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T R Jones

Publications and source records attributed to T R Jones.

At least 73 records · Page 4Linked to original sources
PubMed1997

Human cytomegalovirus US2 destabilizes major histocompatibility complex class I heavy chains.

Human cytomegalovirus (HCMV) infection causes down-regulation of major histocompatibility complex class I heavy chains. We determined previously that there are two HCMV loci which encode functions responsible for that phenotype and that US11 is one of these loci (T. R. Jones, L. A. Hanson, L. Sun, J. S. Slater, R. M. Stenberg, and A. E. Campbell, J. Virol. 69:4830-4841, 1995). Through the construction and analysis of defined viral mutants and stably transfected cell lines, we identify US2 as the other locus. US2 is expressed from very early through late times postinfection, with its predominant product being a relatively unstable 24-kDa endoglycosidase H-resistant glycoprotein. In cell lines constitutively expressing US2, free class I heavy chains are proximal targets for US2-induced degradation, shortly after their synthesis. Both US2 and US11 can function in concert with US3 to down-regulate class I. Beta-2-microglobulin-associated heavy chains which are retained in the endoplasmic reticulum as a result of binding to the US3 glycoprotein are susceptible to destabilization caused by both US2 and US11 gene products. Thus, three HCMV genes which affect either the stability or the transport of class I heavy chains have been identified. The observation that each of these proteins is most abundant early in the replicative cycle suggests that they may play an important immunomodulatory role in vivo prior to productive infection, either during the latent or persistent phase or during reactivation.

Antigens, Viral↗
PubMed1997

Transrectal US-guided seminal vesiculography.

Transrectal ultrasound (US)-guided seminal vesiculography is a technique that couples US with radiography to evaluate male-factor infertility. Seminal vesiculography was performed in 12 patients after needle puncture of the seminal vesicle to inject contrast material for radiography. Seminal vesiculography helped imaging of the distal male reproductive tract (vas deferens, seminal vesicles, ejaculatory ducts). This method is an improvement over standard vasography for evaluation of infertility in men with suspected ejaculatory-duct obstruction.

Humans↗
PubMed1997

Plasmodium falciparum gametocytemia in Kenyan children: associations among age, intensity of exposure to transmission, and prevalence and density of subsequent gametocytemia.

Recently, an association was described between the density of Plasmodium falciparum asexual parasitemia in Kenyan children and the entomologic inoculation rate (EIR) measured prior to measurement of asexual parasitemia. This study examined whether transmission pressure, as represented by the EIR, was associated with the prevalence or density of gametocytemia in Kenyan children. Each month for 19 months, a cohort of approximately 50 children was given a radical cure and enrolled in the study. Blood films were taken on days 0, 7, and 14. The EIR was calculated for the 28-day period ending 14 days prior to enrollment: the relationship between blood film data from day 7 and exposure variables was explored. We found that younger children were more likely to be gametocytemic than older children and, if gametocytemic, were more likely to have a dense gametocytemia. There was an inverse relationship between the number of infective bites per night received and prevalence but not density of gametocytemia, even after age adjustment. Concordance of gametocytemia prevalence on days 0 (64%), 7 (66%), and 14 (52%) was poor; 84% of the children were positive on at least one day. This indicates that in many subjects the detectable gametocytemia varied over the 14 days. Under these holoendemic transmission conditions, the EIR is inversely correlated with prevalence of gametocytemia, and point measurements of gametocytemia by conventional microscopy underestimate the number of infective donor hosts.

Age Factors↗
PubMed1997

Assessment of age-dependent immunity to malaria in transmigrants.

Sixty-six Javanese transmigrants moving from Java, an area of very low malaria transmission, to Irian Jaya, an area of high malaria transmission, were monitored to evaluate the effects of exposure to malaria transmission and age on resistance to infection and the induction of humoral immunity. The risk of acquiring Plasmodium falciparum parasitemia was not statistically greater in children (5-15 years of age) than in adults (> 15 years of age) during the first 14 months of exposure. However, during the cross-sectional survey at 14 months of exposure. children did have significantly higher P. falciparum asexual blood-stage parasite densities. Serum antibody titers to R32LR, a peptide containing sequences from the P. falciparum circumsporozoite repeat region, and MSP19, a proteolytic fragment of merozoite surface protein-1 (MSP-1) from P. falciparum, were measured by enzyme-linked immunosorbent assay. Exposure for both six and 14 months produced statistically significant increased antibody titers to both R32LR and MSP-1; no age-dependent difference in antibody titers was observed. In this population, exposure to malaria transmission induced antibodies to antigens associated with immunity to malaria. In addition, we noted an age-dependent difference in the parasitemia density of P. falciparum.

