The Effects of Exercise Training on Mitochondrial Function in Cardiovascular Diseases: A Systematic Review and Meta-Analysis

Mitochondria dysfunction is implicated in the pathogenesis of cardiovascular diseases (CVD). Exercise training is potentially an effective non-pharmacological strategy to restore mitochondrial health in CVD. However, how exercise modifies mitochondrial functionality is inconclusive. We conducted a systematic review using the PubMed; Scopus and Web of Science databases to investigate the effect of exercise training on mitochondrial function in CVD patients. Search terms included “mitochondria”, “exercise”, “aerobic capacity”, and “cardiovascular disease” in varied combination. The search yielded 821 records for abstract screening, of which 20 articles met the inclusion criteria. We summarized the effect of exercise training on mitochondrial morphology, biogenesis, dynamics, oxidative capacity, antioxidant capacity, and quality. Amongst these parameters, only oxidative capacity was suitable for a meta-analysis, which demonstrated a significant effect size of exercise in improving mitochondrial oxidative capacity in CVD patients (SMD = 4.78; CI = 2.99 to 6.57; p < 0.01), but with high heterogeneity among the studies (I² = 75%, p = 0.003). Notably, aerobic exercise enhanced succinate-involved oxidative phosphorylation. The majority of the results suggested that exercise improves morphology and biogenesis, whereas findings on dynamic, antioxidant capacity, and quality, were inadequate or inconclusive. A further randomized controlled trial is clearly required to explain how exercise modifies the pathway of mitochondrial quantity and quality in CVD patients.     

Assessing the DNA Damaging Effectiveness of Ionizing Radiation Using Plasmid DNA

Plasmid DNA is useful for investigating the DNA damaging effects of ionizing radiation. In this study, we have explored the feasibility of plasmid DNA-based detectors to assess the DNA damaging effectiveness of two radiotherapy X-ray beam qualities after undergoing return shipment of ~8000 km between two institutions. The detectors consisted of 18 μL of pBR322 DNA enclosed with an aluminum seal in nine cylindrical cavities drilled into polycarbonate blocks. We shipped them to Toronto, Canada for irradiation with either 100 kVpor 6 MV X-ray beams to doses of 10, 20, and 30 Gy in triplicate before being shipped back to San Diego, USA. The Toronto return shipment also included non-irradiated controls and we kept a separate set of controls in San Diego. In San Diego, we quantified DNA single strand breaks (SSBs), double strand breaks (DSBs), and applied Nth and Fpg enzymes to quantify oxidized base damage. The rate of DSBs/Gy/plasmid was 2.8±0.7greater for the 100 kVp than the 6 MV irradiation. The 100 kVp irradiation also resulted in 5±2 times more DSBs/SSB than the 6 MV beam, demonstrating that the detector is sensitive enough to quantify relative DNA damage effectiveness, even after shipment over thousands of kilometers.     

Conformational Heterogeneity and Frustration of the Tumor Suppressor p53 as Tuned by Punctual Mutations

The conformational heterogeneity of the p53 tumor suppressor, the wild-type (p53wt) and mutated forms, was investigated by a computational approach, including the modeling and all atoms of the molecular dynamics (MD) simulations. Four different punctual mutations (p53R175H, p53R248Q, p53R273H, and p53R282W) which are known to affect the DNA binding and belong to the most frequent hot-spot mutations in human cancers, were taken into consideration. The MD trajectories of the wild-type and mutated p53 forms were analyzed by essential dynamics to extract the relevant collective motions and by the frustration method to evaluate the degeneracy of the energy landscape. We found that p53 is characterized by wide collective motions and its energy landscape exhibits a rather high frustration level, especially in the regions involved in the binding to physiological ligands. Punctual mutations give rise to a modulation of both the collective motions and the frustration of p53, with different effects depending on the mutation. The regions of p53wt and of the mutated forms characterized by a high frustration level are also largely involved in the collective motions. Such a correlation is discussed also in connection with the intrinsic disordered character of p53 and with its central functional role.     

