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Biomedical subjects

M Henry

Publications and source records attributed to M Henry.

At least 127 records · Page 7Linked to original sources
PubMed1997

Five frequent polymorphisms of the PAI-1 gene: lack of association between genotypes, PAI activity, and triglyceride levels in a healthy population.

The main function of plasminogen activator inhibitor type 1 (PAI-1) is to decrease fibrinolysis, which leads to fibrin accumulation. An elevated plasma PAI-1 concentration has been identified as a risk factor for the development of myocardial infarction, and an association between 1 polymorphism of the PAI-1 promoter and plasma PAI-1 levels has been described. Our aim was to identify new polymorphisms in the PAI-1 gene and to further examine the relationship between PAI-1 genotypes and circulating PAI-1 levels. We report the presence of 4 new polymorphisms that were identified by non-isotopic single-strand conformational polymorphism analysis followed by sequencing. These polymorphisms were investigated in relation to PAI-1 levels in a sample of 256 healthy men, aged 50-59 years, from France and Northern Ireland. Two G/A substitutions were detected at positions -844 and +9785. The former is in strong positive linkage disequilibrium with the previously described 4G/5G polymorphism at position -675. Two polymorphisms in the 3' untranslated region were identified. One corresponds to a T/G substitution at position +11,053 and is in negative linkage disequilibrium with the G/A substitution (+9785). The other is a 9-nucleotide insertion/deletion located between nucleotides +11,320 and +11,345 in a threefold-repeated sequence. This polymorphism is in strong positive linkage disequilibrium with the G/A substitution (+9785). The overall heterozygosity provided by the 5 PAI-1 polymorphisms (including the 4 new variants and the 4G/5G polymorphism) was .77. No significant association was found between PAI activity and genotypes; furthermore, the well known associations between PAI activity and body mass index, serum triglycerides, or insulin were homogeneous according to PAI-1 genotypes.

France↗
PubMed1997

Intracellular calcium mobilization suppresses the TNF-alpha-stimulated synthesis of PAI-1 in human endothelial cells. Indications that calcium acts at a translational level.

We investigated in human umbilical vein endothelial cells (HUVECs) the interaction between the signaling pathways triggered by calcium mobilization and those affected by human recombinant tumor necrosis factor-alpha (TNF) on the expression of type-1 plasminogen activator inhibitor (PAI-1). Calcium ionophore A23187 alone exerted a modest increase (50%) on PAI-1 synthesis. TNF alone increased PAI-1 accumulation in the culture medium in a time- and dose-dependent fashion, but this increase was abolished when A23187 was added simultaneously with TNF. The downregulating effect of A23187 was not the result of impaired protein secretion, proteolysis, cytotoxicity, or an apoptotic process. A23187 did not decrease the TNF-enhanced PAI-1 mRNA level but did provoke a significant shift in the distribution pattern of PAI-1 transcripts by increasing the 2.3-kb relative to the 3.2-kb form. Comparable inhibitory effects on PAI-1 protein synthesis were observed when A23187 was added 7 hours after the onset of TNF stimulation, strongly suggesting a posttranscriptional inhibitory action of calcium signaling on TNF-stimulated PAI-1 synthesis. However, treatment with actinomycin D showed that PAI-1 mRNA stability was not altered by the various treatments. Chelation of extracellular calcium by EGTA did not prevent the A23187-induced inhibition of TNF-stimulated PAI-1 protein synthesis, emphasizing the role of internal calcium stores in the inhibition of PAI-1 synthesis. Sucrose gradient fractionation of cell lysates revealed that regardless of which treatment was used, both PAI-1 mRNA transcripts exhibited similar sedimentation profiles in the actively translating polysomal pool, suggesting that the A23187-induced shift had no functional consequence on translation. However, in TNF-stimulated cells, A23187 induced a higher proportion of PAI-1 mRNAs that sedimented in fractions corresponding to less dense polysomes, a phenomenon that usually reflects a slower initiation rate during mRNA translation. A23187 also abolished the increase in PAI-1 synthesis induced by recombinant human interleukin 1 beta, and thapsigargin exerted effects comparable to those of A23187 on PAI-1 synthesis in TNF-stimulated cells. It is proposed that in HUVECs, the A23187-induced release of calcium from endoplasmic stores suppresses at the translational level the increase in PAI-1 synthesis triggered by proinflammatory cytokines.

