Assessment of Dynamic Cerebral Autoregulation During Long-Term Exposure to High Altitude in Normal Subjects by Ultrasonography.

PURPOSE: To evaluate changes in dynamic cerebral autoregulation (CA) during short-term and long-term exposure to high altitude with ultrasonography, and also study the sex differences in the response of CA to altitude. METHODS: We assessed the differences in dynamic CA and measured with Doppler ultrasound of the bilateral internal carotid artery (ICA), vertebral artery (VA), and middle cerebral artery (MCA) and the values of basic information within 48 hours and at 2 years after arrival at Tibet in 65 healthy Han young Chinese volunteers, meanwhile, we compared the resistance index (RI) and pulsatility index (PI) of the right MCA at inhale oxygen 8 minutes when a newcomer with 2 years after arrival at Tibet. RESULTS: With 2 years of altitude exposure, the SaO2 of all subjects was above 90%, the mean PEF, DAP, and HR values decreased, HGB increased compared within 48 hours in same-gender groups. Comparisons of cerebral hemodynamics between before 2 years and after 2 years within male and female groups, the mean RI and PI values of bilateral MCA after 2 years were significantly higher than before 2 years, at the same time, the mean RI and PI values of bilateral ICA were significant differences (P < .05) between male groups, with regard to female groups, showed that the mean RI and PI values of bilateral VA were significant differences (P < .05). Comparisons of Right MCA hemodynamics between after oxygen uptake 8 minutes and 2 years, the mean RI and PI values were no significant difference within male and female groups (P > .05). CONCLUSIONS: Acute mountain sickness could result from an alteration of dynamic autoregulation of cerebral blood flow, but the impaired autoregulation may be corrected with the extension of time, furthermore, the response of CA to altitude in males and females are different.

Bioactive Components of Lycium barbarum and Deep-Processing Fermentation Products.

Lycium barbarum, a homology of medicine and food, contains many active ingredients including polysaccharides, polyphenol, betaine, and carotenoids, which has health benefits and economic value. The bioactive components in Lycium barbarum exhibit the effects of antioxidation, immune regulation, hypoglycemic effects, and vision improvement. Recently, the development of nutrition and health products of Lycium barbarum has been paid more and more attention with the increase in health awareness. A variety of nutrients and bioactive components in wolfberry can be retained or increased using modern fermentation technology. Through fermentation, the products have better flavor and health function, which better meet the needs of market diversification. The main products related to wolfberry fermentation include wolfberry fruit wine, wolfberry fruit vinegar, and lactic acid fermented beverage. In this review, the mainly bioactive components of Lycium barbarum and its deep-processing products of fermentation were summarized and compared. It will provide reference for the research and development of fermented and healthy products of Lycium barbarum.

Cigarette smoke exposed airway epithelial cell-derived EVs promote pro-inflammatory macrophage activation in alpha-1 antitrypsin deficiency.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder most commonly secondary to a single mutation in the SERPINA1 gene (PI*Z) that causes misfolding and accumulation of alpha-1 antitrypsin (AAT) in hepatocytes and mononuclear phagocytes which reduces plasma AAT and creates a toxic gain of function. This toxic gain of function promotes a pro-inflammatory phenotype in macrophages that contributes to lung inflammation and early-onset COPD, especially in individuals who smoke cigarettes. The aim of this study is to determine the role of cigarette exposed AATD macrophages and bronchial epithelial cells in AATD-mediated lung inflammation. METHODS: Peripheral blood mononuclear cells from AATD and healthy individuals were differentiated into alveolar-like macrophages and exposed to air or cigarette smoke while in culture. Macrophage endoplasmic reticulum stress was quantified and secreted cytokines were measured using qPCR and cytokine ELISAs. To determine whether there is "cross talk" between epithelial cells and macrophages, macrophages were exposed to extracellular vesicles released by airway epithelial cells exposed to cigarette smoke and their inflammatory response was determined. RESULTS: AATD macrophages spontaneously produce several-fold more pro-inflammatory cytokines as compared to normal macrophages. AATD macrophages have an enhanced inflammatory response when exposed to cigarette smoke-induced extracellular vesicles (EVs) released from airway epithelial cells. Cigarette smoke-induced EVs induce expression of GM-CSF and IL-8 in AATD macrophages but have no effect on normal macrophages. Release of AAT polymers, potent neutrophil chemo attractants, were also increased from AATD macrophages after exposure to cigarette smoke-induced EVs. CONCLUSIONS: The expression of mutated AAT confers an inflammatory phenotype in AATD macrophages which disposes them to an exaggerated inflammatory response to cigarette smoke-induced EVs, and thus could contribute to progressive lung inflammation and damage in AATD individuals.

