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A study finding an oestrogen-sensing signalling pathway that promotes melanoma metastasis only in female mice emphasizes the importance of recognizing sex-specific factors in cancer management.

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.

Analysis of genomic data from 981 colorectal cancers from participants in 11 countries reveals variations in mutational signatures of microsatellite-stable cancers that are dependent on geographical origin and age at which the cancer was diagnosed.

MacDonald et al. show that EGF triggers de-sialylation of plasma membrane glycoproteins like integrins in a mechanism that depends on the Na⁺/H⁺ antiporter NHE1 and the neuraminidases Neu1 and Neu3. Integrins are trafficked to the Golgi and re-sialylated.

Taniguchi et al. structurally analyse nuclear pore complex architecture in situ during differentiation, which is associated with mechanical constraints on the nuclear envelope. They link nuclear pore complex elasticity to nuclear envelope integrity in differentiation.

Here, integrating ribosome profiling, RNA-seq and proteomics to reveal transcriptional and post-translational regulation in HIV-infected T cells, the authors show that non-AUG translation of viral upstream ORFs elicits distinct immune responses and regulates viral gene expression in a DDX3-dependent manner.

A cluster randomized trial in Tanzania showed that the implementation of a decision support algorithm decreased antibiotic prescriptions to children considerably, without impacting clinical outcomes.

Epigenetic coregulators ENL (eleven-nineteen-leukemia) and MOZ (monocytic leukemia zinc finger) are implicated in leukemias. Here, the authors report the acetylation-dependent and acetylation-independent mechanism for the ENL–MOZ complex formation and show the colocalization of ENL and MOZ at active promoters.

HIV remission was achieved for 32 months after allogeneic hematopoietic stem cell transplantation with wild-type CCR5 donor cells.

In a phase 2 trial, the oral type II RAF inhibitor tovorafenib exhibited an overall response rate of 67% in patients with BRAF-altered relapsed/refractory pediatric low-grade glioma.

Here, the authors show that there is a pretumorigenic T_H17 subset in the intestines that can convert to being tumorigenic under the control of KLF6 and that this process can be prevented by TGFβ1 production from intestinal epithelial cells.

Enzyme promiscuity seeds evolutionary innovation, but how flexible a single enzyme can be (re-)used during evolution remains unclear. Here, the authors show that various evolutionary trajectories applied to succinate semialdehyde dehydrogenase can compensate for the loss of two different functions in E. coli.

HIV-1 can be transmitted by infected cells in body fluids and an efficient prophylaxis should prevent this. Here the authors show that the HIV-1 antibody 10-1074, when applied as topical vaginal gel, inhibits cell-associated transmission in non-human primates.

A rare sub-population of people living with HIV-1 experience long-lasting viral remission after interrupting antiretroviral therapy and are considered post-treatment controllers. Here the authors characterise the humoral immune response to HIV-1 in a cohort of post-treatment controllers.

Exposing cerebral organoids and post-mortem brain explants to SARS-CoV-2 virus particles alters expression of synaptic proteins and potentially affects synaptic function by blocking LPHN3 and FLRT3 synapses.

Sjögren’s syndrome, a disease that primarily affects women, is poorly understood. Here, the authors combine data from a large cohort of patients and healthy controls to identify biomarkers that distinguish patient subgroups to improve our understanding of the disease and facilitate drug development.

Lifespan can be affected by both physiological ageing and specific sets of pathologies associated with old age. Here the authors report a resource of large-scale cross-sectional phenotyping of aging male mice at different time points to analyse a large set of phenotypes and molecular markers, including during genetic and diet interventions affecting lifespan.

An HLA- and gluten-dependent mouse model of coeliac disease with villous atrophy provides evidence for the cooperative role of IL-15 and gluten-specific CD4⁺ T cells in licensing the full activation of cytotoxic T cells that are necessary for inducing epithelial damage.

HIV remission has been seen in people living with HIV after the cessation of antiretroviral therapy and is termed post treatment control. Here Passaes and colleagues present an SIV model that shows early initiation of antiretroviral therapy after SIV infection is linked to improved post treatment control upon cessation of antiviral therapy and associates with the expansion of an enhanced memory pool of CD8 + T cells‘.

Natural buffer molecules ensure the controlled and precise delivery of specific molecules in biology. Here, the authors replicate the natural buffer systems using aptamers with controlled binding efficiency to control and maintain the levels of free drugs both in vitro and in vivo.

Defective viral genomes (DVGs) can interfere with virus replication and provide a potential approach to control infection. Here, Rezelj et al. use a combined experimental evolution and computational approach to identify DVG sequences that optimally interfere with Zika virus infection and show antiviral activity in mice and mosquitoes.

Multiple variants of SARS-CoV-2 are inhibited by a trispecific DARPin.

What is the role of disorder in non-homologous end-joining proteins? The authors use nuclear magnetic resonance to reveal that disordered regions mediate a network of multivalent interactions, promoting biomolecular condensation that accelerates DNA ligation kinetics.

Non-small cell lung cancer with EGFR mutations are known to develop resistance to EGFR tyrosine kinase inhibitors. Here, the authors show AURKB activation to be associated with resistance in EGFR mutant lung cancer cells, and that AURKB is a therapeutic target in resistant tumours that lack the p.T790M or other acquired mutations.

