The synergistic effect of curcumin and mitoquinol mesylate on cognitive impairment and the neuropathology of Alzheimer's disease.

Given the complexity and heterogeneity of Alzheimer's disease (AD) pathology, targeted monotherapy drugs may not be effective. Therefore, synergistic combination therapy of curcumin and Mito Q was proposed and evaluated in a triple-transgenic AD model mice (3 × Tg-AD mice). The cognitive ability was assessed using behavioral tests and typical pathological changes were observed through Western blotting and histological analysis. The results demonstrated a significant enhancement in cognitive ability along with the mitigation of typical AD pathological features such as Aß aggregation, tau phosphorylation, and synaptic damage. Notably, the combination therapy demonstrated superior efficacy over individual drugs alone. These findings provide valuable insights for optimizing the development of AD drugs.

Mechanical properties of rock under uniaxial compression tests of different control modes and loading rates.

To study the influence of control mode and loading rate on mechanical property of rock, uniaxial compression tests of four types of rocks (gray sandstone, red sandstone, mudstone and granite) are carried out under axial strain control mode and lateral strain control mode respectively. The characteristics of complete stress and strain curves, strength, brittleness and failure modes are analyzed. The results show that control mode has little influence on the pre-peak deformation, stress thresholds, while it has a greater impact on post-peak stress and strain curve, which makes the post-peak deformation stable and controllable, and shows the feature of Class II behavior. With lateral loading rates decrease, post-peak stress and strain curves appear more and more obvious fluctuations in the post-peak stage, and the time required for rock failure increases sharply, but the lateral control rate has little effect on the brittleness of rock. The failure mode of rock samples under axial strain control mode is mainly splitting failure, while that under lateral strain control is gradually changed to shear failure. The smaller the lateral loading control rate is, the more obvious the characteristics of shear failure is. Compared with uniaxial compression tests, under high confining pressure, the lateral dilation deformation is restricted, so peak strength is larger and stress redistribution can be better adjusted and stress fluctuation reduced accordingly in post-peak stage. The research results are an effective supplement to rate-dependent property of rocks and can provide some reference for deformation and strength characteristics research of brittle rock under lateral control mode.

ER-α36 is involved in calycosin inhibition of IL-6 production in macrophages.

The tumour microenvironment (TME) is crucial for tumour development and progression. Tumour-associated macrophages (TAMs) in the TME can promote tumour progression and metastasis by releasing cytokines, such as IL-6. Calycosin, a phytoestrogen that is one of the active compounds in Radix Astragali, has been shown to inhibit tumour growth and metastasis. However, the underlying mechanism by which calycosin inhibits tumour growth remains unclear. Thus, this study aimed to investigate the effect of calycosin on IL-6 production in peripheral blood mononuclear cell (PBMC)- and THP-1-derived macrophages and explore its potential mechanisms using co-immunoprecipitation, western blotting, immunofluorescence, chromatin immunoprecipitation and luciferase assays. We found that calycosin treatment substantially upregulated the expression of ER-α36, a variant of the ER, and reduced IL-6 production in macrophages. Mechanistically, ER-α36 physically interacted with NF-κBp65 and retained p65 in the cytoplasm to attenuate NF-κB function as an IL-6 transcriptional inducer. In conclusion, our result indicated that calycosin inhibited IL-6 production by enhancing ER-α36 expression and its interaction with p65, which attenuated NF-κB function as an IL-6 inducer. Therefore, calycosin can be developed as an effective agent for cancer therapy by targeting TAMs.

Screening for Fungicide Efficacy in Controlling Blackleg Disease in Wasabi (Eutrema japonicum).

