bluuebunny/crossref_metadata_2025 huggingface dataset:
Peroxisome proliferator–activated receptor delta and liver diseases
Authors: Yamazaki Tomoo , Cable Edward E. , Schnabl Bernd
Published: February 2025

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors involved in transcriptional regulation and play an important role in many physiological and metabolic processes. Unlike PPAR-alpha and PPAR-gamma, PPAR-delta is ubiquitously expressed, and its activity is key to maintaining proper metabolic homeostasis within the liver. PPAR-delta not only regulates physiologic processes of lipid, glucose, and bile acid metabolism but also attenuates pathologic responses to alcohol metabolism, inflammation, fibrosis, and carcinogenesis, and is considered an important therapeutic target in liver diseases. Promising results have been reported in clinical trials for PPAR-delta agonists in liver disease, and the selective agonist seladelpar was recently conditionally approved in the United States as a new treatment option for primary biliary cholangitis. This review provides an overview of PPAR-delta’s function and biology in the liver, examines its kinetics and therapeutic potential across different liver diseases, and discusses the current status of clinical trials involving its agonists.
Panax notoginseng polysaccharides: A review focusing on the extraction, isolation, structural characterization, biological activities and applications
Authors: Huang Jiaqi , Zhao Yuheng , Wang Mengyao , Tian Xiaojin , Cui Dianxin , Wang Qilong , Li Xue , Wu Honghua , Yang Wenzhi
Published: February 2025

Panax notoginseng is a traditional Chinese medicine containing various constituents, including the saponins, polysaccharides, polyacetylenes, and amino acids, etc. It has beneficial functions, such as the anti-inflammatory, antitumor, hepatoprotective, and anti-aging effects. Among these, P. notoginseng polysaccharides (PNPs) have been exploited because of their extensive pharmacological effects, being ranked as one of the current research hotspots, especially for the functional foods and medical practice. In this review, the literature related to PNPs in the past 20 years was surveyed and analyzed using both the China National Knowledge Infrastructure (CNKI) and Web of Science (WOS) databases. The visualization diagram shows that current studies on PNPs mainly focus on the antioxidant and immunomodulatory activities, and structural characterization. In addition, the extraction, separation, purification, chemical analysis, structural characteristics, bioactivities, and applications of PNPs are outlined, in detail, aimed to provide valuable information for the further study, development, and utilization regarding PNPs.

Graphical abstract: http://links.lww.com/AHM/A151.
Pathogenesis of Ectopic Inner Foveal Layers (EIFL) and Its Impact on Visual Recovery after Epiretinal Membrane Peeling
Authors: Mafi Mostafa , Govetto Andrea , Mahmoudinezhad Golnoush , Prasad Pradeep , Bousquet Elodie , Voichanski Shilo , Feo Alessandro , Sarraf David
Published: February 2025

Purpose:

To determine the pathoanatomical alteration of ectopic inner foveal layers (EIFL) and its relationship to visual recovery after epiretinal membrane (ERM) peeling surgery.

Methods:

Clinical charts and tracked spectral-domain optical coherence tomography images of patients diagnosed with stage 3 and 4 ERM were reviewed and analyzed preoperatively and at 3 and 6 months postoperatively. Central macular thickness (CMT) and EIFL thickness were measured at these time points. Wilcoxon signed-rank test was used for analysis and P < 0.05 was considered statistically significant.

Results:

The study cohort consisted of 54 eyes of 54 patients, 27 of whom were female. The mean age was 69.2 years. The mean Snellen VA improved from 20/50 preoperatively to 20/35 at 3 months (P<0.001) and remained 20/35 at 6 months, significantly better than preoperative levels (P=0.002). The mean preoperative EIFL thickness was 169.15 µm and decreased to 95.70 µm at 3 months (P = 0.001) and 90.95 µm at 6 months (P = 0.02). Similarly, CMT reduced from 510.00 µm preoperatively to 444.56 µm at 3 months (P < 0.001) and 415.50 µm at 6 months (P < 0.001). Reduction in EIFL thickness was significantly correlated with improvement in log-MAR VA (P =0.02) 6 months after surgery.

Conclusion:

ERM peeling results in reduced EIFL thickness, restoration of the normal foveal pit structure, and a corresponding improvement in visual acuity. Reduction in EIFL thickness is correlated with visual improvement.
Evaluating Short-Course Antibiotic Therapy for Pediatric Community-Acquired Pneumonia: A Systematic Review and Meta-Analysis
Authors: Bolormaa Erdenetuya , Kang Cho Ryok , Choe Young June , Yoo Young , Lee Jue Seong , Park Ji Young , Choe Seung Ah , Tansarli Giannoula S. , Mylonakis Eleftherios
Published: February 2025

Background:

The optimal duration of antibiotic therapy for community-acquired pneumonia (CAP) in children remains uncertain. In this study, we aimed to evaluate whether short-course antibiotic therapy (≤6 days) is associated with poor clinical outcomes compared with long-course antibiotic therapy (>7 days) in children with CAP.

Methods:

A comprehensive search was conducted across databases, including PubMed, Embase, Cochrane Library, and KoreaMed. Studies comparing the efficacy and safety of short-course with long-course antibiotic regimens in children with CAP were eligible. We assessed the risk of bias using the RoB 2 and ROBINS-I tools. Study characteristics such as publication year, country, setting, study design and antibiotic regimens were recorded. Pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated for clinical outcomes, including clinical cure, treatment failure, total adverse events, serious adverse events, relapse and hospitalization. The primary outcomes were clinical cure and treatment failure. Secondary outcomes included total and serious adverse events, relapse and hospitalization rates.

