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Structure based de novo design of IspD inhibitors as anti-tubercular agents
Get PDFTuberculosis is one of the leading contagious diseases, caused by Mycobacterium tuberculosis. Despite improvements in anti-tubercular agents, it remains one of the most prevalent infectious diseases worldwide, responsible for a total of 1.6 million deaths annually. The emergence of multidrug resistant strains highlighted the need of discovering novel drug targets for the development of anti-tubercular agents. 2-C-methyl-D-erythritol-4-phosphate cytidyltransferase (IspD) is an enzyme involved in MEP pathway for isoprenoid biosynthesis, which is considered an attractive target for the discovery of novel antibiotics for its essentiality in bacteria and absence in mammals. In the present study, we have employed structure based drug design approach to develop novel and potent inhibitors for IspD receptor. To explore binding affinity and hydrogen bond interaction between the ligand and active site of IspD receptor, docking studies were performed. ADMET and synthetic accessibility filters were used to screen designed molecules. Finally, ten compounds were selected and subsequently submitted for the synthesis and in vitro studies as IspD inhibitors
An insight into the kinships of the fungi
Get PDFThe evolutionary origin of fungi is important in determining the phylogenetic relationships between fungi, animals and plants. However, determining the true relationship of fungi has been somewhat difficult owing to their simple morphology and presence of convergent characters. With the advent of newer molecular techniques, analysis of conserved protein sequences, cytochrome systems, mitochondrial and nuclear genetic material and rRNAs are being employed in elucidating phylogenetic kinships among the eukaryotes. These emerging evidences suggest that the derivation of the fungi from plants or algae would require more evolutionary changes than its derivation from protozoa, the unicellular ancestor of the animals. To gain an overview of the current state of the science, we have extensively reviewed the existing literatures and it appeared to us that fungi are more closely related to animals than to plants
Human neuromaturation, juvenile extreme energy liability, and adult cognition/cooperation
Get PDFHuman childhood and adolescence is the period in which adult cognitive competences (including those that create the unique cooperativeness of humans) are acquired. It is also a period when neural development puts a juvenile’s survival at risk due to the high vulnerability of their brain to energy shortage. The brain of a 4 year-old human uses ≈50% of its total energy expenditure (TEE) (cf. adult ≈12%). This brain expensiveness is due to (1) the brain making up ≈6% of a 4 year-old body compared to 2% in an adult, and (2) increased energy metabolism that is ≈100% greater in the gray matter of a child than in an adult (a result of the extra costs of synaptic neuromaturation). The high absolute number of neurons in the human brain requires as part of learning a prolonged neurodevelopment. This refines inter- and intraarea neural networks so they become structured with economical “small world” connectivity attributes (such as hub organization and high cross-brain differentiation/integration). Once acquired, this connectivity enables highly complex adult cognitive capacities. Humans evolved as hunter-gatherers. Contemporary hunter-gatherers (and it is also likely Middle Paleolithic ones) pool high energy foods in an egalitarian manner that reliably supported mothers and juveniles with high energy intake. This type of sharing unique to humans protects against energy shortage happening to the immature brain. This cooperation that protects neuromaturation arises from adults having the capacity to communicate and evaluate social reputation, cognitive skills that exist as a result of extended neuromaturation. Human biology is therefore characterized by a presently overlooked bioenergetic-cognition loop (called here the “HEBE ring”) by which extended neuromaturation creates the cooperative abilities in adults that support juveniles through the potentially vulnerable period of the neurodevelopment needed to become such adults
Strong and weak competitors can coexist in the same niche
Get PDFThe competitive exclusion principle postulates that two trophically identical but fitness different species can not stably coexist in the same niche. However, this principle contradicts the observed nature's species richness. This fact is known as the biodiversity paradox. Here, using a simple cellular automaton model, we mechanistically show how two trophically identical, but fitness different species may stably coexist in the same niche. As environment is stable and any trade-offs are absent in this model, it strongly violates the competitive exclusion principle
Kinetic resolution of racemates under chiral catalysis: connecting the dots
Get PDFThe current theory of the titled phenomenon is apparently based on an inconsistent use of concentration units, as employed in the derivation of the fundamental equations. Thus, manifestly, whilst the relation between extent of conversion and e.e. is derived with mole fractions, the succeeding kinetic equations employ units of molarity. This invalidates the derivation in the general case. Fortuitously, however, it is applicable in the majority of simple cases, wherein the total number of moles involved in the reaction remains constant. Herein is presented a rigorous approach which is generally valid
Analysis of DTC nutrigenetic services in Italy: state of the art, agreement to the ESHG statement and future outlooks
Get PDFBackground: In both USA and Europe operate companies selling Direct-to-consumer genetic tests (DTC). These tests are offered to healthy people aiming to identify predispositions to complex diseases and to take preventive measures. Several DTC-nutrigenetic tests (DNTs) are available on the market. They propose the definition of a personalized diet, on the basis of the investigated genetic variants, which would reduce the risk of developing those diseases which have been associated to specific genetic markers. However, the risk/benefit balance of exposing unselected population to genetic testing without any medical surveillance is far from be established. Furthermore, it lacks an accepted procedure to select which genetic markers needs to be investigated, to evaluate their specific role and, as consequence, to define a personalized diet. Within this context, the European Society of Human Genetics (ESHG) released a statement regarding the DTC tests that has been ratified by several national societies including the Italian one. 
