From Text to Translation: Using Language Models to Prioritize Variants for Clinical Review.

Despite rapid advances in genomic sequencing, most rare genetic variants remain insufficiently characterized for clinical use, limiting the potential of personalized medicine. When classifying whether a variant is pathogenic, clinical labs adhere to diagnostic guidelines that comprehensively evaluate many forms of evidence including case data, computational predictions, and functional screening. While a substantial amount of clinical evidence has been developed for these variants, the majority cannot be definitively classified as 'pathogenic' or 'benign', and thus persist as 'Variants of Uncertain Significance' (VUS).

Locus coeruleus signal intensity and emotion regulation in agitation in Alzheimer's disease.

Hyperphosphorylated tau accumulation is seen in the noradrenergic locus coeruleus from the earliest stages of Alzheimer's disease onwards and has been associated with symptoms of agitation. It is hypothesized that compensatory locus coeruleus-noradrenaline system overactivity and impaired emotion regulation could underlie agitation propensity, but to our knowledge this has not previously been investigated. A better understanding of the neurobiological underpinnings of agitation would help the development of targeted prevention and treatment strategies.

Cryo-SEM and large volume FIB-SEM of Arabidopsis cotyledons: Degradation of lipid bodies, biogenesis of glyoxysomes and reorganisation of organelles during germination.

Until recently, the lack of three-dimensional visualisation of whole cells at the electron microscopic (EM) level has led to a significant gap in our understanding of the interaction of cellular organelles and their interconnection. This is particularly true with regard to the role of the endoplasmic reticulum (ER). In this study, we perform three-dimensional reconstructions of serial FIB/SEM stacks and anaglyphs derived from volume rendering, cryo-scanning electron microscopy (cryo-SEM) and state-of-the-art electron microscopy immobilisation and imaging techniques.

Clinical validation of artificial intelligence-based single-subject morphometry without normative reference database.

Background: Single-subject voxel-based morphometry (VBM) is a powerful technique for reader-independent detection of brain atrophy in structural magnetic resonance imaging (MRI) to support the (differential) diagnosis and staging of neurodegenerative diseases in individual patients. However, VBM is sensitive to the MRI scanner platform and details of the acquisition sequence. To mitigate this limitation, we recently proposed and validated a convolutional neural network (CNN)-based VBM which does not rely on a normative reference database.

Blarcamesine for the treatment of Early Alzheimer's Disease: Results from the ANAVEX2-73-AD-004 Phase IIB/III trial.

Background: There are no approved oral disease-modifying treatments for Alzheimer's disease (AD).

Objectives: The objective of this study was to assess efficacy and safety of blarcamesine (ANAVEX®2-73), an orally available small-molecule activator of the sigma-1 receptor (SIGMAR1) in early AD through restoration of cellular homeostasis including autophagy enhancement.

Design: ANAVEX2-73-AD-004 was a randomized, double-blind, placebo-controlled, 48-week Phase IIb/III trial.

Technical Advances Drive the Molecular Understanding of Effectors from Wheat and Barley Powdery Mildew Fungi.

Pathogens manipulate host physiology through the secretion of virulence factors (effectors) to invade and proliferate on the host. The molecular functions of effectors inside plant hosts have been of interest in the field of molecular plant-microbe interactions. Obligate biotrophic pathogens, such as rusts and powdery mildews, cannot proliferate outside of plant hosts.

DNA-binding affinity and specificity determine the phenotypic diversity in BCL11B-related disorders.

BCL11B is a Cys2-His2 zinc-finger (C2H2-ZnF) domain-containing, DNA-binding, transcription factor with established roles in the development of various organs and tissues, primarily the immune and nervous systems. BCL11B germline variants have been associated with a variety of developmental syndromes. However, genotype-phenotype correlations along with pathophysiologic mechanisms of selected variants mostly remain elusive.

Rye secalin isolates to develop reference materials for gluten detection.

Gluten-free products must not contain more than 20 mg/kg of gluten to be safe for consumption by celiac disease patients. Almost all analytical methods are calibrated to wheat, wheat gluten or gliadin, and there is no rye-specific reference material available. The aim of this study was to assess the effect of the harvest year on rye gluten composition and to generate distinct rye isolates to serve as calibration standards.

Neural invasion severity is a strong predictor of local recurrence in pancreatic ductal adenocarcinoma.

Background: In pancreatic ductal adenocarcinoma, neural invasion is being increasingly recognized as an unfavorable predictor of patient outcomes. Neural invasion severity seems to have a stronger clinical impact on patient prognosis than neural invasion status alone. Therefore, this study aims to assess the impact of severity of neural invasion on overall survival and disease-free survival in pancreatic ductal adenocarcinoma.

Growth modeling of the European grayling (Thymallus thymallus L.) in a large alpine river based on age-at-length, mark-recapture, and length-frequency data.

Animal growth is a fundamental component of population dynamics, which is closely tied to mortality, fecundity, and maturation. As a result, estimating growth often serves as the basis of population assessments. In fish, analysing growth typically involves fitting a growth model to age-at-length data derived from counting growth rings in calcified structures.

Superior Anti-Tumor Response After Microbeam and Minibeam Radiation Therapy in a Lung Cancer Mouse Model.

Objectives: The present study aimed to compare the tumor growth delay between conventional radiotherapy (CRT) and the spatially fractionated modalities of microbeam radiation therapy (MRT) and minibeam radiation therapy (MBRT). In addition, we also determined the influence of beam width and the peak-to-valley dose ratio (PVDR) on tumor regrowth.

Methods: A549, a human non-small-cell lung cancer cell line, was implanted subcutaneously into the hind leg of female CD1 mice.