Blackleg disease is devastating for wasabi (Eutrema japonicum) production, occurring at any time and everywhere within the main production area of the Sichuan Province, China. There have been very few studies on the chemical control of this disease. In this study, we isolated and identified a local popular strain of the pathogen Plenodomus wasabiae. The isolated fungus strain caused typical disease spots on the leaves and rhizomes upon inoculation back to wasabi seedlings. The symptoms of blackleg disease developed very quickly, becaming visible on the second day after exposure to P. wasabiae and leading to death within one week. We then evaluated the efficacy of ten widely used fungicides to screen out effective fungicides. The efficacy of the tested fungicides was determined through mycelial growth inhibition on medium plates. As a result, tebuconazole and pyraclostrobin were able to inhibit the mycelial growth of P. wasabiae, and the most widely used dimethomorph in local production areas produced the lowest inhibition activity (13.8%). Nevertheless, the highest control efficacy of tebuconazole and pyraclostrobin on wasabi seedlings was only 47.48% and 39.03%, respectively. Generally, the control efficacy of spraying the fungicide before inoculation was better than that after inoculation. An increase in the application concentration of the two fungicides did not proportionately result in improved performance. We cloned the full-length sequence of sterol 14-demethylase (CYP51) and cytochrome B (CYTB) of which the mutations may contribute to the possible antifungalresistance. These two genes of the isolated fungus do not possess any reported mutations that lead to fungicide resistance. Previous studies indicate that there is a significant difference between fungicides in terms of the effectiveness of controlling blackleg disease; however, the control efficacy of fungicides is limited in blackleg control. Therefore, field management to prevent wound infection and unfavorable environmental conditions are more important than pesticide management.

A corticoamygdalar pathway controls reward devaluation and depression using dynamic inhibition code.

Reward devaluation adaptively controls reward intake. It remains unclear how cortical circuits causally encode reward devaluation in healthy and depressed states. Here, we show that the neural pathway from the anterior cingulate cortex (ACC) to the basolateral amygdala (BLA) employs a dynamic inhibition code to control reward devaluation and depression. Fiber photometry and imaging of ACC pyramidal neurons reveal reward-induced inhibition, which weakens during satiation and becomes further attenuated in depression mouse models. Ablating or inhibiting these neurons desensitizes reward devaluation, causes reward intake increase and ultimate obesity, and ameliorates depression, whereas activating the cells sensitizes reward devaluation, suppresses reward consumption, and produces depression-like behaviors. Among various ACC neuron subpopulations, the BLA-projecting subset bidirectionally regulates reward devaluation and depression-like behaviors. Our study thus uncovers a corticoamygdalar circuit that encodes reward devaluation via blunted inhibition and suggests that enhancing inhibition within this circuit may offer a therapeutic approach for treating depression.

Absorption, translocation, and accumulation of the fungicide triadimefon in Pak choi (Brassica rapa var chinensis), pepper (Capsicum annuum), and cucumber (Cucumis sativus).

Triadimefon is a typical systemic fungicide that is widely used in the management of powdery mildew, rust disease, and southern blight. In this study, we measured fungicide residue to profile its absorption, translocation, and accumulation in three representative vegetable crops (Pak choi, cucumber, and pepper) after over-application. The fungicides were applied through entire-plant spraying (EPS), root-irrigation (RI), and middle-leaf-daubing (MLD). The half-life of triadimefon depends on the application method and plant species. In EPS, the half-life was 5.42 days (Pak choi), 6.86 days (cucumber), and 6.73 days (pepper), while in RI it was 4.39 days (Pak choi), 6.30 days (cucumber), and 5.98 days (pepper). In the EPS treatment, triadimefon is translocated both upward/outside and downward/inner-side from the daubed leaves in all the three vegetable crops. The transfer amount to each organ reached a peak on the 2nd day after fungicide application. The mesophyll of Pak choi exhibited a higher fungicide deposition compared to the petiole. In cucumber and pepper, the leaves demonstrated the highest accumulation of triadimefon (approximately 0.3-0.5 mg·kg-1), followed by stems. Roots and fruits displayed the lowest levels of triadimefon accumulation. Furthermore, triadimefon was found to have an impact on chlorophyll content, root activity, as well as the activity of superoxide dismutase and catalase in Pak choi, indicating its potential as a plant growth regulator. These aforementioned studies provide novel insights for the safe and efficient application of triadimefon in the production of Pak choi, cucumber, and pepper.

Zinc exacerbates tau-induced Alzheimer-like pathology in C57BL/6J mice.

