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Biomedical subjects

A K Ghosh

Publications and source records attributed to A K Ghosh.

At least 37 records · Page 2Linked to original sources
PubMed2002

Plasmodium-mosquito interactions, phage display libraries and transgenic mosquitoes impaired for malaria transmission.

Malaria continues to kill millions of people every year and new strategies to combat this disease are urgently needed. Recent advances in the study of the mosquito vector and its interactions with the malaria parasite suggest that it may be possible to genetically manipulate the mosquito in order to reduce its vectorial capacity. Here we review the advances made to date in four areas: (1) the introduction of foreign genes into the mosquito germ line; (2) the characterization of tissue-specific promoters; (3) the identification of gene products that block development of the parasite in the mosquito; and (4) the generation of transgenic mosquitoes impaired for malaria transmission. While initial results show great promise, the problem of how to spread the blocking genes through wild mosquito populations remains to be solved.

Animals↗
PubMed2002

Memapsin 2 (beta-secretase) as a therapeutic target.

As beta-secretase, memapsin 2 cleaves amyloid-beta precursor protein, which leads ultimately to the onset of Alzheimer's disease. As such, memapsin 2 is an excellent target of inhibitor drugs for the treatment of this disease. Here we describe the tools for memapsin 2 inhibitor design that have been developed and results from the structure-based inhibitor design. Strategy for the design of memapsin 2 inhibitors with pharmaceutical potential is also discussed.

Alzheimer Disease↗
PubMed2002

Left sided cervical and thoracic malignant extra-adrenal pheochromocytoma.

Extra-adrenal Pheochromocytomas are rare entities. High index of suspicion among diastolic hypertensives followed by screening test for 24-hour urinary catecholamine level helps in diagnosis. 123I MIBG scintigraphy is specific for tumour localisation and surgical debulking of tumour or 131I MIBG therapy are alternative modes of treatment.

3-Iodobenzylguanidine↗
PubMed2002

Induced liver tumour further support to a genetic marker with its high correlation with chorioallantoic membrane phenotypes in selected layer lines.

The conventional chorioallantoic membrane (CAM) phenotype assay was conducted using 11-day-old embryonatic eggs of white Leghorn strains, each inoculated with 0.2 ml of subgroup A Rous sarcoma virus (RSV) and subgroup C RSV separately containing 10(3)pfu ml(-1). Eggs were further incubated for hatching. Harvesting of CAMs for counting of pocks and monitoring chicks for liver tumour (LT) mortality during 4 weeks of post-hatching period were followed. The conversely associated phenotype (CAP) incidence i.e. CAM(+) LT(-) and CAM(-) LT(+) was observed in all three lines for both subgroup A and C virus infection. The LT deaths of chicks in all strains occurred within 21 days post-hatch irrespective of virus subgroups. The regression analysis of %LT death (transformed data) distributed within pock count range (PCR) basis was performed. The regression coefficients (b(i)'s) were found to be non-significant, indicating that %LT death did not correlate with number of particles that entered the cells because the chicks that had at least 25 pock counts in CAMs died with few exceptions. This study upheld the view that the CAM phenotypes (S and R) under the control of a pair of alleles, a(s) and a(r) at the tva locus and c(s) and c(r) at the tvc locus as reported extensively. Because of a high correlation coefficients between CAM and LT phenotypes [S and LT(+)] in respect of subgroup A (r = 0.72) and subgroup C (r = 0.81) infection, it is obvious that one could postulate a pleiotropic control of the two traits by the tva and tvc genes, respectively. Indeed fitting a 4-allele model in both tva and tvc locus, suggesting that CAPs are the indicator for nullifying the conventional 2-allele model proposed for the induced tumour expression phenotypes by leukosis sarcoma viruses.

Alleles↗
PubMed2001

Total synthesis of microtubule-stabilizing agent (-)-laulimalide.

An enantioselective first total synthesis of laulimalide (1) is described. Laulimalide, a remarkably potent antitumor macrolide, has been isolated from the Indonesian sponge Hyattella sp. and the Okinawan sponge Fasciospongia rimosa. Laulimalide represents a new class of antitumor agents with significant clinical potential. The synthesis is convergent and involved the assembly of C(3)-C(16) segment 4 and C(17)-C(28) segment 5 by Julia olefination. The sensitive C(2)-C(3) cis-olefin functionality was installed by Yamaguchi macrolactonization of a hydroxy alkynic acid followed by hydrogenation of the resulting alkynoic lactone over Lindlar's catalyst. Initial attempts of intramolecular Still's variant of Horner-Emmons olefination between the C(19)-phosphonocetate and C(3)-aldehyde provided a 1:2 mixture of cis- and trans-macrolactones. The trans-isomer was photoisomerized to a mixture of cis- and trans-isomers. The other key steps involved ring-closing olefin metathesis to construct both dihydropyran units, stereoselective anomeric alkylation to functionalize the dihydropyran ring, stereoselective reduction of the resulting alkynyl ketone to set the C(20)-hydroxyl stereochemistry, and a novel Julia olefination protocol for the installation of the C(13)-exo-methylene unit. The sensitive epoxide at C(16)-C(17) was introduced in a highly stereoselective manner by Sharpless epoxidation at the final stage of the synthesis.

