Cost-Effectiveness Analysis of Combined Chemotherapy Regimen Containing Bedaquiline in the Treatment of Multidrug-Resistant Tuberculosis in China / 生物医学与环境科学（英文）

OBJECTIVE@#This study aims to estimate the cost-effectiveness of the combined chemotherapy regimen containing Bedaquiline (BR) and the conventional treatment regimen (CR, not containing Bedaquiline) for the treatment of adults with multidrug-resistant tuberculosis (MDR-TB) in China.@*METHODS@#A combination of a decision tree and a Markov model was developed to estimate the cost and effects of MDR patients in BR and CR within ten years. The model parameter data were synthesized from the literature, the national TB surveillance information system, and consultation with experts. The incremental cost-effectiveness ratio (ICER) of BR vs. CR was determined.@*RESULTS@#BR ( vs. CR) had a higher sputum culture conversion rate and cure rate and prevented many premature deaths (decreased by 12.8%), thereby obtaining more quality-adjusted life years (QALYs) (increased by 2.31 years). The per capita cost in BR was as high as 138,000 yuan, roughly double that of CR. The ICER for BR was 33,700 yuan/QALY, which was lower than China's 1× per capita Gross Domestic Product (GDP) in 2020 (72,400 yuan).@*CONCLUSION@#BR is shown to be cost effective. When the unit price of Bedaquiline reaches or falls below 57.21 yuan per unit, BR is expected to be the dominant strategy in China over CR.

Factors associated with malnutrition in infants with congenital heart disease within one year after surgery / 中华儿科杂志

Objective: To explore the risk factors of malnutrition in infants with congenital heart disease within one year after surgery. Methods: This retrospective cohort study selected 502 infants with congenital heart disease who underwent surgical treatment in Guangzhou Women and Children's Medical Center from February 2018 to January 2019. Their basic information and clinical data were analyzed, and their nutrition status after the surgery was followed up by questionnaire survey. Weight-for-age Z score (WAZ)≤-2 one year after operation was defined as malnutrition group, and WAZ>-2 was non-malnutrition group. The perioperative indicators and complementary food advancement were compared between the two groups by chi-square test, t-test, and Kruskal-Wallis test. The risk factors of malnutrition were analyzed by Logistic regression. Results: A total of 502 infants were selected, including 301 males and 201 females, with the age of 4.1 (2.0, 6.8) months. There were 90 cases in malnutrition group and 412 cases in non-malnutrition group. The body length and weight at birth in the malnutrition group were lower than those in the non-malnutrition group ((47.8±3.8) vs. (49.3±2.5) cm, (2.7±0.6) vs.(3.0±0.5) kg, both P<0.001). The proportion of paternal high school education or above and the proportion of family per capita income of 5 000 yuan or above in the malnutrition group were lower than those in the non-malnutrition group ((18.9% (17/90) vs. 30.8% (127/412), 18.9% (17/90) vs. 33.7% (139/412), both P<0.05). Compared to the non-malnutrition group, the proportion of complex congenital heart disease in the malnutrition group was higher (62.2% (56/90) vs. 47.3% (195/412), P<0.05). The postoperative mechanical ventilation time, postoperative intensive care unit (ICU) stay time, postoperative hospital stay, total length of ICU stay and total hospital stay in the malnutrition group were significantly longer than those in non-malnutrition group (all P<0.05). The proportion of egg and fish supplementation over 2 times/week within one year after the surgery was also lower in the malnutrition group (both P<0.05). Logistic regression analysis showed that mother's weight at delivery (OR=0.95,95%CI 0.91-0.99), the pre-operative WAZ≤-2 (OR=6.04, 95%CI 3.13-11.65), the complexity of the cardiac disease (OR=2.23, 95%CI 1.22-4.06), the hospital stay after the surgery over 14 days (OR=2.61, 95%CI 1.30-5.26), the types of complementary food<4 (OR=2.57, 95%CI 1.39-4.76), and the frequency of meat and fish<2 times/week (OR=2.11, 95%CI 1.13-3.93) were the risk factors associated with malnutrition within one year after the surgery. Conclusion: Mother's weight at delivery pre-operative nutritional status, complexity of cardiac disease, postoperative hospital stay, types of daily supplements and frequency of fish are risk factors associated with malnutrition within one year after surgery in children with congenital heart disease.

