Today, the understanding of the sequence and structure of biologically relevant targets is growing rapidly and researchers from many disciplines, physics and computational science in particular, are making significant contributions to modern biology and drug discovery. However, it remains challenging to rationally design small molecular ligands with desired biological characteristics based on the structural information of the drug targets, which demands more accurate calculation of ligand binding free-energy. With the rapid advances in computer power and extensive efforts in algorithm development, physics-based computational chemistry approaches have played more important roles in structure-based drug design. Here we reviewed the newly developed computational chemistry methods in structure-based drug design as well as the elegant applications, including binding-site druggability assessment, large scale virtual screening of chemical database, and lead compound optimization. Importantly, here we address the current bottlenecks and propose practical solutions.

Today, the understanding of the sequence and structure of biologically relevant targets is growing rapidly and researchers from many disciplines, physics and computational science in particular, are making significant contributions to modern biology and drug discovery. However, it remains challenging to rationally design small molecular ligands with desired biological characteristics based on the structural information of the drug targets, which demands more accurate calculation of ligand binding free-energy. With the rapid advances in computer power and extensive efforts in algorithm development, physics-based computational chemistry approaches have played more important roles in structure-based drug design. Here we reviewed the newly developed computational chemistry methods in structure-based drug design as well as the elegant applications, including binding-site druggability assessment, large scale virtual screening of chemical database, and lead compound optimization. Importantly, here we address the current bottlenecks and propose practical solutions.
Computational Biology ; Drug Design ; Drug Discovery ; High-Throughput Screening Assays ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Quantitative Structure-Activity Relationship

Ultramicroelectrode was usually used in scanning electrochemical microscope(SECM) as a probe. The redox reaction on the probe is a diffusion process. But the fast moving of probe in SECM will affect the diffusion process, resulting in unclear obtained images. A new SECM image-processing technique was proposed in this paper involving combination of LoG algorithm and New edge-directed interpolation (NEDI) interpolation algorithm. LoG algorithm is helpful for the clarity of SECM images, but leading to some loss of edge information. Fortunately, NEDI algorithm based on edge directed interpolation can solve this problem well. Two substrates with gold interdigitated electrode and gold electrode array were prepared by ion sputtering method. The SECM images were obtained of the gold interdigitated electrode, gold electrode array and ITO substrate printed with fingerprints. The corresponding images treated by LoG filter and these for NEDI interpolation were compared and analyzed. The image-processing technique combining the LoG algorithm with the NEDI interpolation algorithm can significantly improve the clarity and resolution of SECM image.

OBJECTIVETo investigate the clinicopathological features and prognosis of chromophobe renal cell carcinoma (ChRCC).

METHODSThe clinical data of 68 ChRCC cases treated in our department between January 2003 and September 2010 were collected and retrospectively analyzed. The prognostic factors were evaluated by Log-rank test. Kaplan-Meier survival curve was used to estimate the survival rate.

RESULTSFifty cases were treated with radical nephrectomy and 18 with partial nephrectomy. The mean tumor size was 5.7 cm (1.5 - 16.0 cm). The TNM stages were as follows: pT1aN0M0 in 25, pT1bN0M0 in 22, pT2aN0M0 in 9, pT2bN0M0 in 5, and pT3aN0M0 in 7. According to the Fuhrman grading system, 8 patients were classified as grade I, 42 cases were grade II, 14 cases were grade III, and 4 cases were grade IV. The 3-year and 5-year survival rates were 93.0% and 90.0%, respectively. The log-rank test showed that tumor size (> 7 cm vs. ≤ 7 cm) (P = 0.004), TNM stage (T1-2 vs. T3-4) (P = 0.008) and urinary collecting system invasion (P = 0.024) were associated with survival time. The multivariable Cox regression model revealed that tumor size (> 7 cm vs. ≤ 7 cm) was an independent predictor of aggressive ChRCC (P = 0.038).

CONCLUSIONSChRCC is a distinct type of renal cell carcinoma exhibiting a low degree of malignancy. Most tumors are larger, but predominantly with a favorable prognosis. Fuhrman nuclear grading is not suitable for ChRCC. Tumor size (> 7 cm vs. ≤ 7 cm) is an independent predictor of prognosis of ChRCC.

Adult ; Aged ; Carcinoma, Renal Cell ; pathology ; surgery ; Female ; Follow-Up Studies ; Humans ; Kidney Neoplasms ; pathology ; surgery ; Male ; Middle Aged ; Neoplasm Staging ; Nephrectomy ; methods ; Proportional Hazards Models ; Retrospective Studies ; Survival Rate ; Tumor Burden ; Young Adult

OBJECTIVETo assess the time course of Q value after myopic laser-assisted in situ keratomileusis (LASIK) and preliminarily evaluate the determinants of the difference of Q value between before and after LASIK.