Results:

Seventeen studies comprising 155,944 children met the inclusion criteria, with 15 of these studies being randomized controlled trials. There were no significant differences between short-course and long-course treatments in clinical cure [21,156 patients; RR, 1.01 (95% CI, 0.97–1.05); P = 0.73; I² = 81%], treatment failure [28,942 patients; RR, 0.88 (95% CI, 0.51–1.51); P = 0.64; I²= 94%] or total adverse events [24,446 children; RR, 0.94 (95% CI, 0.61–1.44); P = 0.77; I² = 90%]. However, short-course treatment was associated with fewer serious adverse events [4194 patients; RR, 0.89 (95% CI, 0.79–0.99); P = 0.04; I² = 11%]. Relapse rates were nominally lower with short-course treatment compared with long-course treatments (5.5% vs. 6.2%; P = 0.04). This difference was primarily observed in the subgroup analysis comparing 5-day treatments to ≥10-day treatments. Hospitalization rates were similar between the two groups [122,607 patients; RR, 1.20 (95% CI, 0.85–1.68); P = 0.29; I² = 0%].

Conclusions:

Short-course antibiotic treatment is as effective as long-course treatment for pediatric CAP in terms of clinical cure and treatment failure while resulting in fewer serious adverse events.
Working From Dusk to Dawn
Authors: Salmond Susan , Weaver Susan H. , Marcus-Aiyeku Ulanda , Markiewicz Dorothy
Published: February 2025

Nurses are needed to work night shift because patients in acute care, subacute, and long-term care facilities require round-the-clock care. A systematic review on the experiences and perceptions of nurses working the night shift in varied settings found the night shift work environment is different and night shift nurses juggle their sleep and deal with ongoing sleep deprivation. Based on the systematic review and the evidence that forewarns of the physical and psychological burden of night shift work, recommendations are made for employers and nurses to navigate the challenges posed to those working against their circadian rhythm.
Steatotic Liver Disease: Navigating Pathologic Features, Diagnostic Challenges, and Emerging Insights
Authors: Jiao Jingjing , Zhang Xuchen
Published: February 2025

Steatotic liver disease (SLD) is now used as an overarching category encompassing five subcategories: metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic and alcohol related/associated liver disease (MetALD), alcohol-related/associated liver disease (ALD), SLD with specific etiology, and cryptogenic SLD. This review summarizes foundational and recent advances in the histologic evaluation of SLD, including common pathologic features across all subcategories, distinctions associated with different etiologies, scoring and grading systems, and the evolution of digital pathology techniques for SLD assessment.
Interface conditions for a polyelectrolyte gel in a salt solution with a thin electrical double layer
Authors: Hennessy M. G.
Published: February 2025

Polyelectrolyte gels are electro-active soft materials that are often surrounded by a viscous salt solution. The formation of an electrical double layer (EDL) at the interface between the gel and the solution can give rise to fluid-structure interactions driven by Coulomb forces. However, these interactions are usually neglected in modelling studies due to the difficulty of resolving the EDL, which has a thickness that is orders of magnitude smaller than the characteristic gel size. In this paper, an asymptotically consistent model of a polyelectrolyte gel that is surrounded by a salt solution is derived in the thin-EDL limit. The model consists of bulk equations describing an electrically neutral gel and bath, along with interfacial conditions that capture the electro-mechanical impact of the EDL. A key result is the derivation of a Helmholtz–Smoluchowski slip condition that describes how shear stresses in the EDL lead to a bulk flow in the surrounding salt solution. The impact of this flow on gel-gel friction and swelling-driven instabilities is discussed. The model derived here will lead to a better understanding of how polyelectrolyte gels interact with an external salt solution, which is crucial for applications.
HumanRAP2AHomolog of theDrosophilaAsymmetric Cell Division RegulatorRap2lTargets the Stemness of Glioblastoma Stem Cells
Authors: Franco Maribel , Gargini Ricardo , Barberá Víctor M. , Saceda Miguel , Carmena Ana
Published: February 2025

Asymmetric cell division (ACD) is a fundamental process to balance cell proliferation and differentiation during development and in the adult. Cancer stem cells (CSCs), a very small but highly malignant population within many human tumors, are able to provide differentiated progeny by ACD that contribute to the intratumoral heterogeneity, as well as to proliferate without control by symmetric, self-renewing divisions. Thus, ACD dysregulation in CSCs could trigger cancer progression. Here we consistently find low expression levels ofRAP2A, the human homolog of theDrosophilaACD regulatorRap2l, in glioblastoma (GBM) patient samples, and observe that scarce levels ofRAP2Aare associated with poor clinical prognosis in GBM. Additionally, we show that restitution of RAP2A in GBM neurosphere cultures increases the ACD of glioblastoma stem cells (GSCs), decreasing their proliferation and expression of stem cell markers. Our results support that ACD failures in GSCs increases their spread, and that ACD amendment could contribute to reduce the expansion of GBM.
Revitalizing systemic immune responses in advanced NSCLC using FLT3L and SBRT
Authors: Mathew Divij , Ohri Nitin , Ngiow Shin Foong , Halmos Balazs , Wumesh KC , Garg Madhur , Levsky Jeffrey M , Cheng Haiying , Gucalp Rasim A. , Bodner William Raymond , Kabarriti Rafi , Gutierrez-Chavez Claudia , Zakharia Adel , Kalnicki Shalom , Keler Tibor , Yellin Michael , Minn Andy J , Maity Amit , Giles Josephine R , Guha Chandan , Wherry E. John
Published: February 2025

Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. For patients who develop progressive disease after treatment with chemotherapy and immunotherapy, treatment options are limited. Here, we report the results of a Phase II clinical trial where twenty-nine patients with advanced, previously treated NSCLC were treated with stereotactic body radiotherapy (SBRT) targeting a single site of disease along with CDX-301, a recombinant human Fms-like tyrosine kinase 3 ligand (FLT3L). The primary study endpoint was progression-free survival four months after study entry (PFS4), which was achieved for 14 patients (48%). Abscopal responses were observed on fludeoxyglucose-18 positron emission tomography (FDG-PET) in nine patients (31%). The median overall survival for all participants was 18 months, with a median overall survival for participants with abscopal response of 31 months. To identify underlying immune signatures of response, we developed a high dimensional flow cytometric approach that quantified 31 distinct cell subsets from peripheral blood, and performed multiplex proteomic analysis of 92 proteins from plasma. SBRT combined with CDX-301 significantly increased circulating myeloid cells, including monocytes, myeloid derived suppressor cells (MDSCs) and dendritic cells (DCs). Among DCs, FceR1-expressing DC2 and DC3 subsets changed most robustly upon treatment. These dynamic changes in DCs and MDSCs following initiation of SBRT and CDX-301 returned to baseline by 8 weeks. However, these changes were also associated with treatment-induced T cell activation with quantitatively robust activation of CD4 T cells. Abscopal responses were associated with a prolonged increase in DC1 cells, Th1-like CD4 T cells, circulating IL-12 and FLT3L. Integrated analysis of multiple types of immune parameters revealed a strong association between coordinated DC induction, CD4 T cell and CD8 T cell activation, and inflammatory cytokine activity in patients with abscopal responses, compared to a stark lack of immune coordination in patients without abscopal responses. These coordinated immune responses were sustained for over 4 weeks in responders, highlighting a potential therapeutic axis engaged in a systemic immune response against multiple lesions in NSCLC. Overall, these findings underscore the potential of combiningin situvaccination, using SBRT, with strategies to enhance the activation of innate immune cells, such as DCs through FLT3L, to potentiate robust anti-tumor T cell responses.
The beta-triketone, nitisinone, kills insecticide-resistant mosquitoes through cuticular uptake
Authors: Stavrou-Dowd Zachary Thomas , Parsons George , Rose Clair , Brown Faye , Lees Rosemary Susan , Acosta-Serrano Álvaro , Haines Lee Rafuse
Published: February 2025

The efficacy of numerous vector control initiatives is compromised by growing insecticide resistance among disease-transmitting arthropods of agricultural, veterinary, and public health significance. Previous investigations on hematophagous (blood-feeding) arthropod vectors, including mosquitoes, have indicated that ingesting blood containing inhibitors of the second enzyme in the tyrosine metabolism pathway, 4-hydroxyphenylpyruvate dioxygenase (HPPD), results in high insect mortality. Building upon this foundation, we evaluated the insecticidal efficacy of the HPPD inhibitor, nitisinone, against susceptible and pyrethroid-resistant strains of three mosquito species:Anopheles gambiae, Aedes aegypti and Culex quinquefasciatus. These mosquitoes are vectors of historical diseases such as malaria, emerged diseases such as Dengue and Zika and emerging viral diseases such as the Oropouche and Usutu viruses. We demonstrate, by employing standard screening assays designed to assess the cuticular uptake of mosquitocidal agents, that nitisinone has mosquitocidal activity when blood-fed mosquitoes contact a nitisinone-coated surface. Notably, there is no discernible disparity in susceptibility to nitisinone between an insecticide-susceptible strain ofAnopheles gambiaeand two strains carrying multiple insecticide-resistance mechanisms. We conclude that the mosquitocidal mode of action of nitisinone differs from any of the current 37 classes of insecticides as none have a mode of action that specifically interferes with blood digestion. By highlighting the efficacy of nitisinone as a contact-based insecticide, our findings support the potential expansion of vector control strategies where nitisinone is incorporated into classic interventions like treated bednets and indoor residual spraying.
The kin-selected context of duelling in horned aphids: cooperation or conflict?
Authors: Uematsu Keigo , Yang Man-Miao , Foster William
Published: February 2025

In one-on-one (dyadic) contests in group-living animals, relatedness is of potentially critical importance in determining the relative value of the resources for which the individuals are fighting. We investigated the function of dyadic contests over access to a food resource (plant phloem) in the horned aphidAstegopteryx bambusae, by observing competing aphids in the field and genotyping them with microsatellite markers. Each aphid colony consists of a small number of clones, creating levels of relatedness that can be both high and variable. The contests involve only low costs in terms of time or injury.

Our results indicate that there is no kin-discrimination in the duelling pairs of aphids. Genetic relatedness between duelling pairs did not differ significantly from that of randomly selected pairs and showed no association with contest duration or outcome. The mean relatedness between a duelling pair was 0.79 ± 0.12 (mean ± SD,N= 75), with 56% (42/75) of duels occurring between clonal pairs.

