APOE4 impairs the microglial response in Alzheimer's disease by inducing TGFß-mediated checkpoints.

The APOE4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). The contribution of microglial APOE4 to AD pathogenesis is unknown, although APOE has the most enriched gene expression in neurodegenerative microglia (MGnD). Here, we show in mice and humans a negative role of microglial APOE4 in the induction of the MGnD response to neurodegeneration. Deletion of microglial APOE4 restores the MGnD phenotype associated with neuroprotection in P301S tau transgenic mice and decreases pathology in APP/PS1 mice. MGnD-astrocyte cross-talk associated with ß-amyloid (Aß) plaque encapsulation and clearance are mediated via LGALS3 signaling following microglial APOE4 deletion. In the brains of AD donors carrying the APOE4 allele, we found a sex-dependent reciprocal induction of AD risk factors associated with suppression of MGnD genes in females, including LGALS3, compared to individuals homozygous for the APOE3 allele. Mechanistically, APOE4-mediated induction of ITGB8-transforming growth factor-ß (TGFß) signaling impairs the MGnD response via upregulation of microglial homeostatic checkpoints, including Inpp5d, in mice. Deletion of Inpp5d in microglia restores MGnD-astrocyte cross-talk and facilitates plaque clearance in APP/PS1 mice. We identify the microglial APOE4-ITGB8-TGFß pathway as a negative regulator of microglial response to AD pathology, and restoring the MGnD phenotype via blocking ITGB8-TGFß signaling provides a promising therapeutic intervention for AD.

Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy.

Extracellular deposition of amyloid-ß as neuritic plaques and intracellular accumulation of hyperphosphorylated, aggregated tau as neurofibrillary tangles are two of the characteristic hallmarks of Alzheimer's disease1,2. The regional progression of brain atrophy in Alzheimer's disease highly correlates with tau accumulation but not amyloid deposition3-5, and the mechanisms of tau-mediated neurodegeneration remain elusive. Innate immune responses represent a common pathway for the initiation and progression of some neurodegenerative diseases. So far, little is known about the extent or role of the adaptive immune response and its interaction with the innate immune response in the presence of amyloid-ß or tau pathology6. Here we systematically compared the immunological milieux in the brain of mice with amyloid deposition or tau aggregation and neurodegeneration. We found that mice with tauopathy but not those with amyloid deposition developed a unique innate and adaptive immune response and that depletion of microglia or T cells blocked tau-mediated neurodegeneration. Numbers of T cells, especially those of cytotoxic T cells, were markedly increased in areas with tau pathology in mice with tauopathy and in the Alzheimer's disease brain. T cell numbers correlated with the extent of neuronal loss, and the cells dynamically transformed their cellular characteristics from activated to exhausted states along with unique TCR clonal expansion. Inhibition of interferon-γ and PDCD1 signalling both significantly ameliorated brain atrophy. Our results thus reveal a tauopathy- and neurodegeneration-related immune hub involving activated microglia and T cell responses, which could serve as therapeutic targets for preventing neurodegeneration in Alzheimer's disease and primary tauopathies.

Realizing a Superior Conversion Efficiency of ≈11.3% in the Group IV-VI Thermoelectric Module.

GeTe-based materials exhibit superior thermoelectric performance, while the development of power generation devices has mainly been limited by the challenge of designing the interface due to the phase transition in GeTe. In this work, via utilizing the low-temperature nano-Ag sintering technique and screening suitable Ti-Al alloys, a reliable interface with excellent connection performance has been realized. The Ti-Al intermetallic compounds effectively inhibit the diffusion process at Ti-34Al/Ge0.9Sb0.1Te interface. Thus, the thickness of the interfacial reaction layer only increases by ≈2.08 µm, and the interfacial electrical contact resistivity remains as low as ≈15.2 µΩ cm2 even after 30 days of isothermal aging at 773 K. A high conversion efficiency of ≈11.3% has been achieved in the GeTe/PbTe module at a hot-side temperature of 773 K and a cold-side temperature of 300 K. More importantly, the module's performance and the reliability of the interface remain consistently stable throughout 50 thermal cycles and long-term aging. This work promotes the application of high-performance GeTe materials for thermoelectric power generation.

