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Influenza virus neuraminidase (NA) is a drug target and a potential vaccine antigen. Here, the authors provide a detailed analysis of the conformational stability of NA, and show how expression and stability of recombinant NA antigens can be strengthened through structure-based design.

Antibody Mediated Prevention (AMP) trials showed that the broadly neutralizing antibody VRC01 could prevent some HIV-1 acquisitions. Here the authors use VRC01 levels and the sensitivity of each acquired HIV virus to predict viral loads in the AMP studies and show that VRC01 influenced viral loads, though potency was lower in vivo than expected.

Different neoadjuvant therapies have been proposed to improve immunotherapy for cancer treatment. Here, the authors perform a phase Ib clinical trial where an agonist OX40 antibody provided prior to surgery is well tolerated and increases proliferation and activation of tumor antigen-specific T cells in head and neck cancer patients.

A dataset of 3D images from more than 200,000 human induced pluripotent stem cells is used to develop a framework to analyse cell shape and the location and organization of major intracellular structures.

Chondroitinase injections into monkey spinal cords 4 weeks after hemisection injury increased corticospinal axon growth and corticospinal synapse formation and improved functional outcomes.

Structural analysis reveals the iron scavenging mechanism used by Neisseria species, involving TbpA and TbpB proteins, and sheds light on how human transferrin is specifically targeted.

A study demonstrates that sustained membrane blebs in cancer cells recruit curvature-sensing septins that form plasma membrane-proximal signalling hubs that promote cancer cell survival.

A pyrrolidine-based small-molecule inhibitor competes with H3K27me3 for binding to EED leading to inactivation of PRC2 and global reduction in H3K27me3 levels.

Tropical forests store vast amounts of carbon that might be liberated as temperatures increase. A 2-year experiment of tropical forest soil warming reveals that microbial diversity is reduced, but enzyme activity is increased, resulting in CO₂ emissions threefold greater than modelling predicts.

Tumors can overproduce pro-angiogenic ligands overcoming currently approved anti-angiogenic therapies and hindering their success. Here, the authors show that targeting phosphoinositide recycling during tumor angiogenesis harnesses the tumor’s own production of angiogenic ligands to deplete adjacent endothelial cells of the capacity to respond to these signals.

Mixed responses to targeted therapy within a patient are a clinical challenge. Here the authors show that TP53 loss-of-function cooperates with whole genome doubling which increases chromosomal instability. This leads to greater cellular diversity and multiple routes of resistance, which in turn promotes mixed responses to treatment.

Cells under environmental stress, including viral infections, accumulate RNA molecules stalled in pre-initiation complexes known as stress granules (SG). Here the authors show that the viral protein Gag counters anti-viral stress responses by inhibiting SG assembly during HIV-1 infection.

Brain tumor initiating cells (BTICs) are self-renewing, tumorigenic cells that often reside in a necrotic and hypoxic niche in the brain. Here the authors show that BTICs can become more tumorigenic upon glucose restriction and compensate for this cellular stress by upregulating their capacity to take up glucose.

Short- and long-term cultures of human stem-cell-derived neurons reveal that a pattern of restricted selection of clustered protocadherin isoforms, pre-established in pluripotent cells, distinguishes immature from mature neurons.

Getting synthetic biology circuit-based sensors into field applications is still a challenge. Here the authors combine a circuit sensor with a glucose meter for small analyte and nucleic acid detection.

Gene fitness and essentiality analyses using in vivo cancer models are challenging due to multiple confounders. Here, the authors develop a quantitative approach to study CRISPR-transduced patient-derived xenografts, which they use to analyse in vivo gene fitness in breast cancers and the biological features that influence uncertainty in fitness estimation.

In this study, the authors show that NgR1 and NgR3 can act as functional receptors for chondroitin sulfate proteoglycans (CSPGs), mediating inhibition of axonal growth and regeneration. This suggests a convergent mechanism for CSPG- and myelin-associated inhibitor activities after axonal injury in the CNS.

Here, Hiatt et al. report the knock-out of over 400 genes in primary CD4+ T cells to assess their functional role in HIV replication, finding 86 initial candidates of which 47 are validated as HIV host factors, including 23 with restrictive activity.

Spin-crossover molecules offer a potential route towards molecular spintronics, but retaining the bistability of the spin state upon surface deposition is challenging. Here, the authors study the spin-crossover behaviours of an Fe(II) complex deposited on graphite, determining the scale limit at which cooperative spin switching becomes effective.

Large-scale loss-of-function screens and TP53 saturation mutagenesis screens in human cancer cell lines suggest that mutational processes combine with phenotypic selection to shape the landscape of somatic mutations at the TP53 locus.

Single-cell DNA sequencing identifies recurrent copy number changes in healthy breast tissue from women with wild-type or germline BRCA1 or BRCA2 mutations.

How cells respond to denaturation of extracellular protein domains remained largely unknown. Here, authors describe an aggregation-dependent endocytosis pathway, facilitating uptake and degradation of antibody- and stress-induced protein aggregates.

Circadian clocks are critical timing regulators of physiology and behaviour that are ubiquitous in eukaryotes. Most mechanistic models of the this clock are based on transcription cycles, but some evidence for post-translational regulation has recently surfaced in plants and cyanobacteria. This is one of two groups demonstrating a role for the oxidation of peroxiredoxin proteins in maintaining an entrainable oscillation in human red blood cells and a unicellular alga. These data indicate a role for non-transcriptional mechanisms in clock models and open the door to future work exploring the connections between the transcriptional and non transcriptional circadian machinery.