Animals↗
PubMed2001

The non-receptor tyrosine kinase Syk is a target of Cbl-mediated ubiquitylation upon B-cell receptor stimulation.

The negative regulator Cbl functions as a ubiquitin ligase towards activated receptor tyrosine kinases and facilitates their transport to lysosomes. Whether Cbl ubiquitin ligase activity mediates its negative regulatory effects on cytoplasmic tyrosine kinases of the Syk/ZAP-70 family has not been addressed, nor is it known whether these kinases are regulated via ubiquitylation during lymphocyte B-cell receptor engagement. Here we show that B-cell receptor stimulation in Ramos cells induces the ubiquitylation of Syk tyrosine kinase which is inhibited by a dominant-negative mutant of Cbl. Intact tyrosine kinase-binding and RING finger domains of Cbl were found to be essential for Syk ubiquitylation in 293T cells and for in vitro Syk ubiquitylation. These same domains were also essential for Cbl-mediated negative regulation of Syk as measured using an NFAT-luciferase reporter in a lymphoid cell. Association with Cbl did not alter the kinase activity of Syk. Altogether, our results support an essential role for Cbl ubiquitin ligase activity in the negative regulation of Syk, and establish that ubiquitylation provides a mechanism of Cbl-mediated negative regulation of cytoplasmic targets.

Cell Line↗
PubMed2001

Targeting Plasmodium ligands on mosquito salivary glands and midgut with a phage display peptide library.

Despite vast efforts and expenditures in the past few decades, malaria continues to kill millions of persons every year, and new approaches for disease control are urgently needed. To complete its life cycle in the mosquito, Plasmodium, the causative agent of malaria, has to traverse the epithelia of the midgut and salivary glands. Although strong circumstantial evidence indicates that parasite interactions with the two organs are specific, hardly any information is available about the interacting molecules. By use of a phage display library, we identified a 12-aa peptide--salivary gland and midgut peptide 1 (SM1)--that binds to the distal lobes of the salivary gland and to the luminal side of the midgut epithelium, but not to the midgut surface facing the hemolymph or to ovaries. The coincidence of the tissues with which parasites and the SM1 peptide interact suggested that the parasite and peptide recognize the same surface ligand. In support of this hypothesis, the SM1 peptide strongly inhibited Plasmodium invasion of salivary gland and midgut epithelia. These experiments suggest a new strategy for the genetic manipulation of mosquito vectorial capacity.

Animals↗
PubMed2001

Structure-based design: potent inhibitors of human brain memapsin 2 (beta-secretase).

Memapsin 2 (beta-secretase) is one of two proteases that cleave the beta-amyloid precursor protein (APP) to produce the 40-42 residue amyloid-beta peptide (Abeta) in the human brain, a key event in the progression of Alzheimer's disease. On the basis of the X-ray crystal structure of our lead inhibitor (2, OM99-2 with eight residues) bound to memapsin, we have reduced the molecular weight and designed potent memapsin inhibitors. Structure-based design and preliminary structure-activity studies have been presented.

Amyloid Precursor Protein Secretases↗
PubMed2001

Subsite specificity of memapsin 2 (beta-secretase): implications for inhibitor design.

Memapsin 2 is the protease known as beta-secretase whose action on beta-amyloid precursor protein leads to the production of the beta-amyloid (Abeta) peptide. Since the accumulation of Abeta in the brain is a key event in the pathogenesis of Alzheimer's disease, memapsin 2 is an important target for the design of inhibitory drugs. Here we describe the residue preference for the subsites of memapsin 2. The relative k(cat)/K(M) values of residues in each of the eight subsites were determined by the relative initial cleavage rates of substrate mixtures as quantified by MALDI-TOF mass spectrometry. We found that each subsite can accommodate multiple residues. The S(1) subsite is the most stringent, preferring residues in the order of Leu > Phe > Met > Tyr. The preferences of other subsites are the following: S(2), Asp > Asn > Met; S(3), Ile > Val > Leu; S(4), Glu > Gln > Asp; S(1)', Met > Glu > Gln > Ala; S(2)', Val > Ile > Ala; S(3)', Leu > Trp > Ala; S(4)', Asp > Glu > Trp. In general, S subsites are more specific than the S' subsites. A peptide comprising the eight most favored residues (Glu-Ile-Asp-Leu-Met-Val-Leu-Asp) was found to be hydrolyzed with the highest k(cat)/K(M) value so far observed for memapsin 2. Residue preferences at four subsites were also studied by binding of memapsin 2 to a combinatorial inhibitor library. From 10 tight binding inhibitors, the consensus preferences were as follows: S(2), Asp and Glu; S(3), Leu and Ile; S(2)', Val; and S(3)', Glu and Gln. An inhibitor, OM00-3, Glu-Leu-Asp-LeuAla-Val-Glu-Phe (where the asterisk represents the hydroxyethylene tansition-state isostere), designed from the consensus residues, was found to be the most potent inhibitor of memapsin 2 so far reported (K(i) of 3.1 x 10(-10) M). A molecular model of OM00-3 binding to memapsin 2 revealed critical improvement of the interactions between inhibitor side chains with enzyme over a previous inhibitor, OM99-2 [Ghosh, A. K., et al. (2000) J. Am. Chem. Soc. 14, 3522-3523].