The pathogenesis of Alzheimer's disease (AD) is highly complex and multifactorial. Compared with Aß, the pathological changes associated with tau are more related to the clinical symptoms and more indicative of the severity of AD. Studies have shown that the direct interaction between tau and Zn2+ plays an important role in tau toxicity, however, the mechanism by which Zn2+ contributes to tau-induced neurotoxicity is not fully understood. Our previous studies have found that Zn2+ bound to the third repeat unit of the microtubule-binding domain of tau (R3) with moderate affinity and induced R3 to form oligomers, thus increased the toxicity of R3 to nerve cells. Here, we demonstrated that Zn2+ binding to R3 (Zn2++R3) significantly reduced cognitive ability and increased blood lipid and glucose levels of C57BL/6J mice. In addition, Zn2++R3, not Zn2+ or R3 alone, markedly enhanced the endogenous Aß and tau pathology and damaged the neurons of C57BL/6J mice. The study suggests that the main reason for the toxicity of Zn2+ may be the formation of Zn2+ and tau complex. Thus, preventing the combination of Zn2+ and tau may be a potential strategy for AD treatment. Furthermore, as the C57BL/6J mice injected with Zn2++R3 complex showed behavioral deficits, deposition of Aß plaques and tau tangles, and the death of neurons within 45 days. Thus, they can be considered as a fast sporadic AD or other tauopathies mouse model.

Revisiting the mechanisms of mid-Tertiary uplift of the NE Tibetan Plateau.

Contrasting views exist on timing and mechanisms of Tertiary crustal uplift in the NE Tibetan Plateau based on different approaches, with many models attributing surface uplift to crustal shortening. We carry out a comprehensive investigation of mid-Tertiary stratigraphy, sedimentology, and volcanism in the West Qinling, Hoh Xil and Qaidam basin, and the results challenge previous views. It was held that the discordance between Oligocene and Miocene strata is an angular unconformity in the West Qinling, but our field observations show that it is actually a disconformity, indicative of vertical crustal uplifting rather than crustal shortening at the Oligocene to Miocene transition. Widespread occurrence of synsedimentary normal faults in mid-Tertiary successions implicates supracrustal stretching. Miocene potassic-ultrapassic and mafic-ultramafic volcanics in the Hoh Xil and West Qinling suggest a crucial role of deep thermomechanical processes in generating crust- and mantle-sourced magmatism. Also noticeable are the continuity of mid-Tertiary successions and absence of volcanics in the Qaidam basin. Based on a holistic assessment of stratigraphic-sedimentary processes, volcanic petrogenesis, and spatial variations of lithospheric thicknesses, we speculate that small-sale mantle convection might have been operating beneath northeast Tibet in the mid-Tertiary. It is assumed that northward asthenospheric flow was impeded by thicker cratonic lithosphere of the Qaidam and Alxa blocks, thereby leading to edge convection. The edge-driven convection could bring about surface uplift, induce supracrustal stretching, and trigger vigorous volcanism in the Hoh Xil and West Qinling in the mid-Tertiary period. This mechanism satisfactorily explains many key geologic phenomena that are hardly reconciled by previous models.

Fluorescent probes based on the core-shell structure of molecular imprinted materials and gold nanoparticles for highly selective glutathione detection.

Glutathione (GSH) is a polypeptide with important physiological functions. Real-time and accurate detection of GSH is of great significance for clinical diagnosis, disease treatment and pathogen detection. A fluorescent nanosensor based on composite core-shell nanoparticles for the highly selective detection of GSH is reported. In the cores, the fluorescence of rhodamine b was quenched by using gold nanoparticles (AuNPs), and GSH could competitively combine with AuNPs to cause rhodamine b to fall off, thereby recovering the fluorescence. In the shell part, molecularly imprinted materials using oxidized glutathione (GSSG) as a pseudotemplate provide GSH/GSSG specific pores and improve the specificity and anti-interference ability of the sensor. The GSH sensor has a detection range of 0-100 µM and limit of detection (LOD) of 0.18 µM, and robust sensing performance in fetal bovine serum, indicating its great potential for clinical diagnosis.

Ebselen Interferes with Alzheimer's Disease by Regulating Mitochondrial Function.

