bluuebunny/crossref_metadata_2025 huggingface dataset:
TAK-925 (danavorexton), an Orexin Receptor 2 Agonist, Reduces Opioid-Induced Respiratory Depression and Sedation Without Affecting Analgesia in Healthy Adult Males
Authors: van Lemmen Maarten , Dahan Albert , Hang Yaming , Jansen Simone C. , Lu Hong , Naylor Melissa , Olsson Tina , Sheikh Sarah , Sullivan Danielle , Tolkoff Max , van der Schrier Rutger , van Velzen Monique , von Rosenstiel Philipp , Wu Rebecca L. , Meyer Seetha
Published: January 2025

Background:

Orexin neuropeptides help regulate sleep/wake states, respiration, and pain. However, their potential role in regulating breathing, particularly in perioperative settings, is not well understood. TAK-925 (danavorexton), a novel, orexin receptor 2-selective agonist, directly activates neurons associated with respiratory control in the brain and improves respiratory parameters in rodents undergoing fentanyl-induced sedation. This study assessed the safety and effect of danavorexton on ventilation in healthy men in an established remifentanil-induced respiratory depression model.

Methods:

This single-center, double-blind, placebo-controlled, two-way crossover, phase 1 trial randomized (1:1) 13 healthy men to danavorexton (11mg [low-dose] then 19mg [high-dose]) or placebo, under remifentanil infusion, on two occasions separated by a ≥36-hour washout period. Remifentanil infusion was titrated under isohypercapnic conditions to achieve ~30% to 40% decrease in minute ventilation (from ~20 to ~14 L/minute) before danavorexton/placebo administration. Assessments included safety, ventilation measurements, sedation, and pain tolerance.

Results:

4 (30.8%) danavorexton-treated participants and 1 (8.3%) placebo-treated participant experienced treatment-emergent adverse events (all mild in severity). Insomnia, lasting 1 day, occurred in 1 participant, and was considered related to danavorexton. Compared with placebo, low- and high-dose danavorexton significantly increased ventilation variables (observed mean [95% confidence interval] change, sensitivity analysis model-based p-values) including minute volume (8.2[5.0, 11.4] and 13.0[9.4, 16.5] L/min), tidal volume (312[180, 443] and 483[309, 657] mL), and respiratory rate (3.8[1.9, 5.7] and 5.2[2.7, 7.7] breaths/min) (all P<0.001). High-dose danavorexton significantly decreased sedation on visual analog scale (–29.7[–54.1, –5.3] mm, P<0.001) and Richmond Agitation Sedation Scale (0.4[0.0, 0.7], P<0.001), compared with placebo. Improvements in respiratory variables continued beyond completion of danavorexton infusion. No significant differences in pain tolerance were observed between danavorexton doses or between danavorexton and placebo (~13% increase from baseline; low-dose:P=0.491; high-dose:P=0.140).

Conclusions:

Danavorexton has effects on respiration and wakefulness in an opioid-induced respiratory depression setting without reversing opioid analgesia.
The Psychometric Properties of the EuroQol 5D Five Level in Survivors of Critical Illness
Authors: De Silva Sheraya , Neto Ary Serpa , Sathe Aditya , Higgins Alisa M. , Hodgson Carol L.
Published: January 2025

OBJECTIVES:

The EuroQol 5D five level (EQ-5D-5L) instrument is a standardized measure of health-related quality of life and is routinely used in survivors of critical illness. However, information on its psychometric properties and minimal clinically important difference (MCID) in this patient group is lacking.

DESIGN:

Secondary analysis of data from the previously published PREDICT (a registry in critically ill patients to determine predictors of disability-free survival) study, a prospective, multicenter cohort study.

SETTING:

Six ICUs in the state of Victoria, Australia.

PATIENTS:

Four hundred fifty adult patients admitted to the ICU and ventilated for over 24 hours.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

The EQ-5D-5L was administered by telephone at 6 months following ICU admission. Internal consistency (inter-item correlations, Cronbach’s α, and split-half reliability coefficients), construct validity (against age, body mass index, and other outcome measures), responsiveness (observing change over time and effect sizes), percentage of participants presenting no change, and MCID (triangulation of distribution-based and anchor-based estimates) were evaluated. The EQ-5D-5L showed high internal consistency, Cronbach α coefficients of 0.82 (between dimensions) and 0.79 (between the EuroQol-Visual Analogue Scale [EQ-VAS] and utility score), and average split-half coefficients of 0.79 each (between dimensions and between EQ-VAS and utility score). Construct validity was confirmed with a strong correlation between the EQ-5D-5L and the World Health Organization Disability Assessment Schedule 2.0 (EQ-VAS: r = 0.72; p < 0.001 and utility score: r = 0.81; p < 0.001). Effect sizes for change over time for EQ-VAS and utility score were low. The final MCID estimates were 10 (EQ-VAS) and 0.11 (utility score).

