Natriuretic peptide receptor-C is up-regulated in the intima of advanced carotid artery atherosclerosis

OBJECTIVE: Natriuretic peptide receptor-C (NPR-C/NPR-3) is a cell surface protein involved in vascular remodelling that is up-regulated in atherosclerosis. NPR-C expression has not been well characterized in human carotid artery occlusive lesions. We hypothesized that NPR-C expression correlates with intimal features of vulnerable atherosclerotic carotid artery plaque. METHODS: To test this hypothesis, we evaluated NPR-C expression by immunohistochemistry (IHC) in carotid endarterectomy (CEA) specimens isolated from 18 patients. The grade, location, and co-localization of NPR-C in CEA specimens were evaluated using two tissue analysis techniques. RESULTS: Relative to minimally diseased CEA specimens, we observed avid NPR-C tissue staining in the intima of maximally diseased CEA specimens (65%; p=0.06). Specifically, maximally diseased CEA specimens demonstrated increased NPR-C expression in the superficial intima (61%, p=0.17), and deep intima (138% increase; p=0.05). In the superficial intima, NPR-C expression significantly co-localized with vascular smooth muscle cells (VSMCs) and macrophages. The intensity of NPR-C expression was also higher in the superficial intima plaque shoulder and cap regions, and significantly correlated with atheroma and fibroatheroma vulnerable plaque regions (β=1.04, 95% CI=0.46, 1.64). CONCLUSION: These findings demonstrate significant NPR-C expression in the intima of advanced carotid artery plaques. Furthermore, NPR-C expression was higher in vulnerable carotid plaque intimal regions, and correlate with features of advanced disease. Our findings suggest that NPR-C may serve as a potential biomarker for carotid plaque vulnerability and progression, in patients with advanced carotid artery occlusive disease

Ökologie, Virulenz und Genomanalyse von Legionella pneumophila Isolaten aus der West Bank, Palästina

