A triple-synergistic small-molecule sulfur cathode promises energetic Cu-S electrochemistry.

Metal-sulfur batteries have received great attention for electrochemical energy storage due to high theoretical capacity and low cost, but their further development is impeded by low sulfur utilization, poor electrochemical kinetics, and serious shuttle effect of the sulfur cathode. To avoid these problems, herein, a triple-synergistic small-molecule sulfur cathode is designed by employing N, S co-doped hierarchical porous bamboo charcoal as a sulfur host in an aqueous Cu-S battery. Expect the enhanced conductivity and chemisorption induced by N, S synergistic co-doping, the intrinsic synergy of macro-/meso-/microporous triple structure also ensures space-confined small-molecule sulfur as high utilization reactant and effectively alleviates the volume expansion during conversion reaction. Under a further joint synergy between hierarchical structure and heteroatom doping, the resulting sulfur cathode endows the Cu-S battery with outstanding electrochemical performance. Cycled at 5 A g-1, it can deliver a high reversible capacity of 2,509.8 mAh g-1 with a good capacity retention of 97.9% after 800 cycles. In addition, a flexible hybrid pouch cell built by a small-molecule sulfur cathode, Zn anode, and gel electrolytes can firmly deliver high average operating voltage of about 1.3 V with a reversible capacity of over 2,500 mAh g-1 under various destructive conditions, suggesting that the triple-synergistic small-molecule sulfur cathode promises energetic metal-sulfur batteries.

Altered intestinal microbiome and metabolome correspond to the clinical outcome of sepsis.

BACKGROUND: The gut microbiome plays a pivotal role in the progression of sepsis. However, the specific mechanism of gut microbiota and its metabolites involved in the process of sepsis remains elusive, which limits its translational application. METHOD: In this study, we used a combination of the microbiome and untargeted metabolomics to analyze stool samples from patients with sepsis enrolled at admission, then microbiota, metabolites, and potential signaling pathways that might play important roles in disease outcome were screened out. Finally, the above results were validated by the microbiome and transcriptomics analysis in an animal model of sepsis. RESULTS: Patients with sepsis showed destruction of symbiotic flora and elevated abundance of Enterococcus, which were validated in animal experiments. Additionally, patients with a high burden of Bacteroides, especially B. vulgatus, had higher Acute Physiology and Chronic Health Evaluation II scores and longer stays in the intensive care unit. The intestinal transcriptome in CLP rats illustrated that Enterococcus and Bacteroides had divergent profiles of correlation with differentially expressed genes, indicating distinctly different roles for these bacteria in sepsis. Furthermore, patients with sepsis exhibited disturbances in gut amino acid metabolism compared with healthy controls; namely, tryptophan metabolism was tightly related to an altered microbiota and the severity of sepsis. CONCLUSION: Alterations in microbial and metabolic features in the gut corresponded with the progression of sepsis. Our findings may help to predict the clinical outcome of patients in the early stage of sepsis and provide a translational basis for exploring new therapies.

IL-17A/IL-17RA promotes invasion and activates MMP-2 and MMP-9 expression via p38 MAPK signaling pathway in non-small cell lung cancer.

The present study is to investigate the effect and mechanism of action of interleukin (IL)-17A and its receptor IL-17RA on non-small cell lung cancer (NSCLC). A total of 139 NSCLC patients were included in the study. NSCLC tissues and tumor-adjacent tissues were collected from the patients. Human NSCLC cell lines H157, H1975, and A549 were used for in vitro studies. MTT assay was performed to determine cell proliferation. Wound healing assay was used to determine cell motility. Transwell assay was carried out to detect migration and invasion. Quantitative real-time polymerase chain reaction was conducted to measure mRNA expression, while Western blotting was used for determine protein expression. Immunohistochemistry was employed to evaluate IL-17RA expression in 139 primary human NSCLC tissues. Levels of IL-17RA in NSCLC tissues were higher than tumor-adjacent normal tissues, and associated with clinical outcomes. Kaplan-Meier survival analysis indicated that NSCLC patients with positive IL-17RA expression had a poor survival. In addition, IL-17A/IL-17RA affected NSCLC cell migration and invasion in vitro. Treatment with IL-17A/IL-17RA increased the expression of MMP-2 and MMP-9 in NSCLC cells. Furthermore, phosphorylation of p38 was enhanced in IL-17RA-overexpressing NSCLC cells. P38 MAPK-specific inhibitor SB203580 suppressed the migration and invasion of NSCLC cells. MMP-2 and MMP-9 were downstream effectors of IL-17RA and p38 signaling pathways. The present study demonstrates that P38 MAPK activity is crucial for IL-17A/IL-17RA to promote NSCLC metastasis. In addition, IL-17A/IL-17RA signaling may be a novel and promising cancer therapeutic target for the treatment of NSCLC.

