Genetics update: monogenetics, polygene disorders and the quest for modifying genes

The genetic channelopathies are a broad collection of diseases. Many ion channel genes demonstrate wide phenotypic pleiotropy, but nonetheless concerted efforts have been made to characterise genotype-phenotype relationships. In this review we give an overview of the factors that influence genotype-phenotype relationships across this group of diseases as a whole, using specific individual channelopathies as examples. We suggest reasons for the limitations observed in these relationships. We discuss the role of ion channel variation in polygenic disease and highlight research that has contributed to unravelling the complex aetiological nature of these conditions. We focus specifically on the quest for modifying genes in inherited channelopathies, using the voltage-gated sodium channels as an example. Epilepsy related to genetic channelopathy is one area in which precision medicine is showing promise. We will discuss the successes and limitations of precision medicine in these conditions

Influence of quantum confinement on the ferromagnetism of (Ga,Mn)As diluted magnetic semiconductor

We investigate the effect of quantum confinement on the ferromagnetism of diluted magnetic semiconductor Ga$_{1-x}$Mn$_x$As using a combination of tight-binding and density functional methods. We observe strong majority-spin Mn $d$-As $p$ hybridization, as well as half metallic behavior, down to sizes as small as 20 \AA in diameter. Below this critical size, the doped holes are self-trapped by the Mn-sites, signalling both valence and electronic transitions. Our results imply that magnetically doped III-V nanoparticles will provide a medium for manipulating the electronic structure of dilute magnetic semiconductors while conserving the ferromagnetic properties and even enhancing it in certain size regime.Comment: 4 pages, 3 figure

B_c meson spectrum and hyperfine splittings in theshifted large-N-expansion technique

In the framework of potential models for heavy quarkonium, we compute the mass spectrum of the bottom-charmed $B_{c}$ meson system and spin-dependent splittings from the Schr\"{o}dinger equation using the shifted-large-N expansion technique. The masses of the lightest vector $B_{c}^{+}$ and pseudoscalar $B_{c}$ states as well as the higher states below the threshold are estimated. Our predicted result for the ground state energy is $6253_{-6}^{+15}$ $MeV$ and are generally in exact agreement with earlier calculations. Calculations of the Schr\"{o}dinger energy eigenvalues are carried out up to third order of the energy series. The parameters of each potential are adjusted to obtain best agreement with the experimental spin-averaged data (SAD). Our findings are compared with the observed data and with the numerical results obtained by other numerical methods.Comment: 28 pages, Late

Simultaneous control of nanocrystal size and nanocrystal-nanocrystal separation in CdS nanocrystal assembly

We report an easy, one pot synthesis to prepare ordered CdS nanocrystals with varying inter-particle separation and characterize the particle separation using x-ray diffraction at low and wide angles

Chemical Modulation of Phospho-Signaling Pathways Involved in Cancer.

Advancements in our understanding of the molecular causes of cancer have led to the therapeutic targeting of key enzymes involved in cell growth. Kinase inhibitors have been the most successful forms of such targeted therapy for a select group of cancers. However, a comprehensive understanding of the biological roles of individual kinases is necessary for therapies to be effective in a majority of cancers. Thus, the development of selective kinase inhibitors is essential for continued improvement in cancer chemotherapy. Additionally, the exploration of non-kinase targets is indispensable in adding to the toolbox of effective anti-cancer agents. To increase the number of tools available for targeted therapy, we aimed to develop selective inhibitors for critical proteins involved in phospho-signaling pathways. Our studies include the development of an inhibitor of the fusion protein, Bcr-Abl, which is the primary driver of Chronic Myelogenous Leukemia (CML). Most current FDA-approved drugs are ineffective against a resistant form of CML bearing a T315I mutation in the kinase domain of Bcr-Abl. Through a hypothesis based on the prevailing model of selectivity, we developed an extremely selective compound with high potency for both the wild-type and mutant forms of Bcr-Abl. The adaptor protein Grb2 is an under-explored, non-kinase target for the treatment of CML and other cancers. Our efforts for targeting Grb2 centered on the hypothesis that utilizing conformational constraint for inhibitor development could lead to compounds with increased potency due to a lowered entropic cost of binding. Through the systematic development of conformationally constrained cyclic peptides, we identified a novel scaffold for the inhibition of Grb2 with in cellulo efficacy in a CML cell line. Lastly, while protein kinases have been traditionally targeted with small molecules directed to their ATP-binding site, targeting the peptide substrate-binding site of kinases offers an attractive alternative with several advantages. Our efforts attempted to circumvent the problems typically associated with substrate-competitive inhibitors by covalently inhibiting the target Akt1 kinase. As a whole, results from this dissertation should advance the development of potent and selective inhibitors and aid in the understanding of signaling pathways involved in cancer.PHDChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/113580/1/sdphadke_1.pd

