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James Brugarolas and colleagues identify recurrent BAP1 mutations in clear cell renal cell carcinoma (ccRCC). They show that BAP1 binds to HCF-1 and suppresses cell proliferation, and they find that BAP1 loss is associated with high tumor grade.

Chemically modified DNA aptamers enable quantitative super-resolution imaging.

When making decisions, new information sometimes calls for a change of mind. New results indicate that regions of the prefrontal cortex play distinct roles in evaluating new evidence in light of a previous choice and translating the result of this evaluation process into an explicit report of one’s subjective confidence.

Cruz-Acuña et al. develop synthetic hydrogels that support the generation and expansion of viable human intestinal organoids from pluripotent stem cells and can be used as injectable vehicles for organoid engraftment and wound healing.

The dorsal anterior cingulate cortex is one of the most beguiling regions of the brain. Understanding its essential function has become a holy grail for many cognitive neuroscientists. With this scrutiny has come contention. In this issue, two teams of neuroscientists with different views argue for their favored interpretation of neural activity in this region. Here, we provide some background and context for this debate.

Comparative genomic analyses of primary tumors and metastases within individuals with pancreatic cancer have exposed the complex clonal dynamics that underlie the dissemination of cancer cells to distant sites. Recent studies implicate non-genetic mechanisms in this process, particularly fluctuations in chromatin states and metabolism, which can endow rare cells within a primary tumor with metastatic potential.

The cure and elimination of malaria caused by Plasmodium vivax is hindered by the threat of relapse infections from undetectable dormant forms of the parasite in the liver. In a new breakthrough, using a related parasite, Plasmodium cynomolgi, it has been shown that the small nongrowing forms of the parasite, termed hypnozoites, can be reactivated in primary simian hepatocytes that have been infected and maintained in culture for 40 days, providing a system to study this parasite form with the development of potential new antihypnozoite drugs in mind (pages 307–312).

With a flood of new tools for genome engineering, we can benefit from choosing the tool that best fits the job.

Dendritic cell progenitors commit to a specific conventional dendritic cell fate earlier than previously thought, by initiating transcription-factor regulatory circuits unique to their subtype.

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.

An atlas of targeted mass spectrometry coordinates provides a starting point for measuring the unmodified human proteome.

Selecting compounds for the chemical library is the foundation of high-throughput screening (HTS). After some years and multiple HTS campaigns, many molecules in the Novartis and NIH Molecular Libraries Program screening collections have never been found to be active. An in-depth exploration of the bioactivity of this 'dark matter' does in fact reveal some compounds of interest.

Rapid insertion and extraction of lithium ions from a cathode material is imperative for lithium-ion battery function. Here, the authors present evidence of inhomogeneities in charge localization, local structural distortions and polaron formation induced upon lithiation using scanning transmission X-ray microscopy.

An example of complex population dynamics (the midge Tanytarsus gracilentus in Lake Myvatn, Iceland) is described and modelled.

The start-up of the new femtosecond hard X-ray laser facility in Stanford, the Linac Coherent Light Source, has brought high expectations for a new era for biological imaging. The intense, ultrashort X-ray pulses allow diffraction imaging of small structures before radiation damage occurs. This new capability is tested for the problem of structure determination from nanocrystals of macromolecules that cannot be grown in large crystals. Over three million diffraction patterns were collected from a stream of nanocrystals of the membrane protein complex photosystem I, which allowed the assembly of a three-dimensional data set for this protein, and proves the concept of this imaging technique.

Femtosecond X-ray laser pulses are used to probe the structure of liquid water in micrometre-sized droplets that have been cooled below the homogeneous ice nucleation temperature, revealing the existence of metastable bulk liquid water down to temperatures of 227 kelvin.

The goal of characterizing solid-tumor genomes with nothing more than a blood sample is now within reach.

Macrophages are responsive to local tissue signals and alter their phenotypes accordingly. In disease tissues this means that macrophage phenotypes may change with disease progression, exacerbating or facilitating the resolution of the pathology.

The start-up of the new femtosecond hard X-ray laser facility in Stanford, the Linac Coherent Light Source, has brought high expectations for a new era for biological imaging. The intense, ultrashort X-ray pulses allow diffraction imaging of small structures before radiation damage occurs. This new capability is tested for the problem of imaging a non-crystalline biological sample. Images of mimivirus are obtained, the largest known virus with a total diameter of about 0.75 micrometres, by injecting a beam of cooled mimivirus particles into the X-ray beam. The measurements indicate no damage during imaging and prove the concept of this imaging technique.

Caenorhabditis elegans has the potential to be used to discover new, biologically active small molecules in a high-throughput fashion and also to identify the protein targets of those small molecules.

Malaria remains a devastating human disease. Although malaria vaccines are available, their limited efficacy and protective duration are problematic. In this Review, the authors discuss how immunoregulatory networks that likely develop to prevent disease during malaria may also impede prevention and control measures.

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.

Using a temporal series of growth factor manipulations to mimic embryonic intestinal development in culture, this study has successfully directed the differentiation of human pluripotent stem cells (both embryonic stem cells and induced pluripotent stem cells) into intestinal tissue. This approach may provide therapeutic benefit for disease studies.

Femtosecond XFEL crystallography is used to identify dynamic changes in the adenine riboswitch aptamer domain, with at least four states identified in real time, two in the apo form before binding and two with the ligand bound.

Anxiety disorders are characterized by prolonged fear or anxiety, the avoidance of perceived threats and, in some cases, panic attacks. Here, Craske et al. discuss the mechanisms, diagnosis and management of anxiety disorders, and provide an overview of the quality-of-life issues faced by patients.

Crystal lattice disorder, which gives rise to a continuous diffraction pattern, is exploited to determine the structure of the integral membrane protein complex photosystem II to a higher resolution than could be achieved using Bragg diffraction alone.

Expression of a protein in Sf9 insect cells at high concentration triggers formation of in vivo crystals that can be analyzed by serial femtosecond X-ray crystallography.

An integrated analysis of over 100 single-cell and single-nucleus transcriptomics studies illustrates severe acute respiratory syndrome coronavirus 2 viral entry gene coexpression patterns across different human tissues, and shows association of age, smoking status and sex with viral entry gene expression in respiratory cell populations.

3D printing is becoming a mainstream technology with considerable increase in access to affordable desktop printers. However, specific design principles and material considerations need to be weighed when printing functional devices that integrate catalytic and/or analytical functionalities, as well as when printing common laboratory hardware.

The in vitro generation, from pluripotent stem cells, of three-dimensional human gastric organoids (hGOs) that contain a physiological gastric epithelium comprising both progenitor and differentiated cell types, and have expected functional characteristics is described, as is modelling the pathophysiological response of the human stomach to Helicobacter pylori using these hGOs.

An in vivo model of the human small intestine is established in mice using human pluripotent stem cells.

Femtosecond X-ray pulses were used to obtain diffraction data on photosystem II, revealing conformational changes as the complex transitions from the dark S₁ state to the double-pumped S₃ state; the time-resolved serial femtosecond crystallography technique enables structural determination of protein conformations that are highly prone to traditional radiation damage.