CONCLUSIONS:

The EQ-5D-5L, using the Australian value set, demonstrated evidence of good internal consistency and validity, but poor responsiveness in a critically ill population.
Navigating a complex dance: the interplay between RNA-binding proteins and T cells in oral epithelial plasticity
Authors: Vijayakumar Anitha , Vasudevan Sekar , John Samu , Ozbun Michelle A. , Bartee Eric , Palanisamy Viswanathan
Published: January 2025

The oral epithelium, a dynamic interface constantly facing environmental challenges, relies on intricate molecular pathways to maintain its homeostasis. This comprehensive review delves into the nuanced interplay between T-lymphocytic cells (T cells) and RNA-binding proteins (RBPs) within the oral epithelium, elucidating their roles in orchestrating immune responses and influencing tissue plasticity. By synthesizing current knowledge, we aim to unravel the molecular intricacies that govern this interplay, with a focus on potential therapeutic implications for oral health and diseases. Understanding the regulatory networks shaped by T cells and RBPs in the oral epithelial microenvironment holds promise for innovative strategies in managing conditions associated with epithelial dysfunction.
Clinical and Demographic Predictors of Early Clozapine Discontinuation Across Mood and Psychotic Disorders
Authors: Ercis Mete , Cole Kristin C. , Dierkhising Ross A. , Ozerdem Aysegul , Markota Matej , Singh Balwinder , McElroy Susan L. , Frye Mark A. , Leung Jonathan G.
Published: January 2025

Background

Clozapine is effective for treatment-resistant schizophrenia and bipolar disorder but is often discontinued due to adverse effects. This study compared early clozapine discontinuation rates and reasons in patients with mood and psychotic disorders.

Methods

Data from all individuals with mood or psychotic disorders who initiated clozapine for the first time at the inpatient psychiatric unit of Mayo Clinic, Rochester, Minnesota, between 2014 and 2022 were retrospectively analyzed. Early clozapine discontinuation, defined as discontinuation within 90 days of initiation, was the primary outcome. Cox proportional hazards regression was used to assess factors associated with discontinuation.

Results

Of 83 patients (mood group n = 37, psychosis group n = 46), those in the mood group were older (P = 0.022) and more likely to be nonsmokers (P = 0.034). The overall 90-day clozapine discontinuation rate was 45.7%. Early discontinuation was significantly higher in the mood group than in the psychosis group (hazard ratio = 2.41, 95% confidence interval = 1.26–4.64, P = 0.008). Other factors associated with early discontinuation were female sex (P = 0.033), older age (P = 0.026), and nonsmoking (P = 0.001). In multivariable analysis, smoking status was the only factor significantly inversely associated with early clozapine discontinuation (hazard ratio = 0.47, 95% confidence interval = 0.22–0.99, P = 0.048), while diagnostic group, sex, and age did not show significant associations (all P > 0.05). Discontinuations were primarily due to adverse drug reactions in both groups.

Conclusions

Nearly half of the patients discontinued clozapine early, with higher rates in the mood group. Studies should further explore potential pharmacodynamic and pharmacokinetic factors associated with discontinuation, including the influence of smoking. Careful monitoring and personalized management of side effects are crucial for optimizing clozapine therapy and improving treatment outcomes.
Posttranslational histone 3 modification patterns in experimental septic and cardiogenic shock
Authors: Su Fuhong , Herpain Antoine , Garcia Bruno , Moiroux-Sahraoui Alexander , Manicone Francesca , Moreau Anthony , Annoni Filippo , Giuseppe Casu , Picod Adrien , Vincent Jean-Louis , Creteur Jacques , Taccone Fabio Silvio
Published: January 2025

Background:

Histones are released during cellular damage and cell death. In addition to their intrinsic toxicity, posttranslational modifications (PTMs) in histones impact the sepsis response. Histone PTMs in cardiogenic shock (CS) remain unclear. We explored the temporal dynamics of nucleosomes and histone 3 (H3) PTM patterns in septic shock (SS) and CS and whether histone neutralization by the administration of sodium-β-O-methyl cellobioside sulfate (mCBS) could influence H3 PTMs in SS.

Methods:

Two experiments were conducted. In the first, SS was induced in 24 female sheep by fecal peritonitis. These animals were randomized into three groups: control, early mCBS, and late mCBS (n = 8 each), with mCBS given as a bolus (1 mg/kg) followed by a continuous infusion (1 mg/kg/h) immediately after sepsis induction (early group) or 4 h later (late group). The experiment lasted 24 h, during which plasma samples were collected at baseline and every 4 h. In the second experiment, CS was induced in 8 pigs by partial occlusion of the anterior interventricular and circumflex arteries for 120 min using two angioplasty balloons. The CS experiment lasted 12 h, with serum samples collected at baseline, post-ischemia, and thereafter every 4 h. All animals were mechanically ventilated, hemodynamically monitored, fluid resuscitated, and received norepinephrine throughout the experiment. Concentrations of nucleosomes and H3 PTMs (H3K27ac, H3K27me3, and H3R8Cit) were measured using an enzyme-linked immunoassay.

Results:

Circulating nucleosome levels increased in SS but not in CS. H3K27ac and H3R8Cit reached peak levels rapidly following the onset of sepsis, whereas H3K27me3 showed a gradual increase during the later phases of SS. During CS, there were no significant changes in H3R8Cit, H3K27ac, or H3K27me3 levels. The mCBS treatment was associated with a nonsignificant reduction in H3 PTM levels.

