The current study aimed to develop a reliable targeted array comparative genomic hybridization (aCGH) to detect microdeletions and microduplications in congenital conotruncal defects (CTDs), especially on 22q11.2 region, and for some other chromosomal aberrations, such as 5p15-5p, 7q11.23 and 4p16.3.
Twenty-seven patients with CTDs, including 12 pulmonary atresia (PA), 10 double-outlet right ventricle (DORV), 3 transposition of great arteries (TGA), 1 tetralogy of Fallot (TOF) and one ventricular septal defect (VSD), were enrolled in this study and screened for pathogenic copy number variations (CNVs), using Agilent 8 x 15K targeted aCGH. Real-time quantitative polymerase chain reaction (qPCR) was performed to test the molecular results of targeted aCGH.
Four of 27 patients (14.8%) had 22q11.2 CNVs, 1 microdeletion and 3 microduplications. qPCR test confirmed the microdeletion and microduplication detected by the targeted aCGH.
Chromosomal abnormalities were a well-known cause of multiple congenital anomalies (MCA). This aCGH using arrays with high-density coverage in the targeted regions can detect genomic imbalances including 22q11.2 and other 10 kinds CNVs effectively and quickly. This approach has the potential to be applied to detect aneuploidy and common microdeletion/microduplication syndromes on a single microarray.
The cytochrome P450 is the major enzyme involved in drug metabolism. Single CYP genotypes and metabolic phenotypes have been widely studied, but no combination analysis has been conducted in the context of specific populations and geographical areas. This study is the first to systematically analyze the combined genotypes and functional combinations of 400 samples of major CYP genes—CYP2E1, CYP2D6, CYP2C9, and CYP2C19 in four geographical areas of mainland China. 167 different genotype combinations were identified, of which 25 had a greater than 1% frequency in the Chinese Han population. In addition, phenotypes of the four genes for each sample were in line with the predictions of previous studies of the four geographical areas. On the basis of the genotype classification, we were able to produce a systemic functional combinations analysis for the population. 25 of the combinations detected had at least two non-wild phenotypes and four showed a frequency above 1%. A bioinformatics analysis of the relationship between particular drugs and multi-genes was conducted. This is the first systematic study to analyze genotype combinations and functional combinations across whole Chinese population and could make a significant contribution in the field of personalized medicine and therapy.
A novel thermostable alcohol dehydrogenase (ADH) showing activity toward aromatic secondary alcohols was identified from the hyperthermophilic archaeon Thermococcus kodakarensis KOD1 (TkADH). The gene, tk0845, which encodes an aldo-keto reductase, was heterologously expressed in Escherichia coli. The enzyme was found to be a monomer with a molecular mass of 31 kDa. It was highly thermostable with an optimal temperature of 90°C and a half-life of 4.5 h at 95°C. The apparent Km values for the cofactors NAD(P)+ and NADPH were similar within a range of 66 to 127 μM. TkADH preferred secondary alcohols and accepted various ketones and aldehydes as substrates. Interestingly, the enzyme could oxidize 1-phenylethanol and its derivatives having substituents at the meta and para positions with high enantioselectivity, yielding the corresponding (R)-alcohols with optical purities of greater than 99.8% enantiomeric excess (ee). TkADH could also reduce 2,2,2-trifluoroacetophenone to (R)-2,2,2-trifluoro-1-phenylethanol with high enantioselectivity (>99.6% ee). Furthermore, the enzyme showed high resistance to organic solvents and was particularly highly active in the presence of H2O–20% 2-propanol and H2O–50% n-hexane or n-octane. This ADH is expected to be a useful tool for the production of aromatic chiral alcohols.
Background and objective
The incidence of traumatic hemipelvectomy is rare, but it is a devastating injury. Recently, an increasing number of patients with traumatic hemipelvectomy are admitted to trauma centers alive due to improvements of the pre-hospital care. Successful management requires prompt recognition of the nature of this injury and meticulous surgical technique. We present our successful experiences on four cases of traumatic hemipelvectomy in the past nine years.