METHODSWe performed a retrospective, longitudinal investigation on patients undergoing wavefront optimized LASIK therapy for emmetropization. A total of 418 eyes from 222 cases were examined preoperatively, and partly followed up at one week (172 eyes), one month (134 eyes) and three months (51 eyes) after surgery. The horizontal, vertical and total Q values of cornea were calculated from eccentricity measured at the central 6-mm corneal zones respectively. Potential determinants of the change of Q value were analyzed using multiple linear regressions.

RESULTSThe mean Q value was -0.17 +/- 0.13 preoperatively, and 0.99 +/- 0.70, 0.97 +/- 0.66, and 0.86 +/- 0.41 one week, one and three months postoperatively, respectively. One way analysis of variance (ANOVA) demonstrated significant differences between measurements made before surgery and at all postoperative times (at one week, one and three months; all P<0.0001, Bonferroni post hoc), but no significant differences were found among postoperative groups. Significant differences of Q values between horizontal and vertical meridians were found before surgery and at all postoperative times (all P<0.0001). Multiple regression analysis revealed that change of Q value significantly correlated with manifest refraction spherical equivalent (r=0.116, P<0.0001) and axial length (r=0.264, P<0.0001).

CONCLUSIONSOver the study period, the primary changes in Q value occur within 1 week after surgery, and then become slightly decreased and nearly stable. Manifest refraction spherical equivalent and axial length play a significant role in the change of postoperative Q value.

Adolescent ; Adult ; Cornea ; surgery ; Female ; Humans ; Keratomileusis, Laser In Situ ; methods ; Male ; Middle Aged ; Myopia ; surgery ; Retrospective Studies ; Treatment Outcome ; Young Adult

OBJECTIVETo scan for mutations of polycystic kidney disease 1 gene (PKD1) in Chinese population in order to find some features about Chinese patients and a better approach to detect mutations.

METHODSTwenty-five PKD-affected individuals from twenty-one unrelated genealogies and sixteen controls participated in the study. Thirty-five blood samples and six tissues were obtained after receiving informed consent and were in accordance with institutional ethical guidelines. Genomic DNA was isolated from peripheral blood using standard procedures. PCR amplification of genomic DNA was performed to generate the aimed fragments. Amplified fragments were analyzed by denaturing gradient gel electrophoresis (DGGE). A GC clamp was attached to the 5' primer. After that, the abnormal fragments were sequenced on freshly amplified specific PCR products with the dideoxynucleotide chain termination method. Sequencing was performed for all samples to evaluate DGGE.

RESULTSAimed fragments of exons 44 and 45 were amplified. DGGE detected eleven abnormal PCR fragments. Two novel mutations were identified by sequencing, included one nonsense mutation (C12217T) and one frameshift (12431delCT). In addition, one polymorphism (A50747C) was identified. The mutation detection rate is 8% in our study.

CONCLUSIONTwo novel pathogenic mutations were detected, including one nonsense mutation (C12217T) and one frameshift (12431delCT).

Asian Continental Ancestry Group ; genetics ; Codon, Nonsense ; DNA Mutational Analysis ; Exons ; genetics ; Family Health ; Female ; Frameshift Mutation ; Genotype ; Humans ; Male ; Middle Aged ; Mutation ; Pedigree ; Phenotype ; Polycystic Kidney, Autosomal Dominant ; genetics ; Polymorphism, Single Nucleotide ; Proteins ; genetics ; TRPP Cation Channels

OBJECTIVETo further investigate the genetic basis of hereditary X-linked spondyloepiphyseal dysplasia tarda (SEDL) and provide useful information for the prevention and treatment of the disease.

METHODSRT-PCR and cDNA sequencing were used to test mRNA expression of SEDL gene in a patient with 13 bp deletion of SEDL gene involving the acceptor splice site of intron 5.

RESULTSOf two different sizes of mRNA products identified in the patient, the 393 bp product was created due to the activation of cryptic splice site within exon 6; the 433 bp product was completely consistent with the part of genomic sequence on chromosome 8.

CONCLUSIONThe intragenic deletion that occurred in the acceptor splice site of the 3'region of intron 5 and the 5' coding region of exon 6 results in the activation of a cryptic splice site within exon 6, which causes 47 bp deletion of the resulting mRNA followed by a frameshift that would add two missense amino acids and then be followed by a termination codon (D109-S123del; S124fsX126). In addition, the mutation may activate the transcription of pseudogene SEDLP2 on chromosome 8 to partly complement the function of SEDL protein.

