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Langstein-Skora, Schmid, Huth et al. propose that intrinsically disordered region functionality can be driven by the interplay between linear binding motifs and contextual chemical characteristics such as charge and hydrophobicity.

Here the authors compare genetic testing strategies in rare movement disorders, improve diagnostic yield with genome analysis, and establish CD99L2 as an X-linked spastic ataxia gene, showing that CD99L2–CAPN1 signaling disruption likely drives neurodegeneration.

The Akt-mTOR axis influences cell activation, differentiation and metabolism. Jordan and colleagues show that thymic and inducible T_H17 cells exhibit different requirements for mTORC1 and mTORC2 as well as Akt isoforms.

The combination of within-species variation in pathogen load, the shape of the relationship between pathogen load and infectiousness, and vector feeding preferences shape transmission of multi-host vector-borne pathogens. Here, the authors use experimental and wild bird infection data to characterize the role of 17 host bird species in avian malaria transmission in Hawaii.

Drug-controlled DROP-CARs enable reversible extracellular control of CAR T cell function via human-derived protein switches that modulate cell–cell interactions and support dual-antigen targeting as well as logic-gated signaling.

Expression of agouti signalling protein in neurons in the medial preoptic area is increased by group housing and negatively associated with care, and overexpression of Agouti reduces care and enhances infanticide in previously tolerant mice.

The HIV-1 RNA-binding protein rev facilitates nuclear export of viral RNA. Here, the authors use native mass spectrometry to study the interactions between rev-derived peptides and rev response elements of HIV-1 RNA, providing mechanistic insights into rev recognition and recruitment.

KRAS mutations are keenly associated with pancreatic ductal adenocarcinoma and represent a potential therapeutic target. Here the authors present the findings from a phase I clinical trial testing pooled KRAS mutant peptides in combination with immune checkpoint blockade in patients with resected pancreatic ductal adenocarcinoma.

A pangenome of the Cannabis genus including 193 genomes demonstrates high variability in most of the genome but low diversity in cannabinoid synthesis genes and provides a resource for future genetic studies and crop optimization.

After spinal cord injury, lesion-remote astrocytes acquire heterogeneous, spatially restricted reactivity states that shape neuroinflammation, neural repair and neurological recovery.

There are limited vaccines available for Ebola virus and none for broad protection from filoviruses. Here, the authors rationally design vaccines using nanoparticles and stabilized Ebola virus and other filovirus glycoproteins, characterize antibody epitopes and profile lymph node and antibody responses in mice.

Combining time-resolved IR spectroscopy, activation energy analyses, and computations, authors provide mechanistic insight into genetically altered reaction kinetics of light-driven oxygen evolution in photosystem II.

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.

Disease course and pathology an infection may cause can change owing to the structural and functional physiological changes that accumulate with age, but therapy can be tailored accordingly; disease tolerance genes show antagonistic pleiotropy.

Saito et al. identify sphingosine kinase 1 as a critical regulator of physiological ductus arteriosus closure and pathological supravalvular aortic stenosis through its role in smooth muscle cell proliferation and propose potential therapeutics.

Whole-genome sequencing of polioviruses in Uganda following nOPV2 use showed high genetic stability and no sustained transmission, even though a rare double recombinant strain regained virulence, but did not spread due to high vaccination coverage.

The transcription factor ATF4 and its effector lipocalin 2 (LCN2) have a key role in immune evasion and tumour progression, and targeting the ATF4–LCN2 axis might provide a way to treat several types of solid tumour by increasing anti-cancer immunity.

Lo and colleagues report that double-positive thymocytes from neonates express less Zap70 and show reduced Ca^2⁺/NFAT signaling compared to double-positive thymocytes from older thymi. This diminished Ca^2⁺ signaling alters negative selection for self-reactive TCRs, resulting in a cell-intrinsic temporal window for regulatory T versus conventional T cell development in the thymus.

One of three back-to-back papers to show dosage of BACH2 can modulate T cell differentiation and function and how we might apply this to enhance chimeric antigen receptor T cell therapies for cancer.

Variants in the PSMC5 gene impair proteasome function and cellular homeostasis, altering brain development in children. This study reveals underlying molecular mechanisms contributing to this neurodevelopmental phenotype, and suggests therapeutic leads for neurodevelopmental proteasomopathies.

Long-term high-resolution data on social relationships, space use and microhabitat in a wild population of mice (Apodemus sylvaticus), accompanied by sampling of the gut microbiota, show that distinct sets of microorganisms dominate social and environmental transmission routes of microbiota. Microorganisms with low oxygen tolerance are more reliant on social transmission.

A new strategy that uses prime editing to convert an endogenous tRNA into a suppressor tRNA shows therapeutic potential for multiple genetic diseases that are caused by premature stop codons.

Polyamines prevent the action of kinases on acidic phosphorylatable motifs in spliceosomal proteins, thus providing a mechanism for metabolite-mediated regulation of alternative splicing in cells.

HIV-1 integrase forms an RNA-binding module on the luminal side of the mature capsid lattice.