Patients and methods
Four cases with traumatic hemipelvectomy were admited to our hospital from June 21, 2002 to September 3, 2011. All injuries occurred due to vehicle accident and all patients were in a state of severe hypotension, with two of them having anal lacerations. These four cases were treated immediately with resuscitation, control of hemorrhage, early amputation, repeated debridement and closure of the wounds. An angiographic embolization was given to control hemorrhage in two of the cases preoperatively. One case underwent fecal diversion. Wound infection occurred in all of cases which was successfully controlled by repeated debridements, effective anti-biotic regimen, split-thickness skin grafts.
All four cases were saved successfully with well-healed wounds during follow up from 1 to 7 years. They were able to walk by themself using crutches.
Adhering to the surgery principles of damage control including appropriate resuscitation, hemorrhage control, coagulopathy correction and multiple debridements and closure of the wounds in reasonable period of time can save the life of cases suffering from severe pelvic ring injury.
Trauma; Hemipelvectomy; Damage control
A susceptibility locus for tuberculosis, a re-emerging infectious disease throughout the world, was previously discovered to exist on chromosome 11p15. IFITM3 gene encoding for interferon inducible transmembrane protein 3, is located at 11p15. It acts as an effector molecule for interferon-gamma, which is essential for anti-tuberculosis immune response. In order to investigate the association between susceptibility to TB and genetic polymorphisms of the IFITM3 core promoter, a case-control study including 368 TB patients and 794 healthy controls was performed in Han Chinese children in northern China. The rs3888188 polymorphism showed significant association with susceptibility to TB. The rs3888188 G allele, acting recessively, was more frequent in TB patients (95% confidence interval: 1.08–1.56, Bonferroni P-value: 0.039). We further assessed the effect of rs3888188 polymorphism on IFITM3 transcription in vitro. As based on luciferase promoter assays, the promoter activity of haplotypes with rs3888188 G allele was lower than that of haplotypes with rs3888188 T allele. Moreover, peripheral-blood mononuclear cells carrying rs3888188 GG genotype showed a reduced IFITM3 mRNA level compared to cells carrying TT or GT genotype. In conclusion, rs3888188, a functional promoter polymorphism of IFITM3, was identified to influence the risk for pediatric TB in Han Chinese population.
Acupuncture as an oriental natural healing therapy with prolonged history has been extensively utilized in the management of great numbers of disorders. Deqi, a renowned acupuncture needling sensation, is profoundly regarded as the predictor and also the prerequisite of a preferable acupuncture treatment efficacy. Till now, there is still no consistency being reached towards the mechanism of acupuncture Deqi as a result of the discrepancy for publicly acknowledged evidence. Recent visualized research on Deqi using modern technologies has demonstrated possible central mechanism towards it. However, there is a conspicuous paradox underway in the research of cerebral response to acupuncture Deqi. This paper provided a view of up-to-date studies using visualized tools to characterize the brain response to acupuncture Deqi, such as functional magnetic resonance imaging (fMRI) and positron emission tomography/computed tomography (PET/CT). The paradox was extruded to highlight certain reasons from a TCM view. It is hypothesized that acupoints located at different dermal sites, state of participant, and needling manipulation can all contribute to the current paradox. Hence, further studies on acupuncture Deqi should pay more attention to the strategy of experiment design with generalized measurement, valid sham control methods, and more to subjects in diseased condition.
Genome-wide association studies (GWAS) have identified several genetic susceptibility loci for breast cancer (BC). One of them, conducted among Chinese women, found an association of rs2046210 at 6q25.1 with the risk of BC recently. Since then, numerous association studies have been carried out to investigate the relationship between this polymorphism and BC risk in various populations. However, these have yielded contradictory results. We therefore performed a meta-analysis to clarify this inconsistency. Overall, a total of 235003 subjects based on 13 studies were included in our study. Significantly increased BC risk was detected in the pooled analysis [allele contrast: OR = 1.13, 95%CI = 1.10–1.17, P(Z) <10−5, P(Q) <10−4; dominant model: OR = 1.21, 95%CI = 1.14–1.27, P(Z) <10−5, P(Q) <10−4; recessive model: OR = 1.18, 95%CI = 1.12–1.24, P(Z) <10−5, P(Q) = 0.04]. In addition, our data revealed that rs2046210 conferred greater risk in estrogen receptor (ER)-negative tumors [OR = 1.27, 95%CI = 1.15–1.40, P(Z) <10−5, P(Q) <10−4] than in ER-positive ones [OR = 1.18, 95%CI = 1.09–1.28, P(Z) <10−4, P(Q) = 0.0003]. When stratified by ethnicity, significant associations were found in Caucasian and Asian populations, but not detected among Africans. There was evidence of heterogeneity (P<0.05), however, the heterogeneity largely disappeared after stratification by ethnicity. The present meta-analysis demonstrated that the rs2046210 polymorphism may be associated with increased BC susceptibility, but this association varies in different ethnicities.