Alzheimer Disease↗
PubMed2001

Stereoselective synthesis of pseudopeptide microbial agent AI-77-B.

[structure: see text]. An efficient and highly stereoselective synthesis of the gastroprotective natural product AI-77-B is described. The stereocenters of the hydroxy amino acid moiety were generated by an ester-derived titanium-enolate-mediated syn-aldol reaction, a Curtius rearrangement, and application of Dondoni's aldehyde homologation. Condensation with the dihydroisocoumarin fragment and subsequent deprotecting transformations furnished optically active AI-77-B.

Anti-Bacterial Agents↗
PubMed2001

Small quartz silica spheres induced disorder in octylcyanobiphenyl (8CB) liquid crystals: a thermal study.

A photopyroelectric technique has been applied to the study of specific heat and thermal conductivity of homeotropically aligned mixtures of small quartz spheres (aerosil) and octylcyanobiphenyl (8CB) with concentration 0</=rho(s)</=0.04 g/cm(3). Thermal conductivity data show that, even at these very low concentrations, an annealing of the disorder introduced by the aerosil takes place on cooling at the smectic-A-nematic (Sm-A-N) phase transition and not only at the nematic-isotropic (N-I) one. This means that there is some elastic strain in the nematic phase of the sample which is not quenched. Accordingly the suppression of the N-I transition temperature as a function of rho(s) does not fit a random field with a random dilution model that accounts for random quenched disorder only. High resolution specific heat measurements at the A-N and N-I transition show the effect of the aerosil is not the same. While in the first case its peak is suppressed with increasing concentration, in the second case there are some indications that outside the two-phase coexistence region it is enhanced. The effect of surface-induced alignment is also discussed to explain some discrepancies between our data and the ones reported in literature. It is concluded that the amount of disorder in the sample does not depend on rho(s) only, but also on other variables such as external fields. Finally, a relaxation phenomenon in the aerosil network that partially compensate the disordering effect of the particles is suggested to explain the concentration dependence of the transition temperatures.

Journal Article↗
PubMed2001

An economised craniofacial identification system.

It has been attempted to develop an economised craniofacial identification system, as a special automated version of photo/video superimposition technique, that can deal with common cases of personal identification with the aid of a skull and a nearly front view face photograph of the suspected victim. The proposed method is economic in respect of (i) cost of hardware configuration, (ii) processing time as well as (iii) manual labour involved. Over and above, it has got a capability to take care of ambiguities due to soft tissue thickness during the selection of facial features, which is a part of the procedure. In order to reconstruct a 2-D cranial image, superimposable over the facial one, the new method does not need any reconstruction of a digitised 3-D cranial image. It works simply by a suitable segment-wise processing of a 2-D cranial image with the aid of the symmetry perceiving adaptive neuronet (SPAN), that has recently been introduced in connection with nearly front view facial image recognition. The final comparison of the facial and the superimposable cranial images is as versatile as the same for facial image recognition by SPAN.A practical application of this extended version of SPAN has been demonstrated in the present paper.

Child↗
PubMed2001

Total synthesis of antitumor depsipeptide (-)-doliculide.

[reaction: see text] (-)-Doliculide, a potent antitumor agent, is synthesized stereoselectively in a convergent manner. The key strategy involves a stereoselective synthesis of the polyketide unit and synthesis of the D-tyrosine derivative, followed by assembly of the fragments by an esterification and cycloamidation reaction sequence. The synthesis of the polyketide fragment was achieved by an iterative asymmetric synthesis to install stereoselectively both 1,3-dimethyl groups and the 1,3-diol unit by utilizing asymmetric cyclopropanations and Sharpless asymmetric epoxidations as the key steps.

Antineoplastic Agents↗
PubMed2001

Purification and characterization of fibroin from the tropical Saturniid silkworm, Antheraea mylitta.

The fibroin protein isolated from the posterior silkgland of the tropical Saturniid silkworm Antheraea mylitta, was solubilized in lithium dodecyl sulfate and purified by gel filtration. The major fraction from gel filtration was analyzed by SDS-PAGE under non-reducing and reducing conditions. One major protein band of ca 395 kDa was obtained under non-reducing conditions and a doublet band of approximately 197 kDa under reducing conditions. The appearance of a single spot in two-dimensional electrophoresis confirmed the purity of the protein indicating that it may be a homodimeric protein of two similar sized polypeptides. Amino acid composition analysis showed that, like other Saturniid fibroins, it is rich in glycine, alanine and serine amino acids. N-terminal amino acid sequence shows significant homology with other Antheraea species. The enzymatic deglycosylation analysis indicates that the fibroin protein is glycosylated and the oligosaccharides are O-linked to the protein backbone by N-acetylgalactoseamine moiety which conforms to a Core 1 mucin-type glycosylation pattern.

Amino Acid Sequence↗