GPR40-Mediated Gα12 Activation by Allosteric Full Agonists Highly Efficacious at Potentiating Glucose-Stimulated Insulin Secretion in Human Islets.

GPR40 is a clinically validated molecular target for the treatment of diabetes. Many GPR40 agonists have been identified to date, with the partial agonist fasiglifam (TAK-875) reaching phase III clinical trials before its development was terminated due to off-target liver toxicity. Since then, attention has shifted toward the development of full agonists that exhibit superior efficacy in preclinical models. Full agonists bind to a distinct binding site, suggesting conformational plasticity and a potential for biased agonism. Indeed, it has been suggested that alternative pharmacology may be required for meaningful efficacy. In this study, we described the discovery and characterization of Compound A, a newly identified GPR40 allosteric full agonist highly efficacious in human islets at potentiating glucose-stimulated insulin secretion. We compared Compound A-induced GPR40 activity to that induced by both fasiglifam and AM-1638, another allosteric full agonist previously reported to be highly efficacious in preclinical models, at a panel of G proteins. Compound A was a full agonist at both the Gαq and Gαi2 pathways, and in contrast to fasiglifam Compound A also induced Gα12 coupling. Compound A and AM-1638 displayed similar activity at all pathways tested. The Gα12/Gα13-mediated signaling pathway has been linked to protein kinase D activation as well as actin remodeling, well known to contribute to the release of insulin vesicles. Our data suggest that the pharmacology of GPR40 is complex and that Gα12/Gα13-mediated signaling, which may contribute to GPR40 agonists therapeutic efficacy, is a specific property of GPR40 allosteric full agonists.

Discovery of a novel potent GPR40 full agonist.

Compound 12 is a GPR40 agonist that realizes the full magnitude of efficacy possible via GPR40 receptor agonism. In vitro and in vivo studies demonstrated superior glucose lowering by 12 compared to fasiglifam (TAK-875), in a glucose dependent manner. The enhanced efficacy observed with the full agonist 12 was associated with both direct and indirect stimulation of insulin secretion.

Discovery of novel benzo[b]thiophene tetrazoles as non-carboxylate GPR40 agonists.

GPR40 partial agonism is a promising new mechanism for the treatment of type 2 diabetes mellitus with clinical proof of concept. Most of the GPR40 agonists in the literature have a carboxylic acid functional group, which may pose a risk for idiosyncratic drug toxicity. A novel series of GPR40 agonists containing a tetrazole as a carboxylic acid bioisostere was identified. This series of compounds features a benzo[b]thiophene as the center ring, which is prone to oxidation during phase 1 metabolism. Following SAR optimization targeting GPR40 agonist activity and intrinsic clearance in microsomes (human and rat), potent and metabolically stable compounds were selected for in vivo evaluation. The compounds are efficacious at lowering blood glucose in a SD rat oGTT model.

Carbon nanotubes kirigami mechanical metamaterials.

Imparting elasticity and functionality to materials is one of the key objects of materials science research. Here, inspired by the art of kirigami, mechanical metamaterials comprising carbon nanotubes (CNTs) are hypothetically constructed. Using classical molecular dynamics (MD) simulations, a systematic study of the elastic limit, extensibility and yield stress of as-generated CNTs kirigami (CNT-k) is performed. Three designated kirigami patterns are employed to achieve high stretchability of CNTs. It is shown that CNT-k typically exhibits three distinct deformation stages, of which the first stage, which is referred to as geometric deformation, contributes quite a high proportion of the ductility. Various geometric parameters of CNT-k that influence the key mechanical properties of interest are respectively discussed. Three types of CNT-k with specifically identical geometric parameters exhibit distinct mechanical characteristics. This study provides an interesting example of interplay between the geometry, ductility, and mechanical characteristics of tubular materials.

