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Biomedical subjects

H Do

Publications and source records attributed to H Do.

At least 19 recordsLinked to original sources
PubMed2006

Exhaustive genotyping of the interferon alpha receptor 1 (IFNAR1) gene and association of an IFNAR1 protein variant with AIDS progression or susceptibility to HIV-1 infection in a French AIDS cohort.

We have undertaken a systematic genomic approach in order to explore the role of the interferon alpha (IFN-alpha) pathway in AIDS disease development. As it is very difficult to genotype the IFN-alpha gene itself since it has many pseudo-genes, we have focused our interest on the genetic polymorphisms of the IFN-alpha receptor 1 (IFNAR1). We genotyped the Genetics of Resistance to Immunodeficiency Virus (GRIV) cohort composed of patients with extreme profiles of progression to AIDS, slow progressors (SP) and rapid progressors (RP), as well as seronegative controls (CTR). We identified 19 single nucleotide polymorphisms (SNPs) with a minor allele frequency (MAF) greater than 1% among which two were newly characterized by our study. We found putative associations with AIDS disease development for four SNP alleles and for three haplotypes. The most interesting signals were found for two SNPs in linkage disequilibrium, the SNP IFNAR1_18339 corresponding to a Val168Leu mutation in the extracellular domain of the protein and the intronic SNP, IFNAR1_30127. The intronic SNP IFNAR1_30127 yielded a strong signal both when comparing SP with CTR (P=0.002) and RP with CTR (P=0.005) while IFNAR1_18339 yielded a smaller signal because less patients were analyzed; these SNPs could thus be involved in AIDS progression or in susceptibility to human immunodeficiency virus 1 (HIV-1) infection. Interestingly, two independent studies have previously pointed out the SNP IFNAR1_18339 in susceptibility to multiple sclerosis and to malaria. This is the first work investigating the polymorphisms of the IFNAR1 gene in AIDS. Our results which point out a possible role for the IFN-alpha pathway in susceptibility to HIV-1 infection or progression to AIDS need a necessary confirmation by genomic studies in other AIDS cohorts.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Genomic analysis of Fas and FasL genes and absence of correlation with disease progression in AIDS.

Apoptosis has been suggested as a major mechanism for the CD4(+) T-lymphocyte depletion observed in patients infected with human immunodeficiency virus 1 (HIV-1). To evaluate the impact of genetic variations to apoptosis during progression of acquired immunodeficiency syndrome (AIDS), we have performed an extensive genetic analysis of Fas and Fas ligand ( FasL) genes. The coding regions and promoters of these genes were resequenced in a cohort of 212 HIV-1-seropositive patients presenting extreme disease phenotypes and 155 healthy controls of Caucasian origin. Overall, 33 single nucleotide polymorphisms (SNPs) with an allele frequency >1% were identified and evaluated for their association with disease progression. Among them, 14 polymorphisms were newly characterized. We did not find any statistically significant association of Fas and FasL polymorphisms and haplotypes with AIDS progression.

Acquired Immunodeficiency Syndrome↗
PubMed2003

High statistics measurement of the K+-->pi0e+nu (K+e3) branching ratio.

E865 at the Brookhaven National Laboratory AGS collected about 70 000 K(+)(e3) events to measure the K(+)(e3) branching ratio relative to the observed K+-->pi(+)pi(0), K+-->pi(0)micro(+)nu, and K+-->pi(+)pi(0)pi(0) decays. The pi(0) in all the decays was detected using the e(+)e(-) pair from pi(0)-->e(+)e(-)gamma decay and no photons were required. Using the 2002 Particle Data Group branching ratios for the normalization decays, we obtain BR(K(+)(e3(gamma)))=(5.13+/-0.02(stat)+/-0.09(syst)+/-0.04(norm))%, where K(+)(e3(gamma)) includes the effect of virtual and real photons. This result is approximately 2.3sigma higher than the current Particle Data Group value. Implications for the V(us) element of the CKM matrix, and the matrix's unitarity are discussed.

