Diabetes is a disorder of glucose metabolism, and over 90% are type 2 diabetes. Diabetic cardiomyopathy (DCM) is one of the type 2 diabetes complications, usually accompanied by changes in myocardial ...structure and function, together with cardiomyocyte apoptosis. Our study investigated the effect of curcumin on regulating oxidative stress (OS) and apoptosis in DCM. In vivo, diabetes was induced in an experimental rat model by streptozoticin (STZ) together with high‐glucose and high‐fat (HG/HF) diet feeding. In vitro, H9c2 cardiomyocytes were cultured with high‐glucose and saturated free fatty acid palmitate. Curcumin was orally or directly administered to rats or cells, respectively. Streptozoticin ‐induced diabetic rats showed metabolism abnormalities and elevated markers of OS (superoxide dismutase SOD, malondialdehyde MDA, gp91phox, Cyt‐Cyto C), enhanced cell apoptosis (Bax/Bcl‐2, Cleaved caspase‐3, TUNEL‐positive cells), together with reduced Akt phosphorylation and increased Foxo1 acetylation. Curcumin attenuated the myocardial dysfunction, OS and apoptosis in the heart of diabetic rats. Curcumin treatment also enhanced phosphorylation of Akt and inhibited acetylation of Foxo1. These results strongly suggest that apoptosis was increased in the heart of diabetic rats, and curcumin played a role in diabetic cardiomyopathy treatment by modulating the Sirt1‐Foxo1 and PI3K‐Akt pathways.
Conducting polymers (CPs) have been widely studied for electrochemical energy storage. However, the dopants in CPs are often electrochemically inactive, introducing “dead‐weight” to the materials. ...Moreover, commercial‐level electrode materials with high mass loadings (e.g., >10 mg cm−2) often encounter the problems of inferior electrical and ionic conductivity. Here, a redox‐active poly‐counterion doping concept is proposed to improve the electrochemical performance of CPs with ultra‐high mass loadings. As a study prototype, heptamolybdate anion (Mo7O246−) doped polypyrrole (PPy) is synthesized by electro‐polymerization. A 2 mm thick PPy electrode with mass loading of ≈192 mg cm−2 reaches a record‐high areal capacitance of ≈47 F cm−2, competitive gravimetric capacitance of 235 F g−1, and volumetric capacitance of 235 F cm−3. With poly‐counterion doping, the dopants also undergo redox reactions during charge/discharge processes, providing additional capacitance to the electrode. The interaction between polymer chains and the poly‐counterions enhances the electrical conductivity of CPs. Besides, the poly‐counterions with large steric hindrance could act as structural pillars and endow CPs with open structures for facile ion transport. The concept proposed in this work enriches the electrochemistry of CPs and promotes their practical applications.
A redox poly‐counterion doping concept is proposed to synthesize high performance conducting polymers for pseudocapacitive applications. As a study prototype, heptamolybdate anion doped polypyrrole is synthesized via electro‐polymerization. A 2 mm‐thick polypyrrole electrode (active mass: ≈0.2 g cm−2) reaches a record‐high areal capacitance of ≈47 F cm−2 with good rate capability.
Wadsley–Roth phased niobates are promising anode materials for lithium‐ion batteries, while their inherently low electrical conductivity still limits their rate‐capability. Herein, a novel doped ...Mo1.5W1.5Nb14O44 (MWNO) material is facilely prepared via an ionothermal‐synthesis‐assisted doping strategy. The detailed crystal structure of MWNO is characterized by neutron powder diffraction and aberration corrected scanning transmission electron microscope, unveiling the full occupation of Mo6+‐dopant at the t1 tetrahedral site. In half‐cells, MWNO exhibits enhanced fast‐rechargeability. The origin of the improved performance is investigated by ultraviolet–visible diffuse reflectance spectroscopy, density functional theory (DFT) computation, and electrochemical impedance spectroscopy, revealing that bandgap narrowing improves the electrical conductivity of MWNO. Furthermore, operando X‐ray diffraction elucidates that MWNO exhibits a typical solid‐solution phase conversion‐based lithium‐ion insertion/extraction mechanism with reversible structural evolution during the electrochemical reaction. The boosted lithium‐ion diffusivity of MWNO, due to the Mo6+/W6+ doping effect, is confirmed by a galvanostatic intermittent titration technique and DFT. With the simultaneously enhanced electrical conductivity and lithium‐ion diffusivity, MWNO successfully demonstrates its fast‐rechargeability and practicality in the LiNi0.5Mn1.5O4‐coupled full‐cells. Therefore, this work illustrates the potential of ionothermal synthesis in energy storage materials and provides a mechanistic understanding of the doping effect on improving material's electrochemical performance.
A new high‐performance nanoporous Mo1.5W1.5Nb14O44 lithium‐ion battery anode material is facilely prepared by a novel ionothermal‐synthesis‐assisted doping strategy, which concurrently enables the improvement of lithium‐ion diffusivity via a doping effect and a templating effect of the ionic liquid together with the enhancement of electrical conductivity via doping‐induced cation redistribution and bandgap narrowing. Therefore, the obtained Mo1.5W1.5Nb14O44 exhibits superb fast‐rechargeability in half‐cells and full‐cells.
