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Preventing endosomal damage sensing or using lipids that create reparable endosomal holes reduces inflammation caused by RNA-lipid nanoparticles while enabling high RNA expression.

N-methyl-D-aspartate receptors (NMDARs) play a central role in synaptic plasticity, learning and memory. Here the authors describe azobenzene-triazole-glutamate (ATG), a new diffusible photoswitchable agonist that allows precise temporal control over NMDAR activity.

On the anniversary of the Boyden et al. (2005) paper that introduced the use of channelrhodopsin in neurons, Nature Neuroscience asks selected members of the community to comment on the utility, impact and future of this important technique.

Bile acids have a crucial role in the digestion of dietary lipids and as signalling molecules in a number of metabolic pathways. Bile acid receptors have become attractive therapeutic targets for liver disease and metabolic disorders. Here, the authors provide an overview of bile acid signalling in humans and highlight the therapeutic potential of compounds that target these pathways.

A tethered macrocyclic peptide antibiotic class described here—which shows potent antibacterial activity against carbapenem-resistant Acinetobacter baumannii—blocks the transport of bacterial lipopolysaccharide from the inner membrane to its destination on the outer membrane through inhibition of the LptB₂FGC complex.

FXR regulates the levels of ACE2 in tissues of the respiratory and gastrointestinal systems that are affected by COVID-19, and inhibiting FXR with ursodeoxycholic acid downregulates ACE2 and reduces susceptibility to SARS-CoV-2 infection.

Over the past decade, inflammation-induced alterations at the hepatocellular, bile ductular and ductal level have been linked to different clinical presentations of cholestasis in sepsis. In this Review, the authors give a comprehensive overview of the molecular and cellular mechanisms that underlie sepsis-associated cholestasis and the potential clinical and therapeutic implications that these mechanisms have for critically ill patients.

Unbiased screening for insect gene function has been largely restricted to Drosophila. Here, Schmitt-Engel et al. perform an unbiased large-scale RNAi screen in the red flour beetle Tribolium castaneumto identify putative gene functions.

The beetle Tribolium castaneum is a commonly used laboratory model, combining the ease of systematic RNAi experiments like those in Caenorhabditis elegans, with biology that is more representative of most insects than Drosophila melanogaster. A large consortium has sequenced and analysed the genome of the red flour beetle, creating a resource for biologists everywhere.

Sebastien Gagneux and colleagues analyze a global collection of Mycobacterium tuberculosis clinical isolates to classify sublineages by phylogeography. They find globally distributed ‘generalist’ and geographically restricted ‘specialist’ sublineages of lineage 4, indicating that different evolutionary strategies were adopted to succeed in various ecological niches.

Sibilia and colleagues report that IL-1-dependent EGFR induction in liver macrophages is needed to stimulate IL-6 production, which in turn promotes hepatocyte proliferation and hepatocellular carcinoma formation.

Primary sclerosing cholangitis (PSC) is a chronic progressive inflammation and fibrosis of the intrahepatic and extrahepatic bile tracts. This Primer presents the available knowledge on PSC as well as the numerous challenges and unmet needs while shedding light into the ‘black box of hepatology’.

To restore sight after retinal degeneration, one approach is to express light-sensitive proteins in remaining cells. Here the authors combine a light-sensitive engineered G protein-coupled receptor and ion channels to restore ON and OFF responses as well as superior visual pattern discrimination.

People with mutations in ATGL, a gene involved in lipid catabolism, suffer from neutral lipid storage disease and often from cardiomyopathy. Rudolf Zechner and his colleagues now show in mice that Atgl activity in cardiac muscle produces key lipid ligands for PPAR-α, a transcription factor that regulates proper lipid metabolism and fuel burning in this tissue. These results may explain the mechanisms responsible for the cardiomyopathy and offer a potential target for treatment.

HIV-1 integrase (IN) binds the host factor INI1/SMARCB1, which is required at multiple stages of HIV-1 replication. Here, the authors show that the same IN residues are involved in INI1 and RNA binding and in influencing particle morphogenesis and suggest that the IN-binding INI1 domain is structurally similar to HIV TAR RNA.

Vitamin D and its analogues demonstrated in this study antifibrotic effects in a murine fibrosis model compared to calcitriol. In this study, the hypocalcemic vitamin D analog paricalcitol was superior in respect to side effects and efficacy, indication that such analogs could be considered for the treatment of liver fibrosis.

Two-photon absorption capacity of azobenzene photoswitches usually comes with a reduction in thermal stability. Here, the authors developed photoswitches with high two-photon sensitivity and enhanced cis isomer thermal lifetime for the control of glutamate receptors.

Non-alcoholic fatty liver disease (NAFLD) is a potentially serious liver disease with a substantial burden worldwide. In this Consensus Statement, a global multidisciplinary group of experts develop consensus statements and recommendations addressing a broad range of topics on NAFLD to raise awareness and spur action.

Here, the authors describe the role of bile acids and their receptors in health and in gastrointestinal and liver disease. This Review provides insights on therapeutic strategies based on targeting bile acid homeostasis.

Cholangiocarcinomas are a heterogeneous group of bile duct cancers and the second most common primary liver tumour worldwide. In this Consensus statement, the newly formed European Network for the Study of Cholangiocarcinoma (ENS-CCA) detail the classification, pathophysiology and underlying mechanisms, and current therapies for cholangiocarcinoma, as well as future perspectives.

Joseph Gleeson and colleagues report whole-exome sequencing of a cohort of over 1,000 individuals from the Greater Middle East, characterizing common and rare variants. They find evidence of subregional diversity and historical migrations and use the GME Variome to identify disease-causing mutations.