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The targeted integration of large DNA payloads into primary human T cells can be efficiently achieved non-virally by leveraging Cas9-based editing and the DNA-repair pathway homology-mediated end joining.

Nutrient acquisition is crucial for the growth of pathogens within their hosts. Here, Bateman et al. identify a set of proteins required for heme uptake from host hemoglobin and serum albumin in the pathogen Acinetobacter baumannii.

The human mitochondrial protease LONP1 is an AAA+ ATP-dependent quality control protease. Here, the authors present the cryo-EM structures of human LONP1 in three distinct states and provide insights into the mechanism and regulation of this important protease.

Accurate cell detection in dense bacterial biofilms is challenging. Here, the authors report an image analysis pipeline that is able to accurately segment and classify single bacterial cells in 3D fluorescence images: Bacterial Cell Morphometry 3D (BCM3D).

Fish lack immunoglobulin A, which suggests that they lack specialized mucosal antibodies. Sunyer and colleagues show that immunoglobulin T fulfills this mucosal antibody function and engenders protection against gut parasites.

Bacteria can be trapped by neutrophil extracellular traps (NETs) in vitro, but their relevance in vivo is uncertain, in part because NETs are thought to be released by dying neutrophils, thereby eliminating the other antimicrobial functions of these cells. Paul Kubes and his colleagues report in this issue that NET release need not kill neutrophils and that NETosis can by dynamically imaged in vivo.

A sulfonamide series lacking the prototypical side chain behave as full antagonists or inverse agonists of estrogen receptor (ERα) signaling in a graded fashion dependent on coactivator recruitment and helix-11 positioning.

The natural product nimbolide covalently reacts with a functional cysteine of the E3 ubiquitin ligase RNF114, resulting in impaired substrate recognition and degradation, enabling the use of nimbolide for targeted protein degradation.

Flanigan et al. show that activation of inhibitory neurons in the lateral habenula by the neuropeptide orexin (hypocretin) promotes both inter-male aggression and conditioned place preference for contexts associated with winning aggressive contests.

Many RNA systems possess highly ordered 3-D structures that are essential to their function. Here the authors demonstrate that the long non-coding RNA Braveheart possesses a flexible but defined 3-D structure which is remodeled upon binding the protein CNBP.

Ageing is associated with clonal hematopoiesis of indeterminate potential (CHIP), which is linked to increased risks of hematological malignancies. Here the authors uncover an epigenetic mechanism through which mutant p53 drives clonal hematopoiesis through interaction with EZH2.

A trans-ancestry genome-wide association study of serum urate levels identifies 183 loci influencing this trait. Enrichment analyses, fine-mapping and colocalization with gene expression in 47 tissues implicate the kidney and liver as key target organs and prioritize potential causal genes.

Multiple samples collected at autopsy from women with homologous recombination-deficient high-grade serous ovarian cancer highlight substantial inter- and intratumoral heterogeneity. A plethora of resistance mechanisms were identified within and between patients.

The bacterium Borrelia burgdorferi, which causes Lyme disease and is transmitted by ticks, has a linear chromosome and multiple plasmids. Here, Takacs et al. show that the pathogen is polyploid, the number of genome copies decreases during stationary phase, and chromosome copies are regularly spaced along the cell’s length.

DCAF1/VprBP contributes to epigenetic gene inactivation and cancer development. Here the authors show that DCAF1/VprBP phosphorylates and stabilises EZH2 to induce oncogenic gene silencing and colon cancer growth.

Tryptophan C-mannosyltransferase (CMT) enzymes append a mannose to the first tryptophan of select sequences, which is important for the trafficking, folding and function of secretory and transmembrane proteins involved in cellular communication processes. A study reveals the structure, mode of peptide recognition and catalytic mechanism for the eukaryotic C-mannosyltransferase DPY19.

Follicular lymphoma can transform to a more aggressive histology. Here, the authors use bulk and single cell analysis to create a 26 marker panel which could be used to profile FL samples and predict the risk of transformation using flow cytometry.

AMPK regulates the metabolism and so drugs that activate AMPK might have potential for the treatment of metabolic disease. Here, the authors report the structure of AMPK bound to an activating compound, revealing two binding sites and indicating that dual therapy might be a good drug strategy.

Bioadhesives are materials frequently used as surgical sealants, though to date, these typically possess limited antibacterial properties. Here, the authors present a novel injectable and antibacterial bioadhesive hydrogel and demonstrate its performance in vivo.

Central to the lineage commitment of multipotent mesenchymal stem cells is the nuclear receptor PPARγ, the master regulator of adipogenesis. Here the authors use a variety of structural approaches to rationally design PPARγ inverse agonist SR2595, and demonstrate its ability to promote osteogenesis.

The impact of humans on megafaunal extinction is Australia is unclear. Here, the authors show burn patterns on eggshells of the extinct megafaunal bird, Genyornis newtoni, created by humans across Australia, suggesting that human predation contributed to the extinction of this bird around 47 thousand years ago.

