1,833 research outputs found
Stage-specific action of matrix metalloproteinases influences progressive hereditary kidney disease.
Get PDFBackgroundGlomerular basement membrane (GBM), a key component of the blood-filtration apparatus in the in the kidney, is formed through assembly of type IV collagen with laminins, nidogen, and sulfated proteoglycans. Mutations or deletions involving alpha3(IV), alpha4(IV), or alpha5(IV) chains of type IV collagen in the GBM have been identified as the cause for Alport syndrome in humans, a progressive hereditary kidney disease associated with deafness. The pathological mechanisms by which such mutations lead to eventual kidney failure are not completely understood.Methods and findingsWe showed that increased susceptibility of defective human Alport GBM to proteolytic degradation is mediated by three different matrix metalloproteinases (MMPs)--MMP-2, MMP-3, and MMP-9--which influence the progression of renal dysfunction in alpha3(IV)-/- mice, a model for human Alport syndrome. Genetic ablation of either MMP-2 or MMP-9, or both MMP-2 and MMP-9, led to compensatory up-regulation of other MMPs in the kidney glomerulus. Pharmacological ablation of enzymatic activity associated with multiple GBM-degrading MMPs, before the onset of proteinuria or GBM structural defects in the alpha3(IV)-/- mice, led to significant attenuation in disease progression associated with delayed proteinuria and marked extension in survival. In contrast, inhibition of MMPs after induction of proteinuria led to acceleration of disease associated with extensive interstitial fibrosis and early death of alpha3(IV)-/- mice.ConclusionsThese results suggest that preserving GBM/extracellular matrix integrity before the onset of proteinuria leads to significant disease protection, but if this window of opportunity is lost, MMP-inhibition at the later stages of Alport disease leads to accelerated glomerular and interstitial fibrosis. Our findings identify a crucial dual role for MMPs in the progression of Alport disease in alpha3(IV)-/- mice, with an early pathogenic function and a later protective action. Hence, we propose possible use of MMP-inhibitors as disease-preventive drugs for patients with Alport syndrome with identified genetic defects, before the onset of proteinuria
High Performance Computing Applications in Remote Sensing Studies for Land Cover Dynamics
Get PDFGlobal and regional land cover studies require the ability to apply complex models on selected subsets of large amounts of multi-sensor and multi-temporal data sets that have been derived from raw instrument measurements using widely accepted pre-processing algorithms. The computational and storage requirements of most such studies far exceed what is possible on a single workstation environment. We have been pursuing a new approach that couples scalable and open distributed heterogeneous hardware with the development of high performance software for processing, indexing, and organizing remotely sensed data. Hierarchical data management tools are used to ingest raw data, create metadata, and organize the archived data so as to automatically achieve computational load balancing among the available nodes and minimize I/O overheads. We illustrate our approach with four specific examples. The first is the development of the first fast operational scheme for the atmospheric correction of Landsat TM scenes, while the second example focuses on image segmentation using a novel hierarchical connected components algorithm. Retrieval of global BRDF (Bidirectional Reflectance Distribution Function) in the red and near infrared wavelengths using four years (1983 to 1986) of Pathfinder AVHRR Land (PAL) data set is the focus of our third example. The fourth example is the development of a hierarchical data organization scheme that allows on-demand processing and retrieval of regional and global AVHRR data sets. Our results show that substantial improvements in computational times can be achieved by using the high performance computing technology
Investigation of Axial and Angular Sampling in Multi-Detector Pinhole-SPECT Brain Imaging
Get PDFWe designed a dedicated multi-detector multi-pinhole brain SPECT scanner to generate images of higher quality compared to general-purpose systems. The system, AdaptiSPECT-C, is intended to adapt its sensitivity-resolution trade-off by varying its aperture configurations allowing both high-sensitivity dynamic and high-spatial-resolution static imaging. The current system design consists of 23 detector heads arranged in a truncated spherical geometry. In this work, we investigated the axial and angular sampling capability of the current stationary system design. Two data acquisition schemes using limited rotation of the gantry and two others using axial translation of the imaging bed were also evaluated concerning their impact on image quality through improved sampling. Increasing both angular and axial sampling in the current prototype system resulted in quantitative improvements in image quality metrics and qualitative appearance of the images as determined in studies with specifically selected phantoms. Visual improvements for the brain phantoms with clinical distributions were less pronounced but presented quantitative improvements in the fidelity (normalized root-mean-square error (NRMSE)) and striatal specific binding ratio (SBR) for a dopamine transporter (DAT) distribution, and in NRMSE and activity recovery for a brain perfusion distribution. More pronounced improvements with increased sampling were seen in contrast recovery coefficient, bias, and coefficient of variation for a lesion in the brain perfusion distribution. The negligible impact of the most cranial ring of detectors on axial sampling, but its significant impact on sensitivity and angular sampling in the cranial portion of the imaging volume-of-interest were also determined