Apoptosis↗
PubMed1997

Production of plasminogen activator inhibitor 1 by human adipose tissue: possible link between visceral fat accumulation and vascular disease.

Plasminogen activator inhibitor type 1 (PAI-1) contributes to the pathogenesis of atherothrombosis. Its plasma level is strongly correlated with parameters that define the insulin resistance syndrome, in particular with BMI and visceral accumulation of body fat, suggesting that PAI-1 may be an adipose tissue-derived circulating peptide. The present study was designed to investigate PAI-1 expression by human adipose tissue and its different cellular fractions. Special interest has been paid to the amount of PAI-1 antigen produced by omental versus subcutaneous fat. PAI-1 protein detected by immunolocalization was present at the stromal and adipocyte levels. PAI-1 mRNA was detected in stromal vascular cells freshly isolated and under culture conditions. It was also detected in whole adipose tissue and adipocyte fraction under culture conditions. The mRNA signal from the adipocyte fraction was detected as early as 2 h of incubation. The increase in PAI-1 mRNA was followed by an increase in PAI-1 antigen in the conditioned medium that was suppressed by treatment with cycloheximide. Transforming growth factor-beta1 significantly increased PAI-1 antigen production by the adipocyte fraction, whereas tumor necrosis factor-alpha did not have any effect. Interestingly, after 5 h of incubation, omental tissue explants produced significantly more PAI-1 antigen than did subcutaneous tissue from the same individual, whereas similar production of leptin by the two territories was observed. These results strongly suggest that human adipose tissue, in particular visceral tissue, can be an important contributor to the elevated plasma PAI-1 levels observed in central obesity.

Adipocytes↗
PubMed1997

[Thrombectomy with the hydrolysing catheter. Apropos of 50 cases].

PURPOSE: to present our clinical experience with a new mechanical hydrodynamic thrombectomy system (Hydrolyser), using the Venturi effect, applied for thrombus removal in native arteries, arterial grafts, venous system and pulmonary arteries (diameter > 5 mm). MATERIAL AND METHODS: the Hydrolyser, a 7F, double lumen, over the wire catheter, was used in 50 patients (29 males, 21 females), mean age: 66.2 +/- 13.1 years (40-90). Mean occlusion time: 8.7 +/- 7.3 days (1-30), mean thrombus length: 17.7 +/- 10.2 cm (4-35). Thrombus' location: native arteries (35), arterial grafts (9), superior vena cava (2), axillary vein (2), pulmonary artery (2). Approach ways: arterial femoral antegrade (22), retrograde (7), contralateral (14), popliteal arterial (1), veinous femoral (5) and veinous brachial (1). RESULTS: Immediate technical success in 41 patients (82%): native arteries (27/35), arterial graft (7/9), pulmonary artery (2/2), superior vena cava (2/2) axillary vein (2/2). Percentage of thrombus estimated angiographically to be removed by the Hydrolyser: 72.5 +/- 22%. Adjunctive therapy: angioplasty (38, with 19 immediate stents implantations), thromboaspiration (17), reduced time fibrinolysis (11). One complication: distal embolism cured by thromboaspiration. In 9 patients the procedure failed, requiring surgery. CONCLUSION: the Hydrolyser system seems a promising concept for percutaneous thrombectomy. It is a quick reliable, efficient device. This technique may also offer an alternative to thrombolysis and surgical thrombectomy.

Adult↗
PubMed1997

[Application of a new covered endoprosthesis in the treatment of occlusive and aneurysmal peripheral arterial diseases].

