Intermittent Theta Burst Stimulation Attenuates Cognitive Deficits and Alzheimer's Disease-Type Pathologies via ISCA1-Mediated Mitochondrial Modulation in APP/PS1 Mice / 神经科学通报·英文版

Intermittent theta burst stimulation (iTBS), a time-saving and cost-effective repetitive transcranial magnetic stimulation regime, has been shown to improve cognition in patients with Alzheimer's disease (AD). However, the specific mechanism underlying iTBS-induced cognitive enhancement remains unknown. Previous studies suggested that mitochondrial functions are modulated by magnetic stimulation. Here, we showed that iTBS upregulates the expression of iron-sulfur cluster assembly 1 (ISCA1, an essential regulatory factor for mitochondrial respiration) in the brain of APP/PS1 mice. In vivo and in vitro studies revealed that iTBS modulates mitochondrial iron-sulfur cluster assembly to facilitate mitochondrial respiration and function, which is required for ISCA1. Moreover, iTBS rescues cognitive decline and attenuates AD-type pathologies in APP/PS1 mice. The present study uncovers a novel mechanism by which iTBS modulates mitochondrial respiration and function via ISCA1-mediated iron-sulfur cluster assembly to alleviate cognitive impairments and pathologies in AD. We provide the mechanistic target of iTBS that warrants its therapeutic potential for AD patients.

Aureane-type sesquiterpene tetraketides as a novel class of immunomodulators with interleukin-17A inhibitory activity

Interleukin (IL)-17A, a pro-inflammatory cytokine, is a fundamental function in the onset and advancement of multiple immune diseases. To uncover the primary compounds with IL-17A inhibitory activity, a large-scale screening of the library of traditional Chinese medicine constituents and microbial secondary metabolites was conducted using splenic cells from IL-17A-GFP reporter mice cultured under Th17-priming conditions. Our results indicated that some aureane-type sesquiterpene tetraketides isolated from a wetland mud-derived fungus, Myrothecium gramineum, showed remarkable IL-17A inhibitory activity. Nine new aureane-type sesquiterpene tetraketides, myrogramins A-I ( 1, 4- 11), and two known ones ( 2 and 3) were isolated and identified from the strain. Compounds 1, 3, 4, 10, and 11 exhibited significant IL-17A inhibitory activity. Among them, compound 3, with a high fermentation yield dose-dependently inhibited the generation of IL-17A and suppressed glycolysis in splenic cells under Th17-priming conditions. Strikingly, compound 3 suppressed immunopathology in both IL-17A-mediated animal models of experimental autoimmune encephalomyelitis and pulmonary hypertension. Our results revealed that aureane-type sesquiterpene tetraketides are a novel class of immunomodulators with IL-17A inhibitory activity, and hold great promise applications in treating IL-17A-mediated immune diseases.

Thirteen new peptaibols with antimicrobial activities from Trichoderma sp / 中国天然药物

From the fungus Trichoderma sp., we isolated seven novel 18-residue peptaibols, neoatroviridins E-K (1-7), and six new 14-residue peptaibols, harzianins NPDG J-O (8-13). Additionally, four previously characterized 18-residue peptaibols neoatroviridins A-D (14-17) were also identified. The structural configurations of the newly identified peptaibols (1-13) were determined by comprehensive nuclear magnetic resonance (NMR) and high-resolution electrospray ionization tandem mass spectrometry (HR-ESI-MS/MS) data. Their absolute configurations were further determined using Marfey's method. Notably, compounds 12 and 13 represent the first 14-residue peptaibols containing an acidic amino acid residue. In antimicrobial assessments, all 18-residue peptaibols (1-7, 14-17) exhibited moderate inhibitory activities against Staphylococcus aureus 209P, with minimum inhibitory concentration (MIC) values ranging from 8-32 μg·mL-1. Moreover, compound 9 exhibited moderate inhibitory effect on Candida albicans FIM709, with a MIC value of 16 μg·mL-1.

On the accuracy of code complexity metrics: A neuroscience-based guideline for improvement.