A series of F‐substituted Na2/3Ni1/3Mn2/3O2−xFx (x = 0, 0.03, 0.05, 0.07) cathode materials have been synthesized and characterized by solid‐state 19F and 23Na NMR, X‐ray photoelectron spectroscopy, ...and neutron diffraction. The underlying charge compensation mechanism is systematically unraveled by X‐ray absorption spectroscopy and electron energy loss spectroscopy (EELS) techniques, revealing partial reduction from Mn4+ to Mn3+ upon F‐substitution. It is revealed that not only Ni but also Mn participates in the redox reaction process, which is confirmed for the first time by EELS techniques, contributing to an increase in discharge specific capacity. The detailed structural transformations are also revealed by operando X‐ray diffraction experiments during the intercalation and deintercalation process of Na+, demonstrating that the biphasic reaction is obviously suppressed in the low voltage region via F‐substitution. Hence, the optimized sample with 0.05 mol f.u.−1 fluorine substitution delivers an ultrahigh specific capacity of 61 mAh g−1 at 10 C after 2000 cycles at 30 °C, an extraordinary cycling stability with a capacity retention of 75.6% after 2000 cycles at 10 C and 55 °C, an outstanding full battery performance with 89.5% capacity retention after 300 cycles at 1 C. This research provides a crucial understanding of the influence of F‐substitution on the crystal structure of the P2‐type materials and opens a new avenue for sodium‐ion batteries.
In this cathode system, F‐substitution induces Ni/Mn cation redistribution and disrupts Na ordering. The underlying charge compensation mechanism indicates a partial reduction of Mn4+ to Mn3+ upon F‐substitution and the reduced Mn ions participate in the redox reaction process during cycling, contributing to an increase in discharge specific capacity.
Mare volcanics on the Moon are the key record of thermo-chemical evolution throughout most of lunar history
. Young mare basalts-mainly distributed in a region rich in potassium, rare-earth elements ...and phosphorus (KREEP) in Oceanus Procellarum, called the Procellarum KREEP Terrane (PKT)
-were thought to be formed from KREEP-rich sources at depth
. However, this hypothesis has not been tested with young basalts from the PKT. Here we present a petrological and geochemical study of the basalt clasts from the PKT returned by the Chang'e-5 mission
. These two-billion-year-old basalts are the youngest lunar samples reported so far
. Bulk rock compositions have moderate titanium and high iron contents with KREEP-like rare-earth-element and high thorium concentrations. However, strontium-neodymium isotopes indicate that these basalts were derived from a non-KREEP mantle source. To produce the high abundances of rare-earth elements and thorium, low-degree partial melting and extensive fractional crystallization are required. Our results indicate that the KREEP association may not be a prerequisite for young mare volcanism. Absolving the need to invoke heat-producing elements in their source implies a more sustained cooling history of the lunar interior to generate the Moon's youngest melts.
Macroautophagy/autophagy deficit induces intracellular MAPT/tau accumulation, the hallmark pathology in Alzheimer disease (AD) and other tauopathies; however, the reverse role of MAPT accumulation in ...autophagy and neurodegeneration is not clear. Here, we found that overexpression of human wild-type full-length MAPT, which models MAPT pathologies as seen in sporadic AD patients, induced autophagy deficits via repression of autophagosome-lysosome fusion leading to significantly increased LC3 (microtubule-associated protein 1 light chain 3)-II and SQSTM1/p62 (sequestosome 1) protein levels with autophagosome accumulation. At the molecular level, intracellular MAPT aggregation inhibited expression of IST1 (IST1 factor associated with ESCRT-III), a positive modulator for the formation of ESCRT (the Endosomal Sorting Complex Required for Transport) complex that is required for autophagosome-lysosome fusion. Upregulating IST1 in human MAPT transgenic mice attenuated autophagy deficit with reduced MAPT aggregation and ameliorated synaptic plasticity and cognitive functions, while downregulating IST1 per se induced autophagy deficit with impaired synapse and cognitive function in naïve mice. IST1 can facilitate association of CHMP2B (charged multivesicular body protein 2B) and CHMP4B/SNF7-2 to form ESCRT-III complex, while lack of IST1 impeded the complex formation. Finally, we demonstrate that MAPT accumulation suppresses IST1 transcription with the mechanisms involving the ANP32A-regulated mask of histone acetylation. Our findings suggest that the AD-like MAPT accumulation can repress autophagosome-lysosome fusion by deregulating ANP32A-INHAT-IST1-ESCRT-III pathway, which also reveals a vicious cycle of MAPT accumulation and autophagy deficit in the chronic course of AD neurodegeneration.Abbreviations: AAV: adeno-associated virus; Aβ: β-amyloid; aCSF: artificial cerebrospinal fluid; AD: Alzheimer disease; ANP32A: acidic nuclear phosphoprotein 32 family member A; ATG: autophagy related; AVs: autophagic vacuoles; CEBPB: CCAAT enhancer binding protein beta; CHMP: charged multivesicular body protein; DMEM: Dulbecco's modified eagle's medium; EBSS: Earle's balanced salt solution; EGFR: epidermal growth factor receptor; ESCRT: endosomal sorting complex required for transport; fEPSPs: field excitatory postsynaptic potentials; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GSK3B: glycogen synthase kinase 3 beta; HAT: histone acetyl transferase; HDAC: histone deacetylase; INHAT: inhibitor of histone acetyl transferase; IST1: IST1 factor associated with ESCRT-III; LAMP2: lysosomal associated membrane protein 2; LTP: long-term potentiation; MAP1LC3: microtubule associated protein 1 light chain 3; MAPT/tau: microtubule associated protein tau; MVB: multivesicular bodies; MWM: Morris water maze; PBS: phosphate-buffered saline solution; RAB7: member RAS oncogene family; SNAREs: soluble N-ethylmaleimide-sensitive factor attachment protein receptors; SQSTM1/p62: sequestosome 1
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.