We suggest that the duels in theseAstegopteryxaphids are not an aggressive fight for resources between different genotypes, but rather a low-cost method by which the aphids assess each other’s reproductive value. 83% (50/60) of the contests between aphids of different ages were won by the aphid that was older, and therefore of greater reproductive value, providing an indirect fitness benefit for the losing younger individual. Younger nymphs, when attacked by older aphids, yield feeding sites altruistically and gain inclusive fitness benefits: this provides a compelling selective context for the evolution of the young, rather than old, altruistic soldiers that are observed in the open colonies of many cerataphidine species.
Concordant yet unique neutral and adaptive genomic responses to anthropogenically modified landscapes in Rhinella horribilis
Authors: Soria-Ortiz Gerardo J. , Ochoa-Ochoa Leticia M. , Jaramillo-Correa Juan P. , Martínez-Solano Íñigo , Vázquez-Domínguez Ella
Published: February 2025

Anthropized environments are significantly challenging for wild species. Rapid adaptation to such habitats is thus key for their long-term persistence. Deciphering the environmental factors associated with species tolerance to modified habitats is fundamental for understanding the genetic and connectivity patterns of individuals and the local adaptation of their populations. We studied the Giant Toad, Rhinella horribilis, from two landscapes with distinct levels of anthropogenic habitat modification, assessed their genomic diversity, structure and connectivity with ddRAD-seq genomic data, identified potential outlier loci and their relationship with environmental and physicochemical water variables, and evaluated if populations from the two study sites showed signals of parallel adaptation. Both concordant and unique patterns were found regarding landscape factors and genotype-environment associations related with the degree of anthropic modification between landscapes. Genomic structure and connectivity were significantly associated with the presence of temporary water bodies, low vegetation cover, high humidity, solar radiation, and temperature. Notably, we identified both shared and distinct outlier SNPs and annotated functional genes for the two landscapes. Genes were enriched for biological processes and metabolic pathways, which were in turn correlated with environmental and physicochemical water variables. Genes and metabolic pathways were associated mainly with embryonic development, sexual maturation and immune responses. Studies such as this one, in an often-disregarded species, illustrate how parallel and un-parallel adaptive landscape genomic patterns arise in the stressful conditions of anthropized habitats.
MassVision: An open-source end-to-end platform for AI-driven mass spectrometry image analysis
Authors: Jamzad Amoon , Syeda Ayesha , Warren Jade , Kaufmann Martin , Iaboni Natasha , Nicol Christopher J. B. , Rudan John , Ren Kevin Y. M. , Hurlbut David , Varma Sonal , Fichtinger Gabor , Mousavi Parvin
Published: February 2025

Mass spectrometry imaging (MSI) combines spatial and spectral data to reveal detailed molecular compositions within biological samples. Despite their immense potential, MSI workflows are hindered by the complexity and high dimensionality of the data, making their analysis computationally intensive and often requiring expertise in coding. Existing tools frequently lack the integration needed for seamless, scalable, and end-to-end workflows, forcing researchers to rely on local solutions or multiple platforms, hindering efficiency and accessibility. We introduce MassVision, a comprehensive soft-ware platform for MSI analysis. Built on the 3D Slicer ecosystem, MassVision integrates MSI-specific functionalities while addressing general user requirements for accessibility and usability. Its intuitive interface lowers barriers for researchers with varying levels of computational expertise, while its scalability supports high-throughput studies and multi-slide datasets. Key functionalities include visualization, co-localization, dataset curation, dataset merging, spectral and spatial preprocessing, AI model training, and AI deployment on full MSI data. We detail the workflow and functionalities of MassVision and demonstrate its effectiveness through different experimental use cases such as exploratory data analysis, ion identification, and tissue-type classification, on in-house and publicly available data from different MSI modalities. These use cases underscore the MassVision’s ability to seamlessly integrate MSI data handling steps into a single platform, and highlight its potential to reveal new insights and structures when examining biological samples. By combining cutting-edge functionality with user-centric design, MassVision addresses longstanding challenges in MSI data analysis and provides a robust tool for advancing the user’s ability to achieve biologically-meaningful insights from MSI data.
CDK8 remodels the tumor microenvironment to resist the therapeutic efficacy of targeted KRASG12Dinhibition in pancreatic ductal adenocarcinoma
Authors: McAndrews Kathleen M. , Mahadevan Krishnan K. , Li Bingrui , Sockwell Amari M. , Morse Sami J. , Kelly Patience J. , Patel Sarah I. , Kirtley Michelle L. , Moreno Diaz Barbara A. , Lyu Hengyu , Zhou Xunian , Sugimoto Hikaru , Sthanam Lakshmi Kavitha , Conner Meagan R. , Kumbhar Shreyasee V. , Arian Kent A. , Barekatain Yasaman , Paradiso Francesca , Guerrero Paola A. , Bernard Vincent , Sobhani Navid , Camacho-Acevedo Alondra N. , Bornes Kiara E. , Tran Phuong Thao , Maitra Anirban , Heffernan Timothy P. , Kalluri Raghu
Published: February 2025