Legionella pneumophila is an environmental bacterium and a human pathogen causing life-threating outbreaks of an atypical pneumonia called Legionnaires’ disease. This study aimed to understand the diversity of L. pneumophila isolates, their clonal populations and the environmental driver of their abundance and prevalence in the West Bank. For this, a multi-annual seasonal sampling of nine drinking water sites in the West Bank were performed with a detailed recording of physico-chemical parameters. A total of 180 L. pneumophila isolates were obtained and analysed by high resolution genotyping (Multi-Locus Variable Number of Tandem Repeats (MLVA-8(12)). Also, physiological and virulence traits were studied. Genotyping and the studied traits led to the selection of representative strains submitted to high through-put genome sequencing (Illumina HiSeq and Pacific Biosciences platforms). Analysis of genotype prevalence in correspondence to environmental factors was used to elucidate genotype consortia and their environmental niches. The 180 isolates represented twenty-six individual MLVA-8(12) genotypes (Gt). The most frequently genotype was Gt4(17) (41.1%). All MLVA genotypes were clustered into four MLVA clonal complexes. Analysis of the prevalence of genotype indicated genotype consortia that seemed to be triggered by a set of environmental drivers. The concentration of several ions (Mg, Ca, Cl, SO4 and TDS) and turbidity seemed to determine niches for three different sets of genotypes and may explain their regional variability. Also, the abundance of L. pneumophila was influenced by these environmental drivers with Mg having a negative effect. The virulence of a representative subset of sixty environmental strains was assessed by five different in-vitro assays. Virulence traits were shown to be genotype dependent. A carefully selected subset of thirty-eight L. pneumophila isolates were genome sequenced and compared to already published reference genomes. Genome sequences were aligned with the sequence of the respective reference genome and analysed with respect to core-single nucleotide polymorphisms (core-SNPs), genomic islands and genes related to virulence traits. Overall, this study provided important insights into detailed population structure, the ecology and pathogenicity of this pathogen in the West Bank.Legionella pneumophila ist ein Umweltbakterium in Süsswassersystemen und humanpathogen; es verursacht lebensbedrohliche Ausbrüche der Legionärskrankheit, einer atypischen Pneumonie. Das Ziel der Doktorarbeit ist es, in der West Bank die Diversität von L. pneumophila-Isolaten, ihre clonale Populationsstruktur und die wesentlichen Umweltfaktoren, die Abundanz und Prävalenz steuern, zu verstehen. Hierzu wurde ein mehrjähriges saisonales Probenahmeprogramm für 9 Trinkwasserprobe-nahmestellen repräsentatv für die West Bank durchgeführt, bei dem physico-chemische und mikrobiologische Parameter mitaufgezeichnet wurden. 180 Isolate wurden hierbei gewonnen, hochauflösend genotypisiert (Multi-Locus Variable Number of Tandem Repeats (MLVA-8(12)), und hinsichtlich relevanter physiologischer Eigenschaften und Virulenzfaktoren analysiert. Die umfassende Charakterisierung der Isolate bildete die Grundlage zur Auswahl repräsentativer Stämme für die Genomsequenzierung mittels Illumina HiSeq und der Pac-Biosciences Platform. Die statistische Analyse von regionaler Genotypprävalenz und Umweltfaktoren wurde dazu genutzt um Genotypkonsortien und ihre Umweltnischen zu charakterisieren. Die 180 Isolate aus der Westbank zeigten eine hohe Genotypdiversität von 26 MLVA-8(12)-Genotypen, zugehörig zu vier MLVA clonalen Komplexen. Analysen der Prävalenz von Genotypen im Hinblick auf Umweltfaktoren zeigte, daß Konsortien von Genotypen durch Umweltfaktoren getriggert wurden. Unterschiedliche Konzentrationen von Ionen im Trinkwasser (Mg, Ca, Cl, SO4, TDS) and Trübung schienen Nischen für drei unterschiedliche Konsortien von Genotypen zu bestimmen, und könnten die räumliche Variabilität der Genotypen in der West Bank erklären und die Abundanz von L. pneumophila zu beeinflussen. Dabei schien Mg eine relevante Rolle zu spielen. Die Virulenz einer repräsentativen Untergruppe von 60 Isolaten wurde mit 5 in-vitro Ansätzen getestet. Die Virulenzstärke variierte in Abhängigkeit vom Genotyp mit relativ hoher Virulenz der häufigen Genotypen Gt4(17) und Gt6(18). Eine repräsentative Auswahl von 38 L. pneumophila Isolaten wurden genomsequenziert und mit Referenzgenomen und generierten eigenen Referenzgenomen verglichen, und hinsichtlich core-SNPs, genomischen Inseln und Virulenz-assoziierten Genen analysiert. Insgesamt gesehen, liefert die vorliegende Studie wichtige Einblicke zum Verständnis von Populationsstruktur, Ökologie und Pathogenität dieses pathogenen Bakteriums in der West Bank

On Fields with Finite Information Density

The existence of a natural ultraviolet cutoff at the Planck scale is widely expected. In a previous Letter, it has been proposed to model this cutoff as an information density bound by utilizing suitably generalized methods from the mathematical theory of communication. Here, we prove the mathematical conjectures that were made in this Letter.Comment: 31 pages, to appear in Phys.Rev.

An extensive computational approach to analyze and characterize the functional mutations in the galactose-1-phosphate uridyl transferase (GALT) protein responsible for classical galactosemia

Type I galactosemia is a very rare autosomal recessive genetic metabolic disorder that occurs because of the mutations present in the galactose-1-phosphate uridyl transferase (GALT) gene, resulting in a deficiency of the GALT enzyme. The action of the GALT enzyme is to convert galactose-1-phosphate and uridine diphosphate glucose into glucose-1-phosphate (G1P) and uridine diphosphate-galactose, a crucial second step of the Leloir pathway. A missense mutation in the GALT enzyme leads to variable galactosemia's clinical presentations, ranging from mild to severe. Our study aimed to employ a comprehensive computational pipeline to analyze the most prevalent missense mutations (p.S135L, p.K285 N, p.Q188R, and p.N314D) responsible for galactosemia; these genes could serve as potential targets for chaperone therapy. We analyzed the four mutations through different computational analyses, including amino acid conservation, in silico pathogenicity and stability predictions, and macromolecular simulations (MMS) at 50 ns The stability and pathogenicity predictors showed that the p.Q188R and p.S135L mutants are the most pathogenic and destabilizing. In agreement with these results, MMS analysis demonstrated that the p.Q188R and p.S135L mutants possess higher deviation patterns, reduced compactness, and intramolecular H-bonds of the protein. This could be due to the physicochemical modifications that occurred in the mutants p.S135L and p.Q188R compared to the native. Evolutionary conservation analysis revealed that the most prevalent mutations positions were conserved among different species except N314. The proposed research study is intended to provide a basis for the therapeutic development of drugs and future treatment of classical galactosemia and possibly other genetic diseases using chaperone therapy

