Clinical rabies: is cure possible?

Rabies is a fatal disease in humans and till date survivors of the disease after the clinical onset of the illness are rare. The approach to management of rabies is usually palliative. In rare cases of paralytic rabies a trial for cure has been tried. No single therapeutic agent is likely to be effective, but a combination of specific therapies could be considered, including rabies vaccine, rabies immunoglobulin, monoclonal antibodies, ribavirin, interferon alpha, ketamine etc. the only reported cases in literature were with rare success of the Milwaukee protocol. This is the case report of a 45 year old male who presented with clinical rabies and was started on the trial. Has the treatment had any benefit is to be debated and further options discussed

QTL analysis and marker assisted selection for improvement in grain protein content and pre-harvest sprouting tolerance in bread wheat

With the ever expanding possibilities to build supramotecutar structures, chemists are challenged to mimic nature including the construction of artificial cells or function thereof. Within the field of immunology, effective immunotherapy critically depends on efficient production of antigen-specific cytotoxic T-cells. Herein lies an opportunity for chemists to design and synthesize so-called artificial antigen presenting cells (aAPCs) that can promote T-cell activation and their subsequent expansion. In this review we discuss the current status of aAPC development, also focusing on developments in nanoscience which might improve future designs. As synthetic mimics of natural antigen-presenting cells, aAPCs encompass three basic signals required for T-cell activation: MHC-antigen complexes, costimulatory molecules and soluble immune modulating compounds. Both spatial and temporal organization of these signals during aAPC/T-cell contact is important for efficient T-cell activation. We discuss how signals have been incorporated in several aAPC designs, but also how physical properties such as size and shape are essential for targeting the aAPCs to T-cell rich areas in vivo

Effect of integration of supplemental nutrition with public health programmes in pregnancy and early childhood on cardiovascular risk in rural Indian adolescents: long term follow-up of Hyderabad nutrition trial.

OBJECTIVE: To determine whether integration of nutritional supplementation with other public health programmes in early life reduces the risk of cardiovascular disease in undernourished populations. DESIGN: Approximately 15 years' follow-up of participants born within an earlier controlled, community trial of nutritional supplementation integrated with other public health programmes. SETTING: 29 villages (15 intervention, 14 control) near Hyderabad city, south India. PARTICIPANTS: 1165 adolescents aged 13-18 years. INTERVENTION: Balanced protein-calorie supplementation (2.51 MJ, 20 g protein) offered daily to pregnant women and preschool children aged under 6 years, coupled with integrated delivery of vertical public health programmes. MAIN OUTCOME MEASURES: Height, adiposity, blood pressures, lipids, insulin resistance (homoeostasis model assessment (HOMA) score), and arterial stiffness (augmentation index). RESULTS: The participants from the intervention villages were 14 mm (95% confidence interval 4 to 23; P=0.007) taller than controls but had similar body composition. The participants from the intervention villages had more favourable measures of insulin resistance and arterial stiffness: 20% (3% to 39%; P=0.02) lower HOMA score and 3.3% (1% to 5.7%; P=0.008) lower augmentation index. No strong evidence existed for differences in blood pressures and serum lipids. CONCLUSIONS: In this undernourished population, integrated delivery of supplemental nutrition with other public health programmes in pregnancy and early childhood was associated with a more favourable profile of cardiovascular disease risk factors in adolescence. This pragmatic study provides the most robust evidence to date on this important hypothesis for which classic trials are unlikely. Improved maternal and child nutrition may have a role in reducing the burden of cardiovascular disease in low income and middle income countries

The pestivirus N terminal protease N(pro) redistributes to mitochondria and peroxisomes suggesting new sites for regulation of IRF3 by N(pro.)

The N-terminal protease of pestiviruses, N(pro) is a unique viral protein, both because it is a distinct autoprotease that cleaves itself from the following polyprotein chain, and also because it binds and inactivates IRF3, a central regulator of interferon production. An important question remains the role of N(pro) in the inhibition of apoptosis. In this study, apoptotic signals induced by staurosporine, interferon, double stranded RNA, sodium arsenate and hydrogen peroxide were inhibited by expression of wild type N(pro), but not by mutant protein N(pro) C112R, which we show is less efficient at promoting degradation of IRF3, and led to the conclusion that N(pro) inhibits the stress-induced intrinsic mitochondrial pathway through inhibition of IRF3-dependent Bax activation. Both expression of N(pro) and infection with Bovine Viral Diarrhea Virus (BVDV) prevented Bax redistribution and mitochondrial fragmentation. Given the role played by signaling platforms during IRF3 activation, we have studied the subcellular distribution of N(pro) and we show that, in common with many other viral proteins, N(pro) targets mitochondria to inhibit apoptosis in response to cell stress. N(pro) itself not only relocated to mitochondria but in addition, both N(pro) and IRF3 associated with peroxisomes, with over 85% of N(pro) puncta co-distributing with PMP70, a marker for peroxisomes. In addition, peroxisomes containing N(pro) and IRF3 associated with ubiquitin. IRF3 was degraded, whereas N(pro) accumulated in response to cell stress. These results implicate mitochondria and peroxisomes as new sites for IRF3 regulation by N(pro), and highlight the role of these organelles in the anti-viral pathway

