Identification of novel drug targets is a critical step in drug development. Many recent studies have produced multiple types of data, which provides an opportunity to mine the relationships among ...them to predict drug targets. In this study, we present a novel integrative approach that combines ontology reasoning with network-assisted gene ranking to predict new drug targets. We utilized colorectal cancer (CRC) as a proof-of-concept use case to illustrate the approach. Starting from FDA-approved CRC drugs and the relationships among disease, drug, gene, pathway, and SNP in an ontology representing PharmGKB data, we inferred 113 potential CRC drug targets. We further prioritized these genes based on their relationships with CRC disease genes in the context of human protein-protein interaction networks. Thus, among the 113 potential drug targets, 15 were selected as the promising drug targets, including some genes that are supported by previous studies. Among them, EGFR, TOP1 and VEGFA are known targets of FDA-approved drugs. Additionally, CCND1 (cyclin D1), and PTGS2 (prostaglandin-endoperoxide synthase 2) have reported to be relevant to CRC or as potential drug targets based on the literature search. These results indicate that our approach is promising for drug target prediction for CRC treatment, which might be useful for other cancer therapeutics.
Psychiatric disorders are highly heterogeneous syndromes often explained by underlying and internalized personality disorder(PD) traits that are affected by externalized childhood trauma ...experiences(CTE). The present study investigated the differential subtype model by examining the association between PD traits and CTE in a clinical sample with transdiagnostic psychopathology. Outpatients(n = 2090) presenting for psychiatric treatment completed self-reported measures of PD traits(Personality Diagnostic Questionnaire) and the childhood adversity(Child Trauma Questionnaire). Canonical variates were generated by canonical correlation analysis(CCA) and then used for hierarchical cluster analysis to produce subtypes. A support vector machine(SVM) model was used and validated using a linear kernel to assess the utility of the extracted subtypes of outpatients in clinical diagnosis classifications. The CCA determined two linear combinations: emotional abuse related dissociality PD traits(antisocial and paranoid PD) and emotional neglect related sociality PD traits(schizoid, passive-aggressive, depressive, histrionic, and avoidant PD). A cluster analysis revealed three subtypes defined by distinct and relatively homogeneous patterns along two dimensions, and comprising 17.5%(cluster-1, n = 365), 34.8%(cluster-2, n = 727), and 47.8%(cluster-3, n = 998) of the sample, each with distinctive features of PD traits and CTE. These subtypes suggest more distinct PD trait correlates of CTE manifestations than were captured by clinical phenomenological diagnostic definitions. Our results highlight important subtypes of psychiatric patients that highlight PD traits and CTE that transcend current diagnostic boundaries. The three different subtypes reflect significant differences in PD and CTE characteristics and lend support to efforts to develop PD and childhood trauma targeted psychotherapy that extends to clinical diagnosis-based interventions.
The implementation of perfect absorption of optical waves in artificial nanostructures has attracted tremendous attention among the scientific community. Traditional approaches based on metamaterials ...can only absorb optical waves in one direction while reflecting optical waves in the other direction. Here, a polarization‐insensitive bidirectional perfect absorber that is composed of bilayer gold nano disks embedded into a silicon nitride substrate is demonstrated. The bidirectional perfect absorption in the proposed bilayer metasurface, which is irrelevant to the coherent of optical waves, is attributed to the multiple reflections and interference of optical waves in the bilayer structures. The proposed perfect absorber shall boost its applications in optical anti‐counterfeiting, integrated photodetectors, and solar thermal applications.
A bilayer plasmonic metasurface is utilized to realize polarization‐insensitive bidirectional perfect absorption of optical waves. With the advantages of having a polarization‐insensitive and bidirectional optical response, being alignment‐free, and irrelevant to the coherence of optical waves, the proposed bilayer metasurface shall boost its applications in optical anti‐counterfeiting, integrated photodetectors and solar thermal applications.
To investigate the chemical characters of water-extract of Baqi Lingmao formula (BQLM formula) and its effects on anti-liver injury in model mice and live cells.