Structural connectivity between cortical regions of the human brain can be characterized non-invasively with diffusion tensor imaging (DTI) based fiber tractography. In this paper, a novel fiber tractography technique, globally optimized fiber tracking and hierarchical fiber clustering, is presented. The proposed technique uses k-means clustering in conjunction with modified Hubert statistic to partition fiber pathways, which are evaluated with simultaneous consideration of consistency with underlying DTI data and smoothness of fiber courses in the sense of global optimality, into individual anatomically coherent fiber bundles. In each resulting bundle, fibers are sampled, perturbed and clustered iteratively to approach the optimal solution. The global optimality allows the proposed technique to resist local image artifacts, and to possess inherent capabilities of handling complex fiber structures and tracking fibers between gray matter regions. The embedded hierarchical clustering allows multiple fiber bundles between a pair of seed regions to be naturally reconstructed and partitioned. The integration of globally optimized tracking and hierarchical clustering greatly benefits applications of DTI based fiber tractography to clinical studies, particularly to studies of structure-function relations of the complex neural network of the human. Experiments with synthetic and in vivo human DTI data have demonstrated the effectiveness of the proposed technique in tracking complex fiber structures, thus proving its significant advantages over traditionally used streamline fiber tractography.
Diffusion Tensor Imaging; Fiber Tracking; Fiber Clustering; Global Optimization
There is a huge variability of hepatic CYP3A4 level in human populations, which was believed to contribute to different responses to drugs among individuals. Transcription of CYP3A4 was regulated by transcription factors such as pregnane X receptor (PXR). MiRNA hsa-miR-148a was previously reported to influence PXR expression in HepG2 cells and in Japanese populations. In this study, we conducted a similar correlation study in Chinese Han population (N = 24). No significant correlation of hsa-miR-148a was found with PXR expression or CYP3A4 expression. Our results suggest that hsa-miR-148a does not play a major role in the regulation of PXR or CYP3A4 expression in human livers from Chinese Han population.
The objective of this study was to investigate the relationship between serum levels of OPG, TGF-β1, and TGF-β2 and BMD decrease rate (BDR) in native Chinese women. This cross-sectional study was performed on 465 healthy native Chinese women aged 35–80 years. Serum levels of OPG, TGF-β1, and TGF-β2 were determined. BDR was measured by DXA at the posteroanterior spine, hip, and distal forearm. At all skeletal sites tested, there was a negative correlation between BDR and serum levels of both OPG (r = −0.122 to –0.230, all P = 0.007–0.000) and TGF-β2 (r = −0.100 to –0.173, all P = 0.029–0.000) and a positive correlation between BDR and serum TGF-β1 (r = 0.245 − 0.365, all P = 0.000). After adjustment for age and BMI, there were no statistically significant correlations between serum levels of OPG or TGF-β2 and BDR. However, statistically significant correlations between serum TGF-β1 and BDR at the lumbar spine and ultradistal forearm remained. Multiple linear regression stepwise analysis showed that serum OPG could explain 1.4–3.7% of BDR variation. Serum TGF-β1 was a positive determinant of BDR and could explain 5.3–13.3% of BDR variation.
Background and Purpose
Hemodynamic factors are commonly believed to play an important role in the pathogenesis, progression, and rupture of cerebral aneurysms. In this study, we aimed to identify significant hemodynamic and morphological parameters that discriminate intracranial aneurysm rupture status using 3-dimensional-angiography and computational fluid dynamics technology.
Materials and Methods
3D-DSA was performed in 8 patients with mirror posterior communicating artery aneurysms (Pcom-MANs). Each pair was divided into ruptured and unruptured groups. Five morphological and three hemodynamic parameters were evaluated for significance with respect to rupture.
