Serum repressing efflux pump CDR1 in Candida albicans

BACKGROUND: In the past decades, the prevalence of candidemia has increased significantly and drug resistance has also become a pressing problem. Overexpression of CDR1, an efflux pump, has been proposed as a major mechanism contributing to the drug resistance in Candida albicans. It has been demonstrated that biological fluids such as human serum can have profound effects on antifungal pharmacodynamics. The aim of this study is to understand the effects of serum in drug susceptibility via monitoring the activity of CDR1 promoter of C. albicans. RESULTS: The wild-type C. albicans cells (SC5314) but not the cdr1/cdr1 mutant cells became more susceptible to the antifungal drug when the medium contained serum. To understand the regulation of CDR1 in the presence of serum, we have constructed CDR1 promoter-Renilla luciferase (CDR1p-RLUC) reporter to monitor the activity of the CDR1 promoter in C. albicans. As expected, the expression of CDR1p-RLUC was induced by miconazole. Surprisingly, it was repressed by serum. Consistently, the level of CDR1 mRNA was also reduced in the presence of serum but not N-acetyl-D-glucosamine, a known inducer for germ tube formation. CONCLUSION: Our finding that the expression of CDR1 is repressed by serum raises the question as to how does CDR1 contribute to the drug resistance in C. albicans causing candidemia. This also suggests that it is important to re-assess the prediction of in vivo therapeutic outcome of candidemia based on the results of standard in vitro antifungal susceptibility testing, conducted in the absence of serum

A powerful and efficient multivariate approach for voxel-level connectome-wide association studies

We describe an approach to multivariate analysis, termed structured kernel principal component regression (sKPCR), to identify associations in voxel-level connectomes using resting-state functional magnetic resonance imaging (rsfMRI) data. This powerful and computationally efficient multivariate method can identify voxel-phenotype associations based on the whole-brain connectivity pattern of voxels, and it can detect linear and non-linear signals in both volume-based and surface-based rsfMRI data. For each voxel, sKPCR first extracts low-dimensional signals from the spatially smoothed connectivities by structured kernel principal component analysis, and then tests the voxel-phenotype associations by an adaptive regression model. The method's power is derived from appropriately modelling the spatial structure of the data when performing dimension reduction, and then adaptively choosing an optimal dimension for association testing using the adaptive regression strategy. Simulations based on real connectome data have shown that sKPCR can accurately control the false-positive rate and that it is more powerful than many state-of-the-art approaches, such as the connectivity-wise generalized linear model (GLM) approach, multivariate distance matrix regression (MDMR), adaptive sum of powered score (aSPU) test, and least-square kernel machine (LSKM). Moreover, since sKPCR can reduce the computational cost of non-parametric permutation tests, its computation speed is much faster. To demonstrate the utility of sKPCR for real data analysis, we have also compared sKPCR with the above methods based on the identification of voxel-wise differences between schizophrenic patients and healthy controls in four independent rsfMRI datasets. The results showed that sKPCR had better between-sites reproducibility and a larger proportion of overlap with existing schizophrenia meta-analysis findings. Code for our approach can be downloaded from https://github.com/weikanggong/sKPCR. [Abstract copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Patients with chronic periodontitis are more likely to develop upper urinary tract stone: a nation-wide population-based eight-year follow up study

Background The purpose of this study was to investigate the relationship between chronic periodontitis (CP) and upper urinary tract stone (UUTS) in Taiwan by using a population-based data set. Methods A total of 16,292 CP patients and 48,876 randomly-selected controls without chronic periodontitis were selected from the National research database and studied retrospectively. Subjects selected have not been diagnosed with UUTS previously. These subjects were prospectively followed for at least eight years. Cox regression models were used to explore the connection between risk factors and the development of UUTS. Results The CP patients have a greater chance of developing UUTS compared to controls (1761/16292, 10.8% vs. 4775/48876, 9.8%, p-values < 0.001). Conditioned logistic regression suggested CP increases the risk of UUTS development (HR 1.14, 95% CI [1.08–1.20], p < 0.001). After respective adjustment for age, gender, hypertension and diabetes, results showed that CP still increases the risk of developing UUTS (HR 1.14, 95% CI [1.08–1.20], p < 0.001). Conclusion By using a population-based database with a minimum eight 8 follow-up of CP in Taiwan, we discovered patients with CP are more likely to develop UUTS