Adolescent↗
PubMed1996

Sec61-mediated transfer of a membrane protein from the endoplasmic reticulum to the proteasome for destruction.

The human cytomegalovirus genome encodes proteins that trigger destruction of newly synthesized major histocompatibility complex (MHC) class I molecules. The human cytomegalovirus gene US2 specifies a product capable of dislocating MHC class I molecules from the endoplasmic reticulum to the cytosol and delivering them to the proteasome. This process involves the Sec61 complex, in what appears to be a reversal of the reaction by which it translocates nascent chains into the endoplasmic reticulum.

Adenosine Triphosphate↗
PubMed1996

Human cytomegalovirus US3 impairs transport and maturation of major histocompatibility complex class I heavy chains.

The human cytomegalovirus (HCMV) early glycoprotein products of the US11 and US2 open reading frames cause increased turnover of major histocompatibility complex (MHC) class I heavy chains. Since US2 is homologous to another HCMV gene (US3), we hypothesized that the US3 gene product also may affect MHC class I expression. In cells constitutively expressing the HCMV US3 gene, MHC class I heavy chains formed a stable complex with beta 2-microglobulin. However, maturation of the N-linked glycan of MHC class I heavy chains was impaired in US3+ cells. The glycoprotein product of US3 (gpUS3) occurs mostly in a high-mannose form and coimmunoprecipitates with beta 2-microglobulin associated class I heavy chains. Mature class I molecules were detected at steady state on the surface of US3+ cells, as in control cells. Substantial perinuclear accumulation of heavy chains was observed in US3+ cells. The data suggest that gpUS3 impairs egress of MHC class I heavy chains from the endoplasmic reticulum.

Antibodies, Monoclonal↗
PubMed1996

Dioxabicyclooctanyl naphthalenenitriles as nonredox 5-lipoxygenase inhibitors: structure-activity relationship study directed toward the improvement of metabolic stability.

Naphthalenic lignan lactone 3a (L-702,539), a potent and selective 5-lipoxygenase (5-LO) inhibitor, is extensively metabolized at two different sites: the tetrahydropyran and the lactone rings. Early knowledge of the metabolic pathways triggered and directed a structure-activity relationship study aimed toward the improvement of metabolic stability in this series. The best modifications discovered, i.e., replacement of the lactone ring by a nitrile group, replacement of the tetrahydropyran ring by a 6,8-dioxabicyclo[3.2.1]octanyl moiety, and replacement of the pendant phenyl ring by a 3-furyl ring, were incorporated in a single molecule to produce inhibitor 9ac (L-708,780). Compound 9ac inhibits the oxidation of arachidonic acid to 5-hydroperoxy-eicosatetraenoic acid by 5-LO (IC50 = 190 nM) and the formation of leukotriene B4 in human polymorphonuclear leukocytes (IC50 = 3 nM) as well as in human whole blood (IC50 = 150 nM). The good inhibitory profile shown by naphthalenenitrile 9ac is accompanied by an improved resistance to oxidative metabolism. In addition, 9ac is orally active in the functional model of antigen-induced bronchoconstriction in allergic squirrel monkeys (95% inhibition at 0.1 mg/kg).

Animals↗
PubMed1996

Inhibition of human cytomegalovirus UL80 protease by specific intramolecular disulfide bond formation.

A symmetrically substituted disulfide compound, CL13933, was identified as a potent inhibitor of human cytomegalovirus UL80 protease. Two types of inhibited protease were observed, depending on inhibitor concentration. At high concentrations, CL13933 formed a covalent adduct with the protease on Cys residues. At lower concentrations, this compound induced specific intramolecular disulfide formation between Cys84 and Cys87, and between Cys138 and Cys161. In contrast, Cys202 did not form disulfide bonds. Inhibition was reversed upon reduction of the protease. Each of the five cysteines of the UL80 protease was individually mutated to Ala. Each of the mutant proteases retained enzymatic activity, but mutants C138A and C161A were resistant to inhibition by CL13933, suggesting that disulfide bond formation between Cys138 and Cys161 is responsible for inhibition. This disulfide is apparently not induced by air oxidation. Examination of the CL13933 loading patterns of wild type and the five mutant proteases by mass spectrometry revealed that residues Cys87, Cys138, and Cys161 react with CL13933, and that the disulfide pair partner of each (Cys84, Cys161, and Cys138, respectively) is able to displace the compound via thiol-disulfide exchange. The possible significance of these reactive thiols in the protease is discussed.

Amino Acid Sequence↗
PubMed1996

The human cytomegalovirus US11 gene product dislocates MHC class I heavy chains from the endoplasmic reticulum to the cytosol.

