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Our annual survey highlights several academic startups developing immunotherapies as well as ventures focusing on microbiomes, proteostasis, integrin biology, nucleic acid delivery and subcellular imaging.

EchoNext, a deep learning model for electrocardiograms trained and validated in diverse health systems, successfully detects many forms of structural heart disease, supporting the potential of artificial intelligence to expand access to heart disease screening at scale.

Kumazawa, Xu, Wang and colleagues identify nuclear egress as the mechanism by which cytoplasmic chromatin fragments relocate from the nucleus to the cytoplasm in senescence. They link inflammation to metabolism by showing this egress is regulated by AMPK and metformin.

New treatments are needed for muscle invasive bladder cancers. Here, the authors show that combined Pparg activation and MEK inhibition using FDA approved drugs shrinks tumor volume and induces a Basal/Squamous-to-Luminal shift in the urothelium as well as in invading tumors.

Aberrant signalling pathway activity is relevant for tumour growth and resistance to therapy, but remains hard to understand and target. Here, the authors develop VESPA, a phosphoproteomics-based machine learning algorithm that can elucidate response and adaptation to drug perturbations in cancer signalling pathways.

7DW8-5 is a glycolipid that binds CD1d and stimulates invariant natural killer T (iNKT) cells. Here the authors show that 7DW8-5, when administered intranasally, provides prophylactic anti-viral effects against influenza, RSV, and SARS-CoV-2 in mice or hamsters, and that this effect is mediated by iNKT cells and IFN-γ.

Findings from a systematic antigenic analysis of these surging Omicron subvariants that this lineage of SARS-CoV-2 continues to evolve, successively yielding subvariants that are not only more transmissible but also more evasive to antibodies.

Due to the limited efficacy of vaccines against SARS-CoV-2 and resistance to current therapies additional anti-viral therapeutics with pan-coronavirus activity are of high interest. Here, the authors screened 2.8 billion compounds from a DNA-encoded chemical library and identified small molecules that are non-covalent inhibitors targeting the conserved 3CL protease of SARS-CoV-2 and other coronaviruses.

Antibodies against SARS-CoV-2 provide protection against infection, but the virus has evolved to evade them. Here, the authors characterize a human antibody with incomplete neutralization of SARS-CoV-2 variants and engineer it to enhance potency and expand coverage to all tested variants by increasing conformational flexibility.

The dynamics of the spread of the SARS-CoV-2 variant B.1.526 suggest that resistance to neutralization by antibodies may evolve in other variants and contribute to the spread of COVID-19.

SIRPa is most commonly known as a phagocytosis inhibitory receptor expressed by myeloid cells. Here the authors show SIRPa is expressed on a subset of CD8+ T cells with higher proliferative and effector activity during the chronic phase of the immune response to viral infection.

Brain mitochondria play crucial roles that influence cognition, yet their diversity is often overlooked. This study in mice identifies distinct mitochondrial phenotypes distributed as large-scale networks, accounting for a large portion of animal-to-animal behavioural variation.

Analyses of imputed ancient genomes and of samples from the UK Biobank indicate that ancient selection and migration were large contributors to the distribution of phenotypic diversity in present-day Europeans.

The B.1.1.529/Omicron variant of SARS-CoV-2 is resistant to neutralization by serum not only from patients who recovered from COVID-19, but also from individuals vaccinated with one of the four widely used COVID-19 vaccines.

The ability to measure signalling responses in single cells following short pulses of stimulus would shed insight into temporal thresholds for cell activation. Here the authors introduce a microfluidic platform that allows downstream phosphorylation cascades to be observed following as little as one second of stimulus exposure.

Genomic and transcriptomic analysis of 393 non-small cell lung cancer patients treated with checkpoint inhibitors identifies molecular features associated with response.

Young children frequently encounter respiratory pathogens that elicit immune responses in developing lungs. Farber and colleagues examine rare lung tissue samples obtained from pediatric organ donors and find age-dependent formation of bronchus-associated lymphoid tissue (BALT), which peaks at 3 years of age and dissipates thereafter. Profiling of BALT lymphocytes indicates that repertoire and functional differences exist between the lung, draining lymph nodes and circulating cells.

Antibody-mediated depletion of myeloid-biased haematopoietic stem cells in aged mice restores characteristic features of a more youthful immune system.

Small molecule drugs promise to remain a valuable tool in controlling the ongoing COVID-19 pandemic. Here the authors describe optimized drug-like small molecule inhibitors of the SARS-CoV-2 3CL protease for potential treatment of COVID-19.

Analysis of a large ancient genome dataset shows that genetic risk for multiple sclerosis rose in steppe pastoralists, providing insight into how genetic ancestry from the Neolithic and Bronze Age has shaped modern immune responses.

