Multi-level Reactive Oxygen Species Amplifier to Enhance Photo-/Chemo-Dynamic/Ca2+ Overload Synergistic Therapy.

Reactive oxygen species (ROS)-involved photodynamic therapy (PDT) and chemodynamic therapy (CDT) hold great promise for tumor treatment. However, hypoxia, insufficient H2O2, and overexpressed glutathione (GSH) in the tumor microenvironment (TME) hinder ROS generation significantly. Herein, we reported CaO2@Cu-TCPP/CUR with O2/H2O2/Ca2+ self-supply and GSH depletion for enhanced PDT/CDT and Ca2+ overload synergistic therapy. CaO2 nanospheres were first prepared and used as templates for guiding the coordination between the carboxyl of tetra-(4-carboxyphenyl)porphine (TCPP) and Cu2+ ions as hollow CaO2@Cu-TCPP, which facilitated GSH-activated TCPP-based PDT and Cu+-mediated CDT. The hollow structure was then loaded with curcumin (CUR) to form CaO2@Cu-TCPP/CUR composites. Cu-TCPP prevented degradation of CaO2, while Cu2+ ions reacted with GSH to deplete GSH, produce Cu+ ions, and release TCPP, CaO2, and CUR. CaO2 reacted with H2O to generate O2, H2O2, and Ca2+ to achieve O2/H2O2/Ca2+ self-supply for TCPP-based PDT, Cu+-mediated CDT, and CUR-enhanced Ca2+ overload therapy. Thus, this multilevel ROS amplifier enhances synergistic therapy with fewer side effects and drug resistance.

Inferring Mycobacterium Tuberculosis Drug Resistance and Transmission using Whole-genome Sequencing in a High TB-burden Setting in China.

Objective: China is among the 30 countries with a high burden of tuberculosis (TB) worldwide, and TB remains a public health concern. Kashgar Prefecture in the southern Xinjiang Autonomous Region is considered as one of the highest TB burden regions in China. However, molecular epidemiological studies of Kashgar are lacking. Methods: A population-based retrospective study was conducted using whole-genome sequencing (WGS) to determine the characteristics of drug resistance and the transmission patterns. Results: A total of 1,668 isolates collected in 2020 were classified into lineages 2 (46.0%), 3 (27.5%), and 4 (26.5%). The drug resistance rates revealed by WGS showed that the top three drugs in terms of the resistance rate were isoniazid (7.4%, 124/1,668), streptomycin (6.0%, 100/1,668), and rifampicin (3.3%, 55/1,668). The rate of rifampicin resistance was 1.8% (23/1,290) in the new cases and 9.4% (32/340) in the previously treated cases. Known resistance mutations were detected more frequently in lineage 2 strains than in lineage 3 or 4 strains, respectively: 18.6% vs. 8.7 or 9%, P < 0.001. The estimated proportion of recent transmissions was 25.9% (432/1,668). Multivariate logistic analyses indicated that sex, age, occupation, lineage, and drug resistance were the risk factors for recent transmission. Despite the low rate of drug resistance, drug-resistant strains had a higher risk of recent transmission than the susceptible strains (adjusted odds ratio, 1.414; 95% CI, 1.023-1.954; P = 0.036). Among all patients with drug-resistant tuberculosis (DR-TB), 78.4% (171/218) were attributed to the transmission of DR-TB strains. Conclusion: Our results suggest that drug-resistant strains are more transmissible than susceptible strains and that transmission is the major driving force of the current DR-TB epidemic in Kashgar.

Respiratory Support After Extubation in Children With Pediatric ARDS.

