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Cox and colleagues develop PXS-5505, a first-in-class selective pan-lysyl oxidase inhibitor and show that it reduces chemotherapy-induced desmoplasia and stiffness, thereby improving chemotherapy response and survival in pancreatic cancer models.

Interpreting the significance of putative splice-altering variants outside canonical splice sites remains challenging. Here, the authors describe ParSE-seq, a high-throughput assay to annotate the effect of germline variants on RNA-splicing. They calibrate the assay and deploy it to study hundreds of variants in the arrhythmia-associated gene SCN5A.

Amaryllidaceae alkaloids, such as the Alzheimer’s medication galantamine, are currently extracted from low-yielding daffodils. Here, authors pair biosensor-assisted screening with machine learning-guided protein design to rapidly engineer an improved Amaryllidaceae enzyme in a microbial host.

Here the authors develop a single molecule array (Simoa) immunoassay for detection of SARS-CoV-2 nucleocapsid protein in venous and dried capillary blood as well as saliva. The assay shows good performance in symptomatic, asymptomatic, and pre-symptomatic PCR+ individuals.

Obesity is a global pandemic with limited treatment options. Here, the authors show evidence in mice that the mitochondrial uncoupler BAM15 effectively induces fat loss without affecting food intake or compromising lean body mass.

A new DNA analysis method termed long fragment read technology is described, and the approach is used to determine parental haplotypes and to sequence human genomes cost-effectively and accurately from only 10 to 20 cells.

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.

Understanding the effect of vaccination on emerging SARS-CoV-2 variants of concern is of increasing importance. Here, James et al. report that two doses of vaccination with the Pfizer-BioNTech vaccine induce more robust immune responses to the B.1.1.7 and B.1.351 SARS-CoV-2 lineages than does natural infection.

A mechanism of lipid transport inhibition has been identified for a class of peptide antibiotics effective against resistant Acinetobacter strains, which may have applications in the inhibition of other Gram-negative pathogens.

Sepsis induces a period of immunosuppression which can be problematic in the face of subsequent infectious challenge. Here the authors show the presence of PD-L1 expressing regulatory plasma cells that can inhibit T cells in a murine model and in patients with sepsis.

Vyas et al. show that epicardial adipose tissue is a reservoir for a subpopulation of tissue-resident memory T cells that can increase the vulnerability of the heart to atrial fibrillation.

Transcriptional profiling of 61,052 cells undergoing epithelial-to-mesenchymal transition (EMT) shows continuous waves of gene regulation, not discrete stages. A CRISPR screen orders EMT regulators along EMT progression.

The natural antisense transcript MAPT-AS1 interferes with translation of mRNA transcript into tau protein in the brain and may represent a general mechanism for controlling levels of intrinsically disordered proteins, with particular relevance for neurodegeneration.

There are currently two types of antiviral drugs – neutralizing antibodies and small molecule inhibitors. Here, the authors report the development of bicyclic peptides that combine the advantages of both and show their antiviral capacity against SARS-CoV-2 in vitro as well as in small animal models.

Primary biliary cirrhosis is an autoimmune liver disease with poor therapeutic options. Here Cordell et al. a perform meta-analysis of European genome-wide association studies identifying six novel risk loci and a number of potential therapeutic pathways.

Here, the authors identify a broadly neutralizing antibody from an HIV-infected person that recognizes the membrane-proximal external region (MPER) of HIV envelope glycoprotein (Env) and has a short CDRH3 and low polyreactivity. Structural analysis shows how the antibody binds the MPER and Env on the viral membrane.

Genomic and transcriptomic analyses of chronic lymphoproliferative disorder of natural killer cells identifies somatic gain-of-function mutations in the chemokine gene CCL22 with cell-extrinsic effects. Mutations caused biased signaling downstream of the G-protein-coupled receptor for CCL22 and deregulated interactions with the hematopoietic microenvironment.

Two screening approaches converge on capzimin, a first-in-class inhibitor of the Rpn11 protease component of the 19S proteasome. Capzimin stabilizes polyubiquitinated substrates, induces the unfolded protein response, and blocks proliferation of cancer cells.

How bone-related sexually dimorphic traits are regulated hasn’t been examined at the stem cell level. Here the authors show that skeletal stem cells (SSC), in female but not male mice, are directly controlled by estrogen signaling, which could be augmented to improve fracture repair.

Binge drinking is a rising issue in women, yet the underlying neurobiology remains underexplored. Here authors show the Edinger-Westphal (EWcp) peptidergic neurons as a critical regulator of binge drinking in female mice via actions at the ghrelin receptor (GHSR).

Genomic evidence reveals that Mycobacterium ulcerans recovered from Aedes notoscriptus mosquitoes are genetically identical to bacteria from possums and humans, implicating mosquitoes as a vector for Buruli’s ulcer transmission in southeastern Australia.

We find that bile salt hydrolase N-acyltransferase activity can form bacterial bile acid amidates that are positively correlated with the colonization of gut bacteria that assist in the regulation of the bile acid metabolic network.

In this study, Giron et al. find that people living with chronic HIV experience accelerated aging-associated alterations in antibody glycans. These alterations, attributed to senescence enzymes, predict comorbidities and reduce the antiviral function of antibodies.

