bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of gut microbiota and plasma metabolites in ulcerative colitis: Insights from Mendelian randomization analysis
Authors: Zheng XuWen , Fan JinNuo , Yin JinNan , Chu Ying
Published: February 2025

Emerging research suggests that alterations in gut microbiota composition may play a significant role in the pathogenesis of ulcerative colitis (UC). Plasma metabolites, which are influenced by gut microbiota, have also been implicated, but their role in UC remains unclear. This study aims to determine whether specific plasma metabolites mediate the causal relationship between gut microbiota and UC using Mendelian randomization (MR) analysis. This study employed publicly available summary-level data from genome-wide association studies and metagenomic datasets. Gut microbiota data were derived from the FINRISK cohort (5959 participants), plasma metabolite data from the Canadian Longitudinal Study on Aging (8299 individuals), and UC data from multiple consortia (17,030 cases and 883,787 controls). Forward and reverse MR analyses, supplemented by linkage disequilibrium score regression (LDSC), were conducted to assess causal relationships. Mediation effects of plasma metabolites between gut microbiota and UC were analyzed using the product of coefficients method. Various sensitivity analyses, including MR-Egger and MR-PRESSO, were applied to detect pleiotropy and ensure robust results. The study identified 20 bacterial taxa and 93 plasma metabolites linked to UC. Forward MR analysis showed that Clostridium S felsineum increased UC risk via reduced carnitine levels, with a mediation proportion of 39.77%. Eubacterium callanderi was associated with decreased UC risk through the tryptophan to pyruvate ratio (16.02% mediation). Additionally, species CAG-590 sp000431135 increased UC risk through elevated mannitol/sorbitol levels, mediating 28.38% of the effect. Sensitivity analyses confirmed the robustness of these findings, with minimal heterogeneity and pleiotropy detected. This study highlights the significant role of gut microbiota and their associated plasma metabolites in the pathogenesis of UC. Specific microbial species influence UC through metabolites, suggesting potential therapeutic targets. Modulating carnitine, tryptophan metabolism, or sugar alcohols could offer promising avenues for UC management.
Brain Findings in Deceased COVID-19 Patients
Authors: Shergill Armaan , Omalu Bennet , Conner Peter , Wilson Machelle
Published: February 2025

As COVID-19 continues to infect millions of people globally, it is essential to understand how SARS-CoV-2 affects the brain. The purpose of this study is to determine if there are any associations or patterns of gross and microscopic neuropathological autopsy findings in the brains of patients who died from COVID-19. We analyzed 32 autopsy cases that met 3 requirements: (1) positive polymerase chain reaction (PCR) SARS-CoV-2 test at autopsy; (2) pulmonary histological features of SARS-CoV-2; (3) complete autopsies conducted during the COVID-19 pandemic from 2020 to 2023. We accounted for the presence of the following gross and microscopic neuropathological findings: cerebral edema (CE), cerebral cortical atrophy (CCA), chronic cerebrovascular disease (CCD), cerebral ischemic injury (CII), cerebral inflammation (CIN), and/or cerebral parenchymal hemorrhage (CPH) in every case. We found that CE, CCA, and CII diagnoses had a statistically significant association with age. There were no distinctive or recurrent neuropathological alterations in the autopsied brains that may be interpreted to be pathognomonic of SARS-CoV-2 infection in our cohort. These findings may suggest that SARS-CoV-2 infection is not associated with any distinct histomorphologic abnormalities that are diagnostic of COVID-19 in the brains of autopsied patients.
Outcomes of Pediatric Venovenous Extracorporeal Membrane Oxygenation Using Dual-Lumen or Multisite Cannulation: Extracorporeal Life Support Database Study, 2000–2019
Authors: Barreto Jessica A. , Qu Pingping , Thiagarajan Ravi R. , McGuire John K. , Brogan Thomas V.
Published: February 2025

Objectives:

In children reported to the Extracorporeal Life Support Organization (ELSO) registry, to compare mortality, the need for additional cannulas, and complications associated with dual-lumen (DL) or multisite cannulation for venovenous extracorporeal membrane oxygenation (ECMO).

Design:

Multicenter retrospective study using the ELSO registry.

Setting:

Centers reporting to ELSO between January 1, 2000, and December 31, 2019.

Patients:

Children 28 days to 18 years old supported with venovenous ECMO.

Interventions:

We performed univariate and multivariable regression analyses to determine the association between venovenous ECMO cannulation strategy and in-hospital mortality, ECMO duration, and need for additional cannulas. We also compared the frequency of venovenous ECMO complications using univariate analysis.

Measurements and Main Results:

We identified a cohort of 2034 patients, of whom 1441 (71%) were supported with DL. Support with DL, as opposed to multisite cannulation, was associated with median (interquartile range) of younger age (23 mo [6–89 mo] vs. 147 mo [64–189 mo]; p < 0.001). We failed to identify an association between in-hospital mortality and whether DL or multisite cannulation had been used (393/1441 [27%] vs. 184/593 [31%]); unadjusted and adjusted risk ratio (aRR) of death using DL as the reference group of 1.1 (95% CI, 0.7–1.9; p = 0.70). The other analyses failed to identify an association between cannulation type, ECMO duration, and the use of additional cannulas. ECMO complications were similar except for more frequent neurologic determination of death in the multisite group.

