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Hefzi et al. engineer cells to nearly eliminate lactate production and increase mitochondrial use of pyruvate by deleting both lactate dehydrogenases and pyruvate dehydrogenase kinases with the goal of circumventing pH and osmolarity issues that arise in bioreactor-based production of biopharmaceuticals.

Mutation of conserved prolines enhances correct pairing of light and heavy chains for bispecific IgG-like antibody production.

Activity in a set of parabranchial neurons in the mouse brain is increased during chronic pain, predicts coping behaviour, and can be modulated by circuits activated by survival threats.

Control of liquid-based materials is important for developing materials based on these, but topological flexibility is limited. Here, the authors report a method for digital fabrication of slippery objects with solid-liquid composite interfaces and geometric design freedom.

Thousands of recombinant antibodies enriched for specificity against defined targets are assembled in multivalent mixtures with enhanced therapeutic activity.

Analysis combining multiple global tree databases reveals that whether a location is invaded by non-native tree species depends on anthropogenic factors, but the severity of the invasion depends on the native species diversity.

Coagonism, the ability of nonstimulatory antigens to promote T-cell activation, has been reported in mice. Here the authors show that coagonism also occurs in human CD8 T cells, in which a nonstimulatory HIV GAG peptide enhances a specific T-cell response to a hepatitis B virus epitope by amplifying T-cell receptor signals.

Polygenic scores for body mass index and obesity constructed using data from 5 million people with different ancestries were associated with distinct weight gain trajectories from early childhood to adulthood.

Polygenic risk scores can help identify individuals at higher risk of type 2 diabetes. Here, the authors characterise a multi-ancestry score across nearly 900,000 people, showing that its predictive value depends on demographic and clinical context and extends to related traits and complications.

Literature mining, such as systematic review and meta-analysis, is crucial for discovering, integrating, and interpreting emerging research. This study presents a specialized large language model for literature that outperforms six general LLMs and helps clinicians in study selection and data extraction tasks.

Spiky hedgehog particles are reported to access a photocatalytic pathway for alkane oxidation directly to industrially relevant epoxides in one step, providing a lower cost and less energy-intensive pathway as compared to common alkene feedstocks.

Single-atom and nanocluster catalysts have been widely studied in heterogeneous catalysis, yet their coexistence and potential synergistic effects remain unclear. Here, the authors investigate atomic-scale Ni-based catalysts for bioethanol reforming and reveal a synergistic interaction between single atoms and nanoclusters.

Liquid glycan arrays (LiGAs), presented on M13 bacteriophage surface proteins through bioorthogonal chemistry, link surface glycans to genetic barcodes in phage DNA, enabling lectin–glycan interaction profiling by DNA sequencing.

Glycan molecules can be modified directly on the cell surface via chemoenzymatic approaches. Here, the authors employ a set of four bacterial glycosyltransferases to develop a live cell-based killing assay to probe host cell glycan-mediated influenza A virus infection.

Proliferative and effector functions of T cells are determined by T cell receptor signalling and modulated by activator and inhibitory co-receptors. Authors report here that the G-protein-coupled receptor GPR171 functions as a co-inhibitor of T cell signalling and might serve as a target for cancer immunotherapy.

Together with a companion paper, the generation of a transcriptomic atlas for the mouse lemur and analyses of example cell types establish this animal as a molecularly tractable primate model organism.

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.

Characterisation of the human antibody response to SARS-CoV-2 can help the design of serological tests and vaccines. Here, the authors identify two linear epitopes in SARS-CoV-2 spike protein that elicit neutralising antibodies in several patients and could thus be useful for serology and vaccine development.

A genome-wide association meta-analysis study of blood lipid levels in roughly 1.6 million individuals demonstrates the gain of power attained when diverse ancestries are included to improve fine-mapping and polygenic score generation, with gains in locus discovery related to sample size.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

The early signalling events that trigger initial T-cell receptor signalling are not clearly defined. Here the authors show that this occurs in two stages, the first between the CD8 coreceptor and CD3 requiring Lck association to CD8, while the second interaction requires binding of major histocompatibility molecules.

How the ensemble encoding of social and anxiety-related behaviors interacts with encoding of context in the prefrontal cortex of mice is not fully understood. Here authors examine how prefrontal neurons encode socioemotional behaviors in different contexts and reveal that the prefrontal cortex encodes context-invariant representations of these behaviors in parallel with representations of context.

