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Early high-resolution images of two 2021 novae reveal eruptions unfolding in multiple stages with colliding outflows that produce shocks and gamma rays, reshaping our understanding of stellar explosions.

Pre-treatment dual immune checkpoint blockade in cervical cancer remains understudied. In this trial, the authors show that neoadjuvant immune checkpoint blockade enhances immune activation and correlates with improved response to subsequent chemoradiation in patients with cervical carcinoma.

Bohlen and colleagues report that the E3 ubiquitin ligase CBL is necessary for the development, tolerance and activation of B cells in humans, unlike in mice where CBL deficiency results in loss of T cells.

The emergence of SARS-CoV-2 variants resistant to neutralizing antibodies poses a constant threat. Here, the authors identify a camelid antibody targeting ACE2 which broadly inhibits infection and provides antiviral protective effects in vivo after nasal inoculation.

Results from the randomized ProfiLER-02 trial, which compared two gene panels in guiding molecular-based treatment in patients with solid tumors, show that a broader gene panel led to more molecular-based recommended therapies compared to a more limited gene panel.

Single domain antibodies block tau entry into neurons, a key step in tau propagation in the brain in Alzheimer’s disease. They prevent tau from binding to surface receptors by competition. The most effective, VHH H3-2, has a unique binding mode to tau.

Single-agent maintenance PARP inhibition may represent an effective strategy for advanced/metastatic endometrial cancer treatment. Here this randomized phase IIb UTOLA trial evaluates the efficacy and safety of orally administered olaparib in female patients (n = 145) without progression following front-line platinum-based chemotherapy for advanced/metastatic endometrial cancer.

Immune checkpoint blockade could improve the complete cytoreduction rate with standard-of-care neoadjuvant chemotherapy (NACT) in patients with ovarian cancer. Here the authors report the results of a randomized phase II trial of NACT alone or in combination with pembrolizumab (anti-PD1) in patients with advanced high-grade serous carcinoma.

Cyclophilins play a key role in the life cycle of many viruses and represent important drug targets for broad-spectrum antiviral therapies. Here, the authors use fragment-based drug discovery to develop non-peptidic inhibitors of human cyclophilins with high activity against replication of a number of viral families.

Changes in the tumour microenvironment have been associated with response and resistance to immunotherapy. Here, by performing longitudinal transcriptomic and spatial analysis, the authors report the exploratory analysis of their phase II trial of neoadjuvant chemotherapy alone or in combination with pembrolizumab (anti-PD1) in patients with advanced high-grade ovarian carcinoma.

Activation of the PPARγ/RXRα pathway in luminal bladder cancers has mainly been linked to PPARG gene amplifications and activating point mutations in RXRα. Here, the authors identify recurrent PPARγ mutations with similar effects and elucidate the structural basis for this mutational PPARγ activation.

How complex organics form in a prebiotic world remains a missing key to establish where life emerged. The authors present a road to abiotic organic synthesis and diversification in hydrothermal contexts involving magmatism and rock hydration.

We describe netrin-1 upregulation in a majority of human endometrial carcinomas and demonstrate that netrin-1 blockade, using the anti-netrin-1 antibody NP137, is effective both in a mouse model and in patients with endometrial carcinomas.

To consider the impact of sex on adaptation to space, the European Space Agency initiated VIVALDI dry immersion microgravity simulation in female subjects. Here, the authors show marked deconditioning with 5-day exposure, and propose comprehensive multi-system physiological assessment in 18 healthy women.

A spinal cord neuroprosthesis targeting leg motor neurons in real time improves walking and reduces freezing of gait in non-human primate models and in one individual with advanced Parkinson’s disease.

Fast charging is driving extensive research on enhanced electrodes for high-performance electrochemical capacitors and micro-supercapacitors. Thick ruthenium nitride pseudocapacitive films are shown to exhibit enhanced capacitance with a time constant of less than 6 s.

The calcium binding protein S100B is an abundantly expressed protein in the brain and has neuro-protective functions by inhibiting Aβ aggregation and metal ion toxicity. Here, the authors combine cell biology and biochemical experiments with chemical kinetics and NMR measurements and show that S100B protein is an extracellular Tau chaperone and further characterize the interactions between S100B and Tau.

