NUMB alternative splicing and isoform specific functions in development and disease.

The NUMB gene encodes a conserved adaptor protein with roles in asymmetric cell division and cell fate determination. First described as an inhibitor of Notch signaling, multi-functional NUMB proteins regulate multiple cellular pathways through protein complexes with ubiquitin ligases, polarity proteins and the endocytic machinery. The vertebrate NUMB protein isoforms were identified over two decades ago, yet the majority of functional studies exploring NUMB function in endocytosis, cell migration and adhesion, development and disease have largely neglected the potential for distinct isoform activity in design and interpretation.

P3 site-directed mutagenesis: An efficient method based on primer pairs with 3'-overhangs.

Site-directed mutagenesis is a fundamental tool indispensable for protein and plasmid engineering. An important technological question is how to achieve the efficiency at the ideal level of 100%. Based on complementary primer pairs, the QuickChange method has been widely used, but it requires significant improvements due to its low efficiency and frequent unwanted mutations.

Mixed reality for preoperative planning and intraoperative assistance of surgical correction of complex congenital heart defects.

Objectives: Mixed reality (MixR) is an innovative visualization tool that presents virtual elements in a real-world environment, enabling real-time interaction between the user and the combined digital/physical reality. We aimed to explore the feasibility of MixR in enhancing preoperative planning and intraoperative guidance for the correction of various complex congenital heart defects (CHDs).

Methods: Patients underwent cardiac computed tomography or cardiac magnetic resonance and segmentation of digital imaging and communications in medicine (DICOM) images was performed.

Analysis of clinical features and prognosis in cardiac amyloidosis patients from Spanish hospitals (2016-2021).

Introduction And Objectives: Cardiac amyloidosis (CA) is a prevalent yet underdiagnosed heart condition characterized by the abnormal accumulation of amyloid fibres, frequently resulting in heart failure (HF), particularly in older people. Despite advancements in non-invasive diagnostic techniques and treatments, the epidemiology of CA patients remains inadequately understood. This nationwide retrospective observational study sought to comprehensively investigate CA patients' characteristics, mortality, and readmission patterns.

Longitudinal integrated proteomic and metabolomic skin changes in atopic dermatitis patients treated with dupilumab.

Background: Inhibition of IL-4/IL-13 driven inflammation by dupilumab has shown significant clinical benefits in treatment of atopic dermatitis (AD).

Objective: To assess longitudinal protein and metabolite composition in AD skin during dupilumab treatment.

Methods: Skin tape strip (STS) were collected from lesional/non-lesional skin of 20 AD patients during 16-week dupilumab treatment and from 20 healthy volunteers (HV) followed for 16-weeks.

Neuropsychiatric manifestations in systemic lupus erythematosus and Sjogren's disease.

Introduction: Autoimmune diseases often present in a systemic manner, affecting various organs and tissues. Involvement of the central and peripheral nervous system is not uncommon in these conditions and is associated with high morbidity and mortality. Therefore, early recognition of the neuropsychiatric manifestations associated with rheumatologic diseases is essential for the introduction of appropriate therapies with the objective of providing a better quality of life for individuals.

Clinical Utility of Systolic Left Ventricular Ejection Fraction in Atrial Fibrillation: Role of Prospective ECG-Triggered Cardiac CT.

Background: The assessment of left ventricular (LV) systolic function and quantification of LV ejection fraction (EF) in patients with atrial fibrillation (AF) can be difficult. We previously demonstrated that LV volume changes over the 100 ms of systole (LVEF) can be used as a measure of LV systolic function.

Objective: We sought to evaluate the applicability of LVEF in AF patients.

Racial and ethnic enrollment disparities in clinical trials leading to FDA approvals for gynecologic malignancies.

Background: Black women and other minorities have higher age adjusted incidence risk for cervical and endometrial cancer than White women. However, the extent of racial and ethnic disparities in clinical trial enrollment among studies performed mainly in North America and Europe for gynecologic malignancy is unknown.

Objective: This study analyzed enrollment rates by race/ethnicity in trials that led to Food and Drug Administration (FDA) approvals for gynecological cancers from 2010 to 2024.

Volumetric alterations in auditory and visual subcortical nuclei following perinatal deafness in felines.

