bluuebunny/crossref_metadata_2025 huggingface dataset:
MGM as a large-scale pretrained foundation model for microbiome analyses in diverse contexts
Authors: Zhang Haohong , Zhang Yuli , Kang Zixin , Song Lulu , Yang Ronghua , Ning Kang
Published: January 2025

Microbial communities significantly impact medicine, biotechnology, and agriculture. Advanced sequencing technologies have generated extensive microbiome data, enabling the discovery of substantial evolutionary and ecological patterns. However, traditional supervised learning methods struggle to capture universal patterns in microbial community data, largely due to the large data heterogeneity and profound batch effects among samples, rendering it difficult to classify samples as well as detect biomarkers from millions of samples, not to say the intricate but important dynamic patterns from a variety of contextualized sceneries. In this study, we introduce the Microbial General Model (MGM), the first microbiome community foundation model pre-trained on a dataset of 263,302 microbiome samples using language modeling techniques. MGM demonstrated significant improvements in microbial community classification compared to traditional machine learning methods. Additionally, MGM has enabled contextualized classification, effectively overcomes cross-regional limitations, showing enhanced performance on intercontinental datasets through transfer learning. Furthermore, fine-tuning MGM on a longitudinal infant dataset revealed distinct keystone genera during development, withBacteroidesandBifidobacteriumexhibiting higher attention weights in vaginal deliveries, andHaemophilusin cesarean deliveries. Finally, through in silico modeling, the model also uncovered novel microbial dynamic patterns in a Crohn’s disease cohort following antibiotic treatment. In conclusion, by leveraging self-attention and autoregressive pre-training, MGM serves as a versatile model for various downstream microbiome tasks and holds significant potential for achieving contextualized aims.

Key points

The Microbial General Model (MGM) is a foundation model with millions of parameters pre-trained on sub-million microbial community data.

MGM outperforms traditional methods in various microbiome classification and prediction tasks, such as microbial community classification.

MGM effectively captures the spatial and temporal dynamics of microbial communities.

MGM could detect the effects of perturbation on microbial community through in silico experiments.
Single-nucleus RNA sequencing revealed the impact of post-mortem interval on the cellular component and gene expression analysis of mouse brains
Authors: Guo Yunxia , Ma Junjie , Ma Xiaoying , Ye Kaiqiang , Jiang Chao , Xu Jitao , Huang Yan , Yang Xi , Ge Qinyu , Zhang Jianyou , Wang Guangzhong , Huang Hao , Zhao Xiangwei
Published: January 2025

Accurate analysis of cell atlas and gene expression in biological tissues using single-nucleus RNA sequencing (snRNA-seq) is dependent on the quality of source material, and post-mortem interval (PMI) is one of the major sources of variation in RNA quality. Although the use of RNA-degraded tissues in transcriptome analysis remains controversial, such samples are sometimes the sole means to address specific questions. Current studies on the impact of PMI on transcriptome data are limited to large-scale RNA-seq, which ignores cellular heterogeneity. Thus, deciphering the non-cell- autonomous effects caused by PMI is imperative for understanding the cellular and molecular disruption it elicits. Here, we investigated the impact of PMI on cellular components and gene expression using snRNA-seq data from mouse brain tissues of post-mortem. We collected samples that were allowed to decay for varying amounts of time at 25°C prior to snRNA-seq, covering the entire range of RIN values. The different effects on the PMI to the degradation rate of mRNA and rRNA within nuclei, and the mRNA presented a more stable state. Multi-channel analysis revealed the preferential transient depletion oligodendrocytes and OPCs with increasing PMI. In addition, a rapid widespread overregulation of ribosomal transient recruitment to protein (RP) genes in various cells, and reached a plateau at PMI of 36h. Although state depletion of neuronal cells was not detected, we reported significant upregulation of PMI-dependent RP genes in its subpopulations and their cell loss. Moreover, RP genes showed the greatest differential expression in the subpopulations with greater cell perturbation, and we speculated that aberrant expression of these genes might be associated with cell death. In this study, we systematically investigated the changes in the transcriptome profile of brain tissue induced by PMI at single-cell resolution, and revealed one of the important factors that might be responsible for the changes. In addition, our data complemented a possible explanation for the changes in the cellular state of brain tissue induced by postmortem hypoxia-ischemia, and provided a reference for transcriptome studies of RNA degradation samples.
Iris Crypts Could Reduce the Chance of Angle Closure: A Computational Biomechanics Study Derived from Clinical and Human Iris Data
Authors: Tan Royston K.Y. , Tun Tin A. , Braeu Fabian A. , Perera Shamira A. , Girard Michaël J.A.
Published: January 2025

Purpose

To investigate the effect of crypts during pupil constriction and dilation on the potential for angle closure by performing finite element analysis using clinical and experimental data on human tissues.

Methods

A computational model was developed to determine the influence of small crypts (surface area of ∼0.015 mm2) and large crypts (surface area of 0.300 mm2) on the anterior chamber angles during pupil dilation. The model needed permeability data from human subjects, hence 21 enucleated human eyes (72 hours post-mortem) were procured and subjected to a flow set-up previously reported. Finally, 66 subjects were recruited to measure pupil constriction and dilation levels from optical coherence tomography (OCT) videos.