Possible Risk Factors for Bone Marrow Fibroplasia in Patients with Polycythemia Vera / 中国实验血液学杂志

OBJECTIVE@#To understand the biological characteristics of polycythemia vera (PV) patients with myeloid fibroplasia, and further analyze the risk factors affecting myeloid fibroplasia in PV patients, so as to provide ideas for predicting the occurrence of myeloid fibroplasia in PV patients.@*METHODS@#Forty patients with PV in the Department of Hematology, Xiyuan Hospital of China Academy of Chinese Medical Sciences were collected and divided into two groups, with (hyperplasia group) and without (Non-proliferative group) hyperplasia of bone marrow fibers. The differences of basic clinical characteristics, blood routine, biochemistry, bone marrow cells, coagulation function and other indicators between the two groups were compared, and the independent risk factors affecting the proliferation of bone marrow fibrous tissue in PV patients were further analyzed by multivariate regression.@*RESULTS@#Compared with Non-proliferative group, the JAK2 mutation rate (95% vs 70%，P=0.037), eosinophilic cell count (0.19 vs 0.11, P=0.047) and eosinophilic percentage (1.84 vs 1.27, P=0.001) in PV patients with hyperplasia were significantly increased, triglycerides (1.55 vs 1.91, P=0.038) and low-density lipoprotein (1.50 vs 3.08, P=0.000) were significantly reduced, bone marrow hematopoietic volume (0.85 vs 0.6, P=0.001), granulocyte/erythrocyte ratio (3.40 vs 1.89, P=0.033), lymphocyte/erythrocyte ratio (0.60 vs 0.42, P=0.033), and granulocyte+lymphocyte/erythrocyte ratio (3.72 vs 2.37, P=0.026) were significantly increased, thrombin time (18.84 vs 18.12, P=0.043) was significantly prolonged. Multivariate regression analysis results showed that peripheral blood eosinophil ≥2% and low-density lipoprotein ≤2 mmol/L were independent risk factors for bone marrow fibrous tissue hyperplasia in PV patients (P<0.05).@*CONCLUSION@#Increased proportion of peripheral blood eosinophils and decreased low density lipoprotein are risk factors for bone marrow fibrous tissue hyperplasia in PV patients.

Comparing Arsenic-Containing Qinghuang Powder and Low-Intensity Chemotherapy in Elderly Patients with Acute Myeloid Leukemia / 中国结合医学杂志

OBJECTIVE@#To compare the clinical effect of arsenic-containing Qinghuang Powder (QHP) and low-intensity chemotherapy (LIC) in treatment of elderly acute myeloid leukemia (eAML) patients.@*METHODS@#Clinical data of 80 eAML patients treated at Xiyuan Hospital of China Academy of Chinese Medical Sciences from January 2015 to December 2020 were retrospectively analyzed. The treatment scheme was designed by real world study according to patients' preference, and patients were divided into a QHP group (35 cases) and a LIC group (45 cases). The median overall survival (mOS), 1-, 2-, and 3-year OS rates, and incidence of adverse events were compared between the two groups.@*RESULTS@#The mOS of 80 patients was 11 months, and the 1-, 2-, and 3-year OS rates were 45.51%, 17.96%, and 11.05%, respectively. The QHP and LIC groups demonstrated no significant difference in mOS (12 months vs. 10 months), 1- (48.57% vs. 39.65%), 2- (11.43% vs. 20.04%), and 3-year OS rates (5.71% vs. 13.27%, all P>0.05). Moreover, the related factors of mOS demonstrated no significant difference in patients with age>75 years (11 months vs. 8 months), secondary AML (11 months vs. 8 months), poor genetic prognosis (9 months vs. 7 months), Eastern Cooperative Oncology Group performance status score ⩾ 3 (10 months vs. 7 months) and hematopoietic stem cell transplant comorbidity index ⩾ 4 (11 months vs. 7 months) between the QHP and LIC groups (all P>0.05). However, the incidence of myelosuppression was significantly lower in the QHP group than that in the LIC group (28.57% vs. 73.33%, P<0.01).@*CONCLUSIONS@#QHP and LIC had similar survival rates in eAML patients, but QHP had a lower myelosuppression incidence. Hence, QHP can be an alternative for eAML patients who do not tolerate LIC.

