thomas , Morgenstern Christian , Knock Edward S. , Hicks Joseph , Pham Anh , Morel Guillaume , Murillo Aurelio Cabezas , Sanderson Mike , Forchini Giovanni , FitzJohn Richard , Hauck Katharina , Ferguson Neil 
Published: January 2025

AbstractWe present a stochastic metapopulation transmission model that simulates the spread of H5N1 avian influenza through individual dairy cows in 35,974 dairy herds in the continental United States. Transmission is enabled through the movement of cattle between herds, as indicated from Interstate Certificates of Veterinary Inspection (ICVI) data. We estimate the rates of under-reporting by state and present the anticipated rates of positivity for cattle tested at the point of exportation over time. We investigate the likely impact of intervention methods to date on the underlying epidemiological dynamics, demonstrating that current interventions have had insufficient impact, preventing only a mean 175.2 reported outbreaks. Our model predicts that the majority of the disease burden is, as of January 2025, concentrated within West Coast states, due to the network of cattle movements and distribution of the respective dairy populations. We quantify the extent of uncertainty in the scale of the epidemic, highlighting the most pressing data streams to capture, and which states are most expected to see outbreaks emerge next, with Arizona and Wisconsin at greatest risk. Our model suggests that dairy herd outbreaks will continue to be a significant public health challenge in 2025, and that more urgent, farm-focused, biosecurity interventions and targeted surveillance schemes are sorely needed.
Bodily Self-Dysfunction in Psychosis: Altered Neural and Spinal Response to Self-produced Sensations
Authors: Salamone Paula C. , Enmalm Adam , Kaldewaij Reinoud , Åman Marie , Medley Charlotte , Pietrzak Michal , Olausson Håkan , Capusan Andrea Johansson , Boehme Rebecca 
Published: January 2025

AbstractPsychosis is often characterized by disturbances in the sense of self, with patients frequently misattributing self-produced sensations to external sources. While somatic hallucinations and misperceptions are common, the underlying disruptions in basic bodily self-processing remain unclear.We aimed to investigate alterations in bodily self-processing, including touch and interoception, in psychosis using a multimodal, multi-method approach.A total of 70 participants were included (35 patients diagnosed with psychotic disorders [DSM-IV F20-29], 35 age-and sex-matched controls).Participants performed self-/other-touch-tasks and interoceptive assessments during functional magnetic resonance imaging (fMRI), evoked potentials (EP) measurements, and/or behavioral and psychophysical tests.Primary outcomes included neural and behavioral responses to self-and externally-generated sensations (touch and heartbeat). Brain activation (fMRI), spinal responses (EPs), heartbeat perception and processing (EPs), and behavioral measures were analyzed, with preregistered hypotheses.Patients demonstrated heightened neural activity during touch tasks, including increased right superior temporal gyrus activation during self-touch and heightened activity in a right temporoparietal cluster during social touch. Tactile self-other distinction impairments were evident at the spinal cord level (EPs). Behaviorally, patients showed reduced differentiation in tactile thresholds for self-vs. other-touch. Interoceptive impairments included diminished cortical responses to heartbeat signals (EPs), lower interoceptive accuracy (heartbeat detection), and reduced self-reported interoceptive sensitivity.These findings reveal pervasive sensory and self-related disturbances in psychotic disorders. Impairments in differentiating self-and externally-evoked responses, detectable as early as the spinal cord level, may contribute to higher-order symptoms of psychosis.
The Language & Memory Test: International feasibility study of an unsupervised digital test of cognition for neurologic populations
Authors: Leavitt Victoria M. , Simani Leila , Koch Marcus , Morrow Sarah A. , Heuer Lauren , Roozbeh Mahrooz , Roozbeh Mehrdad , Traynor Sean 
Published: January 2025

