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Neoadjuvant immunochemotherapy against NSCLC has been tested in clinical trials. Here, the authors follow up longer-term survival and measure immune cell phenotype changes in a single-arm phase II clinical trial of neoadjuvant immunochemotherapy, indicating association of intratumoural TCR diversity and CD8 T cell positioning.

The insulin inhibitory receptor (inceptor) is found to bind to insulin and to regulate insulin stores by directing proinsulin and insulin towards lysosomal degradation.

It remains unclear whether colorectal cancer metastases in the liver arise from intermediate metastases in the lymph nodes or directly from the primary tumour. Enquist et al.demonstrate lymph node-independent metastasis using a mouse model in which tumours are transplanted directly onto the luminal surface of the colon.

Genome-wide association analyses of intracranial and nine subcortical brain volumes in 74,898 participants of European ancestry identify 254 independent loci and yield polygenic scores accounting for brain variation across ancestries.

Droplet chemistry is less susceptible to channel-fouling than single-phase flow chemistry, but is largely limited to simple reactions where all reagents are preloaded into droplets. Here, the authors report a method for multistep chemistry in droplets, using two immiscible liquids and a gas to achieve controlled, sequential reagent addition.

Cilia assembly relies on cargo trains that move bidirectionally on separate tubules of the ciliary microtubular structure, preventing traffic jams. Here, the authors demonstrate that train sorting is governed by tubulin tyrosination levels.

An mRNA vaccine platform to prevent HIV-1 infection generated broadly neutralizing antibodies in non-human primates and protected some animals from infection, raising hope that optimization of this approach might lead to an effective HIV vaccine.

Microglia can help clear amyloid β plaques in the Alzheimer’s disease brain but may also become dysfunctional and can contribute to disease progression. March-Diaz et al. reveal that hypoxia, a potentially modifiable risk factor for Alzheimer’s disease, disrupts the metabolism and function of microglia near plaques, which may contribute to neuropathology.

Causality plays a central role in understanding interactions between variables in complex systems. Here, the authors introduce a state-aware causal inference method that quantifies causality in terms of information gain about future states, demonstrating its applicability in the context of interactions between motions across scales in a turbulent boundary layer and the Walker circulation phenomenon in tropical Pacific climate dynamics.

This systematic review and meta-analysis provides an updated assessment of the efficacy and safety of intravenous iron therapy in patients with heart failure and iron deficiency, incorporating the results of the newly conducted FAIF-HF2 trial.

Noninvasive detection of molecular targets in living subjects could provide valuable insights into healthy function and disease. Here, the authors develop vasoactive imaging probes which allow wide-field in vivo mapping of nanomolar-level molecular species in rat brain.

The thymus is essential for T cell maturation and selection, and thymic defects result in severe immune problems. Here the authors identify a thymus cell population that is expandable in vitro, and can repopulate natural thymic matrix to generate tissue that supports mature T cell development in vitro and in vivo.

Adrian Dingle tells the story of how the name of element 109 represents the lasting recognition that one of the greatest nuclear physicists was in danger of never receiving.

To reveal cellular mechanisms of cognitive decline after stroke the authors established an experimental paradigm in mice monitoring individual nerve cells involved in spatial memory in health and disease allowing to identify functional biomarkers.

Enzymes of central metabolism tend to assemble into transient supramolecular complexes. Here, the authors stoichiometrically perturbed the supramolecular complex of TCA cycle enzymes in B. subtilis and propose that MDH-ICD clustering causes 2-oxoglutartae sequestration by reducing its diffusion rate, a mechanism that has evolved to regulate flux through the carbon-nitrogen metabolic branch-point.

Analysis of tumor biopsies from the pivotal phase 1/2 ZUMA-1 trial identifies pre-treatment T cell–related characteristics that are associated with clinical response and neurologic toxicity after anti-CD19 CAR T cell therapy in patients with large B cell lymphoma.

Misfolding of transthyretin can cause amyloid aggregation disorders that can be treated by stabilizing the tetrameric form with tafamidis. Here the authors show that tolcapone, a drug already FDA-approved for Parkinson disease, has strong transthyretin stabilizing function and might be a superior therapeutic option for CNS amyloidosis as it can cross the blood brain barrier.

An environmentally safe means of mosquito control is the application of Bacillus thuringiensis israelensis, which produces a cocktail of four naturally crystalline proteins exclusively toxic to mosquito. Here the authors report the atomic-resolution structures of Bti Cry11Aa and related Btj Cry11Ba solved de novo through Serial Femtosecond Crystallography on naturally-occurring nanocrystals.

The new European X-Ray Free-Electron Laser (EuXFEL) is the first XFEL that generates X-ray pulses with a megahertz inter-pulse spacing. Here the authors demonstrate that high-quality and damage-free protein structures can be obtained with the currently available 1.1 MHz repetition rate pulses using lysozyme as a test case and furthermore present a β-lactamase structure.

C9orf72 ALS/FTD polyGR and polyPR knock-in mice show cortical hyperexcitability and motor neuron loss accompanied by an increase in extracellular matrix proteins in the spinal cord that is conserved in patient iPS cell-derived neurons and is neuroprotective.

Mechanisms underlying sleep dysfunctions in neurodevelopmental disorders remain elusive. Here, authors use a fly model for the CYFIP haploinsufficiency to show that increased SREBP activity impairs the NADP+/NADPH homeostasis inducing sleep deficits.

This large integrated analysis of the KRAS^G12C inhibitor sotorasib clinical efficacy biomarkers from the phase 2 CodeBreaK 100 and phase 3 CodeBreaK 200 trials shows that low expression of TTF-1 and high expression of NRF2 determine anti-tumor efficacy of sotorasib in non–small-cell lung cancer.