Conclusion:

In these experimental models, the H3 PTM patterns differed in SS and CS. The administration of mCBS did not significantly reduce H3 PTM levels during sepsis.
Racial and ethnic disparities in liver transplant access vary within and across transplant referral regions
Authors: Ayuk-Arrey Arrey-Takor , Nephew Lauren , Caicedo Juan Carlos , Ross-Driscoll Katherine
Published: January 2025

Prior studies have demonstrated racial disparities in access to liver transplantation, but the determinants of these disparities remain poorly understood. We used geographic catchment areas for transplant centers (transplant referral regions, TRRs) to characterize transplant environment contributors to racial and ethnic disparities in liver transplant access. Data were obtained from the Scientific Registry for Transplant Recipients and the National Center for Health Statistics from 2015 to 2021. The primary outcome was the difference in the listing-to-end-stage liver disease death ratio between Black, Hispanic, and non-Hispanic White patients for each TRR. We accounted for demographics, socioeconomic status, health care access, organ availability, and transplant center competition using multivariable linear regression. We examined intra-TRR differences in waitlist composition using Levene’s test of variance. Across the 66 included TRRs, Black patients had lower listing-to-end-stage liver disease death ratios than White patients in 80% of TRRs, while Hispanic patients had equal or higher listing-to-end-stage liver disease death ratios compared to White patients in 56% of TRRs. The majority of variation in racial disparities across TRRs remained unexplained by multivariable models. Disparities were attenuated after excluding patients with HCC-associated mortality. Among the 27 TRRs that contained more than one transplant center, variance across TRRs was statistically significant for Black and Hispanic waitlist composition. We observed substantial geographic variation in the magnitude of racial disparities in liver transplant access across the United States. Findings highlight the need for targeted health equity interventions in regions with high disparities and the development of disparity-sensitive access metrics for transplant centers.
Cerebrospinal Fluid Biomarkers and Cognition in Alzheimer Disease and Frontotemporal Dementia in a Memory Clinic Setting
Authors: Cayir Salih , Sadabad Faranak Ebrahimian , Mecca Adam P. , Matuskey David , Fesharaki-Zadeh Arman
Published: January 2025

Objective:

Currently available literature on the relationships between cerebrospinal fluid (CSF) biomarkers and cognitive performance in frontotemporal dementia (FTD) is very limited and inconclusive. In this study, we investigated the association of cognitive symptoms, as measured with Montreal Cognitive Assessment (MoCA), with CSF levels of total tau (t-tau), phosphorylated tau at threonine 181 (p-tau181), and amyloid β 1–42 (Aβ1–42) in a group of patients with probable FTD and Alzheimer disease (AD).

Methods:

We conducted a retrospective cohort study with participants selected from the electronic records of patients seen at Yale New Haven Hospital’s Memory Clinic, CT. A total of 61 patients, 28 with FTD (mean age=64.1) and 33 with AD (mean age=66.8), with available CSF results and cognitive test scores in their chart were included in analyses.

Results:

T-tau levels negatively and significantly correlated with total MoCA scores as well as the different MoCA index scores in patients with FTD (r=−0.47, P=0.04). There were no significant associations between MoCA scores and p-tau181 levels in patients with FTD (r=−0.22, P=0.25). Patients with AD exhibited significant correlations between MoCA scores and both t-tau (r=−0.54, P<0.01) and p-tau (r=−0.55, P<0.01) levels. Also, Aβ1–42 levels were not significantly correlated with MoCA scores in either of the FTD and AD groups.

Conclusion:

CSF concentrations of t-tau are inversely correlated to cognitive performance in patients with FTD and both t-tau and p-tau181 in AD. This study provides valuable insights into the relationship between clinical cognitive performance and tau-related pathology in FTD in comparison with AD.
Oral hygiene of stroke patients in a stroke unit: a best practice implementation project
Authors: Ferreira Salomé , Lima Andreia , Araújo Paula , Carneiro Silvia , Moreira Teresa , Cardoso Ana Filipa
Published: January 2025

Introduction:

People with stroke are at risk of poor oral hygiene caused by neurological deficits, which can be motor, sensory, or cognitive. Good oral hygiene has been shown to reduce adverse events and improve the patient's quality of life. Although nurses recognize the benefits of oral hygiene, evidence shows that this area of care is frequently overlooked.

Aim:

This evidence implementation project aimed to improve oral hygiene in stroke patients through the application of best practices.

Methods:

This project was conducted in a stroke unit in a hospital in northern Portugal. The project followed the JBI Evidence Implementation Framework, which is grounded in an audit, feedback, and re-audit process. Four audit criteria were used in the baseline and follow-up audits. Observation of nursing care and analysis of nursing records were used to assess current practice against best practice recommendations. Nurses were engaged in the project through brainstorming to identify barriers, co-create strategies to address the barriers, and ensure project sustainability.

Results:

The baseline audit revealed low compliance with the four audit criteria. The follow-up audit showed increased compliance, with Criterion 1 improving from 0% to 100%, with all nurses receiving training on oral hygiene assessment and management. Compliance increased by 40% for Criterion 2 and 36.7% for Criteria 3 and 4, respectively.

Conclusions:

The project successfully promoted compliance with best practice recommendations and increased evidence-based practice for oral hygiene in patients with stroke in a stroke unit.

Spanish abstract:

http://links.lww.com/IJEBH/A302
Urban air pollution and child neurodevelopmental conditions: a systematic bibliometric review
Authors: Kefas Rosalyn , Roy Raymond , D’Angiulli Amedeo
Published: January 2025

Purpose of review

Using advanced bibliometric analysis, we systematically mapped the most current literature on urban air pollution and neurodevelopmental conditions to identify key patterns and associations. Here, we review the findings from the broader literature by discussing a distilled, validated subset of 44 representative studies.

Recent findings

Literature highlights a complex relationship between environmental toxins, neurodevelopmental disorders in children, and neurobehavioral pathways involving oxidative stress, neuroinflammation, and protein aggregation. Chronic prenatal and postnatal exposure to airborne pollutants – such as particulate matter and heavy metals – may contribute to early formation of amyloid plaques through preadolescence. These processes may compromise synaptic plasticity and neural integrity, which can progressively induce cognitive, emotional, and behavioral dysregulation, sharing some pathological features traditionally associated with adult neurodegenerative diseases.

