Domains in complex surfaces with non-compact automorphism groups

Let X be an arbitrary complex surface and D a domain in X that has a non-compact group of holomorphic automorphisms. A characterization of those domains D that admit a smooth, weakly pseudoconvex, finite type boundary orbit accumulation point is obtained.

A Haplotype at the UCP1 Gene Locus Contributes to Genetic Risk for Type 2 Diabetes in Asian Indians (CURES-72)

Background: The gene encoding for uncoupling protein-1 (UCP1) is considered to be a candidate gene for type 2 diabetes because of its role in thermogenesis and energy expenditure. The objective of the study was to examine whether genetic variations in the UCP1 gene are associated with type 2 diabetes and its related traits in Asian Indians. Methods: The study subjects, 810 type 2 diabetic subjects and 990 normal glucose tolerant (NGT) subjects, were chosen from the Chennai Urban Rural Epidemiological Study (CURES), an ongoing population-based study in southern India. The polymorphisms were genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Linkage disequilibrium (LD) was estimated from the estimates of haplotypic frequencies. Results: The three polymorphisms, namely -3826A -> G, an A -> C transition in the 5'-untranslated region (UTR) and Met229Leu, were not associated with type 2 diabetes. However, the frequency of the A-C-Met (-3826A -> G-5'UTR A -> C-Met229Leu) haplotype was significantly higher among the type 2 diabetic subjects (2.67%) compared with the NGT subjects (1.45%, P < 0.01). The odds ratio for type 2 diabetes for the individuals carrying the haplotype A-C-Met was 1.82 (95% confidence interval, 1.29-2.78, P = 0.009). Conclusions: The haplotype, A-C-Met, in the UCP1 gene is significantly associated with the increased genetic risk for developing type 2 diabetes in Asian Indians.

Three-dimensional structure of heat shock protein 90 from Plasmodium falciparum: molecular modelling approach to rational drug design against malaria

We have recently implicated heat shock protein 90 from Plasmodium falciparum (PfHsp90) as a potential drug target against malaria. Using inhibitors specific to the nucleotide binding domain of Hsp90, we have shown potent growth inhibitory effects on development of malarial parasite in human erythrocytes. To gain better understanding of the vital role played by PfHsp90 in parasite growth, we have modeled its three dimensional structure using recently described full length structure of yeast Hsp90. Sequence similarity found between PfHsp90 and yeast Hsp90 allowed us to model the core structure with high confidence. The superimposition of the predicted structure with that of the template yeast Hsp90 structure reveals an RMSD of 3.31 angstrom. The N-terminal and middle domains showed the least RMSD (1.76 angstrom) while the more divergent C-terminus showed a greater RMSD (2.84 angstrom) with respect to the template. The structure shows overall conservation of domains involved in nucleotide binding, ATPase activity, co-chaperone binding as well as inter-subunit interactions. Important co-chaperones known to modulate Hsp90 function in other eukaryotes are conserved in malarial parasite as well. An acidic stretch of amino acids found in the linker region, which is uniquely extended in PfHsp90 could not be modeled in this structure suggesting a flexible conformation. Our results provide a basis to compare the overall structure and functional pathways dependent on PfHsp90 in malarial parasite. Further analysis of differences found between human and parasite Hsp90 may make it possible to design inhibitors targeted specifically against malaria.

Peptide mimics for structural features in proteins. Crystal structures of three heptapeptide helices with a C-terminal 6-->1 hydrogen bond.