Identification of Prophages in Bacterial Genomes by Dinucleotide Relative Abundance Difference

BACKGROUND: Prophages are integrated viral forms in bacterial genomes that have been found to contribute to interstrain genetic variability. Many virulence-associated genes are reported to be prophage encoded. Present computational methods to detect prophages are either by identifying possible essential proteins such as integrases or by an extension of this technique, which involves identifying a region containing proteins similar to those occurring in prophages. These methods suffer due to the problem of low sequence similarity at the protein level, which suggests that a nucleotide based approach could be useful. METHODOLOGY: Earlier dinucleotide relative abundance (DRA) have been used to identify regions, which deviate from the neighborhood areas, in genomes. We have used the difference in the dinucleotide relative abundance (DRAD) between the bacterial and prophage DNA to aid location of DNA stretches that could be of prophage origin in bacterial genomes. Prophage sequences which deviate from bacterial regions in their dinucleotide frequencies are detected by scanning bacterial genome sequences. The method was validated using a subset of genomes with prophage data from literature reports. A web interface for prophage scan based on this method is available at http://bicmku.in:8082/prophagedb/dra.html. Two hundred bacterial genomes which do not have annotated prophages have been scanned for prophage regions using this method. CONCLUSIONS: The relative dinucleotide distribution difference helps detect prophage regions in genome sequences. The usefulness of this method is seen in the identification of 461 highly probable loci pertaining to prophages which have not been annotated so earlier. This work emphasizes the need to extend the efforts to detect and annotate prophage elements in genome sequences

Drosophila Dynein Intermediate Chain Gene, Dic61B, Is Required for Spermatogenesis

This study reports the identification and characterization of a novel gene, Dic61B, required for male fertility in Drosophila. Complementation mapping of a novel male sterile mutation, ms21, isolated in our lab revealed it to be allelic to CG7051 at 61B1 cytogenetic region, since two piggyBac insertion alleles, CG7051c05439 and CG7051f07138 failed to complement. CG7051 putatively encodes a Dynein intermediate chain. All three mutants, ms21, CG7051c05439 and CG7051f07138, exhibited absolute recessive male sterility with abnormally coiled sperm axonemes causing faulty sperm individualization as revealed by Phalloidin staining in Don Juan-GFP background. Sequencing of PCR amplicons uncovered two point mutations in ms21 allele and confirmed the piggyBac insertions in CG7051c05439 and CG7051f07138 alleles to be in 5′UTR and 4th exon of CG7051 respectively, excision of which reverted the male sterility. In situ hybridization to polytene chromosomes demonstrated CG7051 to be a single copy gene. RT-PCR of testis RNA revealed defective splicing of the CG7051 transcripts in mutants. Interestingly, expression of cytoplasmic dynein intermediate chain, α, β, γ tubulins and α-spectrin was normal in mutants while ultra structural studies revealed defects in the assembly of sperm axonemes. Bioinformatics further highlighted the homology of CG7051 to axonemal dynein intermediate chain of various organisms, including DNAI1 of humans, mutations in which lead to male sterility due to immotile sperms. Based on these observations we conclude that CG7051 encodes a novel axonemal dynein intermediate chain essential for male fertility in Drosophila and rename it as Dic61B. This is the first axonemal Dic gene of Drosophila to be characterized at molecular level and shown to be required for spermatogenesis

Anti-HIV-1 Activity of a New Scorpion Venom Peptide Derivative Kn2-7

For over 30 years, HIV/AIDS has wreaked havoc in the world. In the absence of an effective vaccine for HIV, development of new anti-HIV agents is urgently needed. We previously identified the antiviral activities of the scorpion-venom-peptide-derived mucroporin-M1 for three RNA viruses (measles viruses, SARS-CoV, and H5N1). In this investigation, a panel of scorpion venom peptides and their derivatives were designed and chosen for assessment of their anti-HIV activities. A new scorpion venom peptide derivative Kn2-7 was identified as the most potent anti-HIV-1 peptide by screening assays with an EC50 value of 2.76 µg/ml (1.65 µM) and showed low cytotoxicity to host cells with a selective index (SI) of 13.93. Kn2-7 could inhibit all members of a standard reference panel of HIV-1 subtype B pseudotyped virus (PV) with CCR5-tropic and CXCR4-tropic NL4-3 PV strain. Furthermore, it also inhibited a CXCR4-tropic replication-competent strain of HIV-1 subtype B virus. Binding assay of Kn2-7 to HIV-1 PV by Octet Red system suggested the anti-HIV-1 activity was correlated with a direct interaction between Kn2-7 and HIV-1 envelope. These results demonstrated that peptide Kn2-7 could inhibit HIV-1 by direct interaction with viral particle and may become a promising candidate compound for further development of microbicide against HIV-1