NK-derived exosome miR-1249-3p inhibits Mycobacterium tuberculosis survival in macrophages by targeting SKOR1.

Murine Natural Killer cells were cultivated in vitro to isolate NK-derived exosomes. Subsequent quantification via qPCR confirmed enrichment of miR-1249-3p. Ana-1 murine macrophages were cultured in vitro and subsequently inoculated with Mycobacterium tuberculosis (MTB) strain H37Rv. NK-exo and NK-exo miR-1249-3p were separately applied to the infection model, followed by immunological assays conducted post-48-hour co-culture. Western blot analyses corroborated that NK-exo exhibited exosomal marker proteins Granzyme A (GzmA), Granzyme B (GzmB), and Perforin (PFN), alongside a notable enrichment of miR-1249-3p. Functionally, NK-exo augmented the expression levels of Caspase-9,-8, and -3, as well as PARP, while attenuating the expression of NLRP3, ASC, and Cleaved-Caspase-1. Furthermore, qPCR demonstrated an up-regulation of Caspase-9, -8, and -3, along with pro-apoptotic factors Bax and Bid, and a concomitant down-regulation of the anti-apoptotic factor Bcl-2. The expression levels of inflammatory markers ASC, NLRP3, Cleaved-Caspase-1, and IL-1ß were concomitantly decreased. ELISA findings indicated diminished levels of TNF-α and ROS secretion. NK-exo miR-1249-3p specifically targeted and attenuated the expression of SKOR-1, engendering up-regulation of apoptosis-associated proteins and down-regulation of inflammation-related proteins, consequently affecting cellular fate.Our empirical evidence substantiates that NK-exo induces macrophage apoptosis, thereby mitigating MTB survival. Furthermore, NK-exo miR-1249-3p directly targets and inhibits SKOR-1 expression, leading to macrophage apoptosis and consequently hampering the proliferation of MTB. The data implicate the potential therapeutic relevance of NK-exo and miR-1249-3p in managing drug-resistant tuberculosis.

Who can help me? Understanding the antecedent and consequence of medical information seeking behavior in the era of bigdata.

Introduction: The advent of bigdata era fundamentally transformed the nature of medical information seeking and the traditional binary medical relationship. Weaving stress coping theory and information processing theory, we developed an integrative perspective on information seeking behavior and explored the antecedent and consequence of such behavior. Methods: Data were collected from 573 women suffering from infertility who was seeking assisted reproductive technology treatment in China. We used AMOS 22.0 and the PROCESS macro in SPSS 25.0 software to test our model. Results: Our findings demonstrated that patients' satisfaction with information received from the physicians negatively predicted their behavior involvement in information seeking, such behavior positively related to their perceived information overload, and the latter negatively related to patient-physician relationship quality. Further findings showed that medical information seeking behavior and perceived information overload would serially mediate the impacts of satisfaction with information received from physicians on patient-physician relationship quality. Discussion: This study extends knowledge of information seeking behavior by proposing an integrative model and expands the application of stress coping theory and information processing theory. Additionally, it provides valuable implications for patients, physicians and public health information service providers.

An appraisal of current embryo transfer strategies.

Embryo transfer, one of the most essential procedures in assisted reproductive technology, plays a vital role in the success of in-vitro fertilization and intracytoplasmic sperm injection. During the last decades, the strategies for embryo transfer have changed dramatically. In this review, we evaluate the efficacy and safety of several current embryo transfer strategies including fresh versus frozen embryo transfer, cleavage- versus blastocyst-stage embryo transfer, and single- versus double-embryo transfer. Available evidence indicates that the freeze-only strategy improves the live birth rate after the first embryo transfer in high responders while making no difference in normal responders. The risk of ovarian hyperstimulation syndrome is significantly reduced in the freeze-only strategy. Fresh blastocyst-stage embryo transfer increased live birth rate compared to cleavage-stage embryo transfer. The best embryo transfer strategy is one which tailors to individual circumstances and preferences.