(1) Background: With unknown causes and no effective treatment available, Alzheimer's disease (AD) places enormous pressure on families and society. Our previous study had shown that Ebselen at a high concentration (10.94 µM) improved the cognition of triple-transgenic AD (3×Tg-AD) mice and alleviated the related pathological indicators but showed toxicity to the mice. Here, we dedicated to study the therapeutic effect and molecular mechanism of Ebselen at a much lower concentration on 3×Tg-AD mice. (2) Methods: Various behavioral experiments were applied to detect the behavioral ability of mice. Western blot, thioflavin T staining and a transmission electron microscope were used to evaluate the pathology of AD mice. The mitochondrial membrane potential and respiration were assessed with the corresponding assay kit. (3) Results: Ebselen remarkably increased cognitive ability of AD mice, eliminated ß-Amyloid (Aß) oligomers and recovered the synaptic damage in AD mice brain. In addition, the destroyed mitochondrial morphologies and function were repaired by Ebselen through ameliorating mitochondrial energy metabolism, mitochondrial biogenesis and mitochondrial fusion/fission balance in N2a-SW cells and brain tissues of AD mice. (4) Conclusions: This research indicated that Ebselen might exert its therapeutic effect via protecting mitochondria in AD.

Investigating HPV- and HPV Vaccine-Related Knowledge, Perceptions, and Information Sources among Health Care Providers in Three Big Cities in China.

The limited access to vaccination and vaccine hesitancy are prevalent even among health care providers in less developed countries. This study assessed the relationships between (i) health care providers' knowledge on human papillomavirus (HPV) and vaccination for HPV and (ii) their perceptions, demographic characteristics, and the use of information sources. In this large-scale online survey, participants (n = 1394) were recruited from hospitals of three big cities in China (Shanghai, Guangzhou, and Shenzhen). Descriptive analysis, the chi-square test, and logistic regression analysis were used to answer different research questions. Health care providers' overall knowledge scores are consistent with their perceptions about HPV and HPV vaccine. Occupation, specialty, the type of hospitals, and the frequency of participants' search for information using professional informational sources are the most significant characteristics that are closely associated with their knowledge of HPV and its vaccine. Targeted educational interventions are needed to improve health care providers' engagement in the promotion of the HPV vaccine. Such interventions, besides increasing knowledge, should also emphasize the importance of appropriate information sources to acquire information.

Inactivation of Rab27B-dependent signaling pathway by calycosin inhibits migration and invasion of ER-negative breast cancer cells.

Previous studies report the upregulation of the secretory Rab27B small GTPase in human breast cancer, which could promote invasive growth and metastasis in estrogen receptor (ER)-positive breast cancer cells. However, there is limited evidence for its role in ER-negative breast cancer, along with the signaling pathways. Consistent with previous studies, we here confirmed that Rab27B is upregulated in breast tumor tissue in comparison with normal breast tissue. In addition, in ER-negative breast cancer cell line MDA-MB-231, when the levels of Rab27B expression were further elevated by transduction with recombinant lentivirus vector, migration and invasion assays demonstrated that cell migration and invasion was significantly stimulated. Moreover, Rab27B overexpression increased levels of ß-catenin, followed by upregulation of vascular endothelial growth factor (VEGF). Our findings reveal a key function for the Rab27B-mediated modulation of ß-catenin and VEGF in ER-negative breast cancer cell metastasis. Notably, the suppressed expression of Rab27B, ß-catenin and VEGF was found in calycosin-treated MDA-MB-231 cells, accompanied with decreased invasive and migratory potential of these cells. What's more, these inhibitory effects of calycosin were all attenuated by Rab27B overexpression. The results demonstrated that calycosin-induced inhibition of migration and invasion in ER-negative breast cancer cells may be associated with the inactivation of Rab27B-dependent signaling, and suggest that antagonism of this pathway by calycosin may offer alternative therapeutic strategy for the aggressive breast cancer.

A novel dominant mutation in the SOX10 gene in a Chinese family with Waardenburg syndrome type II.

