Acetylated tau exacerbates apoptosis by disturbing mitochondrial dynamics in HEK293 cells.

An increase in tau acetylation at K274 and K281 and abnormal mitochondrial dynamics have been observed in the brains of Alzheimer's disease (AD) patients. Here, we constructed three types of tau plasmids, TauKQ (acetylated tau mutant, by mutating its K274/K281 into glutamine to mimic disease-associated lysine acetylation), TauKR (non-acetylated tau mutant, by mutating its K274/K281 into arginine), and TauWT (wild-type human full-length tau). By transfecting these tau plasmids in HEK293 cells, we found that TauWT and TauKR induced mitochondrial fusion by increasing the level of mitochondrial fusion proteins. Conversely, TauKQ induced mitochondrial fission by reducing mitochondrial fusion proteins, exacerbating mitochondrial dysfunction and apoptosis. BGP-15 ameliorated TauKQ-induced mitochondrial dysfunction and apoptosis by improving mitochondrial dynamics. Our findings suggest that acetylation of K274/281 represents an important post-translational modification site regulating mitochondrial dynamics, and that BGP-15 holds potential as a therapeutic agent for mitochondria-associated diseases such as AD.

Eliminating lattice defects in metal-organic framework molecular-sieving membranes.

Metal-organic framework (MOF) membranes are energy-efficient candidates for molecular separations, but it remains a considerable challenge to eliminate defects at the atomic scale. The enlargement of pores due to defects reduces the molecular-sieving performance in separations and hampers the wider application of MOF membranes, especially for liquid separations, owing to insufficient stability. Here we report the elimination of lattice defects in MOF membranes based on a high-probability theoretical coordination strategy that creates sufficient chemical potential to overcome the steric hindrance that occurs when completely connecting ligands to metal clusters. Lattice defect elimination is observed by real-space high-resolution transmission electron microscopy and studied with a mathematical model and density functional theory calculations. This leads to a family of high-connectivity MOF membranes that possess ångström-sized lattice apertures that realize high and stable separation performance for gases, water desalination and an organic solvent azeotrope. Our strategy could enable a platform for the regulation of nanoconfined molecular transport in MOF pores.

BGP-15 alleviates LPS-induced depression-like behavior by promoting mitophagy.

The high prevalence of major depressive disorder (MDD) frequently imposes severe constraints on psychosocial functioning and detrimentally impacts overall well-being. Despite the growing interest in the hypothesis of mitochondrial dysfunction, the precise mechanistic underpinnings and therapeutic strategies remain unclear and require further investigation. In this study, an MDD model was established in mice using lipopolysaccharide (LPS). Our research findings demonstrated that LPS exposure induced depressive-like behaviors and disrupted mitophagy by diminishing the mitochondrial levels of PINK1/Parkin in the brains of mice. Furthermore, LPS exposure evoked the activation of the NLRP3 inflammasome, accompanied by a notable elevation in the concentrations of pro-inflammatory factors (TNF-α, IL-1ß, and IL-6). Additionally, neuronal apoptosis was stimulated through the JNK/p38 pathway. The administration of BGP-15 effectively nullified the impact of LPS, corresponding to the amelioration of depressive-like phenotypes and restoration of mitophagy, prevention of neuronal injury and inflammation, and suppression of reactive oxygen species (ROS)-mediated NLRP3 inflammasome activation. Furthermore, we elucidated the involvement of mitophagy in BGP-15-attenuated depressive-like behaviors using the inhibitors targeting autophagy (3-MA) and mitophagy (Mdivi-1). Notably, these inhibitors notably counteracted the antidepressant and anti-inflammatory effects exerted by BGP-15. Based on the research findings, it can be inferred that the antidepressant properties of BGP-15 in LPS-induced depressive-like behaviors could potentially be attributed to the involvement of the mitophagy pathway. These findings offer a potential novel therapeutic strategy for managing MDD.

Zeolites and metal-organic frameworks for gas separation: the possibility of translating adsorbents into membranes.