Effects of Alhagi Honey Polysaccharides as Feed Supplement on Intestine Function and Microbiome,Immune Function,and Growth Performance in Chicken

Hy-Line Brown chickens’ health is closely related to poultry productivity and it is mainly maintained by the immune system, healthy intestinal function, and microflora of chicken. Polysaccharides are biological macromolecules with a variety of activities that can be used as a potential prebiotic to improve poultry health. In this experiment, the function of Alhagi honey polysaccharides (AH) as an immunomodulator on the chicken was investigated. All chicken (120) were randomly distributed to four groups (five replicas/group, six hens/replica). A total of 0.5 mL water was taken orally by the chicken in control group. AH (0.5 mL) in different concentrations (three dosages, 0.3 g/kg, 0.6 g/k, and 1.2 g/kg) were used for the AH-0.3 g/kg, AH-0.6 g/k, and AH-1.2 g/kg group, respectively. The results showed that the growth performance of the chickens and the index of immune organs (the weight of immune organs/the body weight) were enhanced significantly after being AH-treated (p < 0.05). The content of sIgA and cytokines was upregulated remarkably in the intestine after being AH-treated (p < 0.05). The AH treatment significantly enhanced the intestinal epithelial barrier (p < 0.05). Moreover, the percentage of CD4⁺ and CD8⁺ T cells in the ileum, spleen, and serum were obviously upscaled (p < 0.05). In addition, the AH treatment significantly enhanced the production of short chain fatty acids (SCFAs) and improved the structure of gut microbiota (p < 0.05). In conclusion, we found that AH-1.2g/kg was the best dosage to improve the chicken’s health, and these data demonstrated that AH could be used as a potential tool to enhance growth performance through improving intestine function, immunity, and gut microbiome in chicken.     

Potent Activation of Human but Not Mouse TRPA1 by JT010

Transient receptor potential (TRP) ankyrin repeat 1 (TRPA1), which is involved in inflammatory pain sensation, is activated by endogenous factors, such as intracellular Zn²⁺ and hydrogen peroxide, and by irritant chemical compounds. The synthetic compound JT010 potently and selectively activates human TRPA1 (hTRPA1) among the TRPs. Therefore, JT010 is a useful tool for analyzing TRPA1 functions in biological systems. Here, we show that JT010 is a potent activator of hTRPA1, but not mouse TRPA1 (mTRPA1) in human embryonic kidney (HEK) cells expressing hTRPA1 and mTRPA1. Application of 0.3–100 nM of JT010 to HEK cells with hTRPA1 induced large Ca²⁺ responses. However, in HEK cells with mTRPA1, the response was small. In contrast, both TRPA1s were effectively activated by allyl isothiocyanate (AITC) at 10–100 μM. Similar selective activation of hTRPA1 by JT010 was observed in electrophysiological experiments. Additionally, JT010 activated TRPA1 in human fibroblast-like synoviocytes with inflammation, but not TRPA1 in mouse dorsal root ganglion cells. As cysteine at 621 (C621) of hTRPA1, a critical cysteine for interaction with JT010, is conserved in mTRPA1, we applied JT010 to HEK cells with mutations in mTRPA1, where the different residue of mTRPA1 with tyrosine at 60 (Y60), with histidine at 1023 (H1023), and with asparagine at 1027 (N1027) were substituted with cysteine in hTRPA1. However, these mutants showed low sensitivity to JT010. In contrast, the mutation of hTRPA1 at position 669 from phenylalanine to methionine (F669M), comprising methionine at 670 in mTRPA1 (M670), significantly reduced the response to JT010. Moreover, the double mutant at S669 and M670 of mTRPA1 to S669E and M670F, respectively, induced slight but substantial sensitivity to 30 and 100 nM JT010. Taken together, our findings demonstrate that JT010 potently and selectively activates hTRPA1 but not mTRPA1.     

微机自控节能技术在乳化液泵站的应用

乳化液泵站微机全自动控制和综合保护装置的最大特点,是根据工作面用液量自动控制乳化液泵开机、停机,能自动执行配液、补液等操作,并配置了吸空、低油位、低油压、过油温四大保护,达到安全运行、节能降耗的目的.文章介绍节能型YKZ-2B乳化液泵站微机全自动控制和综合保护装置原理、工作特点,并论述使用中注意的问题及其节能效果.     