Human cytomegalovirus (HCMV) down-regulates expression of MHC class I products by selective proteolysis. A single HCMV gene, US11, which encodes an endoplasmic reticulum (ER) resident type-I transmembrane glycoprotein, is sufficient to cause this effect. In US11+cells, MHC class I molecules are core-glycosylated and therefore inserted into the ER. They are degraded with a half-time of less than 1 min. A full length breakdown intermediate that has lost the single N-linked glycan in an N-glycanase-catalyzed reaction transiently accumulates in cells exposed to the protease inhibitors LLnL, Cbz-LLL, and lactacystin, identifying the proteasome as a key protease. Subcellular fractionation experiments show this intermediate to be cytosolic. Thus, US11 dislocates newly synthesized class I molecules from the ER to the cytosol, where they are acted upon by an N-glycanase and the proteasome.

Astrocytoma↗
PubMed1996

Structure-based design of lipophilic quinazoline inhibitors of thymidylate synthase.

To develop novel lipophilic thymidylate synthase (TS) inhibitors, the X-ray structure of Escherichia coli TS in ternary complex with FdUMP and the inhibitor 10-propargyl-5,8-dideazafolic acid (CB3717) was used as a basis for structure-based design. A total of 31 novel lipophilic TS inhibitors, lacking a glutamate residue, were synthesized; 26 of them had in common a N-((3,4-dihydro-2-methyl-6-quinazolinyl)methyl)-N-prop-2-ynylaniline+ ++ structure in which the aniline was appropriately substituted with simple lipophilic substituents either in position 3 or 4, or in both. Compounds were tested for their inhibition of E. coli TS and human TS and also for their inhibition of the growth in tissue culture of a murine leukemia, a human leukemia, and a thymidine kinase-deficient human adenocarcinoma. The crystal structures of five inhibitors complexed with E. coli TS were determined. Five main conclusions are drawn from this study. (i) A 3-substituent such as CF(3), iodo, or ethynyl enhances binding by up to 1 order of magnitude and in the case of CF(3) was proven to fill a nearby pocket in the enzyme. (ii) A simple strongly electron-withdrawing substituent such as NO(2) or CF(3)SO(2) in the 4-position enhances binding by 2 orders of magnitude; it is hypothesized that the transannular dipole so induced interacts favorably with the protein. (iii) Attempts to combine the enhancements of i and ii in the same molecule were generally unsuccessful (iv) A 4-C(6)H(5)SO(2) substituent provided both electron withdrawal and a van der Waal's interaction of the phenyl group with a hydrophobic surface at the mouth of the active site. The inhibition (K(is) = 12 nM) of human TS by this compound, 7n, showed that C(6)H(5)SO(2) provided virtually as much binding affinity as the CO-glutamate which it had replaced. (v) The series of compounds were poorly water soluble, and also the potent TS inhibition shown by several of them did not translate into good cytotoxicity. Compounds with large cyclic groups linked to position 4 by an SO or SO(2) group did, however, have IC(50)'s in the range 1-5 microM. Of these, 4-(N-((3,4-dihydro-2-methyl-6-quinazolinyl)methyl)-N-prop-2-ynylamino )phenyl phenyl sulfone, 7n, had IC(50)'s of about 1 microM and was chosen for further elaboration.

Adenocarcinoma↗
PubMed1996

A novel microdialysis probe designed for clinical use: potential analytical and therapeutic applications.

Significant obstacles to the use of microdialysis in the clinic for diagnostic or therapeutic purposes include the production of dedicated entry port through the skull and the formation of a tract by the insertion of a probe into the parenchyma. We have developed a microdialysis probe that is minimally invasive and can be combined with an intracranial pressure probe, recording electrode, or other intracranial probe, that is minimally invasive. Yet the surface area of this probe is very high, permitting high recovery efficiencies even at relatively high flow rates. This probe design makes possible minimally invasive measurement of the peroxidation product, uric acid, and excitatory amino acids, two analytes that increase in experimental traumatic brain injury in animals. Moreover, its large surface area makes therapeutic applications of microdialysis probes in the brain potentially feasible. A pilot evaluation of the ability of microdialysis to have therapeutic benefit in limiting experimental excitotoxin lesions induced in rat striatum by N-methyl-D-aspartate (NMDA) is reported.

Animals↗
PubMed1996

Injuries by emus.

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Animal Husbandry↗
PubMed1996

Multiple regulatory events influence human cytomegalovirus DNA polymerase (UL54) expression during viral infection.

