Shaking table test on damage mechanism of bedrock and overburden layer slope based on the time-frequency analysis method.

To systematically analyze the damage caused by bedrock and overburden layer slope under seismic action, a set of large-scale shaking table test was designed and completed. Interpolation of the acceleration amplification coefficient, Hilbert-Huang transform and transfer function was adopted. The damage mechanisms of the bedrock and overburden layer slopes under seismic action are systematically summarized in terms of slope displacement, acceleration field, vibration amplitude, energy, vibration frequency, and damage level. The results show a significant acceleration amplification effect within the slope under seismic action and a localized amplification effect at the top and trailing edges of the slope. With an increase in the input seismic intensity, the difference in the vibration amplitude between the overburden layer and bedrock increased, low-frequency energy of the overburden layer was higher than that of the bedrock, and the vibration frequency of the overburden layer was smaller than that of the bedrock. These differences cause the interface to experience cyclic loading continuously, resulting in the damage degree of the overburden layer at the interface being larger than that of the bedrock, reduction of the shear strength, and eventual formation of landslides. The displacement in the middle of the overburden is always greater than that at the top. Therefore, under the action of an earthquake and gravity, the damage mode of the bedrock and overburden layer slope is such that the leading edge of the critical part pulls and slides at the trailing edge, and multiple tensile cracks are formed on the slope surface.

Wave Propagation Characteristics and Compaction Status of Subgrade during Vibratory Compaction.

Vibratory compaction status has a significant influence on the construction quality of subgrade engineering. This study carried out field experiments to study the propagation characteristics of the vertical vibration wave in the soil field along the traveling direction of the vibratory roller. The propagation coefficients of the peak acceleration at different positions and compacting rounds are compared in both the time and frequency domains. The compaction status is estimated in the form of dynamic modulus of deformation (Evd) obtained by plate load tests. The experiment results show that the propagation coefficient of peak acceleration is affected by the traveling speed, excitation amplitude, and frequency of the vibratory roller, as well as the compacting rounds. An exponential relationship between the wave amplitudes of the fundamental mode and higher-order modes is revealed. The amplitude of the fundamental wave is maximum at the speed of 3 km/h, whereas the amplitudes of higher-order waves have a maximum of 1.5 km/h. The influences of compaction rounds on the average value of Evd are also investigated to provide a practical reference for engineering construction.

Effects of hydrolysable tannins from Terminalia citrina on type III secretion system (T3SS) and their intestinal metabolite urolithin B represses Salmonella T3SS through Hha-H-NS-HilD-HilC-RtsA-HilA regulatory pathway.

Gamma-proteobacteria is a class of gram-negative opportunistic pathogens existing in the intestinal flora, often leading to diarrhea and intestinal infectious diseases, and plays an important role in maintaining intestinal homeostasis. Type III secretion system (T3SS), an important virulence system, is closely related to the adhesion and invasion and pathogenicity to host cells. Therefore, anti-virulence agents targeting T3SS are important strategies for controlling pathogenic infections. In this study, the anti-Salmonella T3SS active compounds neochebulagic acid (1), ellagic acid (2) and urolithin M5 (3) were isolated from seed extract of Terminalia citrina by activity-guided isolation method. Based on the fact that urolithins are the main and stable intestinal microbiota metabolites of hydrolysable tannins, we found that the metabolite urolithin B repressed translation and secretion of SipC through the Hha-H-NS-HilD-HilC-RtsA-HilA regulatory pathway. The results provide evidence for Terminalia seeds and ellagitannin-rich berries and nuts in regulating intestinal homeostasis and treating bacterial infection.

Evidence summary of intra-abdominal pressure-guided enteral nutrition in patients with intra-abdominal hypertension / 中国实用护理杂志