Results

The hydraulic permeability of the human iris stroma was determined to be 2.55 ± 1.93 × 10-5mm2/Pa·s. The average iris constriction and dilation durations were 0.710 ± 0.213 seconds and 1.24 ± 0.401 seconds, respectively, with pupil diameter changes of 1.16 ± 0.39 mm and 0.75 ± 0.27 mm, respectively. The computational models had starting anterior chamber angles of 51.30° and final anterior chamber angles of 26.81° once steady state has been reached. In an extreme case with decreased anterior border layer (ABL) permeability, the anterior chamber angle narrowed to 12.37°, but the presence of crypts kept the angle above 20.36°, highlighting the potential of crypts in preventing angle closure.

Conclusions

Our findings on the biomechanics of crypts in the iris may drive the development of novel treatments by altering ABL morphology, providing an alternative bypass for angle closure prevention in high-risk patients.
Real World Performance of an Individualized Antitachycardia Pacing Algorithm
Authors: Jackson Troy , Taepke Robert , Birgersdotter-Green Ulrika , Cha Yong-Mei , Singh Jagmeet , Cheng Alan , Yee Raymond
Published: January 2025

Background

A novel individualized antitachycardia pacing (IATP) algorithm using the post-pacing interval for real-time control has been introduced. Performance information is limited to a small safety and feasibility study with additional single-center and case studies. A larger-scale analysis is needed to better understand algorithm performance.

Methods

De-identified remote monitoring transmissions from devices with the IATP therapy applied were randomly selected. Rhythms were classified and effects of the novel algorithm were assessed. For monomorphic ventricular tachycardias (MVTs) proportions of successful therapy, shock-free episodes, and acceleration were calculated using Generalized Estimating Equations to correct for multiple episodes and compute statistics of the algorithm’s performance.

Results

There were 2259 MVT episodes in 336 patients. IATP succeeded in 87.1% of MVT episodes with 89.9% of MVT episodes ultimately free of shock therapy. Based on multivariate analysis, significant factors in therapy success were programming of at least the recommended number of sequences (90% at least recommended vs 73%, p=0.00088) and female sex (95% for female vs 86%, p=0.002). A trend to higher success was found for MVT with cycle length of 320ms or greater (90% vs. 83%, p=0.10). The IATP accelerated 3.6% of MVT episodes. None of the available factors was significantly associated with acceleration in the multivariate analysis.

Conclusions

The IATP algorithm succeeded in large proportion of MVT episodes and with low acceleration in patients randomly selected from remote monitoring transmissions. Using at least the recommended number of sequences had the strongest association with successful therapy.

CLINICAL PERSPECTIVE

What is known

A novel method for delivering antitachycardia pacing therapy using real-time feedback has been shown safe and feasible.

Comparisons in computational studies and smaller case series suggest the novel method’s performance is superior to other antitachycardia pacing methods.

What the study adds

Under real-world programming and use, as evaluated on a large de-identified set of remote monitoring transmissions, the novel antitachycardia pacing algorithm treated monomorphic ventricular tachycardia episodes with high efficacy and a low proportion of acceleration.

The strongest factor associated with successful therapy was programming at least the recommended number of pacing attempts.
Using green space virtual reality to prevent stress-induced working memory impairment
Authors: Xu Yingying , Yang Zixuan , Zhou Xiaoxuan , Yao Qingyi , Dai Guohang , Liu Wei , Zhao Hui
Published: January 2025

Exposure to green space is associated with both physical and mental health benefits, including the potential to buffer acute stress responses, positioning it as a promising non-pharmacological approach to protect cognitive functions against stress. However, urban residents often face significant barriers in accessing green spaces, which are not equitably distributed. Virtual Reality (VR) technology offers a potential solution by simulating green space that could be made accessible to a broader demographic. Here, we explored whether VR-stimulated green space could dampen biological stress responses (i.e., heart rate and cortical response) and prevent stress-induced working memory (WM) impairment. Healthy young participants underwent acute stress induction followed by 15 minutes of VR-based green space (N=36) or control empty space (N=30) intervention. Although we observed the expected stress-induced increase in heart rates and elevated cortisol levels under stress, VR green space exposure failed to temper cortisol responses compared to the control VR space. Further, VR green space exposure did not bring benefits to protect working memory performance under stress across three WM tasks. Applying a Bayesian analysis approach throughout enabled us to find substantial evidence for the absence of an effect of VR-based green space exposure on biological markers of acute stress responses and working memory performance. Our findings suggest that VR-generated green space may not effectively replicate the stress-buffering effects of actual green space exposure. We discussed the implications of our findings regarding the potential and limitations of using VR or green space exposure to buffer stress responses.
Experimental assessment of large mammal population estimates from airborne thermal videography
Authors: McElhinny Julia S. , Larsen Gregory D. , Messinger Max , Newbolt Chad H. , Whitworth Andrew , Ditchkoff Stephen S. , Silman Miles R. , Beaver Jared T.
Published: January 2025