ABSTRACTBackgroundCurrent cognitive outcomes are insufficient to monitor subtle change over time in neurologic populations. Challenging cognitive tests (i.e., cognitive “stress test”) unaffected by practice effects and learning are ideal for monitoring and tracking change. Here we describe the Language & Memory Test (LMT), an unsupervised digital test we developed to measure rapid naming, visuospatial memory, and fine motor dexterity, that takes approximately 4 minutes to complete.ObjectiveConduct feasibility study of the LMT in adults recruited across three countries; in English and non-English speaking participants; employing in-person, remote, and unsupervised administration modalities.MethodsWe investigated retest reliability, usability / tolerability, and equivalence across centers, administration modalities, and English / non-English speakers. We also evaluated performance across adult age groups: 18-40, 41-60, and 61+ years.ResultsThe LMT was administered 555 times to 440 individuals ages 18-84 years in Canada, Iran, and the United States. Our sample was geographically and racially/ethnically diverse. Participants included a control sample of adults (n=115) and adults with a diagnosed neurologic disease (n=325). Of those invited to complete the LMT, 95.3% agreed; 99% of those who began the test completed it. Retest reliability was acceptable for finger tapping (Cronbach’sα=0.942) and language (α=0.872), and marginally acceptable for memory 1 (α=0.604). Equivalence varied across administration modalities, centers/countries, settings, and English / non-English speakers. Expected age-related performance decrements were shown for all three subtests.ConclusionsThe LMT shows promise as a culturally adaptable tool for use in diverse neurologic populations.
Variant Scientists in Genomic Medicine: Survey of Demographics, Training, Duties, and Professional Development
Authors: Dickson Alexa , Cone Kelsey R. , Fortini Barbara K. , Goldstein Jennifer , Thompson Michelle L. , Wilke Matheus V.M.B. , Hurst Anna C.E. , Schroeder Molly C. , Polonis Katarzyna , Bowling Kevin M. 
Published: January 2025

ABSTRACTPurposeGenomic testing has proven utility in disease diagnostics, guiding clinical management and improving outcomes. Use of high throughput sequencing by clinical laboratories has generated opportunities and challenges in data analysis resulting in the emergence of a laboratory role termed Variant Scientist. The aim of this study was to characterize this laboratory role.MethodsWe developed a thirty-item survey to collect information describing the current demographic landscape, salary ranges, work environments, training options, and professional development of Variant Scientists. The survey was disseminated to individuals conducting variant analysis in the United States from November 6, 2023, to March 15, 2024.ResultsSurvey responders (n=87) are predominantly female (78%), age 40 or less (64%), hold advanced degrees (92%), and report four or more years of experience (75%). Responders report involvement in a diverse set of laboratory tasks and received relevant training on the job (78%). This workforce is satisfied with their career path (70%) and reports adequate support from employers. They note that resources and recognition from professional organizations are currently lacking.ConclusionsVariant Scientists are a group of diverse genetics professionals that are highly educated and perform a variety of complex tasks within a clinical genomics laboratory.
Post-Ictal Sleep Changes in Human Focal Epilepsy
Authors: Kremen Vaclav , Cao Yurui , Gerla Vaclav , Mivalt Filip , Sladky Vladimir , St.Louis Erik , Bower Mark , Brinkmann Ben , Miller Kai , VanGompel Jamie , Cook Mark , Denison Tim , Leyde Kent , Worrell Gregory A. 
Published: January 2025

AbstractBidirectional interactions between sleep, seizures, and epilepsy remain incompletely understood. Evidence from animal models and people with focal epilepsy suggest that seizures may engage mechanisms of memory consolidation to reinforce and strengthen synaptic connections within the pathological networks that generates seizures, termed seizure-related consolidation (SRC). Human studies of SRC, however, are limited by small sample size and restricted observations of post-ictal sleep. Using continuous local field potential (LFP) recordings from novel investigational devices implanted in 11 people with drug-resistant focal epilepsy living in their natural environments, we used automated methods to create accurate sleep-wake and seizure catalogs for investigating the interplay between seizures and sleep. Our findings demonstrate that post-ictal slow-wave sleep duration, slow-wave LFP spectral power and waveform slope are increased compared to inter-ictal nights without preceding seizures. The most significant changes localize to the epileptogenic networks generating the subjects’ habitual seizures. These results reveal parallels between SRC and physiological memory consolidation, providing new insights into the role of post-ictal sleep in epilepsy and underscoring the potential of targeting post-ictal sleep for therapeutic interventions in drug-resistant focal epilepsy.
Combined mitral and tricuspid TEER with a single TriClip steerable guide catheter: A single-center study
Authors: Papadopoulos Georgios E. , Ninios Ilias , Evangelou Sotirios , Ioannides Andreas , Ninios Vlasis 
Published: January 2025

