Competing addition processes give distinct growth regimes in the assembly of 1D filaments.

We present a model to describe the concentration-dependent growth of protein filaments. Our model contains two states, a low entropy/high affinity ordered state and a high entropy/low affinity disordered state. Consistent with experiments, our model shows a diffusion-limited linear growth regime at low concentration, followed by a concentration-independent plateau at intermediate concentrations, and rapid disordered precipitation at the highest concentrations.

IQ Survey Results on Current Industry Practices-Part 1: Immunogenicity Risk Assessment.

An immunogenicity risk assessment (IRA) is a relatively new expectation of health authorities that is increasingly incorporated into the drug development process across the pharmaceutical/biotech industry. The guiding principle for an IRA includes a comprehensive evaluation of product- and patient-related factors that may influence the immunogenic potential of a biotherapeutic drug and a potential action plan. The Immunogenicity Working Group from the IQ Consortium (Clinical Pharmacology Leadership Group) has conducted a survey to understand the current practices for conducting IRAs and relevant aspects of bioanalysis.

Integrated Longitudinal Population Dose-Hemoglobin Response of Daprodustat Following Dose Titration in Patients With Anemia in Chronic Kidney Disease.

Daprodustat, a novel oral hypoxia-inducible factor prolyl hydroxylase inhibitor is approved in the United States for the treatment of anemia due to chronic kidney disease (CKD) in adults receiving dialysis for at least 4 months. Pharmacodynamic dose-hemoglobin (Dose-Hgb) models were developed as daprodustat progressed through development. To support global phase III development, a dose-titration algorithm, guided by simulations from the initial Dose-Hgb model based on phase II clinical data, was implemented.

The disparities and development trajectories of nations in achieving the sustainable development goals.

The Sustainable Development Goals (SDGs) provide a comprehensive framework for societal progress and planetary health. However, it remains unclear whether universal patterns exist in how nations pursue these goals and whether key development areas are being overlooked. Here, we apply the product space methodology, widely used in development economics, to construct an 'SDG space of nations'.

Noisy-channel language comprehension in aphasia: A Bayesian mixture modeling approach.

Individuals with "agrammatic" receptive aphasia have long been known to rely on semantic plausibility rather than syntactic cues when interpreting sentences. In contrast to early interpretations of this pattern as indicative of a deficit in syntactic knowledge, a recent proposal views agrammatic comprehension as a case of "noisy-channel" language processing with an increased expectation of noise in the input relative to healthy adults. Here, we investigate the nature of the noise model in aphasia and whether it is adapted to the statistics of the environment.

Multimodal learning for mapping genotype-phenotype dynamics.

How complex phenotypes emerge from intricate gene expression patterns is a fundamental question in biology. Integrating high-content genotyping approaches such as single-cell RNA sequencing and advanced learning methods such as language models offers an opportunity for dissecting this complex relationship. Here we present a computational integrated genetics framework designed to analyze and interpret the high-dimensional landscape of genotypes and their associated phenotypes simultaneously.

Coeliac disease: complications and comorbidities.

Coeliac disease is an autoimmune disease characterized by small intestinal villus atrophy and inflammation upon exposure to gluten. It has a global prevalence of approximately 1%. Although the gluten-free diet can be an effective treatment, this diet is burdensome with practical difficulties and frequent inadvertent gluten exposure.

Associations between common genetic variants and income provide insights about the socio-economic health gradient.

We conducted a genome-wide association study on income among individuals of European descent (N = 668,288) to investigate the relationship between socio-economic status and health disparities. We identified 162 genomic loci associated with a common genetic factor underlying various income measures, all with small effect sizes (the Income Factor). Our polygenic index captures 1-5% of income variance, with only one fourth due to direct genetic effects.

Unveiling inverted D genes and D-D fusions in human antibody repertoires unlocks novel antibody diversity.

Antibodies, essential components of adaptive immunity, derive their remarkable diversity primarily from V(D)J gene rearrangements, particularly within the heavy chain complementarity-determining region 3 (CDR-H3) where D genes play a major role. Traditionally, D genes were thought to recombine only in the forward direction, despite having identical recombination signal sequences (12 base pair spacers) at both ends. This observation led us to question whether these symmetrical sequences might enable bidirectional recombination.

Rapid structural analysis of bacterial ribosomes in situ.

Rapid structural analysis of purified proteins and their complexes has become increasingly common thanks to key methodological advances in cryo-electron microscopy (cryo-EM) and associated data processing software packages. In contrast, analogous structural analysis in cells via cryo-electron tomography (cryo-ET) remains challenging due to critical technical bottlenecks, including low-throughput sample preparation and imaging, and laborious data processing methods. Here, we describe a rapid in situ cryo-ET sample preparation and data analysis workflow that results in the routine determination of sub-nm resolution ribosomal structures.

