bluuebunny/crossref_metadata_2025 huggingface dataset:
Small molecules reveal differential shifts in stability and protein binding for G-quadruplex RNA
Authors: Martyr Justin G , Zafferani Martina , Bailey Morgan A , Zorawski Marek D , Montalvan Nadeska I , Muralidharan Dhanasheel , Fitzgerald Michael C , Hargrove Amanda E
Published: February 2025

The potential of therapeutically targeting RNA with small molecules continues to grow yet progress is hindered by difficulties in determining specific mechanisms of action, including impacts on RNA-protein binding. RNA G-quadruplexes (rGQs) are a particularly promising target due to their range of biological functions, structural stability, and hydrophobic surfaces, which promote small molecule and protein interactions alike. Challenges arise due to 1) the low structural diversity among rGQs, thereby limiting binding selectivity, and 2) a lack of knowledge regarding how small molecules can manipulate rGQ-protein binding on a global scale. We first leveraged a small molecule library privileged for RNA tertiary structures that displayed differential binding to rGQs based on loop length, consistent with computational predictions for DNA GQs. We next utilized an RT-qPCR-based assay to measure stability against enzymatic readthrough, expected to be a common mechanism in rGQ function. We discovered small molecules with significant, bidirectional impacts on rGQ stability, even within the same scaffold. Using Stability of Proteins from Rates of Oxidation (SPROX), a stability-based proteomics method, we then elucidated proteome level impacts of both stabilizing and destabilizing rGQ-targeting molecules on rGQ-protein interactions. This technique revealed small molecule-induced impacts on a unique subset of rGQ-binding proteins, along with proteins that exhibited differential changes based on the identity of the small molecule. The domain and peptide-level insights resulting from SPROX allow for the generation of specific hypotheses for both rGQ function and small molecule modulation thereof. Taken altogether, this methodology helps bridge the gap between small molecule-RNA targeting and RNA-protein interactions, providing insight into how small molecules can influence protein binding partners through modulation of target RNA structures.
Spike Train Scalograms (STS): a Deep Learning Classification Pipeline for Neuronal Cell Types
Authors: Amprimo Gianluca , Martini Lorenzo , Bilir Begum , Bardini Roberta , Savino Alessandro , Olmo Gabriella , Di Carlo Stefano
Published: February 2025

Classifying neuronal cell types is crucial for understanding the intricate circuitry of the cerebral cortex, which comprises diverse specialized neurons essential for brain function. Traditional Machine Learning (ML) approaches rely on manually engineered electrophysiological (EP) features, often overlooking subtle and complex patterns within spike train data. This study introduces a novel Spike Train Scalograms (STS)-based Deep Learning (DL) pipeline that integrates Continuous Wavelet Transform (CWT) scalograms with pre-trained Convolutional Neural Networks (CNN) architectures to classify neuronal cell types with high accuracy. Utilizing patch-clamp EP recordings from 5,590 murine cortical neurons, the pipeline transforms spike trains into time-frequency representations via CWT, capturing both transient and sustained signal characteristics. These scalograms are then processed by fine-tuned CNN architectures, includingInceptionV3, which achieved a balanced accuracy and weightedF1-Score of 90.53% and 90.03%, respectively. The STS pipeline effectively distinguishes between major neuronal types such as Pvalb, Sst, Vip/Lamp5, and Excitatory neurons, even in the presence of class imbalances. Moreover, an explainability analysis using saliency maps and SHAP revealed high correspondence between the DL approach, the ML baseline and biological knowledge of these neuronal types. The results demonstrate the efficacy of combining advanced spectral analysis with DL techniques, offering a scalable and automated method for precise neuronal classification.
Deep Learning-Driven EEG Analysis for Personalized Deep Brain Stimulation Programming in Parkinson’s Disease
Authors: Calvo Peiro Nicolas , Haugland Mathias Ramm , Kutuzova Alena , Graef Cosima , Bocum Aminata , Tai Yen Foung , Borovykh Anastasia , Haar Shlomi
Published: February 2025

Deep Brain Stimulation (DBS) is an invasive procedure used to alleviate motor symptoms in Parkinson’s Disease (PD) patients. While brain activity can be used to optimise DBS parameters, the impact of DBS parameters on brain activity remains unclear. We aimed to identify the cortical neural response to changes in DBS parameters, which are sensitive to the effect of small changes in the stimulation parameters and could be used as neural biomarkers. We recorded in-clinic EEG data from seven hemispheres of PD patients during DBS programming sessions.

Here we developed a siamese adaptation of the EEGNet deep learning architecture and trained it to distinguish whether two short (1-sec-long) segments of brain activity were taken with the same stimulation parameters, or if either the strength or location of the stimulation had changed. 13 independent models were trained independently in each hemisphere for stimulation amplitude or contact, and all achieved high accuracy with an average of 78%. Our models are sensitive to changes in brain activity recorded at the scalp of the patients following changes as small as 0.3mA in the DBS parameters.

Next, we interpreted what our black-box AI models learned with an ablation-based explainability method, that extracts frequency bands learned by the models through a perturbation of the input’s frequency spectrum. We found that fast Narrow-Band Gamma oscillations (60-90Hz), contributed most to the models across all 7 hemispheres.