In response to sensory deprivation, the brain adapts to efficiently navigate a modified perceptual environment through a process referred to as compensatory crossmodal plasticity, allowing the remaining senses to repurpose deprived regions and networks. A mechanism that has been proposed to contribute to this plasticity involves adaptations within subcortical nuclei that trigger cascading effects throughout the brain. The current study uses 7T MRI to investigate the effect of perinatal deafness on the volumes of subcortical structures in felines, focusing on key sensory nuclei within the brainstem and thalamus.

Dynamic cycles between brain states during creative storytelling.

Many theories suggest that creative thinking involves a dynamic transition between different mental states, yet empirical evidence supporting this notion remains scarce. The dual process model proposes that spontaneous thinking and deliberate thinking drive the dwell in and the transitions between different mental states during creative thinking, but there is a debate over whether the two types of thinking operate in parallel or in sequence. To address these gaps, we conducted a functional magnetic resonance imaging (fMRI) study in 41 college students during a creative storytelling task.

Bladder rupture in late-pregnancy mares: Four cases.

This case series reports four late pregnancy broodmares that were diagnosed with bladder rupture. The initial presentations were abdominal discomfort (n = 3) and dystocia (n = 1). All mares (n = 4) were overdue or at their expected time of delivery.

An umbrella review and meta-analysis of 87 meta-analyses examining healthcare workers' mental health during the COVID-19 pandemic.

During the COVID-19 pandemic, healthcare workers (HCWs) experienced several changes in their work (e.g., longer hours, new policies) that affected their mental health.

Virtual reality for reduction of intraprocedural pharmacological sedation and analgesia in adult patients: A systematic review and meta-analysis.

Background: Pharmacological sedation and analgesia are used to alleviate discomfort during awake medical procedures but can cause adverse effects like apnea and hypoxemia, increasing the need for airway management and prolonging recovery. Virtual reality (VR) has emerged as a non-pharmacological intervention to reduce the need for procedural sedatives and analgesics.

Methods: A systematic review and meta-analysis were conducted, assessing the impact of VR immersion on intraprocedural sedation and analgesia usage in adults (≥ 18 years).

Scoping review of registration of observational studies finds inadequate registration policies, increased registration, and a debate converging towards pro-registration.

Objective: We aimed to examine a) the policies of national and international clinical trial registries regarding observational studies; b) the time-trends of observational study registration; c) the published arguments for and against observational study registration.

Study Design And Setting: Scoping review of registry practices and published arguments. We searched the websites and databases of all 19 members of the World Health Organization's Registry Network to identify policies relating to observational studies and the number of observational studies registered annually from the beginning of the registries to 2022.

Stereotactic body radiotherapy for non-spine bone metastases: A meta-analysis and international stereotactic radiosurgery society (ISRS) clinical practice guidelines.

Background: While SBRT to NSBM has become common, particularly in the oligometastatic population, the approach to treating non-spine bone metastases (NSBM) with stereotactic body radiotherapy (SBRT) varies widely across institutions and clinical trial protocols. We present a comprehensive systematic review of the literatures to inform practice recommendations on behalf of the International Stereotactic Radiosurgery Society (ISRS).

Methods: A systematic literature review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Dosimetric comparison of CyberKnife and conventional linac prostate SBRT plans: analysis of the PACE-B Study.

Purpose: In the PACE-B study, a non-randomised comparison of toxicity outcomes between stereotactic body radiotherapy (SBRT) platforms revealed fewer urinary side-effects with CyberKnife (CK) compared to conventional linac (CL) SBRT. This analysis compares baseline characteristics and planning dosimetry between the CK-SBRT and CL-SBRT cohorts in PACE-B, aiming to provide insight into possible reasons for differing toxicity outcomes between the platforms.

Methods: Dosimetric parameters for the surrogate urethra (SU), contoured urethra, bladder, bladder trigone (BT), and rectum were extracted from available CT planning scans of PACE-B SBRT patients.

Amyotrophic lateral sclerosis caused by FUS mutations: advances with broad implications.

Autosomal dominant mutations in the gene encoding the DNA and RNA binding protein FUS are a cause of amyotrophic lateral sclerosis (ALS), and about 0·3-0·9% of patients with ALS are FUS mutation carriers. FUS-mutation-associated ALS (FUS-ALS) is characterised by early onset and rapid progression, compared with other forms of ALS. However, different pathogenic mutations in FUS can result in markedly different age at symptom onset and rate of disease progression.