The human cytomegalovirus (HCMV) DNA polymerase gene (UL54; also called pol) is a prototypical early gene in that expression is mandatory for viral DNA replication. Recently, we have identified the major regulatory element in the UL54 promoter responsive to the major immediate early (MIE) proteins (UL122 and UL123) (J.A. Kerry, M.A. Priddy, and R. M. Stenberg, J. Virol. 68:4167-4176, 1994). Mutation of this element, inverted repeat sequence 1 (IR1), abrogates binding of cellular proteins to the UL54 promoter and reduces promoter activity in response to viral proteins in transient-transfection assays. To extend our studies on the UL54 promoter, we aimed to examine the role of IR1 in UL54 regulation throughout the course of infection. These studies show that viral proteins in addition to the MIE proteins can activate the UL54 promoter. Proteins from UL112-113 and IRS1/TRS1, recently identified as essential loci for transient complementation of HCMV oriLyt-dependent DNA replication, were found to function as transactivators of the UL54 promoter in association with MIE proteins. UL112-113 enhanced UL54 promoter activation by MIE proteins three- to fourfold. Constitutive expression of UL112-113 demonstrated that the MIE protein dependence of UL112-113 transactivational activity was not related to activation of cognate promoter sequences, suggesting that UL112-113 proteins function in cooperation with the MIE proteins. Mutation of IR1 was found to abrogate stimulation of the UL54 promoter by UL112-113, suggesting that this element is also involved in UL112-113 stimulatory activity. These results demonstrate that additional viral proteins influence UL54 promoter expression in transient-transfection assays via the IR1 element. To confirm the biological relevance of IR1 in regulating UL54 promoter activity during viral infection, a recombinant virus construct containing the UL54 promoter with a mutated IR1 element regulating expression of the chloramphenicol acetyltransferase (CAT) reporter gene (RVIRmCAT) was generated. Analysis of RVIRmCAT revealed that mutation of IR1 dramatically reduces UL54 promoter activity at early times after infection. However, at late times after infection CAT expression by RVIRmCAT, as assessed by RNA and protein levels, was approximately equivalent to expression by wild-type RVpolCAT. These data demonstrate IR1-independent regulation of the UL54 promoter at late times after infection. Together these results show that multiple regulatory events affect UL54 promoter expression during the course of infection.

Base Sequence↗
PubMed1995

Thiopyranol[2,3,4-c,d]indoles as inhibitors of 5-lipoxygenase, 5-lipoxygenase-activating protein, and leukotriene C4 synthase.

The attachment of an arylacetic or benzoic acid moiety to the thiopyrano[2,3,4-c,d]indole nucleus results in compounds which are highly potent and selective 5-lipoxygenase (5-LO) inhibitors. These compounds are structurally simpler than previous compounds of similar potency in that they contain a single chiral center. From the data presented, 2-[[1-(3-chlorobenzyl)-4-methyl-6-[(5-phenylpyridin-2-yl)methoxy]- 4, 5-dihydro-1H-thiopyrano[2,3,4-c,d]indol-2-yl]methoxy]-phenylacetic acid, 14b, was shown to inhibit 5-hydroperoxyeicosatetraenoic acid (5-HPETE) production by human 5-LO (IC50 of 18 nM). The acid 14b is highly selective as an inhibitor of 5-LO activity when compared to the inhibition of ram seminal vesicle cyclooxygenase (IC50 > 5 microM) or human leukocyte leukotriene A4 (LTA4) hydrolase (IC50 > 20 microM). In addition, 14b was inactive in a 5-lipoxygenase-activating protein (FLAP) binding assay at 10 microM. In vivo studies showed that 14b is bioavailable in rat and functionally active in the hyperreactive rat model of antigen-induced dyspnea (74% inhibition at 0.5 mk/kg po; 2 h pretreatment). In the conscious squirrel monkey model of asthma, 14b showed excellent functional activity at 0.1 mg/kg against antigen-induced bronchoconstriction (94% inhibition of the increase in RL and 100% inhibition in the decrease in Cdyn; n = 4). Resolution of this compound gave (-)-14b, the most potent enantiomer (IC50 = 10 nM in the human 5-LO assay), which was shown to possess the S configuration at the chiral center by X-ray crystallographic analysis of an intermediate. Subsequent studies on the aryl thiopyrano[2,3,4-c,d]indole series of inhibitors led to the discovery of potent dual inhibitors of both FLAP and 5-LO, the most potent of which is 2-[[1-(4-chlorobenzyl)-4-methyl-6-(quinolin-2-ylmethoxy)-4, 5-dihydro-1H-thiopyrano[2,3,4-c,d]indol-2-yl]methoxy]phenylacetic acid, 19. Acid 19 has an IC50 of 100 nM for the inhibition of 5-HPETE production by human 5-LO and is active in a FLAP binding assay with an IC50 of 32 nM. Furthermore, thiopyrano[2,3,4-c,d]indoles such as 1 and 14b are capable of inhibiting the LTC4 synthase reaction in a dose dependent manner (IC50s of 11 and 16 microM, respectively, compared to that of LTC2 at 1.2 microM) in contrast to other, structurally distinct 5-LO inhibitors. It has also been observed that the thiopyrano[2,3,4-c,d]indole class of compounds strongly promotes the translocation of 5-LO from the cytosol to a membrane fraction in the presence or absence of the ionophore A23187.(ABSTRACT TRUNCATED AT 400 WORDS)