MPFFPSDC: A multi-pooling feature fusion model for predicting synergistic drug combinations.

Drug combination therapies are common practice in the treatment of cancer, but not all combinations result in synergy. As traditional screening approaches are restricted in their ability to uncover synergistic drug combinations, computer-aided medicine is becoming a increasingly prevalent in this field. In this work, a predictive model of potential interactions between drugs named MPFFPSDC is presented, which can maintain the symmetry of drug inputs and eliminate inconsistencies in predictive results caused by different drug inputting sequences or positions. The experimental results show that MPFFPSDC outperforms comparative models in major performance indicators and exhibits better generalization for independent data. Furthermore, the case study demonstrates that our model can capture molecular substructures that contribute to the synergistic effect of two drugs. These results indicate that MPFFPSDC not only offers strong predictive performance, but also has good model interpretability that may provide new insights for the study of drug interaction mechanisms and the development of new drugs.

A newly discovered glycosyltransferase gene UGT88A1 affects growth and polysaccharide synthesis of Grifola frondosa.

Grifola frodosa polysaccharides, especially ß-D-glucans, possess significant anti-tumor, antioxidant and immunostimulatory activities. However, the synthesis mechanism remains to be elucidated. A newly discovered glycosyltransferase UGT88A1 was found to extend glucan chains in vitro. However, the role of UGT88A1 in the growth and polysaccharide synthesis of G. frondosa in vivo remains unclear. In this study, the overexpression of UGT88A1 improved mycelial growth, increased polysaccharide production, and decreased cell wall pressure sensitivity. Biomass and polysaccharide production decreased in the silenced strain, and the pressure sensitivity of the cell wall increased. Overexpression and silencing of UGT88A1 both affected the monosaccharide composition and surface morphology of G. frondosa polysaccharides and influenced the antioxidant activity of polysaccharides from different strains. The messenger RNA expression of glucan synthase (GLS), UTP-glucose-1-phosphate uridylyltransferase (UGP), and UDP-xylose-4-epimerase (UXE) related to polysaccharide synthesis, and genes related to cell wall integrity increased in the overexpression strain. Overall, our study indicates that UGT88A1 plays an important role in the growth, stress, and polysaccharide synthesis of G. frondosa, providing a reference for exploring the pathway of polysaccharide synthesis and metabolic regulation. KEY POINTS: •UGT88A1 plays an important role in the growth, stress response, and polysaccharide synthesis in G. frondosa. •UGT88A1 affected the monosaccharide composition, surface morphology and antioxidant activity of G. frondosa polysaccharides. •UGT88A1 regulated the mRNA expression of genes related to polysaccharide synthesis and cell wall integrity.

The usage and costs of national drug price-negotiated anticancer medicines in a first-tier city in Northeast China: a study based on health insurance data.

