Structure-Function of Falcipains: Malarial Cysteine Proteases

Evidence indicates that cysteine proteases play essential role in malaria parasites; therefore an obvious area of investigation is the inhibition of these enzymes to treat malaria. Studies with cysteine protease inhibitors and manipulating cysteine proteases genes have suggested a role for cysteine proteases in hemoglobin hydrolysis. The best characterized Plasmodium cysteine proteases are falcipains, which are papain family enzymes. Falcipain-2 and falcipain-3 are major hemoglobinases of P. falciparum. Structural and functional analysis of falcipains showed that they have unique domains including a refolding domain and a hemoglobin binding domain. Overall, the complexes of falcipain-2 and falcipain-3 with small and macromolecular inhibitors provide structural insight to facilitate the design or modification of effective drug treatment against malaria. Drug development targeting falcipains should be aided by a strong foundation of biochemical and structural studies

Prevalence and contributing factors of low birth weight babies in institutional delivery

Introductions: Low Birth Weight (LBW) is a sensitive indicator of socio-economic conditions and indirectly measures the health of mother and child. Though, the health situation of Nepal has improved substantially over the years, LBW rate is still high. The present study explores the prevalence and contributing factors of LBW babies delivered in Patan hospital. Methods: The data were collected retrospectively from patients’ record for babies born at Patan Hospital, Patan Academy of Health Sciences, Kathmandu, Nepal. Records were retrieved through systematic randomization and IBM SPSS 15.0 was used for analysis. Non-parametric tests were applied with correlation done between dependent and independent variables. Results: A total of 4395 birth occurred during the study period of which 527 met the study criteria and remaining were of normal birth weight. The prevalence of LBW was 11.99% and the average LBW was calculated as 2074.97 ± 344.425 grams. The factors associated with LBW included preterm babies (Pearson correlation coefficient= 0.554, p= 0.001 < 0.05) and oligohydamnious (Spearman’s correlation coefficient= 0.307, p= 0.019 < 0.05). Conclusions: This study suggests preterm babies and oligohydramnious to be contributing factors of LBW babies. Keywords: amniotic fluid index, intra uterine growth retardation, maternal risk factors, Patan Hospital, retrospective hospital based studyÂ

Protein-Protein Interactions in Malaria: Emerging Arena for Future Chemotherapeutics

Malaria is one of the most deadly diseases infecting humans. Advances in elimination and vector control have reduced the global malaria burden in the past decade; however, the emerging threat of drug resistance and suboptimal vaccine efficacies threaten global eradication efforts. Unlocking novel drug and vaccine targets while simultaneously mitigating spread of resistant strains seems to be the need of the hour. Protein-protein interactions (PPIs), an integral part of host-pathogen cross-talk and parasite survival, have only recently emerged as promising drug targets. Large PPI networks (interactome) are being developed to better our understanding of various parasite biochemical pathways. In this chapter, we throw light on several newly characterized protein-protein interactions between the host (humans) and parasite (plasmodium) in key processes such as hemoglobin degradation, enzyme regulation, protein export, egress, invasion, and drug resistance and further discuss their viability for development as novel chemotherapeutic targets

Study on dry-sliding wear (DSW) of uncoated IN800 super alloy and sol-gel based dip coated IN800 substrate

631-642In the present paper, sliding wear characteristics of seven weight% yttria stabilized zirconia (7YSZ) sol-gel deposited on to air plasma sprayed CoNiCrAlY bond-coated Inconel 800 superalloy has been studied. For this, sliding wear tests have performed on pin-on-disc friction and wear test rig by varying experimental parameters applied load, sliding velocity, disc speed and temperature as per L16 orthogonal arrays of Taguchi. Taguchi method has been used to perform experiments to know the effect of interaction of variables on dry sliding wear behavior. The optimal experimental parameters have been obtained by orthogonal arrays, signal-to-noise ratio (SNR) and analysis of variance (ANOVA) for uncoated and coated Inconel 800 superalloy substrate. Results have shown temperature as the most influencing parameter for uncoated samples and coated samples, both. However, compared with coated samples, applied load has been found significant factor for uncoated samples. It has been exhibited better wear resistance in the sol-gel derived YSZ coated surface of IN800 superallloy substrate

Structures of falcipain-2 and falcipain-3 bound to small molecule inhibitors: implications for substrate specificity.

Falcipain-2 and falcipain-3 are critical hemoglobinases of Plasmodium falciparum, the most virulent human malaria parasite. We have determined the 2.9 A crystal structure of falcipain-2 in complex with the epoxysuccinate E64 and the 2.5 A crystal structure of falcipain-3 in complex with the aldehyde leupeptin. These complexes represent the first crystal structures of plasmodial cysteine proteases with small molecule inhibitors and the first reported crystal structure of falcipain-3. Our structural analyses indicate that the relative shape and flexibility of the S2 pocket are affected by a number of discrete amino acid substitutions. The cumulative effect of subtle differences, including those at "gatekeeper" positions, may explain the observed kinetic differences between these two closely related enzymes

Study on dry-sliding wear (DSW) of uncoated IN800 super alloy and sol-gel based dip coated IN800 substrate

