Skin disease-associated GJB4 variants differentially influence connexin stability, cell viability and channel function.

Here we characterize seven Cx30.3 gene variants (R22H, S26Y, P61R, C86S, E99K, T130M and M190L) clinically associated with the rare skin disorder erythrokeratodermia variabilis et progressiva (EKVP) in tissue-relevant and differentiation-competent rat epidermal keratinocytes (REKs). We found that all variants, when expressed alone or together with wildtype (WT) Cx30.

Examining Healthy Lifestyles as a Mediator of the Association Between Socially Determined Vulnerabilities and Incident Heart Failure.

Background: Increased burden of socially determined vulnerabilities (SDV), which include nonmedical conditions that contribute to patient health, is associated with incident heart failure (HF). Mediators of this association have not been examined. We aimed to determine if a healthy lifestyle mediates the association between SDV and HF.

Echocardiography of the right heart in pulmonary arterial hypertension: insights from the ULTRA RIGHT VALUE study.

Aims: Outcome in pulmonary arterial hypertension (PAH) is determined by right ventricular (RV) function adaptation to increased afterload. Echocardiography is easily available to assist bedside evaluation of the RV. However, no agreement exists about the feasibility and most relevant measurements.

Multi-modal integration of MRI and global chamber charge density mapping for the evaluation of atrial fibrillation.

Atrial fibrillation (AF) is the most prevalent clinical arrhythmia, posing significant mortality and morbidity challenges. Outcomes of current catheter ablation treatment strategies are suboptimal, highlighting the need for innovative approaches. A major obstacle lies in the inability to comprehensively assess both structural and functional remodelling in AF.

Lipid-mediated resolution of inflammation and survival in amyotrophic lateral sclerosis.

Neuroinflammation impacts on the progression of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. Specialized pro-resolving mediators trigger the resolution of inflammation. We investigate the specialized pro-resolving mediator blood profile and their receptors' expression in peripheral blood mononuclear cells in relation to survival in ALS.

Development and experimental validation of a senescence-related long non-coding RNA signature for prognostic prediction and immune microenvironment characterization in gastric cancer patients.

Background: Cellular senescence is considered a new marker of cancer. It has been suggested that long non-coding RNA (lncRNA) can be used to predict the prognosis of cancers. However, it remains to be seen whether the lncRNAs associated with cellular senescence can be used to predict the prognosis of gastric cancer (GC).

Balancing anticancer therapy efficacy and safety in advanced hepatocellular carcinoma: a case report.

Background: Hepatocellular carcinoma (HCC) is a significant health problem associated with several risk factors, increasingly driven by non-alcoholic steatohepatitis and metabolic syndrome. This association poses a challenge for the primary treatments of HCC, which may include immune checkpoint inhibitors and vascular endothelial growth factor inhibitors, due to their potential cardiotoxic effect. Therefore, it is imperative to balance the therapeutic effects of these agents with their potential cardiovascular adverse events.

Proteolysis-targeting influenza vaccine strains induce broad-spectrum immunity and in vivo protection.

Generating effective live vaccines from intact viruses remains challenging owing to considerations of safety and immunogenicity. Approaches that can be applied in a systematic manner are needed. Here we created a library of live attenuated influenza vaccines by using diverse cellular E3 ubiquitin ligases to generate proteolysis-targeting (PROTAR) influenza A viruses.

Small molecule inhibits KCNQ channels with a non-blocking mechanism.

Voltage-gated ion channels (VGICs) are crucial targets for neuropsychiatric therapeutics owing to their role in controlling neuronal excitability and the established link between their dysfunction and neurological diseases, highlighting the importance of identifying modulators with distinct mechanisms. Here we report two small-molecule modulators with the same chemical scaffold, Ebio2 and Ebio3, targeting a potassium channel KCNQ2, with opposite effects: Ebio2 acts as a potent activator, whereas Ebio3 serves as a potent and selective inhibitor. Guided by cryogenic electron microscopy, patch-clamp recordings and molecular dynamics simulations, we reveal that Ebio3 attaches to the outside of the inner gate, employing a unique non-blocking inhibitory mechanism that directly squeezes the S6 pore helix to inactivate the KCNQ2 channel.

