Protein-protein interaction site predictions with three-dimensional probability distributions of interacting atoms on protein surfaces

Protein-protein interactions are key to many biological processes. Computational methodologies devised to predict protein-protein interaction (PPI) sites on protein surfaces are important tools in providing insights into the biological functions of proteins and in developing therapeutics targeting the protein-protein interaction sites. One of the general features of PPI sites is that the core regions from the two interacting protein surfaces are complementary to each other, similar to the interior of proteins in packing density and in the physicochemical nature of the amino acid composition. In this work, we simulated the physicochemical complementarities by constructing three-dimensional probability density maps of non-covalent interacting atoms on the protein surfaces. The interacting probabilities were derived from the interior of known structures. Machine learning algorithms were applied to learn the characteristic patterns of the probability density maps specific to the PPI sites. The trained predictors for PPI sites were cross-validated with the training cases (consisting of 432 proteins) and were tested on an independent dataset (consisting of 142 proteins). The residue-based Matthews correlation coefficient for the independent test set was 0.423; the accuracy, precision, sensitivity, specificity were 0.753, 0.519, 0.677, and 0.779 respectively. The benchmark results indicate that the optimized machine learning models are among the best predictors in identifying PPI sites on protein surfaces. In particular, the PPI site prediction accuracy increases with increasing size of the PPI site and with increasing hydrophobicity in amino acid composition of the PPI interface; the core interface regions are more likely to be recognized with high prediction confidence. The results indicate that the physicochemical complementarity patterns on protein surfaces are important determinants in PPIs, and a substantial portion of the PPI sites can be predicted correctly with the physicochemical complementarity features based on the non-covalent interaction data derived from protein interiors.     

胚乳性状数量基因的定位方法

将三倍体胚乳性状的数量遗传模型和二倍体性状数量基因（QTL）图构建方法相结合,导出双侧标记基因型下有关胚乳性状QTL的遗传组成、平均数和遗传方差分量,据之提出以某一区间双侧标记基因型胚乳性状的平均值为依变数,以该区间内任一点假定存在的QTL的加性效应d、显性效应h1和／或h2的系数为自变数,进行有重复观察值的多元线性回归分析,根据多元线性回归的显著性测验该点是否存在QTL,并估计出QTL的遗传效应。给定区间内任一点,皆可以此进行分析,从而可在整条染色体上作图,并以之确定QTL的数目和最可能位置,同时,在检测某一区间时,利用多元线性回归方法将该区间外可能存在的QTL的干扰进行统计控制,以提高QTL检测的精度。此外,还讨论了如何将之推广应用于其他类型的DNA不对应资料以及具复杂遗传模型的胚乳性状资料。     

The Association between Individual Income and Aggressive End-of-Life Treatment in Older Cancer Decedents in Taiwan

Objectives

To examine the association of individual income and end of life (EOL) care in older cancer decedents in Taiwan.

Design

Retrospective cohort study.

Setting

National Health Insurance Research Database (NHIRD) in Taiwan.

Participants

28,978 decedents >65 years were diagnosed with cancer and died during 2009-2011 in Taiwan. Of these decedents, 10941, 16535, and 1502 were categorized by individual income as having low, moderate, and high SES, respectively.

Main outcome measures

Indicators of aggressiveness of EOL care: chemotherapy use before EOL, more than one emergency department (ER) visit, more than one hospital admission, hospital length of stay >14 days, intensive care unit (ICU) admission, and dying in a hospital.

Results

Low individual income was associated with more aggressive EOL treatment (estimate -0.30 for moderate income, -0.27 for high income, both p<0.01). The major source of aggressiveness was the tendency for older decedents with low income to die in the acute care hospital. The indicators had an increasing trend from 2009 to 2011, except for hospital stay >14 days.

Conclusions

Low individual income is associated with more aggressive EOL treatment in older cancer decedents. Public health providers should make available appropriate education and hospice resources to these decedents and their families, to reduce the amount of aggressive terminal care such decedents receive.     

Molecular Epidemiology of Tuberculosis in Kaohsiung City Located at Southern Taiwan, 2000-2008

Background

We present the first comprehensive analysis of Mycobacterium tuberculosis (MTB) isolates circulating in southern Taiwan. In this 9-year population-based study, the TB situation in the Kaohsiung region was characterized by genotypic analysis of 421 MTB isolates.

Methods

All 421 isolates of MTB were analyzed by spoligotyping and MIRU-VNTR typing. Drug-resistance patterns were also analyzed.

