Psi: A Silicon Compiler for Very Fast Protocol Processing

Conventional protocols implementations typically fall short, by a few orders of magnitude, of supporting the speeds afforded by high-speed optical transmission media. This protocol processing bottleneck is a key hurdle in taking advantage of the opportunities presented by high-speed communications. This paper describes PSi, a silicon compiler that transforms formal protocol specifications into efficient VLSI implementations. PSi takes advantage of the parallelisms intrinsic to a given protocol to accomplish very high-speed implementations. Initial application of PSi to the IEEE 802.2 (logical link control) leads to processing rates in the order of 106 packets per second (p/s). The 802.2 was selected as a benchmark of complexity; light-weight protocols can accomplish even higher processing rates, reaching the limits set by chip clock rates (i.e., a packet per cycle). These speeds significantly exceed typical of software implementations (up to a few hundred p/s) or special hardware-assisted implementations (up to a few thousands p/s). More importantly, at these rates when the packet size is 103-4 bits the protocol throughput of 109-10 bits/sec reaches the limiting throughput afforded by memory technology. Thus, the protocol processing bottleneck is pushed to the ultimate bounds set by VLSI technologies

Human BRCA1-BARD1 ubiquitin ligase activity counters chromatin barriers to DNA resection

The opposing activities of 53BP1 and BRCA1 influence pathway choice of DNA double-strand break repair. How BRCA1 counters the inhibitory effect of 53BP1 on DNA resection and homologous recombination is unknown. Here we identify the site of BRCA1-BARD1 required for priming ubiquitin transfer from E2~ubiquitin. We demonstrate that BRCA1-BARD1’s ubiquitin ligase activity is required for repositioning 53BP1 on damaged chromatin. We confirm H2A ubiquitylation by BRCA1-BARD1 and show that an H2A-ubiquitin fusion protein promotes DNA resection and repair in BARD1 deficient cells. We show BRCA1-BARD1 function in homologous recombination requires the chromatin remodeler SMARCAD1. SMARCAD1 binding to H2A-ubiquitin, optimal localization to sites of damage and activity in DNA repair requires its ubiquitin-binding CUE domains. SMARCAD1 is required for 53BP1 repositioning and the need for SMARCAD1 in Olaparib or camptothecin resistance is alleviated by 53BP1 loss. Thus BRCA1- BARD1 ligase activity and subsequent SMARCAD1-dependent chromatin remodeling are critical regulators of DNA repair

An unusual mutation in RECQ4 gene leading to Rothmund-Thomson syndrome

Rothmund-Thomson syndrome (OMIM #268400) is a severe autosomal recessive genodermatosis: characterised by growth retardation, hyperpigmentation and frequently accompanied by congenital bone defects, brittle hair and hypogonadism. Mutations in helicase RECQ4 gene are responsible for a subset of cases of RTS. Only six mutations have been reported, thus, far and each affecting the coding sequence or the splice junctions. We report the first homozygous mutation in RECQ4 helicase: 2746-2756-delTGGGCTGAGGC in IVS8 responsible for the severe phenotype associated with RTS in a Malaysian pedigree. We report also a 5321 G-->A transition in exon 17 and the updated list of the RECQ4 gene mutations

Insights from global data for use of rotavirus vaccines in India

Rotavirus vaccines are being introduced in several low- and middle-income countries across the world with and without support from the GAVI Alliance. India has the highest disease burden of rotavirus based on morbidity and mortality estimates and several indigenous vaccine manufacturers are developing rotavirus vaccines. One candidate has undergone phase III testing and others have completed evaluation in phase II. Global data on licensed vaccine performance in terms of impact on disease, strain diversity, safety and cost-effectiveness has been reviewed to provide a framework for decision making in India

Costs and health effects of screening and delivery of hearing aids in Tamil Nadu, India: an observational study

Contains fulltext : 79601.pdf (publisher's version ) (Open Access

Discovery of estrogen receptor α target genes and response elements in breast tumor cells

BACKGROUND: Estrogens and their receptors are important in human development, physiology and disease. In this study, we utilized an integrated genome-wide molecular and computational approach to characterize the interaction between the activated estrogen receptor (ER) and the regulatory elements of candidate target genes. RESULTS: Of around 19,000 genes surveyed in this study, we observed 137 ER-regulated genes in T-47D cells, of which only 89 were direct target genes. Meta-analysis of heterogeneous in vitro and in vivo datasets showed that the expression profiles in T-47D and MCF-7 cells are remarkably similar and overlap with genes differentially expressed between ER-positive and ER-negative tumors. Computational analysis revealed a significant enrichment of putative estrogen response elements (EREs) in the cis-regulatory regions of direct target genes. Chromatin immunoprecipitation confirmed ligand-dependent ER binding at the computationally predicted EREs in our highest ranked ER direct target genes, NRIP1, GREB1 and ABCA3. Wider examination of the cis-regulatory regions flanking the transcriptional start sites showed species conservation in mouse-human comparisons in only 6% of predicted EREs. CONCLUSIONS: Only a small core set of human genes, validated across experimental systems and closely associated with ER status in breast tumors, appear to be sufficient to induce ER effects in breast cancer cells. That cis-regulatory regions of these core ER target genes are poorly conserved suggests that different evolutionary mechanisms are operative at transcriptional control elements than at coding regions. These results predict that certain biological effects of estrogen signaling will differ between mouse and human to a larger extent than previously thought