Multivalent Cations Reverse the Twist-Stretch Coupling of RNA.

When stretched, both DNA and RNA duplexes change their twist angles through twist-stretch coupling. The coupling is negative for DNA but positive for RNA, which is not yet completely understood. Here, our magnetic tweezers experiments show that the coupling of RNA reverses from positive to negative by multivalent cations. Combining with the previously reported tension-induced negative-to-positive coupling reversal of DNA, we propose a unified mechanism of the couplings of both RNA and DNA based on molecular dynamics simulations. Two deformation pathways are competing when stretched: shrinking the radius causes positive couplings but widening the major groove causes negative couplings. For RNA whose major groove is clamped by multivalent cations and canonical DNA, their radii shrink when stretched, thus exhibiting positive couplings. For elongated DNA whose radius already shrinks to the minimum and canonical RNA, their major grooves are widened when stretched, thus exhibiting negative couplings.

Changes in the Phytochemical and Bioactive Compounds and the Antioxidant Properties of Wolfberry during Vinegar Fermentation Processes.

Wolfberry (Lycium barbarum L.), as a kind of functional fruit, has various nutritional and bioactive components, which exhibit healthy benefits. However, wolfberry is not easy to preserve, and the intensive processing of wolfberry needs to be developed. In the present study, the changes in the phytochemical and bioactive compounds, as well as the antioxidant properties of wolfberry, were evaluated in the brewed processes. We found that the sugar contents were significantly decreased, and the total acids values were significantly increased during the fermentation processes. The sugar and fat contents were low in the wolfberry fruit vinegar after fermentation, which is of benefit to human health. In addition, amino acids were examined during the fermentation processes, and histidine, proline, and alanine were found to be the main amino acids in vinegar. The total phenolics and flavonoids contents were significantly increased by 29.4% and 65.7% after fermentation. 4-Hydroxy benzoic acid, 3-hydroxy cinnamic acid, and chlorogenic acid were the primary polyphenols in the wolfberry fruit vinegar. Moreover, the antioxidant activity of wolfberry fruit vinegar was significantly increased compared with that of wolfberry fruit after the fermentation processes. Polysaccharides and polyphenolics were strongly correlated with the antioxidant activity during the fermentation processes. The findings suggest that wolfberry fruit vinegar has a high antioxidant capability, and could be a beneficial food in the human diet.

Nutrition, Bioactive Components, and Hepatoprotective Activity of Fruit Vinegar Produced from Ningxia Wolfberry.

Wolfberry (Lycium barbarum L.) is a nutritious and medicinal fruit, and deeply processed products of wolfberry needs to be improved. In this study, nutrition, bioactive compounds, and hepaprotective activity were explored in wolfberry vinegar (WFV). The contents of nutrients including total sugar and protein in WFV samples were 2.46 and 0.27 g/100 mL, respectively. Total phenolic and flavonoid contents in WFV were 2.42 mg GAE/mL and 1.67 mg RE/mL, respectively. p-Hydroxybenzoic acid and m-hydroxycinnamic acid were the main polyphenols in WFV. The antioxidant activity of WFV were 20.176 mM Trolox/L (ABTS), 8.614 mM Trolox/L (FRAP), and 26.736 mM Trolox/L (DPPH), respectively. In addition, WFV treatment effectively alleviated liver injury by improving histopathological changes and reducing liver biochemical indexes in CCl4-treated mice. WFV alleviated oxidative damage by inhibiting oxidative levels and increasing antioxidant levels. These results suggest that WFV can be utilized as a functional food to prevent oxidative liver injury.

[Clinical trials and evaluation of Chinese patent medicine for chronic obstructive pulmonary disease].