Massively parallel characterization of transcriptional regulatory elements.

The human genome contains millions of candidate cis-regulatory elements (cCREs) with cell-type-specific activities that shape both health and many disease states. However, we lack a functional understanding of the sequence features that control the activity and cell-type-specific features of these cCREs. Here we used lentivirus-based massively parallel reporter assays (lentiMPRAs) to test the regulatory activity of more than 680,000 sequences, representing an extensive set of annotated cCREs among three cell types (HepG2, K562 and WTC11), and found that 41.

Serum Biomarkers of Pulmonary Damage and Risk for Progression of Rheumatoid Arthritis-Associated Interstitial Lung Disease.

Objective: To investigate baseline and change of pulmonary damage biomarkers (serum Krebs von den Lungen 6 [KL-6], human surfactant protein D [hSP-D], and matrix metalloproteinase 7 [MMP-7]) with rheumatoid arthritis-associated interstitial lung disease (RA-ILD) progression.

Methods: In the Korean Rheumatoid Arthritis Interstitial Lung Disease (KORAIL) cohort, a prospective cohort, we enrolled patients with RA and ILD confirmed by chest computed tomography imaging and followed annually. ILD progression was defined as worsening in physiological and radiological domains of the 2022 American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society guideline for progressive pulmonary fibrosis (PPF).

The Golgi complex governs natural killer cell lytic granule positioning to promote directionality in cytotoxicity.

Cytotoxic immune cells mediate precise attacks against diseased cells to maintain organismal health. Their operational unit of killing and host defense is lytic granules (LGs), which are specialized lysosomal-related organelles. Precision in cytotoxicity is achieved by converging the many LGs to the microtubule-organizing center (MTOC) and polarizing these to the diseased cell for secretion.

High-Resolution OCT Reveals Age-Associated Variation in the Region Posterior to the External Limiting Membrane.

Purpose: To evaluate visibility of a sub-band posterior to the external limiting membrane (ELM) and assess its age-associated variation.

Methods: In a retrospective cross-sectional study, normal eyes were imaged using a high-resolution spectral-domain optical coherence tomography (SD-OCT) prototype (2.7-µm axial resolution).

NNFit: A Self-Supervised Deep Learning Method for Accelerated Quantification of High- Resolution Short Echo Time MR Spectroscopy Datasets.

Purpose To develop and evaluate the performance of NNFit, a self-supervised deep-learning method for quantification of high-resolution short echo-time (TE) echo-planar spectroscopic imaging (EPSI) datasets, with the goal of addressing the computational bottleneck of conventional spectral quantification methods in the clinical workflow. Materials and Methods This retrospective study included 89 short-TE whole-brain EPSI/GRAPPA scans from clinical trials for glioblastoma (Trial 1, May 2014-October 2018) and major-depressive-disorder (Trial 2, 2022- 2023). The training dataset included 685k spectra from 20 participants (60 scans) in Trial 1.

Identifying cognitive test scores associated with early tau burden in Alzheimer's disease.

Introduction: This study aimed to identify cognitive tests that optimally relate to tau positron emission tomography (PET) signal in the inferior temporal cortex (ITC), a neocortical region associated with early tau accumulation in Alzheimer's disease (AD).

Methods: We analyzed cross-sectional data from the harvard aging brain study (HABS) (= 128) and the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study (= 393). We used elastic net regression to identify the most robust cognitive correlates of tau PET signal in the ITC.

The impact of highly effective modulator therapy on sinusitis and dysosmia in young children with cystic fibrosis: a prospective study protocol.

Background: Chronic rhinosinusitis (CRS) and olfactory dysfunction (OD) are prevalent disease complications in people with cystic fibrosis. These understudied comorbidities significantly impact quality of life. The impact of highly effective modulator therapy (HEMT) in young children with cystic fibrosis (YCwCF) on these disease complications is unknown.

