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[Display omitted] • Using a promising one-step vacuum space confined with carbon-coated tri-doped reaction method. • A unique novel core/shell structure comprises C N S-TiO 2 nanotubes and N S carbon coating. • Stable nitrogen, carbon and sulfur doping, and cocatalyst have synergistic effects. • Under simulated sunlight and visible light conditions, the photocurrent exhibited an increase of 18.3 times and 32.8 times, respectively. • The photoelectrocatalyst was recyclable and had excellent water splitting performance. The integration of non-metallic doping and carbon coating for TiO 2 -based photoelectrocatalysts can be recognized as a promising strategy to enhance their hydrogen production performance. To this end, this study explored the carbon coating engineering to induce stable multi-element doping with an aim to develop high-performance TiO 2 nanotube array-based photoelectrocatalysts. The resulting structures consisted of carbon–nitrogen-sulfur-tri-doped TiO 2 nanotube arrays with a nitrogen-sulfur-codoped carbon coating (C N S-TNTA/N S C). The fabrication process involved a one-step, low-cost strategy of the carbon-coated tridoped reaction confined in vacuum space, utilizing polymer thiourea sealed in a controlled environment. Compared the photocurrent density of C N S-TNTA/N S C with pristine TNTA, the photocurrent enhancement of approximately 18.3-fold under simulated sunlight and a remarkable increase of 32.8-fold under simulated visible light conditions. The enhanced photocatalytic activity under visible light was ascribed to two factors: First, C, N, and S tri-doping and Ti3+ created a diverse array of impurity energy levels within the band gap, which synergistically narrowed the band gap and further enhanced response to the visible light range. Second, the presence of a carbon coating shell doped with N and S can greatly promote electron transfer and efficient electron-hole pair separation. This study could provide significant insights concerning the design of sophisticated photoanodes. [ABSTRACT FROM AUTHOR]

Moderate acute stress responses are beneficial for adaptation and maintenance of homeostasis. Exposure of male rat to stress induces effects in the bed nucleus of the stria terminalis (BNST), for it can be activated by the same stimuli that induce activation of the hypothalamic-pituitary-adrenal axis. However, the underlying mechanism of the BNST on male stress reactivity remains unclear. In this study, we explored whether systematic administration of dexmedetomidine (DEXM) altered the acute stress reactivity through its effect on the BNST. Male Sprague-Dawley rats in the stress (STRE) group, DEXM group, and the DEXM + GSK-650394 (GSK, an antagonist of serum- and glucocorticoid-inducible kinase 1 (SGK1)) group, except those in the vehicle (VEH) group, underwent 1-h restraint plus water-immersion (RPWI) exposure. All the rats proceeded the open field test (OFT) 24 h before RPWI and 1 h after RPWI. After the second OFT, the rats received VEH, DEXM (75 μg/kg i.p.), or were pretreated with GSK (2 μM i.p.) 0.5 h ahead of DEXM respectively. The third OFT was conducted 6 h after drug administration and then the rats were sacrificed. The rats that experienced RPWI showed dramatically elevated serum corticosterone (CORT), multiplied neuronal nitric oxide synthase (nNOS) and SGK1 in the BNST, and terrible OFT behavior. We discovered when the nNOS and SGK1 were decreased in the rat BNST through DEXM treatment, the serum CORT was reduced and the OFT manifestation was ameliorated, whereas these were restrained by GSK application. Our results reveal that modest interventions to SGK1 and nNOS in the BNST improve the male rat reactivity to acute stress, and DEXM was one modulator of these effects. • We verified effects of the bed nucleus of the stria terminalis (BNST) on acute stress in male rats. • Interventions to SGK1 and nNOS in the BNST improve reactivity to acute stress. • Dexmedetomidine is one modulator of the BNST improving reactivity to acute stress. [ABSTRACT FROM AUTHOR]

[Display omitted] The design and discovery of free-standing hybrid electrode materials with large absolute capacity and high cycling stability for energy storage become desirable and are still challenging. In this work, we demonstrate that the hybrid supercapacitor (HSC) device is assembled by 3D core–shell hierarchical nanorod arrays of Ni 3 S 2 @NiCoP nanocomposite for the first time. The Ni 3 S 2 @NiCoP nanocomposite is successfully synthesized through a facile stratagem containing hydrothermal process and the subsequent electrodeposition method. The 3D architecture of Ni 3 S 2 @NiCoP hybrid electrode composed of vertically aligned "hyperchannel" 1D Ni 3 S 2 nanorods and highly conductive interconnected 2D nanosheets of NiCoP is beneficial to fast electron transfer kinetics, thus leading to enhancing the ionic and electronic conductivity, kinetics of redox reaction, and synergistic behavior of active species. The fabricated HSC device with Ni 3 S 2 @NiCoP electrode delivers outstanding areal capacity of 109 µAh cm−2 at a current density of 1 mA cm−2, brilliant energy density of 74.9 Wh kg−1 at a power density of 700 W kg−1, and prominent cyclic performance of 92% capacity retention even after 144-h floating test. This work demonstrates that the core–shell hierarchical nanorod arrays of Ni 3 S 2 @NiCoP can be viewed as one of the novel battery-type electrode materials for high-performance HSCs. [ABSTRACT FROM AUTHOR]

Lack of acidity in wine is one of the main challenges in warm wine-producing regions. The non- Saccharomyces yeast, Lachancea thermotolerans (LT), is well known for its great potential in wine acidification through the production of lactic acid. In this study, an indigenous LT strain was sequentially inoculated with S. cerevisiae (SC). The influence of the timing of SC inoculation on wine quality was extensively studied. Inoculating SC 72 h after the inoculation of LT delayed the peak of fermentation rate, but had no significant influence on the duration of fermentation. The late inoculation (72 h) of SC effectively increased the production of lactic acid, which consequently increased the total wine acidity and decreased the pH. Higher levels of esters were also achieved by the late inoculation. Pilot-scale fermentations were carried out with both Chardonnay and Cabernet Sauvignon to verify the effect of late inoculation. Lactic acid produced in sequential fermentation was 2.73 g/L for Chardonnay wine and 5.35 g/L for Cabernet Sauvignon wine, and the production of ethyl esters was also enhanced. Overall, the results demonstrated that the late inoculation of SC in sequential fermentation with LT improved wine quality by increasing acidity and producing more balanced and aromatic wines. • SC inoculation timing in sequential fermentation with LT significantly affected wine quality. • Late inoculation of SC markedly increased lactic acid production. • Higher levels of esters were achieved with late SC inoculation. • The quality of Chardonnay and Cabernet Sauvignon wines was improved by late inoculation of SC. [ABSTRACT FROM AUTHOR]

Corticotrophin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN) play a critical role in the modulation of the hypothalamic–pituitary–adrenal (HPA) axis. Early-life exposure to di-(2-ethylhexyl) phthalate (DEHP) has been associated with an increased risk of developing psychiatric disorders in adulthood. The present work was designed to explore the impact of neonatal exposure to DEHP on adult PVN CRH neuronal activity. DEHP or vehicle was given to male rat pups from PND16 to PND22. Then, anxiety-like behaviors, serum corticosterone and testosterone, immunohistochemistry, western blotting, fluorescence in situ hybridization and acute ex vivo slice electrophysiological recordings were used to evaluate the influence of DEHP on adult PVN secretory CRH neurons. Neonatal DEHP-exposed rats exhibited enhanced anxiety-like behaviors in adults, with an increase in CORT. Secretory CRH neurons showed higher spontaneous firing activity but could be inhibited by GABA A R blockers. CRH neurons displayed fewer firing spikes, prolonged first-spike latency, depolarizing shifts in GABA reversal potential and strengthened GABAergic inputs, as indicated by increases in the frequency and amplitude of sIPSCs. Enhancement of GABAergic transmission was accompanied by upregulated expression of GAD67 and downregulated expression of GABA B R 1 , KCC2 and GAT1. These findings suggest that neonatal exposure to DEHP permanently altered the characteristics of secretory CRH neurons in the PVN, which may contribute to the development of psychiatric disorders later in life. • Neonatal DEHP-exposed rats exhibited enhanced anxiety-like behaviors in adulthood. • DEHP-exposure induced higher spontaneous firing rates of secretory CRH neurons in PVN with depolarization shift of E GABA. • DEHP exposure impaired adult male PVN CRH E/I balance with enhancing of GABAergic transmission. • Alteration of CRH neuronal activity was accompanied by upregulation of GAD67 and downregulation of GABA B R 1 , KCC2 and GAT1. [ABSTRACT FROM AUTHOR]