The clinical randomized controlled trials(RCTs) of Chinese patent medicine in the treatment of chronic obstructive pulmonary disease(COPD) were reviewed and analyzed to provide references for clinical research, guideline development, policy formulation, and quality improvement of clinical evidence. On the basis of the collection in the Traditional Chinese Medicine(TCM) Clinical Evidence Database System(EVDS), CNKI, Wanfang, SinoMed, Cochrane Library, PubMed, EMbase were searched for RCTs of Chinese patent medicine for COPD as a source of clinical evidence from database inception to December 31, 2019. The publication time, sample size, intervention and control measures, course of treatment, outcome indicators, and methodological quality of the trials were analyzed and evaluated. A total of 733 RCTs of Chinese patent medicine for COPD were included, among which 228 RCTs had a sample size higher than 100, accounting for 31.1% of total RCTs. Eighty-eight Chinese patent medicines were involved, including 40 oral medicines and 48 injections. A total of 327 RCTs mentioned intervention and control measures(Chinese patent medicine + conventional treatment vs conventional treatment), accounting for 43.0%. In addition, 94.40% of the RCTs reported the course of treatment, and 53.20% of the RCTs determined 8-14 d as the intervention course. The evaluation indicators adopted were numerous, among which physicochemical indicators(70.57%) and symptoms/signs(24.35%) were the most frequently employed. The operation of allocation concealment and blinding was not standard. Registration and the procedure related to ethics were mostly missing. The results indicate that there are prominent methodological problems in the clinical trials of Chinese patent medicine in the treatment of COPD, affecting the reliability and practicability of the trials. It is necessary to further standardize the design, implementation, and quality control of clinical trials of Chinese patent medicine in the treatment of COPD, highlight the clinical value of Chinese patent medicine for COPD, and improve the quality of evidence.

[Clinical trials and evaluation of Chinese patent medicine for pneumonia].

The present study reviewed the clinical randomized controlled trials(RCTs) of Chinese patent medicine for pneumonia to provide references for clinical research, guideline development, and policy formulation, and promote the quality improvement of clinical evidence. On the basis of the collection in the Traditional Chinese Medicine(TCM) Clinical Evidence Database System(EVDS), CNKI, Wanfang, SinoMed were searched for RCTs of Chinese patent medicine for pneumonia from database inception to December 31, 2019. A total of 1 245 RCTs were included, involving 84 Chinese patent medicines, including 45 oral medicines and 39 injections. Specifically, 85.9% of RCTs had treatment course not exceeding 14 d; 43.3% of RCTs had a sample size of more than 100 cases and 6.1% of RCTs more than 200 cases; 13 types of interventions/controls were included in the RCTs, with Chinese patent medicine + western medicine vs western medicine as the top one used(32.6%). In outcome indicators, symptoms/signs(3 285) and physicochemical detection(2 066) were the most frequently applied. In the methodological evaluation, "allocation concealment" was not clearly described or mentioned in 71.2% of RCTs, and "blinding" in 23.9% of RCTs met the normative standards. Registration and research ethics were not clearly reported. There are many methodological deficiencies in terms of design and implementation in included RCTs, which may impact the reliability and practicability of the results of RCTs. Additionally, key standards were unclear(such as disease classification methods and selection of core outcome indicators). In conclusion, RCTs should give priority to the preciseness and scientificity of the protocol, strengthening quality control of the processes and accelerating the standardized research of key links.

[Clinical evidence analysis report of Chinese patent medicine in 2020].

The present study collected, collated, analyzed, and evaluated randomized controlled trial(RCT) of Chinese patent medicine published in Chinese and English journals in 2020, and summarized clinical evidence of Chinese patent medicine in stages, providing references for follow-up clinical research and evidence transformation and application. On the basis of the collection in the Traditional Chinese Medicine(TCM) Clinical Evidence Database System(EVDS), CNKI, Wanfang, SinoMed, Cochrane Library, PubMed, and EMbase were searched for RCTs of Chinese patent medicine published in 2020, and their research characteristics and methodological quality were analyzed and evaluated. A total of 1 285 research papers on Chinese patent medicine(1 257 in Chinese/28 in English) were included, involving 146 054 patients and 639 Chinese patent medicines, including 526 oral drugs, 68 injections, and 45 external drugs. A total of 412 diseases in 23 types were involved, which were dominated by circulatory system diseases and respiratory system diseases, specifically, cerebral infarction and angina pectoris. The sample size ranged from 20 cases to 2 673 cases, and 57.67% of RCTs had samples sizes less than 100. Single-center trials were the main ones, and multi-center trials only accounted for 4.75%(n=61). In terms of methodological quality, 52.91% of the RCTs had unclear descriptions or incorrect application of randomization methods, and the implementation of allocation concealment and blinding methods has not been paid much attention. In conclusion, compared with the conditions in 2019, the number of RCTs published in 2020 has decreased, and the research interest in respiratory diseases has increased, while the quality control in the process of research design and implementation has not been improved. Therefore, it is necessary to strengthen the methodological training of researchers and promote the output of high-quality research evidence.

[Clinical trials and evaluation of Chinese patent medicine for heart failure].