Meta-analysis of the efficacy and safety of 0.05% cyclosporine A in the treatment of dry eye / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To systematically evaluate the safety and efficacy of 0.05% cyclosporine A(CsA)in the treatment of dry eye.METHODS: PubMed, Web of Science, Cochrane Library, Embase, Chinese Bio-Medical Literature Database, CNKI, VIP, and Wan Fang Database were retrieved. Randomized controlled trials related to the treatment of dry eye with 0.05%CsA from January 1, 2016 to March 28, 2022 in each database were included. The CsA group was treated with 0.05% CsA eye drops, and the control group was treated with artificial tears and placebo. ReMan 5.3 was used for Meta-analysis of post-treatment Schirmer Ⅰ test(SⅠt), break up time(BUT), corneal fluorescein staining(CFS), ocular surface disease index(OSDI)and adverse effects.RESULTS: A total of 13 literatures were included, which included 1 164 cases(2 057 eyes). Compared with the control group, the SIt in the CsA group was prolonged(MD=2.04, 95%CI: 1.75～2.33, P&#x0026;#x003C;0.00001), BUT was longer(MD=1.32, 95%CI: 0.87～1.76, P&#x0026;#x003C;0.00001), CFS decreased(MD=-0.79, 95%CI: -1.20～-0.39, P=0.0001)and OSDI decreased(MD=-5.52, 95%CI: -9.14～-1.91, P=0.003). However, the CsA group had more adverse reactions(OR=1.69, 95%CI: 1.06～2.72, P=0.03).CONCLUSION: 0.05% CsA can improve the subjective symptoms and various objective indicators of dry eye patients. However, 0.05% CsA seems to produce more adverse effects, like ocular burning sensation when compared to drugs such as artificial tears.

A unified GCNN model for predicting CYP450 inhibitors by using graph convolutional neural networks with attention mechanism.

Undesirable drug-drug interactions (DDIs) may lead to serious adverse side effects when more than two drugs are administered to a patient simultaneously. One of the most common DDIs is caused by unexpected inhibition of a specific human cytochrome P450 (CYP450), which plays a dominant role in the metabolism of the co-administered drugs. Therefore, a unified and reliable method for predicting the potential inhibitors of CYP450 family is extremely important in drug development. In this work, graph convolutional neural network (GCN) with attention mechanism and 1-D convolutional neural network (CNN) were used to extract the features of CYP ligands and the binding sites of CYP450 respectively, which were then combined to establish a unified GCN-CNN (GCNN) model for predicting the inhibitors of 5 dominant CYP isoforms, i.e., 1A2, 2C9, 2C19, 2D6, and 3A4. Overall, the established GCNN model showed good performances on the test samples and achieved better performances than the recently proposed iCYP-MFE model by using the same datasets. Based on the heat-map analysis of the resulting molecular graphs, the key structural determinants of the CYP inhibitors were further explored.

Development of Simple and Accurate in Silico Ligand-Based Models for Predicting ABCG2 Inhibition.

The ATP binding cassette transporter ABCG2 is a physiologically important drug transporter that has a central role in determining the ADMET (absorption, distribution, metabolism, elimination, and toxicity) profile of therapeutics, and contributes to multidrug resistance. Thus, development of predictive in silico models for the identification of ABCG2 inhibitors is of great interest in the early stage of drug discovery. In this work, by exploiting a large public dataset, a number of ligand-based classification models were developed using partial least squares-discriminant analysis (PLS-DA) with molecular interaction field- and fingerprint-based structural description methods, regarding physicochemical and fragmental properties related to ABCG2 inhibition. An in-house dataset compiled from recently experimental studies was used to rigorously validated the model performance. The key molecular properties and fragments favored to inhibitor binding were discussed in detail, which was further explored by docking simulations. A highly informative chemical property was identified as the principal determinant of ABCG2 inhibition, which was utilized to derive a simple rule that had a strong capability for differentiating inhibitors from non-inhibitors. Furthermore, the incorporation of the rule into the best PLS-DA model significantly improved the classification performance, particularly achieving a high prediction accuracy on the independent in-house set. The integrative model is simple and accurate, which could be applied to the evaluation of drug-transporter interactions in drug development. Also, the dominant molecular features derived from the models may help medicinal chemists in the molecular design of novel inhibitors to circumvent ABCG2-mediated drug resistance.

University Students' Successive Development From Entrepreneurial Intention to Behavior: The Mediating Role of Commitment and Moderating Role of Family Support.

