Electrochemical oxidative thioetherification of aldehyde hydrazones with thiophenols.

An electrochemically promoted oxidative dehydrogenation cross-coupling reaction between aldehyde hydrazones and thiophenols is demonstrated for the first time, which resulted in a variety of (Z)-thioetherified products in moderate to excellent yields. This strategy can be carried out under an air atmosphere, featuring scalability and excellent stereoselectivity. In addition, the transformation efficiently produces readily recyclable disulfide as a by-product with high yields, which significantly reduces the environmental pollution caused by thioetherification.

Targeted regulation of miR-154-5p/Cullin2 pathway by hsa_circ_TRIM22 in promoting human papillomavirus 16 positive cervical cancer progression.

Background. Tripartite motif-containing 22 (TRIM22) is characterized by a canonical RING domain with ubiquitin E3 ligase activity and is closely associated with tumorigenesis. As a product of TRIM22 transcription, whether hsa_circ_TRIM22 has a function of regulating tumorigenesis is unclear. Thus, we aimed to explore the role and mechanism of hsa_circ_TRIM22 in human papillomavirus (HPV) 16 positive cervical cancer (CC). Methods. We collected HPV16-positive cervical tissues including chronic cervicitis, high-grade squamous intraepithelial lesions (HSIL), low-grade squamous intraepithelial lesions (LSIL), and CC, and along with CC cell lines to detect the hsa_circ_TRIM22 level using real-time fluorescence quantitative polymerase chain reaction (RT-qPCR). Hsa_circ_TRIM22 was silenced using specific short hairpin ribonucleic acid (shRNA) in CC cell lines and functional assays were performed thereafter. Mechanistically, the targeting and regulatory relationship between hsa_circ_TRIM22 and miR-154-5p were confirmed using the luciferase report assay and rescue experiments. Results. We found hsa_circ_TRIM22 expression level was significantly higher in CC cells and tissues. Further, hsa_circ_TRIM22 knockdown inhibited migration, proliferation, invasiveness, enhanced apoptosis, and slowed the cell cycle. Mechanistically, hsa_circ_TRIM22 could bind miR-154-5p and prevent miR-154-5p from reducing the levels of Cullin2 (CUL2). Notably, the application of miR-154-5p inhibitor significantly rescued hsa_circ_TRIM22-mediated tumorigenesis. Conclusions. Our observations suggest hsa_circ_TRIM22 is upregulated in HPV16-positive CC and promotes CC progression by regulating the miR-154-5p/CUL2 axis, thereby serving as a promising candidate for diagnosis and treatments of CC.

Application of circulating tumour DNA in terms of prognosis prediction in Chinese follicular lymphoma patients.

Background: Follicular lymphoma (FL), an indolent non-Hodgkin lymphoma (NHL), is generally incurable. Favourable prognosis and durable remission are crucial for FL patients. The genetic mutation spectrum provides novel biomarkers for determining the prognosis of FL patients, but its detection is easily affected by the collection of tumour tissue biopsies. In this study, we aimed to describe the mutational landscape of FL using circulating tumour DNA (ctDNA) samples and to explore the relationship between mutations and prognostic indicators of clinical outcome in patients with newly diagnosed follicular lymphoma and the prognostic value of such mutations. Methods: A total of 28 patients with newly diagnosed FL were included in this study. A targeted NGS-based 59-gene panel was used to assess the ctDNA mutation profiles. Differences in clinical factors between patients carrying mutations and those without mutations were analysed. We also explored the relationship between gene mutation status, mean VAFs (variant allele frequencies) and clinical factors. The Kaplan‒Meier method was applied to analyse the overall survival (OS) and progression-free survival (PFS) of patients carrying mutations and those without mutations. Results: ctDNA mutations were detectable in 21 (75%) patients. The most commonly mutated genes were CREBBP (54%, 15/28), KMT2D (50%, 14/28), STAT6 (29%, 8/28), CARD11 (18%, 5/28), PCLO (14%, 4/28), EP300 (14%, 4/28), BCL2 (11%, 3/28), and TNFAIP3 (11%, 3/28), with a mutation frequency of >10%. Patients with detectable ctDNA mutation tended to present with advanced Ann Arbor stage (III-IV) (p = 0.009), high FLIPI risk (3-5) (p = 0.023) and severe lymph node involvement (No. of involved areas ≥5) (p = 0.02). In addition, we found that the mean VAF was significantly higher in patients with advanced Ann Arbor stage, high-risk FLIPI, elevated lactate dehydrogenase (LDH: 0-248U/L), advanced pathology grade, bone marrow involvement (BMI) and lymph node involvement. Additionally, KMT2D, EP300, and STAT6 mutations were associated with inferior PFS (p < 0.05). Conclusion: We described the ctDNA mutation landscapes in Chinese patients with newly diagnosed FL and found that ctDNA VAF means reflect tumour burden. Moreover, PFS was shorter in patients with KMT2D, EP300 and STAT6 mutations.