Waardenburg syndrome type 2 (WS2) is a rare genetic disorder, characterized by bright blue eyes, moderate to profound hearing loss and pigmental abnormalities of the hair and skin. Between 10 and 20 mutations in the SRY­box 10 (SOX10) gene were previously identified to be associated with WS2. The present study aimed to identify the genetic causes of WS2 in a Chinese family. Clinical and molecular analyses were performed to genetically characterize a Chinese family with two cases of WS2. The clinical data of the proband were collected using a questionnaire. The genomic DNA was extracted from peripheral blood samples of each individual in the family, and 168 candidate genes associated with hearing loss were sequenced using the Illumina HiSeq 2000 and confirmed by Sanger sequencing. A heterozygous nonsense mutation [substitution; position 127; cytosine to thymine (c.127C>T)] was identified in exon 2 of SOX10 (transcript ID: NM_006941.3) in the proband and the mother; however, not in other family members or healthy controls. The novel nonsense heterozygous mutation may cause the replacement of codon 43 [arginine (Arg)] with a stop codon (Arg43stop), leading to premature termination of protein translation. The novel nonsense heterozygous mutation c.127C>T in the SOX10 gene was considered to be the cause of WS2 in the family. This mutation has not been identified in any databases, to the best of the authors' knowledge, including The Single Nucleotide Polymorphism Database, The Human Gene Mutation Database, 1000 Genomes Project and ClinVar and Exome Sequencing Project v. 6500.

A method for determining density based on gamma ray and fast neutron detection using a Cs2LiYCl6 detector in neutron-gamma density logging.

With the increasing demand for radioisotope-free operations, pulsed neutron-gamma density (NGD) has become increasingly important for logging-while-drilling (LWD) development. However, current NGD tools, adopting the multiple-detector array design, are not conducive to the simplification of instrument design and measurement system. To break obstacles, based on the fast neutron-gamma coupled theory, a new density measurement method was proposed. Further, combined with the neutron-gamma simultaneous detection characteristics of the Cs2LiYCl6 (CLYC) detector, an NGD measurement system consisting of a D-T source and one CLYC detector was used. Results show that the new method is capable of determining formation density using a single CLYC detector, which can not only avoid complex instrument systems but also improve density sensitivity. Moreover, the applicability of the new density method was well verified by Monte Carlo simulation. Additionally, the method was successfully applied in a simulated well, and density results are in good agreement with the benchmarked formations. The research provides theoretical guidance for NGD instrument design.

Calycosin Inhibits the Migration and Invasion of Human Breast Cancer Cells by Down-Regulation of Foxp3 Expression.

BACKGROUND/AIMS: Calycosin, a phytoestrogenic compound, has recently emerged as a promising antitumor drug. It has been shown that calycosin suppresses growth and induces apoptosis of breast cancer cells. However, the effect of calycosin on migration and invasion of breast cancer cells and the underlying molecular mechanisms have not been elucidated. METHODS: Human breast cancer cells MCF-7 and T47D were treated with, or without, different doses (0, 6.25, 12.5, 25, 50, 100 or 150 µM) of calycosin, and the viability of different groups was determined by MTT assay. Next, the inhibitory effect of higher doses (50, 100 or 150 µM) of calycosin on migration and invasion of the two cell lines was determined by wound healing and transwell assay. The relative expression levels of forkhead box P3 (Foxp3), vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) in MCF-7 and T47D cells were determined by quantitative RT-PCR and Western blot. RESULTS: Treatment with lower doses (6.25 or 12.5 µM) promoted proliferation of breast cancer cells, but with higher doses significantly reduced the viability of MCF-7 and T47D cells. Furthermore, higher doses of calycosin were found to inhibit migration and invasion of the two cell lines in a dose-dependent manner. Additionally, treatment with a higher dose of calycosin significantly reduced the expression levels of Foxp3, followed by down-regulation of VEGF and MMP-9 in both MCF-7 and T47D breast cancer cells. CONCLUSION: Treatment with a higher dose of calycosin tends to reduce migration and invasion capacity of human breast cancer cells, by targeting Foxp3-mediated VEGF and MMP-9 expression.

Compact shielding design of a portable 241Am-Be source.

A compact shielding tank for portable 241Am-Be neutron source, which is used in nuclear well logging, was designed according to the Monte Carlo simulation. From inner to outer, the proposed tank has two shielding layers to shield the high- and low-energy neutrons. In this study, the shielding properties of several materials were evaluated. Tungsten was selected as the neutron moderator to build the inner layer. The thermal neutron absorber in the outer layer was made of polyethylene containing 1.2% boron carbide. The volume and weight of the new tank reduced by 86% and 54%, respectively, by using this dual-layer shielding model, when compared with those of the old shielding tank. Moreover, the simulation results indicated that the total dose rate anywhere outside the tank is less than 0.025mSv/h and that the intensity of gamma flux at the tank surface becomes lower.

