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There is a desperate need for effective therapies to fight chronic viral infections. The immune response is normally fastidious at controlling the majority of viral infections and a therapeutic strategy aimed at reestablishing immune control represents a potentially powerful approach towards treating persistent viral infections. We examined the potential of genetically programming human hematopoietic stem cells to generate mature CD8+ cytotoxic T lymphocytes that express a molecularly cloned, "transgenic" human anti-HIV T cell receptor (TCR). Anti-HIV TCR transduction of human hematopoietic stem cells directed the maturation of a large population of polyfunctional, HIV-specific CD8+ cells capable of recognizing and killing viral antigen-presenting cells. Thus, through this proof-of-concept we propose that genetic engineering of human hematopoietic stem cells will allow the tailoring of effector T cell responses to fight HIV infection or other diseases that are characterized by the loss of immune control.

Reinforcing weak cyberspace assets is an urgent requirement to defend national cybersecurity. Cyberspace key terrain (CKT) is a theory recently proposed for sensing cyberspace posture. Identifying CKT in the asset layer is essential for supporting cyberspace defense decisions. Existing methods ignore the influence of the multi-attribute correlation of cyberspace nodes and cyber attack mission (CAM) diversity, which restricts the recognition accuracy of CKT. To improve the accuracy of CKT identification and explore the relationship between CKT and CAM, we propose an improved cosine similarity technique for order of preference by similarity to the ideal solution (CosS-TOPSIS) method to model CKT and construct a CAM based on the MITRE adversarial tactics, techniques, and common knowledge (ATT&CK) framework to examine the influence of different weighted CAM on modeling CKT. Based on the vulnerability value calculation method of the cyber system in the common vulnerability scoring system version 3.1 (CVSS 3.1), we evaluated the effectiveness of CosS-TOPSIS in identifying CKT using three metrics: correlation coefficient, root mean square error, and mean absolute error. Our experiments showed that, in comparison with the TOPSIS method, the accuracy of the proposed method for identifying CKT improved by 8.9%, and the root mean square error reduced by 16%; simultaneously, CAM was proven to be an essential factor in identifying CKT. The feasibility and reliability of CosS-TOPSIS in identifying CKT and the close relationship between CAM and CKT identification were demonstrated experimentally. In our work, we utilized cosine similarity and FAHP to improve the baseline method. We also introduced three indicators to evaluate the method's reliability. Drawing from ATT&CK, we recommend CAM as a tool for sensing changes in the cyberspace environment and explore its relationship with CKT. Our work has great application potential for identifying cyberspace vulnerabilities, supporting cyberspace defense, and securing national cyberspace facilities. [ABSTRACT FROM AUTHOR]

Although traditional mutation is still an attractive approach for strain improvement, it is tedious, time-consuming, and inefficient to screen for surfactin producing strains. To overcome this, we developed a high-throughput screening method for surfactin producing mutants by applying polydiacetylene (PDA) vesicles as sensors with visible chromatic change from blue to red, detected as colorimetric response (CR%) signal, which can even semi-quantify the yields of surfactin. Bacillus subtilis 723 was used as parent strain and multiply mutated with atmospheric and room temperature plasma (ARTP). Mutants were cultured in MicroFlask by Duetz (24 square deepwell plates, Applikon Biotechnology) and surfactin titers were tested in 96-well plates with PDA vesicles. Mutants with surfactin titers above150 mg/L (CR% value above 26%) were selected as high-yield strains and further quantified by HPLC. By integrating MicroFlask cultivation and the PDA vesicles detection, we screened 27,000 mutants and found 37 high-yield strains. From these, one mutant produced 473.6 mg/L surfactin (including 353.1 mg/L C15 surfactin), which was 5.4-fold than that of the parent strain. This method is efficient, cost-effective and provides wider application in screening for various surfactants. [ABSTRACT FROM AUTHOR]

Although traditional mutation is still an attractive approach for strain improvement, it is tedious, time-consuming, and inefficient to screen for surfactin producing strains. To overcome this, we developed a high-throughput screening method for surfactin producing mutants by applying polydiacetylene (PDA) vesicles as sensors with visible chromatic change from blue to red, detected as colorimetric response (CR%) signal, which can even semi-quantify the yields of surfactin. Bacillus subtilis 723 was used as parent strain and multiply mutated with atmospheric and room temperature plasma (ARTP). Mutants were cultured in MicroFlask by Duetz (24 square deepwell plates, Applikon Biotechnology) and surfactin titers were tested in 96-well plates with PDA vesicles. Mutants with surfactin titers above150 mg/L (CR% value above 26%) were selected as high-yield strains and further quantified by HPLC. By integrating MicroFlask cultivation and the PDA vesicles detection, we screened 27,000 mutants and found 37 high-yield strains. From these, one mutant produced 473.6 mg/L surfactin (including 353.1 mg/L C15 surfactin), which was 5.4-fold than that of the parent strain. This method is efficient, cost-effective and provides wider application in screening for various surfactants. [ABSTRACT FROM AUTHOR]

