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S Lin

Publications and source records attributed to S Lin.

At least 73 records · Page 4Linked to original sources
PubMed2001

[A randomized case-control study on the influence of percutaneous estradiol and progestin in cyclic combined regimen on endometrium and vaginal bleeding pattern in Chinese early postmenopausal women].

OBJECTIVE: To observe the influence of percutaneous estradiol + micronized progesterone or medroxyprogesterone on endometrium and vaginal bleeding in Chinese post-menopausal women. METHODS: A 3-year open randomized clinical study was designed. The estrogen and progestin were used continuous-combined together in a cyclic regimen. The percutaneous estradiol was regarded as estrogen. The microprogesterone (MP) and medroxyprogesterone (MPA) were served as progestin. Sixty healthy women (naturally menopausal for 1 to 5 years) were recruited and divided into four groups. The regimen as follows: (1) percutaneous estradiol gel (gel) containing 1.5 mg of 17 beta-estradiol (E2)/d plus micronized progesterone (MP) 100 mg/d in group 1 (G1, E2 1.5 + MP); (2) gel, 1.5 mg E2/d plus medroxyprogesterone acetate (MPA), 2 mg/d in group 2 (G2, E2 1.5 + MPA); (3) gel, 0.75 mg E2/d plus MP, 100 mg/d in group 3 (G3, E2 0.75 + MP); and (4) gel, 0.75 mg E2/d plus MPA, 2 mg/d in group 4 (G4, E2 0.75 + MPA). All were given for 25 d/month, and 5 days free. The transvaginal sonography was performed 0, 12, 24 and 36 months. The thickness of endometrium were measured. The endometrium biopsy by Pipelle tube was conducted at 24th or 36th months. The vaginal bleeding was recorded. RESULTS: Fifty-nine patients (98.3%) finished 1 year and 56 patients (93.3%) for 2 years, 51 (85%) for 3 years. There was no significant changes of endometrium. The thickness of endometrium before treatment in four groups were 0.25 cm, 0.27 cm, 0.22 cm, 0.28 cm and after treatment 0.37 cm, 0.30 cm, 0.326 7 cm and 0.3 cm respectively. No significant differences was found in four groups (P > 0. 05). Fifty -three patients had the Pipelle biopsy. The pathological result showed: 16 cases (25.8%) proliferated, 1 case (1.6%) secretary; 11 cases (17.7%) atrophy; 23 cases (37.1%) mixed cell; tendency to hyperplasia in 2 cases (3.2%). During the treatment, the vaginal irregular bleeding rate was highest in G2 and lowest in G3. CONCLUSIONS: Daily estrogen containing 0.75 mg and 1.5 mg E2 combined with 100 mg progesterone and 2 mg medroxyprogesterone do not increase the thickness of endometrium significantly. The vaginal bleeding rate was low when combined with 100 mg micronized progesterone. Addition of natural progesterone will low down the bleeding rate and improve the HRT compliance.

Adult↗
PubMed2001

The cellular metabolism and systemic toxicity of arsenic.

Although it has been known for decades that humans and many other species convert inorganic arsenic to mono- and dimethylated metabolites, relatively little attention has been given to the biological effects of these methylated products. It has been widely held that inorganic arsenicals were the species that accounted for the toxic and carcinogenic effects of this metalloid and that methylation was properly regarded as a mechanism for detoxification of arsenic. Elucidation of the metabolic pathway for arsenic has changed our understanding of the significance of methylation. Both methylated and dimethylated arsenicals that contain arsenic in the trivalent oxidation state have been identified as intermediates in the metabolic pathway. These compounds have been detected in human cells cultured in the presence of inorganic arsenic and in urine of individuals who were chronically exposed to inorganic arsenic. Methylated and dimethylated arsenicals that contain arsenic in the trivalent oxidation state are more cytotoxic, more genotoxic, and more potent inhibitors of the activities of some enzymes than are inorganic arsenicals that contain arsenic in the trivalent oxidation state. Hence, it is reasonable to describe the methylation of arsenic as a pathway for its activation, not as a mode of detoxification. This review summarizes the current knowledge of the processes that control the formation and fate of the methylated metabolites of arsenic and of the biological effects of these compounds. Given the considerable interest in the dose-response relationships for arsenic as a toxin and a carcinogen, understanding the metabolism of arsenic may be critical to assessing the risk associated with chronic exposure to this element.