Highly selective performance of rationally designed antimicrobial peptides based on ponericin-W1.

Antimicrobial peptides (AMPs) or host-defence peptides act by penetrating and disrupting the bacterial membranes and are therefore less prone to antimicrobial resistance (AMR) compared to conventional antibiotics. However, there are still many challenges in the clinical application of the naturally occurring AMPs which necessitates further studies to establish the relationship between the chemical structure of AMPs and their antimicrobial activity and selectivity. Herein, we report a study on the relationship between the chemical structure and the biological activity of a series of rationally designed AMPs derived from Ponericin-W1, a naturally occurring AMP from ants. The peptides were designed by modification of the hydrophobic and hydrophilic regions of the lead peptide sequence in a systematic way. Their antibacterial and hemolytic activities were determined in vitro. The antibacterial activity of a representative peptide, At5 was also tested in a mouse model of skin wound infection. Furthermore, the relationship between the physicochemical properties of the peptides and their antibacterial activity was investigated. Replacing the cationic amino acids in the hydrophobic region of the peptides with hydrophobic amino acids enhanced their antibacterial activity and increasing the number of cationic amino acids in the hydrophilic region reduced their toxicity to human red blood cells and thus improved their selectivity for bacteria. Four of the designed peptides, coded as At3, At5, At8, and At10, displayed considerable antibacterial activity and high selectivity for bacteria. At5 also accelerated the wound healing in mice indicating high in vivo efficiency of this peptide. The peptides were more effective against Gram-negative bacteria and no AMR was developed against them in the bacteria even after 25 generations. The results from this study can provide a better understanding of the structural features required for strong antibacterial activity and selectivity, and serve as a guide for the future rational design of AMPs.

Gene Mutation and Its Association with Clinicopathological Features in Young Patients with Non-Small-Cell Lung Cancer.

Background: We investigated the correlation between genetic mutations and clinical-pathological features in young patients with NSCLC. Methods: Clinicopathologic information of 102 young NSCLC patients was collected. Direct ctDNA sequencing of a portion of these patients was performed. The correlation between EGFR mutation and ALK fusions with clinicopathologic parameters was analyzed. Results: In young NSCLC patients, adenocarcinoma is the major histology (86.9%), and the misdiagnosis rate was as high as 45.7%. EGFR gene mutation was found in 13 patients (31.7%) and common mutations were with EGFR19del mutation (7 cases, 17.1%) and EGFR21L858R mutation (4 patients, 9.7%). EGFR mutation was constantly found in adenocarcinoma and male gender, and ever smokers (100%, P < 0.05). Furthermore, ALK fusions were found in 7 patients (31.8%), which include EML-4-ALK fusions; there was a trend that ALK fusions were associated with adenocarcinoma and female gender. However, there was no significant difference in overall survival between patients with or without gene mutations. Conclusions: EGFR mutation and ALK fusions are related to histology, gender, and smoke exposure in young NSCLC patients, and may be effective predictive factors.

Silencing LncRNA CASC9 inhibits proliferation and invasion of colorectal cancer cells by MiR-542-3p/ILK.