Manipulation and formation mechanism of silica one-dimensional periodic structures by roller electrospinning.

A roller electrospinning technique is combined with sol-gel chemistry to fabricate silica and polymeric materials on conductive and nonconductive substrates to verify its ability for controlling the long-range periodic structure of the final product. According to the experimental results, formation of the one-dimensional periodic silica structure was dependent on the electrical conductivity of the collector substrate. The periodic density seems to be related to the width of silica product. No effect from the electrical conductivity of collector substrate on the structure of polymeric system was observed. An energy transformation model was proposed to investigate the formation mechanism of this periodic structure. The theoretical simulation indicates that large width-to-thickness ratio of the product and high-energy transformation efficiency favor the formation of the long-range periodic structure.

Effects of Crocus sativus on glycemic control and cardiometabolic parameters among patients with metabolic syndrome and related disorders: a systematic review and meta-analysis of randomized controlled trials.

Metabolic syndrome (MetS) is a cluster of clinical syndromes that is closely associated with an elevated risk of developing atherosclerotic cardiovascular disease. In a series of animal experiments and clinical trials, crocus sativus and its component crocin have demonstrated promising hypoglycemic effects. However, there is currently insufficient evidence regarding their impact on cardiometabolic parameters. Our study aimed to assess the impact of Crocus sativus and crocin on glycemic control in individuals with metabolic syndrome and associated disorders, as well as their potential effects on improving cardiometabolic parameters. We searched Cochrane Library, PubMed, Embase, and Web of Science databases to ascertain the pertinent randomized controlled trials (RCTs) until December 30, 2023. Q-test and I2 statistics were utilized to evaluate heterogeneity among the included studies. Data were merged using a random-effects model and presented as (WMD) with a 95% confidence interval (CI). The current comprehensive review and meta-analysis, encompassing 13 RCTs involving a total of 840 patients diagnosed with metabolic syndrome and associated disorders, demonstrates that Crocus sativus was superior to placebo on Hemoglobin A1c(HbA1c) (WMD: -0.31;95% CI [-0.44,-0.19]. P = 0.002) and systolic blood pressure(SBP) (WMD:-7.49;95% CI [-11.67,-3.30]. P = 0.99) respectively. Moreover, Crocus sativus improved fasting blood glucose (FBG) (WMD:-7.25;95% CI [-11.82, -2.57]. P = 0.002) when used crocin and on other chronic diseases. Crocus sativus reduced the total cholesterol (TC) among the metabolic syndromepatients (WMD:-13.64;95%CI [-26.26, -1.03]. P = 0.03). We demonstrated that Crocus sativus exerts beneficial effects on glycemic control and cardiometabolic parameters in individuals with metabolic syndrome and related disorders.

Theoretical simulation of TADF character of 3,9'-bicarbazole-modified 2,4,6-triphenyl-1,3,5-triazine.

CONTEXT: Three donor (D)-acceptor (A)-type temperature-activated delayed fluorescent (TADF) molecules of 9-(2-(4,6-diphenyl-1,3,5-triazin-2-yl)phenyl)-9H-3,9'-bicarbazole (o-TrzDCz), 9-(3-(4,6-diphenyl-1,3,5-triazin-2-yl)phenyl)-9H-3,9'-bicarbazole (m-TrzDCz), and 9-(4-(4,6-diphenyl-1,3,5-triazin-2-yl)phenyl)-9H-3,9'-bicarbazole (p-TrzDCz) were designed in this paper, and the photophysical properties, including the intersystem crossing rate, the reorganization energies (λ), and the intersystem crossing/reverse intersystem crossing (ISC/RISC) rate, were simulated to explore the effect of substitution sites on their TADF character. The values of the twist angle between the D and A moieties in ground state and the molecular root-mean-square deviation (RMSD) of the S1 and T1 states referenced to the S0 state indicate that o-TrzDCz possess bigger steric hindrance and stabler molecular configuration. The λ values of the ISC/RISC process should be 0.06/0.04 eV for o-TrzDCz, which are much smaller than those of m-TrzDCz (0.51/0.41 eV) and p-TrzDCz (1.93/1.06 eV). At the same time, o-TrzDCz possess the biggest kRISC (7.28 × 106 s-1) and kr (3.12 × 106 s-1) values and the smallest kp (0.10 s-1) value among the three titled molecules. These data indicate that o-TrzDCz should have more excellent TADF character than m-TrzDCz and p-TrzDCz. In a word, this research presents that adjusting the molecular linking manner should be a charming way to explore novel high-efficient TADF molecules. METHODS: Quantum chemical calculations were performed at PBE0/6-31G* level by Gaussian 09 and ORCA 4.1.0 software packages, and reorganization energies and Huang-Rhys were performed by the DUSHIN program and MOMAP 2019B software package based on the Gaussian 09 output files, while the phosphorescence rates were performed at B3LYP/6-31G* level by Dalton 2021.