Metastatic Lung Lesion Changes in Follow-up Chest CT: The Advantage of Deep Learning Simultaneous Analysis of Prior and Current Scans With SimU-Net.

Purpose: Radiological follow-up of oncology patients requires the detection of metastatic lung lesions and the quantitative analysis of their changes in longitudinal imaging studies. Our aim was to evaluate SimU-Net, a novel deep learning method for the automatic analysis of metastatic lung lesions and their temporal changes in pairs of chest CT scans.

Materials And Methods: SimU-Net is a simultaneous multichannel 3D U-Net model trained on pairs of registered prior and current scans of a patient.

Vitritis following intravitreal faricimab: a retrospective monocentric analysis.

Purpose: Intravitreal injections of anti-VEGF agents are considered as safe, with a very low rate of intraocular inflammations (IOI). Faricimab is a novel intravitreal bispecific antibody targeting both VEGF-A and angiopoietin-Tie2 independently. Despite a safe profile in randomized clinical trials, several real-life studies have reported cases of IOI.

Global Perspectives on Returning Genetic Research Results in Parkinson Disease.

Background And Objectives: In the era of precision medicine, genetic test results have become increasingly relevant in the care of patients with Parkinson disease (PD). While large research consortia are performing widespread research genetic testing to accelerate discoveries, debate continues about whether, and to what extent, the results should be returned to patients. Ethically, it is imperative to keep participants informed, especially when findings are potentially actionable.

The Importance of Frailty in Older Adults With Benign Paroxysmal Positioning Vertigo.

Background And Purpose: Even though Benign Paroxysmal Positioning Vertigo (BPPV) is one of the most reported vestibular disorders, its interaction with frailty and postural control in older adults is hardly or not investigated.

Methods: Thirty-seven older adults (≥65 years) with a diagnosis of BPPV (oaBPPV) (mean age 73.13 (4.

Drug repurposing screen targeting PARP identifies cytotoxic activity of efavirenz in high-grade serous ovarian cancer.

Drug repurposing has potential to improve outcomes for high-grade serous ovarian cancer (HGSOC). Repurposing drugs with PARP family binding activity may produce cytotoxic effects through the multiple mechanisms of PARP including DNA repair, cell-cycle regulation, and apoptosis. The aim of this study was to determine existing drugs that have PARP family binding activity and can be repurposed for treatment of HGSOC.

Abnormal Exercise Electrocardiography With Normal Stress Echocardiography Is Associated With Subclinical Coronary Atherosclerosis.

Background: Patients with abnormal (positive) exercise electrocardiography, but normal stress echocardiography (+ECG/-Echo), have an increased risk of adverse cardiovascular events compared with patients with a normal (negative) ECG and a normal stress Echo (-ECG/-Echo). However, it is unclear if +ECG/-Echo discordance is associated with a greater burden of subclinical coronary atherosclerosis.

Methods: Project Baseline Health Study participants who underwent a stress Echo and coronary artery calcium (CAC) scan were stratified by stress Echo result: -ECG/-Echo or +ECG/-Echo.

Time in Target Range for Blood Pressure and Adverse Health Outcomes: A Systematic Review.

Background: Blood pressure (BP) time in target range (TTR) reflects the proportion of time that BP measurement is within a specified target range. We aim to summarize the evidence for relationships between TTR and adverse health outcomes.

Methods: Seven databases were searched.

Proteomic signature of HIV-associated subclinical left atrial remodeling and incident heart failure.

People living with HIV are at higher risk of heart failure and associated left atrial remodeling compared to people without HIV. Mechanisms are unclear but have been linked to inflammation and premature aging. Here we obtain plasma proteomics concurrently with cardiac magnetic resonance imaging in two independent study populations to identify parallels between HIV-related and aging-related immune dysfunction that could contribute to atrial remodeling and clinical heart failure.