BACKGROUND: The National Drug Price Negotiation (NDPN) policy has entered a normalisation stage, aiming to alleviate, to some extent, the disease-related and economic burdens experienced by cancer patients. This study analysed the use and subsequent burden of anticancer medicines among cancer patients in a first-tier city in northeast China. METHODS: We assessed the usage of 64 negotiated anticancer medicines using the data on the actual drug deployment situation, the frequency of medical insurance claims and actual medication costs. The affordability of these medicines was measured using the catastrophic health expenditure (CHE) incidence and intensity of occurrence. Finally, we used the defined daily doses (DDDs) and defined daily doses cost (DDDc) as indicators to evaluate the actual use of these medicines in the region. RESULTS: During the study period, 63 of the 64 medicines were readily available. From the perspective of drug usage, the frequency of medical insurance claims for negotiated anticancer medicines and medication costs showed an increasing trend from 2018 to 2021. Cancer patients typically sought medical treatment at tertiary hospitals and purchased medicines at community pharmacies. The overall quantity and cost of medications for patients covered by the Urban Employee Basic Medical Insurance (UEBMI) were five times higher than those covered by the Urban and Rural Resident Medical Insurance (URRMI). The frequency of medical insurance claims and medication costs were highest for lung and breast cancer patients. Furthermore, from 2018 to 2021, CHE incidence showed a decreasing trend (2.85-1.60%) under urban patients' payment capability level, but an increasing trend (11.94%-18.42) under rural patients' payment capability level. The average occurrence intensities for urban (0.55-1.26 times) and rural (1.27-1.74 times) patients showed an increasing trend. From the perspective of drug utilisation, the overall DDD of negotiated anticancer medicines showed an increasing trend, while the DDDc exhibited a decreasing trend. CONCLUSION: This study demonstrates that access to drugs for urban cancer patients has improved. However, patients' medical behaviours are affected by some factors such as hospital level and type of medical insurance. In the future, the Chinese Department of Health Insurance Management should further improve its work in promoting the fairness of medical resource distribution and strengthen its supervision of the nation's health insurance funds.

Chemical Manipulation of the Spin-Crossover Dynamics through Judicious Metal-Ion Dilution.

In 2019, our groups described a unique FeII complex, [Fe(2MeL)(NCBH3)2] (2MeL = N,N'-dimethyl-N,N'-bis(2-pyridylmethyl)-1,2-ethanediamine) possessing a low-spin ground state that is not easily accessible due to the extremely slow dynamics of the high-spin to low-spin phase transition. Herein, we report the successful chemical manipulation of this spin-crossover (SCO) process through controlled metal-ion dilutions. The emergence or suppression of the thermally induced SCO behavior was observed depending on the radius of the metal ion used for the dilution (NiII or ZnII). Reversible photo-switching has been confirmed in all mixed-metal complexes whether the low-spin state is thermally accessible. Remarkably, the dilution with ZnII metal ions stabilizes HS FeII complexes with complete suppression of the thermally induced SCO process without destroying the reversible photoswitchability of the material.

Infiltrating myeloid cell-derived properdin markedly promotes microglia-mediated neuroinflammation after ischemic stroke.

BACKGROUND: Emerging evidence has shown that myeloid cells that infiltrate into the peri-infarct region may influence the progression of ischemic stroke by interacting with microglia. Properdin, which is typically secreted by immune cells such as neutrophils, monocytes, and T cells, has been found to possess damage-associated molecular patterns (DAMPs) properties and can perform functions unrelated to the complement pathway. However, the role of properdin in modulating microglia-mediated post-stroke neuroinflammation remains unclear. METHODS: Global and conditional (myeloid-specific) properdin-knockout mice were subjected to transient middle cerebral artery occlusion (tMCAO). Histopathological and behavioral tests were performed to assess ischemic brain injury in mice. Single-cell RNA sequencing and immunofluorescence staining were applied to explore the source and the expression level of properdin. The transcriptomic profile of properdin-activated primary microglia was depicted by transcriptome sequencing. Lentivirus was used for macrophage-inducible C-type lectin (Mincle) silencing in microglia. Conditioned medium from primary microglia was administered to primary cortex neurons to determine the neurotoxicity of microglia. A series of cellular and molecular biological techniques were used to evaluate the proinflammatory response, neuronal death, protein-protein interactions, and related signaling pathways, etc. RESULTS: The level of properdin was significantly increased, and brain-infiltrating neutrophils and macrophages were the main sources of properdin in the ischemic brain. Global and conditional myeloid knockout of properdin attenuated microglial overactivation and inflammatory responses at the acute stage of tMCAO in mice. Accordingly, treatment with recombinant properdin enhanced the production of proinflammatory cytokines and augmented microglia-potentiated neuronal death in primary culture. Mechanistically, recombinant properdin served as a novel ligand that activated Mincle receptors on microglia and downstream pathways to drive primary microglia-induced inflammatory responses. Intriguingly, properdin can directly bind to the microglial Mincle receptor to exert the above effects, while Mincle knockdown limits properdin-mediated microglial inflammation. CONCLUSION: Properdin is a new medium by which infiltrating peripheral myeloid cells communicate with microglia, further activate microglia, and exacerbate brain injury in the ischemic brain, suggesting that targeted disruption of the interaction between properdin and Mincle on microglia or inhibition of their downstream signaling may improve the prognosis of ischemic stroke.

