Emerging strategies, applications and challenges of targeting NAD in the clinic.

Beyond their classical functions as redox cofactors, recent fundamental and clinical research has expanded our understanding of the diverse roles of nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) in signaling pathways, epigenetic regulation and energy homeostasis. Moreover, NAD and NADP influence numerous diseases as well as the processes of aging, and are emerging as targets for clinical intervention. Here, we summarize safety, bioavailability and efficacy data from NAD-related clinical trials, focusing on aging and neurodegenerative diseases.

The WHO global landscape of cancer clinical trials.

Clinical trials are essential to advancing cancer control, yet access and participation remain unequal globally. The World Health Organization (WHO) established the International Clinical Trials Registry Platform (ICTRP) to enable a complete view of interventional clinical research for all those involved in healthcare decision-making and to identify actionable goals to equitable participation at the global level. A review of 89,069 global cancer clinical trials registered in the WHO ICTRP between 1999 and December 2022 revealed a cancer clinical trial landscape dominated by high-income countries and focused on pharmacological interventions, with multinational collaboration limited to only 3% of recruiting trials.

Exploring experiences of the regulatory toxicology system: system-level promoters and inhibitors of new approach methodologies.

The transition from traditional animal-based approaches and assessments to New Approach Methodologies (NAMs) marks a scientific revolution in regulatory toxicology, with the potential of enhancing human and environmental protection. However, implementing the effective use of NAMs in regulatory toxicology has proven to be challenging, and so far, efforts to facilitate this change frequently focus on singular technical, psychological or economic inhibitors. This article takes a system-thinking approach to these challenges, a holistic framework for describing interactive relationships between the components of a system of interest.

Combinatorial prediction of therapeutic perturbations using causally inspired neural networks.

Phenotype-driven approaches identify disease-counteracting compounds by analysing the phenotypic signatures that distinguish diseased from healthy states. Here we introduce PDGrapher, a causally inspired graph neural network model that predicts combinatorial perturbagens (sets of therapeutic targets) capable of reversing disease phenotypes. Unlike methods that learn how perturbations alter phenotypes, PDGrapher solves the inverse problem and predicts the perturbagens needed to achieve a desired response by embedding disease cell states into networks, learning a latent representation of these states, and identifying optimal combinatorial perturbations.

Streptococcus pyogenes EVs induce the alternative inflammasome via caspase-4/-5 in human monocytes.

The sensing of Gram-negative Extracellular Vesicles (EVs) by the innate immune system has been extensively studied in the past decade. In contrast, recognition of Gram-positive EVs by innate immune cells remains poorly understood. Comparative genome-wide transcriptional analysis in human monocytes uncovered that S.

Isotope-dependent Tafel analysis probes proton transfer kinetics during electrocatalytic water splitting.

Proton transfer plays an important role in both hydrogen and oxygen evolution reactions during electrocatalytic water splitting to produce green hydrogen. However, directly adapting the conventional proton/deuterium kinetic isotope effect to study proton transfer in heterogeneous electrocatalytic processes is challenging. Here we propose using the shift in the Tafel slope between protic and deuteric electrolytes, or the Tafel slope isotope effect, as an effective probe of proton transfer characteristics.

DelGrad: exact event-based gradients for training delays and weights on spiking neuromorphic hardware.

Spiking neural networks (SNNs) inherently rely on the timing of signals for representing and processing information. Augmenting SNNs with trainable transmission delays, alongside synaptic weights, has recently shown to increase their accuracy and parameter efficiency. However, existing training methods to optimize such networks rely on discrete time, approximate gradients, and full access to internal variables such as membrane potentials.

Local activity alterations in individuals with autism correlate with neurotransmitter properties and ketamine-induced brain changes.

Autism is a neurodevelopmental condition associated with altered resting-state brain function. An increased excitation-inhibition ratio is discussed as a pathomechanism but in-vivo evidence of disturbed neurotransmission underlying functional alterations remains scarce. We compare local resting-state brain activity and neurotransmitter co-localizations between autism (N = 405, N = 395) and neurotypical controls (N = 473, N = 474) in two independent cohorts and correlate them with excitation-inhibition changes induced by glutamatergic (ketamine) and GABAergic (midazolam) medication.

Contrasting contribution of resident and repopulated brain macrophages in sustaining sleep-wake circuitry.

Sleep is a complex behavior regulated by various brain cell types. However, the roles of brain-resident macrophages, including microglia and CNS-associated macrophages (CAMs), particularly those derived postnatally, in sleep regulation remain poorly understood. Here, we investigated the effects of resident (embryo-derived) and repopulated (postnatally derived) brain-resident macrophages on the regulation of vigilance states in mice.