Zeolites and metal-organic frameworks (MOFs) represent an attractive class of crystalline porous materials that possesses regular pore structures. The inherent porosity of these materials has led to an increasing focus on gas separation applications, encompassing adsorption and membrane separation techniques. Here, a brief overview of the critical properties and fabrication approaches for zeolites and MOFs as adsorbents and membranes is given. The separation mechanisms, based on pore sizes and the chemical properties of nanochannels, are explored in depth, considering the distinct characteristics of adsorption and membrane separation. Recommendations for judicious selection and design of zeolites and MOFs for gas separation purposes are emphasized. By examining the similarities and differences between the roles of nanoporous materials as adsorbents and membranes, the feasibility of zeolites and MOFs from adsorption separation to membrane separation is discussed. With the rapid development of zeolites and MOFs towards adsorption and membrane separation, challenges and perspectives of this cutting-edge area are also addressed.

Confined-Coordination Induced Intergrowth of Metal-Organic Frameworks into Precise Molecular Sieving Membranes.

Metal-organic framework (MOF) membranes with rich functionality and tunable pore system are promising for precise molecular separation; however, it remains a challenge to develop defect-free high-connectivity MOF membrane with high water stability owing to uncontrollable nucleation and growth rate during fabrication process. Herein, we report on a confined-coordination induced intergrowth strategy to fabricate lattice-defect-free Zr-MOF membrane towards precise molecular separation. The confined-coordination space properties (size and shape) and environment (water or DMF) were regulated to slow down the coordination reaction rate via controlling the counter-diffusion of MOF precursors (metal cluster and ligand), thereby inter-growing MOF crystals into integrated membrane. The resulting Zr-MOF membrane with angstrom-sized lattice apertures exhibits excellent separation performance both for gas separation and water desalination process. It was achieved H2 permeance of ~1200 GPU and H2/CO2 selectivity of ~67; water permeance of ~8 L ⋅ m-2 ⋅ h-1 ⋅ bar-1 and MgCl2 rejection of ~95 %, which are one to two orders of magnitude higher than those of state-of-the-art membranes. The molecular transport mechanism related to size-sieving effect and transition energy barrier differential of molecules and ions was revealed by density functional theory calculations. Our work provides a facile approach and fundamental insights towards developing precise molecular sieving membranes.

Fatal Human Rabies Infection With Suspected Host-Mediated Failure of Post-Exposure Prophylaxis Following a Recognized Zoonotic Exposure-Minnesota, 2021.

BACKGROUND: No human rabies post-exposure prophylaxis (PEP) failure has been documented in the United States using modern cell culture-based vaccines. In January 2021, an 84-year-old male died from rabies 6 months after being bitten by a rabid bat despite receiving timely rabies PEP. We investigated the cause of breakthrough infection. METHODS: We reviewed medical records, laboratory results, and autopsy findings and performed whole-genome sequencing (WGS) to compare patient and bat virus sequences. Storage, administration, and integrity of PEP biologics administered to the patient were assessed; samples from leftover rabies immunoglobulin were evaluated for potency. We conducted risk assessments for persons potentially exposed to the bat and for close patient contacts. RESULTS: Rabies virus antibodies present in serum and cerebrospinal fluid were nonneutralizing. Antemortem blood testing revealed that the patient had unrecognized monoclonal gammopathy of unknown significance. Autopsy findings showed rabies meningoencephalitis and metastatic prostatic adenocarcinoma. Rabies virus sequences from the patient and the offending bat were identical by WGS. No deviations were identified in potency, quality control, administration, or storage of administered PEP. Of 332 persons assessed for potential rabies exposure to the case patient, 3 (0.9%) warranted PEP. CONCLUSIONS: This is the first reported failure of rabies PEP in the Western Hemisphere using a cell culture-based vaccine. Host-mediated primary vaccine failure attributed to previously unrecognized impaired immunity is the most likely explanation for this breakthrough infection. Clinicians should consider measuring rabies neutralizing antibody titers after completion of PEP if there is any suspicion for immunocompromise.