The interactions between air pollution exposure levels, developmental timing, and factors such as genetic vulnerability associated with neurodevelopmental disorders are still undetermined. However, accelerated neurodegenerative processes leading to cognitive decline and suboptimal mental health in children and adolescents seem most likely linked with pollutants penetrating the blood–brain barrier, and inducing oxidative stress and neuroinflammation. Urgent precautionary action might reduce environmental exposures during critical early developmental periods, thereby safeguarding children's cognitive function and mental health.
Managing depression in the elderly: real-world clinical considerations and perspectives
Authors: Kasper Siegfried , Incalzi Raffaele Antonelli , Bozzali Marco , Morgado Pedro , Siwek Marcin
Published: January 2025

This study aims to elucidate current trends in clinical practice for managing depression in elderly patients, focusing on the utilization of pharmacotherapeutics and integrated care models to improve patient outcomes. A comprehensive survey was conducted among physicians from various European countries to gather insights into prescribing habits, treatment patterns, and the impact of comorbidities on therapeutic choices, with a focus on trazodone. The participants included psychiatrists, general practitioners, and neurologists actively involved in elderly depression care. The findings reveal a preference among physicians for using antidepressants like trazodone, due to efficacy and tolerability. Selective serotonin reuptake inhibitors and serotonin-noradrenaline reuptake inhibitors were also commonly prescribed, while tricyclic antidepressants and monoamine oxidase inhibitors were less favored. Psychiatric conditions and sleep disturbances significantly influenced treatment decisions. The survey underscored the importance of multidisciplinary management and the crucial role of caregivers in the treatment process. Effective management of depression in the elderly demands a precision approach that incorporates a thorough understanding of pharmacology, comorbidities, and a collaborative approach to maximize the effects of treatment while trying to minimize polypharmacy and the co-occurring side effects. The study highlights the need for tailored treatment strategies that address the complex needs of the elderly to enhance their quality of life and treatment outcomes.
Impact of simulation and reference catalogues on the evaluation of taxonomic profiling pipelines
Authors: Puller Vadim , Plaza Oñate Florian , Prifti Edi , de Lahondès Raynald
Published: January 2025

Microbiome profiling tools rely on reference catalogues, which significantly affect their performance. Comparing them is, however, challenging, mainly due to differences in their native catalogues. In this study, we present a novel standardized benchmarking framework that makes such comparisons more accurate. We decided not to customize databases but to translate results to a common reference to use the tools with their native environment. Specifically, we conducted two realistic simulations of gut microbiome samples, each based on a specific taxonomic profiler, and used two different taxonomic references to project their results, namely the Genome Taxonomy Database and the Unified Human Gastrointestinal Genome. To demonstrate the importance of using such a framework, we evaluated four established profilers as well as the impact of the simulations and that of the common taxonomic references on the perceived performance of these profilers. Finally, we provide guidelines to enhance future profiler comparisons for human microbiome ecosystems: (i) use or create realistic simulations tailored to your biological context (BC), (ii) identify a common feature space suited to your BC and independent of the catalogues used by the profilers and (iii) apply a comprehensive set of metrics covering accuracy (sensitivity/precision), overall representativity (richness/Shannon) and quantification (UniFrac and/or Aitchison distance).
Breaking boundaries: fungi in the “rhizoctonia” species complex exhibit systemic colonization in three terrestrial orchid species
Authors: Jacopo Calevo , Pasquale Alibrandi , Samuele Voyron , Mariangela Girlanda , Silvia Perotto
Published: January 2025

Most green orchids associate with orchid mycorrhizal (OrM) fungi belonging to the ‘rhizoctonia’ complex, a polyphyletic group of Tulasnellaceae, Ceratobasidiaceae and Serendipitaceae (Agaricomycotina), which are generally assumed to live as saprotrophs in soil. However, OrM rhizoctonias were rarely detected by metabarcoding in soil around orchid roots, and we have tested the hypothesis that these fungi may use adult orchid plants as a niche by colonizing not only their roots, but also other organs.

The occurrence of OrM rhizoctonias inside roots, stems and leaves of three terrestrial orchid species (Spiranthes spiralis,Serapias vomeraceaandNeottia ovata) was therefore investigated by metabarcoding. To test the possibility of a vertical transmission of OrM fungi, reproductive structures (capsules, as well as seeds inS. spiralis) were also analyzed in a subset of plants.

In all orchid species, a broad majority of OrM fungi found in roots was also detected in either stems or leaves of the same plant. OrM fungi were also detected in capsules/seeds.

Systemic colonization of orchid tissues by OrM symbionts is a novel finding that raises important questions on the plant-fungus relationship in the aerial organs and opens intriguing perspectives on the potential modes of fungal transmission to the orchid progeny.
Tie that binds- Hill-Robertson Interference can produce signals of sexual antagonism even in the absence of sexually antagonistic selection
Authors: Arun Manas Geeta
Published: January 2025

