ABCB6 mutations cause ocular coloboma

Ocular coloboma is a developmental defect of the eye and is due to abnormal or incomplete closure of the optic fissure. This disorder displays genetic and clinical heterogeneity. Using a positional cloning approach, we identified a mutation in the ATP-binding cassette (ABC) transporter ABCB6 in a Chinese family affected by autosomal-dominant coloboma. The Leu811Val mutation was identified in seven affected members of the family and was absent in six unaffected members from three generations. A LOD score of 3.2 at θ = 0 was calculated for the mutation identified in this family. Sequence analysis was performed on the ABCB6 exons from 116 sporadic cases of microphthalmia with coloboma (MAC), isolated coloboma, and aniridia, and an additional mutation (A57T) was identified in three patients with MAC. These two mutations were not present in the ethnically matched control populations. Immunostaining of transiently transfected, Myc-tagged ABCB6 in retinal pigment epithelial (RPE) cells showed that it localized to the endoplasmic reticulum and Golgi apparatus of RPE cells. RT-PCR of ABCB6 mRNA in human cell lines and tissue indicated that ABCB6 is expressed in the retinae and RPE cells. Using zebrafish, we show that abcb6 is expressed in the eye and CNS. Morpholino knockdown of abcb6 in zebrafish produces a phenotype characteristic of coloboma and replicates the clinical phenotype observed in our index cases. The knockdown phenotype can be corrected with coinjection of the wild-type, but not mutant, ABCB6 mRNA, suggesting that the phenotypes observed in zebrafish are due to insufficient abcb6 function. Our results demonstrate that ABCB6 mutations cause ocular coloboma.     

Myocardial remodeling in rats with metabolic syndrome: role of Rho-kinase mediated insulin resistance

Insulin resistance (IR) plays a critical role in metabolic syndrome (MS). Previous studies have demonstrated that activated ROCK is increased in MS patients. However, the effect of Rho-kinase (ROCK) on IR has not been definitely determined. Thus, the aims of the present study were to determine whether ROCK activation induces IR or affects myocardial structure and function, as well as the possible mechanisms underlying this process. Wistar rats fed high fat, high glucose and high salt diet sewed as model of MS and we used transmission electron microscopy, echocardiogram technology, and terminal deoxynucleotidyl transferase-mediated DNA nick-end labeling staining to identify any myocardial damage. The protein levels of MYPT-1 (characteristic of ROCK activation), IRS-1 and AKT were analyzed by immunohistochemistry and Western blotting. In hearts from MS rats, we found increased protein levels of phospho-MYPT-1 and phospho-IRS-1 (Ser307) and decreased phospho-AKT compared to levels in normal rats. In conclusion, the results suggest that ROCK-mediated IR is involved in the development of myocardial impairments in MS rats and that this effect is mediated probably via the IRS-1/PI3-kinase/AKT pathway.     

Synthesis and antiviral activity of novel HCV NS3 protease inhibitors with P4 capping groups

We have synthesized and evaluated a series of novel HCV NS3 protease inhibitors with various P4 capping groups, which include urea, carbamate, methoxy-carboxamide, cyclic carbamate and amide, pyruvic amide, oxamate, oxalamide and cyanoguanidine. Most of these compounds are remarkably potent, exhibiting single-digit to sub-nanomolar activity in the enzyme assay and cell-based replicon assay. Selected compounds were also evaluated in the protease-inhibitor-resistant mutant transient replicon assay, and they were found to show quite different potency profiles against a panel of HCV protease-inhibitor-resistant mutants.     

Proteomic analysis of the nucleus accumbens in rhesus monkeys of morphine dependence and withdrawal intervention

It has been known that the reinforcing effects and long-term consequences of morphine are closely associated with nucleus accumbens (NAc) in the brain, a key region of the mesolimbic dopamine pathway. However, the proteins involved in neuroadaptive processes and withdrawal symptom in primates of morphine dependence have not been well explored. In the present study, we performed proteomes in the NAc of rhesus monkeys of morphine dependence and withdrawal intervention with clonidine or methadone. Two-dimensional electrophoresis was used to compare changes in cytosolic protein abundance in the NAc. We found a total of 46 proteins differentially expressed, which were further identified by mass spectrometry analysis. The identified proteins can be classified into 6 classes: metabolism and mitochondrial function, synaptic transmission, cytoskeletal proteins, oxidative stress, signal transduction and protein synthesis and degradation. Importantly, we discovered 14 proteins were significantly but similarly altered after withdrawal therapy with clonidine or methadone, revealing potential pharmacological strategies or targets for the treatment of morphine addiction. Our study provides a comprehensive understanding of the neuropathophysiology associated with morphine addiction and withdrawal therapy in primate, which is helpful for the development of opiate withdrawal pharmacotherapies.     