A study of the gravitational wave form from pulsars II

We present analytical and numerical studies of the Fourier transform (FT) of the gravitational wave (GW) signal from a pulsar, taking into account the rotation and orbital motion of the Earth. We also briefly discuss the Zak-Gelfand Integral Transform. The Zak-Gelfand Integral Transform that arises in our analytic approach has also been useful for Schrodinger operators in periodic potentials in condensed matter physics (Bloch wave functions).Comment: 6 pages, Sparkler talk given at the Amaldi Conference on Gravitational waves, July 10th, 2001. Submitted to Classical and Quantum Gravit

Analysis of differentially expressed genes and molecular pathways in familial hypercholesterolemia involved in atherosclerosis: A systematic and bioinformatics approach

Background and Aims: Familial hypercholesterolemia (FH) is one of the major risk factor for the progression of atherosclerosis and coronary artery disease. This study focused on identifying the dysregulated molecular pathways and core genes that are differentially regulated in FH and to identify the possible genetic factors and potential underlying mechanisms that increase the risk to atherosclerosis in patients with FH. Methods: The Affymetrix microarray dataset (GSE13985) from the GEO database and the GEO2R statistical tool were used to identify the differentially expressed genes (DEGs) from the white blood cells (WBCs) of five heterozygous FH patients and five healthy controls. The interaction between the DEGs was identified by applying the STRING tool and visualized using Cytoscape software. MCODE was used to determine the gene cluster in the interactive networks. The identified DEGs were subjected to the DAVID v6.8 webserver and ClueGo/CluePedia for functional annotation, such as gene ontology (GO) and enriched molecular pathway analysis of DEGs. Results: We investigated the top 250 significant DEGs (p-value < 0.05; fold two change ≥ 1 or ≤ −1). The GO analysis of DEGs with significant differences revealed that they are involved in critical biological processes and molecular pathways, such as myeloid cell differentiation, peptidyl-lysine modification, signaling pathway of MyD88-dependent Toll-like receptor, and cell-cell adhesion. The analysis of enriched KEGG pathways revealed the association of the DEGs in ubiquitin-mediated proteolysis and cardiac muscle contraction. The genes involved in the molecular pathways were shown to be differentially regulated by either activating or inhibiting the genes that are essential for the canonical signaling pathways. Our study identified seven core genes (UQCR11, UBE2N, ADD1, TLN1, IRAK3, LY96, and MAP3K1) that are strongly linked to FH and lead to a higher risk of atherosclerosis. Conclusion: We identified seven core genes that represent potential molecular biomarkers for the diagnosis of atherosclerosis and might serve as a platform for developing therapeutics against both FH and atherosclerosis. However, functional studies are further needed to validate their role in the pathogenesis of FH and atherosclerosis

Exploiting macrophage autophagy-lysosomal biogenesis as a therapy for atherosclerosis

Macrophages specialize in removing lipids and debris present in the atherosclerotic plaque. However, plaque progression renders macrophages unable to degrade exogenous atherogenic material and endogenous cargo including dysfunctional proteins and organelles. Here we show that a decline in the autophagy-lysosome system contributes to this as evidenced by a derangement in key autophagy markers in both mouse and human atherosclerotic plaques. By augmenting macrophage TFEB, the master transcriptional regulator of autophagy-lysosomal biogenesis, we can reverse the autophagy dysfunction of plaques, enhance aggrephagy of p62-enriched protein aggregates and blunt macrophage apoptosis and pro-inflammatory IL-1β levels, leading to reduced atherosclerosis. In order to harness this degradative response therapeutically, we also describe a natural sugar called trehalose as an inducer of macrophage autophagy-lysosomal biogenesis and show trehalose's ability to recapitulate the atheroprotective properties of macrophage TFEB overexpression. Our data support this practical method of enhancing the degradative capacity of macrophages as a therapy for atherosclerotic vascular disease