BACKGROUND: Postextubation respiratory support in pediatric ARDS may be used to support the recovering respiratory system and promote timely, successful liberation from mechanical ventilation. This study's aims were to (1) describe the use of postextubation respiratory support in pediatric ARDS from the time of extubation to hospital discharge, (2) identify potential risk factors for postextubation respiratory support, and (3) provide preliminary data for future larger studies. METHODS: This pilot single-center prospective cohort study recruited subjects with pediatric ARDS. Subjects' respiratory status up to hospital discharge, the use of postextubation respiratory support, and how it changed over time were recorded. Analysis was performed comparing subjects who received postextubation respiratory support versus those who did not and compared its use among pediatric ARDS severity categories. Multivariable logistic regression was used to determine variables associated with the use of postextubation respiratory support and included oxygenation index (OI), ventilator duration, and weight. RESULTS: Seventy-three subjects with pediatric ARDS, with median age and OI of 4 (0.6-10.5) y and 7.3 (4.9-12.7), respectively, were analyzed. Postextubation respiratory support was provided to 54/73 (74%) subjects: 28/45 (62.2%), 19/21 (90.5%), and 7/7 (100%) for mild, moderate, and severe pediatric ARDS, respectively, (P = .01). OI and mechanical ventilation duration were higher in subjects who received postextubation respiratory support (8.7 [5.4-14] vs 4.6 [3.7-7], P < .001 and 10 [7-17] d vs 4 [2-7] d, P < .001) compared to those who did not. At hospital discharge, 12/67 (18.2%) survivors received home respiratory support (6 subjects died prior to hospital discharge). In the multivariable model, ventilator duration (adjusted odds ratio 1.3 [95% CI 1.0-1.7], P = .050) and weight (adjusted odds ratio 0.95 [95% CI 0.91-0.99], P = .02) were associated with the use of postextubation respiratory support. CONCLUSIONS: The majority of intubated subjects with pediatric ARDS received respiratory support postextubation, and a substantial proportion continued to require it up to hospital discharge.

A Review on The Pathogenesis of Cardiovascular Disease of Flaviviridea Viruses Infection.

Members of the Flaviviridae family, encompassing the Flavivirus and Hepacivirus genera, are implicated in a spectrum of severe human pathologies. These diseases span a diverse spectrum, including hepatitis, vascular shock syndrome, encephalitis, acute flaccid paralysis, and adverse fetal outcomes, such as congenital heart defects and increased mortality rates. Notably, infections by Flaviviridae viruses have been associated with substantial cardiovascular compromise, yet the exploration into the attendant cardiovascular sequelae and underlying mechanisms remains relatively underexplored. This review aims to explore the epidemiology of Flaviviridae virus infections and synthesize their cardiovascular morbidities. Leveraging current research trajectories and our investigative contributions, we aspire to construct a cogent theoretical framework elucidating the pathogenesis of Flaviviridae-induced cardiovascular injury and illuminate prospective therapeutic avenues.

Scutellarin inhibits oleic acid induced vascular smooth muscle foam cell formation via activating autophagy and inhibiting NLRP3 inflammasome activation.

Abnormalities in vascular smooth muscle cells (VSMCs) are pivotal in the pathogenesis of cardiovascular pathologies such as atherosclerosis and hypertension. Scutellarin (Scu), a flavonoid derived from marigold flowers, exhibits a spectrum of biological activities including anti-inflammatory, antioxidant, antitumor, immunomodulatory and antimicrobial effects. Notably, Scu has demonstrated the capacity to mitigate vascular endothelial damage and prevent atherosclerosis via its antioxidative properties. Nevertheless, the influence of Scu on the formation of VSMC-derived foam cells remains underexplored. In this study, Scu was evidenced to efficaciously attenuate oleic acid (OA)-induced lipid accumulation and the upregulation of adipose differentiation-associated protein Plin2 in a dose- and time-responsive manner. We elucidated that Scu effectively diminishes OA-provoked VSMC foam cell formation. Further, it was established that Scu pretreatment augments the protein expression of LC3B-II and the mRNA levels of Map1lc3b and Becn1, concurrently diminishing the protein levels of the NLRP3 inflammasome compared to the OA group. Activation of autophagy through rapamycin attenuated NLRP3 inflammasome protein expression, intracellular lipid droplet content and Plin2 mRNA levels. Scu also counteracted the OA-induced decrement of LC3B-II levels in the presence of bafilomycin-a1, facilitating the genesis of autophagosomes and autolysosomes. Complementarily, in vivo experiments revealed that Scu administration substantially reduced arterial wall thickness, vessel wall cross-sectional area, wall-to-lumen ratio and serum total cholesterol levels in comparison to the high-fat diet model group. Collectively, our findings suggest that Scu attenuates OA-induced VSMC foam cell formation through the induction of autophagy and the suppression of NLRP3 inflammasome activation.

Near-Infrared Responsive Ag@Au Nanoplates with Exceptional Stability for Highly Sensitive Colorimetric and Photothermal Dual-Mode Lateral Flow Immunoassay.

