BindCraft: one-shot design of functional protein binders.

Protein-protein interactions (PPIs) are at the core of all key biological processes. However, the complexity of the structural features that determine PPIs makes their design challenging. We present BindCraft, an open-source and automated pipeline for protein binder design with experimental success rates of 10-100%.

The impact of the COVID-19 pandemic on first-episode psychosis presentations in two early intervention in psychosis services.

Objectives: To assess the impact of the COVID-19 pandemic on first-episode psychosis (FEP) presentations across two Early Intervention in Psychosis (EIP) services in Ireland, by comparing pre-pandemic and post-pandemic cohorts.

Methods: A cross-sectional observational design with retrospective medical record review was employed. The study population comprised 187 FEP patients (77 in pre-pandemic and 110 in post-pandemic cohort).

Gastrointestinal Device-Mediated Delivery of mRNA-Lipid Nanoparticles Achieves Distinct Expression and Biodistribution in Mice and Pigs.

Recent investigations into autonomous ingestible microjet devices have demonstrated the feasibility of delivering many drug modalities directly into the gastrointestinal (GI) wall via the oral route. However, the expression and biodistribution of mRNA after such injections remain unexplored. mRNA-lipid nanoparticles (mRNA-LNPs) are promising therapeutics for treating or vaccinating against many diseases and pathogens.

Exploring the experiences of GPs in establishing and operating the chronic disease management programme in clinical practice in Ireland. A qualitative study.

Background: The management of chronic diseases, in the context of an ageing population and increasing life expectancy, is one of the major challenges facing the Irish health system. In 2020, a chronic disease management programme [CDM] was introduced in Irish general practice as part of a transformation in health policy to meet the changing needs of the population.

Objectives: To explore GPs' experiences and perceptions of the impact of the introduction of CDM on general practice in Ireland.

Cephalopod-inspired jetting devices for gastrointestinal drug delivery.

Needle-based injections currently enable the administration of a wide range of biomacromolecule therapies across the body, including the gastrointestinal tract, through recent developments in ingestible robotic devices. However, needles generally require training, sharps management and disposal, and pose challenges for autonomous ingestible systems. Here, inspired by the jetting systems of cephalopods, we have developed and evaluated microjet delivery systems that can deliver jets in axial and radial directions into tissue, making them suitable for tubular and globular segments of the gastrointestinal tract.

Pharmacokinetic Properties of a Once-Weekly Fixed-Ratio Combination of Insulin Icodec and Semaglutide Compared with Separate Administration of Each Component in Individuals with Type 2 Diabetes Mellitus.

Background And Objective: IcoSema is being developed as a subcutaneous once-weekly fixed-ratio combination of the once-weekly basal insulin icodec and the once-weekly glucagon-like peptide-1 receptor agonist semaglutide. This study investigated the pharmacokinetics of icodec and semaglutide in IcoSema versus separate administration of each component in individuals with type 2 diabetes mellitus (T2DM).

Methods: In a randomised, double-blind, three-period crossover study, 31 individuals with T2DM (18-64 years, body weight 80-120 kg, glycosylated haemoglobin 6.

Pacritinib Response Is Associated With Overall Survival in Myelofibrosis: PERSIST-2 Landmark Analysis of Survival.

Spleen volume reduction (SVR) is a key endpoint in inhibitors of Janus kinase (JAK) inhibitor studies. Retrospective analyses have demonstrated an association between SVR and improved overall survival (OS) among patients treated with ruxolitinib with a platelet count > 100 × 10/L. Whether this association occurs in patients with thrombocytopenia is unclear.

Bioengineered Nanomedicines Targeting the Intestinal Fc Receptor Achieve the Improved Glucoregulatory Effect of Semaglutide in a Type 2 Diabetic Mice Model.

The oral administration of the glucagon-like peptide-1 analogue, semaglutide, remains a hurdle due to its limited bioavailability. Herein, neonatal Fc receptor (FcRn)-targeted nanoparticles (NPs) were designed to enhance the oral delivery of semaglutide. The nanocarriers were covalently linked to the FcRn-binding peptide FcBP or the affibody molecule Z that specifically binds to the human FcRn (hFcRn) in a pH-dependent manner.

Evaluation of the Master's in Genomic Medicine framework: A national, multiprofessional program to educate health care professionals in NHS England.

Purpose: Genomic medicine is revolutionizing health care but requires health care professionals to update their understanding of genomics and its application to clinical practice for successful implementation. To meet this need, Health Education England developed the Master's in Genomic Medicine, a national multiprofessional program to increase genomic literacy in the National Health Service workforce. This study summarizes an evaluation of the program, which will inform its future development.

National Park visitors perceive benefits for themselves and wildlife under blended red-white outdoor lighting.

Visitors to Colter Bay Village in Grand Teton National Park were surveyed to elicit their evaluations of experimental outdoor lighting conditions. Luminaires capable of dimming and switching between two LED modules (white, blended red-white) were installed in street and parking areas. The blended red-white lamps consisted of 30 narrowband LED with a peak wavelength 623 nm and two 3000 K white LEDs.

Patient and carer perceptions of video, telephone and in-person clinics for Phenylketonuria (PKU).

Background: In phenylketonuria (PKU), attending multidisciplinary clinic reviews is an important aspect of life-long care. Since the COVID-19 pandemic, video and telephone clinics are used as alternative methods for people with PKU to have contact with their care team. There is limited research concerning patient preference, experience and perceptions of alternative types of clinic review.