Ion sieving in graphene oxide membranes via cationic control of interlayer spacing.

Graphene oxide membranes-partially oxidized, stacked sheets of graphene-can provide ultrathin, high-flux and energy-efficient membranes for precise ionic and molecular sieving in aqueous solution. These materials have shown potential in a variety of applications, including water desalination and purification, gas and ion separation, biosensors, proton conductors, lithium-based batteries and super-capacitors. Unlike the pores of carbon nanotube membranes, which have fixed sizes, the pores of graphene oxide membranes-that is, the interlayer spacing between graphene oxide sheets (a sheet is a single flake inside the membrane)-are of variable size. Furthermore, it is difficult to reduce the interlayer spacing sufficiently to exclude small ions and to maintain this spacing against the tendency of graphene oxide membranes to swell when immersed in aqueous solution. These challenges hinder the potential ion filtration applications of graphene oxide membranes. Here we demonstrate cationic control of the interlayer spacing of graphene oxide membranes with ångström precision using K+, Na+, Ca2+, Li+ or Mg2+ ions. Moreover, membrane spacings controlled by one type of cation can efficiently and selectively exclude other cations that have larger hydrated volumes. First-principles calculations and ultraviolet absorption spectroscopy reveal that the location of the most stable cation adsorption is where oxide groups and aromatic rings coexist. Previous density functional theory computations show that other cations (Fe2+, Co2+, Cu2+, Cd2+, Cr2+ and Pb2+) should have a much stronger cation-π interaction with the graphene sheet than Na+ has, suggesting that other ions could be used to produce a wider range of interlayer spacings.

Adiponectin deficiency accelerates brain aging via mitochondria-associated neuroinflammation.

BACKGROUND: A wide spectrum of changes occurs in the brain with age, from molecular to morphological aspects, and inflammation accompanied by mitochondria dysfunction is one of the significant factors associated with age. Adiponectin (APN), an essential adipokine in glucose and lipid metabolism, is involved in the aging; however, its role in brain aging has not been adequately explored. Here, we aimed to explore the relationship between APN deficiency and brain aging using multiple biochemical and pharmacological methods to probe APN in humans, KO mice, primary microglia, and BV2 cells. RESULTS: We found that declining APN levels in aged human subjects correlated with dysregulated cytokine levels, while APN KO mice exhibited accelerated aging accompanied by learning and memory deficits, anxiety-like behaviors, neuroinflammation, and immunosenescence. APN-deficient mice displayed aggravated mitochondrial dysfunction and HDAC1 upregulation. In BV2 cells, the APN receptor agonist AdipoRon alleviated the mitochondrial deficits and aging markers induced by rotenone or antimycin A. HDAC1 antagonism by Compound 60 (Cpd 60) improved mitochondrial dysfunction and age-related inflammation, as validated in D-galactose-treated APN KO mice. CONCLUSION: These findings indicate that APN is a critical regulator of brain aging by preventing neuroinflammation associated with mitochondrial impairment via HDAC1 signaling.

δ-Secretase-cleaved Tau stimulates Aß production via upregulating STAT1-BACE1 signaling in Alzheimer's disease.

δ-Secretase, an age-dependent asparagine protease, cleaves both amyloid precursor protein (APP) and Tau and is required for amyloid plaque and neurofibrillary tangle pathologies in Alzheimer's disease (AD). However, whether δ-secretase activation is sufficient to trigger AD pathogenesis remains unknown. Here we show that the fragments of δ-secretase-cleavage, APP (586-695) and Tau(1-368), additively drive AD pathogenesis and cognitive dysfunctions. Tau(1-368) strongly augments BACE1 expression and Aß generation in the presence of APP. The Tau(1-368) fragment is more robust than full-length Tau in binding active STAT1, a BACE1 transcription factor, and promotes its nuclear translocation, upregulating BACE1 and Aß production. Notably, Aß-activated SGK1 or JAK2 kinase phosphorylates STAT1 and induces its association with Tau(1-368). Inhibition of these kinases diminishes stimulatory effect of Tau(1-368). Knockout of STAT1 abolishes AD pathologies induced by δ-secretase-generated APP and Tau fragments. Thus, we show that Tau may not only be a downstream effector of Aß in the amyloid hypothesis, but also act as a driving force for Aß, when cleaved by δ-secretase.