Complexity is the key element of software quality. This article investigates the problem of measuring code complexity and discusses the results of a controlled experiment to compare different views and methods to measure code complexity. Participants (27 programmers) were asked to read and (try to) understand a set of programs, while the complexity of such programs is assessed through different methods and perspectives: (a) classic code complexity metrics such as McCabe and Halstead metrics, (b) cognitive complexity metrics based on scored code constructs, (c) cognitive complexity metrics from state-of-the-art tools such as SonarQube, (d) human-centered metrics relying on the direct assessment of programmers' behavioral features (e.g., reading time, and revisits) using eye tracking, and (e) cognitive load/mental effort assessed using electroencephalography (EEG). The human-centered perspective was complemented by the subjective evaluation of participants on the mental effort required to understand the programs using the NASA Task Load Index (TLX). Additionally, the evaluation of the code complexity is measured at both the program level and, whenever possible, at the very low level of code constructs/code regions, to identify the actual code elements and the code context that may trigger a complexity surge in the programmers' perception of code comprehension difficulty. The programmers' cognitive load measured using EEG was used as a reference to evaluate how the different metrics can express the (human) difficulty in comprehending the code. Extensive experimental results show that popular metrics such as V(g) and the complexity metric from SonarSource tools deviate considerably from the programmers' perception of code complexity and often do not show the expected monotonic behavior. The article summarizes the findings in a set of guidelines to improve existing code complexity metrics, particularly state-of-the-art metrics such as cognitive complexity from SonarSource tools.

A four-protein metabolon assembled by a small peptide protein creates the pentacyclic carbonate ring of aldgamycins

Organic carbonates (OCs) are a class of compounds featured by a carbonyl flanked by two alkoxy/aryloxy groups. They exist in either linear or cyclic forms, of which the majority encountered in nature adopt a pentacyclic structure. However, the enzymatic basis for pentacyclic carbonate ring formation remains elusive. Here, we reported that a four-protein metabolon (AlmUII-UV) assembled by a small peptide protein (AlmUV) appends a reactive

Extensive expansion of the chemical diversity of fusidane-type antibiotics using a stochastic combinational strategy

Fusidane-type antibiotics, represented by helvolic acid, fusidic acid and cephalosporin P

Biotransformation of α-asarone by Alternaria longipes CGMCC 3.2875 / 中国天然药物

Biotransformation of α-asarone by Alternaria longipes CGMCC 3.2875 yielded two pairs of new neolignans, (+) (7S, 8S, 7'S, 8'R) iso-magnosalicin (1a)/(-) (7R, 8R, 7'R, 8'S) iso-magnosalicin (1b) and (+) (7R, 8R, 7'S, 8'R) magnosalicin (2a)/(-) (7S, 8S, 7'R, 8'S) magnosalicin (2b), and four known metabolites, (±) acoraminol A (3), (±) acoraminol B (4), asaraldehyde (5), and 2, 4, 5-trimethoxybenzoic acid (6). Their structures, including absolute configurations, were determined by extensive analysis of NMR spectra, X-ray crystallography, and quantum chemical ECD calculations. The cytotoxic activity and Aβ

Development of an eco-friendly and fast HPLC method for quantitative analysis of four nucleosides in Cordyceps and related products / 中国天然药物

An eco-friendly and fast HPLC method was developed for the determination of adenosine, inosine, guanosine and uridine in Cordyceps and related products (fermented mycelia of Hirsutella sinensis andPaecilomyces hepiali). The sample was ultrasonically extracted using 0.5% phosphoric acid solutions for 2.5 min. Sample separation was performed on a Poroshell SB-Aq column (50 mm × 4.6 mm, 2.7 μm) using eco-friendly mobile phase consisting of formic acid and ammonium formate aqueous solution at a flow rate of 1.0 mL·min

Tripodalsporormielones A-C, unprecedented cage-like polyketides with complex polyvdent bridged and fused ring systems

A chemical investigation on

A systematic strategy for screening therapeutic constituents of (Turcz) Baill infiltrated blood-brain barrier oriented in lesions using ethanol and water extracts: a novel perspective for exploring chemical material basis of herb medicines