Conclusions:

In the 2000–2019 ELSO pediatric dataset, we failed to identify an association between venovenous ECMO cannulation type—DL or multisite—and greater aRR of ECMO outcomes.
Impact of Therapeutic Plasma Exchange and Rituximab for Prevention of Idiopathic Focal Segmental Glomerulosclerosis Recurrence Post–Kidney Transplantation
Authors: Yun Allison N. , Rogers Alex W. , Krisl Jill C. , Kagan Anna , Adrogue Horacio E. , Khan Abdul J. , Khairallah Pascale , Yi Stephanie G. , Hobeika Mark J. , Gaber Lillian , Truong Luan , Podder Hemangshu , Gaber Ahmed O. , Knight Richard J.
Published: February 2025

Background.

Focal segmental glomerulosclerosis (FSGS) recurs after kidney transplantation (KT) in 30%–50% of recipients. Recurrence is associated with early graft loss in up to 60% of cases. This study aimed to assess the efficacy of therapeutic plasma exchange (TPE) combined with rituximab (RTX) in preventing early FSGS recurrence within 1 y post-KT.

Methods.

This single-center, retrospective cohort study included patients receiving KT for idiopathic FSGS between June 2013 and August 2021. In May 2016, a preventative FSGS protocol was implemented where KT recipients with idiopathic FSGS received perioperative sessions of TPE followed by a dose of RTX with or without IVIG. The incidence of recurrent FSGS within the first year posttransplantation was assessed between the FSGS protocol cohort versus the historical group of patients who did not undergo prophylactic treatment.

Results.

A total of 65 patients received KT for idiopathic FSGS during the study period. Forty patients were included in the FSGS protocol cohort and 25 in the control cohort. When assessing clinical recurrence with proteinuria, there were significantly fewer cases in the FSGS protocol cohort versus the control cohort, 1 versus 5 patients (3% versus 20%, P = 0.03). There were no instances of death-censored graft loss at 1 y in the protocol cohort versus 2 cases in the control cohort (0% versus 8%, P = 0.14).

Conclusions.

TPE combined with RTX may prevent early FSGS recurrence without significant rates of infection.
Preventing peritendinous adhesions using lubricious supramolecular hydrogels
Authors: Meany Emily , Williams Christian Milton , Song Ye Eun , Doulames Vanessa Madelyn , Bailey Sophia J , Williams Shoshana C , Jons Carolyn K , Fox Paige , Appel Eric
Published: February 2025

Of the 1.5 million emergency room visits each year in the United States due to flexor tendon injuries in the hand, over 30-40% result in peritendinous adhesions which can limit range of motion (ROM) and severely impact an individual's quality of life. Adhesions are fibrous scar-like tissues which can form between adjacent tissues in the body in response to injury, inflammation, or during normal healing following surgery. Currently, there is no widespread solution for adhesion prevention in the delicate space of the digit while allowing a patient full ROM quickly after surgery. There is a clear clinical need for a material capable of limiting adhesion formation which is simple to apply, does not impair healing, remains at the application site during motion and initial inflammation (days - weeks), and leaves tendon glide unencumbered. In this work, we developed dynamically crosslinked, bioresorbable supramolecular hydrogels as easy-to-apply lubricious barriers to prevent the formation of peritendinous adhesions. These hydrogels exhibit excellent long-term stability, injectability, and thermally stable viscoelastic properties that allow for simple storage and facile application. We evaluated interactions at the interface of the hydrogels and relevant tissues, including human tendon and skin, in shear and extensional stress modes and demonstrated a unique mechanism of adhesion prevention based on maintenance of a lubricious hydrogel barrier between tissues. Ex vivo studies show that the hydrogels did not impair the gliding behavior nor mechanical properties of tendons when applied in cadaveric human hands following clinically relevant flexor tendon repair. We further applied these hydrogels in a preclinical rat Achilles tendon injury model and observed prolonged local retention at the repair site as well as improved recovery of key functional metrics, including ROM and maximal dorsiflexion. Further, these hydrogels were safe and did not impair tendon strength nor healing compared to the current standard of care. These dynamic, biocompatible hydrogels present a novel solution to the significant problem of peritendinous adhesions with clear translational potential.
Discovering the corky bark ofEucalyptus subereafrom anatomical and chemical perspectives
Authors: Gominho Jorge , Lourenço Ana , Patrício Helena , Quilhó Teresa , Marques António V.
Published: February 2025

This paper presents the first scientific investigation of the corky bark ofEucalyptus suberea(cork mallee). The study involved outer bark samples from two trees with diameters of 23 cm (A) and 47 cm (B), collected from a plantation in Portugal. Anatomical analysis was performed using light and scanning electron microscopy (SEM), enabling detailed observation of bark to reveal the cork cells’ presence. The chemical characterization included summative chemical analysis, FTIR, and GC-MS/FID for suberin composition and Py-GC-MS for lignin composition. The extractive-free bark mass ofE. subereafrom treesAandBcontained 29% and 25% suberin, 30% and 37% lignin, and 39% and 38% polysaccharides, respectively. The barkAexhibited a higher extractives content (49%) than just 14% for barkB. Conversely, dichloromethane extract from barkAwas notably rich in alkanol ferulates. FTIR spectra revealed a characteristic cork tissue pattern, showing a low suberin content but high levels of polysaccharides and free carboxylic acids. The main components ofE. subereaAandBsuberins were glycerol, with 15% and 11%, ω-hydroxyacids, with 45% and 50%, and α,ω-diacids, with 30% and 17%, representing a total of ca. 90% and 78% ofE. subereaAandBsuberins mass, respectively. Both suberins showed low contents of epoxides andvic-diols; also, both presented the particularity of having high contents of free acid groups, especially the suberin of barkB, suggesting a structure with short aliphatic chains.E. subereacorky bark presents a lignin composition that differentiates from the cork G-lignins analyzed until now with a monomer composition exhibiting a GS character, with more G- (53-56%) than S-units (34-37%) with an S/G ratio between 0.64 to 0.66, forAandBlignins, respectively.
Development of an Adaptive, Economical, and Easy-to-Use SP3-TMT Automated Sample Preparation Workflow for Quantitative Proteomics
Authors: Hermanson Jake N , Barny Lea A , Plate Lars
Published: February 2025

