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PubMed2026

Genome-Wide and Rare Variant Association Studies of Amblyopia in Admixed American and African Ancestry Groups.

OBJECTIVE: To identify genetic variants associated with amblyopia in African (AFR) and Admixed American (AMR) ancestry groups, expanding on previous studies conducted in European ancestry. DESIGN: Retrospective ancestry-stratified genome-wide association study (GWAS) and gene-level rare variant association study (RVAS). PARTICIPANTS: Participants in the All of Us Research Program from AFR and AMR ancestry groups who had whole-genome sequencing available. Cases and controls were distinguished based on the presence of International Classification of Diseases 9/10/SNOMED diagnosis codes for amblyopia in electronic health records. This yielded ancestry-stratified subsets of 269 cases and 71 585 controls of AMR ancestry and 366 cases and 79 460 controls of AFR ancestry. METHODS: Stratified logistic regression models were adjusted for age, biological sex, and the top 10 principal components of genomic ancestry. GWAS was limited to common variants (minor allele frequency ≥1%), and RVAS was limited to rare variants with coding sequence-altering effects (minor allele frequency >1%, exonic only, excluding synonymous variants) aggregated at the gene level using the SKAT algorithm. Downstream analyses of the significant variants were performed using KEGG and GO pathway analysis and STRING database queries for protein-protein interactions and gene-gene interactions. MAIN OUTCOME MEASURES: Single-nucleotide polymorphisms were determined to have genome-wide significance if P < 5e-8 in the GWAS, and genes were determined to have significant association with amblyopia in the RVAS if P < 8.0 × 10-4. RESULTS: In the AMR GWAS, 245 unique single-nucleotide polymorphisms mapping to 97 distinct loci were identified, notably within neurodevelopmental and axonal guidance genes, including ROBO1, SEMA4B, PTPRD, NRXN1, and CAMK2D. The AFR GWAS identified 11 significant variants corresponding to 6 loci mapping primarily to long noncoding RNAs and pseudogenes. The AMR RVAS identified 15 genes, including axonal transport genes (KIF1B and KIF7) and growth factor signaling genes (EGF, ERBIN, and AKAP17A). The AFR RVAS identified a single gene, DLG2, which encodes the postsynaptic protein PSD-93, which promotes the closure of the sensitive period of neuroplasticity for vision in early childhood. CONCLUSIONS: Genetic risk architectures for amblyopia differ across ancestries but fundamentally converge on neurodevelopmental signaling, cortical synapse assembly, and sensitive period plasticity rather than ocular structural dynamics. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.

Amblyopia↗

PubMed2004

TIP30 interacts with an estrogen receptor alpha-interacting coactivator CIA and regulates c-myc transcription.

Deregulation of c-myc expression is implicated in the pathogenesis of many neoplasias. Estrogen receptor alpha (ERalpha) can increase the rate of c-myc transcription through the recruitment of a variety of cofactors to the promoter, yet the precise roles of these cofactors in transcription and tumorigenesis are largely unknown. We show here that a putative tumor suppressor TIP30, also called CC3 or Htatip2, interacts with an ERalpha-interacting coactivator CIA. Using chromatin immunoprecipitation assays, we demonstrate that TIP30 and CIA are distinct cofactors that are dynamically associated with the promoter and downstream regions of the c-myc gene in response to estrogen. Both TIP30 and CIA are recruited to the c-myc gene promoter by liganded ERalpha in the second transcription cycle. TIP30 overexpression represses ERalpha-mediated c-myc transcription, whereas TIP30 deficiency enhances c-myc transcription in both the absence and presence of estrogen. Ectopic CIA cooperates with TIP30 to repress ERalpha-mediated c-myc transcription. Moreover, virgin TIP30 knockout mice exhibit increased c-myc expression in mammary glands. Together, these results reveal an important role for TIP30 in the regulation of ERalpha-mediated c-myc transcription and suggest a mechanism for tumorigenesis promoted by TIP30 deficiency.

Acetyltransferases↗

PubMed2003

Anticipation and CAG*CTG repeat expansion in schizophrenia and bipolar affective disorder.

