Inhibition of Cdc42 activity extends lifespan and decreases circulating inflammatory cytokines in aged female C57BL/6 mice

Cdc42 is a small RhoGTPase regulating multiple functions in eukaryotic cells. The activity of Cdc42 is significantly elevated in several tissues of aged mice, while the Cdc42 gain‐of‐activity mouse model presents with a premature aging‐like phenotype and with decreased lifespan. These data suggest a causal connection between elevated activity of Cdc42, aging, and reduced lifespan. Here, we demonstrate that systemic treatment of aged (75‐week‐old) female C57BL/6 mice with a Cdc42 activity‐specific inhibitor (CASIN) for 4 consecutive days significantly extends average and maximum lifespan. Moreover, aged CASIN‐treated animals displayed a youthful level of the aging‐associated cytokines IL‐1β, IL‐1α, and INFγ in serum and a significantly younger epigenetic clock as based on DNA methylation levels in blood cells. Overall, our data show that systemic administration of CASIN to reduce Cdc42 activity in aged mice extends murine lifespan.     

Magnesium isotope fractionation during microbially enhanced forsterite dissolution

Bacillus subtilis endospore‐mediated forsterite dissolution experiments were performed to assess the effects of cell surface reactivity on Mg isotope fractionation during chemical weathering. Endospores present a unique opportunity to study the isolated impact of cell surface reactivity because they exhibit extremely low metabolic activity. In abiotic control assays, ²⁴Mg was preferentially released into solution during forsterite dissolution, producing an isotopically light liquid phase (δ²⁶Mg = ?0.39 ± 0.06 to ?0.26 ± 0.09‰) relative to the initial mineral composition (δ²⁶Mg = ?0.24 ± 0.03‰). The presence of endospores did not have an apparent effect on Mg isotope fractionation associated with the release of Mg from the solid into the aqueous phase. However, the endospore surfaces preferentially adsorbed ²⁴Mg from the dissolution products, which resulted in relatively heavy aqueous Mg isotope compositions. These aqueous Mg isotope compositions increased proportional to the fraction of dissolved Mg that was adsorbed, with the highest measured δ²⁶Mg (?0.08 ± 0.07‰) corresponding to the highest degree of adsorption (~76%). The Mg isotope composition of the adsorbed fraction was correspondingly light, at an average δ²⁶Mg of ?0.49‰. Secondary mineral precipitation and Mg adsorption onto secondary minerals had a minimal effect on Mg isotopes at these experimental conditions. Results demonstrate the isolated effects of cell surface reactivity on Mg isotope fractionation separate from other common biological processes, such as metabolism and organic acid production. With further study, Mg isotopes could be used to elucidate the role of the biosphere on Mg cycling in the environment.     

Proteomic signatures of in vivo muscle oxidative capacity in healthy adults

Adequate support of energy for biological activities and during fluctuation of energetic demand is crucial for healthy aging; however, mechanisms for energy decline as well as compensatory mechanisms that counteract such decline remain unclear. We conducted a discovery proteomic study of skeletal muscle in 57 healthy adults (22 women and 35 men; aged 23–87 years) to identify proteins overrepresented and underrepresented with better muscle oxidative capacity, a robust measure of in vivo mitochondrial function, independent of age, sex, and physical activity. Muscle oxidative capacity was assessed by ³¹P magnetic resonance spectroscopy postexercise phosphocreatine (PCr) recovery time (τ_PCr) in the vastus lateralis muscle, with smaller τ_PCr values reflecting better oxidative capacity. Of the 4,300 proteins quantified by LC‐MS in muscle biopsies, 253 were significantly overrepresented with better muscle oxidative capacity. Enrichment analysis revealed three major protein clusters: (a) proteins involved in key energetic mitochondrial functions especially complex I of the electron transport chain, tricarboxylic acid (TCA) cycle, fatty acid oxidation, and mitochondrial ABC transporters; (b) spliceosome proteins that regulate mRNA alternative splicing machinery, and (c) proteins involved in translation within mitochondria. Our findings suggest that alternative splicing and mechanisms that modulate mitochondrial protein synthesis are central features of the molecular mechanisms aimed at maintaining mitochondrial function in the face of impairment. Whether these mechanisms are compensatory attempt to counteract the effect of aging on mitochondrial function should be further tested in longitudinal studies.     

Increased miR‐34c mediates synaptic deficits by targeting synaptotagmin 1 through ROS‐JNK‐p53 pathway in Alzheimer’s Disease

Alzheimer's disease (AD) and cancer have inverse relationship in many aspects. Some tumor suppressors, including miR‐34c, are decreased in cancer but increased in AD. The upstream regulatory pathways and the downstream mechanisms of miR‐34c in AD remain to be investigated. The expression of miR‐34c was detected by RT–qPCR in oxidative stressed neurons, hippocampus of SAMP8 mice, or serum of patients with amnestic mild cognitive impairment (aMCI). Dual luciferase assay was performed to confirm the binding sites of miR‐34c in its target mRNA. The Morris water maze (MWM) was used to evaluate learning and memory in SAMP8 mice administrated with miR‐34c antagomir (AM34c). Golgi staining was used to evaluate the synaptic function and structure. The dramatically increased miR‐34c was mediated by ROS‐JNK‐p53 pathway and negatively regulated synaptotagmin 1 (SYT1) expression by targeting the 3′‐untranslated region (3′‐UTR) of syt1 in AD. The expression of SYT1 protein was reduced by over expression of miR‐34c in the HT‐22 cells and vice versa. Administration of AM34c by the third ventricle injection or intranasal delivery markedly increased the brain levels of SYT1 and ameliorated the cognitive function in SAMP8 mice. The serum miR‐34c was significantly increased in patients with aMCI and might be a predictive biomarker for diagnosis of aMCI. These results indicated that increased miR‐34c mediated synaptic and memory deficits by targeting SYT1 through ROS‐JNK‐p53 pathway and the miR‐34c/SYT1 pathway could be considered as a promising novel therapeutic target for patients with AD.     