The spatiotemporal matching pattern of Ezrin/Periaxin involved in myoblast differentiation and fusion and Charcot-Marie-Tooth disease-associated muscle atrophy.

BACKGROUND: Clinically, Charcot-Marie-Tooth disease (CMT)-associated muscle atrophy still lacks effective treatment. Deletion and mutation of L-periaxin can be involved in CMT type 4F (CMT4F) by destroying the myelin sheath form, which may be related to the inhibitory role of Ezrin in the self-association of L-periaxin. However, it is still unknown whether L-periaxin and Ezrin are independently or interactively involved in the process of muscle atrophy by affecting the function of muscle satellite cells. METHOD: A gastrocnemius muscle atrophy model was prepared to mimic CMT4F and its associated muscle atrophy by mechanical clamping of the peroneal nerve. Differentiating C2C12 myoblast cells were treated with adenovirus-mediated overexpression or knockdown of Ezrin. Then, overexpression of L-periaxin and NFATc1/c2 or knockdown of L-periaxin and NFATc3/c4 mediated by adenovirus vectors were used to confirm their role in Ezrin-mediated myoblast differentiation, myotube formation and gastrocnemius muscle repair in a peroneal nerve injury model. RNA-seq, real-time PCR, immunofluorescence staining and Western blot were used in the above observation. RESULTS: For the first time, instantaneous L-periaxin expression was highest on the 6th day, while Ezrin expression peaked on the 4th day during myoblast differentiation/fusion in vitro. In vivo transduction of adenovirus vectors carrying Ezrin, but not Periaxin, into the gastrocnemius muscle in a peroneal nerve injury model increased the numbers of muscle myosin heavy chain (MyHC) I and II type myofibers, reducing muscle atrophy and fibrosis. Local muscle injection of overexpressed Ezrin combined with incubation of knockdown L-periaxin within the injured peroneal nerve or injection of knockdown L-periaxin into peroneal nerve-injured gastrocnemius muscle not only increased the number of muscle fibers but also recovered their size to a relatively normal level in vivo. Overexpression of Ezrin promoted myoblast differentiation/fusion, inducing increased MyHC-I+ and MyHC-II + muscle fiber specialization, and the specific effects could be enhanced by the addition of adenovirus vectors for knockdown of L-periaxin by shRNA. Overexpression of L-periaxin did not alter the inhibitory effects on myoblast differentiation and fusion mediated by knockdown of Ezrin by shRNA in vitro but decreased myotube length and size. Mechanistically, overexpressing Ezrin did not alter protein kinase A gamma catalytic subunit (PKA-γ cat), protein kinase A I alpha regulatory subunit (PKA reg Iα) or PKA reg Iß levels but increased PKA-α cat and PKA reg II α levels, leading to a decreased ratio of PKA reg I/II. The PKA inhibitor H-89 remarkably abolished the effects of overexpressing-Ezrin on increased myoblast differentiation/fusion. In contrast, knockdown of Ezrin by shRNA significantly delayed myoblast differentiation/fusion accompanied by an increased PKA reg I/II ratio, and the inhibitory effects could be eliminated by the PKA reg activator N6-Bz-cAMP. Meanwhile, overexpressing Ezrin enhanced type I muscle fiber specialization, accompanied by an increase in NFATc2/c3 levels and a decrease in NFATc1 levels. Furthermore, overexpressing NFATc2 or knocking down NFATc3 reversed the inhibitory effects of Ezrin knockdown on myoblast differentiation/fusion. CONCLUSIONS: The spatiotemporal pattern of Ezrin/Periaxin expression was involved in the control of myoblast differentiation/fusion, myotube length and size, and myofiber specialization, which was related to the activated PKA-NFAT-MEF2C signaling pathway, providing a novel L-Periaxin/Ezrin joint strategy for the treatment of muscle atrophy induced by nerve injury, especially in CMT4F.