The crystal structure determination of three heptapeptides containing alpha-aminoisobutyryl (Aib) residues as a means of helix stabilization provides a high-resolution characterization of 6-->1 hydrogen-bonded conformations, reminiscent of helix-terminating structural features in proteins. The crystal parameters for the three peptides, Boc-Val-Aib-X-Aib-Ala-Aib-Y-OMe, where X and Y are Phe, Leu (I), Leu, Phe (II) and Leu, Leu (III) are: (I) space group P1, Z = 1, a = 9.903 A, b = 10.709 A, c = 11.969 A, alpha = 102.94 degrees, beta = 103.41 degrees, gamma = 92.72 degrees, R = 4.55%; (II) space group P21, Z = 2, a = 10.052 A, b = 17.653 A, c = 13.510 A, beta = 108.45 degrees, R = 4.49%; (III) space group P1, Z = 2 (two independent molecules IIIa and IIIb in the asymmetric unit), a = 10.833 A, b = 13.850 A, c = 16.928 A, alpha = 99.77 degrees, beta = 105.90 degrees, gamma = 90.64 degrees, R = 8.54%. In all cases the helices form 3(10)/alpha-helical (or 3(10)helical) structures, with helical columns formed by head-to-tail hydrogen bonding. The helices assemble in an all-parallel motif in crystals I and III and in an antiparallel motif in II. In the four crystallographically characterized molecules, I, II, IIIa and IIIb, Aib(6) adopts a left-handed helical (hL) conformation with positive phi, psi values, resulting in 6-->1 hydrogen-bond formation between Aib(2) CO and Leu(7)/Phe(7) NH groups. In addition a 4-->1 hydrogen bond is seen between Aib(3) CO and Aib(6) NH groups. This pattern of hydrogen bonding is often observed at the C-terminus of helices proteins, with the terminal pi-type turn being formed by four residues adopting the hRhRhRhL conformation.

Topology design of three-dimensional structures using hybrid finite elements

Conventional three-dimensional isoparametric elements are susceptible to problems of locking when used to model plate/shell geometries or when the meshes are distorted etc. Hybrid elements that are based on a two-field variational formulation are immune to most of these problems, and hence can be used to efficiently model both "chunky" three-dimensional and plate/shell type structures. Thus, only one type of element can be used to model "all" types of structures, and also allows us to use a standard dual algorithm for carrying out the topology optimization of the structure. We also address the issue of manufacturability of the designs.

Trapped waves in the neighborhood of a sonic-type singularity

A model equation is derived to study trapped nonlinear waves with a turning effect, occurring in disturbances induced on a two-dimensional steady flow. Only unimodal disturbances under the short wave assumption are considered, when the wave front of the induced disturbance is plane. In the neighbourhood of certain special points of sonic-type singularity, the disturbances are governed by a single first-order partial differential equation in two independent variables. The equation depends on the steady flow through three parameters, which are determined by the variations of velocity and depth, for example (in the case of long surface water waves), along and perpendicular to the wave front. These parameters help us to examine various relative effects. The presence of shocks in a continuously accelerating or decelerating flow has been studied in detail.

New type of high field electrooptic response in nematics

We have made concurrent measurements of ionic current and optical transmission between crossed polarisers on several nematics with positive dielectric anisotropy under the action of applied low frequency (< 1KHz) square wave voltages. When the field E is low, the measured current is linear in E and there is no electrooptic response. Beyond some value of the field (E(0)similar to 100 esu), the current becomes independent of the field (phenomenon of limiting current). Further an electrooptic signal is measured at twice the frequency of the applied voltage, which exhibits a peak as a function of the field. The width of the peak is 3 to 4 times the value of E-0, and the signal level at the peak decreases as the frequency is increased. These measurements have been made on three highly polar compounds with cyano end groups. Careful observations do not show any evidence of electrohydrodynamic instabilities in the sample. It is argued that the observations can be understood if at the onset of the phenomenon of the limiting current, a strong electric field gradient is established near one of the electrodes due to the sweeping of an ionic species with high mobility. The field gradient produces a flexoelectric deformation of the director field, which in turn gives rise to the electrooptic effect. At higher fields, the stabilising dielectric torque takes over to suppress this instability.

Information Theoretic Results for Three-User Cognitive Channels

In this paper, we introduce the three-user cognitive radio channels with asymmetric transmitter cooperation, and derive achievable rate regions under several scenarios depending on the type of cooperation and decoding capability at the receivers. Two of the most natural cooperation mechanisms for the three-user channel are considered here: cumulative message sharing (CMS) and primary-only message sharing (PMS). In addition to the message sharing mechanism, the achievable rate region is critically dependent on the decoding capability at the receivers. Here, we consider two scenarios for the decoding capability, and derive an achievable rate region for each one of them by employing a combination of superposition and Gel'fand-Pinsker coding techniques. Finally, to provide a numerical example, we consider the Gaussian channel model to plot the rate regions. In terms of achievable rates, CMS turns out to be a better scheme than PMS. However, the practical aspects of implementing such message-sharing schemes remain to be investigated.