Liquid handling robots have been developed to automate various steps of the bottom-up proteomics workflow, however, protocols for the generation of isobarically labeled peptides remain limited. Existing methods often require costly specialty devices and are constrained by fixed workflows. To address this, we developed a cost-effective, flexible, automated sample preparation protocol for TMT-labeled peptides using the Biomek i5 liquid handler. Our approach leverages Single-Pot Solid-Phase-Enhanced Sample Preparation (SP3) with paramagnetic beads to streamline protein cleanup and digestion. The protocol also allows for adjustment of trypsin concentration and peptide-to-TMT ratio to increase throughput and reduce costs, respectively. We compared our automated and manual 18-plex TMT-Pro labeling workflows by monitoring select protein markers of the Unfolded Protein Response (UPR) in pharmacologically activatable, engineered cell lines. Overall, the automated protocol demonstrated equivalent performance in peptide and protein identifications, digestion and labeling efficiency, and an enhancement in the dynamic range of TMT quantifications. Compared to the manual method, the Biomek protocol significantly reduces hands-on time and minimizes sample handling errors. The 96-well format additionally allows for the number of TMT reactions to be scaled up quickly without a significant increase in user interaction. Our optimized automated workflow enhances throughput, reproducibility, and cost-effectiveness, making it a valuable tool for high-throughput proteomics studies.
Computational Translation of Mouse Models of Osteoarthritis Predicts Human Disease
Authors: Frost Maya R. , Ball Brendan K. , Pendyala Meghana , Douglas Stephen R. , Brubaker Douglas K. , Chan Deva D
Published: February 2025

Objective: Translation of biological insights from preclinical studies to human disease is a pressing challenge in biomedical research, including in osteoarthritis. Translatable Components Regression (TransComp-R) is a computational framework that has previously been used to synthesize preclinical and human OA data to identify biological pathways predictive of human disease conditions. We aimed to evaluate the translatability of two common murine models of post-traumatic osteoarthritis - surgical destabilization of the medial meniscus (DMM) and noninvasive anterior cruciate ligament rupture (ACLR) - to transcriptomics cartilage data from human OA outcomes. Design: Transcriptomics cartilage data of DMM and ACLR mouse and human data was acquired from Gene Expression Omnibus. TransComp-R was used to project human OA data into a mouse model (DMM or ACLR) principal component analysis space. The principal components (PCs) were regressed against human OA conditions using increasing complexity of linear regression models incorporating human demographic covariates of OA, sex, and age. Biological pathways of the mouse PCs that significantly stratified human OA and control groups were then interpreted using Gene Set Enrichment Analysis. Results: From the TransComp-R model, we identified different enriched biological pathways across DMM and ACLR models. While PCs among the DMM models revealed pathways associated with cell signaling and metabolism, ACLR PCs represented immune function and cellular pathways associated with OA condition. The immune pathways presented in the ACLR further highlighted the potential relevance of the OA pathways observed in human conditions. Conclusions: The ACLR mouse model more successfully predicted human OA conditions, particularly with the human control groups without a history of joint injury or disease. Cross-species translational approaches support the selection of preclinical models intended for therapeutic discovery and pathway analysis in humans.
Chemical Tools Based on the Tetrapeptide Sequence of IL-18 Reveals Shared Specificities between Inflammatory and Apoptotic Initiator Caspases
Authors: Bourne Christopher M , Raniszewski Nicole R , Kulkarni Madhura , Exconde Patrick M , Liu Sherry , Yost Winslow , Wrong Tristan J , Patio Robert C , Mahale Ashutosh , Kardhashi Matilda , Shosanya Teni , Kambayashi Mirai , Discher Bohdana , Brodsky Igor E , Burslem George , Taabazuing Cornelius Y
Published: February 2025

Caspases are a family of cysteine proteases that act as molecular scissors to cleave substrates and regulate biological processes such as programmed cell death and inflammation. Extensive efforts have been made to identify caspase substrates and to determine factors that dictate substrate specificity. We recently discovered that that the human inflammatory caspases (caspases-1, -4, and -5) cleave the cytokines IL-1β and IL-18 in a sequence-dependent manner. Here, we report the development of a new peptide-based probe and inhibitor based on the tetrapeptide sequence of IL-18 (LESD). We found that this inhibitor was most selective and potent at inhibiting caspase-8 activity (IC50 = 50 nM). We also discovered that our LESD-based inhibitor is more potent than the currently used z-IETD-FMK inhibitor that is thought to be the most selective and potent inhibitor of caspase-8. Accordingly, we demonstrate that the LESD based inhibitor prevents caspase-8 activation during Yersinia pseudotuberculosis infection in primary bone-marrow derived macrophages. Furthermore, we characterize the selectivity and potency of currently known substrates and inhibitors for the apoptotic and inflammatory caspases using the same activity units of each caspase. Our findings reveal that VX-765, a known caspase-1 inhibitor, also inhibits caspase-8 (IC50 = 1 μM) and even when specificities are shared, the caspases have different efficiencies and potencies for shared substrates and inhibitors. Altogether, we report the development of new tools that will facilitate the study of caspases and their roles in biology.
PACAP alleviates the defective epididymis and sperm function in LPS-induced acute mice epididymitis
Authors: Zhang XueYing , Liu Yanan , Gong BenJiao , Wang Xiaoxin , Liu XueXia , Liu FUjun
Published: February 2025

