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Cardiovascular melanocytes impact atrial reactive fresh air species involved with electrical and constitutionnel remodeling in rodents.
The universe abounds with solid helium in polymorphic forms. Therefore, exploring the allotropes of helium remains vital to our understanding of nature. However, it is challenging to produce, observe and utilize solid helium on the earth because high-pressure techniques are required to solidify helium. Here we report the discovery of room-temperature two-dimensional solid helium through the diamond lattice confinement effect. Controllable ion implantation enables the self-assembly of monolayer helium atoms between 100 diamond lattice planes. Using state-of-the-art integrated differential phase contrast microscopy, we decipher the buckled tetragonal arrangement of solid helium monolayers with an anisotropic nature compressed by the robust diamond lattice. These distinctive helium monolayers, in turn, produce substantial compressive strains to the surrounded diamond lattice, resulting in a large-scale bandgap narrowing up to ~2.2 electron volts. This approach opens up new avenues for steerable manipulation of solid helium for achieving intrinsic strain doping with profound applications.Vascular endothelial cells (ECs) play a central role in the pathophysiology of many diseases. The use of targeted nanoparticles (NPs) to deliver therapeutics to ECs could dramatically improve efficacy by providing elevated and sustained intracellular drug levels. However, achieving sufficient levels of NP targeting in human settings remains elusive. Here, we overcome this barrier by engineering a monobody adapter that presents antibodies on the NP surface in a manner that fully preserves their antigen-binding function. This system improves targeting efficacy in cultured ECs under flow by >1000-fold over conventional antibody immobilization using amine coupling and enables robust delivery of NPs to the ECs of human kidneys undergoing ex vivo perfusion, a clinical setting used for organ transplant. Our monobody adapter also enables a simple plug-and-play capacity that facilitates the evaluation of a diverse array of targeted NPs. This technology has the potential to simplify and possibly accelerate both the development and clinical translation of EC-targeted nanomedicines.Blood lipids are heritable modifiable causal factors for coronary artery disease. Despite well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing (WGS), partly due to limited sample sizes, ancestral diversity, and interpretation of clinical significance. Among 66,329 ancestrally diverse (56% non-European) participants, we associate 428M variants from deep-coverage WGS with lipid levels; ~400M variants were not assessed in prior lipids genetic analyses. We find multiple lipid-related genes strongly associated with blood lipids through analysis of common and rare coding variants. We discover several associated rare non-coding variants, largely at Mendelian lipid genes. Notably, we observe rare LDLR intronic variants associated with markedly increased LDL-C, similar to rare LDLR exonic variants. In conclusion, we conducted a systematic whole genome scan for blood lipids expanding the alleles linked to lipids for multiple ancestries and characterize a clinically-relevant rare non-coding variant model for lipids.Human genetic and animal model studies indicate that brain microglial inflammation is a primary driver of cognitive impairment in Alzheimer Disease (AD). Inflammasome-activated Caspase-1 (Casp1) is associated with both AD microglial inflammation and neuronal degeneration. In mice, Casp1 genetic ablation or VX-765 small molecule inhibition of Casp1 given at onset of cognitive deficits strongly supports the association between microglial inflammation and cognitive impairment. Here, VX-765 significantly improved episodic and spatial memory impairment eight months after the onset of cognitive impairment in aged AD mice with significant amyloid beta peptide (Aβ) accumulation and microglial inflammation. Unexpectedly, while cognitive improvement was associated with dendritic spine density and hippocampal synaptophysin level recovery, VX-765 only slightly decreased Aβ deposition and did not alter biochemically-measured Aβ levels. Furthermore, increased hippocampal Iba1+-microglia, GFAP+-astrocytes, IL-1β, and TNF-α levels were unaltered by VX-765. selleck chemicals llc These results support the hypothesis that neuronal degeneration, not Aβ or microglial inflammation, drives cognitive impairment in AD.HIV-1 eradication is hindered by viral persistence in cell reservoirs, established not only in circulatory CD4+T-cells but also in tissue-resident macrophages. The nature of macrophage reservoirs and mechanisms of persistence despite combined anti-retroviral therapy (cART) remain unclear. Using genital mucosa from cART-suppressed HIV-1-infected individuals, we evaluated the implication of macrophage immunometabolic pathways in HIV-1 persistence. We demonstrate that ex vivo, macrophage tissue reservoirs contain transcriptionally active HIV-1 and viral particles accumulated in virus-containing compartments, and harbor an inflammatory IL-1R+S100A8+MMP7+M4-phenotype prone to glycolysis. Reactivation of infectious virus production and release from these reservoirs in vitro are induced by the alarmin S100A8, an endogenous factor produced by M4-macrophages and implicated in "sterile" inflammation. This process metabolically depends on glycolysis. Altogether, inflammatory M4-macrophages form a major tissue reservoir of replication-competent HIV-1, which reactivate viral production upon autocrine/paracrine S100A8-mediated glycolytic stimulation. This HIV-1 persistence pathway needs to be targeted in future HIV eradication strategies.Neonatal heart undergoes metabolic conversion and cell cycle arrest preparing for the increased workload during adulthood. Herein, we report that neonatal ketone body elevation is a critical regulatory factor for postnatal heart development. Through multiomics