Synthesis, colon-targeted studies and pharmacological evaluation of an anti-ulcerative colitis drug 4-Aminosalicylic acid-ß-O-glucoside.

A glycoside prodrug of 4-aminosalicylic acid (4-ASA) with d-glucose was synthesized for targeted drug delivery to inflammatory bowel. The in vitro assessment of 4-aminosalicylic acid-ß-O-glucoside (4-ASA-Glu) as a colon-specific prodrug was studied using colitis rat with the healthy one as control. The stability studies in aqueous buffers (pH 1.2, 6.8 and 7.4) indicated that 4-ASA-Glu was stable over a period of 12 h. The incubation of 4-ASA-Glu with cecal or colonic contents of healthy rats at 37 °C released 4-ASA in 77 or 80% of the dose in 12 h, respectively. The amount of 4-ASA liberated from the incubation of 4-ASA-Glu in cecal or colonic contents of colitis rats at 37 °C was 69 or 79% in 12 h respectively, while less than 9% 4-ASA was detected from the incubation of 4-ASA-Glu with the homogenates of stomach or small intestine. The curative effect of 4-ASA-Glu was evaluated in 2, 4, 6-trinitrobenzenesulfonic acid (TNBS) induced experimental colitis model in male Sprague-Dawley (SD) rats. It was found that 4-ASA-Glu possess significantly ameliorate effect than sulfasalazine, oral 4- and 5-aminosalicylic acid.

Characterization of Rice NADPH oxidase genes and their expression under various environmental conditions.

Plasma membrane NADPH oxidases (Noxs) are key producers of reactive oxygen species under both normal and stress conditions in plants. We demonstrate that at least eleven genes in the genome of rice (Oryza sativa L.) were predicted to encode Nox proteins, including nine genes (OsNox1-9) that encode typical Noxs and two that encode ancient Nox forms (ferric reduction oxidase 1 and 7, OsFRO1 and OsFRO7). Phylogenetic analysis divided the Noxs from nine plant species into six subfamilies, with rice Nox genes distributed among subfamilies I to V. Gene expression analysis using semi-quantitative RT-PCR and real-time qRT-PCR indicated that the expression of rice Nox genes depends on organs and environmental conditions. Exogenous calcium strongly stimulated the expression of OsNox3, OsNox5, OsNox7, and OsNox8, but depressed the expression of OsFRO1. Drought stress substantially upregulated the expression of OsNox1-3, OsNox5, OsNox9, and OsFRO1, but downregulated OsNox6. High temperature upregulated OsNox5-9, but significantly downregulated OsNox1-3 and OsFRO1. NaCl treatment increased the expression of OsNox2, OsNox8, OsFRO1, and OsFRO7, but decreased that of OsNox1, OsNox3, OsNox5, and OsNox6. These results suggest that the expression profiles of rice Nox genes have unique stress-response characteristics, reflecting their related but distinct functions in response to different environmental stresses.

The block of intracellular calcium release affects the pollen tube development of Picea wilsonii by changing the deposition of cell wall components.

Two potent drugs, neomycin and TMB-8, which can block intracellular calcium release, were used to investigate their influence on pollen tube growth and cell wall deposition in Picea wilsonii. Apart from inhibiting pollen germination and pollen tube growth, the two drugs largely influenced tube morphology. The drugs not only obviously disturbed the generation and maintenance of the tip-localized Ca(2+) gradient but also led to a heavy accumulation of callose at the tip region of P. wilsonii pollen tubes. Fourier transform infrared (FTIR) spectroscopy analysis showed that the deposition of cell wall components, such as carboxylic acid, pectins, and other polysaccharides, in pollen tubes was changed by the two drugs. The results obtained from immunolabeling with different pectin and arabinogalactan protein antibodies agreed well with the FTIR results and further demonstrated that the generation and maintenance of the gradient of cross-linked pectins, as well as the proportional distribution of arabinogalactan proteins in tube cell walls, are essential for pollen tube growth. These results strongly suggest that intracellular calcium release mediates the processes of pollen germination and pollen tube growth in P. wilsonii and its inhibition can lead to abnormal growth by disturbing the deposition of cell wall components in pollen tube tips.