This work, using a data-driven approach, joins a recent body of evidence suggesting cortical Narrow-Band Gamma activity as the potential range for digital biomarkers for DBS optimization.
Engaging doctoral students in peer review: a pre-post study evaluating the effectiveness of the “Peerspectives” course on review quality, knowledge and skills
Authors: Rohmann Jessica L. , Wülk Nadja , Rubarth Kerstin , Grillmaier Hannah , Abdikarim Iman , Simoes Mariana Lopes , Schroter Sara , Piccininni Marco , Kurth Tobias , Glatz Toivo
Published: February 2025

Objective

To assess the effectiveness of thePeerspectivescourse on editor-judged quality of peer review

Design

Single arm, pre-post interventional study

Setting

Peerspectivesis a peer review training course developed for doctoral students at the Charité – Universitätsmedizin Berlin, Germany

Participants

Doctoral students in health research domains who enrolled in thePeerspectivescourse between October 2020 and August 2022 and consented to participate (N= 80).Intervention:A semester-long course (approx. 18 weeks) providing training about the structure, purpose, and conduct of peer review and editing processes in biomedical journals. The course consisted of 12 hours of interactive lectures, weekly homework assignments, and 12 hours of hands-on, small-group workshops under guidance of mentors with reviewing and editing experience. Students peer-reviewed real scientific manuscripts under review at a partnering journal,The BMJ.

Main outcome measures

The overall quality of the peer review reports as judged by two independentBMJeditors using the global score of the Review Quality Instrument (RQI) pre- and post-intervention. Additionally, participants’ self-assessed knowledge and skills related to scholarly peer review (1-5 Likert scale).

Results

After course completion, participants’ RQI scores were higher than before the course (median increase of 0.5 points, p<0.001; mean increase of 0.36 points, p<0.001). The RQI scores of participants’ post-course reports were not non-inferior to those of actualBMJreviewers for the same manuscripts. Self-assessed peer review-related knowledge skills increased across all questionnaire items after course completion. Largest improvements were seen in understanding what is expected from a reviewer (increase in means from 2.9 to 4.5), confidence in own ability to review (2.5 to 3.9), and knowing what to look for in a manuscript while reviewing (2.8 to 4.2).

Conclusions

Providing doctoral students with comprehensive training resulted in an editorially significant increase in review report quality and improved understanding of the role and expectations of peer reviewers in the scholarly publishing processes and confidence in giving constructive feedback.

Study pre-registration:https://osf.io/vndcx
Optimisation of Xenium automated in situ sequencing for PAXgene-fixed tissue samples
Authors: Roberts Kenny , Bassett Andrew R.
Published: February 2025

Spatial transcriptomics has transformed the study of gene expression in tissue samples, yet its application to non- standard sample preservation formats beyond fresh frozen and FFPE remains underexplored. PAXgene fixation offers advantages for genomic studies by preserving DNA and RNA without crosslinking but poses challenges for high-quality spatial transcriptomics. Here, we present an optimised workflow for applying Xenium, an automated in situ sequencing platform, to PAXgene-fixed paraffin-embedded (PFPE) tissues. Using our newly developed Xenium Tissue Optimisation (XTO) protocol, we systematically tested permeabilisation conditions across multiple mouse and human tissues. We show that pepsin digestion effectively enhances RNA accessibility in PFPE samples, with tuneable digestion times for tissue-specific optimisation, though a compromise may need to be reached between transcript detection rates and maintaining tissue integrity and morphological staining. Our results indicate that, under optimal conditions, PFPE samples can yield comparable or superior spatial RNA transcript detection to formalin-fixed paraffin-embedded (FFPE) samples. This study provides a framework for adapting in situ sequencing to PFPE tissues, broadening the applicability of spatial transcriptomics to archival and prospective sample collections.

Visual abstract
Chalcone isomerase-like impedes the lactone shunt and enhances flux partitioning in a bifurcated pathway towards isoflavonoid biosynthesis
Authors: Raytek Lee Marie , Saltzman Brandon Corey , Sharma Meha , Lee Soon Goo , Dastmalchi Mehran
Published: February 2025

The reconstitution of biosynthetic pathways in heterologous hosts is often challenged by the switch to a foreign cellular environment, lacking compatible structural or regulatory features. Auxiliary or non-catalytic proteins can play a critical role in modulating metabolic flux and pathway efficiency. Chalcone isomerase-like (CHIL) is a non-catalytic protein known to serve as a partner to chalcone synthase (CHS) in flavonoid biosynthesis, rectifying its promiscuous activity and preventing by-product formation, such as the aberrantp-coumaroyltriacetic acid lactone (CTAL). Here, we extended the characterization of CHILs to the legume-characteristic isoflavonoid pathway. We assessed four CHIL orthologs from diverse plant lineages:Glycine max(GmCHIL),Oryza sativa(OsCHIL),Selaginella moellendorffii(SmCHIL), andMarchantia polymorpha(MpCHIL). Structural modelling suggested that naringenin (flavanone) entry into the CHIL binding cleft may be sterically hindered compared to catalytic CHIs. Moreover, legume CHIL isoforms possess an additional bulky residue, Tyr48, that is expected to impose further constraints on ligand binding.In vitro,CHS produced up to 60% lactone CTAL instead of its desired output; however, CHIL suppressed this aberrant activity to 10%, concomitantly increasing target compound titers. Combinatorial enzyme and yeast biotransformation assays revealed a critical role for CHIL in conducting flux through chalcone, flavanone, and isoflavone biosynthesis. The inclusion of CHIL in our engineered yeast strains enhanced overall titers and, unexpectedly, promoted carbon flux toward the so-called deoxy-branch (isoliquiritigenin, liquiritigenin, and daidzein) by up to 67%, with a 33% increase in final daidzein titers. By extending CHIL characterization to the isoflavonoid pathway, we have revealed an expanded role for this auxiliary protein and underscored its utility in engineered metabolic contexts. Our findings reiterate the often-overlooked impact of non-catalytic proteins in shaping specialized metabolism.