Stem Cell-Based Neuroprotective and Neurorestorative Strategies

Stem cells, a special subset of cells derived from embryo or adult tissues, are known to present the characteristics of self-renewal, multiple lineages of differentiation, high plastic capability, and long-term maintenance. Recent reports have further suggested that neural stem cells (NSCs) derived from the adult hippocampal and subventricular regions possess the utilizing potential to develop the transplantation strategies and to screen the candidate agents for neurogenesis, neuroprotection, and neuroplasticity in neurodegenerative diseases. In this article, we review the roles of NSCs and other stem cells in neuroprotective and neurorestorative therapies for neurological and psychiatric diseases. We show the evidences that NSCs play the key roles involved in the pathogenesis of several neurodegenerative disorders, including depression, stroke and Parkinson’s disease. Moreover, the potential and possible utilities of induced pluripotent stem cells (iPS), reprogramming from adult fibroblasts with ectopic expression of four embryonic genes, are also reviewed and further discussed. An understanding of the biophysiology of stem cells could help us elucidate the pathogenicity and develop new treatments for neurodegenerative disorders. In contrast to cell transplantation therapies, the application of stem cells can further provide a platform for drug discovery and small molecular testing, including Chinese herbal medicines. In addition, the high-throughput stem cell-based systems can be used to elucidate the mechanisms of neuroprotective candidates in translation medical research for neurodegenerative diseases

Role of the CCAAT-Binding Protein NFY in SCA17 Pathogenesis

Spinocerebellar ataxia 17 (SCA17) is caused by expansion of the polyglutamine (polyQ) tract in human TATA-box binding protein (TBP) that is ubiquitously expressed in both central nervous system and peripheral tissues. The spectrum of SCA17 clinical presentation is broad. The precise pathogenic mechanism in SCA17 remains unclear. Previously proteomics study using a cellular model of SCA17 has revealed reduced expression of heat shock 70 kDa protein 5 (HSPA5) and heat shock 70 kDa protein 8 (HSPA8), suggesting that impaired protein folding may contribute to the cell dysfunction of SCA17 (Lee et al., 2009). In lymphoblastoid cells, HSPA5 and HSPA8 expression levels in cells with mutant TBP were also significantly lower than that of the control cells (Chen et al., 2010). As nuclear transcription factor Y (NFY) has been reported to regulate HSPA5 transcription, we focused on if NFY activity and HSPA5 expression in SCA17 cells are altered. Here, we show that TBP interacts with NFY subunit A (NFYA) in HEK-293 cells and NFYA incorporated into mutant TBP aggregates. In both HEK-293 and SH-SY5Y cells expressing TBP/Q61∼79, the level of soluble NFYA was significantly reduced. In vitro binding assay revealed that the interaction between TBP and NFYA is direct. HSPA5 luciferase reporter assay and endogenous HSPA5 expression analysis in NFYA cDNA and siRNA transfection cells further clarified the important role of NFYA in regulating HSPA5 transcription. In SCA17 cells, HSPA5 promoter activity was activated as a compensatory response before aggregate formation. NFYA dysfunction was indicated in SCA17 cells as HSPA5 promoter activity reduced along with TBP aggregate formation. Because essential roles of HSPA5 in protection from neuronal apoptosis have been shown in a mouse model, NFYA could be a target of mutant TBP in SCA17

Genome-Wide Association Study of Young-Onset Hypertension in the Han Chinese Population of Taiwan

Young-onset hypertension has a stronger genetic component than late-onset counterpart; thus, the identification of genes related to its susceptibility is a critical issue for the prevention and management of this disease. We carried out a two-stage association scan to map young-onset hypertension susceptibility genes. The first-stage analysis, a genome-wide association study, analyzed 175 matched case-control pairs; the second-stage analysis, a confirmatory association study, verified the results at the first stage based on a total of 1,008 patients and 1,008 controls. Single-locus association tests, multilocus association tests and pair-wise gene-gene interaction tests were performed to identify young-onset hypertension susceptibility genes. After considering stringent adjustments of multiple testing, gene annotation and single-nucleotide polymorphism (SNP) quality, four SNPs from two SNP triplets with strong association signals (−log10(p)>7) and 13 SNPs from 8 interactive SNP pairs with strong interactive signals (−log10(p)>8) were carefully re-examined. The confirmatory study verified the association for a SNP quartet 219 kb and 495 kb downstream of LOC344371 (a hypothetical gene) and RASGRP3 on chromosome 2p22.3, respectively. The latter has been implicated in the abnormal vascular responsiveness to endothelin-1 and angiotensin II in diabetic-hypertensive rats. Intrinsic synergy involving IMPG1 on chromosome 6q14.2-q15 was also verified. IMPG1 encodes interphotoreceptor matrix proteoglycan 1 which has cation binding capacity. The genes are novel hypertension targets identified in this first genome-wide hypertension association study of the Han Chinese population