Animals↗
PubMed2001

In vitro and in vivo evaluations of biodegradable implants for hormone replacement therapy: effect of system design and PK-PD relationship.

This investigation evaluated the feasibility of using subdermally implantable devices fabricated by nonconventional 3-dimensional printing technology for controlled delivery of ethinyl estradiol (EE2). In vitro release kinetics of EE2 and in vivo pharmacokinetics/pharmacodynamics in ovariectomized New Zealand White rabbits were carried out to study 3 implant prototypes: implant I (single-channel EE2 distribution in polycaprolactone polymer core), implant II (homogeneous EE2 distribution in polycaprolactone polymer matrix), and implant III (concentration-gradient EE2 distribution in polycaprolactone and poly(dl-lactide-co-glycolide) (50:50 matrix). EE2 was found to be released from all the implants in a nonlinear pattern with an order of implant III > implant II > implant I. The noncompartmental pharmacokinetic analysis of plasma EE2 profiles in rabbits indicated a significant difference (p < .05) in Cmax, tmax, and mean residence time between implant I and implants II and III, but no difference in the area under the plasma concentration time curves calculated by trapezoidal rule (AUC) among the implants. For pharmacodynamic studies, endogenous follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were observed to be suppressed following implantation of all implants, which demonstrated that a therapeutically effective dose of EE2 had been delivered. Furthermore, the noncompartmental analysis of plasma FSH and LH profiles in rabbits showed a significant difference (p < .05) in AUC and the mean residence time between implant III and implants I and II. A good in vivo/in vitro relationship was observed between daily amounts of EE2 released and plasma profiles of EE2 for all implants. This relationship suggests that plasma profiles of EE2 could be predicted from in vitro measurement of daily amount of EE2 released. Therefore, performing in vitro drug release studies may aid in the development of an EE2 implant with the desired in vivo release rate.

Absorbable Implants↗
PubMed2001

An agrin minigene rescues dystrophic symptoms in a mouse model for congenital muscular dystrophy.

Congenital muscular dystrophy is a heterogeneous and severe, progressive muscle-wasting disease that frequently leads to death in early childhood. Most cases of congenital muscular dystrophy are caused by mutations in LAMA2, the gene encoding the alpha2 chain of the main laminin isoforms expressed by muscle fibres. Muscle fibre deterioration in this disease is thought to be caused by the failure to form the primary laminin scaffold, which is necessary for basement membrane structure, and the missing interaction between muscle basement membrane and the dystrophin-glycoprotein complex (DGC) or the integrins. With the aim to restore muscle function in a mouse model for this disease, we have designed a minigene of agrin, a protein known for its role in the formation of the neuromuscular junction. Here we show that this mini-agrin-which binds to basement membrane and to alpha-dystroglycan, a member of the DGC-amends muscle pathology by a mechanism that includes agrin-mediated stabilization of alpha-dystroglycan and the laminin alpha5 chain. Our data provides in vivo evidence that a non-homologous protein in combination with rational protein design can be used to devise therapeutic tools that may restore muscle function in human muscular dystrophies.

Agrin↗
PubMed2001

Reduced levels of amyloid beta-peptide antibody in Alzheimer disease.

OBJECTIVE: To investigate whether it was possible to detect the presence and different levels of naturally occurring anti-beta-amyloid (Abeta) antibodies in the CSF of patients with AD and age-matched controls by employing a sensitive ELISA. BACKGROUND: Immunization with preaggregated amyloid beta-peptide (Abeta(1-42)) and administration of antibodies against Abeta into amyloid precursor protein APP(V717F)- transgenic mice (an animal model of AD) have recently been reported to dramatically reduce amyloid plaque deposition, neuritic dystrophy, and astrogliosis, most likely by enhancing Abeta clearance from brain. METHODS: A sensitive ELISA was performed to detect levels of naturally occurring anti-Abeta antibodies in the CSF of patients with AD and age-matched controls. Additionally, an immunoprecipitation assay was performed to confirm that naturally occurring anti-Abeta antibodies also exist in the human blood. RESULT: - Naturally occurring antibodies directed against Abeta were found in the CSF and plasma of patients with AD and healthy control subjects. Moreover, CSF anti-Abeta antibody titers are significantly lower in patients with AD compared with healthy control subjects. CONCLUSION: Naturally occurring antibodies directed against Abeta exist in human CSF and plasma. The CSF anti-Abeta antibody titers may be helpful in better understanding the effects of future immunologic therapies for AD.