Lateral flow immunoassay (LFIA) has played a vital role in point-of-care (POC) testing on account of its simplicity, rapidity, and low cost. However, the low sensitivity and difficulty of quantitation limit its further development. Sensitive markers with new detection modes are being developed to dramatically improve LFIA's performance. Herein, a ligand-complex approach was proposed to uniformly coat a thin layer of Au onto Ag triangular nanoplates (Ag TNPs) without etching the Ag cores, which not only retain the unique optical properties from Ag TNPs but also acquire the surface stability and biocompatibility of gold. The localized surface plasmon resonance absorption of these Ag@Au TNPs could be finely adjusted from visible (550 nm) to the second near-infrared region (NIR-II) (1100 nm), and even longer, by simply adjusting the ratio between edge length and thickness. Utilizing the Ag@Au TNPs as new markers for LFIA, a highly sensitive colorimetric and photothermal dual-mode detection of the SARS-CoV-2 nucleocapsid protein was achieved with a very low background. The Ag@Au TNPs showed an exceedingly high photothermal conversion efficiency of 61.4% (ca. 2 times higher than that of Au nanorods), endowing the LFIA method with a low photothermal detection limit (40 pg/mL), which was 25-fold lower than that of the colorimetric results. The generality of the method was further verified by the sensitive and accurate analysis of cardiac troponin I (cTnI). This method is robust, reproducible, and highly specific and has been successfully applied to SARS-COV-2 detection in 35 clinical samples with satisfactory results, demonstrating its potential for POC applications.

Rhodium-Catalyzed Asymmetric Addition to 4- or 5-Carbonyl-cycloenones through Dynamic Kinetic Resolution: Enantioselective Synthesis of (-)-Cannabidiol.

The reaction of 4/5-carbonyl-cycloalkenone 1 or its achiral isomer 1' with organoboronic acid 2 in the presence of a chiral diene (S,S)-Fc-tfb-rhodium catalyst gave disubstituted trans-cycloalkanone 3 with high diastereo- and enantioselectivity. This highly efficient dynamic kinetic resolution is achieved by fast racemization of 1 through the formation of a dienolate followed by kinetic resolution with the chiral catalyst. The utility is demonstrated by the synthesis of key intermediates en route to (-)-cannabidiol.

Irritable bowel syndrome in children: the placebo response rate and influencing factors a meta-analysis.

BACKGROUND: Irritable bowel syndrome is common in children and exhibits a high placebo response. This study was to explore the placebo response rate and its influencing factors in children with irritable bowel syndrome. METHODS: A systematic search was performed on Pubmed, Embase, MEDLINE, Cochrane Library, CNKI, Wanfang, and CBM from database inception to March 2022. Randomized controlled trials of irritable bowel syndrome in children were included in the study. The primary outcome was the placebo response rate of improvement. RESULTS: Thirteen studies were included, with 445 patients in the placebo group. The rate of improvement and abdominal pain disappearance were 28.2% (95% CI, 16.6-39.9%) and 5% (95% CI, 0-18.4%). The placebo response based on the abdominal pain score was 0.675 (95% CI, 0.203-1.147). The mode of administration (P < 0.01), dosing schedule (P < 0.01), and clinical outcome assessor (P = 0.04) have a significant impact on the magnitude of placebo effect. CONCLUSIONS: The placebo response rate for pediatric irritable bowel syndrome was 28.2%. In clinical trials, reducing dosing frequency, selecting appropriate dosage forms, and using patient-reported outcomes can help mitigate the placebo effect. IMPACT: This is the first meta-analysis to assess the placebo response rates for improvement and disappearance in children with IBS. The finding suggested that the mode of administration, dosing schedule, and clinical outcome assessor could potentially influence the magnitude of the placebo effect in children with IBS. This study would provide a basis for estimating sample size in clinical trial design with a placebo control.

First Observation of Negative Capacitance in Molecular Ferroelectric Thin Films.