The identification of interactions between drugs and target proteins plays a key role in genomic drug discovery. In the present study, the quantitative binding affinities of drug-target pairs are differentiated as a measurement to define whether a drug interacts with a protein or not, and then a chemogenomics framework using an unbiased set of general integrated features and random forest (RF) is employed to construct a predictive model which can accurately classify drug-target pairs. The predictability of the model is further investigated and validated by several independent validation sets. The built model is used to predict drug-target associations, some of which were confirmed by comparing experimental data from public biological resources. A drug-target interaction network with high confidence drug-target pairs was also reconstructed. This network provides further insight for the action of drugs and targets. Finally, a web-based server called PreDPI-Ki was developed to predict drug-target interactions for drug discovery. In addition to providing a high-confidence list of drug-target associations for subsequent experimental investigation guidance, these results also contribute to the understanding of drug-target interactions. We can also see that quantitative information of drug-target associations could greatly promote the development of more accurate models. The PreDPI-Ki server is freely available via: http://sdd.whu.edu.cn/dpiki. [ABSTRACT FROM AUTHOR]

Background: The potential prognostic value of human equilibrative nucleoside transporter1 in pancreatic cancer receiving gemcitabine-based chemotherapy is variably reported., Objective: The objective of this study was to conduct a systematic review of literature evaluating human equilibrative nucleoside transporter1 expression as a prognostic factor in pancreatic cancer receiving gemcitabine-based chemotherapy and to conduct a subsequent meta-analysis to quantify the overall prognostic effect., Methods: Related studies were identified and evaluated for quality through multiple search strategies. Only studies analyzing pancreatic cancer receiving gemcitabine-based chemotherapy were eligible for inclusion. Data were collected from studies comparing overall, disease-free and progression-free survival (OS, DFS and PFS) in patients with low human equilibrative nucleoside transporter1 levels and those having high levels. The hazard ratio (HR) and its 95% confidence interval (95%CI) were used to assess the strength of associations. Hazard ratios greater than 1 reflect adverse survival associated with low human equilibrative nucleoside transporter1 levels., Results: A total of 12 studies (n = 875) were involved in this meta-analysis (12 for OS, 5 for DFS, 3 for PFS). For overall and disease-free survival, the pooled HRs of human equilibrative nucleoside transporter1 were significant at 2.93 (95% confidence interval [95% CI], 2.37-3.64) and 2.67 (95% CI, 1.87-3.81), respectively. For progression-free survival, the pooled HR in higher human equilibrative nucleoside transporter1 expression in pancreatic cancer receiving gemcitabine-based chemotherapy was 2.76 (95% CI, 1.76-4.34). No evidence of significant heterogeneity or publication bias was seen in any of these studies., Conclusion: These results support the case for a low human equilibrative nucleoside transporter1 level representing a significant and reproducible marker of adverse prognosis in pancreatic cancer receiving gemcitabine-based chemotherapy.

Pollen development is disturbed in the early tetrad stage of the YX-1 male sterile mutant of wolfberry (Lycium barbarum L.). The present study aimed to identify differentially expressed anther proteins and to reveal their possible roles in pollen development and male sterility. To address this question, the proteomes of the wild-type (WT) and YX-1 mutant were compared. Approximately 1760 protein spots on two-dimensional differential gel electrophoresis (2D-DIGE) gels were detected. A number of proteins whose accumulation levels were altered in YX-1 compared with WT were identified by mass spectrometry and the NCBInr and Viridiplantae EST databases. Proteins down-regulated in YX-1 anthers include ascorbate peroxidase (APX), putative glutamine synthetase (GS), ATP synthase subunits, chalcone synthase (CHS), CHS-like, putative callose synthase catalytic subunit, cysteine protease, 5B protein, enoyl-ACP reductase, 14-3-3 protein and basic transcription factor 3 (BTF3). Meanwhile, activities of APX and GS, RNA expression levels of apx and atp synthase beta subunit were low in YX-1 anthers which correlated with the expression of male sterility. In addition, several carbohydrate metabolism-related and photosynthesis-related enzymes were also present at lower levels in the mutant anthers. In contrast, 26S proteasome regulatory subunits, cysteine protease inhibitor, putative S-phase Kinase association Protein 1(SKP1), and aspartic protease, were expressed at higher levels in YX-1 anthers relative to WT anthers. Regulation of wolfberry pollen development involves a complex network of differentially expressed genes. The present study lays the foundation for future investigations of gene function linked with wolfberry pollen development and male sterility.