Neural Correlates of Abnormal Cortical Gait Control in Parkinson's Disease: A Whole-Gait-Cycle EEG Study.

OBJECTIVE: Electroencephalography (EEG) with high time-resolution allows for recording dynamic cortical activity during walking and provides new insight into the underlying pathophysiology of gait impairments in PD. However, traditional gait-phase-specific EEG analysis only measures the brain activities in the isolated gait phase, but neglects the between-gait-phase interactions as well as the whole-gait-cycle characteristics, and therefore is unable to effectively reflect the abnormal cortical gait control. METHODS: In this study, we introduced three whole-gait-cycle measures of intra-stride EEG activity (i.e., mean desynchronization, amplitude of fluctuations, and coupling to the gait phase), and investigated their abnormalities in PD and relationships with gait impairments, which were further compared with the traditional gait-phase-specific measures. RESULTS: Compared with healthy controls, PD patients showed overwhelming stronger desynchronizations (ERD) across the whole gait cycle in θ, α and low-ß bands, implying a cortical compensatory strategy in response to the low efficiency of the motor network. Patients also exhibited weaker intra-stride ERD fluctuations in the central area in α and low-ß bands, with reduced amplitude and less coupling to the gait phase, which were correlated with gait impairments in walking speed, gait rhythm and walking stability. However, gait-phase-specific EEG measures did not show any significant correlation with gait impairments in PD. CONCLUSION: Our results demonstrated the efficiency of whole-gait-cycle EEG measures in characterizing the abnormal cortical gait control, and for the first time, associated gait impairments with weak intra-stride electrocortical fluctuations. SIGNIFICANCE: The findings may shed light on the development of cortical-targeted interventions for PD.

Copper oxide nanoparticles inhibited denitrifying enzymes and electron transport system activities to influence soil denitrification and N2O emission.

Nanopesticides are widely applied in modern agricultural systems to replace traditional pesticides, which inevitably leads to their accumulation in soils. Nanopesticides based on copper oxide nanoparticles (CuO NPs) may affect the soil nitrogen cycle, such as the denitrification process; however, the mechanism remains unclear. Here, acute exposure experiments for 60 h were conducted to explore the effects of CuO NPs (10, 100, 500 mg kg-1) on denitrification. In this study, Cu speciation, activities of denitrifying enzymes, electron transport system activity (ETSA), expression of denitrifying functional genes, composition of bacterial communities and reactive oxygen species (ROS) were determined. In all treatments, Cu ions was the dominant form and responsible for the toxicity of CuO NPs. The results indicated that CuO NPs treatments at 500 mg kg-1 remarkably inhibited denitrification, led to an 11-fold increase in NO3- accumulation and N2O emission rates decrease by 10.2-24.1%. In the denitrification process, the activities of nitrate reductase and nitric oxide reductase reduced by 21.1-42.1% and 10.3-16.3%, respectively, which may be a reason for the negative effect of CuO NPs. In addition, ETSA was significantly inhibited with CuO NPs applications, which reflects the ability of denitrification to accept electrons. Denitrifying functional genes and bacterial communities composition were changed, thus further influencing the denitrification process. ROS analysis showed that there were no significant differences among NPs treatments. This research improves the understanding of CuO NPs impact on soil denitrification. Further attention should be paid to the nitrogen transformation in agricultural soils in the presence of nanopesticides.