Colorectal cancer (CRC) ranks the third in cancers and the second in the reasons of cancer-related death. More evidence indicates that long non-coding RNA participates in tumor initiation and progression. It's known that cancer susceptibility candidate 9 is an oncogenic long non-coding RNA in CRC. miR-542-3p is a negative regulator of CRC, while integrin-linked kinase could contribute to tumor progression and chemoresistance. However, the correlation among long non-coding RNA cancer susceptibility candidate 9, miR-542-3p and integrin-linked kinase in CRC is still unclear. We demonstrated long non-coding RNA cancer susceptibility candidate 9 in CRC specimens and cell lines overexpressed via real-time quantitative polymerase chain reaction. Once long non-coding RNA cancer susceptibility candidate 9 was knocked down, it significantly inhibited proliferation, invasion, and migration of CRC cells in real-time quantitative polymerase chain reaction, cell counting kit-8, 5-ethynyl-2'-deoxyuridine, and transwell assays, which also was validated in vivo. Long non-coding RNA cancer susceptibility candidate 9 negatively regulates miR-542-3p in a targeted manner, and the function of up-regulated miR-542-3p was confirmed similarly. While miR-542-3p negatively regulates integrin-linked kinase. Thus, we further verified that overexpression of integrin-linked kinase on down-regulated long non-coding RNA cancer susceptibility candidate 9 or up-regulated miR-542-3p significantly restored CRC cell proliferation via bioinformatic analysis, dual-luciferase report assay, real-time quantitative polymerase chain reaction, RNA immunoprecipitation, and western blot. This study testified that silencing long non-coding RNA cancer susceptibility candidate 9 could inhibit proliferation and invasion of CRC cells by miR-542-3p/integrin-linked kinase.

Molecular dynamic simulation analysis of SARS-CoV-2 spike mutations and evaluation of ACE2 from pets and wild animals for infection risk.

Coronavirus Disease 2019 (COVID-19) is an ongoing global health emergency that has caused tremendous stress and loss of life worldwide. The viral spike glycoprotein is a critical molecule mediating transmission of SARS-CoV-2 by interacting with human ACE2. However, through the course of the pandemics, there has not been a thorough analysis of the spike protein mutations, and on how these mutants influence the transmission of SARS-CoV-2. Besides, cases of SARS-CoV-2 infection among pets and wild animals have been reported, so the susceptibility of these animals requires great attention to investigate, as they may also link to the renewed question of a possible intermediate host for SARS-CoV-2 before it was transmitted to humans. With over 226,000 SARS-CoV-2 sequences obtained, we found 1573 missense mutations in the spike gene, and 226 of them were within the receptor-binding domain (RBD) region that directly interacts with human ACE2. Modeling the interactions between SARS-CoV-2 spike mutants and ACE2 molecules showed that most of the 74 missense mutations in the RBD region of the interaction interface had little impact on spike binding to ACE2, whereas several within the spike RBD increased the binding affinity toward human ACE2 thus making the virus likely more contagious. On the other hand, modeling the interactions between animal ACE2 molecules and SARS-CoV-2 spike revealed that many pets and wild animals' ACE2 had a variable binding ability. Particularly, ACE2 of bamboo rat had stronger binding to SARS-CoV-2 spike protein, whereas that of mole, vole, Mus pahari, palm civet, and pangolin had a weaker binding compared to human ACE2. Our results provide structural insights into the impact on interactions of the SARS-CoV-2 spike mutants to human ACE2, and shed light on SARS-CoV-2 transmission in pets and wild animals, and possible clues to the intermediate host(s) for SARS-CoV-2.