Journal Article↗
PubMed2003

Racial disparity in incidence patterns and outcome of kidney cancer.

OBJECTIVES: To identify the subgroups that primarily contribute to the greater incidence and mortality of renal cancer in black Americans compared with white Americans. METHODS: We analyzed age, stage, and race-related differences in the incidence and survival among patients with renal cancer using the national Surveillance, Epidemiology, and End Results (SEER) registry database. White and black patients with renal cell carcinoma who were older than 19 years of age and had been diagnosed between 1975 and 1998 were included. Incidence trends were analyzed by joinpoint regression with the statistical significance level at P <0.05. The Cox proportional hazards model was used to determine the overall survival of patients with renal cell carcinoma by race (white versus black), age (20 to 59 versus 60+ years), and stage (local versus regional/distant). RESULTS: Localized disease predominantly accounted for the rise in incidence. Both black age groups with localized disease had a greater estimated annual percentage of incidence increase (4.46% for 20 to 59 years and 4.35% for 60+ years) compared with their white counterparts (2.87% and 3.06%, respectively). The magnitude of survival difference was largest between black versus white patients younger than 60 years of age who had local stage disease, with a median survival time of 190 and 259 months, respectively (P <0.0001). CONCLUSIONS: Young black patients with localized renal cancer appear to have had a greater rise in incidence and a poorer outcome than white patients of the same age and disease stage. Additional investigation is warranted to define the role of these race, stage, and age-related disparities in the etiology, prognosis, treatment, and follow-up of kidney cancer.

Adult↗
PubMed2003

Genomic analysis of Th1-Th2 cytokine genes in an AIDS cohort: identification of IL4 and IL10 haplotypes associated with the disease progression.

Polymorphisms of Th1-Th2 cytokine genes have previously been implicated in the rate of progression to AIDS in seropositive patients. To evaluate further the impact of these genes in the development of AIDS, we have performed an extensive genetic analysis of IL2, IL4, IL6, IL10, IL12p35 and p40, IL13 and IFNgamma. The coding regions and promoters of these genes were sequenced in a Caucasian cohort of 337 HIV-1 seropositive extreme patients (the GRIV cohort) consisting of patients with slow progression and rapid progression, and up to 470 healthy controls. In all, 64 single nucleotide polymorphisms (SNPs) and four deleterious polymorphisms with frequency >1% were identified and evaluated for their association with disease. Statistically significant associations were observed with haplotypes of the IL4 and IL10 genes, but no relation was found with variants of other genes. The catalogue of SNP and haplotypes presented here will facilitate further genetic investigations of Th1-Th2 cytokines in AIDS and other immune-related disorders.

Acquired Immunodeficiency Syndrome↗
PubMed2002

Experimental study of the radiative decays K+-->mu(+)nue(+)e(-) and K+-->e(+)nue(+)e(-).

Experiment 865 at the Brookhaven Alternating Gradient Synchrotron obtained 410 K+-->e(+)nue(+)e(-) and 2679 K+-->mu(+)nue(+)e(-) events including 10% and 19% background. The branching ratios were measured to be [2.48+/-0.14(stat)+/-0.14(syst)]x10(-8) (m(ee)>150 MeV) and (7.06+/-0.16+/-0.26)x10(-8) (m(ee)>145 MeV), respectively. Results for the decay form factors are presented.

Journal Article↗
PubMed2001

New measurement of K(+)(e4) decay and the s-pave pi pi-scattering length a(0)(0).

A sample of 4 x 10(5) events from the decay K(+)-->pi(+)pi(-)e(+)nu(e) (K(e4)) has been collected in experiment E865 at the Brookhaven Alternating Gradient Synchrotron. The analysis of these data yields new measurements of the K(e4) branching ratio [(4.11+/-0.01+/-0.11) x 10(-5)], the s-wave pi pi scattering length [a(0)(0) = 0.216+/-0.013(stat)+/-0.004(syst)+/-0.005(theor)], and the form factors F, G, and H of the hadronic current and their dependence on the invariant pi pi mass.