Steve Brown and colleagues report an analysis of 20 phenotyping tests, including 413 data parameters, across 449 mutant mouse alleles. They identify widespread pleiotropy and assign putative functions to genes that lacked previous phenotypic annotation.

Nuclear receptors use DNA- and ligand-binding to regulate gene expression. Here, Maletta et al. report the first structural description of a full inverted repeat-bound nuclear receptor complex, which shows that the protein structure is asymmetric, despite the symmetry of the bound DNA.

Inhibiting insulin-degrading enzyme (IDE) has been proposed as a potential therapeutic strategy for the treatment of patients with diabetes. Here, the authors develop a novel IDE inhibitor but find that, surprisingly, IDE inhibition has negative effects on glucose tolerance in mice.

New X-ray crystal structure and immunoanalyses of alanyl aminopeptidase N (AnAPN1), a gut antigen of the Anopheles mosquito vector of Plasmodium falciparum, reveal how AnAPN1-specific antibodies block transmission of the malarial parasite.

Human protein ANP32E is a histone chaperone that promotes removal of H2A.Z from chromatin.

Sedimentary DNA can be used to infer how organisms responded to changing environmental conditions over millennia. Here, the authors use sedimentary DNA of micro-eukaryotes in low-elevation (human-impacted) and high-elevation (more pristine) lakes to show how human influences have altered lake community composition in the Anthropocene.

Different proteins localised at telomeres ensure chromosome end stability to prevent double strand-end break recognition. Here the authors provide new insight into how in S. cerevisiae the interaction between Rif2 and Rad50 inhibits MRX functions at telomeres.

In the arena of strained heterocyclic chemistry, phosphacycles as appealing electrophilic P-containing building blocks are underestimated. Here, the authors report a class of electrophilic phosphiranium salts bearing fluorinated benzyl quaternizing groups for the direct synthesis of diverselyβ-functionalized phosphines.

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.

Accumulating evidence suggests that disruption of autophagy is associated with neurodegeneration. Here the authors show that Plekhg5 acts as a GEF for Rab26, a small GTPase that promotes the autophagy of synaptic vesicles in neurons; mice lacking Plekgh5 develop late-onset motoneuron degeneration.

Spatially selective and temporally controlled stimulation of the spinal cord, together with rehabilitation, results in substantial restoration of locomotor function in humans with spinal cord injury.

In 2016, novel findings on the role of predisposing gene variants in sarcoma oncogenesis were published, as well as studies addressing novel molecular classifications and results from randomized controlled trials highlighting successful new treatments. Herein, we discuss these meaningful advances.

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disease resulting in reduced mucus clearance and impaired lung function. Here, the authors show that mutations in PIH1D3 are responsible for an X-linked form of PCD, affecting assembly of a subset of inner arm dyneins.

Christer Betsholtz, Christine Klein, Maria Sobrido and colleagues report the identification of mutations in the gene encoding PDGF-B that cause idiopathic basal ganglia calcification. They also show that mice carrying hypomorphic Pdgfb alleles develop brain calcifications.

Francois Le Loarer, Franck Tirode and colleagues identify a new class of undifferentiated thoracic sarcomas characterized by inactivation of SMARCA4, which encodes an ATPase subunit of BAF chromatin-remodeling complexes. They further show that these tumors exhibit transcriptional profiles similar to those of other BAF-deficient malignancies.

Mice deficient in the lipid sensor GPR120 develop obesity, glucose intolerance and fatty liver when fed a high-fat diet, and a loss-of-function variant in the GPR120 gene strongly contributes to increased obesity in human.

X-ray science at modern Synchrotrons and X-ray Free Electron Laser facilities are enabling the study of subtle structural changes of matter from the single atom to the macroscopic scale. This paper reviews new concepts in synchrotron storage rings design and reports on the successful commissioning and operation of the new X-ray storage ring of the European Synchrotron Radiation Facility (ESRF) in Grenoble.