Patient and clinician perspectives on shared decision-making in infertility treatment: A qualitative study.

OBJECTIVES: To explore the considerations and barriers to implementing shared decision-making (SDM) in infertility treatment among female infertility patients, their male spouses, and fertility clinicians. METHODS: Participants were recruited from a reproductive medicine hospital in China's Shandong Province using purposive sampling. One-on-one interviews were held with female infertility patients and their spouses. In addition, a focus group discussion was conducted with fertility clinicians. Data analysis was subjected to open, axial, and selective coding. RESULTS: Nineteen female infertility patients and 10 male spouses were interviewed one-on-one. Five clinicians participated in the focus group discussion. Most female patients wanted to participate in the decision-making process, and that spouses and fertility clinicians supported SDM. Furthermore, key barriers were identified from the perspectives of multiple stakeholders, including communication difficulties, psychological pressure on female patients, patient preferences, multiple treatment stages, male spousal participation, clinician-patient trust, and subjective patient factors. CONCLUSIONS/PRACTICE IMPLICATIONS: This study explored the considerations of and barriers to implementing SDM in infertility treatment. Key barriers were identified from the perspectives of multiple stakeholders. Based on the findings, clinicians should encourage patients and their spouses to actively participate in decision-making, and provide objective and realistic guidance.

The complete mitochondrial genome of Morishitium polonicum (Trematoda, Cyclocoelidae) and its phylogenetic implications.

Trematodes can adversely impact the health and survival of wild animals. The trematode family Cyclocoelidae, which includes large digenean bird parasites, lacks molecular analysis, and reclassifications have not been supported. This study produced the first fully assembled and annotated mitochondrial genome sequence for the trematode Morishitium polonicum. The whole length of the M. polonicum (GenBank accession number: OP930879) mitogenome is 14083 bp, containing 22 transfer ribonucleic acids (tRNAs), 2 ribosomal RNAs (rRNAs, rrnL and rrnS), and a noncoding control section (D-loop) 13777 to 13854 bp in length. The 12 PCG areas have 3269 codons and a total length of 10053 bp, which makes up 71.38% of the mitochondrial genome's overall sequence. Most (10/12) of the PCGs that code for proteins begin with ATG, while the nad4L and nad1 genes have a GTG start codon. Phylogenetic analysis using the concatenated nucleotide sequences of 12 PCGs, and the ML tree analysis results showed that M. polonicum is more closely related to with Echinostomatidae and Fasciolidae, which indicates that the family Cyclocoelidae is more closely associated with Echinochasmidae. This study provides mtDNA information, and analysis of mitogenomic structure and evolution. Moreover, we aimed to understand the phylogenetic relationships of this fluke.

Complete mitogenomes characterization and phylogenetic analyses of Ceratophyllus anisus and Leptopsylla segnis.

Fleas are one of the most common ectoparasites in warm-blooded mammals and an important vector of zoonotic diseases with serious medical implications. We sequenced the complete mitochondrial genomes of Ceratophyllus anisus and Leptopsylla segnis for the first time using high-throughput sequencing and constructed phylogenetic relationships. We obtained double-stranded circular molecules of lengths 15,875 and 15,785 bp, respectively, consisting of 13 protein-coding genes, 22 transfer RNAs, 2 ribosomal RNAs, and two control regions. AT-skew was negative in both C. anisus (-0.022) and L. segnis (-0.231), while GC-skew was positive in both (0.024/0.248), which produced significant differences in codon usage and amino acid composition. Thirteen PCGs encoding 3,617 and 3,711 codons, respectively, isoleucine and phenylalanine were used most frequently. The tRNA genes all form a typical secondary structure. Construction of phylogenetic trees based on Bayesian inference (BI) and maximum likelihood (ML) methods for PCGs. The results of this study provide new information for the mitochondrial genome database of fleas and support further taxonomic studies and population genetics of fleas.

Feasibility of [18F]FSPG PET for Early Response Assessment to Combined Blockade of EGFR and Glutamine Metabolism in Wild-Type KRAS Colorectal Cancer.