Journal Article↗
PubMed2000

Search for lepton flavor violation in K+ decays into a charged pion and two leptons.

A search for lepton flavor violating decays, K+ --> mu+ mu+ pi-, K+ --> e+ e+ pi-, K+ --> pi+ e+ mu-, K+ --> mu+ e+ pi-, and pi0 --> e+ mu-, was performed using the data collected in Experiment E865 at the Brookhaven Alternating Gradient Synchrotron. No signal was found in any of the decay modes. At the 90% confidence level, the branching ratios are less than 3.0x10(-9), 6.4x10(-10), 5. 2x10(-10), 5.0x10(-10), and 3.4x10(-9), respectively.

Journal Article↗
PubMed2000

Improved limit on the rate of the decay K+ --> pi(+)&mgr;(+)e(-)

We report results of a search for the lepton-family number violating decay K+-->pi(+)&mgr;(+)e(-) from data collected by experiment E865 in 1996 at the Alternating Gradient Synchroton of Brookhaven National Laboratory. We place an upper limit on the branching ratio at 3.9x10(-11) ( 90% C.L.). Together with results based on data collected in 1995 and an earlier experiment, E777, this result establishes a combined 90% confidence level upper limit on the branching ratio at 2.8x10(-11). We also report a new upper limit on the branching ratio for pi(0)-->&mgr;(+)e(-) of 3.8x10(-10) ( 90% C. L.).

Journal Article↗
PubMed2000

The interaction of the chaperonin tailless complex polypeptide 1 (TCP1) ring complex (TRiC) with ribosome-bound nascent chains examined using photo-cross-linking.

The eukaryotic chaperonin tailless complex polypeptide 1 (TCP1) ring complex (TRiC) (also called chaperonin containing TCP1 [CCT]) is a hetero-oligomeric complex that facilitates the proper folding of many cellular proteins. To better understand the manner in which TRiC interacts with newly translated polypeptides, we examined its association with nascent chains using a photo-cross-linking approach. To this end, a series of ribosome-bound nascent chains of defined lengths was prepared using truncated mRNAs. Photoactivatable probes were incorporated into these (35)S- labeled nascent chains during translation. Upon photolysis, TRiC was cross-linked to ribosome-bound polypeptides exposing at least 50-90 amino acids outside the ribosomal exit channel, indicating that the chaperonin associates with much shorter nascent chains than indicated by previous studies. Cross-links were observed for nascent chains of the cytosolic proteins actin, luciferase, and enolase, but not to ribosome-bound preprolactin. The pattern of cross-links became more complex as the nascent chain increased in length. These results suggest a chain length-dependent increase in the number of TRiC subunits involved in the interaction that is consistent with the idea that the substrate participates in subunit-specific contacts with the chaperonin. Both ribosome isolation by centrifugation through sucrose cushions and immunoprecipitation with anti-puromycin antibodies demonstrated that the photoadducts form on ribosome-bound polypeptides. Our results indicate that TRiC/CCT associates with the translating polypeptide shortly after it emerges from the ribosome and suggest a close association between the chaperonin and the translational apparatus.

Actins↗
PubMed2000

New measurement of the rare decay K+ --> pi(+)&mgr;(+)&mgr;(-)

More than 400 K+-->pi(+)&mgr;(+)&mgr;(-) events were observed in a rare K+ decay experiment at the Brookhaven Alternating Gradient Synchrotron. Normalized to the K+-->pi(+)pi(+)pi(-) decay, the branching ratio is determined to be [9.22+/-0.60(stat)+/-0. 49(syst)]x10(-8). This branching ratio and the &mgr;&mgr; mass spectrum is in very good agreement with the measurement of the K+-->pi(+)e(+)e(-) decay, but deviates significantly from the previous measurement.