Abstract The system of interest is defined by iterations of the Poincaré map of a time periodic population model with symmetric nonlocal dispersal and periodic time delay. Under the KPP type setting, we show that the system admits the spreading speed c ⁎ ∈ (0 , + ∞ ] that coincides with the minimal speed of traveling waves, where c ⁎ < + ∞ if the nonlocal dispersal kernel J is exponentially bounded and c ⁎ = + ∞ if J is exponentially unbounded. Further, the latter case gives rises to an accelerating propagation that the level set of solutions with compactly supported initial values locate in between two exponential functions in time. [ABSTRACT FROM AUTHOR]

Serpentine soils may be natural sources of metal leaching and pollution. In this study, two contrasting serpentine soils from Taiwan and Austria were selected to evaluate the leaching potential of geogenic nickel (Ni). We applied selective sequential extractions and dissolution kinetics with three inorganic acids (HCl, HNO 3 , and H 2 SO 4 ) and three organic acids (citric, acetic, and oxalic acids) in concentrations ranging from 0.05 to 10 mM to determine the release rate of Ni in the soils with respect to pH and acid types. Chlorite and serpentine were the major Ni-bearing minerals in the studied soils. Ni was dominantly bound in unavailable forms within these silicate minerals, but smaller fractions of acid-soluble, Fe–Mn oxide-bound, and organically bound Ni represented more labile Ni sources in the soils. The release rate of Ni from the soils increased with decreasing pH in all acids. However, the organic acids caused stronger pH dependences than the inorganic acids, likely because of ligand-promoted dissolution. The maximum total rate of Ni dissolution occurred with citric acid in both soils. The dissolution of Ni strongly increased when the ionic strength in the background solutions increased. We observed marked differences in dissolution rates and ligand effects between the Austrian and Taiwanese soils, which reflect differences in labile Ni pools, especially in the organically bound fraction. Our results demonstrate that labile fractions control the leaching potential of Ni in serpentine soils and that Ni associated with soil organic matter may contribute to leaching at moderately acidic pH levels. [ABSTRACT FROM AUTHOR]

An average daily increase of 10 μg/m3 in NO 2 concentrations could lead to an increased mortality in cardiovascular, cerebrovascular of 1.89%, 2.07%, but the mechanism by which NO 2 contributes to cardiotoxicity is rarely reported. In order to assess the cardiotoxicity of NO 2 inhalation (5 ppm), we firstly investigate the change of gut microbiota, serum metabonomics and cardiac proteome. Non-targeted LC-MS/MS metabonomics showed that NO 2 stress could perturb the glycerophospholipid metabolism in the serum, which might destabilize the bilayer configuration of cardiac lipid membranes. Furthermore, we observed that NO 2 inhalation caused augmented intercellular gap and inflammatory infiltration in the heart. Although 16 S rRNA gene amplification sequencing demonstrated that NO 2 exposure did not influence the intestinal microbial abundance and diversity, but glycerophospholipid metabolism disruption might be finally reflected in gut microbiom dysregulation, such as Sphingomonas , Koribacter , Actinomarina and Bradyrhizobium Turicibacter , Rothia , Globicatella and Aerococcus. Proteome mining revealed that differentially expressed genes (DEGs) in the heart after NO 2 stress were involved in necroptosis, mitophagy and ferroptosis. We further revealed that NO 2 increased the number of cardiac mitochondria with depletion of cristae by regulating the expression of Mfn2 and Hsp70. This study indicating Mfn2-meidcated imbalanced mitochondrial dynamics as a potential mechanism after NO 2 -induced heart injury and suggesting microbiome dysregulation/glycerophospholipid metabolism exerts critical roles in cardiotoxicity caused by NO 2. [Display omitted] • The profile of metabolite profiles was dramatically altered under NO 2 stress. • Cardiotoxicity caused by NO 2 partially attributed to gut microbiome dysregulation. • NO 2 increased the number of cardiac mitochondria with depletion of cristae. • Mfn2 deficiency may be responsible for cardiotoxicity caused by NO 2 exposure. • Hsp70 is pathological factor for NO 2 induced-cardiotoxicity. [ABSTRACT FROM AUTHOR]

Abstract: Our long-term goal is the design of a human l-asparaginase (hASNase3) variant, suitable for use in cancer therapy without the immunogenicity problems associated with the currently used bacterial enzymes. Asparaginases catalyze the hydrolysis of the amino acid asparagine to aspartate and ammonia. The key property allowing for the depletion of blood asparagine by bacterial asparaginases is their low micromolar K M value. In contrast, human enzymes have a millimolar K M for asparagine. Toward the goal of engineering an hASNase3 variant with micromolar K M, we conducted a structure/function analysis of the conserved catalytic threonine triad of this human enzyme. As a member of the N-terminal nucleophile family, to become enzymatically active, hASNase3 must undergo autocleavage between residues Gly167 and Thr168. To determine the individual contribution of each of the three conserved active-site threonines (threonine triad Thr168, Thr186, Thr219) for the enzyme-activating autocleavage and asparaginase reactions, we prepared the T168S, T186V and T219A/V mutants. These mutants were tested for their ability to cleave and to catalyze asparagine hydrolysis, in addition to being examined structurally. We also elucidated the first N-terminal nucleophile plant-type asparaginase structure in the covalent intermediate state. Our studies indicate that, while not all triad threonines are required for the cleavage reaction, all are essential for the asparaginase activity. The increased understanding of hASNase3 function resulting from these studies reveals the key regions that govern cleavage and the asparaginase reaction, which may inform the design of variants that attain a low K M for asparagine. [Copyright &y& Elsevier]

Abstract: This study aimed to test the hypothesis that root morphology may play a crucial role in the variation in Cd accumulation among peanut (Arachis hypogaea L.) cultivars. The biomass, Cd accumulation and root morphology of five peanut cultivars were determined under 2 and 20μM CdCl2 in a hydroponic experiment. Excess Cd considerably decreased the root lengths (RL), surface area (SA), specific root length (SRL) and number of root tips, but increased the root diameters (RD). Cd-induced decreases in RL and SA were significant in the 0–0.2 and 0.2–0.4mm diameter classes. Peanut cultivars differ in Cd accumulation and root morphological parameters. A positive correlation was observed between RL and Cd amount in shoots. RD negatively correlated to Cd concentrations in roots and shoots. Positive correlations were also found between RL vs. shoot Cd concentration, SA vs. Cd amount in shoots, SRL vs. root Cd concentration, SRL vs. shoot Cd concentration, and SRL vs. Cd amount in shoots. The fine roots play a crucial role in determining Cd accumulation in peanut plants. Cultivars with more fine roots in their root system (i.e. Haihua 1 and Zhenghong 3) have high capability of Cd accumulation. [Copyright &y& Elsevier]

Abstract: This research explores the Cauchy problem for a class of quasi-linear wave equations with time dependent sources. It can be transformed into the Cauchy problem of hyperbolic integro-differential systems of nonlinear balance laws. We introduce the generalized Glimm scheme in new version and study its stability which is proved by Glimm-type interaction estimates in a dissipativity assumption. The generalized solutions to the perturbed Riemann problems, the building blocks of generalized Glimm scheme, are constructed by Riemann problem method modeled on the source free equations. The global existence for the Lipschitz continuous solutions and weak solutions to the systems is established by the consistency of scheme and the weak convergence of source. Finally, the weak solutions are also the entropy solutions which satisfy the entropy inequality. [Copyright &y& Elsevier]