Effects of exercise on glucose and lipid metabolism in elderly patients / Os efeitos do exercício no metabolismo de glicose e lipídios em pacientes idosos / Los efectos del ejercicio en el metabolismo de glucosas y lípidos en pacientes ancianos

ABSTRACT Introduction: Metabolic syndrome is a condition in which multiple cardiovascular metabolic risk factors gather in the body. Objective: To explore the effects of exercise prescription on glucose and lipid metabolism in elderly patients with metabolic syndrome. Methods: A total of 85 elderly people were selected from a pension community. The influencing factors of physical activity were analyzed by the Pearson correlation analysis method, Mann-Whitneyu test and Kruskal-Wallish test. Finally, we quantitatively analyzed the influence and path of each factor on the physical activity of the elderly. Results: Among the 85 elderly people in nursing homes, 2 cases (1.1%) had a high level of physical activity, 70 cases (38.9%) had a medium level of physical activity, and 51 cases (60.0%) had a low level of physical activity. Conclusions: The improvement of glucose and lipid metabolism and healthy body fitness with the prescription of exercises of high oxygen + low resistance and that of exercises of high resistance + low oxygen is better than that with the prescription of exercises of full oxygen and full resistance. The improvement of sleep quality with the prescription of exercise with high oxygen and low resistance was better than that of exercise with complete oxygen, complete resistance and high resistance and low oxygen. Level of evidence II; Therapeutic studies - investigation of treatment results.

RESUMO Introdução: A síndrome metabólica é uma condição em que múltiplos fatores de risco metabólicos cardiovasculares se juntam no corpo. Objetivo: Explorar os efeitos da prescrição de exercícios no metabolismo de glicose e lipídios em pacientes idosos com síndrome metabólica. Métodos: Um total de 85 idosos foram selecionados de uma comunidade de pensionistas. Os fatores que influenciam a atividade física foram analisados pelo método de análise de correlação de Pearson, o teste Mann-Whitneyu e o teste Kruskal-Wallish. No final, analisamos quantitativamente a influência e o curso de cada fator na atividade física dos idosos. Resultados: entre os 85 idosos em casas de repouso, 2 casos (1,1%) apresentavam alto nível de atividade física, 70 casos (38,9%) apresentavam nível médio de atividade física, e 51 casos (60,0%) apresentavam baixo nível de atividade física. Conclusões: A melhora no metabolismo de glicose e lipídios e preparo físico saudável com a prescrição de exercícios de oxigênio alto + resistência baixa e aquela de exercícios de resistência alta + oxigênio baixo é mais eficaz do que a de prescrição de exercícios de oxigênio pleno e resistência plena. A melhora na qualidade do sono com a prescrição de exercícios de oxigênio alto e resistência baixa foi maior do que aquela de exercícios com oxigênio pleno, resistência completa e resistência alta e oxigênio baixo. Nível de evidência II; Estudos terapêuticos - investigação de resultados de tratamento.

RESUMEN Introducción: El síndrome metabólico es una condición en que múltiples factores de riesgo metabólicos cardiovasculares se juntan en el cuerpo. Objetivo: Explorar los efectos de la prescripción de ejercicios en el metabolismo de glucosa y lípidos en paciente ancianos con síndrome metabólico. Métodos: Se seleccionó un total de 85 ancianos de una comunidad de pensionistas. Los factores que influenciaron la actividad física fueron analizados por el método de análisis de correlación de Pearson, la prueba Mann-Whitneyu y la prueba Kruskal-Wallish. Al final, analizamos cuantitativamente la influencia y el curso de cada factor en la actividad física de los ancianos. Resultados: Entre los 85 ancianos en casas de reposo, 2 casos (1,1%) presentaban alto nivel de actividad física, 70 casos (38,9%) presentaban nivel medio de actividad física y 51 casos (60,0%) presentaban bajo nivel de actividad física. Conclusiones: La mejoría en el metabolismo de glucosa y lípidos y preparo físico saludable con la prescripción de ejercicios de oxígeno alto + resistencia baja y la de ejercicios de resistencia alta + oxígeno bajo es más eficaz que a prescripción de ejercicios de oxígeno pleno y resistencia plena. La mejoría en la calidad del sueño con la prescripción de ejercicios de oxígeno alto y resistencia baja fue mayor que la de ejercicios con oxígeno pleno, resistencia completa y resistencia alta y oxígeno bajo. Nivel de evidencia II; Estudios terapéuticos - investigación de resultados de tratamiento.