Journal Article↗
PubMed1999

Negatively charged residues in the IgM stop-transfer effector sequence regulate transmembrane polypeptide integration.

A non-hydrophobic sequence that contributes to the biogenesis of a transmembrane protein is termed a stop-transfer effector (STE). To examine the mechanism of STE-mediated stop-transfer, a series of fusion proteins were constructed containing variants of a putative STE from murine IgM fused to an otherwise translocated hydrophobic sequence. Unexpectedly, the fraction of molecules adopting transmembrane topology was insensitive to many amino acid substitutions within the STE sequence but varied directly with the number of negative charges. Furthermore, when present at the amino terminus of a reporter, mutants were observed that adopted type I (amino terminus lumenal) and type II (amino terminus cytoplasmic) transmembrane topologies, demonstrating that the STE sequence can be located at either side of the endoplasmic reticulum membrane. Our results suggest that recognition of a broad structural feature formed primarily by negatively charged residues within the STE halts translocation and triggers membrane integration, even when the negative charges end up on the cytoplasmic side of the membrane. Since functional STE sequences photocross-link to two membrane proteins not previously identified at the translocon, these unique proteins are presumably involved in recognizing STE sequences and/or facilitating STE function.

Amino Acid Sequence↗
PubMed1999

Expression of factor VIII by murine liver sinusoidal endothelial cells.

Factor VIII (fVIII) is the procoagulant plasma glycoprotein that is missing or decreased in hemophilia A. The cellular origin of fVIII synthesis is controversial. Liver transplantation cures hemophilia A, demonstrating that the liver is a major site of fVIII synthesis. We detected fVIII mRNA in purified populations of murine liver sinusoidal endothelial cells (LSECs) and hepatocytes, but not Kupffer cells. LSECs and hepatocytes contained comparable numbers of fVIII mRNA (40 and 70 transcripts per cell, respectively) by quantitative competitive reverse transcriptase-polymerase chain reaction analysis. There was not detectable mRNA for factor IX, a hepatocyte marker, in the LSEC preparation, nor was there detectable mRNA for von Willebrand factor, an endothelial cell marker, in the hepatocyte preparation. This excludes the possibility that detectable fVIII mRNA is due to cross-contamination in the hepatocyte or LSEC preparations. Primary cultures of LSECs were established in which fVIII mRNA levels were indistinguishable from purified LSECs. LSECs secreted active fVIII into the culture medium. This finding represents the first demonstration of homologous expression of fVIII mRNA and protein in cell culture and should facilitate studies of fVIII gene regulation. Additionally, LSECs potentially are targets for a fVIII transgene during gene therapy of hemophilia A.

Animals↗
PubMed1999

Human NELL-1 expressed in unilateral coronal synostosis.

Surgical correction of unilateral coronal synostosis offers a unique opportunity to examine the molecular differences between an abnormal and a normal cranial suture. We isolated and identified a cDNA fragment whose expression was up-regulated in the premature fusing and fused coronal sutures, as compared with normal coronal sutures. The nucleotide sequence of the full-length cDNA of this gene, human NELL-1, has approximately 61% homology with the chicken Nel gene. Both chicken Nel and human NELL-1 are comprised of six epidermal growth factor-like repeats. The human NELL-1 messages were localized primarily in the mesenchymal cells and osteoblasts at the osteogenic front, along the parasutural bone margins, and within the condensing mesenchymal cells of newly formed bone in sites of premature sutural fusion. Human multiorgan tissue mRNA blot showed that NELL-1 was specifically expressed in fetal brain but not in fetal kidney, liver, or lung. We also showed that Nell-1 was expressed in rat calvarial osteoprogenitor cells and was largely absent in rat tibiae and fibroblast cell cultures. In conclusion, our data suggest that the NELL-1 gene is preferentially expressed in cranial intramembranous bone and neural tissue (both of neural crest cell origin) and is up-regulated during unilateral premature closure of the coronal suture. The precise role of this gene is unknown.