Early response assessment is critical for personalizing cancer therapy. Emerging therapeutic regimens with encouraging results in the wild-type (WT) KRAS colorectal cancer (CRC) setting include inhibitors of epidermal growth factor receptor (EGFR) and glutaminolysis. Towards predicting clinical outcome, this preclinical study evaluated non-invasive positron emission tomography (PET) with (4S)-4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG) in treatment-sensitive and treatment-resistant WT KRAS CRC patient-derived xenografts (PDXs). Tumor-bearing mice were imaged with [18F]FSPG PET before and one week following the initiation of treatment with either EGFR-targeted monoclonal antibody (mAb) therapy, glutaminase inhibitor therapy, or the combination. Imaging was correlated with tumor volume and histology. In PDX that responded to therapy, [18F]FSPG PET was significantly decreased from baseline at 1-week post-therapy, prior to changes in tumor volume. In contrast, [18F]FSPG PET was not decreased in non-responding PDX. These data suggest that [18F]FSPG PET may serve as an early metric of response to EGFR and glutaminase inhibition in the WT KRAS CRC setting.

Evaluating health-related quality of life and subjective wellbeing among infertility patients: a cross-sectional study in mainland China.

PURPOSE: This study aimed to explore the health-related quality of life (HRQoL) and subjective wellbeing (SWB) of infertility patients in mainland China and to investigate the relationships between HRQoL and SWB instruments in infertility patients. METHODS: We conducted this cross-sectional study in the Hospital for Reproductive Medicine Affiliated of Shandong University between April 2019 and November 2019. Participants self-completed the five-level EQ-5D (EQ-5D-5L) questionnaire, the Assessment of Quality of Life (AQoL)-8D, and the WHO-5 wellbeing index (WHO-5). The agreements between EQ-5D-5L and AQoL-8D were assessed employing intraclass correlation coefficient (ICC) and Bland-Altman plots. Exploratory factor analysis (EFA) was conducted to examine the difference in descriptive systems among the three instruments. RESULTS: We analyzed a valid sample of 618 infertility patients (84.4%). The mean scores of the total EQ-5D-5L, AQoL-8D, and WHO-5 were 0.96 (95%CI 0.96, 0.96), 0.80 (95%CI 0.79, 0.81), and 16.92 (95%CI 16.52, 17.31), respectively. Patients diagnosed with primary infertility had significantly lower HRQoL and SWB than those with secondary infertility. The ICC of EQ-5D-5L and AQoL-8D was 0.14. The AQoL-8D (r = 0.625) was more strongly correlated with WHO-5 than with the EQ-5D-5L (r = 0.262). The EFA results indicated that HRQoL instruments and the WHO-5 instruments were complementary rather than substitutable. CONCLUSIONS: Poorer HRQoL and SWB were found that primary than secondary infertility patients. There exists a poor agreement between EQ-5D-5L and AQoL-8D and the difference in the psychosocial components may explain the difference. Measuring both HRQoL and SWB could provide complementary information for infertility patients.

Emergency medical service utilization among acute ischemic stroke patients in Beijing: An observational study.