Creating RNA Specific C-to-U Editase from APOBEC3A by Separation of Its Activities on DNA and RNA Substrates.

APOBEC3A (A3A) is a cytidine deaminase involved in innate immune response and is able to catalyze deamination on both DNA and RNA substrates. It was used in creating the CRISPR-mediated base editor, but has since been held back due to its dual activities. On the other hand, it has been a challenge to separate A3A's dual activities in order to enable it for single-base RNA editors. Here we developed the reporter system for C-to-U RNA editing and employed rational design for mutagenesis to differentiate deaminase activities on RNA and DNA substrates to obtain an RNA-specific editase. Generation and examination of 23 previous A3A mutants showed their deamination activity on RNA was mostly abolished when their activity on DNA was impaired, with the exception of mutant N57Q that displayed an inverse change. We designed new mutations on Loops 1 and 7 based on A3A's crystal structure and found mutants H29R and Y132G had differential effects on catalytic activity on RNA and DNA substrates. In order to engineer an A3A with RNA-specific deaminase activity, we combined Y132G with mutations in Loop 1 or helix 6 by rational design. Two multipoint mutants, Y132G/K30R and Y132G/G188A/R189A/L190A, were successful in retaining high deaminase activity on RNA substrate while eliminating deaminase activity on DNA. We, for the first time, created novel human A3A variants with RNA-specific cytidine deaminase activity, providing insight into A3A's mechanism on substrate recognition and a new addition of a toolset to the creation of a RNA-specific C-to-U base editor.

Molecular simulation of SARS-CoV-2 spike protein binding to pangolin ACE2 or human ACE2 natural variants reveals altered susceptibility to infection.

We constructed complex models of SARS-CoV-2 spike protein binding to pangolin or human ACE2, the receptor for virus transmission, and estimated the binding free energy changes using molecular dynamics simulation. SARS-CoV-2 can bind to both pangolin and human ACE2, but has a significantly lower binding affinity for pangolin ACE2 due to the increased binding free energy (9.5 kcal mol-1). Human ACE2 is among the most polymorphous genes, for which we identified 317 missense single-nucleotide variations (SNVs) from the dbSNP database. Three SNVs, E329G (rs143936283), M82I (rs267606406) and K26R (rs4646116), had a significant reduction in binding free energy, which indicated higher binding affinity than wild-type ACE2 and greater susceptibility to SARS-CoV-2 infection for people with them. Three other SNVs, D355N (rs961360700), E37K (rs146676783) and I21T (rs1244687367), had a significant increase in binding free energy, which indicated lower binding affinity and reduced susceptibility to SARS-CoV-2 infection.

Ropivacaine inhibits proliferation, invasion, migration and promotes apoptosis of papillary thyroid cancer cells via regulating ITGA2 expression.

The present study aimed to investigate the roles of Ropivacaine in papillary thyroid cancer (PTC) and identify the possible mechanisms. The expression of integrin alpha-2 (ITGA2) in TC cell lines was tested using Western blotting and RT-qPCR. Subsequently, the level of ITGA2 in human PTC cell line (TPC-1) was measured following intervention with a series of concentrations of Ropivacaine. Then, cell counting kit-8 (CCK-8) assay and colony formation assay were executed for detecting proliferation of cells after transfection with ITGA2 pcDNA3.1. The expression of proliferation-related protein was determined by Western blotting. Additionally, the abilities of TPC-1 cell invasion and migration were examined using Transwell assay and scratch wound healing assay. Apoptosis of TPC-1 cells was analyzed using TUNEL assay and the expressions of apoptosis-related proteins were tested via West blotting. The results suggested that ITGA2 was highly expressed in TC cell lines, especially in TPC-1 cells. Ropivacaine decreased the expression of ITGA2 in a dose-dependent manner. Moreover, after treatment with Ropivacaine, cell proliferation was inhibited accompanied by changes of proliferation-related protein expressions, which was reversed following co-transfection with ITGA2 pcDNA3.1. Furthermore, Ropivacaine concentration-dependently suppressed invasion and migration of TPC-1 cells, whereas these inhibitory effects were attenuated after ITGA2 overexpression. Furthermore, apoptosis was promoted, coupled with a decrease of Bcl-2 expression and increases of Bax, cleaved caspase-3 and cleaved caspase-9 expression, in Ropivacaine-treated TPC-1 cells, which was restored following ITGA2 overexpression. These findings demonstrated that Ropivacaine could suppress proliferation, invasion, migration, and accelerate apoptosis of PTC cells via regulating ITGA2 expression.