University students having high entrepreneurial intention while not transferring into actual entrepreneurial behavior is a contradictory issue in need of in-depth research. To explore the successive development mechanism of the entrepreneurial process, this study constructed a moderated mediation model to examine whether entrepreneurial commitment from three dimensions (affective, behavioral, and continuance) mediated the relationship between entrepreneurial intention and behavior, and whether this mediating process was moderated by family support. A survey was conducted among university students from six major universities in south China using the snowball sampling approach. A total of 469 valid responses were obtained (44.6% male and 55.4% female participants). Structural equation modeling was adopted for data analysis. According to the results of the confirmatory factor analysis, it was found that entrepreneurial intention had both direct and indirect positive effects on entrepreneurial behavior, while entrepreneurial commitment worked as the mediator, and family support moderated the relationship between entrepreneurial intention and behavior. Results indicated that entrepreneurial commitment bridged the path from entrepreneurial intention to behavior, and family support created the boundary effect. This finding highlights the importance of guiding students through entrepreneurial commitment toward entrepreneurial behavior, and pays special attention to the crucial role of family support under the national strategy.

High neutralizing antibody levels against SARS-CoV-2 Omicron after UB-612 booster vaccination

The highly transmissible Omicron variant has caused high rates of breakthrough infections among vaccinated and convalescent individuals. Here, we demonstrate that a booster dose of UB-612 vaccine candidate delivered 7-9 months after primary vaccination increases neutralizing antibody levels by 131-, 61- and 49-fold against ancestral SARS-CoV-2, Omicron BA.1 and BA.2 variants, respectively. Based on the RBD protein binding antibody responses, we estimated a [~]95% efficacy against symptomatic COVID-19 caused by the ancestral strain after a UB-612 booster. Our results support UB-612 vaccine as a potent booster against current and emerging SARS-CoV-2 variants.

Nondestructive characterization gender of chicken eggs by odor using SPME/GC-MS coupled with chemometrics.

It's a difficult task for researchers to identify the gender of chicken eggs by nondestructive approach in the early of incubation, which not only could reduce the cost of incubation, but also could improve the welfare of chicks. Therefore, SPME/GC-MS has been applied to investigate its potential as a nondestructive tool for characterizing the differences of odor between male and female chicken eggs during early of incubation and even before hatch. The results showed that more volatiles were found in female White leghorn eggs during early of incubation and 6,10-dimethyl-5,9-undecadien-2-one, 6-methyl-5-hepten-2-one, nonanal, decanal, octanal, 2-nonen-1-ol, etc. were important for the distinction of male and female White leghorn eggs during E1-E9 of incubation. 2-ethyl-1-hexanol; octanal, nonanal, 2,2,4-trimethyl-3-carboxyisopropyl pentanoic acid isobutyl ester; 2-nonen-1-ol, cyclopropanecarboxamide, heptadecane were correlated with gender of unhatched White leghorn, Hy-line brown and Jing fen eggs, respectively. Moreover, sex-related volatiles have been strongly influenced by incubation process and egg breed, and to be related to steroid hormone biosynthesis. What's more, this study enables us to develop a new visual for ovo sexing of chicken eggs and advances our understanding of the biological significance behind volatiles emitted from chicken eggs.

Enhancing cancer chemo-immunotherapy by biomimetic nanogel with tumor targeting capacity and rapid drug-releasing in tumor microenvironment

In the development of chemo-immunotherapy, many efforts have been focusing on designing suitable carriers to realize the co-delivery of chemotherapeutic and immunotherapeutic with different physicochemical properties and mechanisms of action. Besides, rapid drug release at the tumor site with minimal drug degradation is also essential to facilitate the antitumor effect in a short time. Here, we reported a cancer cell membrane-coated pH-responsive nanogel (NG@M) to co-deliver chemotherapeutic paclitaxel (PTX) and immunotherapeutic agent interleukin-2 (IL-2) under mild conditions for combinational treatment of triple-negative breast cancer. In the designed nanogels, the synthetic copolymer PDEA-co-HP-β-cyclodextrin-co-Pluronic F127 and charge reversible polymer dimethylmaleic anhydride-modified polyethyleneimine endowed nanogels with excellent drug-loading capacity and rapid responsive drug-releasing behavior under acidic tumor microenvironment. Benefited from tumor homologous targeting capacity, NG@M exhibited 4.59-fold higher accumulation at the homologous tumor site than heterologous cancer cell membrane-coated NG. Rapidly released PTX and IL-2 enhanced the maturation of dendritic cells and quickly activated the antitumor immune response in situ, followed by prompted infiltration of immune effector cells. By the combined chemo-immunotherapy, enhanced antitumor effect and efficient pulmonary metastasis inhibition were achieved with a prolonged median survival rate (39 days).

