More precise base editors make mitochondrial DNA editing efficient enough to model disease and correct pathogenic mutations in rodents, but they are slow to move into clinical trials.

Merck’s new antibody clesrovimab and other long-lasting shots promise to both expand and simplify care of newborns across the world to combat respiratory syncytial virus.

Chemical biology approaches have enhanced metabolism research through the detection of key metabolites and altering enzymatic reactions. This themed issue features a collection of articles that explore emerging research areas in the continual interplay between chemical biology and metabolism.

Sister-chromatid cohesion mediated by the cohesin complex is critical for accurate chromosome segregation during mitosis. A key aspect of this process is the protection of cohesin at mitotic centromeres to resist spindle pulling-forces until anaphase onset. However, the mechanisms that prevent cohesin removal by its release-factor Wapl at centromeres remain incompletely understood. In this study, we

Cancers have traditionally been classified based on their tissue of origin. However, with advances in sophisticated genome sequencing techniques and progression toward an era of precision medicine, it has become increasingly clear that classifying tumors based on unifying molecular features instead of tissue of origin may hold the key to improving patient outcomes. Various efforts have been undertaken

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor symptoms including tremor, rigidity, and bradykinesia as well as degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). A minority of PD cases are familial and are caused by a single genetic mutation. One of the most common PD-causing genes is leucine-rich repeat kinase 2 (LRRK2), which causes

Leucine-rich repeat kinase 2 (LRRK2) has emerged as a promising therapeutic target for the treatment of neurodegenerative Parkinson's disease (PD). Data from a multitude of pre-clinical models are supportive of a potential role for LRRK2 therapies to ameliorate cellular dysfunctions found in PD, and small molecules to inhibit LRRK2 kinase activity, as well as antisense oligonucleotides to target the

Endoplasmic reticulum/plasma membrane (ER/PM) junctions are a major site of cellular signal transduction including in epithelia; however, whether their lipid membrane environment affects junctional ion transporters function remains unclear. Here, we show that epithelial secretion is governed by phosphatidylserine (PtdSer) levels in ER/PM nanodomains, specified by the antagonistic action of the lipid

Parthenolide is a natural compound that has shown highly promising anticancer activity. Even though its mode of action has been studied for decades, its antimitotic activity has been largely overlooked, limiting the understanding of its full anticancer potential. In this study, we combined click-chemistry with quantitative mass spectrometry and cell biology to elucidate the mechanism of action of parthenolide

Photoorientation in motile fungal zoospores is mediated by rhodopsin guanylyl cyclases (RGCs). In certain chytrids, these photoreceptors form heterodimers consisting of a visible-light-absorbing RGC paired with neorhodopsin (NeoR), a rhodopsin distinguished by its unique spectral properties: far-red absorption and high fluorescence. Leveraging the native fluorescence of NeoR, we detected RGCs in living

The three-dimensional (3D) chromatin structure of Epstein-Barr virus (EBV) within host cells and the underlying mechanisms of chromatin interaction and gene regulation, particularly those involving EBV's noncoding RNAs (ncRNAs), have remained incompletely characterized. In this study, we employed state-of-the-art techniques of 3D genome mapping, including protein-associated chromatin interaction analysis

Ribonuclease HI (rnhA) removes the deleterious RNA:DNA hybrids (RDHs) by cleaving its RNA component. The bacterial transcription terminator Rho is an RNA-dependent 5' → 3' helicase capable of unwinding RDH formed on a single-stranded RNA in vitro. We hypothesize that Rho might be directly involved in RDH removal in vivo. Here, we demonstrate that Rho primary RNA-binding site (PBS) mutants defective

The ubiquitin-like protein ISG15 is activated in response to type 1 interferons and its conjugation to proteins regulates the response to bacterial and viral infection. Its subsequent deconjugation, which is broadly achieved by the human enzyme USP18, critically controls interferon signaling and the defense against pathogens. However, the molecular determinants underlying USP18 specificity for ISG15

Hydrogen (H) atoms account for about half the atoms in biomacromolecules and are essential for their biochemical properties such as enzymatic functions. Obtaining precise enzyme structures that include all the H atoms allows a deeper understanding of their structure-function relationships. Copper-containing nitrite reductases (CuNIRs) catalyze transformation of nitrite to nitric oxide, which has impacts

Unlike terrestrial environments, where humans reside, there is no sunlight in the deep sea. Instead, dim visible light from black-body radiation and bioluminescence illuminates hydrothermal vent areas in the deep sea. A deep-sea hydrothermal vent shrimp, Rimicaris hybisae, is thought to detect this dim light using its enlarged dorsal eye; however, the molecular basis of its photoreception remains unexplored

tRNAs are central players in translation, delivering cognate amino acids to the ribosome. To fulfill this essential function, secondary and tertiary structures of tRNAs are highly conserved. In metazoan, however, several mitochondrial tRNAs show strong structural deviations and lack D- or T-arms. As these elements are important for the interaction with tRNA-binding proteins, these proteins are adapted

ROCK1 plays an important role in phagocytosis by inducing cytoskeletal rearrangement. Although the transcriptional regulation of ROCK1 is known but its post-transcriptional regulation is underexplored. We intended to find a mechanism of microglial phagocytosis through possible post-transcriptional regulation of ROCK1. The study identified miR-129-5p as a regulator of microglial phagocytosis following