Objective: To investigate emergency medical service (EMS) utilization and its associated factors in patients with acute ischemic stroke (AIS), and further explore the urban-rural differences. Methods: Medical records for AIS in all emergency departments in Beijing were obtained from the Beijing Emergency Care Database from January 2018 to December 2021. EMS utilization was described and factors associated with EMS use were examined by multivariable logistic regression models with the generalized estimating equations. Results were compared between urban and rural districts. Results: A total of 24,296 AIS patients were included in the analysis, and 11,190 (46.1%) were transported to hospitals by EMS. The percentage of EMS usage in urban areas was significantly higher than that in rural areas (53.6 vs. 34.4%, P < 0.001). From 2018 to 2021, EMS utilization was on the increase (P-value for trend <0.001) with a higher average annual growth rate in rural areas (12.6%) than in urban (6.4%). Factors associated with EMS utilization were age (OR: 1.20 per 10-year increase, 95% CI: 1.17-1.23), NIHSS scores, off-hour arrival (OR: 1.32, 95% CI: 1.23-1.37), treatment in tertiary hospitals (OR: 1.75, 95% CI: 1.60-1.92), and possessing comorbidities such as coronary artery disease (OR: 1.15, 95% CI: 1.17-1.24), atrial fibrillation (OR: 1.56, 95% CI: 1.41-1.73), prior stroke (OR: 0.84, 95% CI: 0.78-0.90) or dyslipidemia (OR: 0.78, 95% CI: 0.71-0.85). Conclusion: This study demonstrated an inadequate use of EMS among AIS patients in Beijing, especially in rural areas, and revealed several associated factors. Enhanced education programs and EMS accessibility are necessary particularly for high-risk individuals and regions.

Identification of the Hub Genes and the Signaling Pathways in Human iPSC-Cardiomyocytes Infected by SARS-CoV-2.

Severe Acute Respiratory Syndrome Coronavirus Type 2 (SARS-CoV-2) is an enveloped single-stranded RNA virus that can lead to respiratory symptoms and damage many organs such as heart, kidney, intestine, brain and liver. It has not been clearly documented whether myocardial injury is caused by direct infection of cardiomyocytes, lung injury, or other unknown mechanisms. The gene expression profile of GSE150392 was obtained from the Gene Expression Omnibus (GEO) database. The processing of high-throughput sequencing data and the screening of differentially expressed genes (DEGs) were implemented by R software. The R software was employed to analyze the Gene Ontology (GO) analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The protein-protein interaction (PPI) network of the DEGs was constructed by the STRING website. The Cytoscape software was applied for the visualization of PPI network and the identification of hub genes. The statistical analysis was performed by the GraphPad Prism software to verify the hub genes. A total of 516 up-regulated genes and 191 down-regulated genes were screened out. The top 1 enrichment items of GO in biological process (BP), Cellular Component (CC), and Molecular Function (MF) were type I interferon signaling pathway, sarcomere, and receptor ligand activity, respectively. The top 10 enrichment pathways, including TNF signaling pathway, were identified by KEGG enrichment analysis. A PPI network was established, consisting of 613 nodes and 3,993 edges. The 12 hub genes were confirmed as statistically significant, which was verified by GSE151879 dataset. In conclusion, the hub genes of human iPSC-cardiomyocytes infected with SARS-CoV-2 were identified through bioinformatics analysis, which may be used as biomarkers for further research.

Development and validation of the health-related quality of life instrument for Chinese infertile couples: a mixed-methods study protocol.

BACKGROUND: Infertility and its treatment have negative impacts on a couple's marital relationship, sexual life, psychological state and interpersonal relationships, causing personal distress. Health-related quality of life (HRQoL) has become an important component of health outcomes. HRQoL instruments developed in western culture are not always appropriate for use in China due to cultural differences. Probably due to the unique concept of fertility in China, infertility patients can be looked down upon and the family may  feel shameful. This study aims to develop a HRQoL instrument for infertile couples based on the Chinese social and cultural setting. METHODS: Complementary mixed methods will be used to develop a new HRQoL instrument for Chinese infertile couples. The study consists of four stages: the first stage will involve a systematic review and qualitative interviews to construct draft candidate items. In the second stage, quantitative research [e.g., exploratory factor analysis (EFA), item response theory (IRT)] and cognitive interviews will be used for item selection. The third stage will be instrument validation, in which classical test theory (CTT) and IRT will be applied. In the final stage, the minimal clinically important difference (MCID) will be calculated by using distribution-based methods and anchor-based methods (e.g., logistic regression, receiver operating characteristic curve). DISCUSSION: The new HRQoL instrument for Chinese infertile couples will be developed, which will provide a standard and effective HRQoL instrument in clinical outcome assessment and health outcome measurement.