Apixaban versus aspirin for stroke prevention in people with subclinical atrial fibrillation and a history of stroke or transient ischaemic attack: subgroup analysis of the ARTESiA randomised controlled trial.

Background: People with subclinical atrial fibrillation are at increased risk of stroke, albeit to a lesser extent than those with clinical atrial fibrillation, leading to an ongoing debate regarding the benefit of anticoagulation in these individuals. In the ARTESiA trial, the direct-acting oral anticoagulant apixaban reduced stroke or systemic embolism compared with aspirin in people with subclinical atrial fibrillation, but the risk of major bleeding was increased with apixaban. In a prespecified subgroup analysis of ARTESiA, we tested the hypothesis that people with subclinical atrial fibrillation and a history of stroke or transient ischaemic attack, who are known to have an increased risk of recurrent stroke, would show a greater benefit from oral anticoagulation for secondary stroke prevention compared with those without a history of stroke or transient ischaemic attack.

Intranasal oxytocin for apathy in people with frontotemporal dementia (FOXY): a multicentre, randomised, double-blind, placebo-controlled, adaptive, crossover, phase 2a/2b superiority trial.

Background: No treatments exist for apathy in people with frontotemporal dementia. Previously, in a randomised double-blind, placebo-controlled, dose-finding study, intranasal oxytocin administration in people with frontotemporal dementia improved apathy ratings on the Neuropsychiatric Inventory over 1 week and, in a randomised, double-blind, placebo-controlled, crossover study, a single dose of 72 IU oxytocin increased blood-oxygen-level-dependent signal in limbic brain regions. We aimed to determine whether longer treatment with oxytocin improves apathy in people with frontotemporal dementia.

Safety and efficacy of nipocalimab in adults with generalised myasthenia gravis (Vivacity-MG3): a phase 3, randomised, double-blind, placebo-controlled study.

Background: Given burdensome side-effects and long latency for efficacy with conventional agents, there is a continued need for generalised myasthenia gravis treatments that are safe and provide consistently sustained, long-term disease control. Nipocalimab, a neonatal Fc receptor blocker, was associated with dose-dependent reductions in total IgG and anti-acetylcholine receptor (AChR) antibodies and clinically meaningful improvements in the Myasthenia Gravis Activities of Daily Living (MG-ADL) scale in patients with generalised myasthenia gravis in a phase 2 study. We aimed to assess the safety and efficacy of nipocalimab in a phase 3 study.

Long-lived cytokinetic bridges coordinate sister-cell elimination in mouse embryos.

Apoptosis is a key feature of preimplantation development, but whether it occurs in a cell-autonomous or coordinated manner was unknown. Here, we report that plasma membrane abscission, the final step of cell division, is profoundly delayed in early mouse embryos such that a cytokinetic bridge is maintained for the vast majority of the following interphase. Early embryos thus consist of many pairs of sister cells connected by stable cytokinetic bridges that allow them to share diffusible molecules.

A forward genetic screen identifies potassium channel essentiality in SHH medulloblastoma maintenance.

Distinguishing tumor maintenance genes from initiation, progression, and passenger genes is critical for developing effective therapies. We employed a functional genomic approach using the Lazy Piggy transposon to identify tumor maintenance genes in vivo and applied this to sonic hedgehog (SHH) medulloblastoma (MB). Combining Lazy Piggy screening in mice and transcriptomic profiling of human MB, we identified the voltage-gated potassium channel KCNB2 as a candidate maintenance driver.

Ligand interaction landscape of transcription factors and essential enzymes in E. coli.

Knowledge of protein-metabolite interactions can enhance mechanistic understanding and chemical probing of biochemical processes, but the discovery of endogenous ligands remains challenging. Here, we combined rapid affinity purification with precision mass spectrometry and high-resolution molecular docking to precisely map the physical associations of 296 chemically diverse small-molecule metabolite ligands with 69 distinct essential enzymes and 45 transcription factors in the gram-negative bacterium Escherichia coli. We then conducted systematic metabolic pathway integration, pan-microbial evolutionary projections, and independent in-depth biophysical characterization experiments to define the functional significance of ligand interfaces.