On the path of persisting Moore's Law, one of the biggest obstacles is the "Boltzmann tyranny," which defines the lower limit of power consumption of individual transistors. Negative capacitance (NC) in ferroelectrics could provide a solution and has garnered significant attention in the fields of nanoelectronics, materials science, and solid-state physics. Molecular ferroelectrics, as an integral part of ferroelectrics, have developed rapidly in terms of both performance and functionality, with their inherent advantages such as easy fabrication, mechanical flexibility, low processing temperature, and structural tunability. However, studies on the NC in molecular ferroelectrics are limited. In this study, the focus is centered on the fabricated high-quality thin films of trimethylchloromethyl ammonium trichlorocadmium(II), and a pioneering investigation on their NC responses is conducted. The findings demonstrate that the NC exhibited by molecular ferroelectrics is comparable to that of conventional HfO2 -based ferroelectrics. This underscores the potential of molecular material systems for next-generation electronic devices.

Contact Piezoresistive Sensors Based on Electro-Polymerized Polypyrrole and a Regulated Conductive Pathway.

The performance of contact resistive pressure sensors heavily relies on the intrinsic characteristics of the active layers, including the mechanical surface structure, conductivity, and elastic properties. However, efficiently and simply regulating the conductivity, morphology, and modulus of the active layers has remained a challenge. In this study, we introduced electro-polymerized polypyrrole (ePPy) to design flexible contact piezoresistive sensors with tailored intrinsic properties. The customizable intrinsic property of ePPy was comprehensively illustrated on the chemical and electronic structure scale, and the impact of ePPy's intrinsic properties on the sensing performance of the device was investigated by determining the correlation between resistivity, roughness, and device sensitivity. Due to the synergistic effects of roughness, conductivity, and elastic properties of the active layers, the flexible ePPy-based pressure sensor exhibited high sensitivity (3.19 kPa-1, 1-10 kPa, R2 = 0.97), fast response time, good durability, and low power consumption. These advantages allowed the sensor to offer an immediate response to human motion such as finger-bending and grasping movements, demonstrating the promising potential of tailorable ePPy-based contact piezoresistive sensors for wearable electronic applications.

Clinical Characteristics, Diagnosis, and Therapeutics of COVID-19: A Review.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that suddenly emerged at the end of December 2019 and caused coronavirus disease 2019 (COVID-19) continues to afflict humanity, not only seriously affecting healthcare systems but also leading to global social and economic imbalances. As of August 2022, there were approximately 580 million confirmed cases of COVID-19 and approximately 6.4 million confirmed deaths due to this disease. The data are sufficient to highlight the seriousness of SARS-CoV-2 infection. Although most patients with COVID-19 present primarily with respiratory symptoms, an increasing number of extrapulmonary systemic symptoms and manifestations have been associated with COVID-19. Since the outbreak of COVID-19, much has been learned about the disease and its causative agent. Therefore, great effort has been aimed at developing treatments and drug interventions to treat and reduce the incidence of COVID-19. In this narrative review, we provide a brief overview of the epidemiology, mechanisms, clinical manifestations, diagnosis, and therapeutics of COVID-19.

Lactobacillus fermentum Alleviates the Colorectal Inflammation Induced by Low-Dose Sub-Chronic Microcystin-LR Exposure.

Microcystin-LR (MC-LR) contamination is a worldwide environmental problem that poses a grave threat to the water ecosystem and public health. Exposure to MC-LR has been associated with the development of intestinal injury, but there are no effective treatments for MC-LR-induced intestinal disease. Probiotics are "live microorganisms that are beneficial to the health of the host when administered in sufficient quantities". It has been demonstrated that probiotics can prevent or treat a variety of human diseases; however, their ability to mitigate MC-LR-induced intestinal harm has not yet been investigated. The objective of this study was to determine whether probiotics can mitigate MC-LR-induced intestinal toxicity and its underlying mechanisms. We first evaluated the pathological changes in colorectal tissues using an animal model with sub-chronic exposure to low-dose MC-LR, HE staining to assess colorectal histopathologic changes, qPCR to detect the expression levels of inflammatory factors in colorectal tissues, and WB to detect the alterations on CSF1R signaling pathway proteins in colorectal tissues. Microbial sequencing analysis and screening of fecal microorganisms differential to MC-LR treatment in mice. To investigate the role of microorganisms in MC-LR-induced colorectal injury, an in vitro model of MC-LR co-treatment with microorganisms was developed. Our findings demonstrated that MC-LR treatment induced an inflammatory response in mouse colorectal tissues, promoted the expression of inflammatory factors, activated the CSF1R signaling pathway, and significantly decreased the abundance of Lactobacillus. In a model of co-treatment with MC-LR and Lactobacillus fermentum (L. fermentum), it was discovered that L. fermentum substantially reduced the incidence of the colorectal inflammatory response induced by MC-LR and inhibited the protein expression of the CSF1R signaling pathway. This is the first study to suggest that L. fermentum inhibits the CSF1R signaling pathway to reduce the incidence of MC-LR-induced colorectal inflammation. This research may provide an excellent experimental foundation for the development of strategies for the prevention and treatment of intestinal diseases in MC-LR.