In the present paper, sliding wear characteristics of seven weight% yttria stabilized zirconia (7YSZ) sol-gel depositedon to air plasma sprayed CoNiCrAlY bond-coated Inconel 800 superalloy has been studied. For this, sliding wear tests haveperformed on pin-on-disc friction and wear test rig by varying experimental parameters applied load, sliding velocity, discspeed and temperature as per L16 orthogonal arrays of Taguchi. Taguchi method has been used to perform experiments toknow the effect of interaction of variables on dry sliding wear behavior. The optimal experimental parameters have beenobtained by orthogonal arrays, signal-to-noise ratio (SNR) and analysis of variance (ANOVA) for uncoated and coatedInconel 800 superalloy substrate. Results have shown temperature as the most influencing parameter for uncoated samplesand coated samples, both. However, compared with coated samples, applied load has been found significant factor foruncoated samples. It has been exhibited better wear resistance in the sol-gel derived YSZ coated surface of IN800superallloy substrate

Recognition of fold- and function-specific sites in the ligand-binding domain of the thyroid hormone receptor-like family

Background: The thyroid hormone receptor-like (THR-like) family is the largest transcription factors family belonging to the nuclear receptor superfamily, which directly binds to DNA and regulates the gene expression and thereby controls various metabolic processes in a ligand-dependent manner. The THR-like family contains receptors THRs, RARs, VDR, PPARs, RORs, Rev-erbs, CAR, PXR, LXRs, and others. THR-like receptors are involved in many aspects of human health, including development, metabolism and homeostasis. Therefore, it is considered an important therapeutic target for various diseases such as osteoporosis, rickets, diabetes, etc. Methods: In this study, we have performed an extensive sequence and structure analysis of the ligand-binding domain (LBD) of the THR-like family spanning multiple taxa. We have use different computational tools (information-theoretic measures; relative entropy) to predict the key residues responsible for fold and functional specificity in the LBD of the THR-like family. The MSA of THR-like LBDs was further used as input in conservation studies and phylogenetic clustering studies. Results: Phylogenetic analysis of the LBD domain of THR-like proteins resulted in the clustering of eight subfamilies based on their sequence homology. The conservation analysis by relative entropy (RE) revealed that structurally important residues are conserved throughout the LBDs in the THR-like family. The multi-harmony conservation analysis further predicted specificity in determining residues in LBDs of THR-like subfamilies. Finally, fold and functional specificity determining residues (residues critical for ligand, DBD and coregulators binding) were mapped on the three-dimensional structure of thyroid hormone receptor protein. We then compiled a list of natural mutations in THR-like LBDs and mapped them along with fold and function-specific mutations. Some of the mutations were found to have a link with severe diseases like hypothyroidism, rickets, obesity, lipodystrophy, epilepsy, etc. Conclusion: Our study identifies fold and function-specific residues in THR-like LBDs. We believe that this study will be useful in exploring the role of these residues in the binding of different drugs, ligands, and protein-protein interaction among partner proteins. So this study might be helpful in the rational design of either ligands or receptors

Effect of nanosilica on the properties of PEI/silicone rubber blend based nanocomposites

The aim of the present study is to prepare nanocomposites based on binary blends of poly ether imide (PEI)/silicone rubber reinforced with varied loadings of modified nanosilica particles. Nanocomposites have been prepared by melt blending process using twin screw extruder. Thermal behaviour of the developed nanocomposites has been studied with the help of TGA and DMA. Morphological properties have been visualized by SEM. Mechanical properties of the nanocomposites have been determined by universal testing machine. It has been observed that almost all the properties have been found to increase upto 25% with the incorporation of modified nanosilica particles in polymer matrices. Enhancement in various properties may be attributed to better interfacial adhesion and fairly good polymer filler interactions

Antisense expression of a gene encoding a calcium-binding protein in transgenic tobacco leads to altered morphology and enhanced chlorophyll

Entamoeba histolytica contains a novel calcium-binding protein like calmodulin, which was discovered earlier, and we have reported the presence of its homologue(s) and a dependent protein kinase in plants. To understand the functions of these in plants, a cDNA encoding a calcium-binding protein isolated from Entamoeba histolytica (EhCaBP) was cloned into vector pBI121 in antisense orientation and transgenic tobacco plants were raised. These plants showed variation in several phenotypic characters, of which two distinct features, more greenness and leaf thickness, were inherited in subsequent generations. The increase in the level of total chlorophyll in different plants ranged from 60% to 70%. There was no major change in chloroplast structure and in the protein level of D1, D2, LHCP and RuBP carboxylase. These morphological changes were not seen in antisense calmodulin transgenic tobacco plants, nor was the calmodulin level altered in EhCaBP antisense plants

Classification of drugs reviews using W-LRSVM model

Opinion mining provided less opportunity to discuss their experiences about drugs so reviewing about it was difficult. Recent findings show that online reviews and blogs on drugs are important for patients, marketers and industries. Collecting the information for drugs from the website and analyzing is a challenge. A model is designed by proposing an algorithm which crawls information from the web to analyze reviews of drugs. Reviews were crawled for five different drugs using the algorithm. The W-Bayesian Logistic Regression and Support Vector Machine (W-LRSVM) model was trained for different split ratios to obtain the accuracy of 97.46%. Experimental results on reviews of five different drugs showed that the proposed model gave better results compared to other classifier