Aged↗
PubMed2001

Lipid A modifications in polymyxin-resistant Salmonella typhimurium: PMRA-dependent 4-amino-4-deoxy-L-arabinose, and phosphoethanolamine incorporation.

Lipid A of Salmonella typhimurium can be resolved into multiple molecular species. Many of these substances are more polar than the predominant hexa-acylated lipid A 1,4'-bisphosphate of Escherichia coli K-12. By using new isolation methods, we have purified six lipid A subtypes (St1 to St6) from wild type S. typhimurium. We demonstrate that these lipid A variants are covalently modified with one or two 4-amino-4-deoxy-l-arabinose (l-Ara4N) moieties. Each lipid A species with a defined set of polar modifications can be further derivatized with a palmitoyl moiety and/or a 2-hydroxymyristoyl residue in place of the secondary myristoyl chain at position 3'. The unexpected finding that St5 and St6 contain two l-Ara4N residues accounts for the anomalous structures of lipid A precursors seen in S. typhimurium mutants defective in 3-deoxy-d-manno-octulosonic acid biosynthesis in which only the 1-phosphate group is modified with the l-Ara4N moiety (Strain, S. M., Armitage, I. M., Anderson, L., Takayama, K., Quershi, N., and Raetz, C. R. H. (1985) J. Biol. Chem. 260, 16089-16098). Phosphoethanolamine (pEtN)-modified lipid A species are much less abundant than l-Ara4N containing forms in wild type S. typhimurium grown in broth but accumulate to high levels when l-Ara4N synthesis is blocked in pmrA(C)pmrE(-) and pmrA(C)pmrF(-) mutants. Purification and analysis of selected compounds demonstrate that one or two pEtN moieties may be present. Our findings show that S. typhimurium contains versatile enzymes capable of modifying both the 1- and 4'-phosphates of lipid A with l-Ara4N and/or pEtN groups. PmrA null mutants of S. typhimurium produce lipid A species without any pEtN or l-Ara4N substituents. However, PmrA is not needed for the incorporation of 2-hydroxymyristate or palmitate.

Amino Sugars↗
PubMed2001

An inner membrane enzyme in Salmonella and Escherichia coli that transfers 4-amino-4-deoxy-L-arabinose to lipid A: induction on polymyxin-resistant mutants and role of a novel lipid-linked donor.

Attachment of the cationic sugar 4-amino-4-deoxy-l-arabinose (l-Ara4N) to lipid A is required for the maintenance of polymyxin resistance in Escherichia coli and Salmonella typhimurium. The enzymes that synthesize l-Ara4N and transfer it to lipid A have not been identified. We now report an inner membrane enzyme, expressed in polymyxin-resistant mutants, that adds one or two l-Ara4N moieties to lipid A or its immediate precursors. No soluble factors are required. A gene located near minute 51 on the S. typhimurium and E. coli chromosomes (previously termed orf5, pmrK, or yfbI) encodes the l-Ara4N transferase. The enzyme, renamed ArnT, consists of 548 amino acid residues in S. typhimurium with 12 possible membrane-spanning regions. ArnT displays distant similarity to yeast protein mannosyltransferases. ArnT adds two l-Ara4N units to lipid A precursors containing a Kdo disaccharide. However, as shown by mass spectrometry and NMR spectroscopy, it transfers only a single l-Ara4N residue to the 1-phosphate moiety of lipid IV(A), a precursor lacking Kdo. Proteins with full-length sequence similarity to ArnT are present in genomes of other bacteria thought to synthesize l-Ara4N-modified lipid A, including Pseudomonas aeruginosa and Yersinia pestis. As shown in the following article (Trent, M. S., Ribeiro, A. A., Doerrler, W. T., Lin, S., Cotter, R. J., and Raetz, C. R. H. (2001) J. Biol. Chem. 276, 43132-43144), ArnT utilizes the novel lipid undecaprenyl phosphate-alpha-l-Ara4N as its sugar donor, suggesting that l-Ara4N transfer to lipid A occurs on the periplasmic side of the inner membrane.