Abstract: Objective: To determine whether the matrix metalloproteinase-9 (MMP-9) c.1562C>T polymorphism has an effect on the plasma MMP-9 levels and the macroangiopathic complications in type 2 diabetes mellitus (T2DM). Methods: The genotypes and allelic frequencies of the MMP-9 c.1562C>T were examined with polymerase chain reaction and restriction fragment length polymorphism in 320 patients with T2DM and 160 unrelated healthy subjects. The plasma concentrations of MMP-9 were determined in all subjects. Results: The mean plasma concentrations of MMP-9 of patients with T2DM were significantly higher than that of controls and the plasma levels of MMP-9 were higher in diabetic patients with macroangiopathy than in patients without macroangiopathy (P< 0.05). The genotype (CC, CT, and TT) distribution of c.1562C>T polymorphism of the MMP-9 gene was 60.0%, 31.3%, and 8.8% in diabetic patients with macroangiopathy, 76.3%, 21.3%, and 2.5% in patients without macroangiopathy, and 77.5%, 21.3%, 1.3% in controls, respectively, a significant difference was found between diabetic patients with and without macroangiopathy (P <0.05). The frequency of the allele T was higher in patients with macroangiopathy than in patients without macroangiopathy (24.4% vs 13.1%; P <0.05). Moreover, the plasma MMP-9 levels were markedly higher in patients with TT genotype than those with CC or CT genotype in patients with macroangiopathy (P< 0.05). Conclusion: The MMP-9 c.1562C>T gene polymorphism associated with a predisposition to increased plasma MMP-9 levels could constitute a useful predictive marker for diabetic macroangiopathy. [Copyright &y& Elsevier]

Abstract: A reaction–diffusion population model with a general time-delayed growth rate per capita is considered. The growth rate per capita can be logistic or weak Allee effect type. From a careful analysis of the characteristic equation, the stability of the positive steady state solution and the existence of forward Hopf bifurcation from the positive steady state solution are obtained via the implicit function theorem, where the time delay is used as the bifurcation parameter. The general results are applied to a “food-limited” population model with diffusion and delay effects as well as a weak Allee effect population model. [Copyright &y& Elsevier]

To determine the racial disparities in oncology visits of racial minorities before and after COVID-19. Data were obtained from the electronic health records, a multi-specialty healthcare system serving a racially/ethnically diverse patient population in northern California. The study cohort included patients who had at least one oncology visit from January 2019 to August 2020. We examined the trends in the volume of oncology office visits and adoption of video visits during the ongoing COVID-19 pandemic period. Chi-square test and multivariate logistic regression were performed to examine variability in use of video visits by specific patient characteristics (sex, age, race/ethnicity and language barrier). Of 63,903 cancer patients (median age: 66; 68% female), Whites, Blacks, Hispanics, Asians and others composed of 64.8%, 3.5%, 9.2%, 11.7% and 10.8% of our study cohort. Over the 20 month study period, the drop in in-person visits began in March and peaked in April 2020. Compared to the year 2019, the office visits decreased by -16.6%, -55.9%, and -50.9% in March, April, and May of 2020. Although there was a trend towards increased office visits in June (-21.9% compared to 2019), this again decreased to -35% in July 2020. The proportion of visits conducted by video began at 16.6% in the first week after California's shelter-in-place order in March, peaked at a high rate of 43.4% in April, and remained at a rate of 33.8% in August. We focused on variability by specific patient subgroups when telemedicine was offered and used prevalently during early pandemic in April. Based on age, the younger cohorts, 18-50 and 51-64 year olds, were more likely to utilize video visit at 50.6%, and 50.6% compared to only 38.0% and 36.7% of the older groups (65-75 and 76+ years old, p<0.001). In fact, the largest discrepancy, 21% difference between the younger vs older groups, was observed towards the end of April. With respect to race, Asians had the highest use of video visits (51.4%) compared to Hispanic (34.5%) and Black patients (40.3%) in April (p<0.001). Although the gap narrowed over the next 4 months with only a 4% difference by August, these cancelled visits were not recovered in the minority groups. Finally, 44.6% of those who did not require an interpreter utilized video visits as compared to only 19.8% who did require an interpreter (p<0.001). Age and race/ethnicity remain strong predictors of video visit use after adjusting the main and interaction effects of patient characteristics, with Asians 51-64 year old having the highest rate (58%) and Hispanics 76+ year old the lowest rate (30%). Overall office visits have decreased significantly during the COVID-19 pandemic. Older patients, Black patients, Hispanic patients, and patients who required interpreting services were less likely to be treated through video visits. Future studies are needed to better understand the barriers to telemedicine care. [ABSTRACT FROM AUTHOR]

Abstract: The genetic differentiation and phylogeographical pattern of 11 relictual populations of Alsophila spinulosa distributed across Hainan, Guangdong, and Guangxi in southern China were inferred from sequence variations of trnL–F noncoding regions of chloroplast DNA (cpDNA). The length of trnL–F noncoding sequences varied from 863 to 940bp. The A+T content was 62.23–63.36%. Sequences were neutral in terms of evolution (Tajima’s criterion D =−0.62417, P >0.10 and Fu and Li’s test D*=−1.45455, P >0.10; F*=−1.32798, P >0.10). Thirty-four haplotypes were identified based on nucleotide variation. Relatively high levels of haplotype diversity (h =0.929) and nucleotide diversity (Dij =0.022263) were detected in A. spinulosa, probably associated with its long evolutionary history which allowed the accumulation of genetic variation within lineages. Both the minimum spanning network and the strict consensus tree of the most parsimonious trees generated for haplotypes demonstrated that the investigated populations of A. spinulosa were subdivided into two geographical groups: Hainan and Guangdong–Guangxi. An analysis of molecular variance (AMOVA) indicated that most of the genetic variation (87.48%, P &#60;0.001) was partitioned among regions. Spatial structure measurements revealed that population genetic structure was not related to geographical distance. This research suggests that blocked gene flow by Qiongzhou strait and an inbreeding system might result in the geographical subdivision between Hainan and Guangdong–Guangxi (F ST =0.92, Nm =0.09). Within each region, the “star like” pattern of phylogeography of haplotypes implied a population expansion process during evolutionary history. Gene genealogies together with coalescent theory were useful tools for uncovering the phylogeography of A. spinulosa. [Copyright &y& Elsevier]

Nitrogen requirements by S. cerevisiae during wine fermentation are highly strain-dependent. Different approaches were applied to explore the nitrogen requirements of 28 wine yeast strains. Based on the growth and fermentation behaviour displayed at different nitrogen concentrations, high and low nitrogen-demanding strains were selected and further verified by competition fermentation. Biomass production with increasing nitrogen concentrations in the exponential fermentation phase was analysed by chemostat cultures. Low nitrogen-demanding (LND) strains produced a larger amount of biomass in nitrogen-limited synthetic grape musts, whereas high nitrogen-demanding (HND) strains achieved a bigger biomass yield when the YAN concentration was above 100 mg/L. Constant rate fermentation was carried out with both strains to determine the amount of nitrogen required to maintain the highest fermentation rate. Large differences appeared in the analysis of the genomes of low and high-nitrogen demanding strains showed for heterozygosity and the amino acid substitutions between orthologous proteins, with nitrogen recycling system genes showing the widest amino acid divergences. The CRISPR/Cas9-mediated genome modification method was used to validate the involvement of GCN1 in the yeast strain nitrogen needs. However, the allele swapping of gene GCN1 from low nitrogen-demanding strains to high nitrogen-demanding strains did not significantly influence the fermentation rate. • Different methods were used to study wine S. cerevisiae strains' nitrogen requirements. • HND and LND strains were selected and their fermentation characters were thoroughly analysed. • Genome sequencing analysis revealed large differences between HND and LND strains. • Genes of the nitrogen recycling system showed the widest amino acid divergences. • Allele swapping of GCN1 did not have significant influence on nitrogen requirements. [ABSTRACT FROM AUTHOR]