Pivotal role of the RanBP9-cofilin pathway in Aβ-induced apoptosis and neurodegeneration

Neurodegeneration associated with amyloid β (Aβ) peptide accumulation, synaptic loss, neuroinflammation, tauopathy, and memory impairments encompass the pathophysiological features of Alzheimer's disease (AD). We previously reported that the scaffolding protein RanBP9, which is overall increased in brains of AD patients, simultaneously promotes Aβ generation and focal adhesion disruption by accelerating the endocytosis of amyloid precursor protein (APP) and β1-integrin, respectively. Here, we show that RanBP9 protein levels are increased by fourfold in FAD mutant APP transgenic mice. Accordingly, RanBP9 transgenic mice demonstrate significantly increased synapse loss, neurodegeneration, gliosis, and spatial memory deficits. RanBP9 overexpression promotes apoptosis and potentiates Aβ-induced neurotoxicity independent of its capacity to promote Aβ generation. Conversely, RanBP9 reduction by siRNA or gene dosage mitigates Aβ-induced neurotoxicity. Importantly, RanBP9 activates/dephosphorylates cofilin, a key regulator of actin dynamics and mitochondria-mediated apoptosis, and siRNA knockdown of cofilin abolishes both Aβ and RanBP9-induced apoptosis. These findings implicate the RanBP9-cofilin pathway as critical therapeutic targets not only for stemming Aβ generation but also antagonizing Aβ-induced neurotoxicity.     

Redescription of arenicolous dipluran Parajapyx pauliani (Diplura,Parajapygidae) and DNA barcoding analyses of Parajapyx from China

Littoral dipluran Parajapyx pauliani Pagés, 1959 was redescribed based on the specimens collected in Hainan Island, South China. The littoral habitat was confirmed for the species, as the first report of arenicolous dipluran in China. DNA barcoding fragment was sequenced for five Parajapyx species (18 individuals) from China, and this is the first report on DNA barcodes used for dipluran identification. The mean intra- and interspecific divergencesare 1.9% and 19.1% respectively. Synonymy of Parajapyx paucidentis and Parajapyx isabellae was confirmed.     

Selecting Biological Meaningful Environmental Dimensions of Low Discrepancy among Ranges to Predict Potential Distribution of Bean Plataspid Invasion

Background

The Bean plataspid (Megacopta cribraria) (Hemiptera: Pentatomidae), native to Asia, is becoming an invasive species in North America; its potential spread to soybean producing areas in the US is of great concern. Ecological niche modelling (ENM) has been used increasingly in predicting invasive species'' potential distribution; however, poor niche model transferability was sometimes reported, leading to the artifactual conclusion of niche differentiation during species'' invasion.

Methodology/Principals

We aim to improve the geographical transferability of ENM via environmental variable selection to predict the potential distribution of Bean plataspid invasion. Sixteen environmental dimensions between native and introduced Bean plataspid populations were compared, and classified into two datasets with different degrees of discrepancy by the interquartile range (IQR) overlap in boxplot. Niche models based on these two datasets were compared in native model prediction and invading model projection. Classical niche model approaches (i.e., model calibrated on native range and transferred outside) were used to anticipate the potential distribution of Bean plataspid invasion.

Conclusions/Significance

Niche models based on the two datasets showed little difference in native model predictions; however, when projecting onto the introduced area, models based on the environmental datasets showing low discrepancy among ranges recovered good model transferability in predicting the newly established population of Bean plataspid in the US. Recommendations were made for selecting biological meaningful environmental dimensions of low discrepancy among ranges to improve niche model transferability among these geographically separated areas. Outside of its native range, areas with invasion potential include the southeastern US in North America, southwestern Europe, southeastern South America, southern Africa, and the eastern coastal Australia.     

Older men who use computers have lower risk of dementia

Objective

To determine if older men who use computers have lower risk of developing dementia.

Methods

Cohort study of 5506 community-dwelling men aged 69 to 87 years followed for up to 8.5 years. Use of computers measured as daily, weekly, less than weekly and never. Participants also reported their use of email, internet, word processors, games or other computer activities. The primary outcome was the incidence of ICD-10 diagnosis of dementia as recorded by the Western Australian Data Linkage System.

Results

1857/5506 (33.7%) men reported using computers and 347 (6.3%) received a diagnosis of dementia during an average follow up of 6.0 years (range: 6 months to 8.5 years). The hazard ratio (HR) of dementia was lower among computer users than non-users (HR = 0.62, 95%CI = 0.47–0.81, after adjustment for age, educational attainment, size of social network, and presence of depression or of significant clinical morbidity). The HR of dementia appeared to decrease with increasing frequency of computer use: 0.68 (95%CI = 0.41–1.13), 0.61 (95%CI = 0.39–0.94) and 0.59 (95%CI = 0.40–0.87) for less than weekly, at least weekly and daily. The HR of dementia was 0.66 (95%CI = 0.50–0.86) after the analysis was further adjusted for baseline cognitive function, as measured by the Mini-Mental State Examination.

Conclusion

Older men who use computers have lower risk of receiving a diagnosis of dementia up to 8.5 years later. Randomised trials are required to determine if the observed associations are causal.     

Clustering 100,000 protein structure decoys in minutes

Ab initio protein structure prediction methods first generate large sets of structural conformations as candidates (called decoys), and then select the most representative decoys through clustering techniques. Classical clustering methods are inefficient due to the pairwise distance calculation, and thus become infeasible when the number of decoys is large. In addition, the existing clustering approaches suffer from the arbitrariness in determining a distance threshold for proteins within a cluster: a small distance threshold leads to many small clusters, while a large distance threshold results in the merging of several independent clusters into one cluster. In this paper, we propose an efficient clustering method through fast estimating cluster centroids and efficient pruning rotation spaces. The number of clusters is automatically detected by information distance criteria. A package named ONION, which can be downloaded freely, is implemented accordingly. Experimental results on benchmark data sets suggest that ONION is 14 times faster than existing tools, and ONION obtains better selections for 31 targets, and worse selection for 19 targets compared to SPICKER’s selections. On an average PC, ONION can cluster 100,000 decoys in around 12 minutes.