The aim of this study was to report the authors' experience of a new auto-expandable nitinol stent covered by a thin layer of polyester, the Cragg Endopro System 1, for percutaneous internal revascularisation. One hundred and forty-two patients (120 men, 22 women; average age: 63.5 +/- 10 (38-88) received a total of 204 stents (58 iliac, 75 femoral, 9 politeal). The lesions were stenosis in 61 cases, occlusions in 61 cases and aneurysms in 20 cases. The mean length at the femoro-popliteal level was 14.2 +/- 2.4 cm (4-30), at iliac level 9.4 +/- 0.9 (3-15). Implantation was successful in 140/142 cases, a technical success in 136/142 cases (96%). There were 4 acute thromboses requiring surgery and 4 others treated successfully by thrombolysis. There were 18 secondary thromboses. Twenty-nine patients had pyrexia and pain in the treated limb for several days. Over a 27 months follow-up all the iliac stents remained patent; there were 8 restenoses unrelated to the stent, 7 of which were treated by a repeat angioplasty. The primary (PI) and secondary (PII) patency rates at 27 months were: iliac, PI = 97%, PII = 100%; global femoral, PI = 64%, PII = 76% (stenosis PI = 59%, PII = 81%; occlusions, PI = 65%, PII = 74%); lesions of less than 15 cm, PI = 68%, PII = 93%; lesions over 15 cm, PI = 54%, PII: 76%; aneurysms, PI and PII = 88%). The authors conclude that the Cragg Endopro System 1 stent is safe and effective in the treatment of long lesions and aneurysms with encouraging medium term results suggesting that it may be a real alternative to surgery.

Adult↗
PubMed1996

Genetic analysis of macromolecular transport across the nuclear envelope.

Numerous factors that promote movement of macromolecules in and out of the nucleus have now been identified. These include both soluble cytoplasmic and nucleoplasmic proteins and proteins of the nuclear pore complex (NPC). Genetic analyses of the nuclear transport process in the model organism, the budding yeast Saccharomyces cerevisiae, have revealed remarkable conservation of all of these factors. In addition, important clues as to how these factors promote the unique bidirectional movement across the NPC have emerged from studies of yeast. We summarize the characterization and genetic interactions of the soluble transport factors and present data to illustrate how genetic experiments can be used to further define the import and export pathways.

Biological Transport, Active↗
PubMed1996

Intracoronary stent implantation without ultrasound guidance and with replacement of conventional anticoagulation by antiplatelet therapy. 30-day clinical outcome of the French Multicenter Registry.

BACKGROUND: Stenting reduces both acute complications of coronary angioplasty and restenosis rates but increases subacute thrombosis rates and hemorrhagic complications when used with coumadin anticoagulation. METHODS AND RESULTS: To simplify postcoronary stenting treatment and to reduce these drawbacks, we evaluated the 1-month outcome of a prospective registry of 2900 patients in whom successful coronary artery stenting was performed without coumadin anticoagulation. Patients received 100 mg/d aspirin and 250 mg/d ticlopidine for 1 month. Low-molecular-weight heparin (LMWH) treatment was progressively reduced in four consecutive stages, from 1-month treatment to none. Event-free outcome at 1 month was achieved in 2816 patients (97.1%). Major stent-related cardiac events were subacute closure in 51 patients (1.8%), including death in 12 (0.5%), acute myocardial infarction in 17 (0.6%), and coronary artery bypass graft surgery in 9 (0.3%). Stent thrombosis was more frequent with balloon size of < 3.0 mm (< or = 2.5 mm, 10%; 3.0 mm, 2.3%; > or = 3.5 mm, 1.0%; P < .001), bail-out situations (6.67% versus 1.38%, P < .001), and patients with unstable angina or acute myocardial infarction (2.2% versus 1.12%, P = .02). Bleeding complications that required transfusion, surgical repair, or both occurred in 55 patients (1.9%). Bleeding complications were related to female gender (4.0% versus 1.51%, P < .001), duration of LMWH treatment (3.83% in phase II/III versus 0.69% in phase IV/V, P < .001), sheath size (6F, 0.52%; 7F, 1.04%; > or = 8F, 4.23%; P < .001), bail-out situations (4.76% versus 1.67%, P < .01), and saphenous graft stenting (4.38% versus 1.75%, P = .04). CONCLUSIONS: These results suggest that poststenting treatment by ticlopidine/aspirin is an effective alternative to coumadin anticoagulation, achieving low rates of subacute closure and bleeding complications. LMWH treatment does not improve subacute reocclusion rates but increases bleeding complications. Furthermore, as bleeding complications were independently related to sheath size, we suggest that stenting with 6F guiding catheters may prevent local complications. Furthermore, the ticlopidine/aspirin combination allows a low-cost stenting strategy without ultrasound assessment of stent deployment and permits short inhospital stay.