HIGHLIGHTS

Combinatorial enzyme assays reveal a species-dependent preference for CHILs from more closely related plant phyla by soybean CHS, which improved chalcone and downstream flavanone output by suppressing aberrant lactone formation.

Yeast co-expressing CHIL with the components of the isoflavonoid metabolon exhibited a 67% increase in flux through a legume-characteristic branch of the pathway, resulting in a 33% increase in titers of the major isoflavone, daidzein.

CHIL proteins can be included to engineer the output of phenylpropanoid-derived intermediates preferentially toward isoflavonoid biosynthesis.

Auxiliary components, such as CHIL, can be designed to refine metabolic composition in bifurcated pathways, as well as enhancing general flux through pathways.
Glucagon-like peptide-1 receptor activation and mental health: a drug-target Mendelian randomization study
Authors: Yang Guoyi , Burgess Stephen , Schooling C Mary
Published: February 2025

Concerns have been raised about the psychiatric safety of glucagon-like peptide-1 receptor (GLP-1R) agonists, but trial evidence suggests that they ameliorate depressive symptoms. We aimed to assess the associations of GLP-1R activation with mental health well-being and the risk of mental health disorders and substance use disorders. We performed drug-target Mendelian randomization and colocalization analyses using the largest relevant publicly available genome-wide association studies in European ancestry individuals. After correcting for multiple comparisons, genetically predicted lower body mass index (BMI) via GLP-1R activation was associated with a better well-being spectrum (0.06 standard deviation [95% confidence interval 0.03-0.08]) and lower risk of depression (odds ratio 0.83 [0.74-0.94]) and bipolar disorder (odds ratio 0.61 [0.47-0.79]) per 1-kg/m2decrease in BMI. There was also suggestive evidence that genetically predicted lower BMI via GLP-1R activation was associated with lower risk of post-partum depression, attention deficit hyperactivity disorder, and substance use disorders, and that genetically predicted lower glycated hemoglobin (HbA1c) via GLP-1R activation was associated with higher risk of anorexia nervosa but lower risk of Tourette syndrome. These associations were stronger than the associations for genetically predicted lower BMI and lower HbA1c based on genome-wide variants. The posterior probabilities of a shared causal variant affecting both BMI and the outcome at theGLP1Rgene were 59.3% for the well-being spectrum, 3.8% for depression, and 45.9% for bipolar disorder. GLP-1R activation was associated with better mental health well-being and lower risk of depression and bipolar disorder beyond that expected from the reduction in BMI and HbA1c.
The Thermal Grill Elicits Central Sensitization
Authors: Cormie Matthew A. , Seminowicz David A. , Moayedi Massieh
Published: February 2025

The thermal grill, in which innocuous warm and cool stimuli are interlaced, can produce a paradoxical burning pain sensation—the thermal grill illusion (TGI). While the mechanisms underlying TGI remain unclear, prominent theories point to spinal dorsal horn integration of innocuous thermal inputs to elicit pain. It remains unknown whether the TGI activates peripheral nociceptors, or solely thermosensitive afferents and is integrated within the spinal cord. Different types of sensitization have established mechanisms and can inform TGI mechanisms: if the TGI elicits (1) primary hyperalgesia, peripheral nociceptors are activated; (2) secondary hyperalgesia in the absence of primary hyperalgesia, spinal integration is required; and (3) brush allodynia, wide-dynamic range neurons are involved in mediating the TGI. Here, we determine whether the TGI elicits primary hyperalgesia, secondary hyperalgesia or brush allodynia. Fifty-two participants underwent individually calibrated phasic thermal grill stimulation. We found that the TGI elicited primary hyperalgesia, but only in participants with component temperatures in the noxious range (<19°C and >41°C). The TGI also elicited secondary hyperalgesia, even in participants with strictly innocuous thermal inputs. No participants developed brush allodynia. We observed sex differences in primary hyperalgesia: only males exhibited thermal grill-induced primary hyperalgesia. These findings suggest that the TGI is integrated in the spinal dorsal horn, likely mediated by heat-pinch-cold (HPC) neurons, and, to some degree, by primary nociceptive afferents in males. This study shows that the TGI may have sex-dependent mechanisms and determines that HPC cells are involved in the illusory sensation of pain from innocuous thermal inputs.
Observation of ponderomotively driven bow shock using Thomson scattering
Authors: Milder A. L. , Bruulsema C. , Hüller S. , Walsh C. , Rozmus W. , Yin L. , Ludwig J. , Farmer W. A. , Albright B. J. , Rose H. A. , Swadling G.
Published: February 2025

High-energy speckled lasers are known to exert ponderomotive forces on a plasma. This can reduce flow transverse to the propagation of the beams. When coupled with a supersonic flow, this has been shown to lead to the formation of a shock that travels against the flow. Experiments conducted on the OMEGA laser facility have used Thomson scattering to observe density and velocity changes consistent with this ponderomotively driven shock. Comparisons of the data with hydrodynamic simulations with the ponderomotive force, particle-in-cell simulations with a full Maxwell field solver, and hydrodynamic simulations without the ponderomotive force show that this shock feature is only reproduced when accounting for the ponderomotive force.