Phenoxy herbicides are widely applied in agricultural weeding. The determination of herbicides is important in environmental protection, agricultural production, food safety, and public health. In this study, a facile and efficient analytical method was proposed for the trace detection of phenoxy herbicides in soil, cucumber, and tap water samples by coupling pipette tip solid phase extraction (PT-SPE) with high performance liquid chromatography. UiO-66-funtionalized cotton (Cotton@UiO-66) was packed into pipette-tip as sorbent to fabricate extraction device. The modification of UiO-66 on cotton fiber was confirmed using scanning electron microscope, Fourier transform infrared spectroscopy, and X-ray diffraction. The main factors affecting the adsorption of Cotton@UiO-66 for four phenoxy herbicides were evaluated by response surface methodology in detail. Under optimized conditions, Cotton@UiO-66 displayed excellent properties in the extraction of phenoxy herbicides with good peak shape. Linear ranges of 4-chlorophenoxyacetic acid, dicamba, 2,4-dichlorophenoxyacetic acid, and 2-(2,4-dichlorophenoxy) propionic acid were 1.4–72 μg/L, 5.6–280 μg/L, 2.8–140 μg/L and 3.2–160 μg/L (RSDs < 6.3%), respectively. The recoveries were between 83.3 and 106.8% with RSDs <6.7%, with detection limits ranging from 0.1 μg/L to 0.3 μg/L. The results show that Cotton@UiO-66 in PT-SPE is an effective method for monitoring phenoxy herbicides in complex samples. Image 1 • UiO-66 was grown on the surface of cotton fiber at room temperature. • The successful fabrication of Cotton@UiO-66 was confirmed by SEM, FT-IR, XRD. • Modified cotton exhibited good adsorption to four commonly used phenoxy herbicides. • Coupled PT-SPE with HPLC, a facile and efficient analytical method was developed. • The method was successfully applied to real sample of soil, cucumber and tap water. [ABSTRACT FROM AUTHOR]

Highlights: [•] Diabetic nephropathy is a serious complication of diabetes mellitus. [•] Hyperglycemia and other related factors are involved in the pathophysiology of diabetic nephropathy. [•] Understanding of the molecular mechanism may lead to effective therapies. [ABSTRACT FROM AUTHOR]

Abstract: Micro- and macrovascular complications are the main cause of morbidity and mortality in diabetes mellitus. The Na+/H+ exchanger (NHE) is a family of proteins which exchange Na+ for H+ according to their concentration gradients in an electroneutral manner. The exchanger also plays a key role in several other cellular functions including proliferation, differentiation, apoptosis, migration, and cytoskeletal organization. Since not much is known on the relationship between NHE and diabetes mellitus, this review outlines the contribution of NHE to chronic complications of diabetes mellitus, such as diabetic nephropathy; diabetic cardiomyopathy. [Copyright &y& Elsevier]

Wine-related non- Saccharomyces yeasts are becoming more widely used in oenological practice for their ability to confer wine a more complex satisfying aroma, but their metabolism remains unknown. Our study explored the nitrogen utilisation profile of three popular non- Saccharomyces species, Torulaspora delbrueckii , Metschnikowia pulcherrima and Metschnikowia fructicola. The nitrogen source preferences to support growth and fermentation as well as the uptake order of different nitrogen sources during wine fermentation were investigated. While T. delbrueckii and S. cerevisiae strains shared the same nitrogen source preferences, Metschnikowia sp. Displayed a lower capacity to efficiently use the preferred nitrogen compounds, but were able to assimilate a wider range of amino acids. During alcoholic fermentation, the non- Saccharomyces strains consumed different nitrogen sources in a similar order as S. cerevisiae , but not as quickly. Furthermore, when all the nitrogen sources were supplied in the same amount, their assimilation order was similarly affected for both S. cerevisiae and non- Saccharomyces strains. Under this condition, the rate of nitrogen source consumption of non- Saccharomyces strains and S. cerevisiae was comparable. Overall, this study expands our understanding about the preferences and consumption rates of individual nitrogen sources by the investigated non- Saccharomyces yeasts in a wine environment. This knowledge provides useful information for a more efficient exploitation of non- Saccharomyces strains that improves the management of the wine fermentation. • Non- Saccharomyces exhibited a higher growth capacity in poor nitrogen sources. • Metschnikowia strains displayed lower fermentation activity but shorter lag phases. • A similar nitrogen source assimilation order was observed for different species. • The initial proportion of nitrogen sources influences their assimilation order. [ABSTRACT FROM AUTHOR]

Transient receptor potential vanilloid (TRPV) channels are members of the TRP channel superfamily, which are ion channels that sense mechanical and osmotic stimuli and participate in Ca2+ signalling across the cell membrane. TRPV channels play important roles in maintaining the normal functions of an organism, and defects or abnormalities in TRPV channel function cause a range of diseases, including cardiovascular, neurological and urological disorders. Glaucoma is a group of chronic progressive optic nerve diseases with pathological changes that can occur in the tissues of the anterior and posterior segments of the eye, including the ciliary body, trabecular meshwork, Schlemm's canal, and retina. TRPV channels are expressed in these tissues and play various roles in glaucoma. In this article, we review various aspects of the pathogenesis of glaucoma, the structure and function of TRPV channels, the relationship between TRPV channels and systemic diseases, and the relationship between TRPV channels and ocular diseases, especially glaucoma, and we suggest future research directions. This information will help to further our understanding of TRPV channels and provide new ideas and targets for the treatment of glaucoma and optic nerve damage. • To review the relationship between TRPV and ocular disease, particularly glaucoma. • TRPV is essential for maintaining normal physiological function of ocular tissues. • Abnormalities in TRPV can cause glaucoma by various mechanisms. • Understanding TRPV provides new therapeutic targets for glaucoma. [ABSTRACT FROM AUTHOR]

Relevant studies have recognized the important role of hepatic stellate cell (HSC) senescence in anti-liver fibrosis. Cellular senescence is believed to be regulated by the cGAS-STING signaling pathway. However, underlying exact mechanisms of cGAS-STING pathway in hepatic stellate cell senescence are still unclear. Here, we found that Oroxylin A could promote senescence in HSC by activating the cGAS-STING pathway. Moreover, activation of the cGAS-STING pathway was dependent on DNMT3A downregulation, which suppressed cGAS gene DNA methylation. Interestingly, the attenuation of DNMT activity relied on the reduction of methyl donor SAM level. Noteworthy, the downregulation of SAM levels implied the imbalance of methionine cycle metabolism, and MAT2A was considered to be an important regulatory enzyme in metabolic processes. In vivo experiments also indicated that Oroxylin A induced senescence of HSCs in mice with liver fibrosis, and DNMT3A overexpression partly offset this effect. In conclusion, we discovered that Oroxylin A prevented the methylation of the cGAS gene by preventing the production of methionine metabolites, which promoted the senescence of HSCs. This finding offers a fresh hypothesis for further research into the anti-liver fibrosis mechanism of natural medicines. [Display omitted] [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the clinical outcomes and cost-effectiveness of novel therapy sequencing in the treatment of metastatic and recurrent cervical cancer. Methods: Models were simulated based on three potential treatment sequences: 1) doublet first-line chemotherapy+bevacizumab (chemo-bev) from the GOG-240 study, then second-line cemipli- mab (cemi) from the GOG-3016 trial (chemo+bev→cemi), 2) doublet chemo+bev+pembrolizumab (chemo+bev+pemb) from KEYNOTE- 826, then second-line single-agent chemo based on GOG 3016 (chemo+bev+pemb→chemo) and 3) doublet chemo+bev+pemb then second-line tisotumab vedotin (tiso) from GOG 3023 (chemo+bev+pemb→tiso). These were compared to a reference of chemotherapy only, with doublet first line (chemo) from the GOG 240 study followed by single-agent chemotherapy (chemo) based on the GOG 3016 study (chemo→chemo). Results: Based on IBM Micromedex RED BOOK™ and company listed costs, bevacizumab was estimated to cost $8,700 per cycle, cemi- plimab $13,181 per cycle, pembrolizumab $10,067 per cycle, and tisotumab vedotin estimated at $34,000 per month. For the reference sequence therapeutics, doublet chemo was estimated to cost $1,126 per cycle, and single-agent chemo was estimated at $1,944 per cycle. The total cost for each sequence was calculated based on the median cycles of each therapeutic. Each regimen sequence with the total cost and associated median overall survivals are listed in Table 1. The incremental cost-effectiveness ratio (ICER) and willingness to pay analyses are currently pending approval by the FDA, along with definitive costs of drugs. Conclusions: Our data suggest that the combination of immunotherapies and biologics has substantially increased overall survival. Early introduction of targeted therapy is not only associated with prolonged survival but also increased cost. Since treatment cost is primarily related to the cost of medicines, decreasing the price of these agents will make palliative treatments more cost-effective. [ABSTRACT FROM AUTHOR]