Conformations of dehydrophenylalanine containing peptides. NMR studies on three tripeptides with a central dehydrophenylalanyl residue.

Three tripeptides containing a central Z-dehydrophenylalanine residue (Δz-Phe), Boc-L-Phe-Δz-Phe-X-OMe (X = L-Val 1, L-Leu 2 and X = L-Ala 3) have been synthesized and their solution conformations investigated by 270 MHz 1H NMR spectroscopy. In all three peptides, conformations involving the X residue NH in an intramolecular hydrogen bond were favoured in CDCl3 solutions. Studies of the nuclear Overhauser effect (NOE) provided support for a Type II β turn conformation in these peptides with Phe and Δz-Phe occupying the i + 1 and i + 2 positions, respectively. Significantly different conformations lacking any intramolecular hydrogen bonds were observed for peptide 1 in (CD3)2SO. NOE results were consistent with a significant population of molecules having semi-extended conformations (ø > 100°) at the Δz-Phe residue.

Probing the role of the C-H center dot center dot center dot O hydrogen bond stabilized polypeptide chain reversal at the C-terminus of designed peptide helices. Structural characterization of three decapeptides

The structural characterization in crystals of three designed decapeptides containing a double D-segment at the C-terminus is described. The crystal structures of the peptides Boc-Leu-Aib-Val-Xxx-Leu-Aib-Val- (D)Ala-(D)Leu-Aib-OMe, (Xxx = Gly 2, (D)Ala 3, Aib 4) have been determined and compared with those reported earlier for peptide 1 (Xxx = Ala) and the all L analogue Boc-Leu-Aib-Val-Ala-Leu-Aib-Val-Ala-Leu-Aib-OMe, which yielded a perfect right-handed a-helical structure. Peptides 1 and 2 reveal a right-handed helical segment spanning residues 1 to 7, ending in a Schellman motif with Ala(8) functioning as the terminating residue. Polypeptide chain reversal occurs at residue 9, a novel feature that appears to be the consequence of a C-(HO)-O-... hydrogen bond between residue 4 (CH)-H-alpha and residue 9 CO groups. The structures of peptides 3 and 4, which lack the pro R hydrogen at the C-alpha atom of residue 4, are dramatically different. Peptide 3 adopts a right-handed helical conformation over the 1 to 7 segment. Residues 8 and 9 adopt at conformations forming a C-terminus type I' beta-turn, corresponding to an incipient left-handed twist of the polypeptide chain. In peptide 4, helix termination occurs at Aib(6), with residues 6 to 9 forming a left-handed helix, resulting in a structure that accommodates direct fusion of two helical segments of opposite twist. Peptides 3 and 4 provide examples of chiral residues occurring in the less favored sense of helical twist; (D)Ala(4) in peptide 3 adopts an alpha(R) conformation, while (L)Val(7) in 4 adopts an alpha(L) conformation. The structural comparison of the decapeptides reported here provides evidence for the role of specific C-(HO)-O-... hydrogen bonds in stabilizing chain reversals at helix termini, which may be relevant in aligning contiguous helical and strand segments in polypeptide structures.

Role of barriers to conformational changes in ketones undergoing the Norrish type II process

The Norrish type II process is examined in three ketones containing primary, secondary and tertiary C---H bonds in the γ position relative to the carbonyl groups; the MINDO/3 semiempirical self-consistent field (SCF) molecular orbital (MO) method was used with complete geometry optimization in the unrestricted Hartree—Fock frame for the open-shell species. Results show that barriers to conformational change in ketones play an important role in the triplet reaction.