Wildlife resource management requires reliable, fast, and affordable methods of surveying wildlife populations to develop and adaptively adjust policies. Many methods are used to survey populations of large mammals, and thermal video from drones can yield high rates of detection over large extents with relative speed and safety. In wild populations it can be difficult to estimate detection rates and the accuracy of resulting abundance estimates, especially because many factors of study design and natural systems can influence counts from thermal surveillance. We surveyed a captive white-tailed deer (Odocoileus virginianus) population of known size at the 174-ha Auburn Deer Facility in Auburn, AL, USA, and used a designed experiment to investigate the effects of observers, time-of-day, and day-to-day variation on the accuracy of abundance estimates from trial flights using drone-based airborne thermal videography. The experiment consisted of 20 full-census trials, occurring over 4 days, at times-of-day before sunset, after sunset, near midnight, before sunrise, and after sunrise, with each trial video counted by three trained observers. Counts across all trials and observers yielded a mean point estimate of 77 (95% CI 71–83) deer representing 81–97% of the known population range. Flights near sunset yielded estimates of the highest accuracy, within or close to the true range of the population. Variability in estimates was primarily influenced by daily climatic conditions and time-of-day, with only minor observer effects. Results highlight the importance of day-to-day variability in environmental conditions and diel processes, such as nocturnal cooling of the environment and crepuscular peaks in deer activity. The estimates from our experiment and resulting model illustrate that censuses conducted at optimal times-of-day and averaged across multiple days were able to achieve accurate estimates within the known range without correction, and that by averaging across flights, even including suboptimal conditions, thermal videography returned estimates within 4% of the known range with substantial overlap of the estimate. Conversely, single estimates chosen at random from any time-of-day varied widely around the known value, highlighting the need to plan flights with respect to diurnal activity patterns and landscape thermal properties, or, in the absence of information, average multiple surveys across times and days.
Adaptability and yield stability analysis of food barley (Hordeum vulgareL.) in South Gondar zone, Northwest Ethiopia
Authors: Worku Alamir Ayenew , Fentie Dejen Bekis , Shferaw Solomon Sharie
Published: January 2025

In food barley, genotype-environment interaction is a frequent occurrence. By identifying stable genotypes across settings, the impact of G x E can be mitigated. Ten food barley genotypes were investigated for yield stability and adaptation in five different environments. The analyses included stability, genotype, and genotype-environment interaction, as well as additive main effect and multiplicative interaction. However, genotype-environment interaction captured 92.98% of the GGE variance. AMMI analysis only explained 27.87% of G and 20.12% of G x E. Five environments were identified using GGE analysis. Of these, Estie2022 (3591.3 kg ha−1) and Debretabor2022 (3494.47 kg ha−1) had the highest grain yields, indicating that they are suitable for the production of food barley, while Lay-Gaynt2023 (2399.82 kg ha−1) had the lowest grain yields, indicating that they are not a suitable environment. The conditions with the best yields were Estie2022, and the lowest-yielding environments were Lay-Gaynt 2023. The two genotypes with the highest yields were HB-1966 (3592.97 kg ha-1) and HB-1965 (3555.17 kg ha-1). Based on yield stability, the genotypes Biftu, followed by Adoshe and Abdene, were the most stable with the highest mean grain yield performance. The genotypes with the highest-yielding performance but relatively the lowest stability were HB-1966 and HB-1965. The genotype HB-1965 was recommended at the Estie2022 and Debretabor2023 testing environments. The ideal environment was represented by Estie2023, and the winning genotype was HB-1966. This suggests that the two winning genotypes were adapted to the specific environments tested in the current study. Whereas Guta and Harbu were adapted to a more diverse environment than the test environments of the South Gondar Zone, Northwest Ethiopia.
Trogocytosis-mediated transfer of FOLR2 from Nurse-like cells to CLL cells is linked to their activation and proliferation
Authors: Domagala Marcin , Gerby Bastien , Bazile Chloe , Ysebaert Loïc , Pancaldi Vera , Laurent Camille , Poupot Mary
Published: January 2025

This study, conducted on primary human samples, identifies a novel pro-tumoral interaction between nurse-like cells (NLCs) and chronic lymphocytic leukemia (CLL) cells, relying on the trogocytosis-mediated transfer of functional Folate Receptor β (FOLR2) from NLCs to cancer cells. Trogocytic CLL cells carrying NLC-derived FOLR2 exhibit an enhanced capacity for folic acid internalization. Furthermore, induction of the proliferative state of CLL cells with CD40L+IL-15 treatment in the presence of NLCs, to imitate lymph node (LN) environmentin vitro, revealed that trogocytic FOLR2+cancer cells are enriched in the fraction of active and proliferating cells, particularly under condition of folic acid depletion. FOLR2 remains detectable on CLL cells as long as they maintain their proliferative status. Moreover, its level remains stable in the actively cycling cells, implying that cancer cells engage in trogocytosis with NLCs between successive cell divisions. Analysis of the LNs from CLL patients reveals, for the first time, the presence of FOLR2+NLCs, whose frequency correlates with increased proliferation of cancer cells, and allowed detection of FOLR2+CLL cells, providing evidence of trogocytosis between NLCs and CLL cells in vivo. Finally, it proposes FOLR2 as a novel marker of M2-like NLCsin vitroand discovers a presence of heterogenous subpopulations of NLCs in the CLL lymph nodes, with varying expression of CD163 and FOLR2. These results shed light on the underappreciated role of trogocytosis in the increasing adaptability of malignant cells in the tumor microenvironment (TME) context and stress the importance of NLCs in the pathophysiology of CLL.