, a widely used Chinese herbal medicine, was considered as central nervous system (CNS) drug for years. Both ethanol extracts (EES) and water extracts (WES) of it were applied clinically. Unfortunately, the difference of their efficacy and even effective material foundation of remains obscure. In this study, to explore the active constituents of , we compared pharmacodynamics and chemical profiles / of EES/WES for the first time using multiple chemical analysis, pharmacological and data processing approaches. It was proved that there was no significant difference in the anti-depressive effects between WES and EES. However, the contents of most components and in plasma were higher in EES than those in WES, which was unconvincing for their similar efficacy. Therefore, we further explored components of targeted onto brain and the results showed that 5 lignans were identified with definite absorptivity respectively both in EES and WES caused by the limitation of blood-brain barrier. Moreover, bioinformatic analysis predicted their anti-depressive action. Above all, the systematic strategy screened 5 brain-targeted effective substances of and it was suggested that exploring the components into nidi would promote the studies on herbs effective material basis.

Effect of Repetitive Transcranial Magnetic Stimulation Combined with Conventional Rehabilitation on Upper Extremity Function for A Patient with Complex Regional Pain Syndrome I after Distal Radius Fracture / 中国康复理论与实践

Objective:To summarize the development of a patient with complex regional pain syndrome (CRPS) after distal radius fracture and the effect of repetitive transcranial magnetic stimulation (rTMS) combined with conventional rehabilitation on it. Methods:One patient with CRPS after left distal radius fracture was treated with rTMS combined with conventional rehabilitation for three weeks. The pain degree was evaluated with Visual Analogue Score (VAS), the edema was assessed with volume of hand and circumference of finger, and motion of joint was measured with passive range of motion. The activities of daily living was assessed with modified Barthel Index (MBS). Results:Before treatment, the VAS score was 8, the volume of left hand was 330 ml, the temperature of skin was 36.8 ℃. The activity of flexion and extension of left elbow joint, pronation and supination of left forearm, the flexion, extension, ulnar deviation and temporal deviation of left wrist, and metacarpophalangeal joints (MCP), proximal interphalangeal joint (PIP) and distal interphalangeal joint (DIP) of left hand were all limited. The circumference of left finger was larger than right finger, and the score of MBI was 85. After three weeks of treatment, the VAS score was 2, the volume of the left hand was 310 ml, the temperature of the skin was 33.8 ℃. The activities of left elbow joint, left wrist joint and left MCP, PIP, and DIP were better than before. The score of MBI was 100. Conclusion:rTMS combined with conventional rehabilitation is effective on CRPS after distal radius fracture, in the range of motion and edema of upper extremity, and activities of daily living.

Toxicology of Asari Radix et Rhizoma Based on Network Analysis / 中国实验方剂学杂志

Objective:To analyze the known mechanism of toxicology and predict the unknown toxicity in Asari Radix et Rhizoma sinensis by establishing the network relationship of compound, protein, gene and toxicant reaction. Method:After comparing the Asari Radix et Rhizoma candidate compounds obtained from the traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP) database and the toxicological information obtained from the Comparative Toxicogenomics Database(CTD) database, we screened out 13 toxic components from Asari Radix et Rhizoma. And use the Pharm Mapper Server website to find the detailed information of target proteins of the 13 components. The network structure of these 13 chemical components and their corresponding target proteins were drawn by using Cytospace software, and several target proteins with the highest degree of association were found. ClueGO+CluePedia plug-in of Cytospace software was applied in gene ontology(GO) enrichment analysis of genes and kyoto encyclopedia of genes and genomes(KEGG) pathway enrichment analysis, so as to determine the pathways through which toxic substances in Asari Radix et Rhizoma might be harmful to human body. Result:The toxic substances in Asari Radix et Rhizoma may induce tumor and cancer formation through p53 signaling pathway, interleukin(IL)-17 signaling pathway, nuclear factor(NF)-kappa B signaling pathway, tumor necrosis factor(TNF)-signaling pathway. Asari Radix et Rhizoma could inhibit the central nervous system by regulating apoptosis pathways and neurons, and may also cause other autoimmune diseases by IL-17, TNF-α pathway and apoptosis regulation. Conclusion:This study preliminarily explores related mechanisms of toxicity of Asari Radix et Rhizoma,this method can be used to predict toxicity and explain toxicity mechanism of traditional Chinese medicine.