The normalized mean wall shear stress (WSS) of the aneurysm sac in the ruptured group was significantly lower than that in the unruptured group (0.52±0.20 versus 0.81±0.21, P = .012). The percentage of the low WSS area in the ruptured group was higher than that in the unruptured group (4.11±4.66% versus 0.02±0.06%, P = .018). The AR was 1.04±0.21 in the ruptured group, which was significantly higher than 0.70±0.17 in the unruptured group (P = .012). By contrast, parameters that had no significant differences between the two groups were OSI (P = .674), aneurysm size (P = .327), size ratio (P = .779), vessel angle (P = 1.000) and aneurysm inclination angle (P = 1.000).
Pcom-MANs may be a useful disease model to investigate possible causes of aneurysm rupture. The ruptured aneurysms manifested lower WSS, higher percentage of low WSS area, and higher AR, compared with the unruptured one. And hemodynamics is as important as morphology in discriminating aneurysm rupture status.
In the structure of the title compound, C22H21N3O3S, the thiazole ring forms dihedral angles of 88.83 (7) and 9.39 (9)°, respectively, with the benzene and pyrrole rings. The dihydropyrimidine ring adopts a flattened boat conformation. The olefinic double bond is in a Z conformation.
Diffusion tensor imaging(DTI) tractography is a novel technique that can delineate the trajectories between cortical region of the human brain non-invasively. In this paper, a novel DTI based white matter fiber tractography using genetic algorithm is presented. Adapting the concepts from evolutionary biology which include selection, recombination and mutation, globally optimized fiber pathways are generated iteratively. Global optimality of the fiber tracts is evaluated using Bayes decision rule, which simultaneously considers both the fiber geometric smoothness and consistency with the tensor field. This global optimality assigns the tracking fibers great immunity to random image noise and other local image artifacts, thus avoiding the detrimental effects of cumulative noise on fiber tracking. Experiments with synthetic and in vivo human DTI data have demonstrated the feasibility and robustness of this new fiber tracking technique, and an improved performance over commonly used probabilistic fiber tracking.
Diffusion Tensor Imaging; Fiber Tracking; Genetic Algorithm; Global Optimization
Multiple genetic studies have suggested that high-temperature requirement serine protease (HTRA1) is associated with polypoidal choroidal vasculopathy (PCV). To date, no functional studies have investigated the biological effect of HTRA1 on vascular endothelial cells, essential vascular components involved in polypoidal vascular abnormalities and arteriosclerosis-like changes. In vitro studies were performed to investigate the effect of HTRA1 on the regulation of fibronectin, laminin, vascular endothelial growth factor (VEGF), platelet derived growth factor receptor (PDGFR) and matrix metalloparoteinases 2 (MMP-2) and the role of HTRA1 in choroid-retina endothelial (RF/6A) and human umbilical vein endothelial (HUVEC) cells. Lentivirus-mediated overexpression of HTRA1 was used to explore effects of the protease on RF/6A and HUVEC cells in vitro. HTRA1 overexpression inhibited the proliferation, cell cycle, migration and tube formation of RF/6A and HUVEC cells, effects that might contribute to the early stage of PCV pathological lesions. Fibronectin mRNA and protein levels were significantly down-regulated following the upregulation of HTRA1, whereas the expressions of laminin, VEGF and MMP-2 were unaffected by alterations in HTRA1 expression. The decreased biological function of vascular endothelial cells and the degradation of extracellular matrix proteins, such as fibronectin, may be involved in a contributory role for HTRA1 in PCV pathogenesis.