Mutations inKRASare a dominant driver of pancreatic ductal adenocarcinoma (PDAC), with over 40% of PDAC patients presenting withKRASG12Dmutations. The recent development of small molecule inhibitors targeting KRASG12Dhas enabled targeting of mutant KRAS signaling and suppression of PDAC; however, the contribution of the tumor microenvironment (TME) to the sustained therapeutic efficacy of KRASG12Dinhibition and mechanism/s of resistance to KRASG12Dsuppression remain to be elucidated. Here, we employed spatial transcriptomics, single cell RNA sequencing, and CODEX-based spatial proteomics to evaluate cancer cell intrinsic and extrinsic responses to KRASG12Dinhibition with MRTX1133. While KRASG12Dinhibition initially increases CD11c+cells with impactful T cell infiltration within proximity to cancer cells, long-term treatment with MRTX1133 resulted in reversal of the immune responses leading to KRASG12Dtherapy resistance promoted by CDK8, a multiprotein mediator complex associated kinase. CDK8 imparts resistance in part through induction of downstream CXCL2 chemokine secretion, inhibition of FAS expression, and remodeling of the TME to promote immune evasion. Targeting CDK8 by itself and in combination with αCTLA-4 immunotherapy overcomes resistance to KRASG12Dinhibition with prolonged survival with translational implications.
Utilizing Genomics to Identify Novel Immunotherapeutic Targets in Multiple Myeloma High-Risk Subgroups
Authors: Liu Enze , Jaouadi Oumaima , Sharma Riya , Becker Nathan , Johnson Travis S. , Sudha Parvathi , Chopra Vivek S. , Zafar Faiza , Hamidi Habib , Pawlyn Charlotte , Suvannasankha Attaya , Abonour Rafat , Walker Brian A.
Published: February 2025

Immunotherapy is now standard of care for multiple myeloma, where the most common targets are B cell maturation antigen, CD38, and G protein-coupled receptor class C group 5 member D but strategies to identify additional targets are needed. We have utilized two large datasets of genomic data and integrated them with existing databases to identify expressed cell surface targets in myeloma patients. Importantly, we also identify targets specific to genomic defined subgroups of patients including primary translocations and high-risk subgroups. Examples of subgroup targets includeROBO3in t(4;14),CD109in t(14;16),CD20in t(11;14),GPRC5Din 1q+, andADAM28in biallelicTP53samples. Expression was validated by flow cytometry and CRISPR-Cas9 knock out models. Sub-clonal differences in expression were noted, as was alternative splicing of existing immunotherapy targets such asFCRL5. These results highlight the use of genomic stratification to identify novel therapeutic targets.

Graphical Abstract
A SNP Foundation Model: Application in Whole-Genome Haplotype Phasing and Genotype Imputation
Authors: Xu Augix Guohua , Xu Yu , Xing Yiming , Yang Jianbo , Bai Yinqi , Tang Kun
Published: February 2025

Artificial intelligence foundation models are revolutionizing biomedical research. Human genetic diversity data, predominantly in the form of single nucleotide polymorphisms (SNPs), constitutes the largest and fastest growing portions of biobank databases. However, SNP data has been a missing piece in the Bio-AI domain. Here, we present SNPBag, the first SNP foundation model for genome-scale SNP analyses. Built on a large language model (LLM), SNPBag aims to address haplotype phasing and genotype imputation simultaneously. Using data from the 1000 Genome Project, we pre-trained SNPBag on overlapping sequences by masking genotypes. For haplotype phasing task, our model achieved a state-of-the-art (SOTA) 1% switch error rate, outperforming BEAGLE5.2, EAGLE2, and SHAPEIT4. In genotype imputation for the Illumina Omni2.5 SNP array, the model reached an accuracy of 96.88%, comparable to the best available methods. Additionally, when fine-tuned for ancestry inference, the model achieved 97% accuracy in predicting the super-populations of 72 individuals from the 1000 Genome Project. This study demonstrates the great potential of SNPBag in representing and inferring global human genetic diversity. Future research will focus on training SNPBag with large-scale Genome-Wise Association Study (GWAS) data to predict phenotypes from whole-genome genotypes, opening new avenues for understanding human genetics and disease.
Auditory Enhancement of Sleep Slow Waves in People with Parkinson’s Disease: A Proof-of-Concept Study
Authors: Schreiner Simon J. , Horlacher Jana , Fattinger Sara , Renerts Klavs , Brogli Luzius , Kämpf Lydia , Scandella Maurizio , Poryazova Rositsa , Valko Philipp O. , Ferster Laura , Sassenburg Renske , Jaramillo Valeria , Poian Giulia Da , Lustenberger Caroline , Karlen Walter , Huber Reto , Baumann Christian R. , Maric Angelina
Published: February 2025

Deep sleep supports several restorative functions and has emerged as a potential therapeutic target in neurodegenerative disorders, such as Parkinson’s disease (PD). Phase-targeted auditory stimulation (PTAS) is a non-invasive method for enhancing slow waves of deep sleep, measurable by increased slow-wave activity (SWA; spectral power 0.75–4.5 Hz). Here, we report the first study investigating whether PTAS can be successfully applied in PD patients with subjective sleep disturbance.

We conducted a randomized, double-blind, sham-controlled, cross-over, within-subject study assessing the effects of PTAS over three nights with wearable devices at participants’ homes. PTAS was applied in ON and OFF windows for the entire night in 14 participants and first part of the night in nine.

PTAS increased low-frequency SWA by almost 30% during ON windows in 21 analyzed participants. The SWA increased further with higher numbers of stimuli, suggesting a dose- dependent effect. Participants receiving part-night PTAS reported improved subjective daytime sleepiness after the third night.