A face image classification method of autistic children based on the two-phase transfer learning.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder, which seriously affects children's normal life. Screening potential autistic children before professional diagnose is helpful to early detection and early intervention. Autistic children have some different facial features from non-autistic children, so the potential autistic children can be screened by taking children's facial images and analyzing them with a mobile phone. The area under curve (AUC) is a more robust metrics than accuracy in evaluating the performance of a model used to carry out the two-category classification, and the AUC of the deep learning model suitable for the mobile terminal in the existing research can be further improved. Moreover, the size of an input image is large, which is not fit for a mobile phone. A deep transfer learning method is proposed in this research, which can use images with smaller size and improve the AUC of existing studies. The proposed transfer method uses the two-phase transfer learning mode and the multi-classifier integration mode. For MobileNetV2 and MobileNetV3-Large that are suitable for a mobile phone, the two-phase transfer learning mode is used to improve their classification performance, and then the multi-classifier integration mode is used to integrate them to further improve the classification performance. A multi-classifier integrating calculation method is also proposed to calculate the final classification results according to the classifying results of the participating models. The experimental results show that compared with the one-phase transfer learning, the two-phase transfer learning can significantly improve the classification performance of MobileNetV2 and MobileNetV3-Large, and the classification performance of the integrated classifier is better than that of any participating classifiers. The accuracy of the integrated classifier in this research is 90.5%, and the AUC is 96.32%, which is 3.51% greater than the AUC (92.81%) of the previous studies.

High-density Au nanoshells assembled onto Fe3O4 nanoclusters for integrated enrichment and photothermal/colorimetric dual-mode detection of SARS-CoV-2 nucleocapsid protein.

Traditional lateral flow immunoassays (LFIA) suffer from insufficient sensitivity, difficulty for quantitation, and susceptibility to complex substrates, limiting their practical application. Herein, we developed a polyethylenimine (PEI)-mediated approach for assembling high-density Au nanoshells onto Fe3O4 nanoclusters (MagAushell) as LFIA labels for integrated enrichment and photothermal/colorimetric dual-mode detection of SARS-CoV-2 nucleocapsid protein (N protein). PEI layer served not only as "binders" to Fe3O4 nanoclusters and Au nanoshells, but also "barriers" to ambient environment. Thus, MagAushell not only combined magnetic and photothermal properties, but also showed good stability. With MagAushell, N protein was first separated and enriched from complex samples, and then loaded to the strip for detection. By observation of the color stripes, qualitative detection was performed with naked eye, and by measuring the temperature change under laser irradiation, quantification was attained free of sophisticated instruments. The introduction of Fe3O4 nanoclusters facilitated target purification and enrichment before LFIA, which greatly improved the anti-interference ability and increased the detection sensitivity by 2 orders compared with those without enrichment. Moreover, the high loading density of Au nanoshells on one Fe3O4 nanocluster enhanced the photothermal signal of the nanoprobe significantly, which could further increase the detection sensitivity. The photothermal detection limit reached 43.64 pg/mL which was 1000 times lower than colloidal gold strips. Moreover, this method was successfully applied to real samples, showing great application potential in practice. We envision that this LFIA could serve not only for SARS-CoV-2 detection but also as a general test platform for other biotargets in clinical samples.

[Analysis on status quo of outcomes and measurement instruments of randomized controlled trials of acupuncture for post-stroke dysphagia].