Background:To investigate the molecular mechanisms by which PACAP alleviates LPS-induced epididymitis, focusing on its anti-inflammatory and antioxidant pathways in the epididymal microenvironment. Methods: A mouse model of acute epididymitis was induced by LPS injection. The study assessed the levels of inflammatory markers (IL-6 and TNF-α mRNA) in the cauda epididymis, sperm motility and morphology, morphological alterations in the epididymis, and the expression of inflammation and antioxidant-related genes. PACAP treatment was administered to evaluate its effects on these parameters. Results: Results showed elevated levels of IL-6 and TNF-α mRNA in the cauda epididymis due to LPS injection. PACAP treatment effectively reduced these inflammatory markers and improved compromised sperm motility and morphology. PACAP also ameliorated morphological changes in the epididymis and mitigated the LPS-induced increase in leukocyte and macrophage markers. Gene expression analysis revealed that PACAP co-treatment suppressed LPS-induced upregulation of Il-6 and Tnf-ɑ in caput tissues. In cauda tissues, PACAP significantly reduced the expression of LPS-elevated Tnf-ɑ and IL-1β. PACAP up-regulated the antioxidant genes Cat and Sod1, which were down-regulated by LPS. IVF experiments demonstrated that PACAP restored the effects of LPS on sperm-egg fusion and embryo development. In conclusion: PACAP played a crucial role in maintaining epididymal function and sperm quality in the presence of inflammation.
Crafting Mathematical Models for Type 2 Diabetes Progression: Leveraging Longitudinal Data
Authors: Yang Boya , Sherman Arthur
Published: February 2025

Mathematical modelling is a powerful quantitative tool to investigate the pathogenesis of type 2 diabetes (T2D). Most models of T2D progression are based on the pioneering work of Topp et al, which established the paradigm of glucotoxicity as the main driver of pathogenesis. However, certain parameter values in this model diverge from physiological data, leading to predictions that deviate from clinical scenarios. Moreover, the simple structure of the model limits its explanatory capacity for clinical data. Leveraging a four-dimensional longitudinal dataset from Southwest Native Americans progressing from normal glucose tolerance to T2D, we developed a series of obesity-T2D models. Starting with a minimally modified version of the Topp model, we iteratively incorporate new biological mechanisms, refining the model to achieve optimal data fit. A non-linear mixed-effect approach addressed the variability in individual trajectories, allowing the model to capture diverse glucose-insulin dynamics despite the lack of a common trend. The reliability of the model was reinforced by its successful cross-validation against a subset of individuals progressing only to prediabetes. The systematic model selection process aided in navigating the trade-off between model complexity and practicability, culminating in a robust framework to address controversial questions in the diabetes field in future research.
A conserved mechanism of LRRC8 channel inhibition by distinct drugs
Authors: Yamada Toshiki , Bisignano Paola , Karakas Erkan , Denton Jerod S
Published: February 2025

We employed a Leucine Rich Repeat Containing 8 (LRRC8) channel chimera, termed 8C-8A(IL125), to investigate the molecular mechanism of action of the novel volume-sensitive anion channel (VRAC) inhibitor, zafirlukast. 8C-8A(IL125) comprises LRRC8C (8C) and 25 residues from LRRC8A (8A) intracellular loop 1 (IL1) and forms volume-sensitive, structurally defined heptameric channels with normal pharmacological properties. In silico docking and modeling with AlphaFold3 identified a putative zafirlukast binding site comprising the amino (N)-terminal domain (NTD) and inter-subunit fenestrae between transmembrane (TM) helices 1 and 2. Consistent with this model, mutations in NTD, TM1, and TM2 alter 8C-8A(IL125) and heteromeric 8A/8C sensitivity to zafirlukast and the structurally distinct drug pranlukast. Inhibition is not mediated by extracellular pore block or the so-called lipid gate. Mutations or low pH conditions that enhance voltage-dependent inactivation also increase zafirlukast sensitivity. We propose zafirlukast and pranlukast promote channel inactivation through destabilization of the pore.
Six million years of vole dental evolution driven by tooth development
Authors: Lafuma Fabien , Renvoisé Élodie , Clavel Julien , Corfe Ian J. , Escarguel Gilles
Published: February 2025

Morphological change occurs over macroevolutionary timescales under the action of natural selection and genetic drift combined with developmental processes shaping organogenesis. Although determining their relative weight is made difficult by discrepancies between palaeontological and neontological data, mammalian tooth morphology may bridge the gap between fossil record and laboratory observations. Fossils indicate that placentals and marsupials diversified after evolving molars bearing more cusps, which emerge through the iterative signalling of enamel knots. However, this theoretical evo-devo model of mammalian tooth evolution has not been explicitly assessed on empirical data. Here, by combining the fossil record with laboratory experiments, we identify a shared developmental basis for the convergent, ratcheted evolution of increasingly complex molars in arvicoline rodents (voles, lemmings, muskrats). Longer, narrower molars lead to more cusps throughout development and deep time, suggesting a developmental driver for tooth evolution. Both the arvicoline fossil record and vole tooth development show slower transitions toward the highest cusp counts. This newly identified pattern suggests that the developmental processes fuelling the evolution of increasingly complex molars may also limit the potential for further complexity increases. Integrating palaeontological and developmental data shows that long-term evolutionary trends can be accurately explained by the simple tinkering of developmental pathways.
Herbal-based medical device efficiently alleviates the symptoms of temporary gastrointestinal diseases - A prospective comparative study
Authors: Chevts Julia , Schuster Nicole , Sander Kirsten
Published: February 2025