Study on Mechanism of Nephrotoxicity of Tripterygii Radix et Rhizoma Based on Network Pharmacology / 中国实验方剂学杂志

Objective: To explore the mechanism of renal toxicity of Tripterygii Radix et Rhizoma by establishing the active component-target, protein interaction, biological function and pathway network corresponding to the target, and using molecular docking technology. Method: The traditional Chinese medicine(TCM) systems pharmacology database(TCMSP) and the comparative toxicogenomics database (CTD) were used to screen The toxic candidate compounds.In PubChem database, convert all candidate compounds into standard Canonical SMILES format, SMILES format file import SwissTargetPrediction platform, target prediction, will be the target of the corresponding compounds in TCMSP supplement with uniprot converts protein antipodal gene name, and from the human genome database (GeneCards) seek to compare the renal related gene protein,overlapping proteins were screened as potential renal toxicity targets of Tripterygii Radix et Rhizoma.Cytoscape software was used to construct the candidate components-target network of Tripterygii Radix et Rhizoma.Cytoscape software was combined with String database to draw the protein interaction network, DAVID platform was used to analyze the biological function of the target and the pathways involved, and Glide software was used to verify the combination of the key protein and the candidate components of tripterygiumwildiitoxicity. Result: The screening of 30 kinds of candidates for toxic ingredients of Tripterygii Radix et Rhizoma, involving 209 renal toxicity targets, network analysis results showed that Tripterygii Radix et Rhizoma by amino acid metabolism,phospholipid metabolism, catecholamine metabolism, inhibiting renal organic anion transporter Oatl, Oat2, Oat3 function, and inducing apoptosis, and participate in the mitogen-activated protein kinase(MAPK) signaling pathways, JAK-STAT signaling pathway,vascular endothelial growth factor(VEGF)signaling pathways,Toll-like receptor signaling pathway,ERBB signaling pathway, FcεRI signaling pathway, peroxisome proliferators-activated receptors(PPAR) signaling pathway such as toxic to the kidneys. Conclusion: The mechanism of kidney toxicity of Tripterygii Radix et Rhizoma was explored by using the characteristics of multi-component, multi-target and multi-pathway of TCM, which provided new ideas and methods for further research on the mechanism of kidney toxicity of Tripterygii Radix et Rhizoma.

Cardiotoxicity of Aconiti Kusnezoffii Radix Based on Network Toxicology / 中国实验方剂学杂志

Objective:The mechanism of action of cardiac toxicity of Radix Aconiti Agrestis was explored by establishing the active components-targets network of Radix Aconiti Agrestis, protein interaction network, the biological function and pathway network of targets, and using molecular docking technology. Methods:The Traditional Chinese Medicine Systems Pharmacology(TCMSP) database and the Comparative Toxicogenomics Database(CTD) were used to filtrate the toxic candidates of Radix Aconiti Agrestis. Predicting the functional targets of toxic candidates of Radix Aconiti Agrestis by PharmMapper and compared with the cardiac related gene proteins found in the human gene database (GeneCards), and the overlapping proteins were selected as potential cardiac toxicity targets of Radix Aconiti Agrestis. The Cytoscape software was used to construct the network between toxic candidate components and targets. The protein interaction network was mapped by the String database combined with Cytoscape software. The biological functions of the targets and the involved pathways were analyzed with the DAVID platform.The binding of the key proteins with certain toxic candidate components of Radix Aconiti Agrestis was verified by Discover Studio software finally. Results:There were six candidates for toxic ingredients, which involving 27 cardiac toxicity targets. Network analysis results show that the targets were mainly by participating in the heart of phosphorus metabolism, regulation and other related phosphorus metabolism and regulation of phosphorylation and FKBP1A,TGF4-β2, INSR targets to have an important impact on the metabolism,development and form of the heart,and further to have cardiac toxicity. Conclusion:Based on the characteristics of the multi-component, multi-target and multi-pathway of traditional Chinese medicine, the mechanism of cardiac toxicity of Radix Aconiti Agrestis was explored and its possible toxicity was predicted, which provided a new idea and method for further research on the mechanism of cardiac toxicity of Radix Aconiti Agrestis.