screening, we found that the expression of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), the rate-limiting enzyme of ketogenesis, was transiently induced by colostrum in the neonatal heart. Hmgcs2 knockout caused mitochondrial maturation defects. Meanwhile, postnatal heart development was compromised and cardiomyocytes reacquired proliferation capacity in Hmgcs2 knockout mice. Consequently, over 40% of newborn Hmgcs2 knockout mice died before weaning. The heart function of surviving Hmgcs2 knockout mice was also impaired, which could be rescued by ketone body supplementation during the suckling stage. Mechanistically, ketone body deficiency inhibited β-hydroxybutyrylation but enhanced acetylation of mitochondrial proteins, which might be responsible for the inhibition of the enzyme activity in mitochondria. These observations suggest that ketone body is critical for postnatal heart development through regulating mitochondrial maturation and metabolic reprogramming.Mitochondrial ATP synthase forms stable dimers arranged into oligomeric assemblies that generate the inner-membrane curvature essential for efficient energy conversion. Here, we report cryo-EM structures of the intact ATP synthase dimer from Trypanosoma brucei in ten different rotational states. The model consists of 25 subunits, including nine lineage-specific, as well as 36 lipids. The rotary mechanism is influenced by the divergent peripheral stalk, conferring a greater conformational flexibility. Proton transfer in the lumenal half-channel occurs via a chain of five ordered water molecules. The dimerization interface is formed by subunit-g that is critical for interactions but not for the catalytic activity. Although overall dimer architecture varies among eukaryotes, we find that subunit-g together with subunit-e form an ancestral oligomerization motif, which is shared between the trypanosomal and mammalian lineages. Therefore, our data defines the subunit-g/e module as a structural component determining ATP synthase oligomeric assemblies.Discovering multifunctional materials with tunable plasmonic properties, capable of surviving harsh environments is critical for advanced optical and telecommunication applications. We chose high-entropy transition-metal carbides because of their exceptional thermal, chemical stability, and mechanical properties. By integrating computational thermodynamic disorder modeling and time-dependent density functional theory characterization, we discovered a crossover energy in the infrared and visible range, corresponding to a metal-to-dielectric transition, exploitable for plasmonics. It was also found that the optical response of high-entropy carbides can be largely tuned from the near-IR to visible when changing the transition metal components and their concentration. By monitoring the electronic structures, we suggest rules for optimizing optical properties and designing tailored high-entropy ceramics. Experiments performed on the archetype carbide HfTa4C5 yielded plasmonic properties from room temperature to 1500K. Here we propose plasmonic transition-metal high-entropy carbides as a class of multifunctional materials. Their combination of plasmonic activity, high-hardness, and extraordinary thermal stability will result in yet unexplored applications.Stress and craving, it has been found, contribute to the development and maintenance of and relapse in cocaine use disorder. Chronic cocaine users (CU), previous research has shown, display altered physiological responses to psychosocial stress and increased vegetative responding to substance-related cues. However, how psychosocial stress and cue-induced craving interact in relation to the CU's physiological responses remains largely unknown. We thus investigated the interaction between acute psychosocial stress and cocaine-cue-related reactivity in 47 CU and 38 controls. In a crossed and balanced design, the participants were randomly exposed to a video-based cocaine-cue paradigm and the Trier Social Stress Test (TSST) or vice versa to investigate possible mutually augmenting effects of both stressors on physiological stress responses. Over the course of the experimental procedure, plasma cortisol, ACTH, noradrenaline, subjective stress, and craving were assessed repeatedly. To estimate the responses during the cocaine-cue paradigm and TSST, growth models and discontinuous growth models were used. Overall, though both groups did not differ in their endocrinological responses to the TSST, CU displayed lower ACTH levels at baseline. The TSST did not elevate craving in CU, but when the cocaine-cue video was shown first, CU displayed an enhanced cortisol response to the subsequent TSST. In CU, cocaine-cues robustly evoked craving but no physiological stress response, while cue-induced craving was intensified after the TSST. Taken together, though CU did not show an altered acute stress response during the TSST, stress and craving together seemed to have mutually augmenting effects on their stress response.Genetic testing has evolved rapidly over recent years and new developments have the potential to provide insights that could improve the ability to diagnose, treat, and prevent diseases. Information obtained through genetic testing has proven useful in other specialties, such as cardiology and oncology. Nonetheless, a range of barriers impedes techniques, such as whole-exome or whole-genome sequencing, pharmacogenomics, and polygenic risk scoring, from being implemented in psychiatric practice. These barriers may be procedural (e.g., limitations in extrapolating results to the individual level), economic (e.g., perceived relatively elevated costs precluding insurance coverage), or related to clinicians' knowledge, attitudes, and practices (e.g., perceived unfavorable cost-effectiveness, insufficient understanding of probability statistics, and concerns regarding genetic counseling). Additionally, several ethical concerns may arise (e.g., increased stigma and discrimination through exclusion from health insurance).
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