Large-scale CRISPR screening in human T cells holds significant promise for identifying genetic modifications that enhance cellular immunotherapy. Yet, many regulators of T cell performance in solid tumours are not revealed in vitro1,2. In vivo screening in tumour-bearing mice is more physiological but has been limited by low intratumoural T cell recovery. Here we developed an in vivo model that efficiently recovers human T cells from solid tumours, permitting genome-wide CRISPR screens with few mice. Tumour-infiltrating T cells from this model exhibit hallmarks of dysfunction compared with splenic T cells, creating an ideal screening context. We performed two genome-wide CRISPR knockout screens to identify regulators of intratumoural T cell abundance and effector function. The abundance screen revealed the P2RY8-Gα13 GPCR signalling axis as a negative regulator of T cell tumour infiltration. The effector function screen identified GNAS as a key driver of T cell dysfunction in tumours, whose product, Gαs, acts as a convergent node downstream of multiple GPCRs sensing distinct suppressive ligands. Knockout of GNAS rendered T cells resistant to multiple suppressive cues and significantly improved efficacy across diverse solid tumour models in chimeric antigen receptor (CAR) and T cell receptor (TCR) systems. Combinatorial knockout of P2RY8-GNAS further enhanced tumour control, demonstrating that complementary in vivo screens can identify orthogonal targets whose combined editing improves therapeutic potency. This flexible, scalable platform can be adapted for systematic discovery of genetic strategies to improve solid tumour T cell therapies.

Europe has experienced extreme floods in recent decades. However, even larger floods are possible and must be considered in flood risk management1,2. Their characteristics can be clarified by analysing the largest documented historical floods. In Central Europe, the Magdalena Flood of July 1342 is usually considered the largest of the last millennium; however, knowledge of its characteristics is incomplete3-7. Here we show that 16 major flood events occurred across much of Europe between late 1341 and 1343. Four of these events had return periods of 500-1,000 years (the Magdalena, Bartholomew, Candlemas and Jacob Floods). Although Magdalena was thought previously to be the only extreme European flood in 13423,7, our new documentary dataset suggests that it formed part of a broader sequence. The year with the greatest number of extreme floods during the past 700 years was 1342, and 1343 ranks among the top ten. This highly unusual sequence of floods had substantial socio-economic impacts, including a paradigm shift in flood mitigation measures in Europe. A series of volcanic eruptions along with multi-annual Arctic sea ice retreat is a plausible cause of this flood sequence. Clusters of extreme floods occurring within a few months are rarely considered in risk management8. Quick and proactive risk strategies are needed that account for this eventuality.

Atomically thin van der Waals crystals epitomize ideal material systems in the two-dimensional (2D) limit. This reduction in dimensionality often leads to important consequences, best exemplified by the emergence of new physics in graphene and other 2D materials that can be readily tuned by gating1,2. Vast opportunities arise in extending this top-down approach to other material systems. Recent experiments have demonstrated that the essential physics of high-temperature superconductivity in cuprates is contained within just two CuO2 planes3. Here we push dimensionality reduction to the extreme by examining a single layer of Bi2Sr2CuO6+δ (Bi-2201), which comprises only one CuO2 plane. In this ultimate 2D limit, we observe a robust dimensionality effect that manifests as an approximately 10% reduction in the optimal superconducting transition temperature. Moreover, this reduction in dimensionality offers unprecedented tunability-we successfully extended the phase diagram of Bi-2201 into uncharted territories via finely controlled oxygenation of single-monolayer specimens. Leveraging this tunability, we discovered that an anomalous metal state emerges between the insulating and superconducting states as the temperature approaches zero. Concurrently, we observe an anomalous scaling behaviour characterized by a divergent critical exponent. These findings illuminate the nature of the superconductor-to-insulator quantum phase transition in cuprates.

Naturalistic goal-directed behaviour often involves continuous actions directed at dynamically changing goals1-3. Just as microeconomics serves as a rigorous foundation for discrete choices, control theory can serve as a foundation for understanding choice in continuous ones3,4. In continuous contexts, behaviour is composed of blends of goals, and the closest analogue to choice is a strategic reweighting of goal-specific control policies5,6. Here, to understand the algorithmic and neural bases of continuous choice, we examined behaviour and brain activity in humans performing a continuous prey-pursuit task7. Using a newly developed control-theoretic decomposition of behaviour, we find that pursuit strategies are well described by a meta-controller dictating a mixture of lower-level controllers, each linked to specific pursuit goals. Neurons in the anterior cingulate cortex predict major changes in policy blends, whereas hippocampal neurons encode and update the latent policy state supporting early planning. Meanwhile, orbitofrontal cortex activity is consistent with an encoding of the current value structure of the task, rather than policy switching. Together these results are consistent with a tripartite functional division in which hippocampus serves as a state-estimating controller, anterior cingulate cortex serves as a meta-controller, and orbitofrontal cortex provides a value context signal.

