Nuclear speckle rejuvenation alleviates proteinopathies at the expense of YAP1.

Current treatments targeting individual protein quality control have limited efficacy in alleviating proteinopathies, highlighting the prerequisite for a common upstream druggable target capable of global proteostasis modulation. Building on our prior research establishing nuclear speckles as pivotal organelles responsible for global proteostasis transcriptional control, we aim to alleviate proteinopathies through nuclear speckle rejuvenation. We identified pyrvinium pamoate as a small-molecule nuclear speckle rejuvenator that enhances protein quality control while suppressing YAP1 signaling via decreasing the surface tension of nuclear speckle condensates through interaction with the intrinsically disordered region of nuclear speckle scaffold protein SON. In pre-clinical models, pyrvinium pamoate reduced tauopathy and alleviated retina degeneration by promoting autophagy and ubiquitin-proteasome system. Aberrant nuclear speckle morphology, reduced protein quality control and increased YAP1 activity were also observed in human tauopathies. Our study uncovers novel therapeutic targets for tackling protein misfolding disorders within an expanded proteostasis framework encompassing nuclear speckles and YAP1.

Microglial lipid droplet accumulation in tauopathy brain is regulated by neuronal AMPK.

The accumulation of lipid droplets (LDs) in aging and Alzheimer's disease brains is considered a pathological phenomenon with unresolved cellular and molecular mechanisms. Utilizing stimulated Raman scattering (SRS) microscopy, we observed significant in situ LD accumulation in microglia of tauopathy mouse brains. SRS imaging, combined with deuterium oxide (D2O) labeling, revealed heightened lipogenesis and impaired lipid turnover within LDs in tauopathy fly brains and human neurons derived from induced pluripotent stem cells (iPSCs). Transfer of unsaturated lipids from tauopathy iPSC neurons to microglia induced LD accumulation, oxidative stress, inflammation, and impaired phagocytosis. Neuronal AMP-activated protein kinase (AMPK) inhibits lipogenesis and promotes lipophagy in neurons, thereby reducing lipid flux to microglia. AMPK depletion in prodromal tauopathy mice increased LD accumulation, exacerbated pro-inflammatory microgliosis, and promoted neuropathology. Our findings provide direct evidence of native, aberrant LD accumulation in tauopathy brains and underscore the critical role of AMPK in regulating brain lipid homeostasis.

Tunable CO2-to-syngas conversion via strong electronic coupling in S-scheme ZnGa2O4/g-C3N4 photocatalysts.

The conversion of CO2 into syngas, a mixture of CO and H2, via photocatalytic reduction, is a promising approach towards achieving a sustainable carbon economy. However, the evolution of highly adjustable syngas, particularly without the use of sacrifice reagents or additional cocatalysts, remains a significant challenge. In this study, a step-scheme (S-scheme) 0D ZnGa2O4 nanodots (∼7 nm) rooted g-C3N4 nanosheets (denoted as ZnGa2O4/C3N4) heterojunction photocatalyst was synthesized vis a facial in-situ growth strategy for efficient CO2-to-syngas conversion. Both experimental and theoretical studies have demonstrated that the polymeric nature of g-C3N4 and highly distributed ZnGa2O4 nanodots synergistically contribute to a strong interaction between metal oxide and C3N4 support. Furthermore, the desirable S-scheme heterojunction in ZnGa2O4/C3N4 efficiently promotes charge separation, enabling strong photoredox ability. As a result, the S-scheme ZnGa2O4/C3N4 exhibited remarkable activity and selectivity in photochemical conversion of CO2 into syngas, with a syngas production rate of up to 103.3 µ mol g-1 h-1, even in the absence of sacrificial agents and cocatalyst. Impressively, the CO/H2 ratio of syngas can be tunable within a wide range from 1:4 to 2:1. This work exemplifies the effectiveness of a meticulously designed S-scheme heterojunction photocatalyst for CO2-to-syngas conversion with adjustable composition, thus paving the way for new possibilities in sustainable energy conversion and utilization.

Bioorthogonal Stimulated Raman Scattering Imaging Uncovers Lipid Metabolic Dynamics in Drosophila Brain During Aging.