Results

The percentage of EAI (East African-Indian) strains increased across sampling years (2000–2008) in southern Taiwan, whereas the proportion of Beijing lineages remained unchanged. Clustering was more frequent with EAI genotype infections (odds ratio = 3.6, p<0.0001) when compared to Beijing genotypes. Notably, MTB resistance to streptomycin (STR) had significantly increased over time, but resistance to other antibiotics, including multidrug resistance, had not. Three major genes (gidB, rpsL and rrs) implicated in STR resistance were sequenced and specific mutations identified.

Conclusions

This study revealed that EAI strains were highly transmissible and that STR resistance has increased between 2000 and 2008 in Kaohsiung, Taiwan.     

Genomic single nucleotide polymorphisms in the offspring of gastric cancer patients predispose to spasmolytic polypeptide-expressing metaplasia after H. pylori infection

Background

Gastric cancer exhibits familial clustering, and gastric cancer familial relatives (GCF) tend to present with corpus-predominant gastritis and precancerous lesions as SPEM or IM after H. pylori infection. The study determined whether the children of gastric cancer patients (GCA) had genomic single nucleotide polymorphisms (SNPs) predisposed to the gastric precancerous lesions as spasmolytic polypeptide-expressing metaplasia (SPEM) or intestinal metaplasia (IM).

Results

There were 389 family relatives of 193 non-cardiac GCA and 173 duodenal ulcer patients (DU), received blood sampling for DNA collection. The differences of the risk alleles of SNPs in the ITGA5, ITGB1, IL-10, COX-2, RUNX3, and TFF2 genes were compared between 195 children of GCA and 143 DU. The children of GCA had higher allele frequencies of ITGA5-1160 T-carrier (P = 0.006, OR[95% CI] = 2.2[1.2-4]), ITGB1-1949 A-carrier (P = 0.047; OR[95% CI] = 2.8[1.4-5.3]), ITGB1 + 31804 C-carrier (P = 0.013; OR[95% CI] = 4.7[1.7-13.0]), IL-10-592 AA (P = 0.014; OR[95% CI] = 2.3[1.4-4.0]) and COX-2-1195 G-carrier (P = 0.019; OR[95% CI] = 1.7[0.9-3.2]) than DU. The combined genotype with ITGA5-1160/ITGB1-1949/ITGB1 + 31804 as T/A/C carriers and COX-2-1195/IL-10-592 as G-carrier/AA was more prevalent in the children of GCA than in DU (P < 1×10⁻⁴), and predisposed with a 5.3-fold risk of getting SPEM in the H. pylori-infected children of GCA (P = 0.016). Such risk of getting SPEM increased to 112 folds, if combined with RUNX3 + 492/TFF2-308 as A-carrier/CC in this limited study scale (P = 1×10⁻⁴).

Conclusions

The SNPs of ITGA5-1160/ITGB1-1949/ ITGB1 + 31804 as T/A/C carriers and COX-2-1195/IL-10-592 as G-carrier/AA, or more specific to combine RUNX3 + 492/TFF2-308 as A-carrier/CC shall be host factor predisposing to gastric cancer during H. pylori infection, and serve as marker to identify high-risk subjects for H. pylori eradication.

Electronic supplementary material

The online version of this article (doi:10.1186/s12929-015-0121-7) contains supplementary material, which is available to authorized users.     

Requirements for the maintenance of Th1 immunity in vivo following DNA vaccination: a potential immunoregulatory role for CD8+ T cells

Protective immunity against Leishmania major generated by DNA encoding the LACK (Leishmania homologue of receptor for activated C kinase) Ag has been shown to be more durable than vaccination with LACK protein plus IL-12. One mechanism to account for this may be the selective ability of DNA vaccination to induce CD8+ IFN-gamma-producing T cells. In this regard, we previously reported that depletion of CD8+ T cells in LACK DNA-vaccinated mice abrogated protection when infectious challenge was done 2 wk postvaccination. In this study, we extend these findings to study the mechanism by which CD8+ T cells induced by LACK DNA vaccination mediate both short- and long-term protective immunity against L. major. Mice vaccinated with LACK DNA and depleted of CD8+ T cells at the time of vaccination or infection were unable to control infection when challenge was done 2 or 12 wk postvaccination. Remarkably, it was noted that depletion of CD8+ T cells in LACK DNA-vaccinated mice was associated with a striking decrease in the frequency of LACK-specific CD4+ IFN-gamma-producing T cells both before and after infection. Moreover, data are presented to suggest a mechanism by which CD8+ T cells exert this regulatory role. Taken together, these data provide additional insight into how Th1 cells are generated and sustained in vivo and suggest a potentially novel immunoregulatory role for CD8+ T cells following DNA vaccination.     

