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In sub-Saharan Africa, typhoidal and non-typhoidal Salmonella (NTS) are leading causes of invasive disease among young children. Trivalent Salmonella conjugate vaccine (TSCV) consists of Vi capsule polysaccharide conjugated to tetanus toxoid and core-plus-O-polysaccharides from the two most prevalent invasive NTS serovars conjugated to flagellin subunits. We conducted a first-in-human, randomized, placebo-controlled, phase 1 trial evaluating the safety and immunogenicity of TSCV. A total of 22 healthy adults aged 18−45 years were randomly allocated to 6.25-µg TSCV (n = 8), 12.5-µg TSCV (n = 10) or placebo (n = 4). The primary objective was the assessment of safety. The co-primary immunogenicity objective was the serum IgG response against the three vaccine polysaccharides and two flagellin carrier proteins. Here we show that TSCV was safe and well tolerated, meeting the prespecified safety endpoints, with the most common solicited symptom being short-lived injection site pain. For each

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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

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

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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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Fluorescence microscopy has become an indispensable tool to investigate the dynamics of macromolecules directly in living cells on length scales ranging from the nanoscale via super-resolution microscopy (SRM) to the macroscale by light sheet technology. Advances in these microscopy techniques and the desire to perform experiments with high spatial and temporal resolution in living cells increase the requirements imposed on the fluorophores used. Tailor-made synthetic small-molecule fluorophores in combination with innovative labeling strategies help to overcome these challenges and continue to push the boundaries in live-cell microscopy. This Review discusses important advances in improving the performance of synthetic fluorophores for live-cell applications and how synergistic effects can be produced by using clever labeling strategies. We detail how synthetic fluorophores advance different microscopy modalities including live-cell SRM and showcase how they can be implemented into bi

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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

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The survival of antibody-secreting plasma cells is essential for long-lasting humoral immunity. BCMA is proposed to promote APRIL-mediated survival signals. However, extensive shedding of murine BCMA raises doubts about its role as a signaling receptor. To unequivocally establish BCMA’s function in plasma cell survival, we generate two BCMA-deficient mouse lines and examine antigen-specific plasma cells post-immunization. Contrary to previous reports, both BCMA-deficient mouse lines have comparable numbers of antigen-specific long-lived plasma cells following both protein and mRNA immunizations. Transcriptome analysis reveals no reduction in survival signaling upon BCMA deletion. Interestingly, BCMA-deficient mice show increased total plasma cell numbers in the bone marrow and mesenteric lymph nodes after boost immunizations. These results indicate that BCMA has no intrinsic role in maintaining long-lived plasma cells. Instead, we propose that BCMA’s function is limited to acting as a

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This systematic review and network meta-analysis evaluated the efficacy and safety of obesity management medications (OMMs) in terms of reducing body weight and impact on obesity-related complications. Here a Medline and Embase search was performed up to 31 January 2025 for randomized controlled trials comparing OMMs versus placebo/active comparators in adults. Primary endpoint was percentage of total body weight loss (TBWL%) at the end of the study. Secondary endpoints were TBWL% at 1, 2 and ≥3 years, lipid profile, blood pressure, hemoglobin A1c, fasting plasma glucose, mental health, serious adverse events, quality of life, cardiovascular morbidity and mortality, remission of obesity-related complications and all-cause mortality. Fifty-six clinical trials were identified—orlistat (22), semaglutide (14), liraglutide (11), tirzepatide (6), naltrexone/bupropion (5) and phentermine/topiramate (2)—enrolling 60,307 patients (32,598 OMM and 27,709 placebo). All OMMs showed a significantly

In the pre-synapse, vesicle fusion is a crucial process for neurotransmitter release in the nervous system. Under physiological conditions, synaptotagmin-1 (Syt1) locks synaptic vesicles in a priming state, allowing them to undergo synchronized neurotransmitter release upon Ca2+ activation. Elevation of intracellular ions during diseases or injuries may lead to uncontrolled neurotransmitter release independent on Ca2+ influx. However, its underlying molecular mechanism remains elusive. Here we show that elevation of the intracellular Zn2+ concentration leads to the increased frequency of spontaneous neurotransmitter release in hippocampal neurons. In the reconstituted system with neuronal SNAREs and Syt1, Zn2+ markedly enhances the fusion efficiency of liposomes via its binding to the interface between tandem C2 domains of Syt1. Moreover, Syt1 exhibits an elevated capacity to bind to anionic vesicles in the context of interaction with Zn2+, which leads to an augmentation in vesicles do

Chromosome mis-segregation during meiosis in oocytes causes miscarriages and congenital diseases. Ageing-associated premature chromosome separation is a major cause of mis-segregation. Effective prevention of premature chromosome separation has not yet been achieved. Here we design protein-based artificial kinetochores that act as decoys to prevent premature chromosome separation. Designed artificial kinetochore-like decoys are submicroscale clusters of NDC80-NUF2-tethered protein particles that can establish a biorientation-like state by competing with chromosomal kinetochores for HURP-decorated microtubules. This competition reduces excessive bipolar microtubule pulling forces exerted on chromosomes, thereby effectively preventing premature chromosome separation during meiosis I and II in aged mouse oocytes. These effects suppress egg aneuploidy. This study provides a decoy strategy with biocompatible artificial kinetochores to prevent ageing-associated meiotic errors in oocytes. Zho

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