Comparing vector–host and SIR models for dengue transmission

Various simple mathematical models have been used to investigate dengue transmission. Some of these models explicitly model the mosquito population, while others model the mosquitoes implicitly in the transmission term. We study the impact of modeling assumptions on the dynamics of dengue in Thailand by fitting dengue hemorrhagic fever (DHF) data to simple vector–host and SIR models using Bayesian Markov chain Monte Carlo estimation. The parameter estimates obtained for both models were consistent with previous studies. Most importantly, model selection found that the SIR model was substantially better than the vector–host model for the DHF data from Thailand. Therefore, explicitly incorporating the mosquito population may not be necessary in modeling dengue transmission for some populations.     

Spinigerin induces apoptotic like cell death in a caspase independent manner in Leishmania donovani

Antimicrobial peptides (AMPs) are multifunctional components of the innate immune system. Chemotherapeutic agents used for treatment of visceral leishmaniasis (VL) are now threatened due to the emergence of acquired drug resistance and toxicity. AMPs are attractive alternative to conventional pharmaceuticals. In this study, first time we explored the antileishmanial activity of spinigerin originally derived from Pseudacanthotermes spiniger. Leishmania donovani promastigotes present apoptosis-like cell death upon exposure to spinigerin (IC₅₀, 150 μM). The infection rate was reduced by 20% upon exposure to 150 μM spinigerin but no cytotoxicity on host macrophages was observed. Elevation of intracellular ROS level and down-regulation of two ROS detoxifying enzymes, ascorbate peroxidase (APx) and trypanothione reductase (TR) suggested essential role of ROS machinery during spinigerin mediated cell death. About 97% cell population was found to be Annexin-V positive; 44% cells being highly Annexin-V positive. Moreover, we observed morphological changes like cell rounding, nuclear condensation, oligonucleosomal DNA degradation and TUNEL positive cells without loss of membrane integrity upon spinigerin exposure, suggests apoptosis-like death. Interestingly, collapse in mitochondrial membrane potential and increased level of intracellular ROS and calcium were not associated with caspase like activity. Computational analysis suggests spiningerin interacts with trypanothione reductase and thus probably interferes its function to detoxify the toxic ROS level. Therefore, spinigerin induces apoptosis-like cell death in L. donovani in a caspase-independent manner. The study elucidates the antileishmanial property of spinigerin that may be considered for future chemotherapeutic option alone or adjunct with other drug regimens for improved treatment of visceral leishmaniasis.     

Amino acids derived benzoxazepines: Design,synthesis and antitumor activity

Two series of new benzoxazepines substituted with different alkyl amino ethyl chains were synthesized comprising synthetic steps of inter and intramolecular Mitsunobu reaction, lithium aluminium hydride (LAH) reduction, debenzylation, bimolecular nucleophilic substitution (S_N2) reaction. The present study investigates the effect of a tyrosine-based benzoxazepine derivative in human breast cancer cells MCF-7 and MDA-MB-231 and in breast cancer animal model. The anti-proliferative effect of 15a on MCF-7 cells was associated with G1 cell-cycle arrest. This G1 growth arrest was followed by apoptosis as 15a dose dependently increased phosphatidylserine exposure, PARP cleavage and DNA fragmentation that are hallmarks of apoptotic cell death. Interestingly, 15a activated components of both intrinsic and extrinsic pathways of apoptosis characterized by activation of caspase-8 and -9, mitochondrial membrane depolarization and increase in Bax/Bcl2 ratio. However, use of selective caspase inhibitors revealed that the caspase-8-dependent pathway is the major contributor to 15a-induced apoptosis. Compound 15a also significantly reduced the growth of MCF-7 xenograft tumors in athymic nude mice. Together, 15a could serve as a base for the development of a new group of effective breast cancer therapeutics.     

Why individual thermo sensation and pain perception varies? Clue of disruptive mutations in TRPVs from 2504 human genome data

Every individual varies in character and so do their sensory functions and perceptions. The molecular mechanism and the molecular candidates involved in these processes are assumed to be similar if not same. So far several molecular factors have been identified which are fairly conserved across the phylogenetic tree and are involved in these complex sensory functions. Among all, members belonging to Transient Receptor Potential (TRP) channels have been widely characterized for their involvement in thermo-sensation. These include TRPV1 to TRPV4 channels which reveal complex thermo-gating behavior in response to changes in temperature. The molecular evolution of these channels is highly correlative with the thermal response of different species. However, recent 2504 human genome data suggest that these thermo-sensitive TRPV channels are highly variable and carry possible deleterious mutations in human population. These unexpected findings may explain the individual differences in terms of complex sensory functions.     