Published by the American Physical Society
2025
Do negative social media sentiments affect firm risk?
Authors: Benjamin Samuel Jebaraj , Wellalage Nirosha , Biswas Pallab Kumar , Wasiuzzaman Shaista
Published: February 2025

Purpose

This paper aims to empirically examine the link between negative social media sentiments (SMS) and firm risk, measured by total risk.

Design/methodology/approach

This paper collected data from Fortune 500 companies in the USA from 2010 to 2017. The analyses used the pooled ordinary least squares, Fama–McBeth regression, fixed-effects regression and propensity score matching.

Findings

The results show that negative SMS increase firm risk. In addition, this paper considers the effect of corporate social responsibility (CSR) disclosures on the relationship between negative SMS and firm risk. This paper finds that the effects of negative SMS on firm risk are attenuated in firms with better CSR disclosures.

Originality/value

This study offers fresh perspectives for investors and managers on firm risk and the influence of social media on firm outcomes, providing valuable insights for scholars and practitioners to understand the impact of negative social media sentiments on firm risk, along with the crucial roles played by CSR in this relationship.
Male migration, women’s decision-making autonomy and reproductive health-care utilization in Pakistan
Authors: Shah Nasra M. , Quddus Samar
Published: February 2025

Purpose

The purpose of this study is to examine the association between international migration and utilization of reproductive health care among women left behind in Pakistan by male migrants, in comparison with women in non-migrant households.

Design/methodology/approach

From the nationally representative Pakistan Demographic and Health Survey, 2017–2018, 8,158 currently married women who had delivered a child during the five years before the survey were included. Among the 8,158 women, 811 lived in a household that had at least one international migrant, while 7,347 lived in households without migrant. Descriptive statistics as well as logistic regression was used to analyze reproductive health care. Satisfactory reproductive health was defined as: 4+ antenatal visits; 2+ tetanus injections; delivery in a health-care facility; and delivery by a skilled birth attendant.

Findings

Logistic regression indicates that women in migrant households had a significantly higher utilization of all four health-care services, after controlling for their autonomy level. However, once background characteristics (woman’s age, education, rural-urban residence and wealth status) were factored in, women in migrant households were not significantly different from those in non-migrant households, except for delivering in a medical health-care facility, the former being 1.3 times more likely to deliver in a health facility than the latter. A higher level of autonomy was associated significantly with greater utilization of reproductive health services.

Originality/value

This study adds the dimension of international migration to the existing knowledge on utilization of health-care services, a subject that is relatively under researched in Pakistan.
Contextual cues matter: advancing personality research through the interactions of implicit and explicit personality with situations
Authors: Williams Jaime L. , Stewart Susan M. , Davison H. Kristl
Published: February 2025

Purpose

This paper confirms and expands upon the implicit and explicit personality model of Bing et al. (2007) by replicating earlier findings and conducting an exploratory test of the three-way interactive effects of implicit and explicit aggressive personality on positive work behaviors by including the situational context of justice perceptions.

Design/methodology/approach

In total, 186 hospital employees completed a survey of implicit and explicit aggression and organizational justice perceptions. Supervisors rated the employees’ organizational citizenship behaviors directed at the organization (OCBOs) and individuals (OCBIs), and the number of commendations employees received was obtained from the hospital. The data were analyzed with multiple regression analysis.

Findings

Our exploratory results showed that all prototypes tended to withhold OCBOs when justice perceptions were lower. Specifically, when procedural justice was higher, manifest aggressives (higher implicit/higher explicit aggression) had the lowest levels of OCBOs, and prosocials (lower implicit/lower explicit aggression) had the highest levels of OCBOs. Overcompensating prosocials (lower implicit/higher explicit aggression) generally had the highest number of commendations across the three justice dimensions. Nonsignificant interactions were found for interactional justice and OCBIs.

Research limitations/implications

This study can assist researchers and practitioners in understanding how organizations should pair enhanced employee selection with improved organizational support for the best results.

Originality/value

This study confirms and extends previous work on the interaction of implicit and explicit personality by conducting an exploratory test of the role of situations (i.e. justice perceptions) in predicting positive (vs negative) outcomes.
YOLO‐Behaviour: A simple, flexible framework to automatically quantify animal behaviours from videos
Authors: Chan Alex Hoi Hang , Putra Prasetia , Schupp Harald , Köchling Johanna , Straßheim Jana , Renner Britta , Schroeder Julia , Pearse William D. , Nakagawa Shinichi , Burke Terry , Griesser Michael , Meltzer Andrea , Lubrano Saverio , Kano Fumihiro
Published: February 2025

Manually coding behaviours from videos is essential to study animal behaviour but it is labour‐intensive and susceptible to inter‐rater bias and reliability issues. Recent developments of computer vision tools enable the automatic quantification of behaviours, supplementing or even replacing manual annotation. However, widespread adoption of these methods is still limited, due to the lack of annotated training datasets and domain‐specific knowledge required to optimize these models for animal research.

Here, we present YOLO‐Behaviour, a flexible framework for identifying visually distinct behaviours from video recordings. The framework is robust, easy to implement, and requires minimal manual annotations as training data. We demonstrate the flexibility of the framework with case studies for event‐wise detection in house sparrow nestling provisioning, Siberian jay feeding, human eating behaviours and frame‐wise detections of various behaviours in pigeons, zebras and giraffes.