Effective anti-PD-1 immunotherapy is associated with the presence of polyclonal CD8⁺ T cells in the tumour and blood specific for a limited number of immunodominant mutations, which are recurrently recognized over time.

The de novo design of functional membrane proteins is a formidable challenge. Now, water-soluble peptides have been designed that assemble into α-helical barrels with accessible, polar and hydrated central channels. Insights from these structures have been used to produce stable membrane-spanning, cation-selective channels.

In Staphylococcus epidermidis and Staphylococcus aureus, non-specific DNase activity of the type III-A CRISPR–Cas system increases the rate of mutations in the host and accelerates the evolution of resistance to antibiotics and to phage.

One of the main hurdles to curing HIV infection are viral reservoirs. Here, the authors develop a trispecific antibody and demonstrate its ability to simultaneously activate and target latently HIV−1 infected cells for elimination by T cells as an alternative strategy for HIV cure.

A technique for the de novo design of switchable protein systems controlled by induced conformational change is demonstrated for three functional motifs, in vitro and in yeast and mammalian cells.

Clonal haematopoiesis has been thought to occur in less than 10% of individuals younger than 70 years old. Here, the authors use an error corrected next-generation sequencing method to find clonal haematopoiesis in the peripheral blood of 19 of 20 healthy 50–70 year old individuals.

COVID-19 booster immunizations aimed at spike protein from new SARS-CoV-2 variants induce robust germinal centre B cell responses against the original spike protein, as well as de novo B cell responses against the variant spike protein.

Urine can be used to easily analyse the health of patients. Here, the authors identify proteins in urinary extracellular vesicles that distinguish prostate cancer from benign lesions.

Cytidine nucleotide triphosphate (CTP) is a key precursor involved in the metabolism of DNA, RNA and phospholipids. In this study, the authors examine the physiological consequences of CTP synthase (Ctps) 1 and 2 deletion in vivo and demonstrate that Ctps1 protects mice from fatal autoimmunity.

Transition metal dichalcogenide bilayers offer a novel platform for studying correlated electron-hole fluids. Here the authors use optical spectroscopy to probe thermodynamic properties of coupled electron-hole states in MoSe₂/hBN/WSe₂ heterostructures, providing evidence for an excitonic insulator ground state.

Laszlo et al. demonstrate sequence alignment, and proof-of-concept organism identification, genome assembly and polymorphism detection from nanopore analysis of natural DNA.

Many aspects of polariton condensate behaviour can be captured by mean-field theories but interactions introduce additional quantum effects. Here the authors observe quantum depletion in a driven-dissipative condensate and find that deviations from equilibrium predictions depend on the excitonic fraction.

Humans that reach high altitude soon after the first ascent show faster adaptation to hypoxia. Songet al. show that this adaptive response relies on decreased red blood cell uptake of plasma adenosine due to reduced levels of nucleoside transporter ENT1 resulting from coordinated adenosine generation by ectonucleotidase CD73 and activation of A2B receptors.

Cryo-electron microscopy structures of the human lysosomal transmembrane protein LYCHOS show that it comprises a transporter-like domain fused to a G-protein-coupled receptor, and that the transporter domain is similar to the plant PIN family.

Morey and colleagues identify a dual function of CoREST in regulating sensitivity and resistance to endocrine therapies in breast cancer. This work also provides a pre-clinical model for study of the conversion of luminal/ER⁺ to basal/ER⁻ breast cancer.

Emerging SARS-CoV-2 variants raise concerns on immune evasion. Here, the authors evaluate the neutralization efficiency of COVID-19 mRNA vaccinee sera against representative viruses of 13 WHO-designated SARS-CoV-2 variants of concern/interest.

Glucocorticoid resistance is partly due to epigenetic alterations, but the regulatory mechanisms driving these remain poorly understood. Here, a link between the activity of a lineage-specific transcription factor PU.1 and epigenetic modulators mediating the response to glucocorticoids is described in acute lymphoblastic leukemia.

Modifying an E2 ubiquitin-conjugating enzyme with a binding domain creates an encodable strategy for driving targeted protein degradation within eukaryotic cells.

Zika virus infection of pregnant women is associated with congenital neurological disorders. Here, Vermillionet al. develop an immunocompetent mouse model for identification of factors at the maternal-fetal interface that contribute to adverse perinatal outcomes.

Small molecule antagonists of CCR6 are potential drugs for autoimmune disorders. Here the authors present inactive structures of CCR6 bound by different allosteric antagonists from two series simultaneously, offering multiple approaches to inhibit CCR6.

Lanthanides are in high global demand and a sustainable extraction practice is needed to keep pace. Here, Huang and colleagues reengineer fluorescent protein surface charges to bind and detect lanthanides.

Snakebite envenoming remains a critical global health issue due to the diverse antigenic profiles of snake venoms. Here, the authors develop a long-chain consensus α-neurotoxin to identify broadly neutralising heavy-chain-only antibodies, demonstrating structural mechanisms behind the broad neutralization and in vivo potential.

Reprogramming has been shown to involve EMT-MET; however, its role in cell differentiation is unclear. Here the authors show that duringin vitrodifferentiation of hepatocytes, Activin A-induced formation of definitive endoderm requires EMT mediated by TGFβ signalling, followed by a MET process.

Although amorphous calcium carbonate represents an important biomineralization precursor, its structure has been difficult to understand. Now, amorphous calcium carbonate’s structure is shown to arise from the different bridging modes available to the calcium ions. This effective multi-well potential that drives calcium arrangements creates a geometric incompatibility between preferred Ca–Ca distances and frustrates crystallization.