Objective:To retrieve and obtain relevant evidence of intra-abdominal pressure-oriented enteral nutrition assessment and management in patients with intra-abdominal hypertension, in order to provide evidence-based evidence for clinical medical staff to make enteral nutrition-related clinical decisions for patients with intra-abdominal hypertension.Methods:Systematic retrieval of Chinese National Knowledge Infrastructure, Wanfang, Chinese Biomedical Literature, UpToDate, PubMed, Cochrane Library, BMJ Best Practice and other English data, as well as domestic and foreign guidelines such as American Society for Parenteral and Enteral Nutrition, Scottish Intercollegiate Guidelines Network, etc. All evidence available on the Internet in both Chinese and English on intra-abdominal pressure-guided enteral nutrition strategies in adults with intra-abdominal hypertension, study types including clinical decision-making, systematic reviews/meta-analyses, evidence summaries, expert consensus, guidelines or related to the subject of this study closely related high-quality original research. The retrieval time was from the establishment of the database to November 2021. The literature evaluation tool was selected according to the research type. Two researchers trained in the evidence-based system independently evaluate the quality of the included literature, fully considering the clinical situation and expert opinions, and completed the evidence. Extracted and summarized.Results:Totally 13 articles were finally included, including 5 guidelines, 3 expert consensuses, 1 evidence summary and 4 original studies, and 29 evidence-based practice evidence of enteral nutrition in patients with intra-abdominal hypertension were collected, including the monitoring timing of enteral pressure, the pressure of enteral high pressure and the way of enteral nutrition, the pressure measurement of the abdominal cavity, the setting of abdominal pressure, the temperature conditions for early start of enteral nutrition, the selection of enteral pressure, the temperature setting of enteral nutrition nine aspects such as speed and regulation of internal nutrition and abdominal compartment syndrome prevention.Conclusions:This study summarizes the best evidence of intra-abdominal pressure management and enteral nutrition therapy in patients with intra-abdominal hypertension, and provides evidence-based basis for risk management, standardizing clinical practice, and ensuring treatment safety. In the stage of evidence transformation, clinical medical staff need to comprehensively weigh the benefits and risks of early enteral nutrition, and integrate evidence in combination with clinical practical application scenarios, so as to form a standardized early enteral nutrition management plan suitable for patients with intra-abdominal hypertension.

Research progress of biological targeted therapy for bronchial asthma / 国际生物医学工程杂志

Bronchial asthma (hereinafter referred to as asthma) is a chronic inflammatory disease of the airways composed of multiple cells (eosinophils, mast cells, T-lymphocytes, airway epithelial cells, etc.) and cellular components. Severe asthma is often recurrent and prolonged, and symptoms such as cough, chest tightness, shortness of breath, and wheezing are difficult to relieve, which seriously affects the patient's quality of life. At present, standard treatment with a combination of high-dose inhaled corticosteroids (ICS) and long-acting bronchodilators is recommended, but some patients still cannot be adequately controlled. This increases the patients' physical and mental burden and treatment costs. Asthma is a heterogeneous disease with multiple phenotypes, with wide variation in disease severity, type of airway inflammation, and therapeutic drugs, caused by a variety of pathophysiological mechanisms or endotypes. Individualized treatment for different individual pathogenesis in asthma patients is required, and targeted biological agents provide new hope for asthma patients. In this paper, the research progress of biological targeting agents in the treatment of asthma was reviewed.

Specialised metabolites as chemotaxonomic markers of Coptosapelta diffusa, supporting its delimitation as sisterhood phylogenetic relationships with Rubioideae.

From the aerial extracts of Coptosapelta diffusa (Champ. ex Benth.) Steenis, twenty-one compounds were isolated and identified by means of column chromatography and NMR and MS techniques, respectively. Amongst, ten ones were determined to be undescribed compounds including six seco-iridoid glucosides (1-6), 2-(hydroxymethyl)-1,2,3,4-tetrahydroanthracene-9,10-dione (7) and three guaiane-type sesquiterpenes (15-17). Compounds 7, 8 and 9 exhibited inhibitory activities against Staphylococcus aureus ATCC25923 with MIC of 8, 4 and 8 µg/mL. The use of 1-6 (iridoids), 7-14 (anthraquinones) and 15-17 (sesquiterpenes) as chemotaxonomic markers for this species was evidenced. Structurally, 7-14 are similar to those anthraquinones isolated from other species of the family Rubiaceae, confirming their close phylogenetic relationship. Whereas, these iridoids and sesquiterpenes with unique structures provided chemotaxonomic evidence to support the genus Coptosapelta (the tribe Coptosapelteae) as a sister of the subfamily Rubioideae. These results contrast with the general producing tendency of indole alkaloids by the species of the subfamily Cinchonoideae, and merit chemotaxonomic significance for the delimitation of Coptosapelta.