Mossy cell synaptic dysfunction causes memory imprecision via miR‐128 inhibition of STIM2 in Alzheimer's disease mouse model

Recently, we have reported that dentate mossy cells (MCs) control memory precision via directly and functionally innervating local somatostatin (SST) inhibitory interneurons. Here, we report a discovery that dysfunction of synaptic transmission between MCs and SST cells causes memory imprecision in a mouse model of early Alzheimer's disease (AD). Single‐cell RNA sequencing reveals that miR‐128 that binds to a 3′UTR of STIM2 and inhibits STIM2 translation is increasingly expressed in MCs from AD mice. Silencing miR‐128 or disrupting miR‐128 binding to STIM2 evokes STIM2 expression, restores synaptic function, and rescues memory imprecision in AD mice. Comparable findings are achieved by directly engineering MCs with the expression of STIM2. This study unveils a key synaptic and molecular mechanism that dictates how memory maintains or losses its details and warrants a promising target for therapeutic intervention of memory decays in the early stage of AD.     

Acetylation changes tau interactome to degrade tau in Alzheimer’s disease animal and organoid models

Alzheimer's disease (AD) is an age‐related neurodegenerative disease. The most common pathological hallmarks are amyloid plaques and neurofibrillary tangles in the brain. In the brains of patients with AD, pathological tau is abnormally accumulated causing neuronal loss, synaptic dysfunction, and cognitive decline. We found a histone deacetylase 6 (HDAC6) inhibitor, CKD‐504, changed the tau interactome dramatically to degrade pathological tau not only in AD animal model (ADLP^APT) brains containing both amyloid plaques and neurofibrillary tangles but also in AD patient‐derived brain organoids. Acetylated tau recruited chaperone proteins such as Hsp40, Hsp70, and Hsp110, and this complex bound to novel tau E3 ligases including UBE2O and RNF14. This complex degraded pathological tau through proteasomal pathway. We also identified the responsible acetylation sites on tau. These dramatic tau‐interactome changes may result in tau degradation, leading to the recovery of synaptic pathology and cognitive decline in the ADLP^APT mice.     

Assessment of the potential bactericide effect of self‐cleaning floors: a proposed protocol

The antibacterial properties of self‐cleaning coatings are based on bactericide nanoparticles (NPs). Ecotoxicity of these NPs have been assessed mostly in suspension, using standard bioassays. Here a protocol is proposed to test actual coating samples, using the Vibrio fischeri bioluminescence inhibition bioassay. The protocol was designed to test bactericide properties of specially coated PVC floors being used in hospital environments under quasinatural conditions, such as prolonged exposure or room temperature. To take into consideration that the light output of the bacteria under prolonged exposure naturally changes, a correction factor is proposed.     

Molten salt synthesis and luminescence of Dy3+‐doped Y3Al5O12 phosphors

Dy³⁺‐doped Y₃Al₅O₁₂ phosphors were prepared at a relatively low temperature using molten salt synthesis. The phase of the prepared Dy³⁺‐doped Y₃Al₅O₁₂ phosphors was confirmed using X‐ray powder diffraction. Results indicated that Dy³⁺ doping did not change the Y₃Al₅O₁₂ phase. Following excitation at 352 nm, emission spectra of the Dy³⁺‐doped Y₃Al₅O₁₂ phosphors consisted of blue, yellow, and red emission bands. The influence of Dy³⁺ concentration and excitation wavelength on emission was investigated. The ratio of yellow light to blue light varied with change in Dy³⁺ doping concentration, due to changes in the structure around Dy³⁺. Emission intensities also changed when the excitation wavelength was changed. This variation is luminescence generated a system for tunable white light for Dy³⁺‐doped Y₃Al₅O₁₂ phosphors.     

Ultrasensitive Deep-Ultraviolet Surface Plasmon Resonance Sensors Using Aluminum-Graphene Metasurface: a Theoretical Insight

Plasmonics - This study investigates a versatile deep-ultraviolet (DUV) surface plasmon resonance (SPR) sensor by integrating a few graphene layers into low-cost aluminum (Al) thin film. The...     

A cost–benefit analysis of the environmental taxation policy in China: A frontier analysis‐based environmentally extended input–output optimization method

China's high‐speed economic development and reliance on overconsumption of natural resources have led to serious environmental pollution. Environmental taxation is seen as an effective economic tool to help mitigate air pollution. In order to assess the effects of different scenarios of environmental taxation policies, we propose a frontier‐based environmentally extended input–output optimization model with explicit emission abatement sectors to reflect the inputs and benefits of abatement. Frontier analysis ensures policy scenarios are assessed under the same technical efficiency benchmark, while input–output analysis depicts the wide range of economic transactions among sectors of an economy. Four scenarios are considered in this study, which are increasing specific tax rates of SO₂, NO_x, and soot and dust separately and increasing all three tax rates simultaneously. Our estimation results show that: raising tax rates of SO₂, NO_x, and soot and dust simultaneously would have the highest emission reduction effects, with the SO₂ tax rate making the greatest contribution to emission reduction. Raising the soot and dust tax rate is the most environmentally friendly strategy due to its highest abatement to welfare through avoided health costs. The combination of frontier analysis and input–output analysis provides policy makers a comprehensive and sectoral approach to assess costs and benefits of environmental taxation.