Synopsis
Tau accumulation, one hallmark of Alzheimer's disease, induces synaptic impairment by activating JAK2/STAT1 signaling, which transcriptionally suppresses N‐methyl‐D‐aspartate receptors. Downregulation of STAT1 ameliorates synaptic function and memory performance in mice.
Accumulation of hTau triggers JAK2‐dependent STAT1 dimerization, activation and nuclear translocation.
STAT1 activation directly suppresses N‐methyl‐D‐aspartate receptor expression.
Downregulation of STAT1 rescues hTau‐induced N‐methyl‐D‐aspartate receptor suppression.
Tau accumulation, one hallmark of Alzheimer's disease, induces synaptic impairment by activating JAK2/STAT1 signaling, which transcriptionally suppresses N‐methyl‐D‐aspartate receptors. Downregulation of STAT1 ameliorates synaptic function and memory performance in mice.
Objective： This review focuses on the current knowledge on the implication and significance of beta 2 microglobulin （β2M）, a conservative immune molecule in vertebrate.Data Sources： The data used in ...this review were obtained from PubMed up to October 2015.Terms of β2M, immune response, and infection were used in the search.Study Selections： Articles related to β2M were retrieved and reviewed.Articles focusing on the characteristic and function of β2M were selected.The exclusion criteria of articles were that the studies on β2M-related molecules.Results： β2M is critical for the immune surveillance and modulation in vertebrate animals.The dysregulation of β2M is associated with multiple diseases, including endogenous and infectious diseases.β2M could directly participate in the development of cancer cells, and the level of β2M is deemed as a prognostic marker for several malignancies.It also involves in forming major histocompatibility complex （MHC class Ⅰ or MHC Ⅰ） or like heterodimers, covering from antigen presentation to immune homeostasis.Conclusions： Based on the characteristic of β2M, it or its signaling pathway has been targeted as biomedical or therapeutic tools.Moreover, β2M is highly conserved among different species, and overall structures are virtually identical, implying the versatility of β2M on applications.
Background
Immunohistochemistry (IHC) is an essential technique in surgical and clinical pathology for detecting diagnostic, prognostic, and predictive biomarkers for personalized cancer therapy. ...However, the lack of standardization and reference controls results in poor reproducibility, and a reliable tool for IHC quantification is urgently required. The objective of this study was to describe a novel approach in which H3F3B (histone H3, family 3B) can be used as an internal reference standard to quantify protein expression levels using IHC.
Methods
The authors enrolled 89 patients who had human epidermal growth factor receptor 2 (HER2)‐positive breast cancer (BC). They used a novel IHC‐based assay to measure protein expression using H3F3B as the internal reference standard. H3F3B was uniformly expressed at the protein level in all tumor regions in cancer tissues. HER2 expression levels were measured with the H‐score using HALO software.
Results
Kaplan–Meier analysis indicated that, among patients who had HER2‐positive BC in The Cancer Genome Atlas data set and the authors' data set, the subgroup with low HER2 expression had a significantly better prognosis than the subgroup with high HER2 expression. Furthermore, the authors observed that HER2 expression levels were precisely evaluated using the proposed method, which can classify patients who are at higher risk of HER2‐positive BC to receive trastuzumab‐based adjuvant therapy. Dual‐color IHC with H3F3B is an excellent tool for internal and external quality control of HER2 expression assays.
Conclusions
The proposed IHC‐based quantification method accurately assesses HER2 expression levels and provides insights for predicting clinical prognosis in patients with HER2‐positive BC who receive trastuzumab‐based adjuvant therapy.
The proposed immunohistochemistry‐based quantification method allows accurate assessment of human epidermal growth factor receptor 2 (HER2) protein expression levels. The approach provides insights for predicting the clinical prognosis of patients with HER2‐positive breast cancer who receive trastuzumab‐based adjuvant therapy.
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