A pressure injury risk prognosis model for severe trauma patients based on Braden scale combined with microcirculation indicators / 中华急诊医学杂志

Objective:Based on Braden scale, combined with local skin temperature and local tissue oxygen saturation as microcirculation indicators, to construct a pressure injury risk prognosis model for severe trauma patients, and develop a visual nomogram.Methods:All the trauma patients in the Emergency Intensive Care Unit (EICU) of a tertiary hospital in Zhejiang Province from June 1, 2020 to August 31, 2020 were selected. The Braden scale was used to assess the risk of pressure injury in the patient and measure the patient’s sacral injury. The skin temperature and blood oxygen saturation at the pressure site were used as indicators for microcirculation evaluation. Multivariate Logistic regression was used to construct a prognostic model and visual nomogram for severe trauma patients with stress injury based on Braden score combined with microcirculation evaluation indicators, and compared with the prediction model constructed by the Braden scale alone. The discrimination degree was judged by the area under the receiver operating characteristic curve. The C index performed internal verification of the model, H-L goodness-of-fit test, and the overall discrimination index to observe and predict the effect of the model.Results:A total of 152 patients were enrolled in this study, of which 33 (21.71%) had pressure injuries. The area under the curve of the Braden scale combined with local skin temperature and local tissue oxygen saturation was 0.866, and the internal verification C index of the model was 0.847. The H-L goodness of fit test result was 8.37 ( P=0.051), indicating that the model had good discrimination and consistency. The overall discrimination index of the model was 0.144 ( P=0.023). Conclusions:The Braden scale combined with local microcirculation indicators to construct a prognostic model of stress injury in severe trauma patients has good discrimination and consistency, and the predictive power of the Braden scale is improved by 14.4%. The construction of a nomogram can provide clinical rapid convenient and reliable forecasting tool.

Shunt products of aminoansamycins from aas1 overexpressed mutant strain of Streptomyces sp. S35.

Constitutively expression of the pathway-specific activators is an effective method to activate silent gene clusters and improve natural product production. In this study, nine shunt products of aminoansamycins (1-9) were identified from a recombinant mutant strain S35-LAL by overexpressed the large-ATP-binding regulator of the LuxR family (LAL) gene aas1 in Streptomyces sp. S35. All the compounds showed no anti-microbial, anti-T3SS and cytotoxic activities.

Expression of the Clifednamide Biosynthetic Pathway in Streptomyces Generates 27,28-seco-Derivatives.

Polycyclic tetramate macrolactams (PoTeMs) are a group of hybrid PK-NRP natural products having a variable set of carbocyclic rings, a conserved assembly pathway, and diverse bioactivities. We report here the identification of seven new PoTeMs, clifednamides D-J (3-9), along with the known clifednamides A (1) and B (2) through rational pathway refactoring and heterologous expression. Remarkably, clifednamides D (3), G (6), and H (7) feature an unprecedented 27,28-seco skeleton. The cytotoxic activities of compounds 1-9 indicated that the hydroxy group of C-25, the methyl group of C-30, the inner five-membered ring, and the intact macrocycle are all critical for the activities. Meanwhile, the cytochrome P450 enzyme CftS023A and the hydroxylase CftS023E involved in oxidative tailoring of clifednamides were found to decorate the fused 5-6 bicyclic intermediates. Accordingly, the biosynthetic pathway for clifednamides was proposed.

C1orf194 deficiency leads to incomplete early embryonic lethality and dominant intermediate Charcot-Marie-Tooth disease in a knockout mouse model.