Our results show that the framework reliably detects behaviours accurately and retrieve comparable accuracy metrics to manual annotation. However, metrics extracted for event‐wise detection were less correlated with manual annotation, and potential reasons for the discrepancy between manual annotation and automatic detection are discussed. To mitigate this problem, the framework can be used as a hybrid approach of first detecting events using the pipeline and then manually confirming the detections, saving annotation time.

We provide detailed documentation and guidelines on how to implement the YOLO‐Behaviour framework, for researchers to readily train and deploy new models on their own study systems. We anticipate the framework can be another step towards lowering the barrier of entry for applying computer vision methods in animal behaviour.
Population Dynamics of the Endemic and Vulnerable Grauer's Swamp Warbler (Bradypterus graueri): Insights From Long‐Term Monitoring in Volcanoes National Park, Rwanda
Authors: Tuyisingize D. , Faida E. , Musemakweli V. , van der Hoek Y.
Published: February 2025

Wetland‐dwelling birds are indicators of wetland health. We investigated the population dynamics and conservation implications of the endemic and Vulnerable Grauer's swamp warbler (Bradypterus graueri; GSW) across three wetlands (Rugezi, Kabatwa, and Malalo) of varying sizes and elevations within Volcanoes National Park (VNP), Rwanda. We collected visual and auditory count data over 13 years from 19‐point count stations systematically located across the wetlands and applied distance analysis to assess the abundance and distribution of GSW across years and wetlands. Then, we employed Generalised Additive Mixed Models (GAMM) to assess the relationship between GSW abundance and specific factors known to impact wetlands: trampling by large mammals, the presence of non‐wetland plant species, or the absence of water. Additionally, we investigated how wetland sizes influenced this relationship. We found that the focal wetlands within VNP support an approximate mean of 3.143 (95% CI: 2.578–3.831) clusters of GSW per hectare, hosting a mean of 3.634 (95% CI: 2.960–4.462) individuals per cluster. Nonetheless, there were instances of GSW extirpation occurring in Malalo and Kabatwa VNP wetlands. Mammal trampling and non‐wetland plants negatively impacted the GSW population (trampling: estimate = −2. 126, p < 0.043; non‐wetland plants: estimate = −0.735, p = 0.05), while GSW abundance is positively associated with the presence of water (estimate = 0.862, p < 0.002). GSW density also increased with wetland size, though this trend was not significant (p > 0.05). Generally, despite fluctuations in GSW densities within the studied wetlands, VNP remains a crucial habitat for this globally threatened species: wetlands that might require actions highlight the need for efforts to avoid desiccation.
Plain Language Summary of the ACCEPT Guideline for the Management of Recurrent Pregnancy Loss
Authors: Suker Adriana , Li Ying , Marren Anthony , Robson Danielle ,   the Australasian CREI (Certificate of Reproductive Endocrinology and Infertility) Consensus Expert Panel on Trial evidence (ACCEPT) group
Published: February 2025

Recurrent pregnancy loss (RPL) is when a woman experiences two or more pregnancy losses. Investigating for causes of RPL can provide an explanation and possible treatment options. This is a summary of Parts 1 and 2 of Australasian Recurrent Pregnancy Loss Clinical Management Guidelines in an easy‐to‐read patient friendly format. These original publications can be found with a digital object identifier (DOI) 10.1111/ajo.13821 and DOI 10.1111/ajo.13820.
Vincamine ameliorates hepatic fibrosis via inhibiting S100A4‐mediated farnesoid X receptor activation: based on liver microenvironment and enterohepatic circulation dependence
Authors: Jiang Yu‐Chen , Guo Jia , Liu Sai‐Hu , Dai Xu , Wang Chen‐Yu , Lian Li‐Hua , Cui Zhen‐Yu , Nan Ji‐Xing , Wu Yan‐Ling
Published: February 2025

Background and Purpose

Vincamine has extensive biological and pharmaceutical activity. We examined the hepatoprotective effects and mechanisms by which vincamine suppresses hepatic fibrosis.

Experimental Approach

Hepatic stellate cells (HSCs), TGF‐β stimulated, were cultured with either vincamine, farnesoid X receptor (NR1H4; FXR) agonist or antagonist. Further, C57BL/6 mice were given thioacetamide (TAA) to induce hepatic fibrosis and subsequently treated with vincamine or curcumin.

Key Results

Vincamine regulated the deposition of extracellular matrix (ECM), inflammatory factors and S100A4, and up‐regulated FXR and TGR5 (GPBA receptor) in activated HSCs, by activating FXR. FXR deficiency blocked vincamine effect on FXR, TGR5, α‐smooth muscle actin (α‐SMA) and IL1R1 in activated LX‐2 cells. Vincamine corrected ECM imbalance, inflammatory secretion and FXR/TGR5 down‐regulation in activated LX‐2 cells with stimulating medium from LPS‐primed THP‐1 cells. S100A4 deficiency increased FXR and TGR5, and decreased IL‐1β expression in activated THP‐1. Further, S100A4 deficiency in activated macrophages could elevate FXR and TGR5 expression in activated LX‐2, strengthening the impact of vincamine on α‐SMA and IL‐1β expression. Further, vincamine reduced serum ALT/AST levels, liver and intestinal histopathological changes, and caused ECM accumulation and protected the intestinal barrier in thioacetamide‐induced hepatic fibrosis mice. Vincamine decreased inflammatory factors e.g. caspase 1 and IL‐1β, and inhibited the S100A4‐mediated FXR‐TGR5 pathway.