Amino Sugars↗
PubMed2001

Accumulation of a polyisoprene-linked amino sugar in polymyxin-resistant Salmonella typhimurium and Escherichia coli: structural characterization and transfer to lipid A in the periplasm.

Polymyxin-resistant mutants of Escherichia coli and Salmonella typhimurium accumulate a novel minor lipid that can donate 4-amino-4-deoxy-l-arabinose units (l-Ara4N) to lipid A. We now report the purification of this lipid from a pss(-) pmrA(C) mutant of E. coli and assign its structure as undecaprenyl phosphate-alpha-l-Ara4N. Approximately 0.2 mg of homogeneous material was isolated from an 8-liter culture by solvent extraction, followed by chromatography on DEAE-cellulose, C18 reverse phase resin, and silicic acid. Matrix-assisted laser desorption ionization/time of flight mass spectrometry in the negative mode yielded a single species [M - H](-) at m/z 977.5, consistent with undecaprenyl phosphate-alpha-l-Ara4N (M(r) = 978.41). (31)P NMR spectroscopy showed a single phosphorus atom at -0.44 ppm characteristic of a phosphodiester linkage. Selective inverse decoupling difference spectroscopy demonstrated that the undecaprenyl phosphate group is attached to the anomeric carbon of the l-Ara4N unit. One- and two-dimensional (1)H NMR studies confirmed the presence of a polyisoprene chain and a sugar moiety with chemical shifts and coupling constants expected for an equatorially substituted arabinopyranoside. Heteronuclear multiple-quantum coherence spectroscopy analysis demonstrated that a nitrogen atom is attached to C-4 of the sugar residue. The purified donor supports in vitro conversion of lipid IV(A) to lipid II(A), which is substituted with a single l-Ara4N moiety. The identification of undecaprenyl phosphate-alpha-l-Ara4N implies that l-Ara4N transfer to lipid A occurs in the periplasm of polymyxin-resistant strains, and establishes a new enzymatic pathway by which Gram-negative bacteria acquire antibiotic resistance.

Amino Sugars↗
PubMed2001

Piperazine-based CCR5 antagonists as HIV-1 inhibitors. I: 2(S)-methyl piperazine as a key pharmacophore element.

Optimization of the piperidino-piperazines 1 and 2 provided early leads 3 and 4, which showed good activity in the CCR5-RANTES binding assay and in antiviral assays. A systematic study around these structures showed that the 2(S)-methyl piperazine is essential for CCR5 affinity, which is further enhanced by forming the 2,6-dimethyl benzamide of the piperidine.

Anti-HIV Agents↗
PubMed2001

Photoswitched singlet energy transfer in a porphyrin-spiropyran dyad.

A photochromic nitrospiropyran moiety (Sp) has been covalently linked to a zinc (PZn) and to a free-base (P(H2)) porphyrin. In the resulting dyads (P(Zn)-Sp(c) and P(H2)-Sp(c)), the porphyrin first excited singlet states are unperturbed by the closed form of the attached spiropyran. Excitation of the spiropyran moiety of either dyad in the near-UV region results in ring opening to a merocyanine form (P-Sp(o)) that absorbs at 600 nm. The open form re-closes thermally in 2-methyltetrahydrofuran with a time constant of 20 s, or following irradiation into the 600 nm band. Excitation of the zinc porphyrin moiety in the merocyanine form of the dyad yields 1PZn-Sp(o). The lifetime of the zinc porphyrin excited state is reduced from its usual value of 1.8 ns to 130 ps by singlet-singlet energy transfer to the merocyanine moiety to give PZn-1Sp(o). The quantum yield of energy transfer is 0.93. Quenching is also observed in the free base dyad, where 1P(H2)-Sp(o) and P(H2)-1Sp(o) exchange singlet excitation energy. This photoswitchable quenching phenomenon provides light-activated control of the porphyrin excited states, and consequently control of any subsequent energy or electron-transfer processes that might be initiated by these excited states in more complex molecular photonic or optoelectronic devices.

Benzopyrans↗
PubMed2001

Analysis of pancreatic development in living transgenic zebrafish embryos.