Charcot-Marie-Tooth (CMT) disease is the most common inherited peripheral neuropathy and shows clinical and genetic heterogeneity. Mutations in C1orf194 encoding a Ca2+ regulator in neurons and Schwann cells have been reported previously by us to cause CMT disease. In here, we further investigated the function and pathogenic mechanism of C1or194 by generating C1orf194 knockout (KO) mice. Homozygous mutants of C1orf194 mice exhibited incomplete embryonic lethality, characterized by differentiation abnormalities and stillbirth on embryonic days 7.5-15.5. Heterozygous and surviving homozygous C1orf194 KO mice developed motor and sensory defects at the age of 4 months. Electrophysiologic recordings showed decreased compound muscle action potential and motor nerve conduction velocity in the sciatic nerve of C1orf194-deficient mice as a pathologic feature of dominant intermediate-type CMT. Transmission electron microscopy analysis revealed demyelination and axonal atrophy in the sciatic nerve as well as swelling and loss of mitochondrial matrix and other abnormalities in axons and Schwann cells. A histopathologic examination showed a loss of motor neurons in the anterior horn of the spinal cord and muscle atrophy. Shorter internodal length between nodes of Ranvier and Schmidt-Lanterman incisures was detected in the sciatic nerve of affected animals. These results indicate that C1orf194 KO mice can serve as an animal model of CMT with a severe dominant intermediate CMT phenotype that can be used to investigate the molecular mechanisms of the disease and evaluate the efficacy of therapeutic strategies.

Four pairs of proline-containing cyclic dipeptides from Nocardiopsis sp. HT88, an endophytic bacterium of Mallotus nudiflorus L.

Strain HT88 was isolated from the fresh stems of Mallotus nudiflorus L, and it was identified as Nocardiopsis sp. by analyzing its morphology and the 16S rRNA sequence. The extracts of fermented HT88 showed potent antimicrobial activities. Bioassay guided separation of extracts led to eight proline (or hydroxyproline, Hyp)-containing cyclic dipeptides. Their structures were determined by 1D and 2D NMR spectroscopy and ESI mass spectrometry and further comparison with existing 1H and 13C NMR, melting points and specific rotation data. The eight 2,5-diketopiperazines (DKPs) were identified as cyclo(L-Pro-L-Leu) (1), cyclo(Pro-Leu) (2), cyclo(L-trans-Hyp-L-Leu) (3), cyclo(D-trans-Hyp-D-Leu) (4), and cyclo(D-Pro-L-Phe) (5), cyclo(L-Pro-L-Phe) (6), and cyclo(D-cis-Hyp-L-Phe) (7), cyclo(L-trans-Hyp-L-Phe) (8), respectively. Up to date, this is the first isolation of four pairs of proline based DKPs from Nocardiopsis sp.

Effect of peer education on improving compliance of cardiac rehabilitation in patients with coronary heart disease / 中国实用护理杂志

Objective:To evaluate the effect of peer education on improving compliance of cardiac rehabilitation in patients with coronary heart disease.Methods:Totally 64 patients were randomly divided into two groups, namely, the experimental group and the control group with 32 cases in each group. Patients in the experimental group received routine education, nursing, and rehabilitation, plus the peer education treatment, whereas the control group only received routine treatment. The time lasts for 6 months. The compliance of cardiac rehabilitation and the score of China Questionnaire of Quality of Life in Patients with Cardiovascular Diseases (CQQC) were measured after 1 month, 3month and 6 month.Results:After 1, 3, and 6 months of intervention, the compliance of cardiac rehabilitation in the intervention group increased by 18.75%, 21.37%, and 21.88%, respectively, compared with the control group. After the first and third months of intervention, there was a statistically significant difference in the compliance rate of rehabilitation exercise between the intervention group and the control group ( χ2 values were 18.050, 16.946, respectively, P <0.05), and at the sixth month after intervention, the compliance of the two groups of patients with cardiac rehabilitation was not statistically significant ( χ2 value was 6.489, P> 0.05). After 1, 3, and 6 months of intervention, the quality of life scores of the intervention group were (88.68 ± 6.65), (81.90 ± 6.78), and (76.33 ± 5.90) points, and the quality of life scores of the control group were (84.75 ± 4.72), (75.67 ± 5.88), and (74.71 ± 9.47) points. There was significant difference in the scores of the two groups in the first and third months after the intervention ( t values were 2.235, 2.520, respectively, P<0.05); and in the sixth month after the intervention, the difference in the scores of the two groups wasn`t statistically significant ( t value was 1.049, P >0.05). Conclusion:Peer education can improve the compliance of cardiac rehabilitation and the score of CQQC in patients with coronary heart disease in 3 month, but further research is needed to confirm the long-term effect of peer education.