Diagnostic Accuracy of Xpert Xpress Flu/RSV for the Detection of Influenza and Respiratory Syncytial Viruses.

Xpert Xpress Flu/RSV is a fast and automated real-time nucleic acid amplification tool for detecting influenza virus and respiratory syncytial virus (RSV). The aim of this study was to verify the accuracy of Xpert Xpress Flu/RSV for detecting influenza virus and RSV. PubMed, EMBASE, Cochrane Library, and Web of Science databases were searched up to October 2020. The quality of the original research was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 guidelines. Meta-DiSc 1.4 software was used to analyze the sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and summary receiver operating characteristic curve. Deek's funnel plot asymmetry test was used to evaluate the publication bias using the Stata 12.0 software. Ten studies with 25 fourfold tables were included in the analysis. The sensitivity of Xpert Xpress Flu/RSV for detecting influenza A, influenza B, and RSV were 0.97, 0.98, and 0.96, respectively, and the specificities were 0.97, 1.00, and 1.00, respectively. Compared with other common clinical real-time reverse transcription-polymerase chain reaction (RT-PCR), Xpert Xpress Flu/RSV is a valuable tool for diagnosing influenza virus and RSV with high sensitivity and specificity.

The altered immunological status of children conceived by assisted reproductive technology.

BACKGROUND: With the increased use of assisted reproductive technology (ART), assessing the potential health risks of children conceived on ART important to public health. Most research in this area has focused on the effects of ART on perinatal, metabolic, and oncological risks in children. Although an increased risk of immune-related diseases has been reported in children born after ART, there are no studies on the immunological status of these children. This study aimed to evaluate the impact of different embryo transfer methods and fertilization strategies on the immune status of the offspring. METHODS: A total of 69 children born to women treated with ART and a matched control group of 17 naturally conceived (NC) children, all aged from 3 to 6 years, were recruited in the reproductive hospital affiliated to Shandong University. The frequency of immune cells in the peripheral blood was assayed using flow cytometry; plasma cytokine levels were determined by multiplex cytokine immunoassay with human cytokine magnetic beads. RESULTS: Compared to children born after natural conception, children born after ART had elevated interferon-γ (IFN-γ) levels, regardless of embryo transfer and fertilization strategies. Children in the fresh-embryo transfer group had significantly higher IL-4 levels and a lower ratio of IFN-γ to IL-4 than those in the NC group ((P = 0.004, 10.41 ± 5.76 pg/mL vs 18.40 ± 7.01 pg/mL, P = 0.023, 1.00 ± 0.48 vs 0.67 ± 0.32, respectively). Similar results were shown in either the in vitro fertilization (IVF) group or the intra-cytoplasmic sperm injection (ICSI) group (P < 0.05 and P = 0.08 for IVF; P < 0.05 and P < 0.05 for ICSI, respectively). These alterations in IL-4 concentrations and the ratio of IFN-γ to IL-4 were statistically significantly correlated with supra-physical E2 (estradiol) levels on the day of hCG administration (R = 0.502, P = 0.017; R = - 0.537, P = 0.010, respectively). Consistently, the frozen embryo transfer did not result in alterations of these immune indicators in the offspring. Overall, there were no significant differences between the ART group and NC group in the frequencies of T cells, B cells, natural killer (NK) cells, CD4+T cells, CD8+T cells, T helper (TH)1 cells, TH17 cells, and regulatory T (Treg) cells and cytokine levels of IL-10 and IL-17a (all P > 0.05). CONCLUSIONS: Immunological alterations existed in children born after the use of ART. The elevated E2 levels before embryo implantation contributed to the increased IL-4 levels in children conceived by fresh embryo transfer. The assessment of immunological alteration is of importance to children conceived by ART for early monitoring and intervention.

Identification of potential biomarkers in dengue via integrated bioinformatic analysis.