Using DNA constructs containing regulatory sequences of the zebrafish Pdx-1 and insulin genes, germline transgenic zebrafish expressing the green fluorescent protein (GFP) reporter gene in the pancreas were generated. For both constructs, the GFP expression patterns in transgenic embryos were consistent with the mRNA expression patterns detected by RNA in situ hybridization. A deletion promoter analysis revealed that positive and negative cis-acting elements were involved in regulation of insulin gene expression. Three-dimensional reconstructions imaged from living embryos using two-photon laser-scanning microscopy (TPLSM) demonstrated that the zebrafish pancreas is formed from a single dorsal pancreatic cell mass. This is in contrast to mammals where the pancreas derives from both dorsal and ventral anlage. These transgenic fish should be useful for in vivo studies of factors involved in specifying and regulating pancreatic development and function.

5' Untranslated Regions↗
PubMed2001

Purification and characterization of a chymotrypsin inhibitor from the venom of Ophiophagus hannah (King Cobra).

A chymotrypsin inhibitor from the venom of Ophiophagus hannah was isolated by a combination of ion-exchange chromatography and reverse phase HPLC. Amino acid sequence analysis revealed that this protein consists of 58 amino acids, six of these being cysteine residues and is highly homologous to Kunitz-type protease inhibitors. ESI-mass spectrum showed that the protein had a mass of 6493, which is in agreement with that predicted from its primary structure. In contrast to P1 Leu, Met, Phe, Trp, and Tyr appearing in other chymotrypsin inhibitors, a P1 Asn in the novel inhibitor may cause a weak binding (Ki = 3.52 microM) with chymotrypsin. Phylogenetic analysis suggests that the functional variations of the chymotrypsin inhibitor and other Kunitz-type inhibitors probably distinguish from dendrotoxins by accelerated evolution.

Amino Acid Sequence↗
PubMed2001

Transformation of sib-pair values for the Haseman-Elston method.

The squared sib-pair phenotype difference (SQD) has been used as a dependent variable in the Haseman-Elston (H-E) regression quantitative-trait locus (QTL) linkage method, but it has been shown that the SQD does not make full use of linkage information. In this study, we examine the efficiency of SQD in H-E regression compared to other proposed functions of the sib-pair phenotypes. A new function of sib-pair phenotypes, the product of pair values corrected with family mean (PCF), is shown to have desirable properties in many realistic situations. Consistent results were obtained using a combination of large-sample analytic approximations, simulation, and analyses of quantitative-trait data from Genetic Analysis Workshop 10. The advantages of PCF are further improved in the presence of family-specific effects arising from environmental factors or when additional QTLs influence the trait. All of the phenotype functions are incorporated in our new, freely available linkage-mapping program MULTIGENE 1.0 for the PC environment.

Chromosome Mapping↗
PubMed2001

A confidence-set approach for finding tightly linked genomic regions.

As more studies adopt the approach of whole-genome screening, geneticists are faced with the challenge of having to interpret results from traditional approaches that were not designed for genome-scan data. Frequently, two-point analysis by the LOD method is performed to search for signals of linkage throughout the genome, for each of hundreds or even thousands of markers. This practice has raised the question of how to adjust the significance level for the fact that multiple tests are being performed. Various recommendations have been made, but no consensus has emerged. In this article, we propose a new method, the confidence-set approach, that circumvents the need to correct for the level of significance according to the number of markers tested. In the search for the gene location of a monogenic disorder, multiplicity adjustment is not needed in order to maintain the desired level of confidence. For complex diseases involving multiple genes, one needs only to adjust the level of significance according to the number of disease genes--a much smaller number than the number of markers in a genome screen-to ensure a predetermined genomewide confidence level. Furthermore, our formulation of the tests enables us to localize disease genes to small genomic regions, an extremely desirable feature that the traditional LOD method lacks. Our simulation study shows that, for sib-pair data, even when the coverage probability of the confidence set is chosen to be as high as 99%, our approach is able to implicate only the markers that are closely linked to the disease genes.

Chromosome Mapping↗
PubMed2001

Cloning, expression, and characterization of a human inosine triphosphate pyrophosphatase encoded by the itpa gene.