Schematic representation of trogocytosis-mediated acquisition of NLC-derived FOLR2 by CLL cells as a novel mechanism of cancer cell’s interaction with TME and adaptation to the adverse conditions. 1) CLL cells enter the lymph node (LN) and engage in contact with FOLR2+NLCs. 2) Presence of T cells presenting CD40L and stromal cells producing IL-15 promotes the activation and trogocytosis-mediated acquisition of FOLR2 by CLL cells. FOLR2+ trogocytic CLL cells show increased acquisition of folates and are more likely to proliferate, as compared with the remaining population of cancer cells.

KEY POINTS

FOLR2 is a marker of M2-like protective NLCs

CLL cells acquire functional FOLR2 from NLCs through trogocytosis, enabling them to enhance folate uptake

Trogocytic FOLR2+CLL cells are enriched in the fraction of activated and proliferative cells, especially during folic acid scarcity

Detection of FOLR2+NLCs and FOLR2+trogocytic CLL cells in the LNs of CLL patients.
Single-shot label-free nanoscopy for quantitative organelle visualization on standard commercial microscopes
Authors: Inutsuka Yugo , Yamamoto Koki , Kuroda Masafumi , Okada Yasushi
Published: January 2025

Label-free microscopy techniques that overcome the limitations of fluorescence microscopy are increasingly needed in biological research. Quantitative phase imaging has emerged as a powerful label-free method for live cell imaging, particularly at multicellular scales. However, a critical gap exists in achieving easy-to-implement, high-speed, high-resolution microscopy at subcellular scales. Here, we report upgraded polarization-resolved differential phase contrast nanoscopy (UpDPC); this single-shot computational phase microscopy (CPM) enhances resolution and sensitivity to subcellular levels. UpDPC can be readily integrated into commercial fluorescence microscopes, enabling 100 nm gap separation, over 100 Hz imaging via single-shot phase retrieval, and 100 ms computation of phase image during observation. Our results demonstrate that high-performance CPM provides reproducible and comprehensive visualization of various organelles, offering a practical and scalable implementation for basic research and clinical applications.
The Artists’ Brain: A Data Fusion Approach to Characterize the Neural Bases of Professional Visual Artists
Authors: Taskiran Erdem , Bacci Francesca , Melcher David , Grecucci Alessandro , De Pisapia Nicola
Published: January 2025

Artistic creativity relies on complex perceptual, cognitive and motoric functions, yet the specific neural characterization of being an artist remain incompletely understood. To fill this gap in the literature, the present study aims to characterize the gray matter (GM) and white matter (WM) contributions to professional visual artists as compared to non-artists controls. The MRI brain scans of 12 professional artists and 12 matched non-artists were analyzed via an unsupervised machine learning method known as Transposed Independent Vector Analysis (tIVA) to detect joint GM-WM networks. Two independent networks were found. The first network (IC2), more expressed in artists, included increased GM-WM concentration in regions associated with the Default Mode Network (DMN), Executive Control Network (ECN), and sensorimotor networks possibly related with augmented cognitive and ideational control, and increased perceptual-motor integration skills critical for creative tasks. The second network (IC8), less expressed in artists, included decreased GM-WM density in regions related to the Salience Network, such as the Anterior Cingulate Cortex, suggesting attentional regulation processes that may not be as central to visual artists. In sum, these results suggest that artists may rely on specialized brain networks, reflecting unique neural adaptations in individuals with pronounced creativity and extensive creative training.
Enzyme kinetics model for the coronavirus main protease including dimerization and ligand binding
Authors: La Van Ngoc Thuy , Kang Lulu , Minh David D. L.
Published: January 2025

The coronavirus main protease (MPro) plays a pivotal role in viral replication and is the target of several antivirals against SARS-CoV-2. In some species, CRCs of MPro enzymatic activity can exhibit biphasic behavior in which low ligand concentrations activate the enzyme whereas higher ones inhibit it. While this behavior has been attributed to ligand-induced dimerization, quantitative enzyme kinetics models have not been fit to it. Here, we develop a kinetic model integrating dimerization and ligand binding. We perform a Bayesian regression to globally fit the model to multiple types of biochemical and biophysical data. The reversible covalent inhibitor GC376 strongly induces dimerization and binds to the dimer with no cooperativity. In contrast, the fluorescent peptide substrate has a minor effect on dimerization but binds to the dimer with positive cooperativity. The biphasic concentration response curve occurs because compared to substrate, the inhibitor accelerates turnover in the opposite catalytic site.
Promiscuous structural cross-compatibilities between major shell components ofKlebsiella pneumoniaebacterial microcompartments
Authors: Barthe Lucie , Balestrino Damien , Azizi Bessam , Dessaux Delphine , Soldan Vanessa , Esque Jeremy , Schiex Thomas , Barbe Sophie , Garcia-Alles Luis Fernando
Published: January 2025