Gastrointestinal disorders, especially stomach problems, are widespread. This prospective, non-interventional, comparative study investigated safety and efficacy of an herbal medical device for the treatment of stomach disorders. For the first 14 days, the patients did not take the test product and started the intake on day 15 for a duration of 14 days. Full data sets of 100 included patients were assessed. Symptoms were assessed by a visual scale weekly (day 1 to day 28) and changes of the overall recognised symptoms on a 3-stage scale in phase II (day 15 to day 21). Over the whole study duration, the patients documented the daily overall symptom severity in a patient's diary and all adverse events were assessed. During phase I, most of the symptoms remained unchanged. After phase II, the overall mean severity of gastrointestinal disorders as well as the specific symptom severity had improved significantly. The course of symptom severity was significantly different between both phases, in favour of the study product. Additionally, an average of 56% of patients reported a subjectively reduced symptom severity after day 28. The study product has shown a good efficacy and safety profile in the treatment of gastrointestinal disorders.
Contribution of Rare Large High-Penetrance CNVs to Pediatric and MODY Diabetes in Norway
Authors: Artaza Haydee , Priyanka Divya , Molnes Janne , Lavrichenko Ksenia , Wolff Anette S.B. , Røyrvik Ellen C. , Skrivarhaug Torild , Vaudel Marc , Bratland Eirik , Johansson Bente , Njolstad Pål Rasmus , Johansson Stefan
Published: February 2025

Technological advancements have significantly improved our understanding of Copy Number Variants (CNVs) and their role in disease. However, detecting CNVs in clinical diagnostics remains challenging, and important pathogenic CNVs may go undetected. This study systematically assessed the impact of rare, large, high-penetrance CNVs on pediatric diabetes and Maturity-onset Diabetes of the Young (MODY) in Norway. We analyzed data from the nationwide Norwegian Childhood Diabetes Registry (NCDR) covering 2002-2018 and the Norwegian MODY Registry (NMR) from 1997-2019. CNV detection was performed using the Illumina Infinium Global Screen Array-24 v2.0 on a total of 5,889 individuals and we compared the results to diagnostic records. Our findings indicate that 0.63% of the patients in the Norwegian MODY Registry and 0.09% in the Norwegian Childhood Diabetes Registry are attributable to established pathogenic large copy number deletions detectable by array genotyping. Notably, six of the 14 pathogenic deletions identified (in the HNF1B [n=3], HNF1A [n=2], or GATA4 genes [n=1]) had not been detected through standard diagnostic methods in the routine diagnostic screening. For these individuals, accurate molecular diagnoses have significant implications for personalized treatment and follow-up. We found no evidence suggesting a major role for additional rare CNVs beyond the already established pathogenic CNVs in MODY. In conclusion, while pathogenic CNVs are rare, they remain relevant for patients of the Norwegian nationwide diabetes registries. Expanding screening for MODY variants, specifically 17q12-HNF1B and HNF1A deletions, to a larger portion of the pediatric diabetes population should be considered.
Urbanisation and habitat fragmentation favour thermophilic and monogynous ant species
Authors: Finand Basile , Monnin Thibaud , Bocquet Céline , Bultelle Angélique , Fédérici Pierre , Darmedru Léa , Gouffault Solène , Ledamoisel Joséphine , Loeuille Nicolas
Published: February 2025

Environmental changes such as urbanisation and habitat fragmentation profoundly impact ecological communities. We investigated the response of ant communities to urbanisation and habitat fragmentation in the Paris region, comparing urban parks vs rural forests outside the city. We found a clear difference in species composition between urban and rural environments, with a higher prevalence of monogynous and thermophilic species in the city. Forest communities are homogeneous across the three fragmentation levels we studied, i.e. seem little impacted by fragmentation, while park communities differ noticeably depending on park size, with larger parks harbouring more species. Our findings suggest that urbanisation selects specific ant traits favouring more thermophilic species, thereby increasing the mean thermal preference of urban communities. Such selective effects constrain spatial dynamics at the metacommunity level, with important implications for their maintenance in a climate change context.
Consistent Performance of GPT-4o in Rare Disease Diagnosis Across Nine Languages and 4967 Cases
Authors: Chimirri Leonardo , Caufield J. Harry , Matentzoglu Nicolas , Gargano Mike A , Bridges Yasemin , Cazalla Mario , Chen Shihan , Danis Daniel , Dingemanns Alexander J.M. , Gehle Petra J. , Graefe Adam S L. , Gu Weihong , Ladewig Markus S. , Lapunzina Pablo , Nevado Julian , Ogishima Soichi , Seelow Dominik , Tenorio Castano Jair A , Turnovec Marek , de Vries Bert BA , Wang Kai , Wissink Kyran , Yuksel Zafer , Zucca Gabriele , Mungall Christopher J. , Haendel Melissa A. , Reese Justin , Robinson Peter N.
Published: February 2025