1

Sexually antagonistic (SA) selection on a trait with a shared genetic basis between the sexes is thought to lead to Intralocus Sexual Conflict (IaSC). A common way of measuring IaSC involves characterising the joint distribution of breeding values of male and female fitness using the intersexual additive genetic correlation for fitness (rmf,W). However, there is considerable variation in the empirical estimates ofrmf,W- with estimates ranging from significantly negative (suggestive of strong IaSC) to significantly positive (suggesting an absence of IaSC) - even among closely related populations of the same species. Here, we investigate whether SA selection is even necessary forrmf,Wto be negative. We first highlight that the sign ofrmf,Wdepends on a term that describes direct sex-specific selection, and another that describes indirect selection mediated by linkage disequilibria (LD). We show thatrmf,Wcan be negative if (1) selection is perfectly sex-limited - such that every locus affects the fitness of one sex only - and (2) the LD between closely-linked male-beneficial and female-beneficial alleles is on average negative as predicted under Hill-Robertson Interference (HRI). We test this idea using individual-based simulations. Our results suggest that populations evolving under purely sex-limited selection exhibit a prominent negative bias inrmf,Wthat gets strengthened by a reduction in the recombination rate. Therefore, HRI can drivermf,Wto be negative even in the absence of SA selection suggesting that negative estimates ofrmf,Wshould not automatically be considered as evidence of IaSC.
Exosomal miR-145-5p promotes apoptosis of renal tubule epithelial cells through the JNK signalling pathway
Authors: Deng Xiao-long , Yan Le-ping , Lan Yuan , Guo Jun-miao , Yuan Run-qi , Zhang Rong , Mao Pu
Published: January 2025

Acute kidney injury (AKI) is the most prevalent extrapulmonary organ failure observed in patients with acute respiratory distress syndrome (ARDS). However, the underlying mechanisms leading to AKI in ARDS remain unclear. Exosomes facilitate intercellular and inter-organ communication via exosomal microRNAs (miRNAs), which potentially contribute to the crosstalk between the lung and kidney in ARDS. Therefore, the purposes of our study were to investigate the involvement of exosomal miRNAs in the development of AKI in ARDS. In current study, Sprague-Dawley rats were induced to develop ARDS via hydrochloric acid aspiration. Nanoparticle tracking analysis, Transmission electron microscopy and western blotting were conducted to analyse the exosomes. Quantitative reverse transcription-polymerase chain reaction andin situhybridisation showed elevated expression level of miR-145-5p in the circulating exosomes and lung tissue of ARDS rats. Overexpression of miR-145-5p disrupted the proteomic profile of renal proximal tubule epithelial cells, leading to impacts on proteins associated with various biological processes, including apoptosis. We further demonstrate that miR-145-5p overexpression enhanced JNK phosphorylation by directly repressing RBM3 expression and promoted cell apoptosis.Invivo, administration of agomiR-145-5p injection via intravenous route, which subsequently induced renal tubular cell apoptosis. These findings have revealed that miR-145-5p may serve as a novel mediator for the apoptosis of renal cell in the context of ARDS.
Viscoelastic HyA Hydrogel Promotes Recovery of Muscle Quality and Vascularization in a Murine Model of Delayed Rotator Cuff Repair
Authors: Pfaff Morgan R. , Wague Aboubacar , Davies Michael , Killaars Anouk R. , Ning Derek , Garcia Steven , Nguyen Anthony , Nuthalapati Prashant , Liu Mengyao , Liu Xuhui , Feeley Brian T. , Healy Kevin E.
Published: January 2025

Rotator cuff tears are among the most common musculotendinous injuries with high risk of permanent functional disability. Following surgical repair, sub-optimal patient outcomes are directly correlated with poor muscle quality; namely, injury site fatty infiltration (FI), fibrosis, and muscle atrophy. Muscle resident fibro-adipogenic progenitor cells (FAPs) have been identified as key regulators of post-injury skeletal muscle regeneration and repair by maintaining a promyogenic environment. In this work, human-derived FAPs (hFAPs) were encapsulated into hyaluronic acid (HyA)-based hydrogels functionalized with bsp-RGD(15) cell adhesion peptide, heparin, and a matrix metalloproteinase (MMP)-cleavable crosslinker. Hydrogel-encapsulated hFAPs increased expression of the promyogenic marker UCP1 and production of the anti-inflammatory cytokine IL-10, while downregulating the expression of the fibrotic marker αSMA over time. A murine model of unilateral rotator cuff transection, denervation, and delayed repair was treated with the HyA hydrogel or PBS and compared to a contralateral, non-injured control limb. Muscle histology 6 weeks post-repair revealed that the hydrogel reduced fibrosis, FI, and muscle atrophy while supporting vascularization of the injured tissue region. Collectively, these results suggest that the hydrogel alone can promote muscle regeneration in a clinically relevant delayed repair model of rotator cuff tear, which we hypothesize is due to controlled FAP differentiation into promyogenic lineages.
Nuclear pore complex distribution on the nuclear envelope: insights into curvature, chromatin, and actin contributions
Authors: Lachuer Hugo , Faklaris Orestis , Hénon Sylvie , Montel Fabien , Pereira David
Published: January 2025

The Nuclear Pore Complex (NPC) is an ancestral feature of eukaryotic cells, essential for the exchange of material and information between cytoplasm and nucleoplasm. While, typical eukaryotic cells harbor thousands of NPCs covering the nucleus surface, a quantitative characterization of their spatial distribution remains lacking. Taking advantage of super-resolution microscopy, we imaged and segmented individual NPCs in myoblast cells to reconstruct the nuclear surface. Our spatial statistics analysis of NPCs on the nuclear surface reveals the existence of a 400nm repulsion length between NPCs, likely reflecting the mesh size of the underlying lamin network. Furthermore, we identify three key correlates of NPC density. (1) Myoblast actin fibres, which can indent the nucleus, correlate with a decrease in NPC surface density, contrary to what was reported in previous studies; (2) Regions of the nuclear envelope near large heterochromatin domains exhibit reduced NPC surface density; and (3) There is a non-monotonous relationship between NPC density and the nuclear envelope curvature. This last observation is consistent with the existence of NPC-preferred curvature suggesting curvature sensing properties. In conclusion, this study provides new insights into the spatial distribution of NPCs, shedding light on possible new determinants of NPC spatial distribution.
Linking Molecular Tension and Cellular Tractions: A Multiscale Approach to Focal Adhesion Mechanics
Authors: Aytekin Samet , Kimps Laurens , Coucke Quinten , Linhares Débora , Deodhar Swaraj , Cardinaels Ruth , Cóndor Mar , Barrasa-Fano Jorge , Oosterwyck Hans Van , Rocha Susana
Published: January 2025