Obesity has become the second leading cause of death globally after smoking. Probiotic Bacillus has noticeable weight-loss effects. This study aimed to investigate the mechanism of Bacillus natto (B. natto) on insulin resistance in obese rats. The obese rat model was established with a HFD for 8 weeks, and then, B. natto was orally administered at different dosed for 8 weeks. The results showed that B. natto significantly reduced the body weight, epididymis fat weight, total cholesterol, triglyceride, low-density lipoprotein while increasing the level of high-density lipoprotein in HFD rats. B. natto intervention improved liver injury by reducing alanine aminotransferase and aspartate transaminase levels. B. natto intervention was also beneficial for the inhibition of hepatic steatosis and inflammation factors in HFD rats by inhibiting the mRNA expression level of SREBP-1 gene. Moreover, B. natto improved insulin resistance homeostasis by activating PI3K/AKT signaling pathway. Therefore, B. natto could be used as a potential probiotic supplement to provided new strategy for the prevention and treatment of metabolic diseases such as obesity. • Bacillus natto regulates blood lipids and reduces insulin resistance. • B. natto improves obesity by activating PI3K/AKT pathway. • B. natto inhibits lipid synthesis by inhibiting SREBP-1 expression. [ABSTRACT FROM AUTHOR]

Ribosomal protein 25 (RPS25) has been related to male fertility diseases in humans. However, the role of RPS25 in spermatogenesis has yet to be well understood. RpS25 is evolutionarily highly conserved from flies to humans through sequence alignment and phylogenetic tree construction. In this study, we found that RpS25 plays a critical role in Drosophila spermatogenesis and its knockdown leads to male sterility. Examination of each stage of spermatogenesis from RpS25 -knockdown flies showed that RpS25 was not required for initial germline cell divisions, but was required for spermatid elongation and individualization. In RpS25 -knockdown testes, the average length of cyst elongation was shortened, the spermatid nuclei bundling was disrupted, and the assembly of individualization complex from actin cones failed, resulting in the failure of mature sperm production. Our data revealed an essential role of RpS25 during Drosophila spermatogenesis through regulating spermatid elongation and individualization. • RpS25 is required for Drosophila spermatogenesis. • Loss of RpS25 does not affect initial germline divisions. • Loss of RpS25 causes defects in spermatid elongation and individualization. [ABSTRACT FROM AUTHOR]

High myopia is a risk factor for primary open angle glaucoma (POAG). The pathological mechanism of high myopia induced POAG occurrence is not fully understood. In this study, we successfully established the guinea pig model of ocular hypertension with high myopia, and demonstrated the susceptibility of high myopia for the occurrence of microbead-induced glaucoma compared with non-myopia group and the effect of YAP/TGF-β signaling pathway in TM pathogenesis induced by high myopia. Moreover, we performed stretching treatment on primary trabecular meshwork (TM) cells to simulate the mechanical environment of high myopia. It was found that stretching treatment disrupted the cytoskeleton, decreased phagocytic function, enhanced ECM remodeling, and promoted cell apoptosis. The experiments of mechanics-induced human TM cell lines appeared the similar trend. Mechanically, the differential expressed genes of TM cells caused by stretch treatment enriched YAP/TGF-β signaling pathway. To inhibit YAP/TGF-β signaling pathway effectively reversed mechanics-induced TM damage. Together, this study enriches mechanistic insights of high myopia induced POAG susceptibility and provides a potential target for the prevention of POAG with high myopia. • The guinea pig model of ocular hypertension with high myopia was successfully established. • The role of YAP/TGF-β signaling pathway in the POAG pathogenesis induced by high myopia. • Inhibition of YAP/TGF-β signaling pathway can effectively reverse the TM damage caused by axial elongation induced mechanical stress. [ABSTRACT FROM AUTHOR]

Abstract: The accumulation of beta amyloid (Aβ) can cause synaptic impairments, but the characteristics and mechanisms of the synaptic impairment induced by the accumulation of Aβ in Alzheimer''s disease (AD) remain unclear. In identified single neurons in a newly developed Drosophila AD model, in which Aβ accumulates intraneuronally, we found an age-dependent reduction in the synaptic vesicle release probability that was associated with a decrease in the density of presynaptic calcium channel clusters and an increase in the presynaptic and postsynaptic contact length. Moreover, these alterations occurred in the absence of presynaptic bouton loss. In addition, we found that Aβ expression also produced an age-dependent decrease in the amount of Bruchpilot (Brp), which plays an important role in controlling Ca2+ channel clustering and synaptic vesicle release in the presynaptic active zone. Our study indicates that the chronic accumulation of intraneuronal Aβ can induce functional and structural changes in the presynaptic active zone prior to a loss of presynaptic buttons in the same neuron. [Copyright &y& Elsevier]

Abstract: Emodin, a tyrosine kinase inhibitor, is a natural anthraquinone derivative found in the roots and rhizomes of numerous plants. It reportedly exhibits an anticancer effect on lung cancer. Gefitinib (Iressa) is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor for human non-small cell lung cancer (NSCLC). However, the molecular mechanism of how emodin combined with gefitinib decreases NSCLC cell viability is unclear. The recombinase protein Rad51 is essential for homologous recombination repair, and Rad51 overexpression is resistant to DNA double-strand break-inducing cancer therapies. In this study, we found that emodin enhanced the cytotoxicity induced by gefitinib in two NSCLC cells lines, A549 and H1650. Emodin at low doses of 2–10 μM did not affect ERK1/2 activation, mRNA, and Rad51 protein levels; however, it enhanced a gefitinib-induced decrease in phospho-ERK1/2 and Rad51 protein levels by enhancing Rad51 protein instability. Expression of constitutively active MKK1/2 vectors (MKK1/2-CA) significantly rescued the reduced phospho-ERK1/2 and Rad51 protein levels as well as cell viability on gefitinib and emodin cotreatment. Blocking of ERK1/2 activation by U0126 (an MKK1/2 inhibitor) lowered Rad51 protein levels and cell viability in emodin-treated H1650 and A549 cells. Knockdown of Rad51 expression by transfection with si-Rad51 RNA enhanced emodin cytotoxicity. In contrast, Rad51 overexpression protected the cells from the cytotoxic effects induced by emodin and gefitinib. Consequently, emodin–gefitinib cotreatment may serve as the basis for a novel and better therapeutic modality in the management of advanced lung cancer. [Copyright &y& Elsevier]