ITP and dITP exist in all cells. dITP is potentially mutagenic, and the levels of these nucleotides are controlled by inosine triphosphate pyrophosphatase (EC ). Here we report the cloning, expression, and characterization of a 21.5-kDa human inosine triphosphate pyrophosphatase (hITPase), an enzyme whose activity has been reported in many animal tissues and studied in populations but whose protein sequence has not been determined before. At the optimal pH of 10.0, recombinant hITPase hydrolyzed ITP, dITP, and xanthosine 5'-triphosphate to their respective monophosphates whereas activity with other nucleoside triphosphates was low. K(m) values for ITP, dITP, and xanthosine 5'-triphosphate were 0.51, 0.31, and 0.57 mm, respectively, and k(cat) values were 580, 360, and 640 s(-1), respectively. A divalent cation was absolutely required for activity. The gene encoding the hITPase cDNA sequence was localized by radiation hybrid mapping to chromosome 20p in the interval D20S113-D20S97, the same interval in which the ITPA inosine triphosphatase gene was previously localized. A BLAST search revealed the existence of many similar sequences in organisms ranging from bacteria to mammals. The function of this ubiquitous protein family is proposed to be the elimination of minor potentially mutagenic or clastogenic purine nucleoside triphosphates from the cell.

Amino Acid Sequence↗
PubMed2001

A Chlamydia trachomatis UDP-N-acetylglucosamine acyltransferase selective for myristoyl-acyl carrier protein. Expression in Escherichia coli and formation of hybrid lipid A species.

Chlamydia trachomatis lipid A is unusual in that it is acylated with myristoyl chains at the glucosamine 3 and 3' positions. We have cloned and expressed the gene encoding UDP-N-acetylglucosamine 3-O-acyltransferase of C. trachomatis (CtlpxA), the first enzyme of lipid A biosynthesis. C. trachomatis LpxA displays approximately 20-fold selectivity for myristoyl-ACP over R/S-3-hydroxymyristoyl-ACP under standard assay conditions, consistent with the proposed structure of C. trachomatis lipid A. CtLpxA is the first reported UDP-N-acetylglucosamine acyltransferase that prefers a non-hydroxylated acyl-ACP to a hydroxyacyl-ACP. When CtlpxA was expressed in RO138, a temperature-sensitive lpxA mutant of Escherichia coli, five new hybrid lipid A species were made in vivo after 2 h at 42 degrees C, in place of Escherichia coli lipid A. These compounds were purified and analyzed by matrix-assisted laser desorption ionization/time of flight mass spectrometry. In each case, a myristoyl chain replaced one or both of the ester linked 3-hydroxymyristoyl residues of E. coli lipid A. With prolonged growth at 42 degrees C, all the ester-linked 3-hydroxymyristoyl residues were replaced with myristate chains. Re-engineering the structure of E. coli lipid A should facilitate the microbiological production of novel agonists or antagonists of the innate immunity receptor TLR-4, with possible uses as adjuvants or anti-inflammatory agents.

Acyl Carrier Protein↗
PubMed2001

A zebrafish forebrain-specific zinc finger gene can induce ectopic dlx2 and dlx6 expression.

Identification of the earliest forebrain-specific markers should facilitate the elucidation of molecular events underlying vertebrate forebrain determination and specification. Here we report the sequence and characterization of fez (forebrain embryonic zinc finger), a gene that is specifically expressed in the embryonic forebrain of zebrafish. Fez encodes a putative nuclear zinc finger protein that is highly conserved in Drosophila, zebrafish, Xenopus, mouse, and human. In zebrafish, the expression of fez becomes detectable at the anterior edge of the presumptive neuroectoderm by 70% epiboly. During the segmentation period, its expression is completely restricted to the rostral region of the prospective forebrain. At approximately 24 h postfertilization, fez expression is mostly confined to the telencephalon and the anterior-ventral region of the diencephalon. Although fez expression is present in one-eyed pinhead (oep) and cyclops (cyc) zebrafish mutants, the pattern is altered. Forced expression of fez induces ectopic expression of dlx2 and dlx6, two genes involved in brain development. Knockdown of fez function using a morpholino-based antisense oligo inhibited dlx2 expression in the ventral forebrain. Our studies indicate that fez is one of the earliest markers specific for the anterior neuroectoderm and it may play a role in forebrain development by regulating Dlx gene expression.

Amino Acid Sequence↗