This proof-of-concept study demonstrates successful auditory enhancement of slow waves with PTAS in PD. Our observation of the potential advantages of part-night PTAS warrant further exploration. Our data encourage longer and larger trials to fully explore the potential of PTAS in PD and other neurodegenerative diseases.
Mitochondrial and Stress-Related Psychobiological Regulation of FGF21 in Humans
Authors: Kurade Mangesh , Bobba-Alves Natalia , Kelly Catherine , Behnke Alexander , Conklin Quinn , Juster Robert-Paul , Hirano Michio , Trumpff Caroline , Picard Martin
Published: February 2025

FGF21 is a metabolic hormone induced by fasting, metabolic stress, and mitochondrial oxidative phosphorylation (OxPhos) defects that cause mitochondrial diseases (MitoD). Here we report that acute psychosocial stress alone (without physical exertion) decreases serum FGF21 by an average of 20% (p<0.0001) in healthy controls but increases FGF21 by 32% (p<0.0001) in people with MitoD—pointing to a functional interaction between the stress response and OxPhos capacity in regulating FGF21. We further define co-activation patterns between FGF21 and stress-related neuroendocrine hormones and report novel associations between FGF21 and psychosocial factors related to stress and wellbeing, highlighting a potential role for FGF21 in meeting the energetic needs of acute and chronic psychosocial stress.
META-ANALYSIS AND SYSTEMATIC REVIEW OF PULMONARY VALVE ANNULUS Z-SCORE AS A PREDICTOR OF VALVE PRESERVATION IN TETRALOGY OF FALLOT RIGHT VENTRICULAR OUTFLOW TRACT RECONSTRUCTION
Authors: Sitanggang Johan S. , Purba Salomo , Fakhri Dicky , Busro Pribadi W. , Rahmat Budi , Utomo Panji , Hernisa Latifa , Djaka Marshal B. , Pohan Doddy P. , Sitanggang Henry H. , Vinolina Noverita S. , Arvant Anisya Z.
Published: February 2025

Introduction

Tetralogy of Fallot (ToF) is the most prevalent cyanotic congenital heart defect, requiring timely surgical intervention to improve survival. Two primary techniques for right ventricular outflow tract (RVOT) reconstruction are transannular patch (TAP) repair and valve-sparing (VS) surgery as a less invasive alternative. While TAP resolves pulmonary stenosis, it often results in long-term pulmonary regurgitation (PR).

Aim and Objectives

This meta-analysis investigates the pulmonary valve annulus (PVA) z-score as a predictor for choosing VS techniques to minimize complications, mean difference and cut-off analysis.

Methods

A systematic review and meta-analysis were conducted across 32 studies (N=5,931) assessing preoperative PVA z-scores in patients undergoing TAP or VS RVOT reconstruction. Data extraction followed PRISMA guidelines, with statistical analyses using a random-effects model by Review Manager 5.4.1 and receiver operating characteristic (ROC) curve evaluation.

Results

The meta-analysis showed significantly higher preoperative PVA z-scores in the VS group (MD: 0.99, 95% CI: 0.73–1.25, p < 0.00001). The pooled grand mean PVA z-scores were-1.48 for VS and-2.93 for TAP. ROC analysis identified a z-score threshold of ≥-2.59 (sensitivity: 81.3%, specificity: 75%) as optimal for VS surgery.

Conclusion

This study establishes the PVA z-score as a robust predictor for VS approaches in ToF repair, with a proposed threshold of ≥-2.59 for optimal outcomes. Adoption of VS techniques guided by standardized z-score criteria may reduce PR- associated complications and enhance long-term survival and quality of life.
Optimising covariate allocation at design stage using Fisher Information Matrix for Non-Linear Mixed Effects Models in pharmacometrics
Authors: Fayette Lucie , Brendel Karl , Mentré France
Published: February 2025

This work focuses on designing experiments for pharmacometrics studies using Non-Linear Mixed Effects Models including covariates to describe between-subject variability. Before collecting and modelling new clinical trial data, choosing an appropriate design is crucial. Assuming a known model with covariate effects and a joint distribution for covariates in the target population from previous clinical studies, we propose to optimise the allocation of covariates among the subjects to be included in the new trial. It aims achieving better overall parameter estimations and therefore increase the power of statistical tests on covariate effects to detect significance, and more importantly, clinical relevance or non-relevance of relationships. We suggested dividing the domain of continuous covariates into clinically meaningful intervals and optimised their proportions, along with the proportion of each category for the discrete covariates. We used the Fisher Information Matrix and developed a fast and deterministic computation method, leveraging Gaussian quadrature and copula modelling. The optimisation problem was formulated as a convex problem subject to linear constraints, allowing resolution using Projected Gradient Descent algorithm. Different scenarios for a pharmacokinetics model were explored. We showed the benefit of covariate optimisation in reducing the number of subjects needed to achieve desired power in covariate tests.
The Impact of Rural Hospital Closures and Mergers on Health System Ecologies: A Scoping Review
Authors: Coates Alison , Probst Janice , Sarwal Kanika , Riaz Suhaib , Grudniewicz Agnes
Published: February 2025

Despite playing a pivotal role in rural community health services delivery and in local economies, rural hospitals in the United States have closed or merged with larger health networks at alarming rates. This scoping review examines what is known about the impacts of rural hospital closures and mergers, synthesizing the literature across 2010-2024. Most of the identified studies examined closures, primarily reporting on community impacts. Using this literature, we inductively derived a new Health System Ecologies Impact Matrix research tool to assess knowledge related to health system changes. Knowledge gaps remain related to financial, workforce, and utilization-related outcomes, and little is known about closure impacts on neighboring hospitals and communities. Few studies report effects of rural hospital mergers, with those analyses primarily focusing on financial and utilization outcomes for the merged hospital. No studies examined the impacts of rural hospital mergers on patients or individuals and their social environments.