Dengue fever virus (DENV) is a global health threat that is becoming increasingly critical. However, the pathogenesis of dengue has not yet been fully elucidated. In this study, we employed bioinformatics analysis to identify potential biomarkers related to dengue fever and clarify their underlying mechanisms. The results showed that there were 668, 1901, and 8283 differentially expressed genes between the dengue-infected samples and normal samples in the GSE28405, GSE38246, and GSE51808 datasets, respectively. Through overlapping, a total of 69 differentially expressed genes (DEGs) were identified, of which 51 were upregulated and 18 were downregulated. We identified twelve hub genes, including MX1, IFI44L, IFI44, IFI27, ISG15, STAT1, IFI35, OAS3, OAS2, OAS1, IFI6, and USP18. Except for IFI44 and STAT1, the others were statistically significant after validation. We predicted the related microRNAs (miRNAs) of these 12 target genes through the database miRTarBase, and finally obtained one important miRNA: has-mir-146a-5p. In addition, gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were carried out, and a protein-protein interaction (PPI) network was constructed to gain insight into the actions of DEGs. In conclusion, our study displayed the effectiveness of bioinformatics analysis methods in screening potential pathogenic genes in dengue fever and their underlying mechanisms. Further, we successfully predicted IFI44L and IFI6, as potential biomarkers with DENV infection, providing promising targets for the treatment of dengue fever to a certain extent.

Comparison of the triglyceride glucose index and blood leukocyte indices as predictors of metabolic syndrome in healthy Chinese population.

Triglyceride glucose (TyG) index and inflammatory markers are reported to have a positive association with metabolic syndrome (MetS). However, no previous study has assessed the value of TyG index and inflammatory markers as predictors of metabolic syndrome in the same study. This study looks at the comparison of the triglyceride index and blood leukocyte indices as predictors of metabolic syndrome in the Chinese population. The study cohort involved 1542 Chinese population without metabolic syndrome. The subjects underwent comprehensive routine health examination in 2011 and returned for a follow-up examination in 2016. Metabolic syndrome was defined according to Chinese Diabetes Society criteria, using body mass index for the replacement of waist circumference. TyG index, total leukocytes, neutrophils, lymphocytes, and neutrophil-to-lymphocyte ratio (NLR) were measured. Adjust d logistic models were used to assess the relationship between TyG index, blood leukocyte indices, and incident MetS. Receiver operating characteristic (ROC) curves were performed to determine the predictive value of TyG index and blood leukocyte indices for MetS. Results from multivariate logistic regression analysis showed that, in the adjusted model, the subjects with the highest quartile of TyG index and neutrophils had a 3.894- and 1.663-fold increased incidence of MetS (P < 0.0001 and P = 0.027), respectively. No significant association was observed between total leukocytes, lymphocytes, NLR with incident MetS. ROC analysis showed that the AUC of TyG index and neutrophils were 0.674 and 0.568 for incident MetS, respectively. TyG index rather than blood leukocyte indices may have the strongest predictive value in MetS development over a 5-year period.

Evaluation of lateral flow immunochromatographic assay for diagnostic accuracy of cryptococcosis.

BACKGROUND: Cryptococcus is a conditional pathogenic fungus causing cryptococcosis, which is one of the most serious fungal diseases faced by humans. Lateral flow immunochromatographic assay (LFA) is successfully applied to the rapid detection of cryptococcal antigens. METHODS: Studies were retrieved systematically from the Embase, PubMed, Web of Science, and Cochrane Library before July 2019. The quality of the studies was assessed by Review Manager 5.0 based on the Quality Assessment of Diagnostic Accuracy Study guidelines. The extracted data from the included studies were analyzed by Meta-DiSc 1.4. Stata 12.0 software was used to detect the publication bias. RESULTS: A total of 15 articles with 31 fourfold tables were adopted by inclusion and exclusion criteria. The merged sensitivity and specificity in serum were 0.98 and 0.98, respectively, and those in the cerebrospinal fluid were 0.99 and 0.99, respectively. CONCLUSIONS: Compared to the urine and other samples, LFA in serum and cerebrospinal fluid is favorable evidence for the diagnosis of cryptococcosis with high specificity and sensitivity.