High-efficiency and recyclability of ramie degumming catalyzed by FeCl3 in organic solvent.

Although traditional alkaline (TAL) process for ramie degumming is commonly used in the industry, it causes severe environmental concerns. In this work, an emerging organic solvent degumming process utilizing FeCl3 catalyst (FeCl3-OS) was developed in one step. The influences of FeCl3-OS system on fiber properties (e.g. residual gum content, tenacity, degree of polymerization (DP), etc.) were evaluated, and the recyclability of degumming solution was also studied. The results indicated that ramie fiber could be isolated with FeCl3-OS treatment (FeCl3 1.0 %, 200 ℃, 121 min), and the tenacity and residual gum content of refined fibers were 7.9 cN/dtex and 3.88 %, respectively. Fibers treated in FeCl3-OS system were endowed better moisture sorption (9.2 %) and higher yield (75.2 %) compared with that in TAL system. Moreover, fibers with five cycles' treatment possessed outstanding performances, that was 4.44 cN/dtex of tenacity and 4.33 % of residual gum content, which fulfilled the requirements of the spinning process.

In-Plane Mechanical Behavior of a New Star-Re-Entrant Hierarchical Metamaterial.

A novel hierarchical metamaterial with tunable negative Poisson's ratio is designed by a re-entrant representative unit cell (RUC), which consists of star-shaped subordinate cells. The in-plane mechanical behaviors of star-re-entrant hierarchical metamaterial are studied thoroughly by finite element method, non-dimensional effective moduli and effective Poisson's ratios (PR) are obtained, then parameters of cell length, inclined angle, thickness for star subordinate cell as well as the amount of subordinate cell along x, y directions for re-entrant RUC are applied as adjustable design variables to explore structure-property relations. Finally, the effects of the design parameters on mechanical behavior and relative density are systematically investigated, which indicate that high specific stiffness and large auxetic deformation can be remarkably enhanced and manipulated through combining parameters of both subordinate cell and parent RUC. It is believed that the new hierarchical metamaterial reported here will provide more opportunities to design multifunctional lightweight materials that are promising for various engineering applications.

Discovery of a GPR40 Superagonist: The Impact of Aryl Propionic Acid α-Fluorination.

GPR40 is a G-protein-coupled receptor which mediates fatty acid-induced glucose-stimulated insulin secretion from pancreatic beta cells and incretion release from enteroendocrine cells of the small intestine. GPR40 full agonists exhibit superior glucose lowering compared to partial agonists in preclinical species due to increased insulin and GLP-1 secretion, with the added benefit of promoting weight loss. In our search for potent GPR40 full agonists, we discovered a superagonist which displayed excellent in vitro potency and superior efficacy in the Gαs-mediated signaling pathway. Most synthetic GPR40 agonists have a carboxylic acid headgroup, which may cause idiosyncratic toxicities, including drug-induced-liver-injury (DILI). With a methyl group and a fluorine atom substituted at the α-C of the carboxylic acid group, 19 is not only highly efficacious in lowering glucose and body weight in rodent models but also has a low DILI risk due to its stable acylglucuronide metabolite.

Carboxylic acid bioisosteres acylsulfonamides, acylsulfamides, and sulfonylureas as novel antagonists of the CXCR2 receptor.

A series of novel acylsulfonamide, acylsulfamide, and sulfonylurea bioisosteres of carboxylic acids were prepared as CXCR2 antagonists. Structure-activity relationships are reported for these series. One potent orally bioavailable inhibitor had excellent PK properties and was active in a lung injury model in hyperoxia-exposed newborn rats.

6-Benzhydryl-4-amino-quinolin-2-ones as Potent Cannabinoid Type 1 (CB1) Receptor Inverse Agonists and Chemical Modifications for Peripheral Selectivity.

