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Using chemical photoswitchable reagents to exert purely wavelength-dependent control over biological systems in deep tissue and in vivo requires a concentration-independent design paradigm. Here, such photoswitchable ligands are realized by ensuring that E/Z isomers have opposing efficacies yet similarly high affinity, allowing them to probe transient receptor potential C4 and C5 channel functions up to the tissue level.

Astrocytic glycogen dynamics is necessary to support neuronal transmission of long-term inflammatory pain signals in the spinal cord.

A mutation in the sodium channel Nav1.9 has been identified in a family and shown to associate with cold-aggravated pain. Here, the authors characterize the electrophysiological consequences of this mutation and propose a mechanism for the pain that the individuals experience.

Discovering that nociceptive sensory neurons express the receptor for anthrax toxin, Yang et al. show that anthrax toxin can induce potent analgesia in mice and facilitate the delivery of potentially analgesic cargo proteins into nociceptive neurons.

Researchers develop a new way to selectively remove ion channel proteins by recruiting the body’s own NEDD4-2 enzyme using custom nanobodies, offering a precise and general strategy for future drug development.

Ingo Kurth and colleagues show that a specific de novo missense mutation in SCN11A results in an inability to experience pain. They further show that mutant channels display higher activity at resting voltages, causing sustained depolarization of pain receptors, impaired generation of action potentials and aberrant synaptic transmission.

A genome-wide association study meta-analysis combined with multiomics data of osteoarthritis identifies 700 effector genes as well as biological processes with a convergent involvement of multiple effector genes; 10% of these genes express the target of approved drugs.

Choi et al. describe the case of a 3 month-old infant who, on the second day of life, had begun to experience painful paroxysmal events starting with tonic contraction of the whole body followed by erythematous harlequin-type color changes. The patient was diagnosed as having paroxysmal extreme pain disorder. The condition was attributed to a mutation in the SCN9A gene, which encodes the voltage-gated sodium channel Na_V1.7.

Chronic care manages long-term, progressive conditions, while acute care handles short-term ones. Here, authors show chronic conditions account for most of the global health burden, with 68% of DALYs and 93% of YLDs attributed to chronic care needs.

In a prospective study enrolling 1,222 patients from 22 emergency departments, a device using a machine-learning-based signature of blood mRNAs demonstrated clinically acceptable performance to diagnose bacterial and viral infections and to predict the all-cause need for critical care interventions within 7 days, with benchmark to established biomarkers and risk scores.

This study identifies PfAnchor as an adaptor essential for apicoplast fission and inheritance in malaria parasites, uncovering a parasite-specific mechanism that offers a new avenue for antimalarial intervention.

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National implementation of a computed tomographic angiography and AI-diagnostic tool, CT-derived fractional flow reserve (FFR-CT), did not provide significant benefits in reducing mortality but led to fewer invasive coronary angiograms and downstream cardiac tests.

The management of X-linked hypophosphataemia has evolved owing to the availability of burosumab. In this Evidence-Based Guideline, the authors provide updated clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia with the aim of improving patient outcomes and quality of life.

Wall et al. describe the selective activation of an adenosine A1 receptor-mediated intracellular pathway that provides potent analgesia in the absence of sedation or cardiorespiratory depression, paving the way for novel medicines based on the far-reaching concept of selective Gα agonism.

Here, the authors investigate the effect of perioperative levosimendan on postoperative subclinical heart failure, evaluated via NT-proBNP measurements in cardiac risk patients undergoing noncardiac surgery, and show no significant difference between levosimendan and placebo on the postoperative maximum NT-proBNP release.

Embryonal tumour with multilayered rosettes (ETMR) is a rare and aggressive paediatric brain tumour. Here, the authors analyse intratumour heterogeneity and the tumour microenvironment in ETMR using single-cell and spatial transcriptomics, in vitro cultures, and a 3D forebrain organoid model, finding important aspects – such as the communication with pericytes – for ETMR development and response to therapy.

A model developed with data from 19,403 patients with colorectal cancer for prediction of 1-year mortality is used as a decision support tool in a prospective cohort, showing promising results in reducing postoperative complications.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

The Sanitation-related Quality of Life index (SanQoL-5) combines answers to five questions (disgust, privacy, disease, shame and safety) into a score ranging from 0 to 1. This study found good evidence for the validity and cross-cultural comparability of SanQoL-5.

Psoriasis is a partially heritable skin disorder, the genetic basis of which is not fully understood. Here, the authors use genome-wide association meta-analysis to discover psoriasis susceptibility loci and genes, which encode existing and potential new drug targets.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

The principal layer architecture of the sensory cortex is altered with aging. The authors show that overall thinning of the primary somatosensory cortex is driven by deep layer degeneration but that layer IV is more pronounced in old age.

Maatz, Lindberg et al. identify molecular alterations and immune response changes in endomyocardial biopsies from patients with myocarditis after COVID-19 infection, after anti-COVID-19 vaccination or from non-COVID-related causes.

A technique that combines retrograde axon tracing with single-cell transcriptomics is used to characterize neurons innervating pancreatic ductal adenocarcinoma and healthy pancreas, providing insight into the role of neural connections in cancer progression.

Wireless bioresorbable stimulators are promising therapeutic implants that naturally dissolve after use. Here, the authors developed a device that operates for months and enables simultaneous multi-site stimulation, preventing early muscle atrophy and accelerating reinnervation in nerve injury models.

A case–control study investigating the causes of recent cases of acute hepatitis of unknown aetiology in 32 children identifies an association between adeno-associated virus infection and host genetics in disease susceptibility.

The molecular landscape of chromothriptic medulloblastoma remains to be characterised. Here, spatial transcriptomics analysis of 13 chromothriptic and non-chromothriptic medulloblastomas identifies distinct spatial composition patterns and cell communication networks in these tumours.

Preclinical data and results from a phase 1 and 2 trial demonstrate preliminary safety and efficacy of topical gene therapy for recessive dystrophic epidermolysis bullosa

Reported is a recombineering pipeline for efficient and large-scale gene modification in the mouse malarial parasite Plasmodium berghei.

Fas ligand (FasL) regulates immunotherapeutic cancer-cell death. Here, the authors show a human-specific amino-acid substitution which renders human FasL more susceptible for plasmin cleavage and is relevant for the efficacy of T-cell-based immunotherapies.