Amino Acid Sequence↗
PubMed1997

Both lumenal and cytosolic gating of the aqueous ER translocon pore are regulated from inside the ribosome during membrane protein integration.

Portions of the nascent chain are exposed to the lumen, the cytosol, or neither at different stages during the cotranslational integration of a protein into the ER membrane, as shown by compartment-specific collisional quenching of fluorophores incorporated into the polypeptide. The opening or closing of each end of the aqueous translocon pore is tightly controlled and occurs in a sequence that does not compromise the membrane's permeability barrier. Surprisingly, these structural changes at the membrane are effected by the transmembrane segment in the nascent protein from inside the ribosome. Thus, the ribosome, not the translocon, first recognizes the transmembrane segment and triggers long-range structural changes at the translocon that may be involved in shifting its function from translocation to integration.

Animals↗
PubMed1997

Patterns of hemorrhage with ruptured posterior inferior cerebellar artery aneurysms: CT findings in 44 cases.

OBJECTIVE: We intended to characterize the CT patterns of hemorrhage associated with ruptured posterior inferior cerebellar artery (PICA) aneurysms. MATERIALS AND METHODS: CT scans of 44 cases of angiographically confirmed ruptured saccular PICA aneurysms (4) aneurysms at the junction of the vertebral artery and the PICA and three distal PICA aneurysms) were retrospectively reviewed. All scans had been obtained within 2 days of the subarachnoid hemorrhage (SAH) (day 0 [less than 24 hr], 35 patients; day 1, eight patients; day 2, one patient). Presence or absence of hemorrhage in specific subarachnoid, intraventricular, and intraparenchymal locations was noted, as were the presence and degree of hydrocephalus. RESULTS: Posterior fossa SAH was present in 95% of cases. Isolated posterior fossa SAH was present in 30% of cases, but in no case was isolated supratentorial SAH present. Supratentorial SAH was present in 70% of cases. SAH involving the sylvian fissure or the interhemispheric region was present in 25% and 23% of cases, respectively. SAH along the convexity was present in 2% of cases. Intraventricular hemorrhage (IVH) with or without associated SAH was seen in 95% of cases, whereas isolated IVH was seen in 5% of cases. Hydrocephalus was present in 95% of cases and was moderate to marked in 70%. Both IVH and hydrocephalus were present in 93% of cases. CONCLUSION: Ruptured PICA aneurysms almost always coexist with hydrocephalus and IVH, as seen in 93% of cases, and almost never coexist with SAH along the convexity. The most common pattern of hemorrhage associated with such aneurysms includes IVH and posterior fossa hemorrhage. Extensive supratentorial SAH, in conjunction with posterior fossa SAH, is a common finding in patients with ruptured PICA aneurysms. SAH isolated to the posterior fossa is present in a sizeable minority of cases.

Aneurysm, Ruptured↗
PubMed1996

The cotranslational integration of membrane proteins into the phospholipid bilayer is a multistep process.

During the cotranslational integration of a nascent protein into the endoplasmic reticulum membrane, the transmembrane (TM) sequence moves out of an aqueous pore formed by Sec61alpha, TRAM, and other proteins and into the nonpolar lipid bilayer. Photocross-linking reveals that this movement involves the sequential passage of the TM domain through three different proteinaceous environments: one adjacent to Sec61alpha and TRAM and two adjacent to TRAM that place different restrictions on TM domain movement. In addition, the TM sequence is not allowed to diffuse into the bilayer from the final TRAM-proximal site until translation terminates. Cotranslational integration is therefore linked to translation and occurs via an ordered multistep pathway at an endoplasmic reticulum site that is multilayered both structurally and functionally.

Cross-Linking Reagents↗