Biosynthesis of clinically used antibiotic fusidic acid and identification of two short-chain dehydrogenase/reductases with converse stereoselectivity

Fusidic acid is the only fusidane-type antibiotic that has been clinically used. However, biosynthesis of this important molecule in fungi is poorly understood. We have recently elucidated the biosynthesis of fusidane-type antibiotic helvolic acid, which provides us with clues to identify a possible gene cluster for fusidic acid ( cluster). This gene cluster consists of eight genes, among which six are conserved in the helvolic acid gene cluster except and . Introduction of the two genes into the NSAR1 expressing the conserved six genes led to the production of fusidic acid. A stepwise introduction of and revealed that the two genes worked independently without a strict reaction order. Notably, we identified two short-chain dehydrogenase/reductase genes and in the cluster, which showed converse stereoselectivity in 3-ketoreduction. This is the first report on the biosynthesis and heterologous expression of fusidic acid.

A pair of new tirucallane triterpenoid epimers from the stems of Picrasma quassioides / 中国天然药物

A pair of new tirucallane triterpenoid epimers, picraquassins M and N (1> and 2), were isolated from the stems of Picrasma quassioides (D. Don) Benn. Their structures were determined based on comprehensive spectroscopic and X-ray crystallographic analyses. In addition, their AChE inhibitory activity, cytotoxicity against five human tumour cell lines (SW480, MCF-7, HepG2, Hela, and PANC-1), and antimicrobial activity against two bacteria (Staphylococcus. aureus 209P and Escherichia coli ATCC0111) and two fungi (Candida albicans FIM709 and Aspergillus niger R330) were evaluated.

Effect of reactive oxygen species on 1,4-benzoquinone-induced mitophagy / 预防医学

Objective To investigate whether the metabolite of benzene, 1, 4-benzoquinone (1, 4-BQ) , can activate PINK1/Parkin-mediated mitocphagy and the role of reactive oxygen species (ROS) in 1, 4-BQ induced mitophagy in vitro. Methods Human promyelocytic leukemia cells HL60 were used as the test cells, and were divided into control group, 1, 4-BQ group (10 μM 1, 4-BQ treated cells for 24 h), NAC group (5 mM antioxidant N-acetyl cysteine treated cells for 24 h) and 1, 4-BQ+NAC group (5 mM NAC preincubated for 1 h prior to the treatment with 10 μM 1, 4-BQ for 24 h) . The ultra structure of the cells were observed by transmission electron microscopy (TEM), and the expression of mitophagy related protein LC3, PINK1 and Parkin were detected by Western blot, and the intracellular ROS content was determined by DCFH-DA staining. Results The mitochondria in the control group showed a normal rod-shaped structure with clear mitochondrial cristae, while in the 1, 4-BQ group, the mitochondria showed a swollen structure with less mitochondrial cristae, and typical double-membrane mitophagosomes were observed. LC3-Ⅱ/LC3-Ⅰ ratio, the expression of PINK1, Parkin protein and ROS content in 1, 4-BQ group were increased compared with the control group (P <0.05) , and this increase was markedly blocked by the co-treatment of 1, 4-BQ and NAC (P <0.05) . Conclusion The 1, 4-BQ can induce PINK1/Parkin-mediated mitophagy and ROS plays a significant role in 1, 4-BQ-induced mitophagy.