Changes in the structure of intestinal mucosal flora in colorectal cancer patients / 南方医科大学学报

OBJECTIVE@#To investigate the changes in bacterial flora in fecal samples, at the tumor loci and in adjacent mucosa in patients with colorectal cancer (CRC).@*METHODS@#We collected fecal samples from 13 patients with CRC and 20 healthy individuals and tumor and adjacent mucosa samples from 6 CRC patients. The differences in bacterial composition between the fecal and mucosa samples were analyzed with 16S rDNA sequencing and bioinformatics methods. We also detected the total number of bacteria in the feces using flow cytometry, isolated and identified the microorganisms in the fecal and mucosa samples using common bacterial culture media. We further tested the effects of 7 isolated bacterial strains on apoptosis of 3 CRC cell lines using lactate dehydrogenase detection kit.@*RESULTS@#The bacterial α-diversity in the feces of healthy individuals and in adjacent mucosa of CRC patients was significantly higher than that in the feces and tumor mucosa in CRC patients (P < 0.05). Lactobacillaceae is a specific bacteria in the feces, while Escherichia, Enterococcus, and Fusobacterium are specific bacteria in tumor mucosa of CRC patients as compared with healthy individuals. Cell experiment with3 CRC cell lines showed that Bacteroides fragilis isolated from the tumor mucosa of CRC patients produced significant inhibitory effects on cell proliferation (P < 0.0001), while the isolated strain Fusobacterium nucleatum obviously promoted the proliferation of the cell lines (P < 0.001).@*CONCLUSION@#The bacterial flora in the feces, tumor mucosa and adjacent mucosa of CRC patients is significantly different from that in the feces of healthy individuals, and the fecal flora of CRC patients can not represent the specific flora of the tumor mucosa. Inhibition of F. nucleatum colonization in the tumor mucosa and promoting B. fragilis colonization may prove beneficial for CRC treatment.

Analysis of Differential Proteins Related to Platelet Activation in Patients with Essential Thrombocythemia Based on Label-Free Quantitative Technology / 中国实验血液学杂志

OBJECTIVE@#To analysis the specific protein markers of essential thrombocythemia (ET) based on proteomics technology, to explore and verify the differential protein related to platelet activation.@*METHODS@#Blood samples were obtained from ET patients and healthy people and a certain protein mass spectrometry was detected using label-free quantitative technology. The proteins relative abundance increased or down-regulated by 1.3 times in the disease group compared with the control group, and the protein abundance in the two groups t test P＜0.05 were defined as differential proteins. Bioinformatics analysis of the differential proteins was performed using GO and KEGG. The difference in the average protein abundance between the two groups was analyzed by t test and P＜0.05 was considered statistically significant. Differential proteins were selected for verification by parallel reaction monitoring (PRM) technology.@*RESULTS@#A total of 140 differential proteins were found, of which 72 were up-regulated and 68 were down-regulated. KEGG enrichment showed that the differential protein expression was related to the platelet activation pathway. The differential proteins related to platelet activation were GPV, COL1A2, GP1bα, COL1A1 and GPVI. Among them, the expressions of GPV, GP1bα and GPVI were up-regulated, and the expressions of COL1A2 and COL1A1 were down-regulated. PRM verification of COL1A1, GP1bα, GPVI and GPV was consistent with LFP proteomics testing.@*CONCLUSION@#Differential proteins in ET patients are related to platelet activation pathway activation.Differential proteins such as GPV, GPVI, COL1A1 and GP1bα can be used as new targets related to ET platelet activation.