Bacterial microcompartments (BMC) are submicrometric reactors that encapsulate dedicated metabolic activities. BMC-H hexamers, the most abundant components of BMC shells, play major roles for shell plasticity and permeability. In part, chemical exchanges between the BMC lumen and the cellular cytosol will be defined by the disposition of amino acids lining the central BMC-H pores. Current models attribute to BMC-H a homo-oligomeric nature. The hexagonal symmetry of corresponding pores, however, would break down if hetero-hexamers formed, a possibility suggested by the frequent presence of multiple paralogs within BMC operons. Here, we gauged the degree of structural promiscuity between the 11 BMC-H paralogs fromKlebsiella pneumoniae, a potential human pathogen endowed with the capacity to express three different BMC types. Concomitant activation of transcription of several BMC operons was first shown to be possible. By leveraging an adapted tripartite GFP technology, all possible BMC-H pair combinations were screened inE. coli. Multiple structural cross-compatibilities were pinpointed between homologs arising not only from the same BMC operon, but also from different BMC types, results supported by Alphafold and ESMFold predictions. The structural stability and assembly propensity of selected hetero-associations was established by biochemical means. In light of these results, we reinterpreted published lysine cross-linking mass spectrometry data to demonstrate that one of these hetero-hexamers, involving PduA and PduJ, was already detected to form in the shell of a recombinantly-expressed 1,2-propanediol utilization compartment fromSalmonella enterica. Altogether, this study points to the need to embrace an augmented structural complexity in BMC shells.
Fibroblast–Neuron Interactions Driving Persistent Pain in Rheumatoid Arthritis (FiND-Pain RA) - a study protocol
Authors: Xenophontos Mikalena , Baldeweg Friederike C. , Ross Rosie , Rutter-Locher Zoe , Hill Sarah , Ryan Sarah , Awadelkareem Mosab Ali , Law Shing T. , Bennett David L. , Buckley Christopher D. , Humby Frances , Kirkham Bruce W. , Denk Franziska , Taams Leonie S.
Published: January 2025

Introduction

Pain in patients with rheumatoid arthritis (RA) is an unmet clinical need. Targeting joint inflammation with disease modifying antirheumatic drugs (DMARDs) has not resulted in the anticipated reduction in pain for many patients. This can partly be explained by the concept of central sensitisation whereby spinal and supraspinal pathways have a lower threshold of activation leading to increased perception of pain. Synovial stromal cells such as fibroblasts are also thought to play a role through peripheral sensitisation of nerves in the joint. Synovial fibroblasts are known to produce pro-algesic mediators such as interleukin 6 (IL-6) and nerve growth factor (NGF) at the mRNA level. These pro-algesic mediators could activate sensory nerve fibres that send signals from the joint to the spinal cord, thereby driving persistent pain in RA. The purpose of this study is to evaluate which pro-algesic mediators are produced by lining versus sublining fibroblasts and whether the level of these mediators correlates with clinical measures of pain in patients with RA.

Methods and analysis

FiND-Pain RA is a multi-centre observational study which will recruit 50 patients with seropositive RA who attend the rheumatology department of Guy’s and St Thomas’ Hospital, London and the Nuffield Orthopaedic Centre, Oxford. Clinical examination, pain-focused patient reported outcome measures (PROMs), ultrasound examination and ultrasound guided synovial biopsy of the knee will be performed. The levels of known and putative pro-algesic mediators will be measured in fibroblasts from the lining and sublining layer of the synovium. The location and spatial morphology of sensory nerve fibres and their proximity to lining and sub-lining fibroblasts will be characterized. The primary outcome will be to determine whether the knee pain scores of participants correlate with the level of LIF, a novel putative pain-mediator expressed in sub-lining fibroblasts. The secondary outcomes will be to determine whether other pro-algesic mediators produced by lining or sub-lining fibroblasts correlate with clinical measures of pain and to assess the location and proximity of sensory nerve fibres to lining versus sub-lining fibroblasts.

Ethics and dissemination

The study has been approved by the Bromley Research Ethics Committee (REC: 21/LO/0712). The findings of this study will be disseminated through open-access publications, as well as scientific and clinical conferences.
Force Generation by Enhanced Diffusion in Enzyme-Loaded Vesicles
Authors: Eberhard Eike , Burger Ludwig , Pastrana César L. , Seyed-Allaei Hamid , Giunta Giovanni , Gerland Ulrich
Published: January 2025

Recent experiments have shown that the diffusion coefficient of some metabolic enzymes increases with the concentration of their cognate substrate, a phenomenon known as enhanced diffusion. In the presence of substrate gradients, enhanced diffusion induces enzymatic drift, resulting in a non-homogeneous enzyme distribution. Here, we study the effects of enhanced diffusion on enzyme-loaded vesicles placed in external substrate gradients using a combination of computer simulations and analytical modeling. We observe that the spatially inhomogeneous enzyme profiles generated by enhanced diffusion result in a pressure gradient across the vesicle, which leads to macroscopically observable effects, such as deformation and self-propulsion of the vesicle. Our analytical model allows us to characterize dependence of the velocity of propulsion on experimentally tunable parameters. The effects predicted by our work provide an avenue for further validation of enhanced diffusion, and might be leveraged for the design of novel synthetic cargo transporters, such as targeted drug delivery systems.
In vivo itaconate tracing reveals degradation pathway and turnover kinetics
Authors: Willenbockel Hanna F. , Williams Alexander T. , Lucas Alfredo , Dowerg Birte , Cabrales Pedro , Metallo Christian M. , Cordes Thekla
Published: January 2025