Protocol

The registered scoping review protocol may be accessed on OSF:https://doi.org/10.17605/OSF.IO/GEKJC
Prevalence and disease risks for male and female sex chromosome trisomies: a registry-based phenome-wide association study in 1.5 million participants of MVP, FinnGen, and UK Biobank
Authors: Davis Shanlee M. , Liu Aoxing , Teerlink Craig C. , Lapato Dana M. , Gorman Bryan , Genovese Giulio , Singh Madhurbain , Reeve Mary P. , Gentry Amanda Elswick , Donner Kati M. , Sipilä Timo P. , Ghazal Awaisa , Pagadala Meghana S. , Panizzon Matthew S. , Lancaster Eva E. ,   FinnGen banner authorship,   UKB working group authorship, Chatzinakos Chris , Ganna Andrea , Bigdeli Tim B. , Daly Mark J , Lynch Julie A. , Ross Judith , Peterson Roseann E. , Hauger Richard L.
Published: February 2025

Sex chromosome trisomies (SCT) are the most common whole chromosome aneuploidy in humans. Yet, our understanding of the prevalence and associated health outcomes is largely driven by observational studies of clinically diagnosed cases, resulting in a disproportionate focus on 47,XXY and associated hypogonadism. We analyzed microarray intensity data of sex chromosomes for 1.5 million individuals enrolled in three large cohorts—Million Veteran Program, FinnGen, and UK Biobank—to identify individuals with 47,XXY, 47,XYY, and 47,XXX. We examined disease conditions associated with SCTs by performing phenome-wide association studies (PheWAS) using electronic health records (EHR) data for each cohort, followed by meta-analysis across cohorts. Association results are presented for each SCT and also stratified by presence or absence of a documented clinical diagnosis for 47,XXY. We identified 2,769 individuals with (47,XXY: 1,319; 47,XYY: 1,108; 47,XXX: 342), most of whom had no documented clinical diagnosis (47,XXY: 73.8%; 47,XYY: 98.6%; 47,XXX: 93.6%). The identified phenotypic associations with SCT spanned all PheWAS disease categories except neoplasms. Many associations are shared among three SCT subtypes, particularly for vascular diseases (e.g., chronic venous insufficiency (OR [95% CI] for 47,XXY 4.7 [3.9,5.8]; 47,XYY 5.6 [4.5,7.0]; 4 7,XXX 4.6 [2.7,7.6], venous thromboembolism (47,XXY 4.6 [3.7-5.6]; 47,XYY 4.1 [3.3-5.0]; 47,XXX 8.1 [4.2-15.4]), and glaucoma (47,XXY 2.5 [2.1-2.9]; 47,XYY 2.4 [2.0-2.8]; 47,XXX 2.3 [1.4-3.5]). A third sex chromosome confers an increased risk for systemic comorbidities, even if the SCT is not documented. SCT phenotypes largely overlap, suggesting one or more X/Y homolog genes may underlie pathophysiology and comorbidities across SCTs.
Assessing Algorithm Fairness Requires Adjustment for Risk Distribution Differences: Re-considering the Equal Opportunity Criterion
Authors: Hegarty Sarah E. , Linn Kristin A. , Zhang Hong , Teeple Stephanie , Albert Paul S. , Parikh Ravi B. , Courtright Katherine , Kent David M. , Chen Jinbo
Published: February 2025

Abstract

The proliferation of algorithm-assisted decision making has prompted calls for careful assessment of algorithm fairness. One popular fairness metric, equal opportunity, demands parity in true positive rates (TPRs) across different population subgroups. However, we highlight a critical but overlooked weakness in this measure: at a given decision threshold, TPRs vary when the underlying risk distribution varies across subgroups, even if the model equally captures the underlying risks. Failure to account for variations in risk distributions may lead to misleading conclusions on performance disparity. To address this issue, we introduce a novel metric called adjusted TPR (aTPR), which modifies subgroup-specific TPRs to reflect performance relative to the risk distribution in a common reference subgroup. Evaluating fairness using aTPRs promotes equal treatment for equal risk by reflecting whether individuals with similar underlying risks have similar opportunities of being identified as high risk by the model, regardless of subgroup membership. We demonstrate our method through numerical experiments that explore a range of differential calibration relationships and in a real-world data set that predicts 6-month mortality risk in an in-patient sample in order to increase timely referrals for palliative care consultations.
Contrasting patterns of subtelomeric satellite superfamily in theCannabaceaefamily
Authors: Horáková Lucie , Bačovský Václav , Janoušek Bohuslav , Patzak Josef , Hobza Roman
Published: February 2025

Satellite DNA (satDNA) is a rapidly evolving component of plant genomes, often found in centromeric, telomeric, and heterochromatic regions. Due to their variability and species- or population-specific distribution, satDNA serves as valuable cytogenetic markers for studying chromosomal rearrangements and karyotype evolution in closely related species. In dioecious speciesCannabis sativa, Humulus lupulus, andHumulus japonicus, previous studies have identified species-specific subtelomeric repeats CS-1, HSR1, and HJSR. While these satellites have been used to differentiate sex chromosomes from autosomes, their evolutionary origins, sequence variation and pattern of conservation among related species remain largely unexplored. In this study, we combine bioinformatics analysis with molecular cloning to analyze sequence similarity among these shared satellites and determine their inter-specific chromosomal localization using fluorescencein situhybridization (FISH). Our results reveal that HSR1 and HJSR satellites are shared among all studied species suggested oaring from a common ancestor. In contrast, CS-1 satellite exhibit higher sequence divergence. Although all satellites are predominantly localized in subtelomeric regions, CS-1 inH. lupulusand HSR inC. sativaare localized in pericentromeric regions. These findings provide new insight into the evolutionary dynamics of satDNA inCannabaceaefamily and its role in genome organization.
Analysis of The Senescence Secretome During Zebrafish Retina Regeneration
Authors: Konar Gregory J. , Vallone Kyle T. , Nguyen Tu D. , Patton James G.
Published: February 2025