BQLM formula was composed of ten ...herbal medicines. We determined the contents of alkaloids, saponins, phenolic acids and flavonoid in BQLM formula by UV spectrophotometry. The active components of alkaloids and phenolic acids in BQLM formula were identified by HPLC chromatography. The anti-hepatic injury effects of BQLM formula were investigated with concanavalin A (ConA)-induced hepatitis model of mice, human liver LO2 and HepG2.2.15 cells.
BQLM formula (2 and 10 g/kg, orally) significantly improved the damages of liver tissues and functions caused by ConA in mice, reduced the infiltration of inflammatory cells into liver and inhibited the inflammatory cytokine secretion of interferon-γ, tumor necrosis factor-α and interleukin-6. BQLM formula simultaneously decreased the levels of alanine aminotransferase and aspartate aminotransferase of liver and serum, and recovered the superoxide dismutase and catalase activities of liver to normal levels in ConA-induced hepatic-injury mice. The serum of BQLM formula group stimulated the human liver LO2 cell proliferation in vitro. Further, BQLM formula obviously promoted the proliferation of normal hepatocytes (LO2 cells) and inhibited the hepatocytes death induced by ConA. It also significantly inhibited the proliferation of HepG2.2.15 cells and decreased the secretion of HBsAg and HBeAg in vitro.
BQLM formula has anti-inflammation and anti-hepatitis virus Beffects, and is capable of improving liver injury in vivo and in vitro.
Immunotherapy has been used to improve patient immune function, inhibit tumor growth and has become a highly promising method of cancer treatment. Highly agglutinative staphylococcin (HAS), a mixture ...of Staphylococcus aureus culture filtrates, which include staphylococcal enterotoxin (SE) C as the active ingredient, has been used clinically as an immunomodifier in the treatment of a number of tumors for many years. However, the use of HAS has been associated with some unavoidable side-effects such as fever. Previous studies have shown that SEB stimulates a more potent activation of T lymphocytes than SEC3, and mutations of the histidine residues eliminated the toxicity of SEB. SE mutants with decreased side-effects and/or more potent antitumor activities are required.
We built a structural model of the MHC II-SEB-TCR complex and found that a mutation of SEB at Lys173 might decrease the repulsion force between the SEB-TCR, which would facilitate their interaction. From the above results, we designed SEB-H32Q/K173E (mSEB). Analysis of in vitro stimulation of the proliferation of human peripheral blood mononuclear cells (PBMCs), IFN-γ secretion and inhibition of the growth of various tumor cell lines demonstrated that mSEB exhibited higher antitumor activity compared with wild-type SEB (wtSEB). Notably, mSEB inhibited the growth of various tumors at an extremely low concentration with little cytotoxicity against normal cells. Three animal tumor models (C57BL/6 mouse, New Zealand rabbit and a humanized NOD/SCID mouse) were used to evaluate the in vivo immunotherapeutic effects. Compared with wtSEB, mSEB significantly enhanced antitumor effect in more than one animal model with reduced pyrexia toxicity and prolonged the survival of tumor-bearing mice.
Our results suggest that SEB-H32Q/K173E retains superantigen (SAg) characteristics and enhances the host immune response to neoplastic diseases while reducing associated pyrogenic toxicity.
Two-stage screening, involving a self-rating report, followed by a structured interview, has been proposed for identifying clinical high risk of psychosis (CHR) for nearly two decades. This study ...used PRIME Screen-Revised (PS-R) and Structured Interview for Prodromal Syndromes (SIPS) to investigate the predictive validity of the two-stage screening. Of 566 participants who completed two-stage screening in this study, 192 were PS-R(−) and 374 were PS-R(+). After being interviewed with SIPS, 112 were rated as CHR(+), 109 were diagnosed with psychosis, and the other 345 individuals were CHR(−). Those who were rated through SIPS as CHR(+) and CHR(−) were followed up within 2 years to observe their clinical outcome. Ninety one (81.3%) CHR(+) and 171 (49.6%) CHR(−) individuals completed the investigation at baseline and the two-year follow-up. The cumulative conversion rate to psychosis was 27.5% in CHR(+) group, but only 1.7% in CHR(−) group, with a significant difference between the two groups (log-rank test, χ2 = 30.07, p < 0.001). In terms of two-stage screening, PS-R(−)/CHR(−), PS-R(−)/CHR(+), and PS-R(+)/CHR(−) groups were viewed as expected negative (EN), and the PS-R(+)/CHR(+) group as expected positive (EP), and the sensitivity and specificity was 64.3% and 79.1%, respectively. Furthermore, Kaplan-Meyer survival analysis showed that EP group were more likely to convert to psychosis than EN group (log-rank test, χ2 = 16.702, p < 0.001). Two-stage screening indeed saves much time and alleviates the workload, but may exclude some target individuals. Optimizing self-report scale, and forming a nurse-doctor-interviewer coalition are likely to improve the use of self-rating report and structured interview.