Itaconate is an immunomodulatory metabolite that alters mitochondrial metabolism and immune cell function. This organic acid is endogenously synthesized via tricarboxylic acid (TCA) metabolism downstream of TLR signaling. Itaconate-based treatment strategies are being explored to mitigate numerous inflammatory conditions. However, little is known about the turnover rate of itaconate in circulation, the kinetics of its degradation, and the broader consequences on metabolism. By combining mass spectrometry and in vivo13C itaconate tracing, we demonstrate that itaconate is rapidly eliminated from plasma, excreted via urine, and fuels TCA cycle metabolism specifically in the liver and kidneys. These studies further revealed that itaconate is converted into acetyl-CoA, mesaconate, and citramalate in mitochondria. Itaconate administration also influenced branched-chain amino acid metabolism and succinate levels, indicating a functional impact on succinate dehydrogenase (SDH) and methylmalonyl-CoA mutase (MUT) activity. Our findings uncovered a previously unknown aspect of the itaconate metabolism, highlighting its rapid catabolism in vivo that contrasts findings in cultured cells.
The Potential of Dietary Strategies: The Impact of Low-Carbohydrate Diet on Cardiovascular-Kidney-Metabolic Syndrome
Authors: Li Zhuoxing , Liu Xiunan , Ma Xin , Xiao Mao , Zhang Xue , Deng Yanyi , Liu Hao , Sun Yun , Xiao Xiang
Published: January 2025

This study aims to explore the prevalence of Low-carbohydrate diet (LCD) among individuals with cardiovascular-kidney-metabolic (CKM) syndrome and its relationship with prognosis.

Methods

The individuals diagnosed with CKM were included from the National Health and Nutrition Examination Survey (NHANES) database between 2009 and 2018. Participants were divided into two groups: those on a LCD and those not on a LCD. Multivariate logistic regression analysis was conducted to assess the factors influencing the choice of LCD among CKM individuals. Kaplan-Meier survival curve analysis and multivariate Cox regression analysis were performed to evaluate the association between LCD and the risk of all-cause mortality. Stratified analysis was performed to assess the consistency of results.

Results

A total of 1000 non-CKM (stage 0) individuals and 11,141 CKM individuals (stages 1, 2, 3, and 4) were included. The proportions of individuals on LCD for CKM stages 0, 1, 2, 3, and 4 were 1.16%, 2.49%, 1.94%, 1.24%, and 1.68%, respectively. Multivariate logistic regression analysis indicated that age, and race might influence the choice of LCD among CKM individuals. Multivariate Cox regression analysis revealed that compared to non-LCD individuals, those on LCD had a 62% reduced risk of all-cause mortality (HR = 0.38; 95% CI, 0.15-0.92, P = 0.03). Stratified analysis showed no interaction between LCD and CKM stages (Pfor interaction < 0.05).

Conclusion

The proportion of individuals on LCD in CKM is relatively low. Furthermore, LCD can decrease the risk of all-cause mortality among CKM individuals, regardless of CKM stage.
A Randomized Controlled Trial of Cognitive Behavioral Therapy for Insomnia During Early Recovery from Alcohol Use Disorder Among Veterans
Authors: Chakravorty Subhajit , Morales Knashawn H. , Perlis Michael L. , Kuna Samuel T. , He Sean , Oslin David W. , Arnedt J. Todd , Kranzler Henry
Published: January 2025

Study Objectives: 1) To determine the efficacy of Cognitive Behavioral Therapy for Insomnia (CBT-I) for improving insomnia, alcohol-related outcomes, and daytime functioning at post-treatment and at 3- and 6-month follow-up, in a largely African American Veteran sample; 2) Evaluate whether improvement in insomnia is associated with a reduction in alcohol-related outcomes post-treatment. Methods: An RCT of CBT-I (n = 31) compared to Quasi-Desensitization therapy (QDT, n = 32), eight weekly in-person sessions, with assessments at baseline, end of treatment (8 weeks), and 3- and 6-months post-treatment. Primary outcomes were the Insomnia Severity Index (ISI) total score, and Percent Days Abstinent (PDA). Secondary outcomes were sleep diary variables, drinks per day, percentage non-heavy drinking days, Penn Alcohol Craving Scale, PCS and MCS scale (from the SF-12), BDI and STAI-Trait subscale total scores. Results: Post-treatment data were obtained from 88.9% of participants. Although CBT-I improved insomnia with effect sizes (E.S.) larger than the meta-analytic estimates, QDT was equally efficacious in improving insomnia (E.S. = -1.63 vs. -1.50), improving abstinence (E.S. = 1.54 vs. 1.91) and next-day functioning (E.S. = -0.26 vs. -0.17). Across treatment groups, remission from insomnia was associated with a lower post-treatment alcohol craving score (2.79, 95% CI 1.14, 4.44 vs. 9.51, 95% CI 6.06, 12.95 in non-responders), an effect that persisted for 6 months after treatment. Conclusions: CBT-I and QDT are equally effective for treating insomnia during early recovery from AUD. Reduced alcohol craving may be a mechanism by which a remission from insomnia improves drinking outcomes.
Risk of Hypertensive Disorders of Pregnancy in Patients With Cardiac Disease
Authors: Jones Maura , Quist-Nelson Johanna , Fuller Matthew , Volz Elizabeth , Snow Sarah , Habib Ashraf S , Federspiel Jerome , Boggess Kim , Meng Marie-Louise
Published: January 2025

Background

Pregnant patients with cardiovascular disease (CVD) face increased risk of preeclampsia and preterm delivery, yet data is limited data regarding degree of risk and impact of hypertensive disorders of pregnancy (HDP) on gestational age at delivery.

Objectives

To examine HDP risk and impact on delivery timing in patients with CVD.