Background Large language models (LLMs) are increasingly used in the medical field for diverse applications including differential diagnostic support. The estimated training data used to create LLMs such as the Generative Pretrained Transformer (GPT) predominantly consist of English-language texts, but LLMs could be used across the globe to support diagnostics if language barriers could be overcome. Initial pilot studies on the utility of LLMs for differential diagnosis in languages other than English have shown promise, but a large-scale assessment on the relative performance of these models in a variety of European and non-European languages on a comprehensive corpus of challenging rare-disease cases is lacking. Methods We created 4967 clinical vignettes using structured data captured with Human Phenotype Ontology (HPO) terms with the Global Alliance for Genomics and Health (GA4GH) Phenopacket Schema. These clinical vignettes span a total of 378 distinct genetic diseases with 2618 associated phenotypic features. We used translations of the Human Phenotype Ontology together with language-specific templates to generate prompts in English, Chinese, Czech, Dutch, German, Italian, Japanese, Spanish, and Turkish. We applied GPT-4o, version gpt-4o-2024-08-06, to the task of delivering a ranked differential diagnosis using a zero-shot prompt. An ontology-based approach with the Mondo disease ontology was used to map synonyms and to map disease subtypes to clinical diagnoses in order to automate evaluation of LLM responses. Findings For English, GPT-4o placed the correct diagnosis at the first rank 19.8% and within the top-3 ranks 27.0% of the time. In comparison, for the eight non-English languages tested here the correct diagnosis was placed at rank 1 between 16.9% and 20.5%, within top-3 between 25.3% and 27.7% of cases. Interpretation The differential diagnostic performance of GPT-4o across a comprehensive corpus of rare-disease cases was consistent across the nine languages tested. This suggests that LLMs such as GPT-4o may have utility in non-English clinical settings.
Mechanism of giant magnetic field effect in fluorescence of mScarlet3, a red fluorescent protein
Authors: Xiang Katherine M. , Lampson Hana , Hayward Rebecca Frank , York Andrew G , Ingaramo Maria , Cohen Adam Ezra
Published: February 2025

Several fluorescent proteins, when expressed in E. coli, are sensitive to weak magnetic fields1. We found that mScarlet3 fluorescence in E. coli reversibly decreased by 21% in the presence of a 60 mT magnetic field, the largest magnetic field effect (MFE) reported in any fluorescent protein. Purified mScarlet3 did not show an MFE, but addition of flavin mononucleotide (FMN) and simultaneous illumination with blue and yellow light restored the MFE. Through extensive photophysical experiments, we developed a quantitative model of the giant MFE in mScarlet3-FMN mixtures. The key reaction step involved electron transfer from fully reduced FMNH2to triplet-state mScarlet3, to form a triplet spin-correlated radical pair. The magnetic field then controlled the branching ratio between singlet recombination vs. triplet separation. Our quantitative model of the mScarlet3-FMN photocycle provides a framework for design and optimization of magnetic field-sensitive proteins, opening possibilities in fluorescent protein-based magnetometry, magnetic imaging, and magnetogenetic control.
Lipid-mediated mechanism of drug extrusion by a heterodimeric ABC exporter
Authors: Tang Qingyu , Sinclair Matt , Bisignano Paola , Zhang Yunsen , Tajkhorshid Emad , Mchaourab Hassane
Published: February 2025

Multi-drug transport by ATP binding cassette (ABC) exporters entails a mechanism to modulate drug affinity across the transport cycle. Here, we combine cryo-EM and molecular dynamics (MD) simulations to illuminate a model of how lipid competition drives substrate translocation by ABC exporters. Cryo-EM structures of the ABC transporter BmrCD in drug-loaded inward-facing (IF) and outward-facing (OF) conformations in lipid nanodiscs reveal structural mechanism of alternating access, drug-transporter interactions, and the scale of drug movement. Remarkably, the structures uncovered lipid molecules bound to the transporter vestibule along with the drugs. MD trajectories from the IF structure show that these lipid molecules stimulate drug disorder and translocation towards the vestibule apex. Similarly, lipid molecules, poised at the OF vestibule entrance, enter the vestibule and weaken drug-transporter interactions facilitating drug release. Our results complete a near-atomic model of BmrCD conformational cycle and advance a general mechanism of lipid-driven drug transport by ABC exporters.
Müller glial Kir4.1 channel Dysfunction in APOE4-KI model of Alzheimer's disease
Authors: Abhyankar Surabhi , Xiao Yucheng , Mahajan Neha , Luo Qianyi , Cummins Theodore R , Oblak Adrian , Lamb Bruce T , Corson Timothy , Bhatwadekar Ashay D
Published: February 2025