Fast-hyperspectral imaging remote sensing: Emission quantification of NO and SO from marine vessels.

Marine vessels play a vital role in the global economy; however, their negative impact on the marine atmospheric environment is a growing concern. Quantifying marine vessel emissions is an essential prerequisite for controlling these emissions and improving the marine atmospheric environment. Optical imaging remote sensing is a vital technique for quantifying marine vessel emissions.

Effects of a Patient Decision Aid for Nonmetastatic Prostate Cancer Established in Routine Care: The Randomized Controlled EvEnt-PCA Trial.

Background And Objective: Since 2016, >21 000 patients with prostate cancer (PC) used our personalized online decision aid in routine care in Germany. We analyzed the effects of this online decision aid for men with nonmetastatic PC in a randomized controlled trial.

Methods: In the randomized controlled EvEnt-PCA trial, 116 centers performed 1:1 allocation of 1115 patients with nonmetastatic PC to use an online decision aid (intervention = I) or a printed brochure (control = C).

Analyzing Reddit Social Media Content in the United States Related to H5N1: Sentiment and Topic Modeling Study.

Background: The H5N1 avian influenza A virus represents a serious threat to both animal and human health, with the potential to escalate into a global pandemic. Effective monitoring of social media during H5N1 avian influenza outbreaks could potentially offer critical insights to guide public health strategies. Social media platforms like Reddit, with their diverse and region-specific communities, provide a rich source of data that can reveal collective attitudes, concerns, and behavioral trends in real time.

Therapeutic Drug Monitoring for Precision Dosing of Janus Kinase Inhibitors: Protocol for a Prospective Observational Study.

Background: Janus kinase inhibitors (JAKIs) are small molecules used orally to treat inflammatory and hematological disorders. They have demonstrated impressive efficacy across multiple indications. However, concerns have emerged regarding their safety profile.

Effect of Repeated-Sprint Training in Hypoxia in Female National-Level Rugby Union Players.

Purpose: The aim of this study was to investigate the effects of repeated-sprint training in hypoxia (RSH) versus in normoxia (RSN) in female national-level rugby union players.

Methods: In a randomized, controlled, and crossover study, 8 female rugby union players performed 5 sessions of repeated sprints either in normobaric hypoxia (RSH, simulated altitude: 3000 m; FiO2 = 14.5%) or in normoxia (RSN, terrestrial altitude: 165 m; FiO2 = 20.

Functional characterization of Paillotin: an immune peptide regulated by the Immune deficiency (Imd) pathway with pathogen-specific roles in immunity.

Insects, such as , rely on innate immune defences to combat microbial threats. Antimicrobial peptides (AMPs) play an important role in limiting pathogen entry and colonization. Despite intensive research into the regulation and biochemical properties of antimicrobial peptides, their exact significance has remained uncertain due to the challenges of mutating small genes.

Towards real life exposure: nasal epithelial cell stimulation with pollen particle aerosols.

Background: Currently, most researchers apply pollen extracts or -suspensions to assess the effects of pollen exposure on airway epithelia. How respiratory epithelia respond to pollen aerosols is not well studied because standardised methods to aerosolize pollen were not available until recently.

Aim Of Study: To develop and test a near-natural exposure model for pollen grains based on differentiated human nasal epithelial cells and a novel particle aerosoliser.

3D bioprinted cell-laden GrooveNeuroTube: a multifunctional platform forneural cell migration and growth studies.

Extensive peripheral nerve injuries often lead to the loss of neurological function due to slow regeneration and limited recovery over large gaps. Current clinical interventions, such as nerve guidance conduits (NGCs), face challenges in creating biomimetic microenvironments that effectively support nerve repair. The developed GrooveNeuroTube is composed of hyaluronic acid methacrylate and gelatin methacrylate hydrogel, incorporating active agents (growth factors and antibacterial agents) encapsulated within an NGC conduit made of 3D-printed PCL grid fibers.

Single-cell analysis of Barrett's esophagus and carcinoma reveals cell types conferring risk via genetic predisposition.

Inherited genetic variants contribute to Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC), but it is unknown which cell types are involved in this process. We performed single-cell RNA sequencing of BE, EAC, and paired normal tissues and integrated genome-wide association data to determine cell-type-specific genetic risk and cellular processes that contribute to BE and EAC. The analysis reveals that EAC development is driven to a greater extent by local cellular processes than BE development and suggests that one cell type of BE origin (intestinal metaplasia cells) and cellular processes that control the differentiation of columnar cells are of particular relevance for EAC development.