Evolution of exon 1 of the dopamine D4 receptor (DRD4) gene in primates

The dopamine D4 receptor (DRD4) gene exhibits a large amount of expressed polymorphism in humans. To understand the evolutionary history of the first exon of DRD4-which in humans contains a polymorphic 12bp tandem duplication, a polymorphic 13bp deletion, and other rare variants-we examined the homologous exon in thirteen other primate species. The great apes possess a variable number of tandem repeats in the same region as humans, both within and among species. In this sense, the 12bp tandem repeat of exon 1 is similar to the 48bp VNTR of exon 3 of DRD4, previously shown to be polymorphic in all primate species examined. The Old World monkeys show no variation in length, and a much higher conservation of amino acid sequence than great apes and humans. The New World monkeys show interspecific differences in length in the region of the 12bp polymorphism, but otherwise show the higher conservation seen in Old World monkeys. The different patterns of variation in monkeys compared to apes suggest strong purifying selective pressure on the exon in these monkeys, and somewhat different selection, possibly relaxed selection, in the apes.     

Multiscale Entropy of Electroencephalogram as a Potential Predictor for the Prognosis of Neonatal Seizures

Objective

Increasing animal studies supported the harmful effects of prolonged or frequent neonatal seizures in developing brain, including increased risk of later epilepsy. Various nonlinear analytic measures had been applied to investigate the change of brain complexity with age. This study focuses on clarifying the relationship between later epilepsy and the changes of electroencephalogram (EEG) complexity in neonatal seizures.

Methods

EEG signals from 19 channels of the whole brain from 32 neonates below 2 months old were acquired. The neonates were classified into 3 groups: 9 were normal controls, 9 were neonatal seizures without later epilepsy, and 14 were neonatal seizures with later epilepsy. Sample entropy (SamEn), multiscale entropy (MSE) and complexity index (CI) were analyzed.

Results

Although there was no significant change in SamEn, the CI values showed significantly decreased over Channels C3, C4, and Cz in patients with neonatal seizures and later epilepsy compared with control group. More multifocal epileptiform discharges in EEG, more abnormal neuroimaging findings, and higher incidence of future developmental delay were noted in the group with later epilepsy.

Conclusions

Decreased MSE and CI values in patients with neonatal seizures and later epilepsy may reflect the mixed effects of acute insults, underlying brain immaturity, and prolonged seizures-related injuries. The analysis of MSE and CI can therefore provide a quantifiable and accurate way to decrypt the mystery of neonatal seizures, and could be a promising predictor.     

Prognostic Value of Cancer Stem Cell Marker ALDH1 Expression in Colorectal Cancer: A Systematic Review and Meta-Analysis

Objective

Many studies have indicated the prognostic and clinicopathological value of aldehyde dehydrogenase 1 (ALDH1) in colorectal cancer (CRC) patients still remains controversial. Thus we performed this study to clarify the relationship between high ALDH1 expression in CRC and its impact on survival and clinicopathological features.

Methods

Publications for relevant studies in Pubmed, the Cochrane Library, Embase, and China National Knowledge Infrastructure (CNKI) through April 2015 were identified. Only articles describing ALDH1 antigen with immunohistochemistry in CRC were included. The software RevMan 5.1 was used to analyze the outcomes, including 5-year overall survival (OS), disease-free survival (DFS) and clinicopathological features.

Results

9 studies with 1203 patients satisfying the criteria were included. The overall rate of high ALDH1 expression was 46.5% by immunohistochemical staining. High ALDH1 expression as an independent prognostic factor was significantly associated with the 5-year OS and DFS (OR = 0.42, 95%CI: 0.26–0.68, P = 0.0004; OR = 0.38, 95%CI: 0.24–0.59, P < 0.0001, respectively). High ALDH1 expression was highly correlated with the tumor (T) stage (T3 + T4 vs. T1 + T2; OR = 2.16, 95%CI: 1.09–4.28, P = 0.03), lymph node (N) stage (N1 + N2 vs. N0; OR = 1.8; 95%CI: 1.17–2.79, P = 0.008), and tumor differentiation (G3 vs. G1 + G2; OR = 1.88; 95%CI: 1.07–3.30, P = 0.03). However, high ALDH1 expression was not significantly correlated with the patient age (>60 years old vs. <60 years old; OR = 1.11, 95%CI: 0.63–1.94, P = 0.72).

Conclusions

High ALDH1 expression indicates a poor prognosis in CRC patients. Moreover, high ALDH1 expression correlates with the T stage, N stage, and tumor differentiation, but not with age.