Tau acetylates and stabilizes ß-catenin thereby promoting cell survival.

Overexpressing Tau counteracts apoptosis and increases dephosphorylated ß-catenin levels, but the underlying mechanisms are elusive. Here, we show that Tau can directly and robustly acetylate ß-catenin at K49 in a concentration-, time-, and pH-dependent manner. ß-catenin K49 acetylation inhibits its phosphorylation and its ubiquitination-associated proteolysis, thus increasing ß-catenin protein levels. K49 acetylation further promotes nuclear translocation and the transcriptional activity of ß-catenin, and increases the expression of survival-promoting genes (bcl2 and survivin), counteracting apoptosis. Mutation of Tau's acetyltransferase domain or co-expressing non-acetylatable ß-catenin-K49R prevents increased ß-catenin signaling and abolishes the anti-apoptotic function of Tau. Our data reveal that Tau preserves ß-catenin by acetylating K49, and upregulated ß-catenin/survival signaling in turn mediates the anti-apoptotic effect of Tau.

Copper-Catalyzed Phosphorylation of N,N-Disubstituted Hydrazines: Synthesis of Multisubstituted Phosphorylhydrazides as Potential Anticancer Agents.

An efficient copper-catalyzed aerobic oxidative cross-dehydrogenative coupling reaction for the synthesis of multisubstituted phosphorylhydrazides from N,N-disubstituted hydrazines and hydrogen phosphoryl compounds is accomplished. The reaction proceeds under mild conditions without the addition of any external oxidants and bases. This work reported here represents a direct P(═O)-N-N bond formation with the advantages of being operationally simple, good functional group tolerance, and high atom and step economy. Furthermore, the selected compounds exhibit potential inhibitory activity against tumor cells, which can be used in the field of screening of anticancer agents as new chemical entities.

PDMS with Tunable Side Group Mobility and Its Highly Permeable Membrane for Removal of Aromatic Compounds.

Polydimethylsiloxane (PDMS), as the benchmark of organophilic membrane materials, still faces challenges for removal of aromatic compounds due to the undesirable transport channels. In this work, we propose to reconstruct the PDMS conformation with tunable side group mobility by introducing phenyl as rigid molecular spacer to relieve steric hindrance of large-sized aromatic molecules; meanwhile, polymer segments are loosely stacked to provide additional degrees of freedom as increasing the permeant size. Moreover, the reconstructed PDMS is engineered into the composite membrane with prevention of condensation of aromatic compounds in the substrate pores. The resulting thin-film composite membrane achieved one order of magnitude higher flux (11.8 kg m-2 h-1 ) with an equivalent separation factor (12.3) compared with the state-of-the-art membranes for aromatic removal. The permeant-customized membrane molecular and microstructure designing strategy opens a new avenue to develop membranes for specific separation targets.

Tau accumulation triggers STAT1-dependent memory deficits by suppressing NMDA receptor expression.

Intracellular tau accumulation forming neurofibrillary tangles is hallmark pathology of Alzheimer's disease (AD), but how tau accumulation induces synapse impairment is elusive. By overexpressing human full-length wild-type tau (termed hTau) to mimic tau abnormality as seen in the brain of sporadic AD patients, we find that hTau accumulation activates JAK2 to phosphorylate STAT1 (signal transducer and activator of transcription 1) at Tyr701 leading to STAT1 dimerization, nuclear translocation, and its activation. STAT1 activation suppresses expression of N-methyl-D-aspartate receptors (NMDARs) through direct binding to the specific GAS element of GluN1, GluN2A, and GluN2B promoters, while knockdown of STAT1 by AAV-Cre in STAT1flox/flox mice or expressing dominant negative Y701F-STAT1 efficiently rescues hTau-induced suppression of NMDAR expression with amelioration of synaptic functions and memory performance. These findings indicate that hTau accumulation impairs synaptic plasticity through JAK2/STAT1-induced suppression of NMDAR expression, revealing a novel mechanism for hTau-associated synapse and memory deficits.