Anisotropic hydrogel microelectrodes for intraspinal neural recordings in vivo.

Creating durable, motion-compliant neural interfaces is crucial for accessing dynamic tissues under in vivo conditions and linking neural activity with behaviors. Utilizing the self-alignment of nano-fillers in a polymeric matrix under repetitive tension, here, we introduce conductive carbon nanotubes with high aspect ratios into semi-crystalline polyvinyl alcohol hydrogels, and create electrically anisotropic percolation pathways through cyclic stretching. The resulting anisotropic hydrogel fibers (diameter of 187 ± 13 µm) exhibit fatigue resistance (up to 20,000 cycles at 20% strain) with a stretchability of 64.

Cotadutide reversible self-assembly based long-acting injectable depot for sustained delivery of GLP-1 glucagon receptor agonists with controlled burst release.

Cota is a lipidated dual GLP-1 and Glucagon receptor agonist that was investigated for the treatment of various metabolic diseases, it is designed for once daily subcutaneous administration. Invasive daily injections often result in poor patient compliance with chronic disease, and here, we demonstrate an innovative strategy of encapsulating reversible cota self-assembled fibers within an in-situ forming depot of low molecular weight poly(lactic-co-glycolic) acid (LWPLGA) for sustained delivery GLP-1 and Glucagon receptor agonist with controlled burst release. This could be a suitable alternative to other sustained delivery strategies for fibrillating peptides.

What makes a trauma 'pathological'? - Perceived peritraumatic threat influences the development of intrusive memories.

Intrusions are a hallmark symptom of posttraumatic stress disorder (PTSD). While dysfunctional cognitions are known posttraumatic contributors, peritraumatic processes are less understood. Perceived threat, alongside emotional factors, is theorized as significant, but experimental studies are lacking.

Machine learning for synthetic gene circuit engineering.

Synthetic biology leverages engineering principles to program biology with new functions for applications in medicine, energy, food, and the environment. A central aspect of synthetic biology is the creation of synthetic gene circuits - engineered biological circuits capable of performing operations, detecting signals, and regulating cellular functions. Their development involves large design spaces with intricate interactions among circuit components and the host cellular machinery.

Brown adipose tissue is associated with reduced weight loss and risk of cancer cachexia: A retrospective cohort study.

Background & Aims: Brown adipose tissue (BAT) has been mainly investigated as a potential target against cardiometabolic disease, but it has also been linked to cancer-related outcomes. Although preclinical data support that BAT and the thermogenic adipocytes in white adipose tissue may play an adverse role in the pathogenesis of cancer cachexia, results from studies in patients have reported inconsistent results. The purpose of this study was to examine the interrelationship between presence of detectable BAT, changes in body weight, and cachexia in patients with cancer.

bneR: A collaborative workflow for air pollution exposure modeling and uncertainty characterization using the Bayesian Nonparametric Ensemble.

Background: Air pollution is a major public health threat globally. Health studies, regulatory actions, and policy evaluations typically rely on air pollutant concentrations from single exposure models, assuming accurate estimations and ignoring related uncertainty. We developed a modeling framework, bneR, to apply the Bayesian Nonparametric Ensemble (BNE) prediction model that combines existing exposure models as inputs to provide air pollution estimates and their spatio-temporal uncertainty.

Cell-Instructive Biomaterials with Native-Like Biochemical Complexity.

Biochemical signals in native tissue microenvironments instruct cell behavior during many biological processes ranging from developmental morphogenesis and tissue regeneration to tumor metastasis and disease progression. The detection and characterization of these signals using spatial and highly resolved quantitative methods have revealed their existence as matricellular proteins in the matrisome, some of which are bound to the extracellular matrix while others are freely diffusing. Including these biochemical signals in engineered biomaterials can impart enhanced functionality and native-like complexity, ultimately benefiting efforts to understand, model, and treat various diseases.

User and Developer Views on Using AI Technologies to Facilitate the Early Detection of Skin Cancers in Primary Care Settings: Qualitative Semistructured Interview Study.

Background: Skin cancers, including melanoma and keratinocyte cancers, are among the most common cancers worldwide, and their incidence is rising in most populations. Earlier detection of skin cancer leads to better outcomes for patients. Artificial intelligence (AI) technologies have been applied to skin cancer diagnosis, but many technologies lack clinical evidence and/or the appropriate regulatory approvals.

Health and Experiences During the COVID-19 Pandemic Among Children and Young People: Analysis of Free-Text Responses From the Children and Young People With Long COVID Study.

Background: The literature is equivocal as to whether the predicted negative mental health impact of the COVID-19 pandemic came to fruition. Some quantitative studies report increased emotional problems and depression; others report improved mental health and well-being. Qualitative explorations reveal heterogeneity, with themes ranging from feelings of loss to growth and development.