An integrative genomic analysis of several hundred endometrial carcinomas shows that a minority of tumour samples carry copy number alterations or TP53 mutations and many contain key cancer-related gene mutations, such as those involved in canonical pathways and chromatin remodelling; a reclassification of endometrial tumours into four distinct types is proposed, which may have an effect on patient treatment regimes.

The treatment ofMycobacterium tuberculosis with drugs such as isoniazid often results in drug resistance, but the mechanisms leading to the resistance are not fully known. In this study, an M. tuberculosisstrain lacking the sigma factor I is shown to be resistant to isoniazid.

This analysis presents the results of a community-based evaluation of existing software for large-scale glycopeptide data analysis.

Mitochondrial complex I deficiency is frequent in congenital, neurologic and cardiovascular disease. Here the authors demonstrate that Complex I stimulates the turnover of a mitochondrial calcium channel, which becomes stabilized during Complex I deficiency, preserving energetic homeostasis.

Tissue-resident memory T (T_RM) cells are distributed throughout the body as relatively sessile populations. Mackay and colleagues find that the tissue in which T_RM cells are generated dictates their properties and is in turn defined according to T_RM-cell-intrinsic sensitivity to signaling via the cytokine TGFβ.

ATP drives most cellular processes, although ATP production and consumption levels during mitosis remain unreported. Here, the authors combine metabolic measurements and modeling to quantify ATP levels and synthesis dynamics, revealing that ATP synthesis and consumption are lowered during mitosis.

BRCA1-mediated resolution of R-loops has previously been described. Here the authors reveal a functional association of BRCA1 with TERRA RNA at telomeres, which develops in an R-loop-, and a cell cycle-dependent manner.

During meiosis, Mer2 and the Rec114–Mei4 complex form condensates that facilitate the formation of double-strand DNA breaks by recruiting the Spo11 transesterase complex.

While many treatments for prostate cancer suppress the androgen receptor it becomes reactivated during disease progression. Here, the authors show that a KLF5 transcriptional programme is also activated during treatment and promotes migration and the appearance of a basal cell phenotype.

Testosterone replacement therapy is commonly used to treat symptomatic, laboratory-proven testosterone deficiency, but can have detrimental effects on spermatogenesis, which is troublesome in men of reproductive age. This Review describes therapeutic options for testosterone deficiency in the reproductive-aged males, discussing medical therapies with the potential to preserve or restore spermatogenesis in selected patients receiving testosterone replacement therapy.

Strain maps of cardiomyocyte nuclei during contraction indicate that, by integrating environmental mechanical cues, the nuclei of cardiomyocytes stabilize the fate of cells through the reorganization of epigenetically marked chromatin.

An ex vivo 3D culture model of mycobacterial granulomas recapitulates the in vivo physiology of these structures and enables longitudinal imaging studies. The platform allows genetic and pharmacological manipulation of this key structure.

Protein synthesis suppression protects breast cancer cells from clinically relevant stresses like hypoxia. Here, the authors show that unique mRNA isoforms that govern stem cell-like phenotypes escape translational repression to drive tumor progression and chemoresistance.

CD22 inhibits microglial phagocytosis in the ageing brain, and treatment with a CD22-blocking antibody restores microglial homeostasis and cognitive function in ageing mice.

Oxidative stress can promote neurodegeneration. Akassoglou and colleagues describe Tox-seq, a functional single-cell RNA sequencing method to identify oxidative stress transcriptional signatures in CNS-resident cells. Tox-seq identified coagulation and glutathione-redox pathway genes that are coupled to oxidative stress and that could be targeted by the glutathione-regulating small molecule acivicin.

Characterization of medulloblastoma tissues using single-cell transcriptomics shows that the different molecular subtypes consist of distinct developmental phenotypes.

The infant gut is colonized first by temperate bacteriophages induced from pioneer bacteria and later by viruses that replicate in human cells, the populations of which are modulated by breastfeeding.

Cancer cells are metabolically adaptable and the identification of specific vulnerabilities is challenging. Here the authors identify a subset of neuroendocrine cell lines exquisitely sensitive to inhibition of SQLE, an enzyme in the cholesterol biosynthetic pathway, due to the toxic accumulation of pathway intermediate squalene.

Structure determination of large proteins by solution state NMR is challenging due to spectral overlap. Here the authors present a labeling strategy using 2-¹³C and 3-¹³C pyruvate as carbon source for E. coli, which increases the effective resolution of triple-resonance HNCA experiments and helps to overcome this problem.

Calcium/calmodulin-dependent kinase kinase 2 (CaMKK2) is highly expressed in several cancers. Here the authors investigate the role of CaMKK2 expression in the tumour microenvironment and show that CaMKK2 expression in tumour-associated macrophages promotes tumour growth by suppressing T cell anti-tumour activity.

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.