An Epidemiologic Survey and Violent Behavior Analysis of Antisocial Personality Disorder in Young Men in Chengdu / 法医学杂志

OBJECTIVES@#To investigate the epidemiological characteristics of antisocial personality disorder (ASPD) in young men in Chengdu and explore the characteristics and risks of violence.@*METHODS@#Stratified random sampling was used to conduct a self-assessment questionnaire survey in 4 108 males aged from 18 to 34 in Chengdu, including general demographic characteristics, structured clinical interview for the diagnostic and statistical manual of mental disorders-Ⅳ axis Ⅱ disorders (SCID-Ⅱ) personality disorder screen questionnaire, violence questionnaire, psychosis screening questionnaire (PSQ), Alcohol Use Disorders Identification Test (AUDIT) and drug use. χ2 test, univariate and multivariate logistic regression were used for analysis and odds ratio (OR) was calculated.@*RESULTS@#The positive rate of ASPD was 5.91%, which was associated with young age, unmarried, unemployment state, low educational level, violent behavior, psychotic symptoms, alcohol and drug use (P<0.05). Young men with ASPD also had a risk (P<0.05) of violence (OR was 8.51), multiple violence (OR was 16.57), injury (OR was 6.68), intentional violence (OR was 11.41), etc., the risk decreased after controlling for psychotic symptoms and substance abuse, but was still statistically significant.@*CONCLUSIONS@#The risk of violence, severe violence and intentional violence in young men in Chengdu is high, and psychotic symptoms and substance abuse increase the risk of ASPD violence and relate characteristics.

Effect of tumor necrosis factor-α overexpress on the biological properties dental pulp stem cells in microoxidative stress / 解剖学报

Objective To investigate the effect of tumor necrosis factor-α(TNF-α) on biological properties of dental pulp stem cells (DPSCs) in low-oxidation stress. Methods The experimental groups were as follows: normox, normox control plasmid, normox-TNF-α, 3% O

De Novo Molecular Design of Caspase-6 Inhibitors by a GRU-Based Recurrent Neural Network Combined with a Transfer Learning Approach.

Due to their potential in the treatment of neurodegenerative diseases, caspase-6 inhibitors have attracted widespread attention. However, the existing caspase-6 inhibitors showed more or less inevitable deficiencies that restrict their clinical development and applications. Therefore, there is an urgent need to develop novel caspase-6 candidate inhibitors. Herein, a gated recurrent unit (GRU)-based recurrent neural network (RNN) combined with transfer learning was used to build a molecular generative model of caspase-6 inhibitors. The results showed that the GRU-based RNN model can accurately learn the SMILES grammars of about 2.4 million chemical molecules including ionic and isomeric compounds and can generate potential caspase-6 inhibitors after transfer learning of the known 433 caspase-6 inhibitors. Based on the novel molecules derived from the molecular generative model, an optimal logistic regression model and Surflex-dock were employed for predicting and ranking the inhibitory activities. According to the prediction results, three potential caspase-6 inhibitors with different scaffolds were selected as the promising candidates for further research. In general, this paper provides an efficient combinational strategy for de novo molecular design of caspase-6 inhibitors.

One-thousandth-level laser power stabilization based on optical feedback from a well-designed high-split-ratio and nonpolarized beam splitter.

Laser power stabilization plays a significant role in atomic and molecular physics, quantum precision measurement, and optical sensing and measurement. In the classical method of using a feedback control loop to stabilize the laser power, the beam splitter is the conjunction element to connect the feedback beam inside the loop and the output beam outside the loop. The stability of its split ratio will directly affect the result of power stabilization, especially in demand of high split ratios for high-efficiency output. For the compatibility of a high split ratio and high stability in a power-stabilized system, we designed and manufactured a high-split-ratio nonpolarized plate beam splitter, whose split ratio was insensitive to variations of beam intensity, polarization, and ambient temperature. Based on the optical feedback of the designed beam splitter, the light intensity was closed-loop controlled by an acousto-optic modulator; finally, the power outside the loop was stabilized as well. The output power was stabilized at 537 mW and a 6 h long-term test was performed. The relative stability of laser power outside the loop in terms of root mean square and peak to peak was 2.72×10-4 and 1.60×10-3, respectively. The relative Allan standard deviation reached 2.78×10-5 at an average time of 200 s. These results will greatly benefit many practical fields that require laser power stabilization with high split ratios and one-thousandth-level stability.

Conformational transitions of caspase-6 in substrate-induced activation process explored by perturbation-response scanning combined with targeted molecular dynamics.