Focal adhesions (FAs) are mechanosensitive structures that mediate force transmission between cells and the extracellular matrix. While Traction Force Microscopy (TFM) quantifies cellular tractions exerted on deformable substrates, Förster Resonance Energy Transfer (FRET)-based tension probes, such as Vinculin Tension Sensors (VinTS), measure molecular-scale forces within FA proteins. Despite their potential synergy, these methods have rarely been combined to explore the interplay between molecular tension and cellular tractions. Here, we introduce a framework integrating TFM and VinTS to investigate FA mechanics across scales. At cell level, tractions and vinculin tension increased with substrate stiffness. At FA level, vinculin tension correlated with vinculin density, while tractions scaled with FA area, total vinculin content and vinculin density. Direct comparison of tractions to tension revealed a complex, heterogenous relationship between these forces, possibly linked to diverse cell and FA maturation states. Sub-FA analysis revealed conserved spatial patterns, with tension and traction increasing towards the cell periphery. This multiscale approach provides insights into the multiscale dynamics of FA mechanotransduction, bridging the gap between molecular forces and cellular mechanics.j
Plasma membrane mediated GLUT10 mitochondrial targeting regulates intracellular ascorbic acid homeostasis
Authors: Jose Anu Chirackal , Syu Yu-Wei , Lai Hao-Wen , Tsai Ming-Yuan , Jiang Yi-Fan , Hsu Shao-Chun , Lin Po-Yen , Huang Wan-Chen , Chu Wei-Chen , Fu Chi-Yu , Lee Yi-Ching
Published: January 2025

Regulation of intracellular ascorbic acid (AA) levels is critical for connective tissue development and maintenance, but the underlying mechanisms remain unclear. In this study, we uncover a novel regulatory role of glucose transporter 10 (GLUT10) in AA homeostasis through a noncanonical trafficking pathway from the endomembrane system to mitochondria, traditionally considered as separate entities. We demonstrate that GLUT10 transit from ER to mitochondria through the plasma membrane (PM) and endosomes increases under stress conditions. This PM localization enhances the transport of dehydroascorbic acid (DHA), the oxidized form of AA, thereby maintaining intracellular AA levels. Disruption of this trafficking impairs AA homeostasis. Our findings reveal a previously unrecognized localization of GLUT10 at the PM and endosomes, highlighting a novel communication between endomembrane system and mitochondria for proetin redistribution, which is essential for maintaining intracellular AA homeostasis and facilitating environmental adaptation.

Graphical abstract
The transsulfuration pathway suppresses the embryonic lethal phenotype of glutathione reductase mutants in Caenorhabditis elegans
Authors: Valenzuela-Villatoro Marina , Guerrero-Gomez David , Gomez-Orte Eva , Cheng Qing , Zheleva Angelina , Mora-Lorca Jose Antonio , Petrovic Dunja , O'Neil Nigel J , Ceron Julian , Hatakeyama Akiko , Onami Shuichi , Filipovic Milos , Arner Elias SJ , Cabello Juan , Miranda-Vizuete Antonio
Published: January 2025

The gsr-1 gene encodes the only glutathione reductase in Caenorhabditis elegans and gsr-1 loss of function alleles have a fully penetrant embryonic lethal phenotype. Therefore, maintenance of glutathione redox homeostasis is essential for nematode survival. We report here that impairment of the nonsense-mediated mRNA decay (NMD) pathway suppresses the embryonic lethality of gsr-1 mutants, allowing their normal development and growth. This NMD pathway dependent suppression requires cth-1 and cth-2 that encode, respectively, two isoforms of cystathionine-g-lyase that catalyze the conversion of cystathionine to cysteine through the transsulfuration pathway. Interestingly, the thioredoxin system that can also provide cysteine through the cystine reduction pathway is not required for the suppression of the lethal phenotype of gsr-1 embryos when the NMD pathway is inactivated. Together, our data indicate that increasing the activity of the reverse transsulfuration pathway can compensate the detrimental effect of the gsr-1 mutation, raising the interesting question of why C. elegans has not preserved such compensatory mechanism to avoid the embryonic lethality of these mutants.
Autosuggestion and Mental Imagery Bias the Perception of Social Emotions
Authors: Myga Kasia A. , Longo Matthew R. , Kuehn Esther , Azañón Elena
Published: January 2025