Critical Players and Therapeutic Targets in Chronic Itch

Chronic itch is one of the most prominent clinical characteristics of diverse systematic diseases. It is a devastating sensation in pathological diseases. Despite its importance, there are no FDA-labelled drugs specifically geared toward chronic itch. The associated complex pathogenesis and diverse causes escalate chronic itch to being one of the top challenges in healthcare. Humanized antibodies against IL-13, IL-4, and IL-31 proved effective in treatment of itch-associated atopic dermatitis but remain to be validated in chronic itch. There are still no satisfactory anti-itch therapeutics available toward itch-related neuropeptides including GRP, BNP, SST, CGRP, and SP. The newly identified potential itch targets including OSM, NMB, glutamate, periostin, and Serpin E1 have opened new avenues for therapeutic development. Proof-of-principle studies have been successfully performed on antagonists against these proteins and their receptors in itch treatment in animal models. Their translational interventions in humans need to be evaluated. It is of great importance to summarize and compare the newly emerging knowledge on chronic itch and its pathways to promote the development of novel anti-itch therapeutics. The goal of this review is to analyze the different physiologies and pathophysiologies of itch mediators, whilst assessing their suitability as new targets and discussing future therapeutic development.     

CRISPR/Cas9 Technology and Its Utility for Crop Improvement

The rapid growth of the global population has resulted in a considerable increase in the demand for food crops. However, traditional crop breeding methods will not be able to satisfy the worldwide demand for food in the future. New gene-editing technologies, the most widely used of which is CRISPR/Cas9, may enable the rapid improvement of crop traits. Specifically, CRISPR/Cas9 genome-editing technology involves the use of a guide RNA and a Cas9 protein that can cleave the genome at specific loci. Due to its simplicity and efficiency, the CRISPR/Cas9 system has rapidly become the most widely used tool for editing animal and plant genomes. It is ideal for modifying the traits of many plants, including food crops, and for creating new germplasm materials. In this review, the development of the CRISPR/Cas9 system, the underlying mechanism, and examples of its use for editing genes in important crops are discussed. Furthermore, certain limitations of the CRISPR/Cas9 system and potential solutions are described. This article will provide researchers with important information regarding the use of CRISPR/Cas9 gene-editing technology for crop improvement, plant breeding, and gene functional analyses.     

Precision Killing of Sinoporphyrin Sodium-Mediated Photodynamic Therapy against Malignant Tumor Cells

Photodynamic therapy (PDT) has significant advantages in the treatment of malignant tumors, such as high efficiency, minimal invasion and less side effects, and it can preserve the integrity and quality of the organs. The power density, irradiation time and photosensitizer (PS) concentration are three main parameters that play important roles in killing tumor cells. However, until now, the underlying relationships among them for PDT outcomes have been unclear. In this study, human malignant glioblastoma U-118MG and melanoma A375 cells were selected, and the product of the power density, irradiation time and PS concentration was defined as the total photodynamic parameter (TPP), in order to investigate the mechanisms of PS sinoporphyrin sodium (DVDMS)-mediated PDT (DVDMS-PDT). The results showed that the survival rates of the U-118MG and A375 cells were negatively correlated with the TPP value in the curve, and the correlation exactly filed an e-exponential function. Moreover, according to the formula, we realized controllable killing effects of the tumor cells by randomly adjusting the three parameters, and we finally verified the accuracy and repeatability of the formula. In conclusion, the establishment and implementation of a newly functional relationship among the PDT parameters are essential for predicting PDT outcomes and providing personalized precise treatment, and they are contributive to the development of PDT dosimetry.     

Various Approaches to Studying the Phase Transition in an Octamethylcyclotetrasiloxane Crystal: From X-ray Structural Analysis to Metadynamics

The structure, thermodynamic parameters, and the character of thermal motion in octamethylcyclotetrasiloxane (D4) were investigated using the combination of experimental (single-crystal X-ray diffraction, thermochemistry) and theoretical (density functional theory calculations, ab initio molecular dynamics and metadynamics) methods. Single crystals of D4 were grown in a glass capillary in situ and the structures of high- (238–270 K) and low-temperature (100–230 K) phases were studied in detail. In the temperature interval 230–238 K, a phase transition with rather low enthalpy (−1.04(7) kcal/mol) was detected. It was found that phase transition is accompanied by change of conformation of cyclosiloxane moiety from boat-saddle (cradle) to chair. According to PBE0/6-311G(d,p) calculation of isolated D4, such conformation changes are characterized by a low barrier (0.07 kcal/mol). The character of molecular thermal motion and the path of phase transition were established with combination of periodic DFT calculations, including molecular dynamics and metadynamics. The effect of crystal field led to an increase in the calculated phase transition barrier (4.27 kcal/mol from low- to high-temperature phase and 3.20 kcal/mol in opposite direction).