Shunt products of aminoansamycins from aas1 overexpressed mutant strain of Streptomyces sp. S35 / 中国天然药物

Constitutively expression of the pathway-specific activators is an effective method to activate silent gene clusters and improve natural product production. In this study, nine shunt products of aminoansamycins (1-9) were identified from a recombinant mutant strain S35-LAL by overexpressed the large-ATP-binding regulator of the LuxR family (LAL) gene aas1 in Streptomyces sp. S35. All the compounds showed no anti-microbial, anti-T3SS and cytotoxic activities.

Effectiveness and safety of sotagliflozin adjuvant therapy for type 1 diabetes mellitus: A protocol for Systematic review and Meta-analysis.

BACKGROUND: Type 1 Diabetes Mellitus (T1DM) has long required insulin treatment. Sotagliflflozin (SOTA), as a dual SGLT-1/2 inhibitor, has the potential to be the first oral antidiabetic drug (OAD) to be approved for T1DM in the US market. It is important to evaluate the effectiveness of SOTA for T1DM. METHODS: Web of Science, PubMed datebase, Cochrane Library, Embase, Clinical Trials, and CNKI will be searched to identify randomized controlled trials (RCTs) exploring SOTA adjuvant therapy for T1DM. Strict screening and quality evaluation will be performed on the obtained literature independently by 2 researchers; outcome indexes will be extracted. The bias risk of the included studies will be evaluated based on Cochrane assessment tool. Meta-analysis will be performed on the data using Revman 5.3 software. RESULT: We will provide practical and targeted results assessing the efficacy and safety of SOTA for T1DM patients, to provide reference for clinical use of SOTA. CONCLUSION: The stronger evidence about the efficacy and safety of SOTA for T1DM patients will be provided for clinicians. TRIAL REGISTRATION NUMBER: PROSPERO CRD42019133099.

Effectiveness of tenofovir and entecavir in nucleos(t)ide analogue-naive chronic hepatitis B: A protocol for systematic review and meta-analysis.

BACKGROUND: Chronic hepatitis b (CHB) is a serious problem worldwide. Tenofovir disoproxil fumarate (TDF) and entecavir (ETV) both are first-line drugs for CHB, but there is debate about which is more appropriate in nucleos(t)ide analogue-naive CHB. OBJECTIVE: To systematically evaluate the effectiveness and safety of tenofovir and ETV in nucleos(t)ide analogue-naive CHB. METHODS: The Web of Science, PubMed, The Cochrane Library, EMBASE, Clinical Trials, and China National Knowledge Infrastructure databases will be electronically searched to collect randomized controlled trials regarding the comparison between tenofovir and ETV in nucleos(t)ide analogue-naive CHB since the date of database inception to July 2019. Two researchers independently screened and evaluated the obtained studies and extracted the outcome indexes. RevMan 5.3 software will be used for the meta-analysis. RESULT: We will provide practical and targeted results assessing the effectiveness and safety of TDF and ETV for nucleos(t)ide analogue-naive CHB patients, try to compare the advantages of TDF and ETV. CONCLUSION: The stronger evidence about the effectiveness and safety of TDF and ETV for nucleos(t)ide analogue-naive CHB patients will be provided for clinicians. PROTOCOL REGISTRATION NUMBER: PROSPERO CRD42019134194.

Structural Mechanism of the Arrestin-3/JNK3 Interaction.

Arrestins, in addition to desensitizing GPCR-induced G protein activation, also mediate G protein-independent signaling by interacting with various signaling proteins. Among these, arrestins regulate MAPK signal transduction by scaffolding mitogen-activated protein kinase (MAPK) signaling components such as MAPKKK, MAPKK, and MAPK. In this study, we investigated the binding mode and interfaces between arrestin-3 and JNK3 using hydrogen/deuterium exchange mass spectrometry, 19F-NMR, and tryptophan-induced Atto 655 fluorescence-quenching techniques. Results suggested that the ß1 strand of arrestin-3 is the major and potentially only interaction site with JNK3. The results also suggested that C-lobe regions near the activation loop of JNK3 form the potential binding interface, which is variable depending on the ATP binding status. Because the ß1 strand of arrestin-3 is buried by the C-terminal strand in its basal state, C-terminal truncation (i.e., pre-activation) of arrestin-3 facilitates the arrestin-3/JNK3 interaction.