APOE Antibody Inhibits Aß-Associated Tau Seeding and Spreading in a Mouse Model.

APOE is the strongest genetic factor for late-onset Alzheimer's disease (AD). A specific conformation of the ApoE protein is present in amyloid-ß (Aß) containing plaques. Immunotherapy targeting ApoE in plaques reduces brain Aß deposits in mice. Here, we evaluated the effects of the anti-human APOE antibody HAE-4 on amyloid plaques, Aß-mediated tau seeding and spreading, and neuritic dystrophy in the 5XFAD amyloid mice expressing human ApoE4. HAE-4 reduced Aß plaques as well as Aß-driven tau seeding/spreading and neuritic dystrophy. These results demonstrate that HAE-4 may provide therapeutic effects on amyloid removal and Aß driven downstream consequences such as tauopathy. ANN NEUROL 2022;91:847-852.

Characteristics and prognostic implications of peripheral blood lymphocyte subsets in patients with anti-MDA5 antibody positive dermatomyositis-interstitial lung disease.

OBJECTIVES: To examine the characteristics of blood lymphocyte subsets in dermatomyositis-interstitial lung disease (DM-ILD) inflicted patients with positive anti-melanoma differentiation-associated gene 5 (anti-MDA5), as well as its prognosis value in this set of patients. METHODS: Data were retrospectively collected from 253 DM-ILD patients from three hospitals in China between January 2016 to January 2021. Patients were grouped into anti-MDA5 antibody positive group (MDA5+ DM-ILD) and anti-MDA5 antibody negative group (MDA5- DM-ILD) based on myositis-specific autoantibody test results. Demographic characteristics, lymphocyte subsets patterns and other clinical features were compared between the two groups. The association of lymphocyte subsets with 180-day mortality was investigated using survival analysis in MDA5+ DM-ILD. RESULTS: Out of 253 eligible patients with DM-ILD, 59 patients were anti-MDA5+ and 194 were anti-MDA5-. Peripheral blood lymphocyte count, CD3+ count, percentage of CD3+, CD3+CD4+ count, and CD3+CD8+ count was lower in MDA5+ DM-ILD than in MDA5- DM-ILD- (all P < 0.001) as well as CD3-CD19+ count (P = 0.04). In MDA5+ DM-ILD, CD3+CD8+ count ≤ 49.22 cell/µL (HR = 3.81, 95%CI [1.20,12.14]) and CD3-CD19+ count ≤ 137.64 cell/µL (HR = 3.43, 95%CI [1.15,10.24]) were independent predictors of mortality. CD3+CD8+ count ≤ 31.38 cell/µL was associated with a higher mortality risk in all DM-ILD patients (HR = 8.6, 95%CI [2.12,31.44]) after adjusting for anti-MDA5 and other clinical characteristics. CONCLUSION: Significant lymphocytes decrease was observed in MDA5+ DM-ILD patients. CD3+CD8+ cell count was associated with worse prognosis in both MDA5+ DM-ILD and all DM-ILD patients.

NMR-based metabolomics approach to assess the ecotoxicity of prothioconazole on the earthworm (Eisenia fetida) in soil.