Structured AbstractBackgroundCombined M- and T-TEER typically involves two separate systems, complicating logistics and increasing procedural risks. This study aims to evaluate the safety and efficacy of combined mitral (M-TEER) and tricuspid (T-TEER) transcatheter edge-to-edge repair using a single TriClip® steerable guide catheter (SGC).MethodsPatients with moderate-to-severe (3+) or severe (4+) degenerative (DMR) or functional (FMR) mitral regurgitation and massive/torrential or severe functional tricuspid regurgitation (TR), classified as New York Heart Association (NYHA) class III or IV, who underwent combined M- and T-TEER with the same TriClip SGC between January 2022 and December 2024, were included. The primary objectives included procedural outcomes, MR and TR severity reduction, and NYHA class improvement.ResultsAmong 42 patients (64% female; median age: 77 years [IQR: 9]], the implantation success rate was 100%, with mean device and procedure times of 39.2 ± 6.9 and 71.2 ± 9.6 minutes, respectively. There were no in-hospital or 30-day major adverse events (MAEs), except for 2 patients (4.8%) with tricuspid single leaflet device attachment (SLDA), and 1 patient (2.4%) who underwent atrial septal defect (ASD) closure. Over a median follow-up period of 0.91 years, 3 (7.1%) patients were hospitalized for heart failure, with zero mortality. At 1-year follow-up, all patients achieved NYHA class ≤II, along with MR ≤2+ and 34 (81%) patients had only trivial/mild TR.ConclusionsCombined M-TEER and T-TEER using the same TriClip SGC demonstrated exceptional safety and efficacy, along with significant functional and echocardiographic improvements.
Improving wearable-based seizure prediction by feature fusion using growing network
Authors: Hasija Tanuj , Kuschel Maurice , Jackson Michele , Dailey Stephanie , Menne Henric , Reinsberger Claus , Vieluf Solveig , Loddenkemper Tobias 
Published: January 2025

AbstractThe unpredictability of seizures is one of the most compromising features reported by people with epilepsy. Non-stigmatizing and easy-to-use wearable devices may provide information to predict seizures based on physiological data. We propose a patient-agnostic seizure prediction method that identifies group-level patterns across data from multiple patients. We employ supervised long-short-term networks (LSTMs) and add unsupervised deep canonically correlated autoencoders (DCCAE) and 24-hour patterns using time-of-day information. We fuse features from these three techniques using a growing neural network, allowing incremental learning. Our method with all three features improves prediction accuracy over the baseline LSTM by 7.3%, from 74.4% to 81.7%, averaged across all patients, and outperforms the LSTM in 84% of patients. Compared to the all-at-once fusion, the growing network improves the accuracy by 9.5%. We analyze the impact of preictal data duration, wearable data quality, and clinical variables on the prediction performance.
Collective biosynthesis of plant spirooxindole alkaloids through enzyme discovery and engineering
Authors: Chu Danni , Wang Hongkui , Nie Zhiwen , Li Kang-li , Cao Jiaqing , Yang Meijing , Yin Qin , Gu Yang , Jiang Yindi 
Published: January 2025

AbstractCollective synthesis is a well-established strategy to produce natural product collections from common intermediates. Extending this concept to enzymatic systems, collective biosynthesis offers a sustainable approach to diverse molecular collections but faces distinct challenges, including incomplete pathway knowledge and narrow substrate specificity of biosynthetic enzymes. Here, we overcome these limitations through enzyme discovery and protein engineering to achieve collective biosynthesis of spirooxindole alkaloids, an important class of natural products with diverse biological activities. We identified two key enzymes that catalyze enzymatic epimerization, working sequentially with a previously discovered cytochrome P450 enzyme to fully elucidate the biosynthetic pathway of pentacyclic spirooxindole alkaloids. Structure-guided engineering expanded substrate scope, enabling collective biosynthesis of 12 tetracyclic and pentacyclic spirooxindole natural products. We also generated new-to-nature fluorinated and deuterated derivatives through precursor-directed biosynthesis. This work provides crucial insights into plant spirooxindole alkaloid biosynthesis while establishing a powerful approach for sustainable production of complex natural products.
Structural insights into Salinosporamide A mediated inhibition of the human 20S proteasome
Authors: Sülzen Hagen , Fajtova Pavla , O’Donoghue Anthony J , Boura Evzen , Silhan Jan 
Published: January 2025

AbstractThe 20S proteasome, a critical component of the ubiquitin-proteasome system, plays a central role in regulating protein degradation in eukaryotic cells. Marizomib (MZB), a natural γ-lactam-β-lactone compound derived fromSalinispora tropica, is a potent 20S proteasome covalent inhibitor with demonstrated anticancer properties. Its broad-spectrum inhibition of all three proteasome subunits and ability to cross the blood-brain barrier has made it a promising therapeutic candidate for glioblastoma. Here, we present the cryo-EM structure of the human 20S proteasome in complex with MZB at 2.55 Å resolution. This structure reveals the binding mode of MZB to all six catalytic subunits within the two β-rings of the 20S proteasome, providing a detailed molecular understanding of its irreversible inhibitory mechanism. These findings explain the therapeutic potential of MZB at the molecular level and highlight marine-derived natural products in targeting the proteasome for anticancer treatment.
Allostery links hACE2 binding, pan-variant neutralisation and helical extension in the SARS-CoV-2 Spike protein
Authors: Colyer Alice , Wolf Esther , Lento Cristina , Ustav Mart , Sljoka Adnan , Wilson Derek J. 
Published: January 2025