OBJECTIVE: To analyze the report status of outcomes and measurement instruments of randomized controlled trials (RCTs) of acupuncture for post-stroke dysphagia, so as to provide a basis for designing clinical trials and developing the core outcome set in acupuncture for post-stroke dysphagia. METHODS: RCTs of acupuncture for post-stroke dysphagia were searched in databases i.e. CNKI, SinoMed, Wanfang, PubMed, EMbase, Web of Science and clinical trial registries i.e. ClinicalTrials.gov and Chinese Clinical Trial Registry (ChiCTR), from January 1st, 2012 to October 30th, 2021. By literature screening and data extraction, outcomes and measurement instruments were summarized and analyzed. RESULTS: A total of 172 trials (including 165 RCTs and 7 ongoing trials registrations) were included, involving 91 outcomes. The outcomes could be classified into 7 domains according to functional attributes, namely clinical manifestation, physical and chemical examination, quality of life, TCM symptoms/syndromes, long-term prognosis, safety assessment and economic evaluation. It was found that there were various measurements instruments with large differences, inconsistent measurement time point and without discriminatively reporting primary or secondary outcomes. CONCLUSION: The status quo of outcomes and measurement instruments of RCTs of acupuncture for post-stroke dysphagia is not conducive to the summary and comparison of each trial's results. Thus, it is suggested to develop a core outcome set for acupuncture for post-stroke dysphagia to improve the normative and research quality of their clinical trial design.

Seasonal variations of macrozoobenthic community trophic structure in the waters adjacent to the seaweed beds of Dalian Island in the North Yellow Sea.

To investigate the effects of algal detritus export on the trophic structure of macrozoobenthic community in the adjacent benthic habitat during the bloom and decline of macroalgae, we collected macrozoobenthos from the adjacent sea area of Dalian Island in the North Yellow Sea in May (the algal bloom period) and August (the algal decay period) of 2020. We quantifyied the seasonal changes in the trophic structure of macrozoobenthic community by using carbon and nitrogen stable isotope techniques. Results showed that δ13C and δ15N values of macrozoo-benthos in May ranged from -23.14‰ to -14.24‰, 6.21‰ to 12.90‰, respectively, and -22.36‰ to -14.13‰, 5.33‰ to 12.00‰, respectively in August. Results of PERMANOVA analysis showed that δ13C values of macrozoobenthos differed significantly between the two months, while δ15N values were not significantly different. Based on the Euclidean distance, the macrozoobenthic communities in both months could be classified into five trophic functional groups. The trophic levels of macrozoobenthos ranged from 2.00 (Nitidotellina minuta) to 3.97 (Glycera onomichiensis) in May and from 2.00 (N. minuta) to 3.96 (G. onomichiensis) in August. The δ13C range, δ15N range, mean centroid distance, total area and corrected standard ellipse areas which represented community trophic structure indices in August were higher than those in May. Our results indicated that the trophic diversity level and trophic niche width of the macrozoobenthic community in the adjacent sea area of the seaweed bed were higher in the algal decline season.

Transformable nano-antibiotics for mechanotherapy and immune activation against drug-resistant Gram-negative bacteria.

The dearth of antibiotic candidates against Gram-negative bacteria and the rise of antibiotic resistance create a global health concern. The challenge lies in the unique Gram-negative bacterial outer membrane that provides the impermeable barrier for antibiotics and sequesters antigen presentation. We designed a transformable nano-antibiotics (TNA) that can transform from nontoxic nanoparticles to bactericidal nanofibrils with reasonable rigidity (Young's modulus, 21.6 ± 5.9 MPa) after targeting ß-barrel assembly machine A (BamA) and lipid polysaccharides (LPSs) of Gram-negative bacteria. After morphological transformation, the TNA can penetrate and damage the bacterial envelope, disrupt electron transport and multiple conserved biosynthetic and metabolic pathways, burst bacterial antigen release from the outer membrane, and subsequently activate the innate and adaptive immunity. TNA kills Gram-negative bacteria in vitro and in vivo with undetectable resistance through multiple bactericidal modes of action. TNA treatment-induced vaccination results in rapid and long-lasting immune responses, protecting against lethal reinfections.

Preparation of a new resource food-arabinogalactan and its protective effect against enterotoxicity in IEC-6 cells by inhibiting endoplasmic reticulum stress.