A novel series of 6-benzhydryl-4-amino-quinolin-2-ones was discovered as cannabinoid type 1 receptor (CB1R) inverse agonists based on the high-throughput screening hit, compound 1a. Structure-activity relationships were studied to improve in vitro/in vivo pharmacology and restrict distribution to the peripheral circulation. We adopted several strategies such as increasing topological polar surface area, incorporating discrete polyethylene glycol side chains, and targeting P-glycoprotein (P-gp) to minimize access to the brain. Compound 6a is a P-gp substrate and a potent and highly selective CB1R inverse agonist, demonstrating excellent in vivo metabolic stability and a low brain to plasma ratio. However, brain receptor occupancy studies showed that compound 6a may accumulate in brain with repeat dosing. This was evidenced by compound 6a inhibiting food intake and inducing weight loss in diet-induced obese mice. Thus, a strategy based on P-gp efflux may not be adequate for peripheral restriction of the disclosed quinolinone series.

Benzodiazepinedione inhibitors of the Hdm2:p53 complex suppress human tumor cell proliferation in vitro and sensitize tumors to doxorubicin in vivo.

The activity and stability of the p53 tumor suppressor are regulated by the human homologue of the mouse double minute 2 (Hdm2) oncoprotein. It has been hypothesized that small molecules disrupting the Hdm2:p53 complex would allow for the activation of p53 and result in growth suppression. We have identified small-molecule inhibitors of the Hdm2:p53 interaction using our proprietary ThermoFluor microcalorimetry technology. Medicinal chemistry and structure-based drug design led to the development of an optimized series of benzodiazepinediones, including TDP521252 and TDP665759. Activities were dependent on the expression of wild-type (wt) p53 and Hdm2 as determined by lack of potency in mutant or null p53-expressing cell lines or cells engineered to no longer express Hdm2 and wt p53. TDP521252 and TDP665759 inhibited the proliferation of wt p53-expressing cell lines with average IC(50)s of 14 and 0.7 micromol/L, respectively. These results correlated with the direct cellular dissociation of Hdm2 from wt p53 observed within 15 minutes in JAR choriocarcinoma cells. Additional activities of these inhibitors in vitro include stabilization of p53 protein levels, up-regulation of p53 target genes in a DNA damage-independent manner, and induction of apoptosis in HepG2 cells. Administration of TDP665759 to mice led to an increase in p21(waf1/cip1) levels in liver samples. Finally, TDP665759 synergizes with doxorubicin both in culture and in an A375 xenograft model to decrease tumor growth. Taken together, these data support the potential utility of small-molecule inhibitors of the Hdm2:p53 interaction for the treatment of wt p53-expressing tumors.

Effects of p38MAPK-mediated excision repair cross-complementation 1 expression on prognosis of patients with non-small cell lung cancer.

The present study aimed to investigate the effects of excision repair cross-complementation 1 (ERCC1) expression on the prognosis of patients with non-small cell lung cancer (NSCLC). A total of 140 patients with NSCLC who underwent radical resection were included. Immunohistochemical staining was performed on the tissue specimens obtained from patients and correlation analysis was used to determine the association between ERCC1 expression and clinicopathological characteristics. Cell proliferation was assessed using an MTT assay. The mRNA and protein expression levels were detected using reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. The expression of ERCC1 was demonstrated to be significantly elevated in tumor tissue compared with adjacent tissue samples. Furthermore, the expression of ERCC1 in squamous carcinoma was significantly higher compared with in adenocarcinoma samples. The expression of ERCC1 in patients who smoke was significantly higher compared with in the non-smokers. The 3-year disease-free survival (DFS) and overall survival (OS) for ERCC1-negative patients were higher compared with ERCC1-positive patients. Multivariate analysis demonstrated that ERCC1 expression, pathological staging, and tumor staging were important prognostic factors for NSCLC. Subgroup analysis revealed that the 3-year OS rate for ERCC1-negative patients with stage II-III tumors who received systematic adjuvant chemotherapy was higher compared with ERCC1-negative patients. The 3-year DFS and OS rates for ERCC1-negative patients with squamous carcinoma were higher compared with ERCC1-positive patients. In addition, p38 inhibitor treatment significantly inhibited the mRNA and protein expression levels of ERCC1 in A549 cells, and enhanced the sensitivity of cells to cisplatin. The results of the present study suggest that ERCC1 expression is an important prognostic indicator for NSCLC, particularly for patients with stage II-III tumors who receive systematic platinum-based adjuvant chemotherapy.