Aged↗
PubMed1996

Identification of a new antifungal target site through a dual biochemical and molecular-genetics approach.

The target site of the antifungal compound LY214352 [8-chloro-4-(2-chloro-4-fluorophenoxy) quinoline] has been identified through a dual biochemical and molecular-genetics approach. In the molecular-genetics approach, a cosmid library was prepared from an Aspergillus nidulans mutant that was resistant to LY214352 because of a dominant mutation in a single gene. A single cosmid (6A6-6) that could transform an LY214352-sensitive strain of A. nidulans to LY214352-resistance was isolated from the library by sib-selection. Restriction fragments from cosmid 6A6-6 containing the functional resistance gene were identified by transformation, and sequenced. The LY214352-resistance gene coded for a protein of 520 amino acids that had a 34% identity and a 57% similarity in a 333 amino-acid overlap to E. coli dihydroorotate dehydrogenase (DHO-DH). The results of a series of biochemical mechanism-of-action studies initiated simultaneously with molecular-genetic experiments also suggested that DHO-DH was the target of LY214352. Assays measuring the inhibition of DHO-DH activity by LY214352 in a wild-type strain (I50=40 ng/ml) and a highly resistant mutant (I50>100 microgram/ml) conclusively demonstrated that DHO-DH is the target site of LY214352 in A. nidulans. Several mutations in the DHO-DH (pyrE) gene that resulted in resistance to LY214352 were identified.

Antifungal Agents↗
PubMed1996

Hypermutagenic PCR involving all four transitions and a sizeable proportion of transversions.

Very complex mutant libraries of the dihydrofolate reductase (DHFR) gene encoded by the Escherichia coli plasmid R67 were created using hypermutagenic PCR with biased deoxynucleotide triphosphate (dNTP) concentrations. Exploiting the particular stability of the G:T mismatch, the DHFR gene could be enriched in A+T by employing biased deoxypyrimidine triphosphate concentrations, i.e. [dTTP] > [dCTP]. A sizeable fraction of hypermutants were functional. A combination of [dTTP] > [dCTP] and [dGTP] > [dATP] biases generated mutations at unexpectedly low frequencies. This could be overcome by the addition of Mn2+ cations. Overall mutation frequencies of 10% per amplification (range 4-18% per clone) could be attained. All four transitions and a smaller number of transversions were produced throughout the gene. PCR mutagenesis could be so extensive as to inactivate all amplified versions of the gene.

Amino Acid Sequence↗
PubMed1996

A protein that shuttles between the nucleus and the cytoplasm is an important mediator of RNA export.

The connection between RNA and protein export from the nucleus was examined in the budding yeast Saccharomyces cerevisiae. NPL3 encodes an RNA-binding protein that shuttles in and out of the nucleus. Export of poly(A)+ RNA has been shown previously to be blocked in np13-1 mutants. To understand the role of Np13p in RNA export, we have developed a novel assay that effectively uncouples nuclear protein export from reimport. With this assay, we show that Np13p satisfies several of the predicted requirements for a protein carrier for mRNA export. Temperature-sensitive mutations in the RNA recognition motifs of Np13p result in nuclear accumulation of poly(A)+ RNA. One such mutation prevents nuclear export of Np13p. Moreover, Np13p export depends on ongoing RNA polymerase II transcription. Export ceases in either the presence of the RNA synthesis inhibitor thiolutin or in a temperature-sensitive RNA polymerase (rpb1) mutant. Together, these findings support a model in which Np13p exits the nucleus in association with poly(A)+ RNA, deposits the RNA in the cytoplasm, and is rapidly reimported for another cycle of export.