Plant polysaccharides can be used as bioactive natural polymers that provide health benefits, however high molecular weight neutral polysaccharides have not shown good bioactivity. In this study, high molecular weight neutral arabinogalactan was isolated and structurally characterized to investigate it antioxidant activity against IEC-6 cells. In this study, a neutral polysaccharide (AG-40-I-II) was obtained from the roots of Larix gmelinii (Rupr.) Kuzen. and purified using ethanol fractional precipitation and purification on a DEAE-52 cellulose column and a Superose 12 gel filtration column. The structural characteristics of AG-40-I-II was detected by chemical and spectroscopic methods. The results showed that the average molecular weight of AG-40-I-II was 18.6 kDa, the main chain was composed of →4)-ß-D-Gal-(1, â†’ 4, 6)-ß-D-Gal-(1 and →4)-ß- D-Glc-(1, the side chain is composed of T-ß-L-Araf(1 â†’ 6). The effect of AG-40-I-II on H2O2-induced IEC-6 cell injury was determined by MTT method. Besides, AG-40-I-II could reduce the level of MDA and increase SOD activity on IEC-6 cells, which could significantly inhibit the production of ROS. Importantly, AG-40-I-II inhibited the splicing of XBP1 by IRE1α through the ERS pathway and reduced the cell apoptosis induced by H2O2. In summary, the results of this study indicate that AG-40-I-II, as a natural source of plant polysaccharides, has good antioxidant activity, and is expected to become a safe plant source of natural antioxidants, which has great potential in biomedicine potential.

Mechanistic insights into the allosteric inactivation mechanism of ZAP-70 induced by the hot spot W165C mutation.

Zeta chain-associated protein kinase 70 (ZAP-70) is a non-receptor tyrosine kinase that interacts with the activated T-cell receptor to transduce downstream signals, and thus plays an important role in the adaptive immune system. The biphosphorylated immunotyrosine-based activation motifs (ITAM-Y2P) binds to the N-SH2 and C-SH2 domains of ZAP-70 to promote the activation of ZAP-70. The present study explores molecular mechanisms of allosteric inactivation of ZAP-70 induced by the hot spot W165C mutation through atomically detailed molecular dynamics simulation approaches. We report microsecond-length simulations of two states of the tandem SH2 domains of ZAP-70 in complex with the ITAM-Y2P motif, including the wild-type and W165C mutant. Extensive analysis of local flexibility and dynamical correlated motions show that W165C mutation changes coupled motions of protein domains and community networks. The binding affinities of the ITAM-Y2P motif to the wild-type and W165C mutant of ZAP-70 are predicted using binding free energy calculations. The results suggest that the driving force to decrease the binding affinity in the W165C mutant derives from the difference in the protein-protein electrostatic interactions. Moreover, the per-residue free energy decomposition unravels that the contributions from residues in the phosphorylated Tyr315 (pY315) binding site, in particular pY315 of ITAM-Y2P, and Arg43, Tyr240 of ZAP-70, are the key determinants for the loss of binding affinity. This study may insights into our understanding of the pathological mechanism of ZAP-70.Communicated by Ramaswamy H. Sarma.

Dapagliflozin's effect on serum homocysteine in patients with hypertension complicated with insulin resistance.

Most patients with hypertension are complicated with insulin resistance (IR), which is one of the risk factors of hypertension and can increase the level of serum homocysteine (Hcy) by affecting Hcy's metabolic enzyme and insulin level. Investigations in recent years have shown that Hcy is an independent risk factor for cardiovascular diseases. At present, folic acid is the prominent medicine used to reduce Hcy, but its effection for Hcy has an obvious individual difference, which is closely related to individual genes. Moreover, folic acid is chiefly used in patients with Hcy ≥15 µmol/L, but Hcy ≥10 µmol/L has had an adverse effect on the cardiovascular system. Randomized clinical trials have shown that dapagliflozin can improve IR. Therefore, whether it can reduce Hcy has become a new direction. This study was a retrospective case-control study. Patients with high serum Hcy and hypertension complicated with IR were divided into two groups: the dapagliflozin group (n = 166) and the control group (n = 198). Before and after 12 weeks of treatment, the changes in serum Hcy and IR index were measured and compared. We found that dapagliflozin could reduce the serum Hcy level of patients with hypertension and IR to a certain extent. Dapagliflozin could be a viable option for hypertension complicated with IR and hyperhomocysteinemia. However, these findings need to be further confirmed in future randomized clinical trials with a large number of samples.