Analysis of Gga Null Mice Demonstrates a Non-Redundant Role for Mammalian GGA2 during Development

Numerous studies using cultured mammalian cells have shown that the three GGAs (Golgi-localized, gamma-ear containing, ADP-ribosylation factor- binding proteins) function in the transport of cargo proteins between the trans- Golgi network and endosomes. However, the in vivo role(s) of these adaptor proteins and their possible functional redundancy has not been analyzed. In this study, the genes encoding GGAs1-3 were disrupted in mice by insertional mutagenesis. Loss of GGA1 or GGA3 alone was well tolerated whereas the absence of GGA2 resulted in embryonic or neonatal lethality, depending on the genetic background of the mice. Thus, GGA2 mediates a vital function that cannot be compensated for by GGA1and/or GGA3. The combined loss of GGA1 and GGA3 also resulted in a high incidence of neonatal mortality but in this case the expression level of GGA2 may be inadequate to compensate for the loss of the other two GGAs. We conclude that the three mammalian GGAs are essential proteins that are not fully redundant

Molecular Identification of Rickettsial Endosymbionts in the Non-Phagotrophic Volvocalean Green Algae

Background: The order Rickettsiales comprises Gram-negative obligate intracellular bacteria (also called rickettsias) that are mainly associated with arthropod hosts. This group is medically important because it contains human-pathogenic species that cause dangerous diseases. Until now, there has been no report of non-phagotrophic photosynthetic eukaryotes, such as green plants, harboring rickettsias. Methodology/Principal Findings: We examined the bacterial endosymbionts of two freshwater volvocalean green algae: unicellular Carteria cerasiformis and colonial Pleodorina japonica. Epifluorescence microscopy using 49-6-deamidino-2phenylindole staining revealed the presence of endosymbionts in all C. cerasiformis NIES-425 cells, and demonstrated a positive correlation between host cell size and the number of endosymbionts. Strains both containing and lacking endosymbionts of C. cerasiformis (NIES-425 and NIES-424) showed a.10-fold increase in cell number and typical sigmoid growth curves over 192 h. A phylogenetic analysis of 16 S ribosomal (r)RNA gene sequences from the endosymbionts of C. cerasiformis and P. japonica demonstrated that they formed a robust clade (hydra group) with endosymbionts of various non-arthropod hosts within the family Rickettsiaceae. There were significantly fewer differences in the 16 S rRNA sequences of the rickettsiacean endosymbionts between C. cerasiformis and P. japonica than in the chloroplast 16 S rRNA or 18 S rRNA of the host volvocalean cells. Fluorescence in situ hybridization demonstrated the existence of the rickettsiacea

Gallbladder Cancer Predisposition: A Multigenic Approach to DNA-Repair, Apoptotic and Inflammatory Pathway Genes

Gallbladder cancer (GBC) is a multifactorial disease with complex interplay between multiple genetic variants. We performed Classification and Regression Tree Analysis (CART) and Grade of Membership (GoM) analysis to identify combinations of alleles among the DNA repair, inflammatory and apoptotic pathway genetic variants in modifying the risk for GBC. We analyzed 16 polymorphisms in 8 genes involved in DNA repair, apoptotic and inflammatory pathways to find out combinations of genetic variants contributing to GBC risk. The genes included in the study were XRCC1, OGG1, ERCC2, MSH2, CASP8, TLR2, TLR4 and PTGS2. Single locus analysis by logistic regression showed association of MSH2 IVS1+9G>C (rs2303426), ERCC2 Asp312Asn (rs1799793), OGG1 Ser326Cys (rs1052133), OGG1 IVS4-15C>G (rs2072668), CASP8 -652 6N ins/del (rs3834129), PTGS2 -1195G>A (rs689466), PTGS2 -765G>C (rs20417), TLR4 Ex4+936C>T (rs4986791) and TLR2 –196 to –174del polymorphisms with GBC risk. The CART analysis revealed OGG1 Ser326Cys, and OGG1 IVS4-15C>G polymorphisms as the best polymorphic signature for discriminating between cases and controls. In the GoM analysis, the data was categorized into six sets representing risk for GBC with respect to the investigated polymorphisms. Sets I, II and III described low intrinsic risk (controls) characterized by multiple protective alleles while sets IV, V and VI represented high intrinsic risk groups (GBC cases) characterized by the presence of multiple risk alleles. The CART and GoM analyses also showed the importance of PTGS2 -1195G>A polymorphism in susceptibility to GBC risk. In conclusion, the present multigenic approach can be used to define individual risk profiles for gallbladder cancer in North Indian population

Expression of an Epitope-Tagged Virulence Protein in Rickettsia parkeri Using Transposon Insertion

Despite recent advances in our ability to genetically manipulate Rickettsia, little has been done to employ genetic tools to study the expression and localization of Rickettsia virulence proteins. Using a mariner-based Himar1 transposition system, we expressed an epitope-tagged variant of the actin polymerizing protein RickA under the control of its native promoter in Rickettsia parkeri, allowing the detection of RickA using commercially-available antibodies. Native RickA and epitope-tagged RickA exhibited similar levels of expression and were specifically localized to bacteria. To further facilitate protein expression in Rickettsia, we also developed a plasmid for Rickettsia insertion and expression (pRIE), containing a variant Himar1 transposon with enhanced flexibility for gene insertion, and used it to generate R. parkeri strains expressing diverse fluorescent proteins. Expression of epitope-tagged proteins in Rickettsia will expand our ability to assess the regulation and function of important virulence factors