The activation of hepatic stellate cells (HSCs) plays a key role in the occurrence of liver fibrosis，and promoting the apoptosis of activated HSCs or reducing the number of activated HSCs can reverse the development of liver fibrosis. In our previous studies, we have demonstrated that the CCAAT/enhancer binding protein α (C/EBP-α) played an important role in promoting the apoptosis of activated HSCs, thereby exerting an anti-liver fibrosis effect. Unlike apoptosis, autophagy, as a caspase-independent programmed cell death, can promptly remove the abnormal accumulation of substances or damaged organelles in cells and play a key role in regulating the homeostasis of intracellular environment. However, it is still unclear whether C/EBP-α participates in the occurrence of autophagy in HSCs. Therefore, in this study, we firstly used the methods of Western blot and immunofluorescence to characterize the consequence of C/EBP-α overexpression on the expression of proteins LC3B, P62, ATG5 and Beclin1 which were related to autophagy in HSCs. Subsequently, we performed Western blot and site-directed mutagenesis methods to clarify the type and related mechanism of autophagy which was induced by C/EBP-α. Here we show that C/EBP-α promotes the occurrence of autophagy in HSCs and the autophagy induced by C/EBP-α belongs to mitophagy. The stability of C/EBP-α protein regulates the level of autophagy in HSCs. In addition, acetylation of C/EBP-α also regulates the occurrence of autophagy in HSCs. Acetylation of lysine at positions K298, K302 and K326 of C/EBP-α promotes its binding to Beclin1. In conclusion, our study uncovers the role of C/EBP-α in regulating autophagy in HSCs, thereby providing a new strategy for clinical treatment of liver fibrosis. [ABSTRACT FROM AUTHOR]

Abstract: This work investigates the existence of globally Lipschitz continuous solutions to a class of initial–boundary value problem of quasilinear wave equations. Applying the Lax''s method and generalized Glimm''s method, we construct the approximate solutions of initial–boundary Riemann problem near the boundary layer and perturbed Riemann problem away from the boundary layer. By showing the weak convergence of residuals for the approximate solutions, we establish the global existence for the derivatives of solutions and obtain the existence of global Lipschitz continuous solutions of the problem. [Copyright &y& Elsevier]

Viral macrophage inflammatory protein I (vMIP-I) is a chemokine encoded by the Kaposi''s sarcoma-associated herpesvirus (KSHV) that selectively activates the CC chemokine receptor 8 (CCR8), for which the endogenous ligand is CCL1. The crystal structure of vMIP-I was determined at 1.7Å for comparison with other chemokines, especially those that bind CCR8, such as vMIP-II from KSHV, a CCR8 antagonist and the closest homolog (40% identical). vMIP-I has a typical chemokine fold consisting of an extended N-terminal loop, followed by a three-stranded antiparallel β-sheet and a C-terminal α-helix. The four molecules in the asymmetric unit comprise two MIP-1β-like dimers. Electrostatic surface representations of CCR8-binding chemokines reveal only minor areas of correlating surface potential, which must be reconciled with promiscuity in receptor and glycosaminoglycan (GAG) binding. In addition, the biological relevance of chemokine oligomerization is examined by comparing the oligomeric states of all chemokine structures deposited to date in the RCSB PDB. [Copyright &y& Elsevier]

To assess the relationship between the intrapulmonary shunt and PaO 2 /FiO 2 in severe hypoxemic patients after acute type A aortic dissection (ATAAD) surgery and to evaluate the effect of inhaled nitric oxide (iNO) on intrapulmonary shunt. Postoperative ATAAD patients with PaO 2 /FiO 2 ≤ 150 mmHg were enrolled. Intrapulmonary shunt was calculated from oxygen content of different sites (artery [CaO 2 ], mixed venous [CvO 2 ], and alveolar capillary [CcO 2 ]) using the Fick equation, where intrapulmonary shunt = (CcO 2 -CaO 2)/(CcO 2 -CvO 2). Related variables were measured at baseline (positive end expiratory pressure [PEEP] 5 cm H 2 O), 30 min after increasing PEEP (PEEP 10 cm H 2 O), 30 min after 5 ppm iNO therapy (PEEP 10 cm H 2 O + iNO), and 30 min after decreasing PEEP (PEEP 5 cm H 2 O + iNO). A total of 20 patients were enrolled between April 2019 and December 2019. Intrapulmonary shunt and PaO 2 /FiO 2 were correlated in severe hypoxemic, postoperative ATAAD patients (adjusted R2 = 0.467, p < 0.001). A mixed model for repeated measures revealed that iNO, rather than increasing PEEP, significantly decreased the intrapulmonary shunt (by 15% at a PEEP of 5 cm H 2 O and 16% at a PEEP of 10 cm H 2 O, p < 0.001 each) and increased PaO 2 /FiO 2 (by 63% at a PEEP of 5 cm H 2 O and 65% at a PEEP of 10 cm H 2 O, p < 0.001 each). After iNO therapy, the decrement of intrapulmonary shunt and the increment of PaO 2 /FiO 2 were also correlated (adjusted R2 = 0.375, p < 0.001). This study showed that intrapulmonary shunt and PaO 2 /FiO 2 were correlated in severe hypoxemic, postoperative ATAAD patients. Furthermore, iNO, rather than increasing PEEP, significantly decreased the intrapulmonary shunt to improve severe hypoxemic conditions. • Severe hypoxemia is a frequent complication after ATAAD surgery. • Intrapulmonary shunt and PaO 2 /FiO 2 were correlated. • Increasing PEEP from 5 to 10 cm H 2 O did not have any influence on PaO 2 /FiO 2 or the intrapulmonary shunt. • iNO decreased the intrapulmonary shunt to improve the severe hypoxemic conditions. • Hemodynamic variables were not influenced by the iNO therapy. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • A pilot virtual screening was performed to identify RXRα-LBD tetramer stabilizers. • Atorvastatin was identified to bind to RXRα and promote the RXRα-LBD tetramer formation. • Atorvastatin induces PARP cleavage in RXRα-dependent manner. Abstract Retinoid X receptor alpha (RXRα), a central member of the nuclear receptor superfamily and a key regulator of many signal transduction pathways, has been an attractive drug target. We previously discovered that an N-terminally truncated form of RXRα can be induced by specific ligands to form homotetramers, which, as a result of conformational selection, forms the basis for inhibiting the nongenomic activation of RXRα. Here, we report the identification and characterization of atorvastatin as a new RXRα tetramer stabilizer by using structure-based virtual screening and demonstrate that virtual library screening can be used to aid in identifying RXRα ligands that can induce its tetramerization. In this study, docking was applied to screen the FDA-approved small molecule drugs in the DrugBank 4.0 collection. Two compounds were selected and purchased for testing. We showed that the selected atorvastatin could bind to RXRα to promote RXRα-LBD tetramerization. We also showed that atorvastatin possessed RXRα-dependent apoptotic effects. In addition, we used a chemical approach to aid in the studies of the binding mode of atorvastatin. [ABSTRACT FROM AUTHOR]

Purpose To characterize folate receptor alpha (FRα) expression in archival and fresh biopsy tumor samples from relapsed ovarian cancer patients. Methods Patients with ovarian tumors amenable to biopsy were eligible to enroll. Eligibility included a minimum requirement of FRα positivity in archival tumor samples (≥ 25% of cells with ≥ 2 + staining intensity). Patients received mirvetuximab soravtansine at 6 mg/kg once every 3 weeks. Core needle biopsies were collected before and after treatment and FRα levels assessed by immunohistochemistry. Descriptive statistics were used to summarize the association between receptor expression and response. Results Twenty-seven heavily pre-treated patients were enrolled. Six individuals (22%) did not have evaluable pre-treatment biopsies due to insufficient tumor cells. The concordance of FRα expression in archival and biopsy tissues was 71%, and no major shifts in receptor expression were seen in matched pre- and post-treatment biopsy samples. Adverse events were generally mild (≤ grade 2) with keratopathy (48%), fatigue (44%), diarrhea, and blurred vision (each 37%) being the most common treatment-related toxicities. The confirmed objective response rate (ORR) was 22%, including two complete responses and four partial responses. Superior efficacy measures were observed in the subset of patients with the highest FRα levels (ORR, 31%; progression-free survival, 5.4 months). Conclusion Concordance of FRα expression in biopsy versus archival tumor samples suggests that archival tissue can reliably identify patients with receptor-positive tumors and is appropriate for patient selection in mirvetuximab soravtansine clinical trials. Regardless of the tissue source analyzed, higher FRα expression was associated with greater antitumor activity. [ABSTRACT FROM AUTHOR]

