Scientists are developing antibodies to track the evolution of these viruses and better treat infections.

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Mutations that occur in the cell lineages of sperm or eggs can be transmitted to offspring. In humans, positive selection of driver mutations during spermatogenesis can increase the birth prevalence of certain developmental disorders1–3. Until recently, characterizing the extent of this selection in sperm has been limited by the error rates of sequencing technologies. Here we used the duplex sequencing method NanoSeq4 to sequence 81 bulk sperm samples from individuals aged 24–75 years. Our findings revealed a linear accumulation of 1.67 (95% confidence interval of 1.41–1.92) mutations per year per haploid genome driven by two mutational signatures associated with human ageing. Deep targeted and exome NanoSeq5 of sperm samples identified more than 35,000 germline coding mutations. We detected 40 genes (31 newly identified) under significant positive selection in the male germline that have activating or loss-of-function mechanisms and are involved in diverse cellular pathways. Most of t

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Metabolism enables life to sustain dynamics and to repeatedly interact with the environment by storing and consuming chemical energy. A major challenge for artificial molecular machines is to find a universal energy source akin to ATP for biological organisms and electricity for electromechanical machines. More than 20 years ago, DNA was first used as fuel to drive nanomechanical devices1,2 and catalytic reactions3. However, each system requires distinct fuel sequences, preventing DNA alone from becoming a universal energy source. Despite extensive efforts4, we still lack an ATP-like or electricity-like power supply to sustain diverse molecular machines. Here we show that heat can restore enzyme-free DNA circuits from equilibrium to out-of-equilibrium states. During heating and cooling, nucleic acids with strong secondary structures reach kinetically trapped states5,6, providing energy for subsequent computation. We demonstrate that complex logic circuits and neural networks, involving

The composition of tricarboxylic acid cycle metabolites in the external environment of cells determines vital physiological functions, including nutrient and mineral absorption, inflammation, and cellular energy management. Here, we study how the transport of external metabolites into the cells functions as an independent metabolic pathway that controls cellular energy. We show that liver cells orchestrate simultaneous fluxes of glucose and the omnipotent metabolite citrate across the cell membrane, acting as a first line metabolic pathway that responds to nutrient availability. Using functional mapping and gene silencing, we delineate the underlying molecular mechanism showing that the liver citrate transporter (NaCT) interacts with glucose transporters (Glut) and the anion transporters. The interaction is mediated by a specific region of the NaCT protein to reciprocally regulate the transport functions. Our findings describe an independent mechanism that coordinates external metaboli

Epigenetic regulation occurs over many rounds of cell division in higher organisms. However, visualisation of the regulators in vivo is limited by imaging dynamic molecules deep in tissue. We report a technology—Variable-angle Slimfield microscopy (SlimVar)—that enables tracking of single fluorescent reporters to 30 µm depth through multiple Arabidopsis thaliana root tip cell layers. SlimVar uses rapid photobleaching to resolve tracked particles to molecular steps in intensity. By modifying widefield microscopy to minimise optical aberrations and robustly post-process few-photon signals, SlimVar mitigates performance losses at depth. We use SlimVar to quantify chromatin-protein assemblies in nuclei, finding that two homologous proteins key to epigenetic switching at FLOWERING LOCUS C (FLC) —cold-induced VERNALISATION INSENSITIVE3 (VIN3) and constitutively expressed VERNALISATION 5 (VRN5)—exhibit dynamic assemblies during FLC silencing. Upon cold exposure, the number of assembly molecul

Bacteriophages are the most abundant entities on earth and exhibit vast genetic and phenotypic diversity. Exploitation of this largely unexplored molecular space requires identification and functional characterization of genes that act at the phage–host interface. So far, this has been restricted to few model phage–host systems that are amenable to genetic manipulation. Here, to overcome this limitation, we introduce a non-genetic mRNA targeting approach using exogenous delivery of programmable antisense oligomers to silence genes of DNA and RNA phages. A systematic knockdown screen of core and accessory genes of the nucleus-forming jumbo phage ΦKZ, coupled to RNA-sequencing and microscopy analyses, reveals previously unrecognized proteins that are essential for phage propagation and that, upon silencing, elicit distinct phenotypes at the level of the phage and host response. One of these factors is the RNase H-like protein ΦKZ155 (also known as Nlp2), which acts at a major decision po

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The global shortage of suitable donor kidneys is the primary challenge in kidney transplantation, and it is exacerbated by ageing donors with increased numbers of health issues. Improving organ assessment, preservation and conditioning could enhance organ utilization and patient outcomes. Hypothermic machine perfusion (HMP) is associated with better results than static cold storage by reducing delayed graft function and improving short-term graft survival, especially in kidneys recovered from marginal-quality donors. Although HMP is useful for organ preservation, it is difficult to assess organ viability during HMP because of the reduced metabolic activity at low temperatures, and the adoption of HMP has faced logistical challenges. The addition of oxygen during HMP is aimed at reducing ischaemia–reperfusion injury, but has shown mixed results in kidney transplantation, often depending on the duration of perfusion, although some studies found that the addition of oxygen improved o