Oxytocin promotes social behaviors, but its cortical targets remain unclear. Here, authors show that oxytocin activates local interneurons in the rat prefrontal cortex, enhancing sociability through top-down control of the basolateral amygdala.

Species with low genetic diversity have limited capacity to adapt to environmental change. This study finds that the skin microbiome and non-genetic (epigenetic) modifications of the DNA represent additional sources of variation that could help low diversity fish survive environmental challenges.

Despite recent advances in targeting RAS, resistance to anti-RAS therapies limits their effectiveness in KRAS-mutant lung cancer. Here, the authors show that RAS inhibitors impair wild-type KRAS degradation, leading to its accumulation and resistance through mTOR, and demonstrate that targeting mTOR or amino acid transport can overcome this resistance.

Here they show that the adhesion GPCR Gpr126/Adgrg6 regulates trabeculation during heart development. Its N-terminal fragment is required for maintaining cell adhesion and compact wall integrity while its C-terminal fragment is essential to provide trabecular identity.

PARM is a deep-learning model trained on data from massively parallel reporter assays to help predict promoter activity in different human cell types, design synthetic promoters and identify key features of regulatory promoter grammar.

Natural products inspire the development of pseudo-natural products through combinations of fragments of compound classes that are chemically and biologically distinct. Here, the authors report a library of 244 pseudo-natural products, evaluate them in the cell painting essays and identify the phenotypic role of individual fragments.

Human immunodeficiency virus (HIV)-associated gut microbiome dysbiosis correlates with systemic immunodeficiency and opportunistic gut infections. Faecal microbiome transplantation from people living with HIV with high peripheral CD4⁺ T cell counts improved intestinal immunity and protection against Cryptosporidium parvum in mice.

Peripartum cardiomyopathy (PPCM) is a potentially fatal heart condition with poorly understood molecular causes. Here, the authors show that loss of the protein PTRH2 in female mice leads to postpartum heart failure, identifying it as a potential therapeutic target.

Analyses of liver biopsies from a child with spinal muscular atrophy treated with adeno-associated virus gene therapy who developed hepatitis reveal contaminating manufacturing plasmids and disrupted vector genomes, possibly resulting from recombination events.

Maurice et al. examine how cytokines regulate antigen-independent activation of memory CD8⁺ T cells. They show that IL-4 signaling changes the quality of the bystander T cell response by antagonizing IL-18 sensing and subsequent IFNγ production, but increasing granzyme B expression without changing perforin, thereby limiting bystander-mediated protection.

Trends in global H₂ sources and sinks are analysed from 1990 to 2020, and a comprehensive budget for the decade 2010–2020 is presented.

PU.1^low CD28-expressing microglia may act as suppressive cells in Alzheimer’s disease, mitigating its progression by reducing neuroinflammation and amyloid plaque load, indicating potential immunotherapeutic approaches for treatment.

A high-resolution antigenic map of influenza A(H5) haemagglutinin (HA) enables the design of immunogenic and antigenically central vaccine HA antigens that elicit antibody responses broadly covering the A(H5) antigenic space.

Toxoplasma gondii can develop into dormant bradyzoites that persist in tissue and can be reactivated. Here the authors identify an RNA binding protein that they call Regulator of Cystogenesis 1 (ROCY1), and show that it is required for bradyzoite development in vitro and in vivo but is not required for long term persistence of parasites that reactivate in a mouse model of recrudescence.

Genetic factors affecting Aedes aegypti susceptibility to dengue virus infection aren’t well studied. Here the authors show that a cytochrome P450 gene, typically linked to cuticle structure and insecticide resistance, influences dengue infection in Aedes aegypti.

pOXA-48 plasmids have emerged as key vectors of carbapenem resistance within Enterobacteriaceae. In this study, the authors use a transposon sequencing (Tn-seq) approach to identify genetic determinants critical for plasmid stability and conjugative transfer.

Chronic infection with SARS-CoV-2 leads to the emergence of viral variants that show reduced susceptibility to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma.

A combination of large-scale phylogenomic analysis, mouse lethality experiments and bacterial growth assays shows that gene loss in the putrescine utilization pathway has enhanced biofilm formation and transmission-related characteristics in the pandemic clone of a bacterial pathogen, Vibrio parahaemolyticus, promoting successive waves of global transmission events.

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).

Our understanding of how post-translational modification—protein phosphorylation—impacts the complexity of eukaryotic signalling pathways is continuously expanding. Now, protein oligophosphorylation has been characterized as an additional phosphorylation mode. Structural and mass spectrometry methods revealed that NME1 catalysed its own oligophosphorylation, leading to altered protein–protein interactions.

The contribution of ether lipid species in cancer cell fate has not been fully understood yet. Here the authors show that malignant cancer cells employ ether lipids to modulate membrane biophysical properties, enhancing iron endocytosis and ferroptosis susceptibility.

The tumor suppressor RAD51C is mutated in ovarian cancers. Through variant analysis the authors identify a mutation cluster in the RAD51C Walker B region important for the repair of DNA double-strand breaks and replicative damage. By identifying Walker B separation-of-function alleles, they show that these activities can be uncoupled.