Dosimetric impact of statistical uncertainty on Monte Carlo dose calculation algorithm in volumetric modulated arc therapy using Monaco TPS for three different clinical cases

AimTo study the dosimetric impact of statistical uncertainty (SU) per plan on Monte Carlo (MC) calculation in Monaco? treatment planning system (TPS) during volumetric modulated arc therapy (VMAT) for three different clinical cases.BackgroundDuring MC calculation SU is an important factor to decide dose calculation accuracy and calculation time. It is necessary to evaluate optimal acceptance of SU for quality plan with reduced calculation time.Materials and methodsThree different clinical cases as the lung, larynx, and prostate treated using VMAT technique were chosen. Plans were generated with Monaco? V5.11 TPS with 2% statistical uncertainty. By keeping all other parameters constant, plans were recalculated by varying SU, 0.5%, 1%, 2%, 3%, 4%, and 5%. For plan evaluation, conformity index (CI), homogeneity index (HI), dose coverage to PTV, organ at risk (OAR) dose, normal tissue receiving dose ≥5 Gy and ≥10 Gy, integral dose (NTID), calculation time, gamma pass rate, calculation reproducibility and energy dependency were analyzed.ResultsCI and HI improve as SU increases from 0.5% to 5%. No significant dose difference was observed in dose coverage to PTV, OAR doses, normal tissue receiving dose ≥5 Gy and ≥10 Gy and NTID. Increase of SU showed decrease in calculation time, gamma pass rate and increase in PTV max dose. No dose difference was seen in calculation reproducibility and dependent on energy.ConclusionFor VMAT plans, SU can be accepted from 1% to 3% per plan with reduced calculation time without compromising plan quality and deliverability by accepting variations in point dose within the target.     

Indian Biotech Bazaar: a swot analysis

Biotechnology is a life science-based technique especially used in agriculture, medicine and food sciences. It is generally defined as the manipulation in organisms to generate products for the welfare of the world. Biotechnology combines disciplines such as genetics, biochemistry, microbiology, and cell biology along with information technology, chemical engineering, robotics etc. It includes basic industries such as food processing, tissue culture, plant development and other sophisticated ones such as recombinant therapeutics and diagnostics. Biotechnology, globally recognized as a rapidly emerging and far-reaching technology, is aptly described as the "technology of hope" for its promise of food, health and environmental sustainability. In India, biotechnology employs more than 10 000 people and generates roughly US$ 500 million in revenue annually. The biotechnology market has increased its sales from Rs. 50 billion in 1997 to Rs.70 billion in 2000, and is expected to cross Rs. 240 billion by the year 2010. In India, the human health biotech products account for 60% of the total market; agribiotech and veterinary 25%, medical devices, contract research and development (R&D), reagents and supplies constitute the remaining 15% Moreover, to facilitate foreign investment, capital and government policies are being revised. Other important industries include industrial enzyme manufacture, bioinformatics, and medical devices. Biotechnology has had limited appeal so far on our capital markets, and we have less then a dozen biotech companies listed on the public markets.     

The 2-oxoacid dehydrogenase multi-enzyme complex of the archaeon Thermoplasma acidophilum - recombinant expression, assembly and characterization

The aerobic archaea possess four closely spaced, adjacent genes that encode proteins showing significant sequence identities with the bacterial and eukaryal components comprising the 2-oxoacid dehydrogenase multi-enzyme complexes. However, catalytic activities of such complexes have never been detected in the archaea, although 2-oxoacid ferredoxin oxidoreductases that catalyze the equivalent metabolic reactions are present. In the current paper, we clone and express the four genes from the thermophilic archaeon, Thermoplasma acidophilum, and demonstrate that the recombinant enzymes are active and assemble into a large (M(r) = 5 x 10(6)) multi-enzyme complex. The post-translational incorporation of lipoic acid into the transacylase component of the complex is demonstrated, as is the assembly of this enzyme into a 24-mer core to which the other components bind to give the functional multi-enzyme system. This assembled complex is shown to catalyze the oxidative decarboxylation of branched-chain 2-oxoacids and pyruvate to their corresponding acyl-CoA derivatives. Our data constitute the first proof that the archaea possess a functional 2-oxoacid dehydrogenase complex.     

Structure-guided affinity maturation of a single-chain variable fragment antibody against the Fu-bc epitope of the dengue virus envelope protein

Dengue is one of the most dominant arthropod-borne viral diseases, infecting at least 390 million people every year throughout the world. Despite this, there is no effective treatment against dengue, and the only available vaccine has already been withdrawn owing to the significant adverse effects. Therefore, passive immunotherapy using monoclonal antibodies is now being sought as a therapeutic option. To date, many dengue monoclonal antibodies have been identified, most of which are serotype-specific, and only a few of which are cross-reactive. Furthermore, antibodies that cross-react within serotypes are weakly neutralizing and frequently induce antibody-dependent enhancement, which promotes viral entry and replication. Therefore, broadly neutralizing antibodies with no risk of antibody-dependent enhancement are required for the treatment of dengue. Here, we developed a single-chain variable fragment (scFv) antibody from an anti-fusion loop E53 antibody (PDB: 2IGF). We introduced previously predicted favorable complementarity-determining region (CDR) mutations into the gene encoding the scFv antibody for affinity maturation, and the resultant variants were tested in vitro against the highly conserved fusion and bc epitope of the dengue virus envelope protein. We show some of these scFv variants with two to three substitution mutations in three different CDRs possess affinity constants (K_D) ranging from 20 to 200 nM. The scFv-mutant15, containing D31L, Y105W, and S227W substitutions, showed the lowest affinity constant, (K_D = 24 ± 7 nM), approximately 100-fold lower than its parental construct. We propose that the scFv-derivative antibody may be a good candidate for the development of an effective and safe immunotherapy.