Caspase-6 participates in a series of neurodegenerative pathways, and has aroused widespread attentions as a promising molecular target for the treatment of neurodegeneration. Caspase-6 is a homodimer with 6 central-stranded ß-sheets and 5 α-helices in each monomer. Previous crystallographic studies suggested that the 60's, 90's and 130's helices of caspase-6 undergo a distinctive conformational transition upon substrate binding. Although the caspase-6 structures in apo and active states have been determined, the conformational transition process between the two states remains poorly understood. In this work, perturbation-response scanning (PRS) combined with targeted molecular dynamics (TMD) simulations was employed to unravel the atomistic mechanism of the dynamic conformational transitions underlying the substrate-induced activation process of caspase-6. The results showed that the conformational transition of caspase-6 from apo to active states is mainly characterized by structural rearrangements of the substrate-binding site as well as the conformational changes of 60's and 130's extended helices. The H-bond interactions between L1, 130's helix and 90's helix are proved to be key determinant factors for substrate-induced conformational transition. These findings provide valuable insights into the activation mechanism of caspase-6 as well as the molecular design of caspase-6 inhibitors.

A simple pan-specific RNN model for predicting HLA-II binding peptides.

The prediction of human leukocyte antigen (HLA) class II binding peptides plays important roles in understanding the mechanism of immune recognition and developing effective epitope-based vaccines. In this work, gated recurrent unit (GRU)-based recurrent neural network (RNN) was successfully employed to establish a pan-specific prediction model of HLA-II-binding peptides by using only the HLA and peptide sequence information. In comparison with the existing pan-specific models of HLA-II-binding peptides, the GRU-based RNN model covered a broad spectrum of HLA-II molecules including 50 HLA-DR, 47 HLA-DQ, and 19 HLA-DP molecules with peptide lengths varying from 8 to 43 mers. The results demonstrated strong discriminant capabilities of the GRU-based RNN model, of which the AUC values were 0.92, 0.88, and 0.88 for the training, validation, and test sets, respectively. Also, the GRU-based model showed state-of-the-art performances in predicting the binding peptides with the length ranging from 8-32 mers, which provides an efficient method for predicting HLA-II-binding peptides of longer lengths in comparison with the available methods. Overall, taking the advantages of the RNN architecture, the established pan-specific GRU model can be used for predicting accurately the HLA-II-binding peptides in a simple and direct manner.

Expression of MicroRNAs in Peripheral Blood of Patients with Primary Immune Thrombocytopenia and Its Correlation with the Imbalance of Th1/Th2 Cell / 中国实验血液学杂志

OBJECTIVE@#To investigate the expressions of microRNAs in peripheral blood of patients with primary immune thrombocytopenia(ITP) and its correlation with the imbalance of Th1/Th2 cells.@*METHODS@#Thirty patients with ITP (ITP group) and 15 healthy people (control group) were enrolled．Real-time polymerase chain reaction (RT-PCR) was used to detect the expressions of six miRNAs (miR-107,miR-205-5p,miR-138-5p,miR-326,miR-1827,miR-185-5p) and Th1-specific transcription factor T-bet mRNA and Th2-specific transcription factor GATA-3 mRNA in the peripheral blood of the two groups. Th1 and Th2 cells were detected by flow cytometry. The expressions of Th1-cytokines TNF-α and IFN-γ and Th2-cytokines IL-4 and IL-10 were detected by AimPlex multiple immunoassays for Flow. The expression difference of miRNAs, mRNA, Th1, Th2 cells and cytokines of the two groups were compared, and the correlations of miRNAs to mRNA, Th1, Th2 cells and cytokines were analyzed in ITP group.@*RESULTS@#The expressions of miRNAs（miR-107, miR-205-5p, miR-138-5p, miR-326, miR-1827, miR-185-5p）and Th2-specific transcription factor GATA-3 mRNA of the patients in ITP group were significantly decreased (P<0.05) as compared with those in control, while the expressions of Th1 cells and Th1-specific transcription factor T-bet mRNA and Th1-cytokines TNF-α were significantly increased (P<0.05), also for the ratios of T-bet mRNA/GATA-3 mRNA and Th1/Th2 cells were significantly increased (P<0.05). The relative expressions of miR-107, miR-205-5p, miR-138-5p in ITP patients were negatively correlated with Th2 cells (r=-0.411, r=-0.593, r=-0.403,P<0.05) and the relative expression of miR-1827 was negatively correlated with TNF-α (r=-0.390).@*CONCLUSION@#The relative expressions of the six miRNAs in peripheral blood of patients with ITP are significantly decreased, which result in the increasing ratio of T-bet mRNA/GATA-3 mRNA, then lead to the imbalance of Th1/Th2.