In this paper we describe the phosphine-catalyzed [3 + 2], [3 + 3], [4 + 3], and [3 + 2 + 3] annulations of azomethine imines and allenoates. These processes mark the first use of azomethine imines in nucleophilic phosphine catalysis, producing dinitrogen-fused heterocycles, including tetrahydropyrazolo-pyrazolones, -pyridazinones, -diazepinones, and -diazocinones. Counting the two different reaction modes in the [3 + 3] cyclizations, there are five distinct reaction pathways—the choice of which depends on the structure and chemical properties of the allenoate. All reactions are operationally simple and proceed smoothly under mild reaction conditions, affording a broad range of 1,2-dinitrogen–containing heterocycles in moderate to excellent yields. A zwitterionic intermediate formed from a phosphine and two molecules of ethyl 2,3-butadienoate acted as a 1,5-dipole in the annulations of azomethine imines, leading to the [3 + 2 + 3] tetrahydropyrazolodiazocinone products. The incorporation of two molecules of an allenoate into an eight-membered-ring product represents a new application of this versatile class of molecules in nucleophilic phosphine catalysis. The salient features of this protocol—the facile access to a diverse range of nitrogen-containing heterocycles and the simple preparation of azomethine imine substrates—suggest that it might find extensive applications in heterocycle synthesis.
Cigarette smoke (CS), the major cause of chronic obstructive pulmonary disease, contains a variety of oxidative components that were implicated in the regulation of Src homology domain 2-containing protein tyrosine phosphatase 2 (Shp2) activity. However, the contribution of Shp2 enzyme to chronic obstructive pulmonary disease pathogenesis remains unclear. We investigated the role of Shp2 enzyme in blockading CS-induced pulmonary inflammation. Shp2 levels were assessed in vivo and in vitro. Mice (C57BL/6) or pulmonary epithelial cells (NCI-H292) were exposed to CS or cigarette smoke extract (CSE) to induce acute injury and inflammation. Lungs of smoking mice showed increased levels of Shp2, compared with those of controls. Treatment of lung epithelial cells with CSE showed elevated levels of Shp2 associated with the increased release of IL-8. Selective inhibition or knockdown of Shp2 resulted in decreased IL-8 release in response to CSE treatment in pulmonary epithelial cells. In comparison with CS-exposed wild-type mice, selective inhibition or conditional knockout of Shp2 in lung epithelia reduced IL-8 release and pulmonary inflammation in CS-exposed mice. In vitro biochemical data correlate CSE-mediated IL-8 release with Shp2-regulated epidermal growth factor receptor/Grb-2–associated binders/MAPK signaling. Our data suggest an important role for Shp2 in the pathological alteration associated with CS-mediated inflammation. Shp2 may be a potential target for therapeutic intervention for inflammation in CS-induced pulmonary diseases.
In the title molecule, C18H11FN2O4, the fused four- ring system is essentially planar, with an r.m.s. deviation of 0.032 Å. In the crystal, molecules are connected by π–π stacking interactions [centroid–centroid distances = 3.5684 (9) and 3.8247 (9) Å] into chains along .
Translational control at the initiation step has been recognized as a major and important regulatory mechanism of gene expression. eIF3a, a putative subunit of eIF3 complex, has recently been shown to play an important role in regulating translation of a subset of mRNAs and found to correlate with prognosis of cancers. In this study, using nasopharyngeal carcinoma (NPC) cells as a model system we tested the hypothesis that eIF3a negatively regulates synthesis of nucleotide excision repair (NER) proteins and, thus, NER activities and cellular response to treatments with DNA damaging agents such as cisplatin. We found that a cisplatin-sensitive subclone S16 isolated from a NPC cell line CNE2 via limited dilution has increased eIF3a expression. Knocking down its expression in S16 cells increased cellular resistance to cisplatin, NER activity, and synthesis of NER proteins XPA, XPC, RAD23B, and RPA32. Altering eIF3a expression also changed cellular response to cisplatin and UV treatment in other NPC cell lines. Taken together, we conclude that eIF3a plays an important role in cisplatin response and NER activity of nasopharyngeal carcinomas by suppressing synthesis of NER proteins.
cisplatin sensitivity; eIF3a; nasopharyngeal carcinoma; nucleotide excision repair; translational control
CYP2E1 is a member of the cytochrome P450 superfamily, which is involved in the metabolism and activation of both endobiotics and xenobiotics. The genetic polymorphisms of CYP2E1 gene (Chromosome 10q26.3, Accession Number NC_000010.10) are reported to be related to the development of several mental diseases and to be involved in the clinical efficacy of some psychiatric medications. We investigated the possible association of CYP2E1 polymorphisms with susceptibility to schizophrenia in the Chinese Han Population as well as the relationship with response to risperidone in schizophrenia patients.