Alzheimer's disease (AD), particularly late-onset AD (LOAD), affects millions worldwide, with the apolipoprotein E4 (APOE4) allele being a significant genetic risk factor. Retinal abnormalities are a hallmark of LOAD, and our recent study demonstrated significant age-related retinal impairments in APOE4-knock-in (KI) mice, highlighting that retinal impairments occur before the onset of cognitive decline in these mice. Muller cells (MCs), key retinal glia, are vital for retinal health, and their dysfunction may contribute to retinal impairments seen in AD. MCs maintain potassium balance via specialized inwardly rectifying K+ channels 4.1 (Kir4.1). This study posits that Kir4.1 channels will be impaired in APOE4-KI, resulting in MC dysfunction. Additionally, we demonstrate that MC dysfunction in APOE4-KI stems from alterations in mitochondrial dynamics and oxidative stress. Kir4.1 expression and function were studied using immunofluorescence and through the whole-cell voltage clamp, respectively. In parallel, rat Muller cells (rMC-1) were used to create an in vitro model for further mechanistic studies. Mitoquinol (MitoQ) was used to evaluate its potential to mitigate APOE4-induced deficits. APOE4 retinas and APOE4-transfected rMC-1 significantly reduced Kir4.1 expression, K+ buffering capacity, and increased mitochondrial damage. APOE4-transfected rMC-1 showed reduced mitochondrial membrane potential (ΔΨm) and increased mitochondrial reactive oxygen species (ROS). MitoQ treatment significantly reduced mitochondrial ROS and restored Kir4.1 expression in APOE4-expressing cells. Our results demonstrate that APOE4 causes mitochondrial dysfunction and MC impairment, which may contribute to retinal pathology in AD. MitoQ restored mitochondrial health and Kir4.1 expression in APOE4-expressing rMC-1, suggesting targeting mitochondria may offer a promising therapeutic strategy for AD.
Nasal septum deviation correlates with asymmetry in Parkinson's disease
Authors: Wang Jing , Liu Fengtao , Ge Jingjie , Sun Yimin , Tang Yilin , Liang Xiaoniu , Zhao Yixin , Yu Wenbo , Wu Jianjun , Lin Chensen , Zhou Yuanye , Zhang Yichi , Zhang Jianning , Wu Ping , Lu Jiaying , Ju Zizhao , Zhu Yuhua , Lin Huamei , Yang Yunhao , Xu Qian , Zheng Wei , Luo Jianfeng , Guan Yihui , Chen Honglei , Tian Mei , Zuo Chuantao , Wang Jian
Published: February 2025

Background Asymmetry in motor dysfunction and associated dopaminergic deficit is a common characteristic of Parkinson's disease (PD), yet potential explanations remain mysterious. Hereby, we assessed whether asymmetry in the nasal cavity is related to dopaminergic dysfunction asymmetry in PD patients. Methods This cross-sectional, multi-center observational study included 761 PD patients from three cohorts. First, we analyzed data from the Huashan Parkinsonian PET Imaging Database (March 2011 to February 2020), which served as the primary cohort (n=333). Second, we collected de novo data from all PD inpatients in the Hongqiao Campus of Huashan Hospital as internal validation cohort (May 2023 to July 2024, n=77). Finally, we used data from the Parkinson's Progression Markers Initiative as an external validation cohort (n=351). All cohorts included imaging data of structural MRI or CT, as well as dopaminergic neuroimaging using 11C−CFT, 18F−FP−CIT, or 18F−DTBZ on PET or 123I−DaTscan on SPECT. Nasal cavity asymmetry was assessed by visually inspecting the position of nasal septum deviation in structural MRI or CT to determine the dominant side. Both qualitative and quantitative analyses were performed to evaluate the correlations between nasal cavity asymmetry and dopaminergic deficit asymmetry. Results In the primary cohort, 70.2% of patients exhibited consistency between the dominant side of the nasal cavity and the side with a more severe dopaminergic deficit in striatum (φ=0.40, p<0.001). The striatal−specific binding ratios of dopamine uptake were significantly lower on the side ipsilateral to the dominant nasal cavity, and a significantly inverse correlation was found between the asymmetry index of nasal cavity surface area and that of the dopaminergic deficit (r=−0.31, p<0.001). Similar patterns were observed in internal (78.6%, φ=0.57, p<0.001) and external validation cohorts (73.1%, φ=0.45, p<0.001). A stronger correlation was found in sporadic PD (φ=0.67, p<0.001) compared to genetic PD patients (φ=0.31, p=0.3). Conclusions We made a novel and robust observation that the nasal cavity asymmetry is correlated with asymmetry in striatal dopaminergic deficiency in PD patients. The finding may have significant implications for both the etiological and clinical research of PD, supporting the nasal pathway as a potential route for both environmental pathogens and PD treatment.
Evaluating AI Reasoning Models in Pediatric Medicine: A Comparative Analysis of o3-mini and o3-mini-high
Authors: Mondillo Gianluca , Masino Mariapia , Colosimo Simone , Perrotta Alessandra , Frattolillo Vittoria
Published: February 2025

Artificial intelligence (AI) is increasingly playing a crucial role in modern medicine, particularly in clinical decision support. This study compares the performance of two OpenAI reasoning models, o3-mini and o3-mini-high, in answering 900 pediatric clinical questions derived from the MedQA-USMLE dataset. The evaluation focuses on accuracy, response time, and consistency to determine their effectiveness in pediatric diagnostic and therapeutic decision-making. The results indicate that o3-mini-high achieves a higher accuracy (90.55% vs. 88.33%) and faster response times (64.63 seconds vs. 71.63 seconds) compared to o3-mini. The chi-square test confirmed that these differences are statistically significant (χ^2 = 328.9675, p < 0.00001). Error analysis revealed that o3-mini-high corrected more errors from o3-mini than vice versa, but both models shared 61 common errors, suggesting intrinsic limitations in training data or model architecture. Additionally, accessibility differences between the models were considered. While DeepSeek-R1, evaluated in a previous study, offers unrestricted free access, OpenAI's o3 models have message limitations, potentially influencing their suitability in resource-constrained environments. Future improvements should aim at reducing shared errors, optimizing o3-mini's accuracy while maintaining efficiency, and refining o3-mini-high for enhanced performance. Implementing an ensemble approach that leverages both models strengths could provide a more robust AI-driven clinical decision support system, particularly in time-sensitive pediatric scenarios such as emergency care and neonatal intensive care units.
Tubulin Regulates the Stability and Localization of STMN2 by Binding Preferentially to Its Soluble Form
Authors: Deng Xiang , Bradshaw Gary , Kalocsay Marian , Mitchison Timothy
Published: February 2025