The present study systematically collected, analyzed, and evaluated randomized controlled trial(RCT) of Chinese patent medicine in the treatment of heart failure to provide references for follow-up clinical research design, guideline update, and policy formulation, and promote the improvement of clinical evidence quality. On the basis of the collection in the Traditional Chinese Medicine(TCM) Clinical Evidence Database System(EVDS), CNKI, VIP, Wanfang, SinoMed, PubMed, and Web of Science were searched for RCTs of Chinese patent medicine in the treatment of heart failure from database inception to December 31, 2020. The di-sease type, publication time, sample size, intervention/control setting, course of treatment, evaluation indexes, and methodological quality were analyzed and evaluated. A total of 1 631 RCTs were included, including 1 622 in Chinese and 9 in English. It was first published in 1995, with the largest number of publications in 2016. There were only 56 RCTs(3.43%) with a sample size≥200. Seventy-eight types of Chinese patent medicines were involved, including 49 types of oral drugs and 29 types of injections. There were 34 intervention/control protocols, which were dominated by Chinese patent medicine+conventional treatment vs conventional treatment, accounting for 28.51%(n=465). About 94.0% of RCTs reported the course of treatment, mainly 14-56 days. The evaluation indexes were mainly physical and chemical tests and symptoms/signs, and left ventricular ejection fraction(LVEF) was the most frequently used measurement index. In enumeration indexes, clinical efficacy(response rate) was used the most frequently. Methodologically, 92.0% of the research subjects were rated as high risk of blindness. There were only 13 RCTs(0.80%) reporting registered information. It is necessary to further standardize the design, implementation, and quality control of clinical studies in order to improve the quality of evidence and avoid research waste.

Coulomb Instabilities of a Three-Dimensional Higher-Order Topological Insulator.

Topological insulators (TIs) are an exciting discovery because of their robustness against disorder and interactions. Recently, second-order TIs have been attracting increasing attention, because they host topologically protected 1D hinge states in 3D or 0D corner states in 2D. A significantly critical issue is whether the second-order TIs also survive interactions, but it is still unexplored. We study the effects of weak Coulomb interactions on a 3D second-order TI, with the help of renormalization-group calculations. We find that the 3D second-order TIs are always unstable, suffering from two types of topological phase transitions. One is from second-order TI to TI, the other is to normal insulator. The first type is accompanied by emergent time-reversal and inversion symmetries and has a dynamical critical exponent κ=1. The second type does not have the emergent symmetries but has nonuniversal dynamical critical exponents κ<1. Our results may inspire more inspections on the stability of higher-order topological states of matter and related novel quantum criticalities.

Cytosine Methylation Enhances DNA Condensation Revealed by Equilibrium Measurements Using Magnetic Tweezers.

CpG methylation of DNA is common in mammalian cells. In sperm, the DNA has the highest level of CpG methylation and is condensed into toroidal structures. How CpG methylation affects DNA structures and interactions is important to understand its biological roles but is largely unknown. Using an RNA-DNA-RNA structure, we observed the equilibrium hopping dynamics between the condensed and extended states of DNA in the presence of polyamines or polylysine peptide as a reduced model of histone tails. Combing with the measured DNA elasticities, we report that CpG methylation of each cytosine nucleotide substantially increases DNA-DNA attraction by up to 0.2 kBT. For the DNA with 57% GC content, the relative increase caused by CpG methylation is up to 32% for the spermine-induced DNA-DNA attraction and up to 9% for the polylysine-induced DNA-DNA attraction. These findings help us to evaluate the energetic contributions of CpG methylation in sperm development and chromatin regulation.

Opposite Effects of High-Valent Cations on the Elasticities of DNA and RNA Duplexes Revealed by Magnetic Tweezers.

We report that trivalent cobalt hexammine cations decrease the persistence length, stretching modulus, helical density, and size of plectonemes formed under torque of DNA but increase those of RNA. Divalent magnesium cations, however, decrease the persistence lengths, contour lengths, and sizes of plectonemes while increasing the helical densities of both DNA and RNA. The experimental results are explained by different binding modes of the cations on DNA and RNA in our all-atom molecular dynamics simulations. The significant variations of the helical densities and structures of DNA and RNA duplexes induced by high-valent cations may affect interactions of the duplexes with proteins.

Photocatalyzed Intermolecular Aminodifluoromethylphosphonation of Alkenes: Facile Synthesis of α,α-Difluoro-γ-aminophosphonates.