Methods

This retrospective cohort study included patients >18 years old who delivered between 10/1/2015 and 12/31/2020 using the Premier Healthcare Database. Patients with CVD were divided into six categories: congenital, ischemic, aortic pathology, pulmonary hypertension, cardiomyopathy, and valvular disease. The primary outcome was risk of HDP (gestational hypertension/ preeclampsia). The secondary outcome was gestational age at delivery. Multivariable mixed effects regression models were used to estimate adjusted outcomes, adjusting for CVD subtype, >1 CVD subtype present, demographics, hospital characteristics, and comorbidities.

Results

Among 4,606,247 obstetric patients, 20,021 had CVD. The risk of HDP among people with CVD varied by CVD subtype, lowest in those with congenital heart disease (aOR,0.9; 95% CI [0.8, 1.0]) and highest in those with pulmonary hypertension (aOR, 1.5; 95% CI [1.3, 1.8]) and cardiomyopathy (aOR,1.5; 95% CI [1.4,1.6]). Patients with CVD delivered earlier than those without CVD, even in the absence of HDP(36.4–38.0 weeks versus 38.4 weeks). Among those with HDP, patients with severe pre-eclampsia with CVD, delivered earlier than those without CVD (33.1–34.6 weeks versus 35.5 weeks).

Conclusion

Risk of HDP and preterm delivery is higher those with CVD, particularly in pulmonary hypertension and cardiomyopathy. Patients with CVD should be advised of their increased risk.
Effects of Immediate Postpartum Diuretic Treatment on Postpartum Blood Pressure among Individuals with Hypertensive Disorders of Pregnancy: A Systematic Review and Meta-Analysis
Authors: Keen Susan K. , Sall Koura , Koczo Agnes , Wang Yisi , Miller Rebekah S. , Muldoon Matthew F. , Hauspurg Alisse K. , Countouris Malamo E.
Published: January 2025

Background

Hypertensive disorders of pregnancy (HDP) are associated with ongoing postpartum hypertension (HTN) and increased morbidity. Extravascular water and sodium mobilization is implicated in postpartum blood pressure (BP) elevation, however trials of postpartum diuretics in HDP have had mixed results. Our meta-analysis aimed to analyze the impact of postpartum diuretics on postpartum hypertension following HDP.

Methods

Systematic review identified randomized controlled trials (RCTs) studying the efficacy of diuretics in the treatment of postpartum BP. Meta-analysis outcomes included persistent HTN up to 10 days postpartum, mean postpartum systolic and diastolic BPs, and use of additional antihypertensive medications.

Results

From 9 RCTs, 1273 subjects were included in the meta-analysis. Postpartum diuretic use was associated with lower systolic BP (SMD standard mean difference]: -0.36; 95% confidence interval [CI]: -0.72; -0.01) without a difference in diastolic BP (SMD: 0.01; 95% CI: -0.22; 0.23) compared with controls. There was no difference in rates of persistent HTN between the postpartum diuretics group versus controls (OR: 0.70; 95% CI: 0.4; 1.05) or in antihypertensive medication use (OR: 0.66; 95% CI: 0.42; 1.05).

Conclusion

Postpartum diuretic use was associated with lower systolic BP compared with controls and non-significant trends of lower rates of persistent HTN and postpartum antihypertensive medication use. Due to the low certainty of evidence, uniform postpartum diuretic use with HDP cannot be recommended. Future studies are needed to evaluate specific HDP subgroups who may benefit from diuretic use.
Causal mediation analysis of the neuroprotection ofAPOE2through lipid pathways
Authors: Xiang Qingyan , Lok Judith J. , Roth Nicole , Andersen Stacy L. , Perls Thomas T. , Song Zeyuan , Yashin Anatoli I. , Mengel-From Jonas , Patti Gary J. , Sebastiani Paola
Published: January 2025

Background

Recent studies have revealed a strong association between the e2 allele of the Apolipoprotein E (APOE2)gene and lipid metabolites. In addition,APOE2carriers appear to be protected from cognitive decline and Alzheimer’s disease. This correlation supports the hypothesis that lipids may mediate the protective effect ofAPOE2on cognitive function, thereby providing potential targets for therapeutic intervention.

Methods

We conducted a causal mediation analysis to estimate both the direct effect ofAPOE2and its indirect effect through 19 lipid species on cognitive function, using metrics from the digital Clock Drawing Test (CDT) in 1291 Long Life Family Study (LLFS) participants. The CDT metrics included think-time, ink-time, and their sum as total-time to complete the test.

Results

Compared to carriers of the commonAPOE3,APOE2carriers completed the CDT significantly faster. Two lipids showed protective mediation when elevated in the blood, resulting in shorter CDT think-time (CE 18:3), ink-time (TG 56:5), and total completion time (CE 18:3 and TG 56:5). Elevated TG 56:4, in contrast, showed deleterious mediation resulting in increased ink-time. The combined indirect effect through all lipids significantly mediated 23.1% of the total effect ofAPOE2 on total-time, reducing it by 0.92s (95% CI: 0.17, 2.00). Additionally, the sum of total indirect effect from all lipids also mediated 27.3% of the total effect on think-time, reducing it by 0.75s, and 13.6% of the total effect on ink-time, reducing it by 0.17s, though these reductions were statistically insignificant. Sensitivity analysis yielded consistent results of the combined indirect effects and total effects and identified additional significant lipid pathways (CE 22:6, TG 51:3, and TG 54:2).