Impact of peripheral mutations on the access channels of human cytochrome P450 1A2.

Communicated by Ramaswamy H. Sarma.

Abnormal Interactions of the Salience Network, Central Executive Network, and Default-Mode Network in Patients With Different Cognitive Impairment Loads Caused by Leukoaraiosis.

Leukoaraiosis (LA) is associated with cognitive impairment in the older people which can be demonstrated in functional connectivity (FC) based on resting-state functional magnetic resonance imaging (rs-fMRI). This study is to explore the FC changes in LA patients with different cognitive status by three network models. Fifty-three patients with LA were divided into three groups: the normal cognition (LA-NC; n = 14, six males), mild cognitive impairment (LA-MCI; n = 27, 13 males), and vascular dementia (LA-VD; n = 12, six males), according to the Mini Mental State Exam (MMSE) and Clinical Dementia Rating (CDR). The three groups and 30 matched healthy controls (HCs; 11 males) underwent rs-fMRI. The data of rs-fMRI were analyzed by independent components analysis (ICA) and region of interest (ROI) analysis by the REST toolbox. Then the FC was respectively analyzed by the default-mode network (DMN), salience networks (SNs) and the central executive network (CEN) with their results compared among the different groups. For inter-brain network analysis, there were negative FC between the SN and DMN in LA groups, and the FC decreased when compared with HC group. While there were enhanced inter-brain network FC between the SN and CEN as well as within the SN. The FC in patients with LA can be detected by different network models of rs-fMRI. The multi-model analysis is helpful for the further understanding of the cognitive changes in those patients.

Identification of Serum Biomarkers for Systemic Lupus Erythematosus Using a Library of Phage Displayed Random Peptides and Deep Sequencing.

Systemic lupus erythematosus (SLE) is one of the most serious autoimmune diseases, characterized by highly diverse clinical manifestations. A biomarker is still needed for accurate diagnostics. SLE serum autoantibodies were discovered and validated using serum samples from independent sample cohorts encompassing 306 participants divided into three groups, i.e. healthy, SLE patients, and other autoimmune-related diseases. To discover biomarkers for SLE, a phage displayed random peptide library (Ph.D. 12) and deep sequencing were applied to screen specific autoantibodies in a total of 100 serum samples from 50 SLE patients and 50 healthy controls. A statistical analysis protocol was set up for the identification of peptides as potential biomarkers. For validation, 10 peptides were analyzed using enzyme-linked immunosorbent assays (ELISA). As a result, four peptides (SLE2018Val001, SLE2018Val002, SLE2018Val006, and SLE2018Val008) were discovered with high diagnostic power to differentiate SLE patients from healthy controls. Among them, two peptides, i.e. SLE2018Val001 and SLE2018Val002, were confirmed between SLE with other autoimmune patients. The procedure we established could be easily adopted for the identification of autoantibodies as biomarkers for many other diseases.

A dynamic and integrated epigenetic program at distal regions orchestrates transcriptional responses to VEGFA.

