HIV's evasion of the cellular immune response

Despite a strong cytotoxic T-lymphocyte (CTL) response directed against viral antigens, untreated individuals infected with the human immunodeficiency virus (HIV-1) develop AIDS, We have found that primary T cells infected with HIV-1 downregulate surface MHC class I antigens and are resistant to lysis by HLA-A2-restricted CTL clones. In contrast, cells infected with an HIV-1 in which the nef gene is disrupted are sensitive to CTLs in an MHC and peptide-specific manner. In primary T cells HLA-A2 antigens are downmodulated more dramatically than total MHC class I antigens, suggesting that nef selectively downmodulates certain MHC class I antigens. In support of this, studies on ceils expressing individual MHC class I alietes have revealed that nef does not downmodulate HLA-C and HLA-E antigens, This selective downmodulation allows Infected cells to maintain resistance to certain natural killer cells that lyse infected cells expressing low levels of MHC class I antigens. Downmodulation of MHC class I HLA-A2 antigens occurs not only in primary T cells, but also in B and astrocytoma cell lines. No effect of other HIV-1 accessory proteins such as vpu and vpr was observed. Thus Nef is a protein that may promote escape of HIV-1 from immune surveillance.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75570/1/j.1600-065X.1999.tb01283.x.pd

Bootstrap, Bayesian probability and maximum likelihood mapping: exploring new tools for comparative genome analyses

BACKGROUND: Horizontal gene transfer (HGT) played an important role in shaping microbial genomes. In addition to genes under sporadic selection, HGT also affects housekeeping genes and those involved in information processing, even ribosomal RNA encoding genes. Here we describe tools that provide an assessment and graphic illustration of the mosaic nature of microbial genomes. RESULTS: We adapted the Maximum Likelihood (ML) mapping to the analyses of all detected quartets of orthologous genes found in four genomes. We have automated the assembly and analyses of these quartets of orthologs given the selection of four genomes. We compared the ML-mapping approach to more rigorous Bayesian probability and Bootstrap mapping techniques. The latter two approaches appear to be more conservative than the ML-mapping approach, but qualitatively all three approaches give equivalent results. All three tools were tested on mitochondrial genomes, which presumably were inherited as a single linkage group. CONCLUSIONS: In some instances of interphylum relationships we find nearly equal numbers of quartets strongly supporting the three possible topologies. In contrast, our analyses of genome quartets containing the cyanobacterium Synechocystis sp. indicate that a large part of the cyanobacterial genome is related to that of low GC Gram positives. Other groups that had been suggested as sister groups to the cyanobacteria contain many fewer genes that group with the Synechocystis orthologs. Interdomain comparisons of genome quartets containing the archaeon Halobacterium sp. revealed that Halobacterium sp. shares more genes with Bacteria that live in the same environment than with Bacteria that are more closely related based on rRNA phylogeny . Many of these genes encode proteins involved in substrate transport and metabolism and in information storage and processing. The performed analyses demonstrate that relationships among prokaryotes cannot be accurately depicted by or inferred from the tree-like evolution of a core of rarely transferred genes; rather prokaryotic genomes are mosaics in which different parts have different evolutionary histories. Probability mapping is a valuable tool to explore the mosaic nature of genomes

Calpain 3 is important for muscle regeneration: Evidence from patients with limb girdle muscular dystrophies

<p>Abstract</p> <p>Background</p> <p>Limb girdle muscular dystrophy (LGMD) type 2A is caused by mutations in the CAPN3 gene and complete lack of functional calpain 3 leads to the most severe muscle wasting. Calpain 3 is suggested to be involved in maturation of contractile elements after muscle degeneration. The aim of this study was to investigate how mutations in the four functional domains of calpain 3 affect muscle regeneration.</p> <p>Methods</p> <p>We studied muscle regeneration in 22 patients with LGMD2A with calpain 3 deficiency, in five patients with LGMD2I, with a secondary reduction in calpain 3, and in five patients with Becker muscular dystrophy (BMD) with normal calpain 3 levels. Regeneration was assessed by using the developmental markers neonatal myosin heavy chain (nMHC), vimentin, MyoD and myogenin and counting internally nucleated fibers.</p> <p>Results</p> <p>We found that the recent regeneration as determined by the number of nMHC/vimentin-positive fibers was greatly diminished in severely affected LGMD2A patients compared to similarly affected patients with LGMD2I and BMD. Whorled fibers, a sign of aberrant regeneration, was highly elevated in patients with a complete lack of calpain 3 compared to patients with residual calpain 3. Regeneration is not affected by location of the mutation in the <it>CAPN3 </it>gene.</p> <p>Conclusions</p> <p>Our findings suggest that calpain 3 is needed for the regenerative process probably during sarcomere remodeling as the complete lack of functional calpain 3 leads to the most severe phenotypes.</p