Amino Acid Sequence↗
PubMed1996

Surfactant protein B metabolism in newborn rabbits.

Surfactant protein B (SP-B) is critical to the biophysical function of surfactant. To characterize its metabolism in vivo in the newborn, we administered [35S]methionine and [3H]palmitate to newborn rabbits intravascularly. Three groups of 4 rabbits per group were killed at each of 4 time points followed by isolation of SP-B from alveolar wash and lamellar bodies. The labeling kinetics for alveolar wash associated SP-B and saturated phosphatidylcholine (Sat PC) had similar patterns. To characterize SP-B clearance from the airspace, rabbit SP-B was iodinated, mixed with [14C]dipalmitoylphosphatidylcholine and given by intratracheal injection. Alveolar washes and lamellar bodies were recovered from 4 animals at each of 7 time points. Both SP-B and Sat PC were cleared slowly from the total lung (half-life values approximately 25 h). However, SP-B was cleared more rapidly from the airspaces than was Sat PC. The ratio of [125I]SP-B to [14C]Sat PC in lamellar bodies increased 2-fold by 8 h. These results support the concept of linked secretion and clearance pathways for SP-B and Sat PC, although small differences in reuptake were detected.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1996

Chemokines and T lymphocyte activation: II. Facilitation of human T cell trafficking in severe combined immunodeficiency mice.

Previous studies from this laboratory have demonstrated that the chemokines RANTES (recombinant human regulated upon activation, normally T cell expressed and presumably secreted), macrophage chemotactic peptide-1, recombinant human macrophage inflammatory protein-1 alpha (rhMIP-1 alpha) IL-8, and IP-10 are capable of inducing human T cell infiltration into the injection site of severe combined immunodeficiency (SCID) mice reconstituted with human PBL. However, the ability of these chemokines to facilitate T cell homing into various lymphoid tissues has not been examined. Initial studies focused on the ability of rhMIP-1 beta to induce human T cell infiltration into injection sites in human PBL-SCID mice. SCID mice received s.c. injections of rhMIP-1 beta or PBS (1 microgram/injection) in the hindflank for 4 h or sequential injections for 3 days. Biopsies of the MIP-1 beta injection site revealed the presence of significant mononuclear cell accumulation 72 h after injection. Immunohistologic evaluation determined that significant numbers of human CD3+ T cells were recruited in response to MIP-1 beta injections, and this infiltration could be specifically blocked by co-administration of anti-MIP-1 beta antiserum. We subsequently examined these chemokine-injected mice for the effect of trafficking of human T cells to peripheral lymphoid organs. Flow cytometric analysis of the thymus in human PBL-SCID mice revealed that treatment with rhMIP-1 beta or rhRANTES, but not platelet factor-4, resulted in improved thymic homing of the human T cells after 72 h. This trafficking effect was shown to be direct, as pretreatment of the human T cells with the chemokines in vitro also improved peripheral lymphoid trafficking of the human cells. In addition, co-injection of rhMIP-1 beta with anti-1 beta antiserum abrogated the increase in T cell homing to the thymus. These data demonstrate that MIP-1 beta and RANTES directly augment human T cell trafficking to peripheral murine lymphoid tissues. Chemokines may, therefore, under either isogeneic or xenogeneic conditions, play a role in normal lymphocyte recirculation and homing, and may be of potential clinical use in promoting immune cell trafficking and function.

Animals↗
PubMed1996

Increase in cytosolic calcium upregulates the synthesis of type 1 plasminogen activator inhibitor in the human histiocytic cell line U937.