Khawia sinensis is an important species in freshwater fish causing considerable economic losses to the breeding industry. This is the first mt genome of a caryophyllidean cestode characterised. The entire mt genome of K. sinensis is 13,759 bp in length. This mt genome contains 12 protein-coding genes, 22 transfer RNA genes, two ribosomal RNA genes and two non-coding regions. The arrangement of the K. sinensis mt genome is the same as other tapeworms, however, the incomplete stop codon (A) is more frequent that other species. Phylogenetic analyses based on concatenated amino-acid sequences of the 12 protein-coding genes of 17 tapeworms including K. sinensis were conducted to assess the relationship of K. sinensis with other species, the result indicated K. sinensis was closely related with cestode species. This complete mt genome of K. sinensis will enrich the mitochondrial genome databases of tapeworms and provide important molecular markers for ecology, diagnostics, population variation and evolution of K. sinensis and other species. [ABSTRACT FROM AUTHOR]

In this study, a highly active oxygen reduction reaction (ORR) electrocatalyst (MG-15) of Mn 3 O 4 nanoparticles (NPs) supported by reduced graphene oxide (rGO) has been fabricated through one-step microwave-assisted synthetic route. Upon microwave-assisted synthesis, the formation of Mn 3 O 4 NPs and the reduction of GO occurs simultaneously. Transmission electron microscope (TEM) profile reveals that Mn 3 O 4 NPs are uniformly distributed evenly on the winkled rGO sheets. The MG-15 hybrid materials show enhanced electrocatalytic activity compared to rGO, Mn 3 O 4 NPs and the mixture of rGO and Mn 3 O 4 NPs, which indicates that the synergistic effect of Mn 3 O 4 and rGO enhances the overall performance. Additional, the oxygen reduction peak of the MG-15 catalyst in a 0.1 M KOH solution is tested at −0.15 V, which is more positive than Pt/C (−0.154 V). The onset potential of the MG-15 is close to Pt/C. Most importantly, the mechanism analysis shows that it favors the 4e − pathway for ORR. Furthermore, the MG-15 also exhibit excellent durability and methanol. [ABSTRACT FROM AUTHOR]

[Display omitted] • 35 New Ph-C-DIM+Cl- derivatives were designed and synthesized, and A11, B5 and B15 were identified as new Nur77 modulators. • A11, B5 and B15 showed excellent pro-apoptosis activity in colon cancer cell lines HCT116 and SW620, while showed non-significant cytotoxicity against normal colon cell line NCM460. • A11, B5 and B15 bind Nur77 with high affinity, with a K d of 34 nM, 19 nM and 16 nM, respectively. • A11, B5 and B15 induced apoptosis of cancer cells by activating the Nur77/Bcl-2 apoptotic pathway. Nur77, an orphan nuclear receptor, is implicated in regulating diverse cellular biological processes including apoptosis and inflammation. We previously identified BI1071 (DIM-C-pPhCF 3 +MeSO 3 -), an oxidized methanesulfonate salt of (4-CF 3 -Ph-C-DIM), was a direct ligand of Nur77, which could activate the Nur77-Bcl-2 apoptotic pathway. To obtain more effective compounds targeting the Nur77-mediated apoptotic pathway, we designed and synthesized a series of BI1071 analogs by introducing various substituent groups in the indolyl-rings of BI1071. Structure-activity relationship study identified A11, B5 and B15 as improved analogs with stronger binding affinity to Nur77 and enhanced apoptotic activity compared to BI1071. Nur77-binding studies demonstrated that A11, B5 and B15 bind to Nur77 with a K d of 34 nM, 19 nM and 16 nM, respectively. Furthermore, mechanism studies showed that A11, B5 and B15 induced apoptosis through utilizing the Nur77-Bcl-2 pathway. [ABSTRACT FROM AUTHOR]

[Display omitted] • A series of acylhydrazones-based derivatives were designed, synthesized and evaluated for their anti-mitotic activity. • Compound B10 displayed better anti-mitotic activity with lower toxicity compared to XS060(A0). • Compound B10 effectively induced mitotic arrest and catastrophe in cancer cells. • Compound B10 acted in a RXRα-dependent manner. RXRα, a unique and important nuclear receptor, plays a vital role in various biological and pathological pathways, including growth, differentiation, and apoptosis. We recently reported a transcription-independent function of RXRα in cancer cells in which RXRα is phosphorylated by Cdk1 at the onset of mitosis, resulting in its translocation to the centrosome, where the phosphorylated RXRα (p -RXRα) interacts with polo-like kinase 1 (PLK1) to promote centrosome maturation and mitotic progression. Significantly, we also identified that a small molecule XS-060 binds to RXRα and selectively inhibits the p- RXRα/PLK1 interaction to induce mitotic arrest and catastrophe in cancer cells. Here, we report our design, synthesis, and biological evaluation of a series of XS-060 analogs as RXRα-targeted anti-mitotic agents. Our results identified B10 as an improved anti-mitotic agent. B10 bound to RXRα (K d = 3.04 ± 0.58 μM) and inhibited the growth of cervical cancer cells (HeLa, IC 50 = 1.46 ± 0.10 μM) and hepatoma cells (HepG2, IC 50 = 3.89 ± 0.45 μM and SK-hep-1, IC 50 = 5.74 ± 0.50 μM) with low cytotoxicity to nonmalignant cells(LO2, IC 50 > 50 μM). Furthermore, our mechanistic studies confirmed that B10 acted as an anticancer agent by inhibiting the p- RXRα/PLK1 pathway. These results provide a basis for further investigation and optimization of RXRα-targeted anti-mitotic molecules for cancer therapy. [ABSTRACT FROM AUTHOR]

To investigate the differentiation of regulatory T cells (Tregs) induced by methylprednisolone (MP) pulse therapy in patients with Systemic Lupus Erythematosus (SLE). We enrolled 30 patients with SLE and analyzed peripheral blood mononuclear cells (PBMCs) before and after MP pulse therapy. Peripheral Tregs, apoptosis of PBMCs subsets, and TGFβ production by monocytes was quantified by flow cytometry. Proliferation and IFN-γ production of CD4+ T cells were measured. Furthermore, TGFβ1 production by human monocyte-derived macrophages (HMDM) stimulated with MP-treated CD4+ T cells were quantified by ELISA. Peripheral Tregs was significantly increased after MP pulse therapy (6.76 ± 1.46% vs. 3.82 ± 1.02%, p < 0.01), with an expansion of Nrp1− induced Tregs (4.54 ± 0.46% vs. 1.75 ± 0.38%, p < 0.01). Proliferation and IFN-γ production of CD4+ T cells were significantly decreased after MP pulse therapy. MP pulse therapy induced CD4+ T cell apoptosis (early apoptosis, 26.34 ± 3.54% vs. 14.81 ± 2.89%, p < 0.01) and TGFβ expression on monocytes (6.02% vs. 2.45%, p < 0.01). Furthermore, MP induced CD4+ T cell apoptosis in vitro , which stimulated HMDM to produce TGFβ. Moreover, elevated TGFβ level in supernatant from HMDM stimulated with MP-treated CD4+ T cells promoted Tregs differentiation. MP pulse therapy induces CD4+ T cell apoptosis, which promotes monocytes to produce TGFβ and further facilitates Tregs differentiation. Newly-differentiated Tregs suppress proliferation and IFN-γ production of CD4+ T cells and contribute to immunoregulatory milieu after MP pulse therapy. • MP pulse therapy promotes the apoptosis of CD4+ T cells in lupus patients. • Monocytes produce more TGFβ after MP pulse therapy. • The elevated level of TGFβ facilitates the differentiation of Tregs. [ABSTRACT FROM AUTHOR]