Conclusion and Implications

Vincamine significantly reverses hepatic fibrosis via inhibiting S100A4 involved in the crosstalk between macrophages and HSCs, and by activating the FXR‐TGR5 pathway. Targeting the S100A4‐mediated FXR dependence on modulating the liver environment may be the key target of vincamine in inhibiting hepatic fibrosis.
Pharmacokinetics of SARS‐CoV‐2 RNA Polymerase Inhibitor Remdesivir in Participants With Moderate and Severe Hepatic Impairment
Authors: Regan Sean , Humeniuk Rita , Caro Luzelena , Abdelghany Mazin , Davies Santosh , Baysa Amarylliz , Shen Gong , Hyland Robert H. , Kim Aryun
Published: February 2025

Remdesivir is an RNA polymerase inhibitor of severe acute respiratory syndrome coronavirus 2 administered intravenously (IV) that is approved for the treatment of coronavirus disease 2019 in hospitalized and nonhospitalized patients. The clinical dosing regimen is a single loading dose of 200 mg on Day 1 followed by once‐daily maintenance doses of 100 mg from Day 2, for a total duration of up to 10 days. The prodrug, remdesivir, undergoes metabolic activation inside the cell to form the intracellular active metabolite (GS‐443902) along with two plasma metabolites (GS‐704277 and GS‐441524). The pharmacokinetics and safety of a single IV 100‐mg dose of remdesivir were evaluated in a Phase 1, open‐label, multicenter study in participants with moderate (n = 10) or severe (n = 6) hepatic impairment (Child–Pugh–Turcotte Class B or C, respectively) and participants with normal liver function (n = 16). Compared with the normal hepatic function group, plasma exposures (geometric least squares mean ratios of area under the concentration–time curve extrapolated to infinity and maximum concentration) of remdesivir, GS‐704277, and GS‐441524 were similar in the moderate hepatic impairment group and up to 1.56‐fold, 2.41‐fold, and 1.48‐fold higher, respectively, in the severe hepatic impairment group. Remdesivir was generally safe and well tolerated in hepatically impaired individuals, and the modest exposure increases of remdesivir and its metabolites were not associated with adverse events. Based on these findings, no dose adjustment of remdesivir is recommended for patients with mild, moderate, or severe hepatic impairment.
Emapalumab in Patients With Macrophage Activation Syndrome Associated With Still's Disease: A Population Pharmacokinetic/Pharmacodynamic Analysis
Authors: Brossard Patrick
Published: February 2025

Macrophage activation syndrome (MAS) is a life‐threatening form of secondary haemophagocytic lymphohistiocytosis (HLH) associated with rheumatic diseases, most commonly Still's disease. This study aimed to develop a population pharmacokinetic (PK)/pharmacodynamic (PD) model for emapalumab, a fully human monoclonal antibody that targets interferon‐gamma (IFNγ), in patients with MAS associated with Still's disease. A two‐compartment disposition model based on data from patients with primary HLH administered emapalumab (1 mg/kg every 3 days, with possible increases to 3, 6 or 10 mg/kg) was re‐estimated for patients with MAS administered emapalumab (6 mg/kg, then 3 mg/kg every 3 days until day 15 and twice weekly until day 28). An exploratory population PK/PD analysis comprising patients' PD data for total IFNγ, chemokine C‐X‐C motif ligand 9 (CXCL9) and ferritin was performed. Emapalumab clearance was generally linear and independent of total IFNγ levels in patients with MAS (n = 14). Estimated baseline levels of CXCL9 (a marker of IFNγ activity), soluble interleukin‐2 receptor α (sIL‐2Rα; a marker of hyperinflammation) and ferritin (a clinical marker of MAS disease activity) were 8400, 6550 and 15,300 μg/L, respectively. All three PD markers responded rapidly to changes in emapalumab concentration. Emapalumab almost completely suppressed CXCL9, sIL2‐Rα, and ferritin production (estimated reduction in synthesis rate: 98.3%, 87%, and 99.6%, respectively). Population PK/PD modeling indicated that emapalumab rapidly suppresses markers of hyperinflammation in patients with MAS associated with Still's disease. Emapalumab dosing regimen used in clinical trials in patients with MAS is unlikely to need adjustment.
Functional consequences of lysine acetylation of phosphofructokinase isozymes
Authors: Li Xinyu , Fatema Nour , Gan Qinglei , Fan Chenguang
Published: February 2025

Phosphofructokinase (Pfk) catalyzes the phosphorylation of fructose 6‐phosphate and is a key regulatory point in the glycolysis pathway. Multiple lysine residues in both Pfk isozymes, PfkA and PfkB, have been identified to be acetylated in Escherichia coli by proteomic studies, but no studies have been implemented to further characterize these acetylation events. To investigate the role of Pfk acetylation, the genetic code expansion strategy was used to generate homogeneously acetylated Pfk variants at target lysine sites that have been reported to be acetylated in nature. We found that acetylation of K309 of PfkA and K27 of PfkB decreased PfK enzyme activities significantly. We further investigated the deacetylation and acetylation processes of Pfk isozymes biochemically and genetically. Acetyl phosphate‐mediated non‐enzymatic acetylation could be the major mechanism of Pfk isozyme acetylation in E. coli, whereas NAD‐dependent protein deacylase CobB can remove most of the acetylated lysine residues but not K309 of PfkA and K27 of PfkB, which affect enzyme activities. Because of the important role of Pfk in cellular metabolism, the results of the present study are expected to facilitate studies in the fields of metabolic engineering and research.
Psychometric Properties of Self‐Reported Financial Toxicity Measures in Cancer Survivors: An Overview of Systematic Reviews
Authors: Li Leilei , Qu Hui , Fu Chaohong , Niu Jianpei , Yang Changyong
Published: February 2025

Aim(s)

To assess the methodological quality and psychometric properties of self‐reported financial toxicity measures for cancer survivors, to offer evidence‐based guidance for the selection of these measures in clinical practice, and to supply methodological references for the enhancement and development of related measures in the future.