Metal- and Oxidant-Free Green Three-Component Desulfurization and Deamination Condensation Approach to Fully Substituted 1H-1,2,4-Triazol-3-amines and Their Photophysical Properties.

A metal- and oxidant-free three-component desulfurization and deamination condensation of amidines, isothiocyanates, and hydrazines for the synthesis of structurally diverse fully substituted 1H-1,2,4-triazol-3-amines is described. The reaction proceeds without the requirement of any external catalysts, metals, ligands, or oxidants. This [2 + 1 + 2] cyclization strategy involves C-N and C-S bond cleavage and the formation of new C-N bonds in one pot. This transformation provides a series of full substituted 1H-1,2,4-triazol-3-amines with advantages of a broad substrates scope, mild reaction conditions, environmental friendliness, and easy gram-scale applications. The fluorescence and aggregation-induced emission (AIE) properties of selected products were further tested. These synthesized 1H-1,2,4-triazol-3-amines may be worth investigating for further applications in the fields of organic chemistry, medicinal chemistry, and optical materials.

Synthesis of Purine Analogues: Photocatalyst-Free Visible-Light-Enhanced Annulation Approach to Pyrazolo[1,5-a][1,3,5]triazine-2,4-diamines.

A new photocatalyst-free visible-light-enhanced strategy for the synthesis of pyrazolo[1,5-a][1,3,5]triazine-2,4-diamines via the formation of electron donor-acceptor (EDA) complexes is reported. The in situ generated pyrazolthiourea intermediates from 1H-pyrazol-3-amines and isothiocyanates undergo formal [4 + 2] annulation with 1,1,3,3-tetramethylguanidines (TMG) to deliver the corresponding products involved in three C-N bond formations in a one-pot protocol. The formation of EDA complex from pyrazolthiourea and TMG is confirmed by UV-vis spectroscopy and 1H NMR experiments. Moreover, this mild reaction proceeds in the absence of any external transition metals, oxidants, bases, and ligands. This efficient methodology for the synthesis of purine analogues pyrazolo[1,5-a][1,3,5]triazine-2,4-diamines provides potential synthetic applications in the field of drug research and development.

Melatonin ameliorates cognitive deficits through improving mitophagy in a mouse model of Alzheimer's disease.

While melatonin is known to have protective effects in mitochondria-related diseases, aging, and neurodegenerative disorders, there is poor understanding of the effects of melatonin treatment on mitophagy in Alzheimer's disease (AD). We used proteomic analysis to investigate the effects and underlying molecular mechanisms of oral melatonin treatment on mitophagy in the hippocampus of 4-month-old wild-type mice versus age-matched 5 × FAD mice, an animal model of AD. 5 × FAD mice showed disordered mitophagy and mitochondrial dysfunction as revealed by increased mtDNA, mitochondrial marker proteins and MDA production, decreased electron transport chain proteins and ATP levels, and co-localization of Lamp1 and Tomm20. Melatonin treatment reversed the abnormal expression of proteins in the signaling pathway of lysosomes, pathologic phagocytosis of microglia, and mitochondrial energy metabolism. Moreover, melatonin restored mitophagy by improving mitophagosome-lysosome fusion via Mcoln1, and thus, ameliorated mitochondrial functions, attenuated Aß pathology, and improved cognition. Concurrent treatment with chloroquine and melatonin blocked the positive behavioral and biochemical effects of administration with melatonin alone. Taken in concert, these results suggest that melatonin reduces AD-related deficits in mitophagy such that the drug should be considered as a therapeutic candidate for the treatment of AD.