Histone ubiquitylation is emerging as an important protective component in cellular responses to DNA damage. The ubiquitin ligases RNF8 and RNF168 assemble ubiquitin chains onto histone molecules ...surrounding DNA breaks and facilitate retention of DNA repair proteins. Although RNF8 and RNF168 play important roles in repair of DNA double strand breaks, their requirement for cell protection from replication stress is largely unknown. In this study, we uncovered RNF168-independent roles of RNF8 in repair of replication inhibition-induced DNA damage. We showed that RNF8 depletion, but not RNF168 depletion, hyper-sensitized cells to hydroxyurea and aphidicolin treatment. Consistently, hydroxyurea induced persistent single strand DNA lesions and sustained CHK1 activation in RNF8-depleted cells. In line with strict requirement for RAD51-dependent repair of hydroxyurea-stalled replication forks, RNF8 depletion compromised RAD51 accumulation onto single strand DNA lesions, suggesting that impaired replication fork repair may underlie the enhanced cellular sensitivity to replication arrest observed in RNF8-depleted cells. In total, our study highlights the differential requirement for the ubiquitin ligase RNF8 in facilitating repair of replication stress-associated DNA damage.
The dynamic stability of E-mode active-passivation p-GaN gate HEMT (AP- HEMT) is investigated, including dynamic V_{\text{th}} shift, dynamic R_{\text{ON}} degradation, and dynamic leakage current. ...The AP-HEMT features an ohmic-type gate/p-GaN contact that results in a stable dynamic V_{\text{th}} , as the charge storage effect associated with the floating p-GaN layer is avoided. At a 650- V V_{\text{DS}} stress, the AP- HEMT exhibits a low dynamic R_{\text{ON}} /static R_{\text{ON}} ratio of 1.4, which can be attributed to the presence of the p-GaN active-passivation layer that screens the influence of surface traps. The hole injection in the p-GaN gate HEMT is expected to increase the dynamic OFF-state leakage current, as the holes reduce the energy barrier of the buffer layer. Despite a larger injector area, the AP-HEMT exhibits a lower dynamic leakage current increase, which is due to the relocation of the electric field peak from the gate edge towards the drain. This relocation suppresses the lowering of the energy barrier under the gate. Overall, the unique device structure of the AP-HEMT leads to a negligible dynamic V_{\text{th}} shift, a low dynamic R_{\text{ON}} , and a small OFF-state dynamic leakage increase.
The handling stability and control requirements of electric forklift are analyzed. Forklift model with linear two degree of freedom (2DOF) is presented, which provides a verification model for ...variable transmission ratio (VTR) design. The concept of the ideal transmission ratio is described, the VTR control method based on yaw rate gain constant and lateral acceleration gain constant is studied, a new VTR control method based on two kinds of gain constant combination is put forward, and the simulation comparison is made for three kinds of static VTR control methods. A dynamic VTR control method based on fuzzy neural network (FNN) is designed for complex working conditions, simulation results show that the VTR based on FNN has strong resistance to the disturbance of its own parameters. It is only related to the velocity and the hand-wheel angle, and adapts to the complex dynamic conditions, helps to improve the handling stability of forklift. The research shows that the three VTR control methods with fixed gain are derived through mathematical model, which belongs to static control, and the dynamic VTR control method based on FNN has better dynamic adaptability.
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