The chemical interactome space between the human host and the genetically defined gut metabotypes

The bacteria that colonize the gastrointestinal tracts of mammals represent a highly selected microbiome that has a profound influence on human physiology by shaping the host's metabolic and immune system activity. Despite the recent advances on the biological principles that underlie microbial symbiosis in the gut of mammals, mechanistic understanding of the contributions of the gut microbiome and how variations in the metabotypes are linked to the host health are obscure. Here, we mapped the entire metabolic potential of the gut microbiome based solely on metagenomics sequencing data derived from fecal samples of 124 Europeans (healthy, obese and with inflammatory bowel disease). Interestingly, three distinct clusters of individuals with high, medium and low metabolic potential were observed. By illustrating these results in the context of bacterial population, we concluded that the abundance of the Prevotella genera is a key factor indicating a low metabolic potential. These metagenome-based metabolic signatures were used to study the interaction networks between bacteria-specific metabolites and human proteins. We found that thirty-three such metabolites interact with disease-relevant protein complexes several of which are highly expressed in cells and tissues involved in the signaling and shaping of the adaptive immune system and associated with squamous cell carcinoma and bladder cancer. From this set of metabolites, eighteen are present in DrugBank providing evidence that we carry a natural pharmacy in our guts. Furthermore, we established connections between the systemic effects of non-antibiotic drugs and the gut microbiome of relevance to drug side effects and health-care solutions.link_to_subscribed_fulltex

The Connectome Visualization Utility: Software for Visualization of Human Brain Networks

In analysis of the human connectome, the connectivity of the human brain is collected from multiple imaging modalities and analyzed using graph theoretical techniques. The dimensionality of human connectivity data is high, and making sense of the complex networks in connectomics requires sophisticated visualization and analysis software. The current availability of software packages to analyze the human connectome is limited. The Connectome Visualization Utility (CVU) is a new software package designed for the visualization and network analysis of human brain networks. CVU complements existing software packages by offering expanded interactive analysis and advanced visualization features, including the automated visualization of networks in three different complementary styles and features the special visualization of scalar graph theoretical properties and modular structure. By decoupling the process of network creation from network visualization and analysis, we ensure that CVU can visualize networks from any imaging modality. CVU offers a graphical user interface, interactive scripting, and represents data uses transparent neuroimaging and matrix-based file types rather than opaque application-specific file formats

Seminal Plasma Enhances Cervical Adenocarcinoma Cell Proliferation and Tumour Growth In Vivo

Cervical cancer is one of the leading causes of cancer-related death in women in sub-Saharan Africa. Extensive evidence has shown that cervical cancer and its precursor lesions are caused by Human papillomavirus (HPV) infection. Although the vast majority of HPV infections are naturally resolved, failure to eradicate infected cells has been shown to promote viral persistence and tumorigenesis. Furthermore, following neoplastic transformation, exposure of cervical epithelial cells to inflammatory mediators either directly or via the systemic circulation may enhance progression of the disease. It is well recognised that seminal plasma contains an abundance of inflammatory mediators, which are identified as regulators of tumour growth. Here we investigated the role of seminal plasma in regulating neoplastic cervical epithelial cell growth and tumorigenesis. Using HeLa cervical adenocarcinoma cells, we found that seminal plasma (SP) induced the expression of the inflammatory enzymes, prostaglandin endoperoxide synthase (PTGS1 and PTGS2), cytokines interleukin (IL) -6, and -11 and vascular endothelial growth factor-A(VEGF-A). To investigate the role of SP on tumour cell growth in vivo, we xenografted HeLa cells subcutaneously into the dorsal flank of nude mice. Intra-peritoneal administration of SP rapidly and significantly enhanced the tumour growth rate and size of HeLa cell xenografts in nude mice. As observed in vitro, we found that SP induced expression of inflammatory PTGS enzymes, cytokines and VEGF-A in vivo. Furthermore we found that SP enhances blood vessel size in HeLa cell xenografts. Finally we show that SP-induced cytokine production, VEGF-A expression and cell proliferation are mediated via the induction of the inflammatory PTGS pathway

Epstein-Barr Virus Nuclear Antigen 3C Facilitates G1-S Transition by Stabilizing and Enhancing the Function of Cyclin D1