Genetic Epidemiology of Glucose-6-Dehydrogenase Deficiency in the Arab World

A systematic search was implemented using four literature databases (PubMed, Embase, Science Direct and Web of Science) to capture all the causative mutations of Glucose-6-phosphate dehydrogenase (G6PD) deficiency (G6PDD) in the 22 Arab countries. Our search yielded 43 studies that captured 33 mutations (23 missense, one silent, two deletions, and seven intronic mutations), in 3,430 Arab patients with G6PDD. The 23 missense mutations were then subjected to phenotypic classification using in silico prediction tools, which were compared to the WHO pathogenicity scale as a reference. These in silico tools were tested for their predicting efficiency using rigorous statistical analyses. Of the 23 missense mutations, p.S188F, p.I48T, p.N126D, and p.V68M, were identified as the most common mutations among Arab populations, but were not unique to the Arab world, interestingly, our search strategy found four other mutations (p.N135T, p.S179N, p.R246L, and p.Q307P) that are unique to Arabs. These mutations were exposed to structural analysis and molecular dynamics simulation analysis (MDSA), which predicting these mutant forms as potentially affect the enzyme function. The combination of the MDSA, structural analysis, and in silico predictions and statistical tools we used will provide a platform for future prediction accuracy for the pathogenicity of genetic mutations.QUST-CAS-FALL-15/16-24 gran

A Monitoring System for Crimean Congo Hemorrhagic Fever Epidemiology Studies in Afghanistan

In the last few years, tick-borne diseases have been reported as a resurging in the Middle East. Crimean-Congo hemorrhagic fever (CCHF) is endemic in the Middle East, including Turkey, Iran, Afghanistan and Pakistan. Recent studies have explored the causal link between environmental and disease incidence patterns by correlating remote sensing indicators (surface temperature, rainfall, and vegetation indices of plant photosynthetic activity) with spatially explicit epidemiological data. We combined the monitoring of environmental data at monthly temporal resolutions with available reports of confirmed CCHF cases to identify the environmental properties of endemic regions and quantify those properties to CCHF risk. We also conducted a sero-prevalence survey in a sample of households (human and animal specimens) in 9 villages in Engil district surrounding Herat province, in western Afghanistan. We present analysis results from our study villages and validate the associated environmental conditions as predictive for human disease occurrences. Risk prediction is critical for anticipating the type and potential impact of disease threats for timely response action

efam: an expanded, metaproteome-supported HMM profile database of viral protein families

Motivation: Viruses infect, reprogram and kill microbes, leading to profound ecosystem consequences, from elemental cycling in oceans and soils to microbiome-modulated diseases in plants and animals. Although metagenomic datasets are increasingly available, identifying viruses in them is challenging due to poor representation and annotation of viral sequences in databases. Results: Here, we establish efam, an expanded collection of Hidden Markov Model (HMM) profiles that represent viral protein families conservatively identified from the Global Ocean Virome 2.0 dataset. This resulted in 240 311 HMM profiles, each with at least 2 protein sequences, making efam >7-fold larger than the next largest, panecosystem viral HMM profile database. Adjusting the criteria for viral contig confidence from 'conservative' to 'eXtremely Conservative' resulted in 37 841 HMM profiles in our efam-XC database. To assess the value of this resource, we integrated efam-XC into VirSorter viral discovery software to discover viruses from less-studied, ecologically distinct oxygen minimum zone (OMZ) marine habitats. This expanded database led to an increase in viruses recovered from every tested OMZ virome by similar to 24% on average (up to similar to 42%) and especially improved the recovery of often-missed shorter contigs (<5 kb). Additionally, to help elucidate lesser-known viral protein functions, we annotated the profiles using multiple databases from the DRAM pipeline and virion-associated metaproteomic data, which doubled the number of annotations obtainable by standard, single-database annotation approaches. Together, these marine resources (efam and efam-XC) are provided as searchable, compressed HMM databases that will be updated bi-annually to help maximize viral sequence discovery and study from any ecosystem