Studies have shown that brain lipid metabolism is associated with biological aging and influenced by dietary and genetic manipulations; however, the underlying mechanisms are elusive. High-resolution imaging techniques propose a novel and potent approach to understanding lipid metabolic dynamics in situ. Applying deuterium water (D2O) probing with stimulated Raman scattering (DO-SRS) microscopy, we revealed that lipid metabolic activity in Drosophila brain decreased with aging in a sex-dependent manner. Female flies showed an earlier occurrence of lipid turnover decrease than males. Dietary restriction (DR) and downregulation of insulin/IGF-1 signaling (IIS) pathway, two scenarios for lifespan extension, led to significant enhancements of brain lipid turnover in old flies. Combining SRS imaging with deuterated bioorthogonal probes (deuterated glucose and deuterated acetate), we discovered that, under DR treatment and downregulation of IIS pathway, brain metabolism shifted to use acetate as a major carbon source for lipid synthesis. For the first time, our study directly visualizes and quantifies spatiotemporal alterations of lipid turnover in Drosophila brain at the single organelle (lipid droplet) level. Our study not only demonstrates a new approach for studying brain lipid metabolic activity in situ but also illuminates the interconnection of aging, dietary, and genetic manipulations on brain lipid metabolic regulation.

Interfacial engineering of heterostructured Fe-Ni3S2/Ni(OH)2 nanosheets with tailored d-band center for enhanced oxygen evolution catalysis.

Hydrogen production by electrochemical water splitting suffers from high kinetic barriers in the anodic oxygen evolution reaction (OER), which limits the overall efficiency. Herein, we report a structural and electronic engineering strategy by integrating self-standing Fe-doped Ni3S2 (denoted by Fe-Ni3S2) nanosheet arrays with Ni(OH)2 subunits to form heterostructured Fe-Ni3S2/Ni(OH)2 on a Ni Foam substrate. The strong electronic interaction between the Fe-Ni3S2 and Ni(OH)2 constituents contributes abundant catalytic sites and ensures high electron transfer. Moreover, the combined experimental and theoretical study revealed that the coupling of Ni(OH)2 onto the Fe-Ni3S2 is favorable for lowering the activation energy of water oxidation for favorable OER kinetics and upshifting the Ni d-band center to facilitate the adsorption of O-containing intermediates. Consequently, the optimized Fe-Ni3S2/Ni(OH)2 hybrid catalyst exhibits excellent OER performance in alkaline electrolytes with an ultralow overpotential of 202 mV at 10 mA cm-2, a small Tafel slope of 50.6 mV dec-1, and long-term durability under high current density (0.25 A cm-2) for up to 60 h without significant deactivation. Moreover, a two-electrode Fe-Ni3S2/Ni(OH)2||Pt/C electrolyzer requires only a low voltage of 1.54 V at 10 mA cm-2 for overall water splitting. This study emphasizes the importance of interface and surface engineering in achieving highly efficient electrocatalysts.

Microneedle Aptamer-Based Sensors for Continuous, Real-Time Therapeutic Drug Monitoring.

The ability to continuously monitor the concentration of specific molecules in the body is a long-sought goal of biomedical research. For this purpose, interstitial fluid (ISF) was proposed as the ideal target biofluid because its composition can rapidly equilibrate with that of systemic blood, allowing the assessment of molecular concentrations that reflect full-body physiology. In the past, continuous monitoring in ISF was enabled by microneedle sensor arrays. Yet, benchmark microneedle sensors can only detect molecules that undergo redox reactions, which limits the ability to sense metabolites, biomarkers, and therapeutics that are not redox-active. To overcome this barrier, here, we expand the scope of these devices by demonstrating the first use of microneedle-supported electrochemical, aptamer-based (E-AB) sensors. This platform achieves molecular recognition based on affinity interactions, vastly expanding the scope of molecules that can be sensed. We report the fabrication of microneedle E-AB sensor arrays and a method to regenerate them for multiple uses. In addition, we demonstrate continuous molecular measurements using these sensors in flow systems in vitro using single and multiplexed microneedle array configurations. Translation of the platform to in vivo measurements is possible as we demonstrate with a first E-AB measurement in the ISF of a rodent. The encouraging results reported in this work should serve as the basis for future translation of microneedle E-AB sensor arrays to biomedical research in preclinical animal models.