Publisher Correction: Mixed matrix formulations with MOF molecular sieving for key energy-intensive separations.

In the version of this Article originally published, the units of the y axis of Fig. 3b were incorrectly given as '106 cm2 s-1'; they should have been '10-8 cm2 s-1'. This has been corrected in the online versions of the Article.

Melatonin prevents neuroinflammation and relieves depression by attenuating autophagy impairment through FOXO3a regulation.

Major depressive disorder (MDD) is a life-threatening illness characterized by mood changes and high rates of suicide. Although the role of neuroinflammation in MMD has been studied, the mechanistic interplay between antidepressants, neuroinflammation, and autophagy is yet to be investigated. The present study investigated the effect of melatonin on LPS-induced neuroinflammation, depression, and autophagy impairment. Our results showed that in mice, lipopolysaccharide (LPS) treatment induced depressive-like behaviors and caused autophagy impairment by dysregulating ATG genes. Moreover, LPS treatment significantly increased the levels of cytokines (TNFα, IL-1ß, IL-6), enhanced NF-ᴋB phosphorylation, caused glial (astrocytes and microglia) cell activation, dysregulated FOXO3a expression, increased the levels of redox signaling molecules such as ROS/TBARs, and altered expression of Nrf2, SOD2, and HO-1. Melatonin treatment significantly abolished the effects of LPS, as demonstrated by improved depressive-like behaviors, normalized autophagy-related gene expression, and reduced levels of cytokines. Further, we investigated the role of autophagy in LPS-induced depressive-like behavior and neuroinflammation using autophagy inhibitors 3-MA and Ly294002. Interestingly, inhibitor treatment significantly abolished and reversed the anti-depressive, pro-autophagy, and anti-inflammatory effects of melatonin. The present study concludes that the anti-depressive effects of melatonin in LPS-induced depression might be mediated via autophagy modulation through FOXO3a signaling.

Molecular Bridges Stabilize Graphene Oxide Membranes in Water.

Recent innovations highlight the great potential of two-dimensional graphene oxide (GO) films in water-related applications. However, undesirable water-induced effects, such as the redispersion and peeling of stacked GO laminates, greatly limit their performance and impact their practical application. It remains a great challenge to stabilize GO membranes in water. A molecular bridge strategy is reported in which an interlaminar short-chain molecular bridge generates a robust GO laminate that resists the tendency to swell. Furthermore, an interfacial long-chain molecular bridge adheres the GO laminate to a porous substrate to increase the mechanical strength of the membrane. By rationally creating and tuning the molecular bridges, the stabilized GO membranes can exhibit outstanding durability in harsh operating conditions, such as cross-flow, high-pressure, and long-term filtration. This general and scalable stabilizing approach for GO membranes provides new opportunities for reliable two-dimensional laminar films used in aqueous environments.

A Separation-Sensing Membrane Performing Precise Real-Time Serum Analysis During Blood Drawing.

Dynamic and on-site analysis of serum from human blood is crucial, however, state-of-the-art blood-assay methods can only collect single or discrete data of physiological analytes; thus, the online reports of the dynamic fluctuation of key analytes remains a great challenge. Here, we propose a novel separation-sensing membrane by constructing a heterogeneous-nanostructured architecture, wherein a surface nanoporous layer continuously extracts serum, while the biosensing nanochannels underneath dynamically recognise biotargets, thereby achieving a continuous testing of vital clinical indices as blood is drawn. By precisely controlling the pore structure and nanoshape of biosensing crystals, this membrane achieved accurate and online glucose and lactate monitoring in patients with a variety of medical conditions within 1 min, which is one order of magnitude faster than state-of-the-art techniques. Moreover, various kinds of bio-recognisers can be introduced into this membrane to accurately detect glutamate, transaminase, and cancer biomarkers.