A severe acute respiratory syndrome coronavirus 2 Omicron subvariant, BA.2.86, was found to be no more resistant to human sera than the currently dominant XBB.1.5 and EG.5.1, but it had a remarkably higher receptor affinity.

A meta-analysis of genome-wide association studies of type 2 diabetes (T2D) identifies more than 600 T2D-associated loci; integrating physiological trait and single-cell chromatin accessibility data at these loci sheds light on heterogeneity within the T2D phenotype.

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.

Obtaining a high-resolution contact map using current 3D genomics technologies can be challenging with small input cell numbers. Here, the authors develop ChromaFold, a deep learning model that predicts cell-type-specific 3D contact maps from single-cell chromatin accessibility data alone.

In an interim analysis of a phase 1/2 trial, a heterologous prime boost vaccine comprised of a chimpanzee adenovirus and self-amplifying mRNA that encodes neoantigens derived from common oncogenic driver mutations in combination with immune checkpoint blockade was safe and elicited neoantigen-specific T cell responses in patients with advanced solid tumors.

A ‘mouse atlas’, comprising single-cell transcriptomic data from more than 100,000 cells from 20 organs and tissues, has been created as a resource for cell biology.

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.

The number of individuals in a given space influences animal interactions and network dynamics. Here the authors identify general rules underlying density dependence in animal networks and reveal some fundamental differences between spatial and social dynamics.

Cold-sensitive engrams contribute to learned thermoregulation in mice that are returned to an environment in which they previously experienced a cold challenge, through a network formed between the hippocampus and hypothalamus that enables the recall of cold-related memories.

An analysis involving the shotgun sequencing of more than 300 ancient genomes from Eurasia reveals a deep east–west genetic divide from the Black Sea to the Baltic, and provides insight into the distinct effects of the Neolithic transition on either side of this boundary.

Phylogenomic analysis of 7,923 angiosperm species using a standardized set of 353 nuclear genes produced an angiosperm tree of life dated with 200 fossil calibrations, providing key insights into evolutionary relationships and diversification.

A systematic analysis of 115 mammalian genomes, including 10 new bat genomes, reveals prevalent positive selection in immune genes in bats and shows key adaptations in the antiviral gene ISG15 that aid disease resistance in bats, including to coronaviruses.

The SARS-CoV-2 variant B.1.1.7 can be neutralized by convalescent sera or sera from vaccinated individuals, whereas the B.1.351 variant is resistant to neutralization by these sera and by several monoclonal antibodies that are in clinical use.

Dampened activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome in bat primary immune cells in response to infection with multiple zoonotic viruses is caused by decreased transcriptional priming, the presence of a unique splice variant and an altered leucine-rich repeat domain of bat NLRP3.

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).

Interaction networks for any protein can be generated using a machine learning algorithm.

A transcriptomics study demonstrates cell-type-specific responses to differentially aged blood and shows young blood to have restorative and rejuvenating effects that may be invoked through enhanced mitochondrial function.

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.

Together with an accompanying paper presenting a transcriptomic atlas of the mouse lemur, interrogation of the atlas provides a rich body of data to support the use of the organism as a model for primate biology and health.

Nirmatrelvir, an oral antiviral targeting the 3CL protease of SARS-CoV-2, has been demonstrated to be clinically useful against COVID-19, but viral resistance to the drug was found to arise readily via multiple pathways in vitro.

Bulk RNA sequencing of organs and plasma proteomics at different ages across the mouse lifespan is integrated with data from the Tabula Muris Senis, a transcriptomic atlas of ageing mouse tissues, to describe organ-specific changes in gene expression during ageing.

Drawing on 51,269 participants across 9 independent, geographically diverse datasets, an AI model identifies the etiologies contributing to dementia in individuals, harnessing a broad array of data, including demographics, medical history, medication use, neuropsychological assessments, functional evaluations, and multimodal neuroimaging.

Genome-wide association analyses of intracranial and nine subcortical brain volumes in 74,898 participants of European ancestry identify 254 independent loci and yield polygenic scores accounting for brain variation across ancestries.

A study generates a clinicogenomics dataset resource, MSK-CHORD, that combines natural language processing-derived clinical annotations with patient medical data from various sources to improve models of cancer outcome.

A single-cell transcriptomic atlas across the lifespan of the mouse, denoted Tabula Muris Senis, provides molecular information about the hallmarks of ageing in a range of tissues and cell types.

Inflammasomes are multiprotein complexes, including the protein ASC, that assemble in response to inflammatory stimulation. Here the authors characterise the regulation of ASC during inflammasome formation and show the involvement of SUMOylation and zinc-finger and BTB domain-containing protein 16 (ZBTB16).