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When two similar, credible analyses of the same patient database report seemingly contrasting risk estimates for the association with cancer of a widely-prescribed therapy, it is difficult for clinicians, never mind for patients, to make decisions about treatment options. Nevertheless, clinicians can—and must—interpret the available evidence for their patients, helping them to weigh the potential benefits and harms of their prescription.

Common genetic variants associated with plasma lipids have been extensively studied for a better understanding of common diseases. Here, the authors use whole-genome sequencing of 16,324 individuals to analyze rare variant associations and to determine their monogenic and polygenic contribution to lipid traits.

Pathogenic autoreactive antibodies associated with severe COVID-19 can be identified via self-assembled genome-scale libraries of full-length proteins covalently coupled to uniquely identifying DNA barcodes for analysis by sequencing.

Representing the first successful rational reprogramming of function in a de novo protein, the reactivity of a designed di-iron carboxylate protein from the Due Ferri family was altered from hydroquinone oxidation to arylamine N-hydroxylation through the introduction of a critical third histidine ligand in the active site.

A reactive astrocyte subtype termed A1 is induced after injury or disease of the central nervous system and subsequently promotes the death of neurons and oligodendrocytes.

The authors use mouse behavior, electrophysiology and optogenetics to dissect the temporal interactions between whisker movement, neural activity and sensation of touch. Their results suggest that mice integrate coding of touch with movement over timescales of a whisking bout to produce perception of active touch.

Neurons form glutamatergic synapses with glioma cells in mice and humans, and inhibition of AMPA receptors reduces glioma cell invasion and growth.

In an analysis of adult patients with hematologic malignancies who received anti-CD19 chimeric antigen receptor T cell therapy, baseline gut microbiome composition was correlated with clinical response and treatment with broad-spectrum antibiotics in the four weeks prior to infusion was associated with worse survival and increased neurotoxicity.

Cities affect biological evolution, but traditionally researchers focus on the biophysical influence of urban environments. Instead, this Review explores how the social processes of religion, politics and war drive wildlife evolution by shaping urban conditions.

Allogeneic hematopoietic cell transplantation (allo-HCT) has led to the cure of HIV in one individual, but the underlying mechanisms are unclear. Here, the authors present a model of allo-HCT in SHIV-infected nonhuman primates and show that the SHIV reservoir persists in multiple tissues early after transplantation.

Randomized clinical trials are often plagued by selection bias, and expert-selected covariates may insufficiently adjust for confounding factors. Here, the authors develop a framework based on natural language processing to uncover interpretable potential confounders from text.

Dysregulation of microRNAs has been implicated in neurodevelopmental disorders, including schizophrenia. Here the authors show that the TLX-miR-219 cascade regulates the proliferation of neural stem cells during normal development, and this pathway is dysregulated in a schizophrenia iPSC model.

Sequencing data from two large-scale studies show that most of the genetic variation influencing the risk of type 2 diabetes involves common alleles and is found in regions previously identified by genome-wide association studies, clarifying the genetic architecture of this disease.

The cellular function of active DNA demethylation in neurons is not well understood. Here, Song and colleagues show that synaptic activity modulates Tet3 signaling, which in turn regulates glutamatergic synaptic transmission and synaptic scaling. Their work identifies Tet3 as a synaptic activity sensor to epigenetically regulate fundamental properties and meta-plasticity of neurons via active DNA demethylation.

The authors describe a neurogenic niche in the postnatal hypothalamus of mice wherein β2-tanycytes generate neurons in response to high-fat diet. Blocking this neurogenesis leads to attenuated weight gain and increased activity levels.

In this study, Wits and Stanford researchers use short- and long-read DNA sequencing to profile the gut microbiome of women living in rural and urban South Africa and identify transitional composition, high inter-individual diversity, and many undescribed taxa.

Regulatory proteins bind non-coding DNA either at promoters (near to a gene's transcription start site) or at enhancers (far away). Binding at enhancers helps to bring the transcription enzyme RNA polymerase to promoters. Here, studies of some 12,000 enhancers that respond to electrical activity in neurons show that binding to enhancers also brings the polymerase to the enhancers themselves, where it transcribes a novel class of non-coding RNAs. Enhancers may thus be more similar to promoters than hitherto appreciated.

The concepts of comorbidity and multimorbidity consider a patient with multiple diseases from different perspectives, which affects how a clinician approaches treatment. In this Perspectives article, Radner and colleagues discuss the concept of multimorbidity and how its integration into daily clinical practice can improve the care of patients with rheumatic conditions.