EBNA3C, one of the Epstein-Barr virus (EBV)-encoded latent antigens, is essential for primary B-cell transformation. Cyclin D1, a key regulator of G1 to S phase progression, is tightly associated and aberrantly expressed in numerous human cancers. Previously, EBNA3C was shown to bind to Cyclin D1 in vitro along with Cyclin A and Cyclin E. In the present study, we provide evidence which demonstrates that EBNA3C forms a complex with Cyclin D1 in human cells. Detailed mapping experiments show that a small N-terminal region which lies between amino acids 130–160 of EBNA3C binds to two different sites of Cyclin D1- the N-terminal pRb binding domain (residues 1–50), and C-terminal domain (residues 171–240), known to regulate Cyclin D1 stability. Cyclin D1 is short-lived and ubiquitin-mediated proteasomal degradation has been targeted as a means of therapeutic intervention. Here, we show that EBNA3C stabilizes Cyclin D1 through inhibition of its poly-ubiquitination, and also increases its nuclear localization by blocking GSK3β activity. We further show that EBNA3C enhances the kinase activity of Cyclin D1/CDK6 which enables subsequent ubiquitination and degradation of pRb. EBNA3C together with Cyclin D1-CDK6 complex also efficiently nullifies the inhibitory effect of pRb on cell growth. Moreover, an sh-RNA based strategy for knock-down of both cyclin D1 and EBNA3C genes in EBV transformed lymphoblastoid cell lines (LCLs) shows a significant reduction in cell-growth. Based on these results, we propose that EBNA3C can stabilize as well as enhance the functional activity of Cyclin D1 thereby facilitating the G1-S transition in EBV transformed lymphoblastoid cell lines

Dense sampling of bird diversity increases power of comparative genomics (vol 587, pg 252, 2020)

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Characterization of Functional and Structural Integrity in Experimental Focal Epilepsy: Reduced Network Efficiency Coincides with White Matter Changes

BACKGROUND: Although focal epilepsies are increasingly recognized to affect multiple and remote neural systems, the underlying spatiotemporal pattern and the relationships between recurrent spontaneous seizures, global functional connectivity, and structural integrity remain largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: Here we utilized serial resting-state functional MRI, graph-theoretical analysis of complex brain networks and diffusion tensor imaging to characterize the evolution of global network topology, functional connectivity and structural changes in the interictal brain in relation to focal epilepsy in a rat model. Epileptic networks exhibited a more regular functional topology than controls, indicated by a significant increase in shortest path length and clustering coefficient. Interhemispheric functional connectivity in epileptic brains decreased, while intrahemispheric functional connectivity increased. Widespread reductions of fractional anisotropy were found in white matter regions not restricted to the vicinity of the epileptic focus, including the corpus callosum. CONCLUSIONS/SIGNIFICANCE: Our longitudinal study on the pathogenesis of network dynamics in epileptic brains reveals that, despite the locality of the epileptogenic area, epileptic brains differ in their global network topology, connectivity and structural integrity from healthy brains

Products of cells from gliomas: IX. Evidence that two fundamentally different mechanisms change extracellular matrix expression by gliomas

Four human astrocytic gliomas of high grade of malignancy were each evaluated in tissue and in vitro for percentages of cells expressing glial fibrillary acidic protein (GFAP), collagen type IV, laminin and fibronectin assessed by immunofluorescence with counterstaining of nuclear DNA. Percentages of cells with reticulin and cells binding fluorescein-labeled Ulex europaeus agglutinin were also assessed. In tissue, each extracellular matrix (ECM) component was associated with cells in the walls of abnormal proliferations of glioma vessels, and all four tumors had the same staining pattern. Two strikingly different patterns of conversion of gene product expression emerged during in vitro cultivation. (1). In the most common pattern, percentages of all six markers consistently shifted toward the exact phenotype of mesenchymal cells in abnormal vascular proliferations: increased reticulin, collagen type IV, laminin and fibronectin; markedly decreased glial marker GFAP and absent endothelial marker Ulex europaeus agglutinin. The simplest explanation of this constellation of changes coordinated toward expression of vascular ECM markers is that primary glioma cell cultures are overgrown by mesenchymal cells from the abnormal vascular proliferations of the original glioma. These cell cultures were tested for in situ hybridization (ISH) signals of chromosomes 7 and 10. Cells from one glioma had diploid signals. Cells from the other glioma had aneuploid signals indicating they were neoplastic; however, their signals reflected different numerical chromosomal aberrations than those common to neoplastic glia. (2). The second pattern was different. Cells with ISH chromosomal signals of neoplastic glia retained GFAP, and gained collagen type IV. Their laminin and fibronectin diminished, but persisted among a lower percentage of cells. Cloning and double immunofluorescence confirmed the presence of individual cells with glial and mesenchymal markers. A cell expressing GFAP in addition to either fibronectin, reticulin or collagen type IV is not a known constituent of glioblastoma tissue. This provides evidence of a second mechanism of conversion of gene expression in gliomas.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45382/1/11060_2005_Article_BF01052843.pd