Search

In this Viewpoint article, seven experts discuss the challenges that are contributing to the decline in antibiotic drug discovery and development, and the international and national initiatives aimed at incentivizing research and the development of new antibiotics to improve the economic feasibility of antibiotic development.

Targeting peptides from unmutated cancer drivers that are expressed in tumours but not in normal tissues using peptide-centric chimeric antigen receptors shows potential as treatment for cancer.

Cytogenetic and whole-genome-sequencing analyses using CEN-SELECT show that mitotic segregation errors generate a broad spectrum of chromosomal aberrations that recapitulate the complex structural features of cancer genomes.

The actin methyltransferase SETD3, by virtue of its ability to interact with the viral 2A protein and independently of its enzymatic activity, is necessary for RNA replication of several enteroviruses in cell culture and in vivo.

Structural studies of the dimerization quality control E3 ubiquitin ligase SCF–FBXL17 indicate that its selectivity for aberrant complex formation is based on recognizing both shape and complementarity of interacting domains.

Here the authors identify the transcription factor MEF2C as essential for human NK cell function and viral immunity in mice and humans. This control is exerted via regulation of lipid metabolism, and deficiency in MEF2C can be overcome by oleic acid supplementation.

‘Manufacturing CAR-T cells is a streamlined and highly regulated procedure involving T-cell-expansion and activation on a standardised platform. Here, the authors show that a personalized approach, taking the phenotypic attributes of individual patients’ T cells into account, leads to more efficient CAR-T cell manufacturing and better CAR-T cell functionality.

The ESCRT pathway is crucial for membrane remodelling in eukaryotes. Here, Hatano et al. explore the phylogeny, structure, and biochemistry of homologues of the ESCRT machinery and the associated ubiquitylation system in Asgard archaea, the closest living relatives of eukaryotes.

Accurate spectral libraries are essential for analyzing data-independent acquisition (DIA) proteomics data. Here, the authors present Carafe, which trains on DIA data to build experiment-specific spectral libraries, boosting peptide detection across diverse datasets.

Durable agonism of NPR1 achieved with a novel investigational monoclonal antibody could mirror the positive hemodynamic changes in blood pressure and heart failure identified in humans with lifelong exposure to NPR1 coding variants.

Heparan sulfate (HS) and chondroitin sulfate (CS) are different glycosaminoglycan chains that are attached to core proteins via the same linker tetrasaccharide, and it was unclear how core proteins are specifically modified with HS or CS. Here, the authors determine that the CS-initiating glycosyltransferase CSGALNACT2 is promiscuous, whereas the HS-initiating glycosyltransferase EXTL3 selects only certain core proteins for modification.

Rare mutations in the high requirement temperature protein A1 (HTRA1) cause cerebral vasculopathy. Here, authors establish mechanistically distinct protein repair approaches to reverse the deleterious effects of pathogenic mutations interfering with the assembly and protease function of HTRA1.

CarH is a bacterial B₁₂-binding photoreceptor involved in transcriptional regulation. Here, the authors provide insights into B₁₂ dynamics and associated cobalt redox changes following light activation. These demonstrate the CarH response integrates light and oxygen sensing.

Thermoelectric materials are required to be electrically conducting while thermally insulating, which can be challenging to achieve. Here, the authors report a thermoelectric transport regime with defect tolerant charge transport but defect intolerant heat propagation in two-dimensional coordination polymer films.

Photoreceptor proteins utilise biological chromophores to regulate a large range of cellular processes in response to light. Here the authors identify and characterise a sub-family of multi-centre photoreceptors, termed photocobilins, that not only utilise B₁₂ but also contain biliverdin (BV) as an additional chromophore.

A unique case from the Colombian cohort of autosomal dominant Alzheimer’s disease is reported in which disease progression is substantially delayed despite unusually high amyloid plaque pathology, possibly related to a rare mutation in APOE3.

Genome-wide association analyses of blood glucose measurements under nonstandardized conditions provide insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification.

Nichols et al. identify an SHP2 inhibitor that disrupts SOS1-mediated RAS–GTP loading with demonstrated efficacy in various types of tumour driven by mutant BRAF, NF1 or RAS.

Peptide-centric chimeric antigen receptors (PC-CARs) provide a platform to address the challenges involved in targeting intracellular oncoproteins, and PC-CARs based on the neuroblastoma-dependency gene PHOX2B induce elimination of aggressive tumors.

Detailed analyses of the serotonin receptor 5-HT_1A and the psychedelic 5-methoxy-N,N-dimethyltryptamine reveal the differences in receptor structural pharmacology that mediate signalling specificity, efficacy and potency, findings that may facilitate the development of new neuropsychiatric therapeutics.

Crystal structures of human O-GlcNAc hydrolase (hOGA) fragments show that hOGA's dimeric structure is organized by swapping of an α-helical element and reveal features of inhibitor binding to the catalytic domain.

The current ‘second space age’ has enabled multiple studies on the effects of spaceflight on human physiology and health, which are contributing to the development of measures that will be needed to maintain astronaut health in future space missions.

TssA is an important component of the bacterial type VI secretion system (T6SS). Here, Dix et al. integrate structural, phylogenetic and functional analysis of the TssA subunits, providing new insights into their role in T6SS assembly and function.