Loss of the tubulin-binding protein STMN2 is implicated in amyotrophic lateral sclerosis (ALS) but how it protects neurons is not known. STMN2 is known to turn over rapidly and accumulate at axotomy sites. We confirmed fast turnover of STMN2 in U2OS cells and iPSC-derived neurons and showed that degradation occurs mainly by the ubiquitin-proteasome system. The membrane targeting N-terminal domain of STMN2 promoted fast turnover, whereas its tubulin binding stathmin-like domain (SLD) promoted stabilization. Proximity labeling and imaging showed that STMN2 localizes to trans-Golgi network membranes and that tubulin binding reduces this localization. Pull-down assays showed that tubulin prefers to bind to soluble over membrane-bound STMN2. Our data suggest that STMN2 interconverts between a soluble form that is rapidly degraded unless bound to tubulin and a membrane-bound form that does not bind tubulin. We propose that STMN2 is sequestered and stabilized by tubulin binding, while its neuroprotective function depends on an unknown molecular activity of its membrane-bound form.
Glucagon dysfunction in the liver induces hyperplasia of PP cells and the production of glucagon and pancreatic polypeptide double-positive cells
Authors: Nakagawa Yuko , Horii Takuro , Fukunaka Ayako , Sato Takashi , Kobayashi Masaki , Kitamura Tadahiro , Hayashi Yoshitaka , Nishimura Takashi , Hatada Izuho , Fujitani Yoshio
Published: February 2025

Understanding the mechanisms that regulate cellular identity and proliferation is crucial for elucidating cellular functions. Under normal conditions, pancreatic endocrine cells express only a single hormone, and their numbers are tightly regulated. Contrary to this general principle, our study revealed a significant increase in glucagon (GCG) and pancreatic polypeptide (PP) double-positive cells (GCG+PP+double-positive cells), along with hyperplasia of both PP and α cells in proglucagon-deficient mice. Similarly, systemic glucagon receptor-deficient mice exhibited PP-cell hyperplasia and an increase in GCG+PP+double-positive cells, with enhanced PP-cell self-replication observed at 4 weeks and the appearance of GCG+PP+double-positive cells at 10 weeks. Liver-specific glucagon receptor-deficient mice induced similar effects, which were linked to hyperaminoacidemia. Elevated glutamine levels were found to promote GCG+PP+double-positive cell formation via mTOR signaling, suggesting a molecular mechanism driving pancreatic endocrine cell plasticity. Collectively, these findings indicate that increased plasma amino acid levels caused by impaired glucagon action in the liver promotes the proliferation of α cells and PP cells, and disturbs their cellular identity maintenance.
A prophage-encoded anti-phage defense system that prevents phage DNA packaging by targeting the terminase complex
Authors: Azulay Gil , Sigal Nadejda , Tzohar Rabinovich Keren , Koenigsfeld Dan , Stadnyuk Olga , Das Avijit , Lisitzin Polina , Biderman Einat , Borovok Ilya , Herskovits Anat A
Published: February 2025

A unique feature of temperate phages is the ability to protect their host bacteria from a second phage infection. Such protection is granted at the lysogenic state, where the phages persist as prophages integrated within the bacterial chromosome, expressing genes that defend the host and themselves from predation. Here, we report a prophage-encoded anti-phage defense system that inhibits DNA packaging of invading phages in Listeria monocytogenes. This system includes a defense protein, TerI, and two self-immunity proteins, anti-TerI1 and anti-TerI2. TerI targets the terminase complex of invading phages to prevent DNA translocation into procapsids without halting the lytic cycle, leading to the release of unpacked non-infectious procapsids upon bacterial lysis. In contrast, the self-immunity proteins, anti-TerI1 and anti-TerI2, counteract TerI during prophage induction to allow virion production. This unique prophage-encoded anti-phage defense system, TERi, is prevalent in Listeria phages, providing population-level host protection without compromising the prophage lytic lifecycle.
Functional analysis of FW2.2-LIKE proteins in tomato: SlFWL5 regulates leaf size and morphology.
Authors: Beauchet Arthur , Ehrard Lucie , Boutaleb Lina , Rofidal Vaérie , Gonzalez Nathalie , Chevalier Christian , Bollier Norbert
Published: February 2025

The CELL NUMBER REGULATOR/FW2.2-like (CNR/FWL) gene family comprises PLAC8 domain-containing membrane-associated proteins. The CNR/FWL gene family was named in reference to its founding member, the FW2.2 gene, which determines fruit size in tomato via a negative regulation on cell divisions. The functional characterization of PLAC8 domain-containing CNR/FWL proteins in plants is still very scarce, and only recently the molecular and cellular mode of action of FW2.2 was identified as regulating plasmodesmata-mediated cell-to-cell communication. In the present study, we provided a functional analysis of SlFWL genes in tomato, aiming at investigating any direct role in the control of organ growth. Based on a combination of molecular and cellular approaches, we selected three SlFWL proteins, namely SlFWL2, -4 and -5, which are localized at the plasma membrane. Gain- and loss-of-function transgenic plants were generated to explore their putative role as regulators of organ growth in tomato. This allowed us to shed light more specifically on the critical involvement of SlFWL5 in leaf development. We here showed that SlFWL5 is a plasmodesmata-localized protein that regulates leaf size and morphology via cell expansion, most probably through cell-to-cell communication. This original finding underscores further the importance of the CNR/FWL family members in growth regulation.