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In mammals, chromosome-wide regulatory mechanisms ensure a balance of X-linked gene dosage between males (XY) and females (XX). In female cells, expression of genes from one of the two X chromosomes is curtailed, with selective accumulation of Xist-RNA, Xist-associated proteins, specific histone modifications (for example, H3K27me3) and Barr body formation observed throughout interphase. Here we show, using chromosome flow-sorting, that during mitosis, Xist-associated proteins dissociate from inactive X (Xi) chromosomes, while high levels of H3K27me3 and increased compaction of the Xi relative to active X (Xa), are retained. Proteomic comparison of mitotic Xi and Xa revealed that components of Hbo1 and Msl/Mof histone acetyltransferase complexes are significantly enriched on Xa as compared to Xi and autosomes. By contrast, inhibitors of histone acetylation co-enrich with Xi. Furthermore, inhibition of Hbo1 or deletion of Msl/Mof components functionally abolishes mitotic differences in

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Enzymes are the molecular machines of life, and a key property that governs their function is substrate specificity—the ability of an enzyme to recognize and selectively act on particular substrates. This specificity originates from the three-dimensional (3D) structure of the enzyme active site and complicated transition state of the reaction1,2. Many enzymes can promiscuously catalyze reactions or act on substrates beyond those for which they were originally evolved1,3-5. However, millions of known enzymes still lack reliable substrate specificity information, impeding their practical applications and comprehensive understanding of the biocatalytic diversity in nature. Herein, we developed a cross-attention-empowered SE(3)-equivariant graph neural network architecture named EZSpecificity for predicting enzyme substrate specificity, which was trained on a comprehensive tailor-made database of enzyme-substrate interactions at sequence and structural levels. EZSpecificity outperformed th

In adult mice, myocardial infarction (MI) activates the cardiac lymphatics, which undergo sprouting angiogenesis (lymphangiogenesis), drain interstitial fluid and traffic macrophages to mediastinal lymph nodes (MLNs). This prevents edema and reduces inflammatory/fibrotic immune cell content to improve cardiac function. Here we investigated the role of cardiac lymphatics and macrophage clearance across the neonatal mouse regenerative window. The response to injury revealed limited lymphangiogenesis and clearance of macrophages from postnatal day 1 compared to postnatal day 7 infarcted hearts. This coincides with the maturation of lymphatic endothelial cell junctions from impermeable to permeable and with altered signaling between lymphatic endothelial cells and macrophages. Mice lacking the lymphatic endothelial receptor-1 (LYVE-1), where macrophage lymphatic trafficking is impaired in adults, experienced worse long-term outcomes after MI induced at postnatal day 1, suggesting an altern

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In dividing cells, chromosomes are coated in a sheath of proteins and RNA called the mitotic chromosome periphery. This sheath is thought to confer biophysical properties to chromosomes, critical for successful cell division. However, the details of chromosome mechanics, and specifically, if and how the chromosome periphery contributes to them, remain poorly understood. In this study, we present a comprehensive characterisation of single-chromosome mechanics using optical tweezers and an improved broadband microrheology analysis. We extend this analysis to direct measurements of the chromosome periphery by manipulating levels of Ki-67, its chief organiser, and apply a rheological model to isolate its contribution to chromosome mechanics. We report that the chromosome periphery governs dynamic self-reorganisation of chromosomes and acts as a structural constraint, providing force-damping properties. This work provides significant insight into chromosome mechanics and will inform our und

Opioid receptors, a subfamily of G protein-coupled receptors (GPCRs), are key therapeutic targets. In the canonical GPCR activation model, agonist binding is required for receptor–G protein complex formation, while antagonists prevent G protein coupling. However, many GPCRs exhibit basal activity, allowing G protein association without an agonist. The pharmacological impact of agonist-free receptor–G protein complexes is poorly understood. Here we present biochemical evidence that certain κ-opioid receptor (KOR) inverse agonists can act via KOR–Gi protein complexes. To investigate this phenomenon, we determined cryo-EM structures of KOR–Gi protein complexes with three inverse agonists: JDTic, norBNI and GB18, corresponding to structures of inverse agonist-bound GPCR–G protein complexes. Remarkably, the orthosteric binding pocket resembles the G protein-free ‘inactive’ receptor conformation, while the receptor remains coupled to the G protein. In summary, our work challenges the canonic