Postprandial hyperlipidemia, endothelial dysfunction and cardiovascular risk: focus on incretins

Cardiovascular disease (CVD) risk in type 2 diabetes (T2DM) is only partially reduced by intensive glycemic control. Diabetic dyslipidemia is suggested to be an additional important contributor to CVD risk in T2DM. Multiple lipid lowering medications effectively reduce fasting LDL cholesterol and triglycerides concentrations and several of them routinely reduce CVD risk. However, in contemporary Western societies the vasculature is commonly exposed to prolonged postprandial hyperlipidemia. Metabolism of these postprandial carbohydrates and lipids yields multiple proatherogenic products. Even a transient increase in these factors may worsen vascular function and induces impaired endothelial dependent vasodilatation, a predictor of atherosclerosis and future cardiovascular events. There is a recent increased appreciation for the role of gut-derived incretin hormones in controlling the postprandial metabolic milieu. Incretin-based medications have been developed and are now used to control postprandial hyperglycemia in T2DM. Recent data indicate that these medications may also have profound effects on postprandial lipid metabolism and may favorably influence several cardiovascular functions. This review discusses (1) the postprandial state with special emphasis on postprandial lipid metabolism and its role in endothelial dysfunction and cardiovascular risk, (2) the ability of incretins to modulate postprandial hyperlipidemia and (3) the potential of incretin-based therapeutic strategies to improve vascular function and reduce CVD risk

On the stability of shear flows in bounded channels, II: non-monotonic shear flows

We give a proof of linear inviscid damping and vorticity depletion for non-monotonic shear flows with one critical point in a bounded periodic channel. In particular, we obtain quantitative depletion rates for the vorticity function without any symmetry assumptions.Comment: 32 pages, final version, to appea

Optimized Prediction of Hard Keyword Queries Over Databases

Keyword Query Interface on databases gives easy access to data, but undergo from low ranking quality, i.e., low precision and/or recall. It would be constructive to recognize queries that are likely to have low ranking quality to improve the user satisfaction. For example, the system may suggest to the user alternative queries for such difficult queries. Goal of this paper is to predict the characteristics of hard queries and propose a novel framework to measure the degree of difficulty for a keyword query over a database, allowing for both the structure and the content of the database and the results of query. There are query difficulty prediction model but results indicate that even with structured data, finding the desired answers to keyword queries is still a hard task. Further, we will use linguistic features Such as morphological features, syntactical features, and semantic features for effective prediction of difficult keyword queries over database. Due to this, Time required for predicting the difficult keywords over large dataset is minimized and process becomes robust and accurate. DOI: 10.17762/ijritcc2321-8169.15078

Electronic structure of and Quantum size effect in III-V and II-VI semiconducting nanocrystals using a realistic tight binding approach

We analyze the electronic structure of group III-V semiconductors obtained within full potential linearized augmented plane wave (FP-LAPW) method and arrive at a realistic and minimal tight-binding model, parameterized to provide an accurate description of both valence and conduction bands. It is shown that cation sp3 - anion sp3d5 basis along with the next nearest neighbor model for hopping interactions is sufficient to describe the electronic structure of these systems over a wide energy range, obviating the use of any fictitious s* orbital, employed previously. Similar analyses were also performed for the II-VI semiconductors, using the more accurate FP-LAPW method compared to previous approaches, in order to enhance reliability of the parameter values. Using these parameters, we calculate the electronic structure of III-V and II-VI nanocrystals in real space with sizes ranging upto about 7 nm in diameter, establishing a quantitatively accurate description of the band-gap variation with sizes for the various nanocrystals by comparing with available experimental results from the literature.Comment: 28 pages, 8 figures, Accepted for publication in Phys. Rev.