A network meta-analysis by Trelle and colleagues has confirmed that the routine use of all nonsteroidal anti-inflammatory drugs, both nonselective and selective, is associated with an increased risk of cardiovascular events. Although a rigorous method was used in this analysis, comparative safety research in which data from randomized clinical trials is used has some important strengths and weaknesses to consider.

Feedforward and feedback synaptic pathways shape how neural activity evolves across cortical areas, but they are difficult to monitor using traditional methods during behavior. The authors use pathway-specific and cellular-resolution in vivo imaging to quantify sensory and decision-related neural activity both within and propagating between two cortical areas critical for touch perception.

Sensory cortex spiking is well known to predict trial-to-trial variability in perceptual choice, but the origins of this choice-related activity are not fully understood. In the mouse somatosensory system, electrophysiology, imaging and optogenetic experiments reveal a progression of choice-related activity as touch signals flow from primary afferents to cortex.

The electronic structure of copper-based metalloproteins is important for their function in biological processes, but studying this from a computational standpoint can be challenging. Here, the authors report a dynamical mean field theory approach which reveals the role of strong electronic correlation effects in oxygen binding in the hemocyanin protein.

Observational studies are increasingly used to evaluate the safety and effectiveness of drugs for rheumatoid arthritis, but these studies are limited by inherent biases, including confounding by indication. This Perspectives article describes how these methodological limitations could be overcome by using the active-comparator design and the new-user design.

Human settlement and horticulture began in Vanuatu at least 2800 years ago during a wet climatic period, according to an analysis of sedimentary biomarkers and radiocarbon dating of a sediment core which records the past 5,000 years on Efate island.

Highly insulating silicon-based molecules, engineered so that conduction is fully suppressed by σ quantum interference even for molecules less than a nanometre long, could prove useful in molecular-scale electronic circuitry.

A pre-specified meta-analysis of pooled, individual patient-level data from the DELIVER and DAPA-HF trials, testing dapagliflozin in patients with heart failure, demonstrates reductions in risk of cardiovascular-associated deaths and hospital admissions for heart failure, regardless of ejection fraction.

On the anniversary of the Boyden et al. (2005) paper that introduced the use of channelrhodopsin in neurons, Nature Neuroscience asks selected members of the community to comment on the utility, impact and future of this important technique.

Critics have opposed clean energy public investment by claiming that governments must not pick winners, green subsidies enable rent-seeking behaviour, and failed companies means failed policy. These arguments are problematic and should not determine the direction of energy investment policies.

It is generally accepted that specific neuronal circuits in the brain's cortex drive behavioural execution, but the relationship between the performance of a task and the function of a circuit is unknown. Here, this problem was tackled by using a technique that allows many neurons within the same circuit to be monitored simultaneously. The findings indicate that enhanced correlated activity in specific ensembles of neurons can identify and encode specific behavioural responses while a task is learned.

Use of prescription opioids is prevalent in patients with rheumatic diseases. Studies in 2019 reported the trends and safety of opioids in patients with rheumatoid arthritis or osteoarthritis. Treating underlying disease processes must be the rheumatologists’ priority. Without better long-term safety and effectiveness data, opioid use should be generally limited.

Agonism of microglial glucagon-like peptide-1 receptor (GLP1R) using a brain-penetrant peptide prevents the generation of neurotoxic astrocytes and ameliorates disease progression in two rodent models of Parkinson’s disease.

Although the link between bacterial infections and tumor necrosis factor (TNF) inhibitors is becoming increasingly established, much less is known about the risk of viral infections with these agents. The authors of this Review highlight emerging reports of viral infections in patients receiving anti-TNF therapy, and discuss treatment implications and potential strategies for preventing such infections.

Some of the most devastating natural hazards on Earth are caused by subduction zone earthquakes. This Review discusses the conditions required to generate M ≥ 8 megathrust earthquakes, in the context of constraining seismic and tsunami hazards.

Rheumatoid arthritis is a chronic, inflammatory, autoimmune disease that primarily affects the joints. This Primer by Smolen et al. provides the latest insights into the epidemiology, genetics, pathophysiology, diagnostic approaches, clinical assessment and management of rheumatoid arthritis.

Cortical neurons reduce spiking responses to repetitive sensory stimulation, but the perceptual impact of this adaptation has been difficult to assess. Work now shows that it has profound consequences for tactile perception.

Autism is a highly heritable neurodevelopmental disorder, and yet few specific susceptibility genes have been identified to date. A linkage and association mapping study using half a million genome-wide single nucleotide polymorphisms is now described in a common set of 1,031 multiplex autism families. The linkage regions identified provide targets for rare variation screening whereas the discovery of a single novel association, SEMA5A, demonstrates the action of common variants.