Prothioconazole (PTC) is a widely used agricultural fungicide. In recent years, studies have confirmed that it exerts adverse effects on various species, including aquatic organisms, mammals, and reptiles. However, the toxicological effects of PTC on soil organisms are poorly understood. Here, we investigated the toxic effects, via oxidative stress and metabolic responses, of PTC on earthworms (Eisenia fetida). PTC exposure can induce significant changes in oxidative stress indicators, including the activities of superoxide dismutase (SOD) and catalase (CAT) and the content of glutathione (GSH), which in turn affect the oxidative defense system of earthworms. In addition, metabolomics revealed that PTC exposure caused significant changes in the metabolic profiles of earthworms. The relative abundances of 16 and 21 metabolites involved in amino acids, intermediates of the tricarboxylic acid (TCA) cycle and energy metabolism were significantly altered after 7 and 14 days of PTC exposure, respectively. Particularly, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that multiple different metabolic pathways could be disturbed after 7 and 14 days of PTC exposure. Importantly, these alterations in oxidative stress and metabolic responses in earthworms reveal that the effects of PTC on earthworms were time dependent, and vary with exposure time. In conclusion, this study highlights that the effects of PTC on soil organisms are of serious concern.

Glutathione-Bioimprinted Nanoparticles Targeting of N6-methyladenosine FTO Demethylase as a Strategy against Leukemic Stem Cells.

The N6-methyladenosine (m6 A) demethylase FTO plays an oncogenic role in acute myeloid leukemia (AML). Despite the promising recent progress for developing some small-molecule FTO inhibitors, the clinical potential remains limited due to mild biological function, toxic side effects and low sensitivity and/or specificity to leukemic stem cells (LSCs). Herein, FTO inhibitor-loaded GSH-bioimprinted nanocomposites (GNPIPP12MA) are developed that achieves targeting of the FTO/m6 A pathway synergized GSH depletion for enhancing anti-leukemogenesis. GNPIPP12MA can selectively target leukemia blasts, especially LSCs, and induce ferroptosis by disrupting intracellular redox status. In addition, GNPIPP12MA increases global m6 A RNA modification and decreases the transcript levels in LSCs. GNPIPP12MA augments the efficacy of the PD-L1 blockade by increasing the infiltration of cytotoxic T cells for enhanced anti-leukemia immunity. This study offers insights for a GSH-bioimprinted nanoplatform targeting m6 A RNA methylation as a synergistic treatment strategy against cancer stem cells that may translate to clinical applications.

Highly Stable CsSnCl3 Quantum Dots Grown in an Ionic Liquid/Gelatin Composite System through an In Situ Method.

Lead halide perovskite quantum dots (QDs) are controversial due to their high lead content. Tin, a low-toxic element with an outer electronic structure similar to that of Pb, becomes a strong candidate for preparing lead-free perovskite QDs. However, tin-based perovskite QDs, especially CsSnCl3 QDs, exhibit poor environmental stability. Herein, we proposed an strategy for highly stable CsSnCl3 QDs using an ionic liquid as a solvent and antioxidant and gelatin as a multidentate ligand and coating material through an in situ method ([AMIM]Cl/gelatin-QDs). The results showed that the abundant active groups of gelatin served as the nucleation growth center for QDs and further passivated QDs. At the same time, the long molecular chain of gelatin can coat the QDs to isolate the environment and fully protect QDs, and the size of QDs grown in gelatin was 5-10 nm. In addition, the oxidation resistance of ionic liquids and the halogen-rich environment formed also played an important role. Even if [AMIM]Cl/gelatin-QDs were treated with water and ultraviolet light simultaneously, its remaining fluorescence intensity was still above 60% within 72 h. Meaningfully, QDs endowed the composite system mildew resistance, which can resist the erosion of gelatin by molds, thereby realizing the system's long-term protection toward CsSnCl3 QDs.

Toxicity effects of chlorantraniliprole in zebrafish (Danio rerio) involving in liver function and metabolic phenotype.