Identification of Critical Residues of the Mycobacterial Dephosphocoenzyme A Kinase by Site-Directed Mutagenesis

Dephosphocoenzyme A kinase performs the transfer of the c-phosphate of ATP to dephosphocoenzyme A, catalyzing the last step of coenzyme A biosynthesis. This enzyme belongs to the P-loop-containing NTP hydrolase superfamily, all members of which posses a three domain topology consisting of a CoA domain that binds the acceptor substrate, the nucleotide binding domain and the lid domain. Differences in the enzymatic organization and regulation between the human and mycobacterial counterparts, have pointed out the tubercular CoaE as a high confidence drug target (HAMAP database). Unfortunately the absence of a three-dimensional crystal structure of the enzyme, either alone or complexed with either of its substrates/regulators, leaves both the reaction mechanism unidentified and the chief players involved in substrate binding, stabilization and catalysis unknown. Based on homology modeling and sequence analysis, we chose residues in the three functional domains of the enzyme to assess their contributions to ligand binding and catalysis using site-directed mutagenesis. Systematically mutating the residues from the P-loop and the nucleotide-binding site identified Lys14 and Arg140 in ATP binding and the stabilization of the phosphoryl intermediate during the phosphotransfer reaction. Mutagenesis of Asp32 and Arg140 showed catalytic efficiencies less than 5-10% of the wild type, indicating the pivotal roles played by these residues in catalysis. Non-conservative substitution of the Leu114 residue identifies this leucine as the critical residue from the hydrophobic cleft involved in leading substrate, DCoA binding. We show that the mycobacterial enzyme requires the Mg2+ for its catalytic activity. The binding energetics of the interactions of the mutant enzymes with the substrates were characterized in terms of their enthalpic and entropic contributions by ITC, providing a complete picture of the effects of the mutations on activity. The properties of mutants defective in substrate recognition were consistent with the ordered sequential mechanism of substrate addition for CoaE.

High level stable expression of rat brain type IIA sodium channel ?-subunit in CHO cells

The neuronal sodium channels are responsible for the rising phase of action potential and are composed of three subunits, of which the alpha-subunit has been shown to be adequate for most of its functional properties. We have stably expressed the rat brain type IIA sodium channel alpha-subunit in CHO cell tine using a CMV promoter-based vector. The expression was confirmed by detecting a 6.5 kb RNA corresponding to sodium channel alpha-subunit using Northern hybridization. The cells stably expressing the alpha-subunit, yield isolated sodium currents of amplitudes greater than 4nA when studied in whole-cell configuration of the patch-clamp technique. The sodium currents are characterized by activation and inactivation properties similar to neuronal sodium channels, and are blocked by the voltage gated sodium channel blocker tetrodotoxin (TTX).

Endophytic fungal communities in woody perennials of three tropical forest types of the Western Ghats, southern India

Fungal endophytes of tropical trees are expected to be exceptionally species rich as a consequence of high tree diversity in the tropics and the purported host restriction among the endophytes. Based on this premise, endophytes have been regarded as a focal group for estimating fungal numbers because their possible hyperdiverse nature would reflect significantly global fungal diversity. We present our consolidated ten-year work on 75 dicotyledonous tree hosts belonging to 33 families and growing in three different types of tropical forests of the NBR in the Western Ghats, southern India. We conclude that endophyte diversity in these forests is limited due to loose host affiliations among endophytes. Some endophytes have a wide host range and colonize taxonomically disparate hosts suggesting adaptations in them to counter a variety of defense chemicals in their hosts. Furthermore, such polyphagous endophytes dominate the endophyte assemblages of different tree hosts. Individual leaves may be densely colonized but only by a few endophyte species. It appears that the environment (the type of forest in this case) has a larger role in determining the endophyte assemblage of a plant host than the taxonomy of the host plant. Thus, different tropical plant communities have to be studied for their endophyte diversity to test the generalization that endophytes are hyperdiverse in the tropics, estimate their true species richness, and use them as a predictor group for more accurate assessment of global fungal diversity.

Free convection in power-law fluids near a three-dimensional stagnation point

Numerical results are presented for the free-convection boundary-layer equations of the Ostwald de-Waele non-Newtonian power-law type fluids near a three-dimensional (3-D) stagnation point of attachment on an isothermal surface. The existence of dual solutions that are three-dimensional in nature have been verified by means of a numerical procedure. An asymptotic solution for very large Prandtl numbers has also been derived. Solutions are presented for a range of values of the geometric curvature parameter c, the power-law index n, and the Prandtl number Pr.