In a case-control study, we identified 11 polymorphisms in the 5' flanking region of CYP2E1 in 228 schizophrenia patients and 384 healthy controls of Chinese Han origin. From among the cases, we chose 130 patients who had undergone 8 weeks of risperidone monotherapy to examine the relationship between their response to risperidone and CYP2E1 polymorphisms. Clinical efficacy was assessed using the Brief Psychiatric Rating Scale (BPRS).
Statistically significant differences in allele or genotype frequencies were found between cases and controls at rs8192766 (genotype p = 0.0048, permutation p = 0.0483) and rs2070673 (allele: p = 0.0018, permutation p = 0.0199, OR = 1.4528 95%CI = 1.1487–1.8374; genotype: p = 0.0020, permutation p = 0.0225). In addition, a GTCAC haplotype containing 5 SNPs (rs3813867, rs2031920, rs2031921, rs3813870 and rs2031922) was observed to be significantly associated with schizophrenia (p = 7.47E-12, permutation p<0.0001). However, no association was found between CYP2E1 polymorphisms/haplotypes and risperidone response.
Our results suggest that CYP2E1 may be a potential risk gene for schizophrenia in the Chinese Han population. However, polymorphisms of the CYP2E1 gene may not contribute significantly to individual differences in the therapeutic efficacy of risperidone. Further studies in larger groups are warranted to confirm our results.
Background. We illustrated an example of structure equation modelling (SEM) in the research on SHS to explore the diagnosis of the Sub optimal health status (SHS) and provide evidence for the standardization of traditional Chinese medicine (TCM) patterns in SHS. And the diagnosis of 4 TCM patterns in SHS was evaluated in this analysis. Methods. This study assessed data on 2807 adults (aged 18 to 49) with SHS from 6 clinical centres. SEM was used to analyze the patterns of SHS in TCM. Parameters in the introduced model were estimated by the maximum likelihood method. Results. The discussed model fits the SHS data well with CFI = 0.851 and RMSEA = 0.075. The direct effect of Qi deficiency pattern on dampness pattern had the highest magnitude (value of estimate is 0.822). With regard to the construct of “Qi deficiency pattern”, “fire pattern”, “stagnation pattern” and “dampness pattern”, the indicators with the highest load were myasthenia of limbs, vexation, deprementia, and dizziness, respectively. It had been shown that estimate factor should indicate the important degree of different symptoms in pattern. Conclusions. The weights of symptoms in the respective pattern can be statistical significant and theoretical meaningful for the 4 TCM patterns identification in SHS research. The study contributed to a theoretical framework, which has implications for the diagnosis points of SHS.
The nonlocal means (NLM) filter has been proven to be an efficient feature-preserved denoising method and can be applied to remove noise in the magnetic resonance (MR) images. To suppress noise more efficiently, we present a novel NLM filter based on the discrete cosine transform (DCT). Instead of computing similarity weights using the gray level information directly, the proposed method calculates similarity weights in the DCT subspace of neighborhood. Due to promising characteristics of DCT, such as low data correlation and high energy compaction, the proposed filter is naturally endowed with more accurate estimation of weights thus enhances denoising effectively. The performance of the proposed filter is evaluated qualitatively and quantitatively together with two other NLM filters, namely, the original NLM filter and the unbiased NLM (UNLM) filter. Experimental results demonstrate that the proposed filter achieves better denoising performance in MRI compared to the others.
Autophagy can be induced in response to more subtle changes in nutritional state, without severe nitrogen starvation. The Iml1p-Npr2p-Npr3p complex selectively regulates this form of autophagy.