Conclusions

We found that the combined indirect effect through all lipids could mediate 10%-27% of the total direct effect ofAPOE2on CDT times. We identified both protective and deleterious lipids, providing insights for new therapeutics targeting those lipids to modulate the protective effects ofAPOE2on cognition.
Divergent endothelial mechanisms drive arteriovenous malformations in Alk1 and SMAD4 loss-of-function
Authors: Oppenheim Olya , Giese Wolfgang , Park Hyojin , Baumann Elisabeth , Ivanov Andranik , Beule Dieter , Eichmann Anne , Gerhardt Holger
Published: January 2025

Hereditary hemorrhagic telangiectasia is an autosomal dominant disorder caused by mutations in the bone morphogenetic protein signaling pathway, leading to arteriovenous malformations. While previously thought to share molecular and cellular dysregulation, this study reveals highly distinct mechanisms depending on whether mutations occur in Alk1 or SMAD4. Loss of SMAD4 enhances endothelial cell responses to flow, including flow-regulated transcription and cell migration against blood flow, causing excessive pruning of capillaries and the formation of single large shunts. Conversely, Alk1 deficiency disrupts endothelial flow responses, including cell polarization and directional migration, leading to a dense vascular network and the persistence of a malformation nidus. In vivo cell population tracking of mutant cells validates unique endothelial cell migration defects. Mosaic cell culture models further illustrate that mutant cells co-opt wild-type cells driving distinct Alk1 or SMAD4 mutant-like behavioral defects. These findings demonstrate that arteriovenous malformations develop through fundamentally different cellular mechanisms based on the specific genetic mutation emphasizing the need for tailored diagnostic and therapeutic strategies.
Adolescents and adults with FOXP1 syndrome show high rates of anxiety and externalizing behaviors but not psychiatric decompensation or skill loss
Authors: Levy Tess , Silver Hailey , Soufer Renee , Rouhandeh Audrey , Kolevzon Alexander , Buxbaum Joseph D. , Siper Paige M.
Published: January 2025

Background

FOXP1 syndrome is a genetic neurodevelopmental disorder associated with complex clinical presentations including global developmental delay, mild to profound intellectual disability, speech and language impairment, autism traits, attention-deficit/hyperactivity disorder (ADHD), and a range of behavioral challenges.. To date, much of the literature focuses on childhood symptoms and little is known about the FOXP1 syndrome phenotype in adolescence or adulthood.

Methods

A series of caregiver interviews and standardized questionnaires assessed psychiatric and behavioral features of 20 adolescents and adults with FOXP1 syndrome. Interviews captured change in various psychiatric manifestations over time. Medication, social, educational, and vocational history was collected and visual analog scales measured top caregiver concerns during childhood and adolescence/adulthood.

Results

Anxiety and externalizing behaviors were common in this cohort and psychiatric features, such as psychosis or bipolar symptoms, were present in two participants. There was no reported regression or loss of skills, early in development or during adolescence/adulthood. Caregivers reported continued development in adaptive skills even into adolescence/adulthood. Medication use was common particularly for features of ADHD, although multiple trials were required for some participants to achieve benefit. Standardized assessments accurately picked up on externalizing symptoms and were less sensitive to internalizing symptoms. Educational setting varied up until late elementary school and gradually shifted to special education. Cognitive and developmental concerns were reported as primary during childhood and independence/safety and housing concerns became top concerns by adolescence/adulthood. Caregivers reported continued development in adaptive skills even into adulthood.

Conclusions

Taken together, results are reassuring, with many families reporting their adolescent and adult children continued to gain skills over time, particularly related to increased independence in communication and personal care. There were no reports of developmental regression, neuropsychiatric decompensation or catatonia.
The trans-kingdom spectrum of Mpox-like lesion pustules of suspect patients in the Mpox subclade Ib outbreak in Eastern Democratic Republic of the Congo
Authors: Murhula Masirika Leandre , Hewins Benjamin , Toloue Ostadgavahi Ali , Dutt Mansi , Mutimbwa Mambo Léandre , Udahemuka Jean Claude , Ndishymie Pacifique , Bengehya Mbiribindi Justin , Belesi Siangoli Freddy , Kelvin Patricia , Langille Morgan G. I. , Kelvin David J , Flores Luis , Sganzerla Martinez Gustavo , Kumar Anuj
Published: January 2025

During infectious disease outbreaks, acquiring genetic data across various kingdoms offers essential information to tailor precise treatment methodologies and bolster clinical, epidemiological, and public health awareness. Metagenomics sequencing has paved the way for personalized treatment approaches and streamlined the monitoring process for both co-infections and opportunistic infections. In this study, we conducted long-read metagenomic DNA sequencing on Mpox-like lesion pustules in six suspected patients during the MPXV subclade Ib outbreak in Eastern Democratic Republic of the Congo. The sequenced data was taxonomically classified per the bacterial, fungal, and viral composition. Our results show a wide spectrum of microorganisms present in the lesions. Bacteria such asCorynebacterium amycolatum, Gardnerella vaginalis, Enterococcus faecium, Enterobacter clocae, Staphylococcus epidermidis, andStenotrophomonas maltophiliawere found in the lesions. The viral classification of the reads pointed out the absolute predominance of Monkeypox virus. Taken together, the outcomes of this investigation underscore the potential involvement of microorganisms in mpox lesions and the potential role that co-infections play in exacerbating disease severity and transmission during the MPXV subclade Ib outbreak.