Crystal structure and catalytic activity of the PPM1K N94K mutant.

Protein Phosphatase Mg2+ /Mn2+ -Dependent 1K (PPM1K),also named as PP2Cm or branched-chain α-ketoacid dehydrogenase complex phosphatase, is a member of the metal-dependent phosphatase family and an important metabolic regulator. Single nucleotide polymorphisms (SNPs) in PPM1K contributing to protein functional defects have been found to be associated with numerous human diseases, such as cardiovascular disease, maple syrup urine disease, type 2 diabetes, and neurological disease. PPM1K N94K is an identified missense mutant produced by one of the SNPs in the human PPM1K coding sequence. However, the effects of the N94K mutant on its activity and structural property have not been defined. Here, we performed a detailed enzymological study using steady-state kinetics in the presence of pNPP or phospho-peptide substrates and crystallographic analyses of the wild-type and N94K PPM1K. The PPM1K-N94K significantly impaired its Mg2+ -dependent catalytic activity and structural analysis demonstrated that the N94K mutation induced a conformational change in the key residue in coordinating the Mg2+ in the active site. Specifically, three Mg2+ were located in the active site of the PPM1K N94K instead of two Mg2+ in the PPM1K wild type. Therefore, our results provide a structure basis for the metal ion-dependent PPM1K-N94K phosphatase activity.

Allosteric mechanisms underlie GPCR signaling to SH3-domain proteins through arrestin.

Signals from 800 G-protein-coupled receptors (GPCRs) to many SH3 domain-containing proteins (SH3-CPs) regulate important physiological functions. These GPCRs may share a common pathway by signaling to SH3-CPs via agonist-dependent arrestin recruitment rather than through direct interactions. In the present study, 19F-NMR and cellular studies revealed that downstream of GPCR activation engagement of the receptor-phospho-tail with arrestin allosterically regulates the specific conformational states and functional outcomes of remote ß-arrestin 1 proline regions (PRs). The observed NMR chemical shifts of arrestin PRs were consistent with the intrinsic efficacy and specificity of SH3 domain recruitment, which was controlled by defined propagation pathways. Moreover, in vitro reconstitution experiments and biophysical results showed that the receptor-arrestin complex promoted SRC kinase activity through an allosteric mechanism. Thus, allosteric regulation of the conformational states of ß-arrestin 1 PRs by GPCRs and the allosteric activation of downstream effectors by arrestin are two important mechanisms underlying GPCR-to-SH3-CP signaling.

An Explorer of Chemical Biology of Plant Natural Products in Southwest China, Xiaojiang Hao.

Xiaojiang Hao, who obtained Master Degree from Kunming Institute of Botany (KIB), Chinese Academy of Sciences (CAS) in 1985, and Doctor in Pharmacy degree in Pharmacy from Institute for Chemical Research, Kyoto University, in 1990, was born in Chongqing in July, 1951. In 1991, he returned to KIB, CAS, as an Associate professor and served as the chair of the Department of Phytochemistry. In 1994, he was promoted to a full professor at the current institute. He served as the Deputy Director of KIB and the Director of Open Laboratory of Phytochemistry from 1995 to 1997, and the Director of KIB from 1997 to 2005. Professor Hao has published more than 450 peer-reviewed SCI papers, which have been cited over 6000 times. He has obtained one PCT patent and 23 patents in China. Due to his tremendous efforts, one candidate drug, phenchlobenpyrrone, has entered the Phase II clinical trail for the treatment of Alzheimer's disease. Moreover, he won the First Prize of Natural Sciences in Yunnan Province for three times, and Ho Leung Ho Lee Fund Science and Technology Innovation Award in 2017.

Discovery of Novel Topoisomerase II Inhibitors by Medicinal Chemistry Approaches.

DNA topoisomerase II (topo II) is an important enzyme involved in DNA replication, recombination, and repair. Despite the popular applications of topo II inhibitors in cancer therapy, there is still an urgent need to upgrade topo II inhibitors to cope with drug resistance and severe adverse effects. Accordingly, novel topo II catalytic or multitarget topo II inhibitors are gaining more attention and make it possible to ease the toxic limitations of topo II poisons. In this review, medicinal chemistry approaches are mainly discussed toward the development of potent topo II inhibitors with low toxicities.