Quantitative Study on Articular Cartilage By Fourier Transform Infrared Spectroscopic Imaging and Support Vector Machine / 分析化学

Fourier transform infrared spectroscopic imaging (FTIRSI) technology can simultaneously obtain microstructure information and infrared spectral information of the samples. The method of FTIRSI combined with chemometric algorithms can be used for quantitative analysis of sample spectral information and tissue discrimination research. Based on this, FTIRSI and support vector machine classification (SVC) for the first time were used in this work to discriminate healthy and degenerated articular cartilage, with high accuracies of 100％ and 95. 4％ , respectively, and sum accuracy of 97. 7％ . The support vector regression (SVR) model was used to quantitatively study the contents and distribution of two biomacromolecules, collagen and proteoglycan, in articular cartilage. The proteoglycan loss occurred in the degenerated articular cartilage, especially in the superficial area. This study indicates that the combination of FTIRSI and support vector machine (SVM) is expected to become a new diagnostic tool for osteoarthritis, which is of great significance for the early diagnosis and research of osteoarthritis.

Effect of anesthetic sensitivity to propofol after biliary decompression in common bile duct ligation rats / 临床麻醉学杂志

Objective To investigate if anesthetic sensitivity to propofol will be restored after biliary decompression.Methods Twenty-four adult male SD rats were randomly assigned into 3 groups:sham group (group S),irreversible obstructive jaundice group (group Ⅰ) and reversible obstructive jaundice group (group R).The serum total bilirubin (TBL) and total bile acid (TBA) concentratins were detected in the rat blood samples collected from the caudal vein before and after the operation,3,7,14,21 d respectively.Propofol was administered to measure the time of loss of righting reflex and recovery pre or 7th and 21th day post ligation.Results Serum TBL and TBA in group Ⅰ and serum TBA in group R were significantly higher than that in group S on 3rd,7th,14th,21th day post surgery(P＜0.05).Compared with group S,seum TBL in group R were significantly high on 3rd,7th,14th day post-surgery.Serm TBL and TBA in group R were significantly lower than group Ⅰ on 14th,21th day post-surgery (P＜0.05).Compared with group S,the time to loss of righting reflex in group I and group R were significantly shortened and the time to recovery were significantly increased on 7th day post-surgery (P＜0.05).Conclusion Obstructive jaundice could significantly potentiate the ability of propofol to induce a loss of righting reflex,and the increased anesthesia sensitivity will be restored after biliary decompression.

Safety and Effectiveness of High Dose Tigecycline for Treating Patients with Acute Leukemia after Ineffctiveness of Carbapenems Chemotherapy Combinating with Febrile Neutropenia: Retrospective study / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To investigate the safety and efficacy of high dose tigecycline for treatment of fibric neutrope-nia in acute leukemia patients after ineffectiveness of carbapenems chemotherapy of acute leukemia.</p><p><b>METHODS</b>The clinical data of 41 acute leukemia patients with febrile ncutropenia received high dose tigecycline (100 mg q12h), who showed ineffectiveness of treatment with carbapenems, from 20151.30-2017.1. 29 in our hospital were collected and analyzed retrospectively. The temperature, inflammatory indicators as well as hepatic and renal function before and after treatment with tigecycline were compared.</p><p><b>RESULTS</b>Among 41 patients treated with tigecycline due to ineffectiveness of treatment with carbapenems, the infection had been controled in 34 cases, 7 patients died due to ineffectiveness of anti-infective treatment, these patients all were patients with relapse/refractory leukemia. 41 patients were examined etialogically, as a result, 22 patients showed possitive, among them the gram-negative bacill was found in 11(11/22) cases. The average deferves counce time of tigecycline was 28.2±12.0 hours. The temperature of patients treated with tigecycline for 48 hours decreased significantly (P<0.05). There were no significant differences in calcitonin and C-reactive protein levels after treatment with tigecycline (P>0.05), but cacitonin level displayed decrease tread. There was no hepatic and renal impairment after treatment with tigecycline, but levels of as partate aminotransferase, total bilirubin and blood area nitrogen in blood significantly increased as compared with levels before treatment with tigecycline (P<0.05).</p><p><b>CONCLUSION</b>The application of high dose tigecycline for treatment of febrile neutropenia is safety and effective. The high dose tigecycline can decrease the temperature, calcitonin and C-reactive protein levels, and can control infection without the hepatic and renal impairment, but it needs to be confimed by more prospective studies.</p>