Design

An overview of systematic reviews.

Methods

Four academic databases were searched to conduct an overview of systematic reviews published from inception to August 2024. The Overview Quality Assessment Questionnaire (OQAQ) was employed to evaluate the methodological quality of the research included. The consensus‐based standards for the selection of health measurement instruments checklist (COSMIN) and the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) system were employed to assess the methodological and psychometric quality of the financial toxicity measures included.

Results

Six systematic reviews satisfied the inclusion criteria. The OQAQ results indicated that six studies exhibited significant methodological quality defects, each receiving a score of 3 points. COST‐v1, COST‐v2, HARDS, ENRICh, and FinTox were classified as level A. Ten measures were classified as level B, lacking evidence to support content validity and internal consistency as ‘+’. Seven measures were classified at level C, supported by high‐quality evidence indicating certain domains as ‘−’.

Conclusion

COST is advised as the best appropriate measurement standard for research and clinical practice across many global contexts. HARDS and ENRICh were advised to select only after thoroughly evaluating the local socio‐economic context. FinTox is particularly suggested for the assessment of severe FT. SFDQ and FIT are advised for selection following an evaluation of therapy alternatives and the cancer's location.

Implications for the Patient Care

Healthcare professionals can implement evidence‐based measures in clinical practice to effectively assess the financial toxicity experienced by cancer survivors, offer policy‐oriented interventions, and enhance patient‐reported outcomes.
Efficacy and Safety of a Topical Formulation Containing Trihydroxybenzoic Acid Glucoside and α‐Arbutin, Applied Along With a Sunscreen: A Noncomparative, Prospective, Interventional Study in Indian Females With Facial Melasma or Dark Spots
Authors: Gabhane Mukesh , Patil Raji , Dharmadhikari Shruti , Shah Priyank , Khandhedia Chintan , Mehta Suyog
Published: February 2025

Background

Skin hyperpigmentation is a dermatological concern for pigmented skin phototypes. Despite availability of multiple treatment options, hyperpigmentation management continues to be a challenge.

Aims

Efficacy and safety assessment of the skincare regimen [topical formulation of trihydroxybenzoic acid glucoside 10% (THBG) and α‐arbutin 2% (twice‐daily) + sunscreen (once daily)] in Indian females with pigmentary spots (facial dark spots or melasma).

Methods

This prospective, open‐label, single‐arm, interventional study was conducted in Indian females (n = 124), aged 18–45 years, having FitzPatrick skin type III–IV, dull skin, and facial dark spots or melasma. Efficacy of 90‐day skincare regimen was evaluated using mexameter, modified melasma area and severity index (mMASI) score, cross‐polarized light photography, chromameter, and color–luminosity–brightness–transparency (CLBT) technique. Student's t‐test (paired data) was used for statistical analysis.

Results

In efficacy analysis [modified intention‐to‐treat (mITT) population], 120 subjects were included. Melanin content of pigmentary spots (on mexametry) significantly reduced (−16.3%, p < 0.001) at Day 90 versus baseline. Significant reduction in severity of melasma was observed (−18.4% in mMASI score) at Day 90. Significant improvement in ΔEab (−8.7%) (change in color difference between pigmentary spot and normal skin) on cross‐polarized photographs, in skin‐brightening parameters L* (relative brightness/lightness) (−2.7%), ITA° (individual typology angle) (−37.7%), and ΔE* (skin‐tone evenness) (−19.0%) using chromameter. Significant improvement in skin radiance was observed in CLBT parameters, color (pink: 32.8%, yellow: –5.5%, and olive: −7.8%), luminosity (6.0%), brightness (4.6%), and transparency (0.2%). Regimen did not cause itching, burning, or irritation.

Conclusions

Skincare regime of 10% THBG and 2% α‐arbutin along with sunscreen was effective in reducing pigmentary spots (dark spots and melasma) and was well tolerated in Indian women.

Trial Registration: Clinical Trial Registry of India (CTRI Reg. No. CTRI/2021/11/038345; date: 30/11/2021)
Diurnal Variation in Melatonin‐Mediated Cardiac Protection via Per2 Expression in Heart
Authors: Luo Ronghao , Yang Zebin , Liang Wanshi , Chen Yifei , Jie Yinhong , Zhang Yang , Li Le
Published: February 2025