Cognitive processes that modulate social emotion perception are of pivotal interest for psychological and clinical research. Autosuggestion and mental imagery are two candidate processes for such a modulation, however, their precise effects on social emotion perception remain uncertain. Here, we investigated how autosuggestion and mental imagery, employed during an adaptation period, influence the subsequent perception of facial emotions, and to which extent. Separate cohorts of participants took part in five experiments, where they either mentally affirmed (autosuggested, Experiments 1a and 1b) or imagined (Experiment 2) that a neutral face would be expressing a specific emotion (happy or sad). Subsequent facial emotion perception was then assessed by calculating points of subjective equality (PSEs) along a happiness-sadness continuum. Our results show that both autosuggestion and mental imagery induce a bias toward perceiving facial emotions in the direction of the desired emotion, with larger Bayes factors supporting autosuggestion. Experiment 3 confirmed no effects when emotional words were presented instead, suggesting a reduced role of response bias to drive this effect. Finally, experiment 4 validated the experimental setup by demonstrating standard contrastive aftereffects when participants are adapted to actual, physical emotional faces. Together, our findings provide an initial step toward understanding the potential of intentional cognitive processes to modulate social emotions, specifically by biasing emotional face perception. With comparable effect sizes observed for both autosuggestion and mental imagery, both strategies show promise for self-directed interventions. Their practical applicability may vary due to individual responses, preferred cognitive strategies, and potential overlaps in underlying cognitive mechanisms.
CryoVIA - An image analysis toolkit for the quantification of membrane structures from cryo-EM micrographs
Authors: Schönnenbeck Philipp , Junglas Benedikt , Sachse Carsten
Published: January 2025

Imaging of lipid structures and associated protein complexes using electron cryo-microscopy (cryo-EM) is a common visualization and structure determination technique. The quantitative analysis of the membrane structures, however, is not routine and time consuming in particular when large amounts of data are involved. Here, we introduce the automated image-processing softwarecryo-vesicle image analyzer(CryoVIA) that parametrizes lipid structures of large data sets from cryo-EM images. This toolkit combines segmentation, structure identification with methods to automatically perform a large-scale data analysis of local and global membrane properties such as bilayer thickness, size, and curvature including membrane shape classifications. We included analyses of exemplary data sets of different lipid compositions and protein-induced lipid changes through an ESCRT-III membrane remodeling protein. The toolkit opens new possibilities to systematically study structural properties of membrane structures and their modifications from cryo-EM images.
Longitudinal Stability of Mood-Related Resting-State Networks in Youth with Symptomatic Bipolar-I/II Disorder
Authors: Hafeman Danella M. , Feldman Jamie , Mak Jessica , Merranko John , Goldstein Tina R. , Gratton Caterina , Phillips Mary L. , Birmaher Boris
Published: January 2025

Bipolar disorder (BD) is characterized by temporal instability of mood and energy, but the neural correlates of this instability are poorly understood. In previous cross-sectional studies, mood state in BD has been associated with differential functional connectivity (FC) amongst several subcortical regions and ventromedial prefrontal cortex. Here, we assess whether BD is associated with longitudinal instability within this mood-related network of interest (NOI). Young people with BD-I/II were scanned 4-6 times and healthy controls (HC) were scanned 4 times over 9 months. Following preprocessing of 20-minute resting-state scans, we assessed across-scan correlation of FC, focusing on FC between regions previously associated with BD mood state. Utilizing Bayesian models, we assessed the relationship between diagnostic group and within-person, across-scan correlation, adjusting for motion, time-of-day, and inter-scan interval; prediction intervals (PI) are reported. In a sample of 16 youth (11 BD, 5 HC; 16.3-23.3 years old) with 70 scans (50 BD, 20 HC), across-scan NOI stability was higher within-than between-person (0.70 vs. 0.54; p<.0001). BD (vs. HC) within-person scan-pairs showed lower NOI stability (mean -0.109; 95% PI -0.181, -0.038), distinguishing BD vs. HC with excellent accuracy (AUC=0.95). NOI instability was more pronounced with manic symptoms (mean -0.012; 95% PI -0.023, -0.0002) and in BD-II (vs. BD-I; mean -0.071; 90% PI -0.136, -0.007). Results persisted after accounting for medications, comorbidity, and sleep/arousal measures. Within this pilot sample, BD is characterized by less within-person stability of a mood-related NOI. While preliminary, these results highlight a possible role for precision imaging approaches to elucidate neural mechanisms underlying BD.
Rhythmicity of photoreceptor outer segment phagocytosis differs between the cone subtypes in the larval zebrafish
Authors: Partinen Jenni , Nevala Noora , Erämies Sanni , Ihalainen Teemu , Nymark Soile
Published: January 2025

Phagocytosis of retinal rod and cone outer segment (OS) tips by the retinal pigment epithelium (RPE) occurs daily to prevent accumulation of harmful compounds in the photoreceptors. Rhythmic bursts of phagocytosis, seen as increased levels of phagocytosed OS particles in the RPE, are known to appear once or twice a day depending on the animal species. However, differences in the rhythmicity of phagocytosis between distinct photoreceptor types are not well understood. Here, we show that phagocytosis of cone subtype OSs does not have identical rhythmic profiles in young zebrafish larvae. We investigated this by immunolabelling histological sections from the eyes of larvae that were collected at seven different time points throughout a 24 h circadian cycle. Internalized OS particles were then quantified from confocal images. The results revealed that OSs of all cone subtypes are phagocytosed continuously at some levels in young zebrafish. Interestingly, we observed a significant increase in the OS phagosome numbers from UV and blue cones at two time points, whereas green and red cones were phagocytosed more evenly throughout the day. We also investigated whether this rhythmicity is regulated by the external light by keeping the larvae in constant darkness before sample preparation. We found that complete darkness condition dampened the peaks in OS phagosome numbers from UV and blue cones indicating that the rhythmicity is primarily driven by the external light rather than the intrinsic circadian clocks in young larval zebrafish. Our findings provide new understanding on the rhythmicity of cone OS phagocytosis and its regulation.
Immunogenomic profiling of circulating T cells in pediatric cancer patients during standard-of-care
Authors: Nabbi Arash , Jiang Yiyue , Espin Garcia Osvaldo , Mohanraj Suluxan , Pedersen Stephanie , Regala Johanna , Vernau Lauren , Perazzelli Jessica , Barrett David M. , Pugh Trevor J.
Published: January 2025