In the U937 histiocytic cell line, we investigated the effect of calcium-mobilizing agents with or without tumor necrosis factor-alpha (TNF) on the regulation of the synthesis of plasminogen activator inhibitor-type 1 (PAI-1). Cultured U937 cells were stimulated with ionophore A23187 and thapsigargin with or without TNF. The response was analyzed in terms of cytosolic calcium mobilization, PAI-1 accumulation in the medium, and PAI-1 mRNA expression. The study was extended to urokinase (uPA) secretion and surface expression of its receptor (uPAR). Using Fluo-3 as a calcium-indicator dye to measure cytosolic calcium mobilization, we showed by flow cytometry that both agents mobilized calcium in a dose-dependent manner. TNF provoked a slight calcium mobilization that was also observed by digital imaging microscopy. Association of TNF with the calcium-mobilizing agents potentiated the calcium mobilization. Both calcium-mobilizing agents induced at 18 hours a dose-dependent accumulation of PAI-1 in culture medium, whereas uPA was not affected. TNF alone induced a more marked accumulation of PAI-1 than of uPA. Association of TNF with the agents induced a PAI-1 response that was more than additive of the two, whereas the secretion of uPA was not enhanced. Membrane expression of uPAR, measured by flow cytometry, tended to be slightly augmented by the calcium-mobilizing agents only. All the treatments resulted in a significant increase in PAI-1 mRNA level at 3 hours after the stimulation, which was very marked when calcium-mobilizing agents were present. Incubation of U937 cells in a calcium-free medium totally prevented both the mRNA expression and accumulation of PAI-1 induced by calcium-mobilizing agents and, to lesser extent, that induced by TNF. The increase in PAI-1 mRNA expression did not require de novo protein synthesis, as cycloheximide did not suppress the increase in PAI-1 mRNA induced by calcium-mobilizing agents. It is concluded that, in U937 cells, calcium triggers a pathway that upregulates PAI-1 synthesis and positively interacts with the TNF-induced pathway that stimulates PAI-1 synthesis. As uPA and uPAR were differently affected, it is suggested that an increase in cytosolic calcium leads to a reduced pericellular proteolysis.

Calcimycin↗
PubMed1996

Heterogeneity in the performance of outbred Sprague-Dawley rats in an elevated-plus maze test: a possible animal model for anxiety disorder.

A wide variation in the performance of inbred rats measured in the evaluated plus maze test suggests a possible genetic basis for anxiety response (AR). To gain further insight into the role of genetics in AR, we have characterized AR in male outbred S-D rats. Rats were placed in the black compartment (BC) facing the wall opposite the aperture and time needed for the animal to exit BC was noted. All rats underwent 3 successive trials 1-1.5 hrs apart. Naive rats showed a wide variation in their AR in trial 1(mean = 89 +/- 19 sec, range = 5-360 sec). Sixty-eight% of the rats exhibiting low AR exited BC in < 30 sec, whereas 16% stayed in for the entire 360 sec (high AR). On successive testing, there was a progressive increase in AR which reached to max on second trial (Trial 1: 89 +/- 19, Trial 2: 171 +/- 23, Trial 3: 210 +/- 22 sec, p < 0.0001). The time spent in BC on successive trials increased for most rats (33/44), decreased for some (2/44), showed min to no change (5/44) or erratic response (4/44) for others. In conclusion wide variation in the AR in outbred rats could be exploited to study genetic and neurochemical mechanisms of anxiety.

Animals↗
PubMed1996

Sexual behavior of donkey jacks: influence of ejaculatory frequency and season.