Cell behaviors are dictated by epigenetic and transcriptional programs. Little is known about how extracellular stimuli modulate these programs to reshape gene expression and control cell behavioral responses. Here, we interrogated the epigenetic and transcriptional response of endothelial cells to VEGFA treatment and found rapid chromatin changes that mediate broad transcriptomic alterations. VEGFA-responsive genes were associated with active promoters, but changes in promoter histone marks were not tightly linked to gene expression changes. VEGFA altered transcription factor occupancy and the distal epigenetic landscape, which profoundly contributed to VEGFA-dependent changes in gene expression. Integration of gene expression, dynamic enhancer, and transcription factor occupancy changes induced by VEGFA yielded a VEGFA-regulated transcriptional regulatory network, which revealed that the small MAF transcription factors are master regulators of the VEGFA transcriptional program and angiogenesis. Collectively these results revealed that extracellular stimuli rapidly reconfigure the chromatin landscape to coordinately regulate biological responses.

Computational Study of HCV p7 Channel: Insight into a New Strategy for HCV Inhibitor Design.

HCV p7 protein is a cation-selective ion channel, playing an essential role during the life cycle of HCV viruses. To understand the cation-selective mechanism, we constructed a hexameric model in lipid bilayers of HCV p7 protein for HCB JFH-1 strain, genotype 2a. In this structural model, His9 and Val6 were key factors for the HCV cation-selective ion channel. The histidine residues at position 9 in the hexameric model formed a first gate for HCV p7 channel, acting as a selectivity filter for cations. The valines mentioned above formed a second gate for HCV p7 channel, serving as a hydrophobic filter for the dehydrated cations. The binding pocket for the channel blockers, e.g., amantadine and rimantadine, was composed of residues 20-26 in H2 helix and 52-60 in H3 helix in i + 2 monomer. However, the molecular volumes for both amantadine and rimantadine were too small for the binding pocket of HCV p7 channel. Thus, designing a compound similar with rimantadine and having much larger volume would be an effective strategy for discovering inhibitors against HCV p7 channel. To achieve this point, we used rimantadine as a structural template to search ChEMBL database for the candidates employing favorable binding affinities to HCV p7 channel. As a result, six candidates were identified to have potential to be novel inhibitors against HCV p7 channel.

Bilevel Optimization-Based Time-Optimal Path Planning for AUVs.

Using the bilevel optimization (BIO) scheme, this paper presents a time-optimal path planner for autonomous underwater vehicles (AUVs) operating in grid-based environments with ocean currents. In this scheme, the upper optimization problem is defined as finding a free-collision channel from a starting point to a destination, which consists of connected grids, and the lower optimization problem is defined as finding an energy-optimal path in the channel generated by the upper level algorithm. The proposed scheme is integrated with ant colony algorithm as the upper level and quantum-behaved particle swarm optimization as the lower level and tested to find an energy-optimal path for AUV navigating through an ocean environment in the presence of obstacles. This arrangement prevents discrete state transitions that constrain a vehicle's motion to a small set of headings and improves efficiency by the usage of evolutionary algorithms. Simulation results show that the proposed BIO scheme has higher computation efficiency with a slightly lower fitness value than sliding wavefront expansion scheme, which is a grid-based path planner with continuous motion directions.

Cell Lysate Microarray for Mapping the Network of Genetic Regulators for Histone Marks.

Proteins, as the major executer for cell progresses and functions, its abundance and the level of post-translational modifications, are tightly monitored by regulators. Genetic perturbation could help us to understand the relationships between genes and protein functions. Herein, to explore the impact of the genome-wide interruption on certain protein, we developed a cell lysate microarray on kilo-conditions (CLICK) with 4837 knockout (YKO) and 322 temperature-sensitive (ts) mutant strains of yeast (Saccharomyces cerevisiae). Taking histone marks as examples, a general workflow was established for the global identification of upstream regulators. Through a single CLICK array test, we obtained a series of regulators for H3K4me3, which covers most of the known regulators in S. cerevisiae We also noted that several group of proteins are involved in negatively regulation of H3K4me3. Further, we discovered that Cab4p and Cab5p, two key enzymes of CoA biosynthesis, play central roles in histone acylation. Because of its general applicability, CLICK array could be easily adopted to rapid and global identification of upstream protein/enzyme(s) that regulate/modify the level of a protein or the posttranslational modification of a non-histone protein.