While pediatric cancer patients receive intensive chemotherapy, its impact on peripheral T cells and subsequently to disease outcomes are not fully characterized. Here, we assessed T-cell dynamics during treatment, identifying associations with outcomes through immune phenotyping and T-cell Receptor (TCR) sequencing in pediatric solid and hematologic malignancies. We show that while levels of immune checkpoint proteins (PD-1, LAG3, and TIM3) at baseline were highest in lymphomas compared to other cancer groups, they increased significantly in response to therapy in all cancers. Levels of Central Memory (CM) T cells increased in leukemias and solid tumors, while naïve T cells and cell-free TCR diversity decreased in lymphomas. By combining immune cell and TCR repertoire features across all timepoints, we proposed the Dynamic Immunogenomic Score (DIS) to measure patient-specific effects of therapy on the peripheral T-cell population. Higher DIS was associated with high-risk cancer types and logistic regression analysis revealed it may predict incidence of relapse in leukemia patients. TCR specificity analysis revealed patient-specific clonal dynamics and differential detection of virally-associated TCRs in cancer patients compared to healthy individuals. Our results highlight the potential of early upfront immunogenomic profiling in identifying high-risk patients that may be predictive in light of emerging cellular immunotherapies.
A study of pelvic organs’ sizes and findings in transvaginal sonography
Authors: Adrita Farzana Rahman , Sarker Azmal Kabir , Akter Sanjida , Paul Sabuz
Published: January 2025

Purpose

This retrospective cross-sectional study evaluated the correlation among pelvic organs’ size, correlation of sizes with age, the change of uterine and cervical sizes in presence and absence of pathologies, and the pattern of ovarian volume asymmetry in the absence of pathology.

Patients and methods

Measurement of pelvic organs from all consecutive premenopausal, non-pregnant patients who underwent TVS for gynecologic workup were included in the analysis. The correlation of the sizes, and variation of sizes among a finding-based category was checked.

Results

Data from 43 women with mean (±SD) age of 33.4±8.7 years were included. Among the finding-based categories, bulky uteri in comparison to normal uteri were more likely to harbor myoma or adenomyosis (Risk ratio 2.07, p < 0.01). Positive correlations were found between, antero-posterior (AP) diameter of uterus and age (R 0.4, p < 0.01), AP diameter of uterus and its length (R 0.7, p < 0.01), AP diameter of uterus and cervix (R 0.44, p < 0.01), length of uterus and that of cervix (R 0.37, p < 0.05), AP diameter of cervix and it length (R 0.47, p < 0.01) and pair of otherwise healthy ovaries (R 0.53, p < 0.01). This dataset suggests that the presence of pathologies may not always be associated with uterine enlargement (p > 0.05), but the presence of a pathology is associated with enlargement of uterine cervical AP diameter (p < 0.01) as well as its length (p < 0.05). Among the healthy pairs of ovaries, the right one was larger than the left with a significant difference between the mean volumes (p < 0.05), in 70.4% pairs.

Conclusions

Overall, the findings from this small series are expected to add factual evidence to our existing concepts and help to shape some future research questions.
Correlates and Consequences of Clonal Hematopoiesis Expansion Rate: A 15-Year Longitudinal Study of 6,986 Women
Authors: Pershad Yash , Uddin Md Mesbah , Xue Liying , Haessler Jeffrey , Collins Jason M. , Mack Taralynn M. , Glick Elena , Glaser Veronica , Zhao Kun , Jaiswal Siddhartha , Manson JoAnn E. , Pandey Urvashi , Desai Pinkal , Natarajan Pradeep , Honigberg Michael C. , Kooperberg Charles , Whitsel Eric A. , Kitzman Jacob O. , Bick Alexander G. , Reiner Alexander P.
Published: January 2025

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased mortality and malignancy risk, yet the determinants of clonal expansion remain poorly understood. We performed sequencing at >4,000x depth of coverage for CHIP mutations in 6,986 postmenopausal women from the Women’s Health Initiative at two timepoints approximately 15 years apart. Among 3,685 mutations detected at baseline (VAF ≥ 0.5%), 50% progressed to CHIP (VAF ≥ 2%) at follow-up. We confirmed that clonal expansion is highly dependent on initial clone size and CHIP driver gene, withSF3B1andJAK2mutations exhibiting the fastest growth rate. We identified germline variants inTERT,IL6R,TCL1A, andMSI2that modulate clonal expansion rate. Measured baseline leukocyte telomere length showed differential effects on incident CHIP risk, with shorter baseline leukocyte telomere length predisposing to incidentPPM1Dmutations and longer baseline leukocyte telomere length favoring incidentDNMT3Amutations. We discovered that theIL6Rmissense variant p.Asp358Ala specifically impairsTET2clonal expansion, supported by direct measurements of soluble interleukin-6 receptor and interleukin-6. Faster clonal growth rate was associated with increased risk of cytopenia, leukemia, and all-cause mortality. Notably, CHIP clonal expansion rate mediated 34.4% and 43.7% of the Clonal Hematopoiesis Risk Score’s predictive value for leukemia and all-cause mortality, respectively. These findings reveal key biological determinants of CHIP progression and suggest that incorporating growth rate measurements could enhance risk stratification.