Transcription of RNA polymerase II is coupled with remodeling of chromatin. This study reports that transcription of RNA polymerase II is also required to prime and maintain nucleosome depletion at RNA polymerase III loci.

Broadly neutralizing antibodies (bNAbs) are promising as potential therapies targeting HIV-1 but their overall antiviral activity remains to be fully elucidated. Here the authors evaluate the ability of a panel of bNAbs to trigger antibody-dependent cellular cytotoxicity and identify the most effective antibody combinations.

The absence of scaffold protein Ambra1 leads to hyperproliferation and growth in mouse models. Here the authors show that Ambra1 deficiency accelerates melanoma growth and increases metastasis in mouse models of melanoma through FAK1 hyperactivation.

Here the authors generate a measles virus-based vaccine expressing SARSCoV-2 spike protein and show immunogenicity and protection in mice and hamsters, including neutralization of circulating variants of concerns in vitro.

Endocrine-disrupting chemicals act on nuclear hormone receptors, such as PXR. Here, Delfosse et al. show how two such chemicals interact with each other in the PXR ligand-binding pocket, forming a so-called supramolecular ligand that is a more potent PXR activator than each of the two chemicals alone.

Broadly neutralizing antibodies (bNAbs) neutralize HIV-1 and exert Fc-dependent activities against infected cells. Here, Dufloo et al. show that bNAbs also block HIV-1 release by trapping viral particles at the surface of infected cells.

Tougeron et al. evaluate the prognostic value of circulating tumor DNA (ctDNA) in predicting the efficacy of immune checkpoint inhibitors (ICI) plus chemotherapy in advanced gastric adenocarcinoma. An early decrease in ctDNA concentration is associated with a worse objective response rate, shorter progression free survival and overall survival.

STIM proteins sense Ca²⁺ depletion in the ER and activate store-operated Ca²⁺ entry in response, a process associated with dendritic cell (DC) functions. Here, the authors show that optimal antigen cross-presentation in DCs requires the association of the chaperone molecule UNC93B1 with STIM1.

Myeloperoxidase conversion of H₂O₂ to less-diffusible HOCl limits bystander host damage without comprising antibacterial activity during Salmonella infection.

Epithelial tuft cells secretion of IL-25 is shown to regulate type 2 epithelial responses to helminth parasite infection via an IL-13/IL-4Rα-dependent feedback loop.

A limited percentage of patients with non-small cell lung cancer respond to immunotherapy. Here the authors show that HEI3090, a chemical positive modulator of the purinergic P2RX7 receptor, promotes IL-18 mediated anti-tumor immune responses and sensitizes lung cancer to anti-PD-1 therapy in preclinical models.

Comprehensive genomic profiling of human H3K27M mutant diffuse midline gliomas, combining single-cell RNA sequencing and ATAC sequencing with bulk ChIP sequencing and other data, proposes distinct oligodendrocyte populations as potential cells of origin.

Goudreault et al. investigate the role of Afadin downstream of RAS GTPases, substantiating this cell adhesion protein as a true RAS effector that couples its activation to cell polarity through the Scribble protein.

BRCA2-deficient cells fail to complete replication in S-phase, which results in DNA bridges and chromosome mis-segregation at mitosis. Here the authors show that MUS81 helps BRCA2-deficient cells survive replication stress by activating mitotic DNA synthesis and resolving mitotic DNA bridges.

Quail and colleagues demonstrate that neutrophil-derived ROS and extracellular traps (NETs) mediate breast cancer metastasis to the lungs by altering endothelial junctional adhesions, thus favoring vascular permeability and transendothelial migration of cancer cells.

Rat H-1 parvovirus (H-1PV) is in clinical development for oncolytic therapy. Here, Kulkarni et al. identify LAMC1 as a modulator of H-1PV cell attachment and entry and find that LAMC1 levels and H-1PV oncolytic activity correlate in 59 tested cancer cell lines.

Bantscheff et al. use chemoproteomics to measure the affinity of small molecules for megadalton protein complexes in cell extracts. Differences in the selectivity of HDAC inhibitors observed when native HDAC complexes are compared with their purified catalytic subunits suggest the limitations of using isolated recombinant proteins in certain drug screens.

Analyses of primary and relapse samples of embryonal tumours with multilayered rosettes provide insights into the molecular mechanisms that underlie the development and opportunities for the treatment of this deadly disease.

An observational study of more than 13,000 healthcare workers shows that a prime–boost vaccine regimen of AstraZeneca ChAdOx1-S-nCoV-19 with Pfizer BNT162b2 provides enhanced protection against SARS-CoV-2 infection compared with two doses of BNT162b2.

Intranasally administrated fusion-inhibitory lipopeptides derived from the SARS-CoV-2 spike protect mice from different viral variants and induce cross-reactive immunity, offering a innovative antiviral approach against COVID-19

The authors developed small-molecule inhibitors of STOML3 oligomerization, a membrane protein that interacts with mechanosensitive ion channels, such as Piezo2. One of these molecules was effective in silencing touch receptors and reversed touch-evoked pain associated with nerve injury or diabetic neuropathy.

Myoepithelial cells considered terminally differentiated are now shown by Stingl and colleagues to have stem cell properties in vitro, to repopulate a mammary gland on transplantation and to behave as stem cells by lineage tracing.