Role of Direct and Sensitized Photolysis in the Photomineralization of Dissolved Organic Matter and Model Chromophores to Carbon Dioxide.

This study addresses the fundamental processes that drive the photomineralization of dissolved organic matter (DOM) to carbon dioxide (CO), deconvoluting the role of direct and sensitized photolysis. Here, a suite of DOM isolates and model compounds were exposed to simulated sunlight in the presence of various physical and chemical quenchers to assess the magnitude, rate, and extent of direct and sensitized photomineralization to CO. Results suggest that CO formation occurs in a biphasic kinetic system, with fast production occurring within the first 3 h, followed by slower production thereafter.

Consistency of Spleen and Symptom Reduction Regardless of Cytopenia in Patients With Myelofibrosis Treated With Pacritinib.

Background: Pacritinib is a JAK2/IRAK1/ACVR1 inhibitor that is approved in the United States for the treatment of patients with myelofibrosis who have a platelet count < 50 × 109/L. Phase 3 clinical studies of pacritinib included patients across a wide range of baseline platelet and hemoglobin levels.

Patients And Methods: In order to assess the impact of baseline blood counts on pacritinib efficacy, an analysis of efficacy outcomes by baseline platelet and hemoglobin levels was performed using data pooled from 2 Phase 3 studies of pacritinib in patients with MF (PERSIST-1 and PERSIST-2).

Long-term climatic stability drives accumulation and maintenance of divergent freshwater fish lineages in a temperate biodiversity hotspot.

Anthropogenic climate change is forecast to drive regional climate disruption and instability across the globe. These impacts are likely to be exacerbated within biodiversity hotspots, both due to the greater potential for species loss but also to the possibility that endemic lineages might not have experienced significant climatic variation in the past, limiting their evolutionary potential to respond to rapid climate change. We assessed the role of climatic stability on the accumulation and persistence of lineages in an obligate freshwater fish group endemic to the southwest Western Australia (SWWA) biodiversity hotspot.

Diabetic Wound Keratinocytes Induce Macrophage JMJD3-Mediated Nlrp3 Expression via IL-1R Signaling.

Macrophage (Mφ) plasticity is critical for normal wound repair; however, in type 2 diabetic wounds, Mφs persist in a low-grade inflammatory state that prevents the resolution of wound inflammation. Increased NLRP3 inflammasome activity has been shown in diabetic wound Mφs; however, the molecular mechanisms regulating NLRP3 expression and activity are unclear. Here, we identified that diabetic wound keratinocytes induce Nlrp3 gene expression in wound Mφs through IL-1 receptor-mediated signaling, resulting in enhanced inflammasome activation in the presence of pathogen-associated molecular patterns and damage-associated molecular patterns.

A pilot randomised controlled trial of acceptance and commitment therapy for medication decision-making and quality of life in women with breast cancer: The ACTION trial.

Objective: Non-adherence to adjuvant endocrine therapy (AET) in women with breast cancer is common and associated with medication side-effects and distress. We co-designed an Acceptance and Commitment Therapy intervention (ACTION) to enhance medication decision-making and quality of life (QoL). We undertook a pilot trial of ACTION to inform the feasibility of a phase III trial, and to examine intervention acceptability.

Inferring the Molecular Basis for Dissolved Organic Matter Photochemical and Optical Properties.

Despite the widespread use of photochemical and optical properties to characterize dissolved organic matter (DOM), a significant gap persists in our understanding of the relationship among these properties. This study infers the molecular basis for the optical and photochemical properties of DOM using a comprehensive framework and known structural moieties within DOM. Utilizing Suwannee River Fulvic Acid (SRFA) as a model DOM, carboxylated aromatics, phenols, and quinones were identified as dominant contributors to the absorbance spectra, and phenols, quinones, aldehydes, and ketones were identified as major contributors to radiative energy pathways.

Use of UK faith Centre as a COVID-19 community vaccination clinic: exploring a potential model for community-based health care delivery.

Introduction: Effective and safe vaccines against COVID-19 are essential to achieve global control of the coronavirus (SARS-CoV-2). Using faith centres may offer a promising route for promoting higher vaccine uptake from certain minority ethnic groups known to be more likely to be vaccine hesitant.

Methods: This cross-sectional study explored attendees' perceptions, experiences of being offered, and receiving COVID-19 vaccination in a local mosque in Woking, Surrey, UK.

Synthetic protein protease sensor platform.

Protease activity can serve as a highly specific biomarker for application in health, biotech, and beyond. The aim of this study was to develop a protease cleavable synthetic protein platform to detect protease activity in a rapid cell-free setting. The protease sensor is modular, with orthogonal peptide tags at the N and C terminal ends, which can be uncoupled via a protease responsive module located in between.

The solute carrier SLC7A1 may act as a protein transporter at the blood-brain barrier.

Despite extensive research, targeted delivery of substances to the brain still poses a great challenge due to the selectivity of the blood-brain barrier (BBB). Most molecules require either carrier- or receptor-mediated transport systems to reach the central nervous system (CNS). These transport systems form attractive routes for the delivery of therapeutics into the CNS, yet the number of known brain endothelium-enriched receptors allowing the transport of large molecules into the brain is scarce.

Pulmonary Langerhan's cell histocystosis presenting with bilateral simultaneous pneumothoraces - Case report.

We describe the case of a young male, with no significant medical history, who presented to the Emergency Department (ED) with severe respiratory compromise. He suffered a respiratory arrest shortly after presentation. An initial chest x-ray performed post intubation revealed bilateral pneumothoraces with evidence of abnormal underlying lungs.