A quantitative fluorescence-activated cell sorting method for generating fully human conformational antibodies against amyloid aggregates associated with neurodegenerative disorders—without the need for immunization—has now been developed. Engineered antibodies obtained using this approach show properties rivaling those of clinical-stage antibodies specific for tau and α-synuclein amyloid aggregates.

Sera from vaccinated individuals and some monoclonal antibodies show a modest reduction in neutralizing activity against the B.1.1.7 variant of SARS-CoV-2; but the E484K substitution leads to a considerable loss of neutralizing activity.

A genome-wide study by the Long COVID Host Genetics Initiative identifies an association between the FOXP4 locus and long COVID, implicating altered lung function in its pathophysiology.

New delivery platforms are needed to allow broader application of biotherapeutics for CNS diseases. Here, the authors show enhanced CNS delivery with a transport vehicle engineered to bind CD98hc, a highly expressed target at the blood-brain barrier.

Analyses of genome and exome sequencing data identify rare coding and structural variants associated with atrial fibrillation and highlight genetic links between atrial fibrillation and cardiomyopathies.

Monoclonal antibody (mAb) therapy is now commonplace in the clinic, yet such reagents can elicit unwanted side effects due to interactions with Fcγ receptors. Georgiou and colleagues have engineered mAbs that lack such FcγR interactions but retain the ability to activate complement and show that these modified mAbs have efficacious effector function.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

Systematic analysis from the Global Burden of Disease study reported that, despite global improvements from 1990 to 2021, dietary iron deficiency-associated disease burden remains high in women, children and residents in low socio-demographic index countries.

IL-15-driven NK cells mediate anti-tumor immunity, but how IL-15 is negatively regulated remains unclear. Huntington and colleagues find that CIS, a member of the suppressor of cytokine signaling family, suppresses the response to IL-15 and, as a result, CIS-deficient mice are more resistant to cancer metastasis.

A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

Glucagon-like peptide-1 receptor is an important regulator of appetite and glucose homeostasis. Here the authors describe super-resolution microscopy and in vivo imaging compatible fluorescent probes, which reveal endogenous glucagon-like peptide-1 receptor distribution and dynamics in islets and brain.

Meta-analyses in up to 1.3 million individuals identify 87 rare-variant associations with blood pressure traits. On average, rare variants exhibit effects ~8 times larger than the mean effects of common variants and implicate candidate causal genes at associated regions.

A cross-ancestry meta-analysis of genome-wide association studies identifies association signals for stroke and its subtypes at 89 (61 new) independent loci, reveals putative causal genes, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as potential drug targets, and provides cross-ancestry integrative risk prediction.

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.

Atypical antipsychotics show reduced extrapyramidal side effects compared to first generation drugs. Here the authors use time-resolved FRET to measure binding kinetics, and show that side effects correlate with drug association rates to the D₂ receptor, while dissociation rates correlate with prolactin elevation.

A new somite compartment, called the endotome, that contributes to the formation of the embryonic dorsal aorta by providing endothelial progenitors is identified here; endotome-derived endothelial progenitors, whose formation is regulated by the activity of the meox1 gene, induce haematopoietic stem cell formation upon colonization of the nascent dorsal aorta.

Nanostructures with high-aspect ratios—for example, nanowires—are finding applications as cell delivery systems, but the mechanism is largely unknown. Here the authors study nanostraws and show that cell penetration is in fact a rare event, in addition to being adhesion dependent.

With the generation of large pan-cancer whole-exome and whole-genome sequencing projects, a question remains about how comparable these datasets are. Here, using The Cancer Genome Atlas samples analysed as part of the Pan-Cancer Analysis of Whole Genomes project, the authors explore the concordance of mutations called by whole exome sequencing and whole genome sequencing techniques.

Transfer hydrogenation is challenging to apply to aryl halide reductive cross-couplings because of competing hydrogenolysis. Now aryl halide cross-couplings mediated by sodium formate have been developed. These processes display orthogonality to Suzuki and Buchwald–Hartwig couplings as pinacol boronates and anilines are tolerated and, owing to chelated intermediates, effective for challenging 2-pyridyl systems.

Species’ traits and environmental conditions determine the abundance of tree species across the globe. Here, the authors find that dominant tree species are taller and have softer wood compared to rare species and that these trait differences are more strongly associated with temperature than water availability.