Unravelling the molecular basis of hypertension remains a major challenge. Here, the authors identify the transcription factor GATA5 as a novel regulator of blood pressure and potential genetic determinant of human hypertension and describe a unique mouse model for research of salt-sensitive hypertension.

A new method facilitates high-throughput sequencing of the repertoire of immunoglobulin heavy-light chain pairs in human B cells.

A subcutaneous colon-specific niche consisting of colon epithelial cells, decellularized colon extracellular matrix and immunosuppressive nanofibres reduced inflammation in the gastrointestinal tract of mice with established ulcerative colitis.

Insufficient AHR activation has been suggested in SLE, and augmenting AHR activation therapeutically may prevent CXCL13⁺ T_PH/T_FH differentiation and the subsequent recruitment of B cells and formation of lymphoid aggregates in inflamed tissues.

Whole-genome sequencing of human cancer cells in patient-derived mouse xenograft models indicates a key role for TP53 in determining the fitness landscape of polyclonal cancer cell populations.

Transcriptome mining, phylogenetic analysis, bioimaging and serology experiments reveal a widespread diverse virome present in ~70% of parasitic nematodes, such as Brugia malayi and Onchocerca volvulus, where some viruses are abundant in the reproductive tract and are associated with seropositivity in vertebrate hosts.

Mechanisms underlying tumor cell plasticity remain poorly understood. Here, the authors show the presence of a dormant-invasive SOX10- subpopulation in cutaneous melanoma that can be targeted by cIAP1/2 inhibitors.

A machine learning isolation and genotyping platform enable high-throughput bacterial culture generation.

Treatment with a specific inhibitor of the N⁶-methyladenosine methyltransferase METTL3 leads to reduced growth of cancer cells, indicating the potential of approaches targeting RNA-modifying enzymes for anticancer therapy.

Current influenza vaccine approaches largely focus on highly variable epitopes with high immunogenicity or epitopes of low variability that often have low immunogenicity. Here, Thompson et al. identify a highly immunogenic epitope of limited variability in the head domain of the H1 haemagglutinin and show protection from diverse H1N1 strains in mice.

HIV-1 vaccine design aims to induce broadly neutralizing antibodies such as IOMA, the only described antibody in its class. Here, the authors present the isolation, characterisation and structure of three additional antibodies within the IOMA class

Caenorhabditis elegans has the potential to be used to discover new, biologically active small molecules in a high-throughput fashion and also to identify the protein targets of those small molecules.

Evidence from trials suggests SARS-CoV-2 binding antibody thresholds could serve as surrogate markers of neutralising capacity, but whether this is accurate in the context of variants of concerns, or in the event of prior infection or vaccination remains unclear. Authors explore the performance of receptor binding domain IgG thresholds in predicting a level of neutralising capacity that has demonstrated protection against infection in vaccine trials

R9AP is a key receptor for entry of Epstein–Barr virus into human epithelial and B cells, and interacts directly with the viral glycoprotein gH/gL complex to mediate virus–host membrane fusion.

Two-photon fluorescence gives a quadratic response, which improves imaging in thick samples but requires extremely intense illumination. Here, the authors describe two-step fluorescent imaging, a much lower intensity approach to quadratic excitation, via reversible photoswitchable fluorophores.

Blockade of ERK signaling in KRAS-mutant pancreatic cancer increases the dependence on autophagic flux through different mechanisms and provides a rationale for combinatorial targeting with autophagy inhibitors.

Results are presented that indicate that alterations to gene regulatory three-dimensional architecture are a critical mechanism that enables structural variant-based oncogene activation in cancer genomes and sheds light on the essential elements for such gene activation events.

CrY2H-seq, a Cre recombinase reporter-mediated yeast two-hybrid method coupled with next-generation sequencing, enables ultra-high-throughput screening of transcription factor interactions in Arabidopsis thaliana.

Watson et al. demonstrate that astrocyte mitochondria can be horizontally transferred to glioblastoma cells in a GAP43-dependent manner, leading to changes in mitochondrial respiration and metabolism that promote proliferation and tumor growth.

The histone demethylase KDM6B is reported to be essential for neuroblastoma cell survival. Here the authors show that KDM6B regulates CDK4/6-pRB-E2F pathway through H3K27me3-dependent enhancer-promoter interactions in neuroblastoma.

Here the authors show that lowering IGF-1R levels in endothelial cells improves insulin sensitivity, boosts energy use, and supports beneficial changes in adipose tissue, offering insights into potential treatments for obesity-related metabolic disorders.

Andrew Johnston et al. present a genome-editing protocol for lymphoblastoid cell lines, using a single-stranded donor oligonucleotide strategy for ‘scarless’ editing. This protocol streamlines the genome-editing procedure used for lymphoblastoid cell lines by waiving the need for lentiviruses or stable transfection.

Circulating tumor cell (CTC) clusters are more efficient at mediating metastasis as compared to single cells and are associated with poor prognosis in breast cancer. Here, the authors show that ICAM1 is enriched in CTC clusters and its loss suppresses cell-cell interaction and CTC cluster formation, and propose ICAM1 as a therapeutic target for treating breast cancer metastasis.