The establishment of the infant gut microbiome is critical for later health1,2, yet how it is shaped by maternal and early-life factors remains unclear. Here we metagenomically sequenced 4,526 longitudinal faecal samples from 714 mother-infant pairs in the Dutch birth cohort Lifelines NEXT, spanning 12 weeks of pregnancy to 1 year postpartum. We integrated these data with 474 clinical and exposure variables, and with ultra-deep sequencing of breast milk and vaginal microbiomes. We observe that the maternal gut microbiome undergoes only subtle changes during pregnancy and postpartum, influenced by diet, infections and pre-pregnancy smoking. The maternal gut microbiome is a major reservoir for infant gut strains, with only occasional transmission from vaginal and breast milk microbiomes. Mother-infant gut strain sharing is time dependent, and higher maternal gut species abundance increases the likelihood of strain transmission. We find that the maternal gut microbiome is a predictor of infant eczema. Mode of delivery and feeding mode primarily shaped the infant gut microbiome and its functional profiles, with maternal exposures also having a role. Of 585 vaginally delivered infants, 155 were born at home, but home delivery was only moderately associated with infant gut microbiome composition, similar to other birth parameters such as duration of pushing and ruptured membranes. Overall, we highlight the central role of the mother and her microbiome in shaping the infant gut ecosystem and early health outcomes.

The hippocampus forms memories of our experiences in populations of coactive pyramidal neurons (PNs)1-3. Fast-spiking parvalbumin-expressing inhibitory neurons (PV INs) in the dentate gyrus-CA3/CA2 circuit of the hippocampus precisely control PN activity through mossy fibre-dependent feedforward inhibition4-11. PV INs coordinate experience-dependent changes in their intrinsic excitability, synaptic connectivity, physiology and plasticity properties9,12-15-referred to here as experience-dependent PV IN plasticity-to regulate PN activity. PV IN impairments in early life, when neural circuitry is highly sensitive to experience, are thought to result in network hyperexcitability, seizures and impaired cognition, which are hallmarks of neurodevelopmental disorders (NDDs)16-18. Here we designed an input-specific translatome screen to identify regulators of experience-dependent PV IN plasticity genes (XPGs) in the CA3/CA2 subregion of adult hippocampus. We demonstrate that a substantial proportion of upregulated candidate XPGs exhibit haploinsufficiency in autism spectrum disorder, epilepsies, bipolar disorder and schizophrenia, which suggests that there is impaired experience-dependent PV IN plasticity in NDDs. In proof-of-concept experiments, targeted upregulation of a candidate XPG, the homeobox gene Meis2 (ref. 19), in CA3/CA2 PV INs in an NDD risk mouse model in adulthood is sufficient to restore experience-dependent PV IN plasticity. Moreover, ensemble and sharp-wave ripple properties and cognition were improved, and seizures were suppressed. Thus, experience-dependent PV IN plasticity is a convergent mechanism for NDD risk genes that can be re-instated in adulthood to reverse developmental deficits in circuitry, network excitability and cognition.

Perioperative nivolumab significantly improved event-free survival (EFS) compared with placebo in patients with resectable non-small cell lung cancer (NSCLC) in the CheckMate 77T study (ClinicalTrials.gov NCT04025879 )1. Here, after randomization, 98 out of 229 patients who received nivolumab and 92 out of 232 patients who received placebo had evaluable biomarkers (41% of randomized patients). Of the 98 patients receiving nivolumab, 83 (85%) had detectable circulating tumour DNA (ctDNA) before initiating neoadjuvant treatment and 90 (92%) at neoadjuvant treatment completion. Of the 92 placebo-treated patients, 75 (82%) had detectable ctDNA at the treatment start and 78 (85%) at completion. Among the 98 nivolumab-treated patients, 76 (78%) had detectable and evaluable ctDNA before and after neoadjuvant treatment, and 50 of them (66%) had pre-surgical ctDNA clearance, and 25 out of 50 (50%) had pathologic complete response (pCR). For the placebo-treated group, these values were 64 out 92 (70%) for detectable and evaluable ctDNA before and after neoadjuvant treatment, and 24 out of 64 (38%) had pre-surgical ctDNA clearance, and 3 out of 24 (12%) had pCR. Furthermore, 4 out of 48 (8%) patients in the nivolumab group and 9 out of 44 (20%) in the placebo group who were negative for molecular residual disease (MRD) after surgery and before adjuvant treatment initiation became positive during the adjuvant treatment period; all had disease recurrence. EFS seemed to be prolonged with nivolumab (n = 60) versus placebo (n = 45) in patients with single or co-alterations in any of the KEAP1, STK11, CDKN2A and/or SMARCA4 driver genes (hazard ratio, 0.48; 95% confidence interval, 0.28-0.83). In a machine-learning model trained using biomarker-evaluable patients, top predictors of prolonged EFS included pre-surgical ctDNA clearance, non-N2 NSCLC, pCR, squamous tumour histology and nivolumab treatment. These findings provide insights into predictive markers for outcomes with perioperative nivolumab in resectable NSCLC.