Myocardial ischemia/reperfusion (MIR) injury, a primary cause of mortality in acute myocardial infarction, exhibits diurnal variation associated with disruptions in diurnal rhythm. Melatonin (MLT), a potent antioxidant known for its cardioprotective properties, also demonstrates diurnal rhythmicity. This study aimed to investigate the time‐dependent cardioprotective effects of MLT in MIR and to clarify the role of the circadian gene Per2 in mediating these effects. Using in vivo (mice) and in vitro (H9c2 cardiomyocytes) models of MIR, we administered MLT at two distinct diurnal time points: ZT1 and ZT13. We evaluated infarct size, cardiac function, apoptosis, and the expression levels of Per2 and other circadian genes. Pretreatment with MLT at ZT13 significantly reduced infarct size and enhanced cardiac function compared to ZT1 administration. This time‐dependent cardioprotective effect correlated with the diurnal expression pattern of Per2, which was notably augmented by dark phase administration of MLT without phase alteration. Crucially, Per2 knockdown in both models abrogated the cardioprotective effects of MLT. Our findings underscore that MLT confers superior cardioprotection against MIR injury when administered at dark phase, aligning with the circadian variation of Per2 expression. These effects reveal the therapeutic potential of targeting the MLT‐Per2 axis in chronotherapy to mitigate MIR injury.
Alterations in Milk Biomolecular Profiles and Piglet Performances Due to Dietary Probiotic Bacillus licheniformis DSMZ 28710 Supplementation
Authors: Ruampatana Jakavat , Settachaimongkon Sarn , Kaewsirikool Jedsadakorn , Iamraksa Pornpavit , Choompoo Sirawit , Suwimonteerabutr Junpen , Homyog Kunaporn , Mekboonsonglarp Wanwimon , Feyera Takele , Nuntapaitoon Morakot
Published: February 2025

The present study aimed to investigate the effects of probiotic Bacillus licheniformis DSMZ 28710 supplementation on sow performance, Preweaning piglet performance, and the biochemical profiles of colostrum and milk. Sixty‐eight crossbred sows (Landrace Yorkshire) were allocated to either a standard lactation diet (Control; n = 35) or the Control diet supplemented with 10 g/sow/day of B. licheniformis DSMZ 28710 (Treatment; n = 33), from day 109 of gestation until day 21 of lactation. Sow and piglet performance, as well as the incidence of piglet diarrhea, were recorded. Moreover, the study investigated the changes in major chemical compositions, immunoglobulins, fatty acids, and non‐volatile polar metabolites in colostrum, transient milk, and mature milk of sows. Supplementation of B. licheniformis increased piglet body weight on day 21 of lactation in old parity sows (p = 0.037). Moreover, the incidence of diarrhea was reduced in piglets suckled by sows supplemented with B. licheniformis DSMZ 28710, regardless of sow's parity or lactation stage (p < 0.05). Probiotic supplementation decreased fat content in transient milk (p = 0.026) and increased lactose content in mature milk (p = 0.011). Chemometric analysis revealed clear distinctions between the Control and Treatment group in the fatty acid profiles of colostrum, transient milk, and mature milk, while notable differences in non‐volatile polar metabolite profiles were observed specifically in mature milk. In conclusion, supplementation with B. licheniformis DSMZ 28710 reduced the incidence of diarrhea in piglets, increased body weight of the piglets in old parity sows and altered the biomolecular profiles in colostrum, transit milk, and mature milk of the sows.
The Making of a Ruler: Haitham bin Tariq on the Omani Throne
Authors: Kéchichian Joseph Albert
Published: February 2025

Oman's leadership transition from Qaboos bin Sa‘id to Haitham bin Tariq validated Al Sa‘id authority in more ways than one. While the 15th Al Sa‘id sultan has only been in power for slightly more than four years, his initial governance preferences indicate that he will manage with poise. Haitham has developed a new doctrine that emphasizes wealth creation, acceleration of education levels, ensuring norms of social security, improving civil rights, and promoting closer ties with the sultanate's neighbors. In key speeches, he has promised to address core challenges and, over the course of four years, has ushered in laws that translate his pledges into actions. This preliminary assessment of Haitham evaluates his early decisions, appraises his declared priorities, and identifies his major preferences. It further highlights some of the internal as well as foreign challenges that confront Omanis. Given his measured and contemplative personality, Haitham has adopted pragmatic policies to preserve and defend Omani interests—not only to continue on his predecessor's path but to further validate long‐term Al Sa‘id aspirations.
Network models for temporal data reconstruction for dam health monitoring
Authors: Chen Yongjiang , Wang Kui , Zhao Mingjie , Liu JianFeng
Published: February 2025

The reconstruction of monitoring data reconstruction is an important step in the process of structural health monitoring. Monitoring data reconstruction involves generating values that are close to the true or expected values, and then using the generated values to replace the anomalous data or fill in the missing data. Deep learning models can be used to reconstruct dam monitoring data, but current models suffer from the inabilities to reconstruct data when the dataset is significantly incomplete, and the reconstruction accuracy and speed have needs for improvement. To this end, this paper proposes a dam temporal reconstruction nets (DTRN) based on generative adversarial nets, which is used to accurately reconstruct dam monitoring data for cases of incomplete datasets. To improve the accuracy of the reconstruction values, this paper embeds a gated recurrent unit network based on a sequence‐to‐sequence model into DTRN to extract the temporal features of the dam monitoring data. In addition, given that random matrices with different distributions lead to different reconstruction results, maximum probability reconstruction based on multiple filling is adopted. Finally, several experiments show that (1) DTRN is not only applicable to the reconstruction of various types of dam monitoring data (e.g., dam displacement monitoring data, dam seepage pressure monitoring data, seam gauge monitoring data, etc.) but also can be applied to other relatively smooth time series data. (2) The average root mean square error of DTRN (0.0618) indicates that its accuracy is 92.3%, 57.5%, and 71.99% higher than that of generative adversarial imputation nets (GAIN), timing GAIN (TGAIN), and dam monitoring data reconstruction network (DMDRN), respectively. (3) The average elapsed time of DTRN (522.6 s) is 68.45% and 48.10% shorter than that of TGAIN and DMDRN, respectively.