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Sepsis is poorly understood, largely untreatable and frequently fatal. Netea and colleagues assess both mouse sepsis and human sepsis to demonstrate that its late phase is characterized by immunoparalysis and broad metabolic alterations in cells of the immune system.

Opioids are potent analgesics but also have addiction risk. Here a lateral preoptic area to lateral habenula connection is identified by which opioids relieve ongoing pain but do not produce reward in animals that do not have ongoing pain.

An ex vivo platform of patient-derived tumor fragments enables the assessment of intratumoral immune reactivation after PD-1 blockade that is predictive of clinical outcomes in patients with cancer.

Eph receptor tyrosine kinases and their ephrin ligands mediate cell-cell communication. Here, the authors assess the structure and dynamics of the EphA2 intracellular region and uncover complex effects of phosphorylation within the linker region between EphA2 kinase and SAM domains.

Analysis of live-cell imaging and single-cell genome sequencing data of colorectal cancer organoids identifies temporal dynamics of sub-chromosomal copy-number amplifications.

Chromodomain Helicase DNA-binding (CHD) proteins have been implicated in neurodevelopmental processes. Here, the authors identify missense variants in CHD3 that disturb its chromatin remodeling activities and cause a neurodevelopmental disorder with macrocephaly and speech and language impairment.

Here, Brotherton and colleagues sequence 39 mitochondrial genomes from ancient human remains. They track population changes across Central Europe and find that the foundations of the European mitochondrial DNA pool were formed during the Neolithic rather than the post-glacial period.

Long-range magnetic order hardly ever emerges in a two-dimensional system due to the competition of fundamental magnetic interactions. Here, Girovskyet al. directly observe a long-range ferrimagnetic order emerging in a two-dimensional supramolecular Kondo lattice.

Whole-exome analysis of individuals with developmental disorders shows that de novo mutations can equally cause loss or altered protein function, but that most mutations causing altered protein function have not yet been described.

Ganesh et al. describe the rationale for using immunotherapy in select patients with colorectal cancer, discuss clinical findings supporting its use and highlight current strategies and future directions for expanding the scope of immunotherapy in this disease.

Rectal cancer organoids retain the pathological features of matched patient tumors and recapitulate clinical responses to chemoradiation.

An international blind study confirms that smFRET measurements on dynamic proteins are highly reproducible across instruments, analysis procedures and timescales, further highlighting the promise of smFRET for dynamic structural biology.

Exome-wide genetic analysis on >300,000 individuals identifies associations with plasma lipid traits. Loci significantly associated with cholesterol and triglycerides are examined together to determine the effects of alleles on type 2 diabetes and coronary artery disease risk.

Paul Elliott, Martin Tobin, Cornelia van Duijn and colleagues report a genome-wide association study for pulse pressure and mean arterial pressure, identifying six new loci influencing these two traits.

Multi-ancestry genome-wide association analyses for birth weight in 153,781 individuals identified 60 genomic loci in which birth weight and fetal genotype were associated and found an inverse genetic correlation between birth weight and cardiometabolic risk.

The next step after sequencing a genome is to figure out how the cell actually uses it as an instruction manual. A large international consortium has examined 1% of the genome for what part is transcribed, where proteins are bound, what the chromatin structure looks like, and how the sequence compares to that of other organisms.

Christopher Walsh and colleagues identify mutations in CHMP1A in human cerebellar hypoplasia and microcephaly. Cells lacking CHMP1A show decreased cell proliferation and decreased expression of BMI1, a negative regulator of stem cell proliferation.

The severity and extent of cardiovascular complications in patients with chronic kidney disease is disproportionate to the number and severity of traditional risk factors, such as diabetes and hypertension. Could uremia-related factors—including anemia, microalbuminuria, inflammation, oxidative stress, and abnormalities in bone and mineral metabolism—account for this discrepancy? Authors from the University of Colorado Health Sciences Center weigh up the evidence from randomized controlled trials of interventions for these so-called 'nontraditional' risk factors.

Warthi et al. generated an alpha 8 integrin-cre driver that enables gene targeting preferentially in vascular smooth muscle cells (SMCs) and showed in a proof-of-principle study, that using the Itga8-CreER^T2 knock-in mouse for selective ablation of the Srf gene caused vascular defects but not a lethal visceral myopathy observed in an SMC-specific Myh11-CreER^T2-driven Srf loss.

Analysis of data from the COVID Symptom Study app reveals fatigue, headache, dyspnea and anosmia as key attributes of long COVID, with those experiencing five or more symptoms during the first week of being at increased risk of prolonged disease.

Stéphanie Debette and colleagues report the results of a genome-wide association study of cervical artery dissection, a major cause of ischemic stroke in young adults. They show that common variation in PHACTR1, previously associated with lower risk of migraine and increased risk of myocardial infarction, is associated with reduced risk of cervical artery dissection.

Matthew Hurles and colleagues report exome sequencing of 1,891 individuals with syndromic or nonsyndromic congenital heart defects (CHD). They found that nonsyndromic CHD patients were enriched for protein-truncating variants in CHD-associated genes inherited from unaffected parents and identified three new syndromic CHD disorders caused by de novo mutations.

Genome-wide association studies are used to identify common genetic variants that affect the structure of selected subcortical regions of the human brain; their identification provides insight into the causes of variability in brain development and may help to determine mechanisms of neuropsychiatric dysfunction.

Vaccination offers protection against infectious diseases, yet pre-existing criteria that predict vaccine efficacy or adverse events remain unknown. Hayday and colleagues identify cellular and molecular signatures in humans immunized with adjuvanted swine flu vaccine.

Jonathan Sebat and colleagues report the association of microduplication on chromosome 16p11.2 with schizophrenia, while the reciprocal microdeletion was associated with autism and developmental disorders.

Patrick Ellinor and colleagues report meta-analyses of common and rare variant association studies for atrial fibrillation across multiple populations. They identify 12 new loci, some of which implicate genes in atrial electrical and mechanical function.