AbstractThe SARS-CoV-2 spike protein is highly antigenic, with epitopes in three distinct regions of the receptor binding domain (RBD) alone that have known mechanisms of neutralization. In previous work, we predicted a fourth RBD epitope based on allosteric conformational perturbations measured by hydrogen-deuterium exchange mass spectrometry (HDX-MS) upon complexation with the canonical spike protein target, human angiotensin-converting enzyme 2 (hACE2). We subsequently identified a pan-neutralizing antibody (ICO-hu104) with the predicted epitope, however, as the epitope was somewhat distant from the hACE2 binding interface, and our previous work limited to the spike RBD, the neutralization mechanism was unclear. Using HDX-MS, we investigated the binding of ICO-hu104 to the full-length SARS-CoV-2 spike protein from Wuhan, Delta and Omicron variants. We demonstrate that binding of ICO-hu104 at its epitope results in an increase in deuterium uptake in the distant HR1 domain for variants of concern, which in a biological context could be indicative of destabilisation of the helices within this region, promoting S1 shedding or failure of helical extension during S2-mediated fusion. This is supported by our computational modelling, highlighting propagation of allosteric effects to the S2 coiled-coil region. Collectively, this work demonstrates an alternative neutralization mechanism for ICO-hu104 which is distinct from its first-generation predecessors and thus opens alternative avenues targeting non-RBD epitopes through assessment of allosteric perturbations.HighlightsHDX-MS reveals decreased deuterium uptake within the HR1 region of S2 for SARS-CoV-2 spike protein for variants of concern when bound to ICO-hu104.Computational modelling validates high allosteric coupling between ICO-hu104 epitope and HR1 region.Suggests an alternative neutralization mechanism from its predecessor ICO-hu23, whereby destabilisation of helices within the HR1 region promotes S1 shedding and/or failure of helical extension during S2-mediated fusion.Graphical abstract
A single mutation in the ‘DSL’ motif of acyl carrier protein can prevent itsin vivomodification byE. coliHolo-acyl carrier protein synthase (AcpS)
Authors: Dhembla Chetna , Sadhukhan Debodyuti , Prem Rashima , Vaish Shivangi , Verma Shalini , Kundu Suman , Sundd Monica 
Published: January 2025

ABSTRACTE. coliexpression system is the method of choice to obtain high yields of a pure protein. However, there is always a chance that an overexpressed protein shares structural or sequence homology with the substrate of anE. colienzyme. In such cases, the expressed protein may be partially or fully converted into the product. A notable example is the expression of acyl carrier proteins (ACP) inE. coli. Since most type II ACPs of the fatty acid synthesis pathway (FAS) have a conserved helix II, the carrier proteins are recognized as a substrate by Holo-acyl carrier protein synthase (AcpS). Thus, most ACPs express as partially or fully loaded proteins inE. coli. This undesirable modification is a concern when the objective is to obtain milligram amounts of apo-ACP. Here, using an approach combining mutagenesis, enzyme activity, and NMR, we probed for residues in ACP that can prevent thisin vivomodification, without affecting Sfp (Surfactin synthetase activating enzyme) function. Taking cues from theE. coliACP-AcpS structure (PDB 5VCB), charge neutralization mutations were designed at five different positions inEcACP that participate in ion-pair interaction with AcpS. Three of the mutants expressed solely as apo-ACP inE. coli viz.D35N, E41A and E47A/E48A. However, only the D35N mutant could be converted into holo-/acyl-ACP using Sfpin vitro, establishing mutagenesis as a viable strategy to prevent undesired modificationsin vivo. As proof of principle, the mutation was applied to two unrelated ACPs that express primarily as modified proteins inE. coli-Mus musculusmitochondrial FAS ACP (MmACP) andSalmonellaTyphimurium invasion acyl carrier protein (IacP). Single D35N mutation of the ACPs prevented theirin vivomodification by AcpS, and the mutants were efficiently converted into holo-ACP by Sfpin vitro. These results demonstrate that D35N mutagenesis is a useful strategy to express apo-ACP inE. coliand is applicable across all type II ACPs. Furthermore, we show that holo-IacP and holo-MmACP are not recognized as substrates by AcpH (E. coliAcyl carrier protein hydrolase), and therefore they express predominantly as modified proteins inE. coli.