Adolescent ; Base Sequence ; Chromosomes, Human, Pair 8 ; genetics ; DNA Mutational Analysis ; Exons ; genetics ; Genetic Diseases, X-Linked ; genetics ; pathology ; Humans ; Introns ; genetics ; Male ; Membrane Transport Proteins ; genetics ; Mutation ; Osteochondrodysplasias ; genetics ; pathology ; RNA Splice Sites ; genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Transcription Factors ; genetics

OBJECTIVE: The study aimed to estimate the benchmark dose (BMD) of coke oven emissions (COEs) exposure based on mitochondrial damage with the mitochondrial DNA copy number (mtDNAcn) as a biomarker. METHODS: A total of 782 subjects were recruited, including 238 controls and 544 exposed workers. The mtDNAcn of peripheral leukocytes was detected through the real-time fluorescence-based quantitative polymerase chain reaction. Three BMD approaches were used to calculate the BMD of COEs exposure based on the mitochondrial damage and its 95% confidence lower limit (BMDL). RESULTS: The mtDNAcn of the exposure group was lower than that of the control group (0.60 ± 0.29 vs. 1.03 ± 0.31; P < 0.001). A dose-response relationship was shown between the mtDNAcn damage and COEs. Using the Benchmark Dose Software, the occupational exposure limits (OELs) for COEs exposure in males was 0.00190 mg/m ³. The OELs for COEs exposure using the BBMD were 0.00170 mg/m ³ for the total population, 0.00158 mg/m ³ for males, and 0.00174 mg/m ³ for females. In possible risk obtained from animal studies (PROAST), the OELs of the total population, males, and females were 0.00184, 0.00178, and 0.00192 mg/m ³, respectively. CONCLUSION Based on our conservative estimate, the BMDL of mitochondrial damage caused by COEs is 0.002 mg/m ³. This value will provide a benchmark for determining possible OELs.
Male ; Female ; Animals ; Coke ; Polycyclic Aromatic Hydrocarbons ; DNA Copy Number Variations ; Benchmarking ; Occupational Exposure/analysis* ; DNA, Mitochondrial/genetics* ; DNA Damage

Objective: To analyze the course of disease and epidemiological parameters of COVID-19 and provide evidence for making prevention and control strategies. Methods: To display the distribution of course of disease of the infectors who had close contacts with COVID-19 cases from January 1 to March 15, 2020 in Guangdong Provincial, the models of Lognormal, Weibull and gamma distribution were applied. A descriptive analysis was conducted on the basic characteristics and epidemiological parameters of course of disease. Results: In total, 515 of 11 580 close contacts were infected, with an attack rate about 4.4%, including 449 confirmed cases and 66 asymptomatic cases. Lognormal distribution was fitting best for latent period, incubation period, pre-symptomatic infection period of confirmed cases and infection period of asymptomatic cases; Gamma distribution was fitting best for infectious period and clinical symptom period of confirmed cases; Weibull distribution was fitting best for latent period of asymptomatic cases. The latent period, incubation period, pre-symptomatic infection period, infectious period and clinical symptoms period of confirmed cases were 4.50 (95%CI:3.86-5.13) days, 5.12 (95%CI:4.63-5.62) days, 0.87 (95%CI:0.67-1.07) days, 11.89 (95%CI:9.81-13.98) days and 22.00 (95%CI:21.24-22.77) days, respectively. The latent period and infectious period of asymptomatic cases were 8.88 (95%CI:6.89-10.86) days and 6.18 (95%CI:1.89-10.47) days, respectively. Conclusion: The estimated course of COVID-19 and related epidemiological parameters are similar to the existing data.
COVID-19 ; Cohort Studies ; Contact Tracing ; Humans ; Incidence ; Prospective Studies

Based on the strategy of metabolomics combined with bioinformatics, this study analyzed the potential allergens and mechanism of pseudo-allergic reactions (PARs) induced by the combined use of Reduning injection and penicillin G injection. All animal experiments and welfare are in accordance with the requirements of the First Affiliated Experimental Animal Ethics and Animal Welfare Committee of Henan University of Chinese Medicine (approval number: YFYDW2020002). Based on UPLC-Q-TOF/MS technology combined with UNIFI software, a total of 21 compounds were identified in Reduning and penicillin G mixed injection. Based on molecular docking technology, 10 potential allergens with strong binding activity to MrgprX2 agonist sites were further screened. Metabolomics analysis using UPLC-Q-TOF/MS technology revealed that 34 differential metabolites such as arachidonic acid, phosphatidylcholine, phosphatidylserine, prostaglandins, and leukotrienes were endogenous differential metabolites of PARs caused by combined use of Reduning injection and penicillin G injection. Through the analysis of the "potential allergen-target-endogenous differential metabolite" interaction network, the chlorogenic acids (such as chlorogenic acid, neochlorogenic acid, cryptochlorogenic acid, and isochlorogenic acid A) and β-lactam allergens in the combination of the two may be mainly regulated by PLD1, PLA2G12A and CYP1A1. The three upstream signal target proteins mainly activate the arachidonic acid metabolic pathway, promote the degranulation of mast cells, release downstream endogenous inflammatory mediators, and induce PARs.