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Stage-Specific Action of Matrix Metalloproteinases Influences Progressive Hereditary Kidney Disease
Get PDFBackground: Glomerular basement membrane (GBM), a key component of the blood-filtration apparatus in the in the kidney, is formed through assembly of type IV collagen with laminins, nidogen, and sulfated proteoglycans. Mutations or deletions involving 3(IV), 4(IV), or 5(IV) chains of type IV collagen in the GBM have been identified as the cause for Alport syndrome in humans, a progressive hereditary kidney disease associated with deafness. The pathological mechanisms by which such mutations lead to eventual kidney failure are not completely understood. Methods and Findings: We showed that increased susceptibility of defective human Alport GBM to proteolytic degradation is mediated by three different matrix metalloproteinases (MMPs)—MMP-2, MMP-3, and MMP-9—which influence the progression of renal dysfunction in mice, a model for human Alport syndrome. Genetic ablation of either MMP-2 or MMP-9, or both MMP-2 and MMP-9, led to compensatory up-regulation of other MMPs in the kidney glomerulus. Pharmacological ablation of enzymatic activity associated with multiple GBM-degrading MMPs, before the onset of proteinuria or GBM structural defects in the mice, led to significant attenuation in disease progression associated with delayed proteinuria and marked extension in survival. In contrast, inhibition of MMPs after induction of proteinuria led to acceleration of disease associated with extensive interstitial fibrosis and early death of 3(IV)−/− mice. Conclusions: These results suggest that preserving GBM/extracellular matrix integrity before the onset of proteinuria leads to significant disease protection, but if this window of opportunity is lost, MMP-inhibition at the later stages of Alport disease leads to accelerated glomerular and interstitial fibrosis. Our findings identify a crucial dual role for MMPs in the progression of Alport disease in mice, with an early pathogenic function and a later protective action. Hence, we propose possible use of MMP-inhibitors as disease-preventive drugs for patients with Alport syndrome with identified genetic defects, before the onset of proteinuria
Inclusion of quasi-vertex views in a brain-dedicated multi-pinhole SPECT system for improved imaging performance
Get PDFWith brain-dedicated multi-detector systems employing pinhole apertures the usage of detectors facing the top of the patient\u27s head (i.e., quasi-vertex views) can provide the advantage of additional viewing from close to the brain for improved detector coverage. In this paper, we report the results of simulation and reconstruction studies to investigate the impact of the quasi-vertex views on the imaging performance of AdaptiSPECT-C, a brain-dedicated stationary SPECT system under development. In this design, both primary and scatter photons from regions located inferior to the brain can contribute to SPECT projections acquired by the quasi-vertex views, and thus degrade AdaptiSPECT-C imaging performance. In this work, we determined the proportion, origin, and nature (i.e., primary, scatter, and multiple-scatter) of counts emitted from structures within the head and throughout the body contributing to projections from the different AdaptiSPECT-C detector rings, as well as from a true vertex view detector. We simulated phantoms used to assess different aspects of image quality (i.e., uniform sphere and Derenzo), as well as anthropomorphic phantoms with multiple count levels emulating clinical(123)I activity distributions (i.e., DaTscan and perfusion). We determined that attenuation and scatter in the patient\u27s body greatly diminish the probability of the photons emitted outside the volume of interest reaching to detectors and being recorded within the 15% photopeak energy window. In addition, we demonstrated that the inclusion of the residual of such counts in the system acquisition does not degrade visual interpretation or quantitative analysis. The addition of the quasi-vertex detectors increases volumetric sensitivity, angular sampling, and spatial resolution leading to significant enhancement in image quality, especially in the striato-thalamic and superior regions of the brain. Besides, the use of quasi-vertex detectors improves the recovery of clinically relevant metrics such as the striatal binding ratio and mean activity in selected cerebral structures
Efficiency of gene silencing in \u3ci\u3eArabidopsis\u3c/i\u3e: direct inverted repeats vs. transitive RNAi vectors
Get PDFWe investigated the efficiency of RNA interference (RNAi) in Arabidopsis using transitive and homologous inverted repeat (hIR) vectors. hIR constructs carry self-complementary intron-spliced fragments of the target gene whereas transitive vectors have the target sequence fragment adjacent to an intron-spliced, inverted repeat of heterologous origin. Both transitive and hIR constructs facilitated specific and heritable silencing in the three genes studied (AP1 , ETTIN and TTG1 ). Both types of vectors produced a phenotypic series that phenocopied reduction of function mutants for the respective target gene. The hIR yielded up to fourfold higher proportions of events with strongly manifested reduction of function phenotypes compared to transitive RNAi. We further investigated the efficiency and potential off-target effects of AP1 silencing by both types of vectors using genome-scale microarrays and quantitative RT-PCR. The depletion of AP1 transcripts coincided with reduction of function phenotypic changes among both hIR and transitive lines and also showed similar expression patterns among differentially regulated genes. We did not detect significant silencing directed against homologous potential off-target genes when constructs were designed with minimal sequence similarity. Both hIR and transitive methods are useful tools in plant biotechnology and genomics. The choice of vector will depend on specific objectives such as cloning throughput, number of events and degree of suppression required