Autophagy is an evolutionarily conserved pathway for the degradation of intracellular contents. How autophagy is regulated, especially upon changes in metabolic and nutritional state, remains poorly understood. By using a prototrophic strain of Saccharomyces cerevisiae, we observed that, unexpectedly, autophagy is strongly induced simply upon switch from a rich medium to a minimal medium in the complete absence of nitrogen starvation. This novel form of autophagy was termed “non-nitrogen-starvation (NNS)–induced autophagy.” A visual screen uncovered three regulators of autophagy—Iml1p, Npr2p, and Npr3p—which function in the same complex and are selectively required for NNS-induced autophagy. During NNS-induced autophagy, Iml1p localized to either preautophagosomal structures (PAS) or non-PAS punctate structures. This localization suggests that Iml1p or the Iml1p-Npr2p-Npr3p complex might regulate autophagosome formation. Ultrastructural analysis confirmed that autophagosome formation was strongly impaired in Δiml1, Δnpr2, and Δnpr3 cells during NNS-induced autophagy. Moreover, Iml1p contains a conserved domain that is required for NNS-induced autophagy as well as complex formation. Collectively, our findings have revealed the existence of additional mechanisms that regulate autophagy under previously unrecognized conditions, in response to relatively more subtle changes in metabolic and nutritional state.
State Space Model (SSM) is a relatively new approach to inferring gene regulatory networks. It requires less computational time than Dynamic Bayesian Networks (DBN). There are two types of variables in the linear SSM, observed variables and hidden variables. SSM uses an iterative method, namely Expectation-Maximization, to infer regulatory relationships from microarray datasets. The hidden variables cannot be directly observed from experiments. How to determine the number of hidden variables has a significant impact on the accuracy of network inference. In this study, we used SSM to infer Gene regulatory networks (GRNs) from synthetic time series datasets, investigated Bayesian Information Criterion (BIC) and Principle Component Analysis (PCA) approaches to determining the number of hidden variables in SSM, and evaluated the performance of SSM in comparison with DBN.
True GRNs and synthetic gene expression datasets were generated using GeneNetWeaver. Both DBN and linear SSM were used to infer GRNs from the synthetic datasets. The inferred networks were compared with the true networks.
Our results show that inference precision varied with the number of hidden variables. For some regulatory networks, the inference precision of DBN was higher but SSM performed better in other cases. Although the overall performance of the two approaches is compatible, SSM is much faster and capable of inferring much larger networks than DBN.
This study provides useful information in handling the hidden variables and improving the inference precision.
DNA topoisomerase I (Top1) is an essential nuclear enzyme and a validated target for anticancer agent screening. In a previous study, we found that indolizinoquinoline-5,12-dione derivatives show significant biological activity against several human cancer cell lines. To understand their mechanism of inhibition of cancer cell growth, one indolizinoquinoline-5,12-dione derivative, CY13II, was further studied as lead. Our present results indicate that CY13II shows more potent antiproliferative activity against K562 cells than camptothecin. Additionally, K562 cells were arrested in G2/M and their growth rate decreased after treatment with CY13II at micromolar concentration. Biochemical Top1 assays indicate that CY13II exhibits a different inhibitory mechanism from camptothecin. Unlike camptothecin, CY13II specifically inhibits the catalytic cleavage activity of Top1 instead of forming drug-enzyme-DNA covalent ternary complex.
Opiate use is common in HIV- and hepatitis C virus (HCV)-infected individuals, however its contribution to the risk of diabetes mellitus is not well understood.
Prospective study of 1,713 HIV-infected and 652 uninfected participants from the Women’s Interagency HIV Study between October 2000 and March 2006. Diabetes defined as fasting glucose ≥126 mg/dl, or self-report of diabetes medication use or confirmed diabetes diagnosis. Opiate use determined using an interviewer-administered questionnaire. Detectable plasma HCV RNA confirmed HCV infection.
Current opiate users had a higher prevalence of diabetes (15%) than non-users (10%, p=.03), as well as a higher risk of incident diabetes (adjusted relative hazard [RHadj] 1.58, 95% CI 1.01, 2.46), after controlling for HCV infection, HIV/antiretroviral therapy status and diabetes risk factors including age, race/ethnicity, family history of diabetes and body mass index. HCV infection was also an independent risk factor for diabetes (RHadj 1.61, 95% CI 1.02, 2.52). HCV-infected women reporting current opiate use had the highest diabetes incidence (4.83 cases/100 person-years).
Among women with or at-risk for HIV, opiate use is associated with increased diabetes risk independently of HCV infection. Diabetic screening should be part of care for opiate users, and those infected with HCV.
opiate use; diabetes mellitus; fasting glucose; Hepatitis C virus; HIV; women