In the present study we analyzed the DNT offered in Italy, the state of the art and the abidance with the ESHG statement. 
Methods: We queried web search engine for the DNT offered to italian population, portraying a non-specialized customer. We examined the DNTs vendor websites and/or directly contacted the companies to collect information on: 1) genetic marker essayed, 2) diseases and phenotypes considered and 3) kind of dietary advices provided. Finally, we evaluated the abidance to the ESHG statement. The study was conducted between November, 2010 and May, 2011.
Results: Six companies operate in Italy with a total of seven different DNTs offered. Both studied phenotypes and investigated genetic markers were very different among companies, with a relative higher level of agreement for phenotype than for genes. None of the companies described the methods used to select markers and to define diet advices. None of the companies showed a complete agreement to the statement of the ESHG. 
Conclusion: Although DNT companies' efforts are worthy, a standardization of methods and a more strictly agreement with ESHG statement should be encouraged
Genome Replikin Count Predicts Increased Lethality of Resistant Tuberculosis
No full textThe genomic Replikin Count of all the sequences on Pubmed of different strains of tuberculosis were analyzed. The lowest Counts occurred with species within the lowest drug resistance, the highest Counts with sequences of the highest drug resistance and lethality
Empirical predictions of an intrinsically disordered protein theory approach to glycan/lectin reaction kinetics
Get PDFNewly-developed methods from the theory of intrinsically disordered proteins can be applied to the flexible glycan structures that coat cellular surfaces and provide rich channels for biological information transmission. Extension of a mechanistic 'arm-in-sleeve' model via a nonrigid molecule symmetry analysis leads to expectation of empirical observation of punctuated 'spectral' classifications in glycan/lectin interaction, parameterized by an appropriate index of glycan frond length or other index of topological complexity, possibly requiring groupoid classifications analogous to quasicrystals
Bacteriophages as a model for studying carbon regulation in aquatic system
Get PDFThe interconversion of carbon in organic, inorganic and refractory carbon is still beyond the grasp of present environmentalists. The bacteria and their phages, being the most abundant constituents of the aquatic environment, represent an ideal model for studing carbon regulation in the aquatic system. The refractory dissolved organic carbon (DOC), a recently coined terminology from the microbe-driven conversion of bioavailable organic carbon into difficult-to-digest refractory DOC by microbial carbon pump (MCP), is suggested to have the potential to revolutionize our view of carbon sequestration. It is estimated that about 95% of organic carbon is in the form of refractory DOC, which is the largest pool of organic matter in the ocean. The refractory DOC is supposed to be the major factor in the global carbon cycle whose source is not yet well understood. A key element of the carbon cycle is the microbial conversion of dissolved organic carbon into inedible forms. The time studies of phage-host interaction under control conditions reveal their impact on the total carbon content of the source and their interconversion among organic, inorganic and other forms of carbon with respect to control source. The TOC- analysis statistics stipulate an increase in inorganic carbon content by 15-25 percent in the sample with phage as compared to the sample without phage. The results signify a 60-70 fold increase in inorganic carbon content in sample with phage, whereas, 50-55 fold in the case of sample without phages as compared with control. This increase in inorganic carbon content may be due to lysis of the host cell releasing its cellular constituents and utilization of carbon constituent for phage assembly and development. It also proves the role of phages in regulating the carbon flow in aquatic systems like oceans, where their concentration outnumbered other species
Solubilization of M2 Transmembrane Peptide of Influenza A in Pure Water: Implications for Emergence of Proteins and Protein-embedded Primeval Membranes in Unsalted Oceans
Get PDFWe demonstrated that M2 transmembrane peptide, one of the most hydrophobic sequences in nature, can be solublized to at least ~100 µM in unsalted water without any lipid molecules. Strikingly, the M2 peptide also forms a highly-helical conformation in water which remains almost unchanged even at 95 ºC, as characterized by CD spectroscopy. Our result has critical implications in understanding emergence of proteins and protein-embedded primeval membranes in unsalted oceans