The courtship of 5 jacks was evaluated weekly for 12 mo. The characteristics of sexual behavior were recorded before the collection of 2 ejaculates, at 4-h intervals, into an artificial vagina in the presence of a female in either natural or induced estrus. The maximum time given to the jack to perform the ejaculatory mount was 1 h. If the jacks did not ejaculate, another attempt was made the following week. At the time of collection, the male and female remained free in a paddock (20 m2). The data presented in this study is based on results in which the first and second ejaculates occurred successively. Statistical analysis was done by a 2 x 2 factorial design in randomized blocks. The mean +/- SEM of sexual behavior characteristics for the first and second ejaculate were, respectively: time until first mount = 0.7 +/- 0.2 and 0.9 +/- 0.2 min; time until first erection = 11.9 +/- 1.1 and 11.6 +/- 1.1 min; time until ejaculation = 15.0 +/- 1.2 and 13.6 +/- 1.2 min; frequency of partial exposure of penis = 3.4 +/- 0.4 and 3.2 +/- 0.4; frequency of total exposure of penis = 1.0 + 0.2 and 1.1 +/- 0.2; frequency of flehmen responses = 6.6 +/- 0.5 and 4.6 +/-0.5; frequency of erections = 1.3 +/- 0.1 and 1.2 +/- 0.1; frequency of retreats away from the female = 1.8 +/- 0.2 and 1.0 +/- 0.2; frequency of mounts with erection but without ejaculation = 0.3 +/- 0.1 and 0.1 +/- 0.1; frequency of mounts without erection = 2.0 +/-0.1 and 1.2 +/- 0.1 ; and frequency of pelvic copulatory movements = 4.8 +/- 0.4 and 4.4 +/- 0.4. Individual differences were observed (P<0.05) for partial and total exposure, flehmen responses, mounts without erection and pelvic copulatory movements. The variables flehmen responses, retreats away from the female and mounts without erection showed significant differences (P<0.05) between ejaculates. Seasonal effects on sexual behavior characteristics were not found. However, a monthly effect was noted for flehmen responses, partial exposure of the penis, mounts without erection, retreats away from the female and pelvic copulatory movements when the 2 ejaculates were combined.

Journal Article↗
PubMed1996

Potential RNA binding proteins in Saccharomyces cerevisiae identified as suppressors of temperature-sensitive mutations in NPL3.

The NPL3 gene of the yeast Saccharomyces cerevisiae encodes a protein with similarity to heterogeneous nuclear ribonucleoproteins (hnRNPs). Npl3p has been implicated in many nuclear-related events including RNA export, protein import, and rRNA processing. Several temperature-sensitive alleles of NPL3 have been isolated. We now report the sequence of these alleles. For one allele, npl3-1, four complementation groups of suppressors have been isolated. The cognate genes for the two recessive mutants were cloned. One of these is the previously known RNA15, which, like NPL3, also encodes a protein with similarity to the vertebrate hnRNP A/B protein family. The other suppressor corresponds to a newly defined gene we term HRP1, which also encodes a protein with similarity to the hnRNP A/B proteins of vertebrates. Mutations in HRP1 suppress all npl3 temperature-sensitive alleles but do not bypass an npl3 null allele. We show that HRP1 is essential for cell growth and that the corresponding protein is located in the nucleus. The discovery of two hnRNP homologues that can partially suppress the function of Npl3p, also an RNA binding protein, will be discussed in terms of the possible roles for Npl3p in RNA metabolism.

Alleles↗
PubMed1996

The skin immune system in the course of HIV-1 infection.

In human immunodeficiency virus-1 (HIV-1) infection, diseases of the skin and mucous membranes frequently dominate the clinical picture as a consequence of progressive immunodeficiency. Functional impairment of the skin immune system, manifesting as a loss of the skin delayed-type hypersensitivity response is very likely due to the infection of immunocompetent cells of the skin by HIV-1. Besides CD4+ T cells, antigen-presenting Langerhans cells have been established as major targets of HIV-1 infection. The close physical contact of Langerhans with T lymphocytes during immune activation suggests central role of these cells in the dissemination of HIV-1 and the subsequent breakdown of the skin immune system. In addition, there are indications that mucosal Langerhans cells may represent preferred target cells for certain HIV-1 subtypes and thereby facilitate mucocutaneous transmission of HIV-1.

HIV Infections↗