Combined blockade of EGFR and glutamine metabolism in preclinical models of colorectal cancer.

Improving response to epidermal growth factor receptor (EGFR)-targeted therapies in patients with advanced wild-type (WT) RAS colorectal cancer (CRC) remains an unmet need. In this preclinical work, we evaluated a new therapeutic combination aimed at enhancing efficacy by targeting cancer cell metabolism in concert with EGFR. We hypothesized that combined blockade of glutamine metabolism and EGFR represents a promising treatment approach by targeting both the "fuel" and "signaling" components that these tumors need to survive. To explore this hypothesis, we combined CB-839, an inhibitor of glutaminase 1 (GLS1), the mitochondrial enzyme responsible for catalyzing conversion of glutamine to glutamate, with cetuximab, an EGFR-targeted monoclonal antibody in preclinical models of CRC. 2D and 3D in vitro assays were executed following treatment with either single agent or combination therapy. The combination of cetuximab with CB-839 resulted in reduced cell viability and demonstrated synergism in several cell lines. In vivo efficacy experiments were performed in cell-line xenograft models propagated in athymic nude mice. Tumor volumes were measured followed by immunohistochemical (IHC) analysis of proliferation (Ki67), mechanistic target of rapamycin (mTOR) signaling (pS6), and multiple mechanisms of cell death to annotate molecular determinants of response. In vivo, a significant reduction in tumor growth and reduced Ki67 and pS6 IHC staining were observed with combination therapy, which was accompanied by increased apoptosis and/or necrosis. The combination showed efficacy in cetuximab-sensitive as well as resistant models. In conclusion, this therapeutic combination represents a promising new precision medicine approach for patients with refractory metastatic WT RAS CRC.

Betulin alleviates on myocardial inflammation in diabetes mice via regulating Siti1/NLRP3/NF-κB pathway.

The aim of this study is to study the effect of betulin (BE) on myocardial injury in diabetic mice. Insulin-related indexes and inflammation-related cytokines are detected by commercial kits. The mechanism of BE on diabetic myocardial injury was studied by modern molecular biology techniques. BE significantly improved glocose tolerance, reduced lipid accumulation and reduced the content of inflammatory cytokines in diabetic mice. Furthermore, BE regulated Siti1/NLRP3/NF-κB signaling pathway in db/db mice and H9C2 cells. Siti1 inhibitor (EX-57) counteracted those changes. BE significantly protected against diabetic cardiomyopathy, which was related to the regulation of Siti1/NLRP3/NF-κB pathway.

Artificial intelligence-based multi-objective optimization protocol for protein structure refinement.

MOTIVATION: Protein structure refinement is an important step of protein structure prediction. Existing approaches have generally used a single scoring function combined with Monte Carlo method or Molecular Dynamics algorithm. The one-dimension optimization of a single energy function may take the structure too far away without a constraint. The basic motivation of our study is to reduce the bias problem caused by minimizing only a single energy function due to the very diversity of different protein structures. RESULTS: We report a new Artificial Intelligence-based protein structure Refinement method called AIR. Its fundamental idea is to use multiple energy functions as multi-objectives in an effort to correct the potential inaccuracy from a single function. A multi-objective particle swarm optimization algorithm-based structure refinement is designed, where each structure is considered as a particle in the protocol. With the refinement iterations, the particles move around. The quality of particles in each iteration is evaluated by three energy functions, and the non-dominated particles are put into a set called Pareto set. After enough iteration times, particles from the Pareto set are screened and part of the top solutions are outputted as the final refined structures. The multi-objective energy function optimization strategy designed in the AIR protocol provides a different constraint view of the structure, by extending the one-dimension optimization to a new three-dimension space optimization driven by the multi-objective particle swarm optimization engine. Experimental results on CASP11, CASP12 refinement targets and blind tests in CASP 13 turn to be promising. AVAILABILITY AND IMPLEMENTATION: The AIR is available online at: www.csbio.sjtu.edu.cn/bioinf/AIR/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.