Recent studies showed that increased mitochondrial fission is an early event of cell death during cerebral ischemia and dynamin-related protein 1 (Drp1) plays an important role in mitochondrial fission, which may be regulated by PTEN-induced putative kinase 1 (PINK1), a mitochondrial serine/threonine-protein kinase thought to protect cells from stress-induced mitochondrial dysfunction and regulate mitochondrial fission. However, the roles of PINK1 and Drp1 in hippocampal injury caused by transient global ischemia (TGI) remain unknown. We therefore tested the hypothesis that TGI may induce PINK1 causing downregulation of Drp1 phosphorylation to enhance hippocampal neuronal survival, thus functioning as an endogenous neuroprotective mechanism. We found progressively increased PINK1 expression in the hippocampal CA1 subfield1-48 h following TGI, reaching the maximal level at 4 h. Despite lack of changes in the expression level of total Drp1 and phosphor-Drp1 at Ser637, TGI induced a time-dependent increase of Drp1 phosphorlation at Ser616 that peaked after 24 h. Notably, PINK1-siRNA increased p-Drp1(Ser616) protein level in hippocampal CA1 subfield 24 h after TGI. The PINK1 siRNA also aggravated the TGI-induced oxidative DNA damage with an increased 8-hydroxy-deoxyguanosine (8-OHdG) content in hippocampal CA1 subfield. Furthermore, PINK1 siRNA also augmented TGI-induced apoptosis as evidenced by the increased numbers of TUNEL-positive staining and enhanced DNA fragmentation. These findings indicated that PINK1 is an endogenous protective mediator vital for neuronal survival under ischemic insult through regulating Drp1 phosphorylation at Ser616. [ABSTRACT FROM AUTHOR]

Abstract: Hyperglycemia is the major cause of diabetic angiopathy. The aim of our study was to evaluate the impact of KB-R7943, an inhibitor of Na+/Ca2+ exchanger (NCX) on cell growth and function of human “diabetic” endothelial cells (EC). Intercellular adhesion molecule-1 (ICAM-1) expression and NCX activity were determined after EC were exposed to high glucose in the absence and presence of KB-R7943. Coincubation of EC with high glucose for 24h resulted in a significant increase of monocyte-endothelial cell adhesion and the expression of ICAM-1. These effects were abolished by KB-R7943 and KB-R7943 significantly decreased the activation of NCX induced by high glucose. These findings suggested that KB-R7943 may play a role in inhibiting expression of adhesion molecules by inhibiting the reverse activation of NCX. [Copyright &y& Elsevier]

Abstract: Traditional mitochondrial 16S rRNA is commonly used in many species identification studies. However, it is difficult to apply to the phylogenetic studies among the Oncorhynchus subspecies, which is a crucial need for management purposes for Oncorhynchus masou formosanus, Taiwan salmon. In this study, we have developed an improved species identification method for Taiwan salmon distinguished with other Oncorhynchus subspecies tested by exploiting PCR for growth hormone (GH) 1 gene. By comparing DNA sequences for GH1 from 11 species of Oncorhynchus subspecies we designed novel PCR primers that exploit differences between Taiwan salmon and other Oncorhynchus subspecies. Therefore, the technique is an important tool in the management of populations of the endangered land-locked Taiwan salmon preventing from their possible hybrids with other Oncorhynchus subspecies once tested. [Copyright &y& Elsevier]

Abstract: We investigate the effect of rosiglitazone, a ligand for peroxisome proliferator-activated receptor-γ (PPARγ) with anti-inflammatory and anti-oxidative actions, on hippocampal injury and its roles in mitochondrial uncoupling protein 2 (UCP2) expression caused by transient global ischemia (TGI) in rats. Increased UCP2 expression was observed in mitochondria of hippocampal CA1 2–24h after TGI/reperfusion, with maximal expression levels at 6–18h. Administration of rosiglitazone to hippocampus 30min prior to the onset of TGI further enhanced mitochondrial UCP2 expression 2–6h following TGI/reperfusion. Rats subjected to TGI/reperfusion displayed a significant increase in lipid peroxidation, based on increased malondialdehyde (MDA) levels, in hippocampal CA1 mitochondria 2–6 h after reperfusion. Rosiglitazone significantly attenuated TGI/reperfusion-induced lipid peroxidation and suppressed hippocampal CA1 neuronal death based on the surviving neuronal counts. In conclusion, our results provide correlative evidence for the “PPARγ→UCP2→neuroprotection” cascade in ischemic brain injury. [Copyright &y& Elsevier]

Most cancer deaths are due to the colonization of tumor cells in distant organs. More evidence indicates that overexpression of RACGAP1 plays a critical role in cancer metastasis. However, the underlying mechanism still remains poorly understood. Here we found that RACGAP1 promoted breast cancer metastasis through regulating mitochondrial quality control. Overexpression of RACGAP1 in breast cancer cells led to the fragmentation of mitochondria, increased mitophagy intensity, mitochondrial turnover, and aerobic glycolysis ATP production. We showed that RACGAP1 promoted mitochondrial fission through recruiting ECT2 during anaphase and subsequently had activated ERK-DRP1 pathway. We further demonstrated the phosphorylation of RACGAP1 is essential for its ability of binding with ECT2 and its downstream effects. RACGAP1 overexpression also increased the expression of PGC-1a, a key mitochondrial biogenesis regulator, presumably by the increased mitophagy intensity induced by RACGAP1. PGC-1a increased the enrichment of DNMT1 in mitochondria, mitochondrial DNMT1 augmented mitochondrial DNA methylation and upregulated mitochondrial genome transcription. Our data indicated that RACGAP1 simultaneously facilitated mitophagy and mitochondrial biogenesis through regulating DRP1 phosphorylation and PGC-1a expression, eventually improved mitochondrial quality control in breast cancer cells. Our study provided a new angle in understanding the RACGAP1-overexpression related malignancy in breast cancer patients. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum (ER) stress is easily observed in chronic liver disease, which often causes accumulation of unfolded or misfolded proteins in the ER, leading to unfolded protein response (UPR). Regulating protein degradation is an integral part of UPR to relieve ER stress. The major protein degradation system includes the ubiquitin-proteasome system (UPS) and autophagy. All three arms of UPR triggered in response to ER stress can regulate UPS and autophagy. Accumulated misfolded proteins could activate these arms, and then generate various transcription factors to regulate the expression of UPS-related and autophagy-related genes. The protein degradation process regulated by UPR has great significance in many chronic liver diseases, including non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), viral hepatitis, liver fibrosis, and hepatocellular carcinoma(HCC). In most instances, the degradation of excessive proteins protects cells with ER stress survival from apoptosis. According to the specific functions of protein degradation in chronic liver disease, choosing to promote or inhibit this process is promising as a potential method for treating chronic liver disease. [ABSTRACT FROM AUTHOR]

Abstract: Cardiovascular complications account for significant morbidity and mortality in the diabetic population. Diabetic cardiomyopathy (DCM), a prominent cardiovascular complication, has been recognized as a microvascular disease that may lead to heart failure. During the past few decades, research progress has been made in investigating the pathophysiology of the disease; however, the exact molecular mechanism has not been elucidated, making therapeutic a difficult task. In this review article, we have discussed a number of diabetes-induced metabolites such as glucose, advanced glycation end products, protein kinase C, free fatty acid and oxidative stress and other related factors that are implicated in the pathophysiology of the DCM. An understanding of the biochemical and molecular changes especially early in the DCM may lead to new and effective therapies toward prevention and amelioration of DCM, which is important for the millions of individuals who already have or are likely to develop the disease before a cure becomes available. [Copyright &y& Elsevier]

Abstract: Diabetes mellitus (DM) is a serious metabolic disorder with micro- and macrovascular complications that results in significant morbidity and mortality. It is well established that cytosolic Ca2+ play an important role in controlling insulin secretion in pancreatic β-cells. The Na+/Ca2+ exchanger (NCX), an ion transport protein, is expressed in the plasma membrane of virtually all animal cells. NCX is a reversible carrier that can mediate the transport of Ca2+ across the plasma membrane in both directions. Therefore, great efforts have been made to identify NCX associated with DM. NCX is expressed in several tissues, and acts in the protection against intracellular calcium overload; in the regulation of insulin secretion by beta cells, and in improving vascular endothelium-dependent relaxation. All these mechanisms are associated with DM pathogenesis and its chronic complications. Therefore, NCX is a candidate protein for the development of these disorders. Only a few studies investigated NCX in relation to chronic complications of diabetes, with inconclusive results. [Copyright &y& Elsevier]