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Activation of l-histidine biosynthesis as a new antibiotic strategy against Mycobacterium tuberculosis
Abstract The increasing prevalence of antimicrobial resistance is an important challenge that warrants new approaches to antibiotic development. Currently, all antibiotics inhibit biological processes. To explore whether activation of a biochemical pathway can elicit bactericidal effects we engineered variants of Mycobacterium tuberculosis ATP-phosphoribosyltransferase (ATP-PRT) that are resistant to allosteric inhibition by l -histidine, leading to supraphysiological activation of ATP-PRT and l -histidine overproduction. Upregulation of L-histidine biosynthesis significantly reduces the growth of M. tuberculosis in culture and causes a loss of fitness owing to nutrient and energy depletion. Moreover, the expression of allosteric variants in M. tuberculosis significantly reduced infections in human macrophages and in a mouse model of infection. Thus, metabolic activation represents a new mycobactericidal mechanism that could be applied to antimycobacterial drug discovery.
Revealing the intrinsic ethical vulnerability of aligned large language models
Supercurrent-controlled spontaneous ferromagnetism of magnetic impurities in a spin-orbit-coupled superconductor
Multi-omic identification of key transcriptional regulatory programs during endurance exercise training in rats
Additive-mediated interfacial engineering of H2SO4-catalyzed isobutane alkylation from molecular design to industrial process intensification
An epithelial morphogenetic program for maximal urine concentration
An ultrafast plenoptic-camera system for high-resolution 3D particle tracking in unsegmented scintillators
Abstract Neutrino detectors, particle calorimeters and some dark matter detectors require dense and massive active materials. An extremely fine segmentation is desirable to achieve precise three-dimensional particle tracking. However, such systems introduce significant challenges in construction and demand a large number of readout electronics channels, leading to extremely high costs. In this article, we propose an alternative approach to elementary particle detection that enables ultrafast three-dimensional high-resolution imaging in large volumes of unsegmented scintillator. Enabling technologies are plenoptic systems and time-resolving single-photon avalanche diode array imaging sensors. Together, they enabled us, using a plenoptic camera, to reconstruct the origin of single photons in the scintillator. A case study focused on neutrino detection demonstrates full event reconstruction with a spatial resolution of two hundred micrometres. This work paves the way for a class of particle detectors whose capabilities should be further enhanced through future developments and expanded to Cherenkov light detection, medical imaging and neutron detection.
Macroscopic particle transport in dissipative long-range bosonic systems
Smallest acyclic tricationic molecule containing a Bis(phosphine)-stabilized low-valent triantimony-based Unit
Proton transfer regulated photocured robust room-temperature phosphorescence from naphthalimide
Abstract Photocured room-temperature phosphorescence (RTP) materials have considerable potential applications but are rarely reported. Here, we reported photocured RTP materials from naphthalimide, which simultaneously acts as RTP chromophore and photo-initiator. Specifically, naphthalimide generates radicals to polymerize acrylic acid and acrylamide upon UV irradiation. The resulting naphthalimide is tightly restricted in in-situ formed crosslinked matrix to achieve robust RTP (τ p = 389.58 ms, φ p = 17.83%, water and organic solvents resistance). Significantly, carboxyl can bind onto lone-pair electrons of tertiary amine in naphthalimide through proton transfer hydrogen-bonds (PTHBs), inhibiting nonradiative decay of S 1 induced by photoinduced electron transfer (PET); increasing spin-orbit coupling (SOC) to promote intersystem crossing (ISC); cooperating with intermolecular hydrogen-bonds afford rigid microenvironment to stabilize triplet excitons. Moreover, afterglow colors are continuously tuned after loading different mass RhB via energy transfer. The as prepared materials are used as RTP inks for fabricating 3D printing and photopatterning for anti-counterfeiting and information encryption applications.
In-utero exposure to chikungunya and child morbimortality: a population-based study using linked routine data
Abstract Chikungunya exposure in-utero is linked to neonatal morbidity and neurodevelopmental effects. We examined the long-term morbidity associated with in-utero Chikungunya. This registry-based cohort study linked records of infants born in Brazil between 2015 and 2018, with all-cause first hospitalization and death as outcome. Infants were followed until the outcome, their third birthday, or the end of the study. Adjusted stratified Cox models were used to estimate hazard ratios (HR), 95% confidence intervals (95% CIs), and absolute risk differences. A total of 1,821 exposed and 18,210 unexposed infants were included. The HR for hospitalization was 1.21 (95% CI: 1.11–1.36), corresponding to 37 excess hospitalizations per 1000 exposed (95% CI: 16-64). The risk was twofold for intrapartum exposure (HR 2.08, 95% CI: 1.33–3.44) and elevated for first- and second-trimester exposure. Evidence for risk of death was limited. Here we show an elevated hospitalization risk associated with in-utero Chikungunya exposure.
X-ray preactivated reversible persistent luminescence enables photodynamic immunotherapy of deep tumors
Flat band induced quasi-one-dimensional magnon transport in a two-dimensional spin lattice
Cell-type-specific immune programs orchestrate spatial defense in the Arabidopsis leaf epidermis
Abstract Sessile plants rely on individual cells to perceive pathogens and coordinate defense. Guard cells (GCs), best known for regulating stomatal aperture, have poorly understood intrinsic immune roles. Here, we integrate single-cell and spatial analyses of Arabidopsis thaliana leaves infected with diverse phytopathogens, combining live and fixed imaging of transgenic immune reporters with single cell transcriptomic data. Powdery mildew infection triggers strong salicylic acid (SA) biosynthesis and transport in pavement cells, spreading to neighboring uninfected cells. In contrast, GCs fail to activate SA biosynthesis or SA-responsive genes. These cell-type-specific immune programs distinguishing GC and pavement cells are conserved across infections by the hemibiotrophic fungus Colletotrichum higginsianum and the bacterial pathogen Pseudomonas syringae . Despite impaired SA signaling and response, GCs display rapid calcium influx and pronounced reactive oxygen species bursts, transmitting immune signals to adjacent pavement cells via the apoplast. Notably, GCs are incompatible with adapted fungal pathogens and underwent hypersensitive cell death. Together, these findings uncover distinct immune programs among epidermal cell types, highlight GC-autonomous defense mechanisms, and provide a framework for understanding spatial immune coordination in plants.
In vivo metabolic tagging and targeting of circulating red blood cells
Abstract Engineering red blood cells (RBCs) has been widely explored for drug delivery, imaging, vaccination, and other applications. However, effective strategies to directly engineer RBCs in vivo are still lacking. Here, we report successful metabolic glycan labeling of RBCs in vivo. We demonstrate that systemically administered azido-sugars can metabolically label circulating RBCs with azido groups, through labeling of both mature RBCs and RBC precursor cells. The surface azido tags on RBCs can persist for over 42 days in female mice (nearly the lifespan of RBCs), while tags on leukocytes decay to negligible levels within 3 days. Azido-labeled RBCs can covalently capture dibenzocyclooctyne-bearing cargos in vivo via click chemistry, extending cargo circulation from hours to over 35 days. This RBC tagging and targeting technology can improve fluorescence imaging of blood vessels, enable long-term MRI of brain vasculatures with a single gadolinium dose, and improve the pharmacokinetics of drugs.