Chlorantraniliprole (CAP), a representative bisamide insecticide, is widely used in rice fields around the world, posing potential toxicity risks to aquatic organisms. In this study, we examined the effects of exposure to CAP on growth and metabolic phenotype of zebrafish (Danio rerio) and oxidative stress and apoptosis in the liver of zebrafish (Danio rerio). First, we identified that CAP had a low bioaccumulation in zebrafish. Subsequently, growth phenotype analysis revealed that CAP could significantly increase liver weight and liver index in zebrafish. In addition, we found that CAP exposure could cause significant changes in indicators of oxidative stress, resulting in a significant increase in the content of malondialdehyde (MDA), causing oxidative stress in the liver of zebrafish. Meanwhile, the expression levels of apoptosis-related genes were also significantly changed and apoptosis was promoted in the liver of zebrafish with CAP exposure. Importantly, the results of metabolomics analysis shown that CAP exposure could significantly disrupt the metabolic phenotype of zebrafish, interfering with multiple metabolic pathways, mainly including valine, leucine and isoleucine biosynthesis and degradation, alanine, aspartate and glutamate metabolism and d-glutamine and D-glutamate metabolism. Last but not least, correlation analysis identified strong links between changes in liver function involving oxidative stress and apoptosis and changes in metabolic phenotype of zebrafish following CAP exposure. In brief, these results indicate that potential environmental risks of CAP to aquatic organisms should receive more attention.

Rutaecarpine targets hERG channels and participates in regulating electrophysiological properties leading to ventricular arrhythmia.

Drug-mediated or medical condition-mediated disruption of hERG function accounts for the main cause of acquired long-QT syndrome (acLQTs), which predisposes affected individuals to ventricular arrhythmias (VA) and sudden death. Many Chinese herbal medicines, especially alkaloids, have risks of arrhythmia in clinical application. The characterized mechanisms behind this adverse effect are frequently associated with inhibition of cardiac hERG channels. The present study aimed to assess the potent effect of Rutaecarpine (Rut) on hERG channels. hERG-HEK293 cell was applied for evaluating the effect of Rut on hERG channels and the underlying mechanism. hERG current (IhERG ) was measured by patch-clamp technique. Protein levels were analysed by Western blot, and the phosphorylation of Sp1 was determined by immunoprecipitation. Optical mapping and programmed electrical stimulation were used to evaluate cardiac electrophysiological activities, such as APD, QT/QTc, occurrence of arrhythmia, phase singularities (PSs), and dominant frequency (DF). Our results demonstrated that Rut reduced the IhERG by binding to F656 and Y652 amino acid residues of hERG channel instantaneously, subsequently accelerating the channel inactivation, and being trapped in the channel. The level of hERG channels was reduced by incubating with Rut for 24 hours, and Sp1 in nucleus was inhibited simultaneously. Mechanismly, Rut reduced threonine (Thr)/ tyrosine (Tyr) phosphorylation of Sp1 through PI3K/Akt pathway to regulate hERG channels expression. Cell-based model unables to fully reveal the pathological process of arrhythmia. In vivo study, we found that Rut prolonged QT/QTc intervals and increased induction rate of ventricular fibrillation (VF) in guinea pig heart after being dosed Rut for 2 weeks. The critical reasons led to increased incidence of arrhythmias eventually were prolonged APD90 and APD50 and the increase of DF, numbers of PSs, incidence of early after-depolarizations (EADs). Collectively, the results of this study suggest that Rut could reduce the IhERG by binding to hERG channels through F656 and Y652 instantaneously. While, the PI3K/Akt/Sp1 axis may play an essential role in the regulation of hERG channels, from the perspective of the long-term effects of Rut (incubating for 24 hours). Importantly, the changes of electrophysiological properties by Rut were the main cause of VA.

Thermodriven, Acidity-Driven, and Photodriven Spin-State Switching in Pyridylacylhydrazoneiron(II) Complexes at or above Room Temperature.

The magnetic bistability of spin-crossover (SCO) materials is highly appealing for applications as molecular switches and information storage. However, switching of the spin state around room temperature remains challenging. In this work, we reported the successful manipulation of the spin states of two iron(II) complexes (1-Fe and 2-Fe) based on pyridylacylhydrazone ligands in manifold ways. Both complexes are stabilized in the low-spin (LS) state at room temperature because of the strong ligand-field strength imposed by the ligands. 2-Fe shows thermoinduced SCO above room temperature with a very large and reproducible hysteresis (>50 K), while 1-Fe remains in the LS state up to 400 K. Acidity-driven spin-state switching of the two complexes was achieved at room temperature as a result of the complex dissociation and release of iron(II) in its high-spin (HS) state. Recovery of the complex is feasible upon further alkalization treatment in the case of 1-Fe, allowing bidirectional modulation of the spin state of the metal center. Light-driven one-way switching from LS to HS is also achieved by virtue of E-to-Z isomerization at the C═N double bond, which results in dissociation of the complex because of the poor binding affinity in the Z configuration.