Multi-cancer computational analysis reveals invasion-associated variant of desmoplastic reaction involving INHBA, THBS2 and COL11A1
Get PDF<p>Abstract</p> <p>Background</p> <p>Despite extensive research, the details of the biological mechanisms by which cancer cells acquire motility and invasiveness are largely unknown. This study identifies an invasion associated gene signature shedding light on these mechanisms.</p> <p>Methods</p> <p>We analyze data from multiple cancers using a novel computational method identifying sets of genes whose coordinated overexpression indicates the presence of a particular phenotype, in this case high-stage cancer.</p> <p>Results</p> <p>We conclude that there is one shared "core" metastasis-associated gene expression signature corresponding to a specific variant of stromal desmoplastic reaction, present in a large subset of samples that have exceeded a threshold of invasive transition specific to each cancer, indicating that the corresponding biological mechanism is triggered at that point. For example this threshold is reached at stage IIIc in ovarian cancer and at stage II in colorectal cancer. Therefore, its presence indicates that the corresponding stage has been reached. It has several features, such as coordinated overexpression of particular collagens, mainly <it>COL11A1 </it>and other genes, mainly <it>THBS2 </it>and <it>INHBA</it>. The composition of the overexpressed genes indicates invasion-facilitating altered proteolysis in the extracellular matrix. The prominent presence in the signature of INHBA in all cancers strongly suggests a biological mechanism centered on activin A induced TGF-β signaling, because activin A is a member of the TGF-β superfamily consisting of an INHBA homodimer. Furthermore, we establish that the signature is predictive of neoadjuvant therapy response in at least one breast cancer data set.</p> <p>Conclusions</p> <p>Therefore, these results can be used for developing high specificity biomarkers sensing cancer invasion and predicting response to neoadjuvant therapy, as well as potential multi-cancer metastasis inhibiting therapeutics targeting the corresponding biological mechanism.</p
Dynamic Monitoring of Cellular Remodeling Induced by the Transforming Growth Factor-β1
Get PDFThe plasticity of differentiated adult cells could have a great therapeutic potential, but at the same time, it is characteristic of progression of serious pathological states such as cancer and fibrosis. In this study, we report on the application of a real-time noninvasive system for dynamic monitoring of cellular plasticity. Analysis of the cell impedance profile recorded as cell index using a real-time cell analyzer revealed its significant increase after the treatment of prostate epithelial cells with the transforming growth factor-β1. Changes in the cell index profile were paralleled with cytoskeleton rebuilding and induction of epithelial–mesenchymal transition and negatively correlated with cell proliferation. This novel application of such approach demonstrated a great potential of the impedance-based system for noninvasive and real-time monitoring of cellular fate
Diabetes Complications: The MicroRNA Perspective
Get PDFThere remains a critical need to better understandthe underlying disease mechanisms responsiblefor diabetes complications in order to developnew and improved therapeutic strategies for these chronic conditions. These complications are broadly classified as microvascular, including neuropathy, nephrop-athy, and retinopathy, or macrovascular, including car-diovascular and peripheral vascular disease. The risk for developing complications is influenced by many factors including duration of diabetes and genetic factors. Current treatments have resulted in only a partial reduction in this risk, and the management of these conditions remains a major unmet need for those with diabetes. New insights have come from an unlikely ally, the worm C. elegans, in which research has identified a novel family of endoge-nous, small (;22 nucleotides), single stranded, noncoding RNA molecules known as microRNAs (miRNAs) as de-velopmental regulators (1,2). These molecules, only iden
Understanding the links between hearing impairment and dementia : development and validation of the social and emotional impact of hearing impairment (SEI-HI) questionnaire
Get PDFBackground
The links between hearing impairment (HI) and dementia have been well documented, but factors mediating this relationship remain unknown. Major consequences of HI are social and emotional dysfunction, and as the risk of dementia increases linearly with the severity of HI, it is plausible that socio-emotional difficulties may play a role in this association.
Objective
The aim of this study was to develop and validate a tool to analyse levels of hearing-related disability, to investigate ultimately whether subjective disability contributes to risk of cognitive impairment compared with hearing thresholds alone.
Methods
Development and validation of the questionnaire, the Social and Emotional Impact of Hearing Impairment (SEI-HI), was conducted in four phases: (1) content; (2) scoring and outcomes; (3) validation; (4) feasibility in a sample of people with cognitive impairment.
Results
Considerable evidence was found for the internal and external reliability of the tool with high construct validity, concurrent validity and test-retest values of the SEI-HI questionnaire. A feasibility check on 31 patients with mild cognitive impairment or dementia showed the SEI-HI questionnaire was easy to administer and well-received.
Conclusion
The SEI-HI questionnaire is a relevant instrument to assess hearing-related disability which can be used in people with cognitive decline to assess further impact on risk of developing dementia
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