An efficient and practical method for the synthesis of α,α-difluoro-γ-aminophosphonates through photocatalyzed intermolecular aminodifluoromethylphosphonation of alkenes has been developed. In this reaction, difluoromethylphosphonate is used as an important fluorinated reagent. Furthermore, the mild reaction conditions, simple operation, and broad substrate scope make this protocol very practical and attractive. The derivatization reaction in the synthesis of difluoromethylphosphonated chiral binaphthylamine ligands and α,α-difluoro-γ-aminophosphoric acid highlight the applicability of this method.

Ectopic Expression of a Thellungiella salsuginea Aquaporin Gene, TsPIP1;1, Increased the Salt Tolerance of Rice.

Aquaporins play important regulatory roles in the transport of water and small molecules in plants. In this study, a ThellungiellasalsugineaTsPIP1;1 aquaporin was transformed into Kitaake rice, and three transgenic lines were evaluated by profiling the changes of the physiological metabolism, osmotic potential, and differentially expressed genes under salt stress. The TsPIP1;1 protein contains six transmembrane domains and is localized in the cytoplasm membrane. Overexpression of the TsPIP1;1 gene not only increased the accumulation of prolines, soluble sugars and chlorophyll, but also lowered the osmotic potential and malondialdehyde content in rice under salt stress, and alleviated the amount of salt damage done to rice organs by regulating the distribution of Na/K ions, thereby promoting photosynthetic rates. Transcriptome sequencing confirmed that the differentially expressed genes that are up-regulated in rice positively respond to salt stimulus, the photosynthetic metabolic process, and the accumulation profiles of small molecules and Na/K ions. The co-expressed Rubisco and LHCA4 genes in rice were remarkably up-regulated under salt stress. This data suggests that overexpression of the TsPIP1;1 gene is involved in the regulation of water transport, the accumulation of Na/K ions, and the translocation of photosynthetic metabolites, thus conferring enhanced salt tolerance to rice.

miR-20a promotes prostate cancer invasion and migration through targeting ABL2.

The aberrant expression of microRNAs (miRNAs) has been found in various types of cancer. The present study found miR-20a was significantly up-regulated in prostate cancer compared with normal prostate tissues. Patients with a higher miR-20a expression had a Gleason score of 7-10 and shorter survival time. The transwell and wound healing assays revealed that blocking expression of miR-20a by miR-20a ASO suppresses the invasion and migration of PC-3 and DU145 cells in vitro and also inhibits tumor growth in vivo. Furthermore, we identified miR-20a directly targets the ABL family non-receptor tyrosine kinases ABL2 and negatively regulates the phosphorylation of its downstream gene p190RhoGAP. Knockdown of ABL2 promoted cell invasion and migration and we identified miR-20a-induced cell invasion and migration can be rescued by ABL2. In conclusion, our findings show that miR-20a significantly contributes to the progression of prostate cancer by targeting ABL2.

Beneficial effect of vinegar consumption associated with regulating gut microbiome and metabolome.

Vinegar is used as fermented condiment and functional food worldwide. Vinegar contains many nutrients and bioactive components, which exhibits health benefits. In this study, the potential effects of Shanxi aged vinegar (SAV) on gut microbiome and metabolome were explored in normal mice. The levels of inflammatory factors were significantly decreased in SAV-treated mice. Immunoglobulin, NK cells and CD20 expression were significantly increased after SAV administration. In addition, SAV intake altered gut microbiota structure by up-regulating Verrucomicrobia, Akkermansia, Hungatella and Alistipes, and down-regulating Firmicutes, Lachnospiraceae_NK4A136_group and Oscillibacter. The differential metabolites were mainly included amino acids, carbohydrates and bile acids. Furthermore, after SAV intake, Verrucomicrobia, and Akkermansia closely impacted the related gut metabolites. These alterations of gut microbiota-related metabolism further modulated some immunoregulatory and inflammatory factors, and confer potential health benefits. Our results imply that vinegar consumption has beneficial effects on regulating gut microbiome and metabolome.

Copper-catalyzed [3+2] annulation of O-acyl ketoximes with 2-aryl malonates for the synthesis of 3-aryl-4-pyrrolin-2-ones.

A copper-catalyzed [3+2] annulation of O-acyl ketoximes with 2-aryl malonates for the concise synthesis of 3-aryl-4-pyrrolin-2-ones has been developed. The advantage of this method lies in the use of O-acyl oximes as an internal oxidant to generate the nucleophilic enamines and electrophilic p-quinone methides concurrently. The subsequent nucleophilic addition undergoes selectively on the α-C of malonates.