Seismic tomography and the isotope geochemistry of Cenozoic volcanic rocks suggest the existence of a large, sheet-like region of upwelling in the upper mantle which extends from the eastern Atlantic Ocean to central Europe and the western Mediterranean. A belt of extension and rifting in the latter two areas appears to lie above the intersection of the centre of the upwelling region with the base of the lithosphere. Lead, strontium and neodymium isotope data for all three regions converge on a restricted composition, inferred to be that of the upwelling mantle.

Stapled α-helical peptides are promising for targeting challenging targets such as transcription factors, but achieving sufficient cell permeability while avoiding off-target cleavage is difficult. Here, the authors present workflows for identifying stapled peptides against Mdm2(X) with in vivo activity and no off-target effects based on comprehensive investigations of their properties.

Using cryo-electron tomography, Lopez-Robles, Scaramuzza, Astorga-Simon, Ishida et al. solve the architecture of ESCPE-1, a protein scaffold that mediates the recycling of cargo from endosome to trans-Golgi network and plasma membrane in tubular carriers.

Non-small cell lung cancer (NSCLC) is often associated with metastasis to the lungs. Here, the authors perform independent screens and identify NuRD as a co-repressor of ZEB1, and demonstrate TBC1D2b as a downstream target of ZEB1/NuRD complex regulating NSCLC metastasis.

Fluorescent protein reporters based on GFP exist, but have intrinsic disadvantages. Here the authors incorporate pH, Ca²⁺ and protein–protein interaction sensing modalities into de novo designed mini-fluorescence-activating proteins (mFAPs), with increased photostability and smaller size, which bind a range of DFHBI chromophore variants.

Viral infection is a common risk for immune-compromised individuals, particularly pediatric patients receiving hematopoietic stem cell transplants. Here the authors report a phase II trial testing adoptive transfer of third party, virus-specific T cells on the feasibility, safety, clinical responses, as well as homeostasis of antiviral immunity in the recipients.

Oncolytic viruses are under development for tumor treatment. David Kirn and colleagues now report their results of a randomized phase 2 dose-finding trial of JX-594, an oncolytic immunotherapeutic vaccinia virus, in patients with advanced hepatocellular carcinoma. The study shows that high-dose JX-594 was associated with significantly improved overall survival and induced radiographic responses and antitumor immunity.

Psychedelic alkaloids served as lead structures for the development of tabernanthalog, a non-hallucinogenic and non-toxic analogue that reduces alcohol- and heroin-seeking behaviour and produces antidepressant-like effects in rodents.

Adhesion of the human pathogen Mycoplasma pneumoniae to pulmonary epithelial cells is mediated by a transmembrane complex composed of proteins P1 and P40/P90. Here, the authors present the structures of M. pneumoniae P1 and P40/P90, show that P40/P90 binds sialylated oligosaccharides and have also determined the crystal structures of P40/P90 complexes with 3’-Sialyllactose and 6’-Sialyllactose, which provide insights into the mechanisms of adhesion and gliding on host cell surfaces.

Here, the authors enhance their nasally delivered chimpanzee adenoviral-vectored SARS-CoV-2 vaccine with an Omicron-matched vaccine (ChAd-SARS-CoV-2-BA.5-S) that stimulates mucosal immunity in mice and hamsters and shows cross-reactive CD8⁺ memory T cell-driven protection against antigenically distant strains.

M. pneumoniae, a model organism for a minimal cell, has a dedicated protein, namely P116, to specifically extract essential lipids. The structure of P116 has a previously unseen fold, resembling a left-handed baseball glove forming a huge hydrophobic cavity.

HIV envelope is a target for vaccine development, but induction of broadly neutralizing antibodies has been difficult. Here, the authors show that electroporation with a synthetic DNA vaccine construct allows in vivo production of HIV envelope native like trimers to induce autologous tier-2 neutralizing antibodies targeting a C3/V5 epitope in mice.

A close-up look at the action of space weathering on carbonaceous asteroids, provided by Ryugu’s returned samples, highlights its role on the dehydration of the first micrometre-thick layer of the surface, possibly hiding a water-rich interior. The depth of the 2.7 µm hydration band may be an indication of the level of space weathering withstood by a C-type asteroid.

The S9.6 monoclonal antibody is widely used to map R-loops genome wide. Here, Bou-Nader et al., define the nucleic acid-binding specificity of S9.6 and report its crystal structures free and bound to a hybrid, which reveal the asymmetric recognition of the RNA and DNA strands and its A-form conformation.

Structures of the human sodium-dependent citrate transporter NaCT in complexes with citrate or a small-molecule inhibitor reveal how the inhibitor—which binds to the same site as citrate—arrests the transport cycle of NaCT.

Two de novo designed protein classes that link phosphorylation by tyrosine and serine kinases to protein-protein association provide potential new avenues to regulating cell function.

Sexual reproduction in eukaryotes involves gamete fusion, mediated by fusogenic proteins. Here, the authors identify fusogenic protein homologs encoded within mobile genetic elements in archaeal genomes, solve the crystal structure of one of the proteins, and show that its ectopic expression can fuse mammalian cells, suggesting potential roles in cell-cell fusion and gene exchange.