Demoralization and depression in Chinese cancer patients.

OBJECTIVE: Demoralization and depression are common in cancer patients and closely related to suicide. But the association and difference between them are not clear. The aim of this study is to investigate demoralization and depression in Chinese cancer patients. METHODS: This study is a cross-sectional study. Two hundred ninety-six cancer patients completed the questionnaire. First is using the DS-II to evaluate demoralization in advanced cancer patients and using the PHQ-9 to evaluate their depression. Then determine the association between demoralization and depression by Pearson rank correlation test. Finally, an ANOVA was conducted using DS-II as the categorical variable and PHQ-9 as the continuous variable and using PHQ-9 as the categorical variable and DS-II as the continuous variable. RESULTS: There is a positive association between demoralization and depression. A special case that patients with high demoralization but low depression was discovered, which accounted for a large proportion. CONCLUSION: Demoralization and depression are two different psychological states, which require medical staff to identify and take corresponding intervention measures in time. Patients with high demoralization but low depression require further attention.

Hypoglycemic effect of insulin-loaded hydrogel-nanogel composite on streptozotocin-induced diabetic rats.

At present, how to increase insulin rapidly, availably and stably is still a conundrum in the treatment of diabetes mellitus. In vitro studies have shown that insulin can be released from hydrogel-nanogel composite according to the changes of glucose level. This study aimed to observe the glucose-lowering effects and evaluate the safety of the insulin-loaded hydrogel-nanogel composite in diabetic rats. We found that significant glycemic regulation could be observed up to 30 hours after subcutaneous injection, and the fasting blood glucose was reduced effectively. The result of an oral glucose tolerance test showed that the level of insulin expressed a stable increase from 0.5 hours to 3.5 hours, which led to a reduction of glucose with steady steps. Also, compared with Ins group, the Gel+Ins group showed slighter skin and pancreas damage, while the oxidative stress and inflammation response were similar to the normal control group. In conclusion, these results demonstrated that the glucose-lowering action of the insulin-loaded hydrogel-nanogel composite was superior to that of the regular insulin, and might thus become an insulin carrier in the future.

Comparative genomics and analysis of the mechanism of PQQ overproduction in Methylobacterium.

Methylobacterium sp. CLZ was isolated from soil contaminated with chemical wastewater. This strain simultaneously synthesizes Pyrroloquinoline quinone (PQQ), Coenzyme Q10 (CoQ10), and carotenoids by utilizing methanol as a carbon source. Comparative genomic analysis was performed for five Methylobacterium strains. As per the outcomes, the Methylobacterium CLZ strain showed the smallest genome size and the lowest number of proteins. Thus, it can serve as an ideal cell model for investigating the biological process of Methylobacterium and constructing genetically engineered Methylobacterium. The Methylobacterium CLZ strain's pqqL gene, which does not occur in other Methylobacterium strains but plays a crucial role in PQQ synthesis. This was a surprising finding for the study of PQQ biosynthesis in Methylobacterium. Methylobacterium sp. NI91 strain was generated by random mutagenesis of CLZ strain, and NI91 strain showed a 72.44% increase in PQQ yield. The mutation in the mxaJ gene involved in the methanol dehydrogenase (MDH) synthesis was identified through comparative genomic analysis of the whole genome of mutant strain NI91 and wild-type strain CLZ. The mxaJ gene was found to be upregulated in the NI91 strain. Thus, the up-regulation of the mxaJ gene could be correlated with the high yield of PQQ, and it could provide valuable clues for strain engineering to improve PQQ production.