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by loss of dopaminergic neurons, particularly in the substantia nigra of the brain. α-Synuclein is a major causative factor in both familial and sporadic forms of PD, and its protein aggregates play critical roles in neuronal cell death and PD pathogenesis. This study explored the role of ubiquitin-specific protease

A functional mitochondrial respiratory chain requires coordinated and tightly regulated assembly of mitochondrial- and nuclear-encoded subunits. For bc1 complex (complex III) assembly, the iron-sulfur protein Rip1 must first be imported into the mitochondrial matrix to fold and acquire its 2Fe-2S cluster, then translocated and inserted into the inner mitochondrial membrane (IM). This translocation

Actin, a ubiquitous protein essential for numerous cellular functions, is found in all eukaryotes. Despite extensive research across molecular to organismal scales, fundamental questions persist regarding the regulation of dynamic actin architectures, their interaction with membranes, and their mechanical properties. Characterizing the factors governing these processes presents significant challenges

Nicotinamide adenine dinucleotide phosphate (NADPH) is a reducing cofactor present in cytosolic and mitochondrial pools, with each pool requiring distinct NAD+ kinases (NADK and NADK2). NADK2 mediates production of mitochondrial NADP(H) and is essential for proline biosynthesis. To uncover new roles for NADK2 in metabolism, Kim et al. used a cancer dependency map database (DepMap) and identified NADK2

Mitochondria serve as the energy factories of cells, powering various biological processes, and their dysfunction is linked to many types of disease, such as cancer, neurodegenerative diseases and metabolic disorders. For example, mutations in DNA polymerase γ (POLγ), the enzyme responsible for mitochondrial DNA (mtDNA) replication, can cause mtDNA depletion, leading to severe clinical symptoms associated

The mitochondrial cristae — the folds of the inner mitochondrial membrane — undergo structural remodeling during respiration and apoptosis that also triggers outer mitochondrial membrane permeabilization. Such remodeling is likely to influence the composition and potentially the functional roles of the large protein complexes abundant in the cristae. Yet, how cristae remodeling affects the structure

Paraneoplastic syndrome represents severe and complex systemic clinical symptoms manifesting in multiple organs of cancer patients, but its cause and cellular underpinnings remain little explored. In this study, establishing a Drosophila model of paraneoplastic syndrome triggered by tumor transplantation, we found that the innate immune response, initiated by translocated commensal bacteria from a

The structural and mechanistic complexity of Escherichia coli's type I CRISPR-Cas system compared to the multidomain, single effector protein-based type II systems, limits its application in genome editing and silencing. Despite higher prevalence of the type I endogenous systems in bacteria, significant research has focused on improving the type II systems. While the type-I CRISPR system possesses

Tau is subject to a broad range of post-translational modifications (PTMs) that regulate its biological activity in health and disease, including microtubule (MT) dynamics, aggregation, and adoption of pathogenic conformations. The most studied PTMs of tau are phosphorylation and acetylation; however, the salience of other PTMs is not fully explored. Tissue transglutaminase (TG) is an enzyme whose

Syntenin-1 is a promising therapeutic target for cancer, as its inhibitors have shown positive efficacy in preclinical models of various cancer types. Posttranslational modifications including phosphorylation play an important role in regulating syntenin-1 activity, but the underlying molecular mechanisms have not been completely understood. To figure out the enzymes that catalyze syntenin-1 modifications

Vancomycin-resistant enterococci (VRE) are high-priority targets for new therapeutic development. In VRE, expression of the resistance phenotype is controlled by the VanRS two-component system, which senses the presence of the antibiotic and responds by initiating transcription of resistance genes. VanS is a transmembrane sensor histidine kinase that is known to detect the antibiotic and then transduce

Major Histocompatibility Complex I (MHC-I) and MHC-I-like molecules play a central role in mediating immunity. Through their conservation across all taxa of jawed vertebrates, the MHC-I-like proteins have adapted to present non-peptidic antigens to distinct T cell populations. While our understanding of the structure-function relationship of MHC-I and MHC-I-like molecules in humans and mice is well

PARP4 is an ADP-ribosyltransferase typically associated with the cytoplasmic vault organelle. PARP4 has a distinct domain composition relative to other PARP enzymes; however, the N-terminal region of PARP4 is homologous to a collection of domains found in PARP1, a regulator of multiple nuclear processes including the cellular response to DNA damage. The N-terminal region of PARP4 interacts in vitro

In their mammalian hosts, African trypanosomes abundantly express GPI-anchored variant surface glycoproteins (VSGs) on their cell surfaces. These provide a protective surface coat that has been studied best in Trypanosoma brucei. The genome of this single-celled parasite contains more than 2000 VSG genes and pseudogenes, a rich foundation based on which only one functional VSG is expressed at any given

The importance of phosphatidylinositol 3,4,5- trisphosphate (PIP3) in cell signaling has been well established. Despite phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2] emerging as an actor independent of PIP3, its exact signaling role remains poorly understood and the precise dynamics of PI(3,4)P2 and PIP3 upon receptor tyrosine kinase (RTK) stimulation are still inadequately investigated. In this