Zebrafish possess the innate ability to regenerate any lost or damaged retinal cell type with Müller glia serving as resident stem cells. Recently, we discovered that this process is aided by a population of damage-induced senescent immune cells. As part of the Senescence Associated Secretory Phenotype (SASP), senescent cells secrete numerous factors that can play a role in the modulation of inflammation and remodeling of the retinal microenvironment during regeneration. However, the identity of specific SASP factors that drive initiation and progression of retina regeneration remains unclear. Here, we mined the SASP Atlas and RNAseq datasets to identify differentially expressed SASP factors after retina injury, including two distinct acute damage regimens, as well as a chronic, genetic model of retina degeneration. We discovered a 31-factor “Regeneration-associated Senescence Signature” (RASS) that represents SASP factors and senescence markers that are conserved across all data sets and are upregulated after damage. Among these, we show that depletion of Nucleophosmin 1 (npm1a)inhibits retina regeneration. Our data support the model that differential expression of SASP factors promotes regeneration after both acute and chronic retinal damage.
Financial barriers to accessing mental healthcare services among visually impaired people
Authors: Pan Annabelle A. , Aguirre Bani A. , Betzler Bjorn K. , Singh Mandeep S.
Published: February 2025

Aims

Visual impairment (VI) is associated with heightened levels of loneliness, anxiety, and depression – yet few people with VI use mental healthcare services (MHS). The reasons for this are incompletely understood. Here, we aimed to understand possible financial barriers by analyzing the association of VI with delaying or foregoing MHS due to cost in a population database.

Methods

We conducted a cross-sectional study using the National Health Interview Survey (NHIS) of the U.S. Centers for Disease Control and Prevention (2019 to 2022). The primary outcome measure was the rate of delaying and foregoing obtaining MHS due to cost among participants with VI. Secondary outcomes included associations between sociodemographic characteristics and delaying or foregoing MHS due to cost. Logistic regressions were adjusted for demographic characteristics including household income.

Results

Among 18,475 participants, 27% reported VI. Participants with VI were more likely to be older, female, have lower income, and had lower educational attainment than those without VI. VI was associated with greater odds of delaying (adjusted odds ratio (aOR): 1.5, 95% confidence interval (CI) 1.3-1.6) and foregoing (aOR: 1.5, 95% CI 1.3-1.6) MHS due to cost. Among individuals with VI, those who were female and younger had higher odds of delaying and foregoing MHS due to cost.

Conclusions

Individuals with VI and depression or anxiety may be at higher risk of delaying or foregoing MHS due to cost. These findings underscore the importance of addressing financial barriers to ensure equitable access to MHS for individuals with VI.
ROR2 drives right ventricular heart failure via disruption of proteostasis
Authors: Hartman Hali , Uy Genevieve , Uchida Keita , Scarborough Emily A. , Yang Yifan , Barr Eric , Williams Spencer , Kavar Sanam L. , Brandimarto Jeff , Li Li , Lai Ling , Griffin Joanna , Yucel Nora , Shewale Swapnil , Rajagopal Hari , Eaton Deborah M. , Dorwart Tanis , Bedi Kenneth C. , Conn Crystal S. , Margulies Kenneth , Prosser Benjamin , Arany Zoltan , Edwards Jonathan J.
Published: February 2025

Background

No therapies exist to reverse right ventricular failure (RVF), and the molecular mechanisms that drive RVF remain poorly studied. We recently reported that the developmentally restricted noncanonical WNT receptor ROR2 is upregulated in human RVF in proportion to severity of disease. Here we test mechanistic role of ROR2 in RVF pathogenesis.

Methods

ROR2 was overexpressed or knocked down in neonatal rat ventricular myocytes (NRVMs). ROR2-modified NRVMs were characterized using confocal microscopy, RNAseq, proteomics, proteostatic functional assays, and contractile properties with pacing. The impact of cardiac ROR2 expression was evaluated in mice by AAV9-mediated overexpression and by AAV9-mediated delivery of shRNA to knockdown ROR2 in a pulmonary artery banded pressure overload RVF model. ROR2-modified mice were evaluated by echocardiography, RV protein synthetic rates and proteasome activity.

Results

In NRVMs, we find that ROR2 profoundly dysregulates the coordination between protein translation and folding. This imbalance leads to excess protein clearance by the ubiquitin proteasome system (UPS) with dramatic impacts on sarcomere and cytoskeletal structure and function. In mice, forced cardiac ROR2 expression is sufficient to disrupt proteostasis and drive RVF, while conversely ROR2 knockdown partially rescues proteostasis and cardiac function in a pressure overload model of RVF.

Conclusions

In sum, ROR2 is a key driver of RVF pathogenesis through proteostatic disruption and, thus, provides a promising target to treat RVF.