5-Lipoxygenase-Activating Proteins↗
PubMed1995

Ancestry of an isolated subspecies of salamander, Ambystoma tigrinum stebbinsi Lowe: the evolutionary significance of hybridization.

Most phylogenetic systematists assume speciation results in dichotomously branching phylogenies. Hybridization that gives rise to a new lineage can produce character homoplasty that might obscure a species' true history. We report the results of a restriction-enzyme analysis of mitochondrial DNA (mtDNA) variation in three tiger salamander subspecies (Ambystoma trigrinum mavortium, Ambystoma tigrinum nebulosum, and Ambystoma trigrinum stebbinsi) and compare the results to studies of morphological and allozymic variation in these taxa. Allozymically, A. t. mavortium and A. t. nebulosum share most of their genomes (although each has several unique alleles), yet color pattern and mtDNA haplotypes are distinct. Color pattern and allozyme data suggest that A. t. stebbinsi shares a common ancestor with A. t. mavortium, while the A. t. stebbinsi mtDNA haplotype is derived from an A. t. nebulosum haplotype. Thus, our data suggest that A. t. stebbinsi originated through hybridization between A. t. mavortium and A. t. nebulosum. That hybridization can produce recognizably distinct evolutionary entities has long been recognized for plants, but the evolutionary significance of hybridization in animals should be examined more closely. Conservation agencies must recognize that hybrids and hybrid taxa are not necessarily evolutionary "mistakes," and they might have significant importance in the production of natural biodiversity.

Animals↗
PubMed1995

Free colon transfer for resurfacing large oral cavity defects.

Ideal reconstruction of the oral cavity includes a durable lining that is thin, supple, and innervated, and that provides a lubricated surface that facilitates deglutition and speech. This paper describes the use of free colon transfer for relining the oral cavity. In three patients, segments of transverse colon, split along the antimesenteric border, were transferred as free flaps on the middle colic vessels for large defects involving the alveolar ridge, buccal mucosa, floor of the mouth, tongue, and pharyngeal walls. All flaps were transferred successfully without adverse vascular events, abdominal complications, or oro-cutaneous fistulas. One flap was re-elevated 2 weeks postoperatively for additional mandibulectomy. Two patients received postoperative radiation therapy and another patient received planned preoperative radiotherapy. The mucosal surface of the colon flattens to provide a thin, smooth, supple oral lining that produces moderate mucus, coapts well to the convoluted surfaces of the defects, and is durable to mastication and denture wear. Mucosal biopsy 2 years postoperatively in the nonradiated flap reveals normal colon mucosa with abundant mucin-producing cells. Free colon transfer is a "functional" reconstruction of the oral lining. The donor tissue is abundant and capable of resurfacing large, convoluted oral cavity surfaces with a thin, supple, mucus-secreting tissue that allows unimpaired tongue mobility, swallowing, speech, and denture wear. Furthermore, the presence of nonirradiated, mucus-secreting cells provides an avenue to further augment mucin production by topical and systemic agents.

Alveoloplasty↗
PubMed1995

Lymphoepithelioma-like carcinoma of the skin treated by Mohs micrographic surgery.

BACKGROUND: Lymphoepithelioma-like carcinoma of the skin (LELCS) is a rare malignant tumor thought to be of adnexal origin. Because of its rarity, treatment parameters have not been defined. OBJECTIVE: To examine the role and success of Mohs micrographic surgery in the treatment of LELCS versus other forms of treatment previously documented in the literature. METHODS/RESULTS: A review of the previous reported cases and their treatment outcomes was compared with the present case. Three of the 12 previously reported cases were incompletely treated with initial surgical management, with one patient subsequently dying of metastatic tumor. The present case was treated with Mohs micrographic surgery for recurrent LELCS, following initial treatment with electrodessication and curettage, and is without evidence of disease 20 months postoperatively. CONCLUSION: LELCS may be successfully treated by Mohs micrographic surgery.

Aged↗