Celiac Disease, Gluten-Free Diet, and Eating Disorders: From Bench to Bedside.

Celiac disease (CD) and eating disorders (EDs) are complex chronic conditions in adolescents, sharing symptoms such as weight change, malnutrition, and gastrointestinal symptoms. CD, an autoimmune disorder triggered by gluten ingestion, is managed through a strict gluten-free diet that can unintentionally foster disordered eating behaviors due to dietary restrictions. Conversely, EDs may mask and complicate CD symptoms, leading to diagnostic delays and treatment challenges.

Hypoxia Regulates Brown Adipocyte Differentiation and Stimulates miR-210 by HIF-1α.

MicroRNAs (miRNAs) are short sequences of single-stranded non-coding RNAs that target messenger RNAs, leading to their repression or decay. Interestingly, miRNAs play a role in the cellular response to low oxygen levels, known as hypoxia, which is associated with reactive oxygen species and oxidative stress. However, the physiological implications of hypoxia-induced miRNAs ("hypoxamiRs") remain largely unclear.

Evaluation of as a Feed Additive in Low-Protein Diets of Broilers.

is a natural antioxidant product that has the ability to improve the performance of poultry. Therefore, the present study aimed to evaluate the effect of using as a feed additive in broiler diets. A total of 252 daily male Ross 308 chicks were randomly assigned to six groups.

Painful vision loss during air travel after vitrectomy with air tamponade: a case report.

Background: While the potentially hazardous effects of intraocular perfluorocarbon gases during air travel have been recognized, the equivalent risk of intraocular air tamponade is less known and has, to the best of our knowledge, not been reported yet.

Case Presentation: A 52-year-old white female experienced a complete loss of vision and pain in her left eye during air travel following pars plana vitrectomy with air tamponade. Clinical and multimodal imaging findings only a few hours after emergency landing indicated a transient central retinal artery occlusion due to a significant increase in intraocular pressure during the flight.

Tissue Determinants of Antiviral Immunity in the Liver.

The liver is an organ bearing important metabolic and immune functions. Hepatocytes are the main metabolically active cells of the liver and are the target of infection by hepatotropic viruses. Virus-specific CD8 T cells are essential for the control of hepatocyte infection with hepatotropic viruses but may be subject to local regulation of their effector function.

Neuropathology, pathomechanism, and transmission in zoonotic Borna disease virus 1 infection: a systematic review.

Borna disease, which is a severe encephalitis that primarily affects horses and sheep, has been recognised for over two centuries. Borna disease virus 1 (BoDV-1) has been identified as a cause of a predominantly fatal encephalitis in humans. Little scientific data exist regarding the virus' transmission, entry portal, and excretion routes.

A first-in-human phase 1/2 dose-escalation study of MAK683 (EED inhibitor) in patients with advanced malignancies.

Purpose: MAK683, a first-in-class and highly selective allosteric inhibitor of the embryonic ectoderm development subunit of polycomb repressive complex 2, has shown sustained antitumor activity in tumor xenograft models. This first-in-human phase 1/2 study evaluated the safety, pharmacokinetics (PK), and clinical activity of single-agent MAK683 in advanced malignancies.

Methods: MAK683 was administered fasted once daily or twice daily continuously in 28-day treatment cycles.

A lightweight generative model for interpretable subject-level prediction.

Recent years have seen a growing interest in methods for predicting an unknown variable of interest, such as a subject's diagnosis, from medical images depicting its anatomical-functional effects. Methods based on discriminative modeling excel at making accurate predictions, but are challenged in their ability to explain their decisions in anatomically meaningful terms. In this paper, we propose a simple technique for single-subject prediction that is inherently interpretable.

Unlocking the diagnostic potential of electrocardiograms through information transfer from cardiac magnetic resonance imaging.

Cardiovascular diseases (CVD) can be diagnosed using various diagnostic modalities. The electrocardiogram (ECG) is a cost-effective and widely available diagnostic aid that provides functional information of the heart. However, its ability to classify and spatially localise CVD is limited.

Continuum of non-targeted data for long term study of complex samples generated by direct infusion ultra-high resolution mass spectrometry.

Non-targeted chemical analysis is a powerful tool for exploration of the unknown chemistry of complex matrices such as food, biological, geochemical, environmental and even extra-terrestrial samples. It allows researchers to ask open, unbiased questions about their system chemistry. Fourier Transform Ion Cyclotron Resonance Mass Spectrometry (FT-ICR-MS) offers these options and has been widely used to study complex mixtures, with its unmatched mass resolution enabling direct infusion methods and eliminating the challenges of chromatographic alignment in large-scale longitudinal projects.

Twins with at least one with CHD and their immunisation status in direct comparison-are both twins complying with the German immunisation recommendations?

Background: Patients with congenital heart defects (CHDs) are at higher risk for infectious diseases. This may partly be due to frequent hospital stays and the associated exposure to pathogens. This study aims to provide a comprehensive overview of immunisation coverage among twins in which at least one twin has CHD.

Pregnancy & cardiovascular disease: the PREG-CVD-HH registry.

Background: Cardiovascular disease (CVD) remains the leading cause of death in pregnant and peripartal women in western countries. Physiological changes during pregnancy can lead to cardiovascular complications in the mother; women with pre-existing heart disease may not tolerate these changes well, increasing their susceptibility to adverse cardiovascular outcomes during pregnancy. The aim of this study is to characterize pregnancy-induced changes in cardiac function, biomarker concentrations and cardiovascular outcomes in women with CVD during pregnancy at a tertiary care hospital in Germany.