Cytonemes are specialized filopodia-like structures known to be involved in signal transduction. Here they propose a new predictive model for cytoneme guidance in Hedgehog signaling, which is based on Ihog, Dally, and Dlp protein levels.

Deficiency in Wiskott-Aldrich syndrome protein (WASP) has been associated with autoimmune colitis, but the underlying mechanism is still unclear. Here the authors show that WASP deficiency is associated with defective WASP/DOCK8 complex formation, altered IL-10 signalling, and impaired anti-inflammatory macrophage functions.

The Hedgehog signalling gradient is established by dynamic signalling filopodia (cytonemes). Here, the authors show that EGF signalling may regulate cytoneme dynamics by maintaining basal plasma membrane levels of the Hedgehog co-receptor Ihog in the wing disc epithelium.

The SARS-CoV-2 Alpha variant suppresses innate immune responses more effectively than isolates of first-wave SARS-CoV-2, and this is a result of mutations outside of the spike coding region that lead to upregulation of viral innate immune antagonists.

The complement pathway has been proposed as a therapeutic target for Alzheimer’s disease (AD). Pharmacologic inhibition of C5aR1 suppresses disease-enhancing processes and promotes disease mitigating pathways in an aggressive model of AD.

A gene therapy phase 1 trial in patients with β-thalassemia shows transplantation of autologous CD34⁺ cells transduced with a lentiviral globin vector after reduced-intensity conditioning achieves long-term engraftment, albeit not transfusion independence, with benign clonal expansions, warranting cautious monitoring of patients.

Dense calcium imaging combined with co-registered high-resolution electron microscopy reconstruction of the brain of the same mouse provide a functional connectomics map of tens of thousands of neurons of a region of the primary cortex and higher visual areas.

Star-shaped engineered peptide nanoparticles are effective at killing a variety of multidrug-resistant Gram-negative pathogens in vivo with low host toxicity and resistance.

The paper describes a Genome in a Bottle benchmark for the X and Y chromosomes enabled by complete chromosome assemblies. This benchmark enables users to evaluate small variant accuracy in challenging repetitive regions of the sex chromosomes.

Systemic lipid homeostasis requires hepatic autophagy to recycle intracellular fat. Here, the authors identify peripheral mechanisms regulating energy homeostasis, showing that MC3R is a regulator of hepatic autophagy, hepatic fat accumulation, and fat partitioning, controlling systemic adiposity.

Forced expression of C-X-C chemokine receptor type 6 in antigen-specific T cells enhanced the recognition and lysis of pancreatic cancer cells and the efficacy of adoptive cell therapy for pancreatic cancer.

The small molecule DNMDP acts as a velcrin by inducing complex formation between phosphodiesterase PDE3A and SLFN12, which kills cancer cells that express sufficient levels of both proteins. Here, the authors present the cryo-EM structure of the DNMDP-stabilized PDE3A-SLFN12 complex and show that SLFN12 is an RNase. PDE3A binding increases SLFN12 RNase activity, and SLFN12 RNase activity is required for DNMDP-mediated cancer cell killing.

Family 1 glycosidases (GH1) are present in the three domains of life and share classical TIM-barrel fold. Structural and biochemical analyses of a resurrected ancestral GH1 enzyme reveal heme binding, not known in its modern descendants. Heme rigidifies the TIM-barrel and allosterically enhances catalysis.

Interactions with the extracellular matrix (ECM) control tumor proliferation, invasion and metastasis. Here, authors provide spatial information on ECM organization and how it influences tumor cell invasive and metastasis properties through induction of cytoskeletal and transcriptional memory.

Light-based modulation of the microtubule (MT) cytoskeleton is an attractive goal for spatiotemporally-resolved MT studies. Here the authors develop a first generation photoswitchable small molecule MT stabiliser based on paclitaxel, allowing optical control over cellular MT dynamics.

Due to the pulsed nature of X-ray free electron laser (XFEL) instruments the majority of protein crystals, which are injected using continuous jet injection techniques are wasted. Here, the authors present a microfluidic device to deliver aqueous protein crystal laden droplets segmented with an immiscible oil and demonstrate that with this device an approx. 60% reduction in sample waste was achieved for data collection of 3-deoxy-D-manno-octulosonate 8-phosphate synthase crystals at the EuXFEL.

A potential drug should specifically interact with its intended target in order to limit unwanted side effects. Here, the authors fabricate a biodegradable polymer nanoparticle with a fluorescent hepatic uptake transporter ligand to achieve targeted in vivosiRNA delivery and imaging of delivery.

Through a mechanochemical feedback loop involving Min proteins of Escherichia coli, liposomes start to move, which may help to design motile artificial cells.

Groos et al. show that lateral habenula activity reflects individual risk preference before action selection. This activity is modulated by behavior-relevant synaptic input from the medial hypothalamus capable of glutamate and GABA co-release.

The ASAP4 family of genetically encoded voltage indicators allows recording of action potentials and subthreshold activity with either one- or two-photon microscopy over extended periods of time.

Posfai, Schell, Janiszewski et al. assess candidate totipotent stem cells with in vitro and in vivo assays of increasing stringency to evaluate their developmental potential and lineage contributions.

A mechanism for the unfolding of guanine-rich DNA ‘quadruplexes’ by helicases is suggested, based on the structure of a DNA-bound helicase.

Phosphoregulation is a key mechanism of signal processing. Here the authors build a phosphoregulated relay system in mammalian cells for orthogonal signal transduction.

A study of genetic associations identifies 46 new loci associated with alcohol consumption. By assessing their function and potential pleiotropy, the authors suggest genetic mechanisms that are shared with neuropsychiatric disorders, including schizophrenia.