The genetic contribution to the etiologies of schizophrenia and bipolar affective disorder (BPAD) has been considered for many decades, with twin, family, and adoption studies indicating consistently that the familial clustering of affected individuals is accounted for mainly by genetic factors. Despite the strong evidence for a genetic component, very little is understood about the underlying genetic and molecular mechanisms for schizophrenia and BPAD. In the early 1990s, after the discovery of "dynamic mutation" or "unstable DNA" as a molecular basis for the genetic anticipation observed in Huntington's disease, myotonic dystrophy, and many others, and the recently rediscovered, albeit still controversial, evidence for genetic anticipation in major psychoses, the genetic epidemiology of schizophrenia and BPAD was re-evaluated to demonstrate strong endorsement for the unstable DNA model. Many of the non-Mendelian genetic features of schizophrenia and BPAD could be explained by the behaviour of unstable DNA, and several molecular genetic approaches became available for testing the unstable DNA hypothesis. However, despite promising findings in the mid-1990s, no trinucleotide repeat expansion has yet been identified as a cause of idiopathic schizophrenia or BPAD.

Bipolar Disorder↗

PubMed2003

Reproductive character displacement and the genetics of gamete recognition in tropical sea urchins.

Reproductive character displacement occurs when sympatric and allopatric populations of a species differ in traits crucial to reproduction, and it is commonly thought of as a signal of selection acting to limit hybridization. Most documented cases of reproductive character displacement involve characters that are poorly understood at the genetic level, and rejecting alternative hypotheses for biogeographic shifts in reproductive traits is often very difficult. In sea urchins, the gamete recognition protein bindin evolves under positive selection when species are broadly sympatric, suggesting character displacement may be operating in this system. We sampled sympatric and allopatric populations of two species in the sea urchin genus Echinometra for variation in bindin and for the mitochondrial cytochrome oxidase I to examine patterns of population differentiation and molecular evolution at a reproductive gene. We found a major shift in bindin alleles between central Pacific (allopatric) and western Pacific (sympatric) populations of E. oblonga. Allopatric populations of E. oblonga are polyphyletic with E. sp. C at bindin, whereas sympatric populations of the two species are reciprocally monophyletic. There is a strong signal of positive selection (P(N)/P(S) = 4.5) in the variable region of the first exon of bindin, which is associated with alleles found in sympatric populations of E. oblonga. These results indicate that there is a strong pattern of reproductive character displacement between E. oblonga and E. sp. C and that the divergence is driven by selection. There is much higher population structure in sympatric populations at the bindin locus than at the neutral mitochondrial locus, but this difference is not seen in allopatric populations. These data suggest a pattern of speciation driven by selection for local gamete coevolution as a result of interactions between sympatric species. Although this pattern is highly suggestive of speciation by reinforcement, further research into hybrid fitness and egg-sperm interactions is required to address this potential mechanism for character displacement.

Amino Acid Sequence↗

PubMed2005

A new strategy to identify novel genes and gene isoforms: Analysis of human chromosomes 15, 21 and 22.

We present here a novel methodology for the identification of genome regions potentially spanning one or more protein coding genes. It is based on the detection of clusters of conserved sequence tags whose evolutionary dynamics, based on the observation of an excess bias of synonymous substitutions at nucleotide level and of conservative replacements at protein level, suggests a likely protein coding role. A benchmark test carried out on a 236 Mbp of human-mouse syntenic regions from human chromosomes 15, 21 and 22 identified 25 CST clusters potentially containing unannotated genes. A further annotation update of the human genome assembly revealed that 11/25 clusters actually contained a total of 20 validated genes and 10 of the remaining 14 clusters had several experimental evidence in support of the presence of protein coding genes. These findings demonstrate the effectiveness and high prediction reliability of the proposed methodology which could specifically be applied to the annotation of novel genome sequences.

Animals↗

PubMed2001

Molecular structure, dynamic expression, and promoter analysis of zebrafish (Danio rerio) myf-5 gene.

We isolated a 1,438 bp cDNA fragment that encoded Myf-5 myogenic factor of zebrafish. The deduced amino acid contained 237 residues, including the basic helix-loop-helix domain that is conserved in all known Myf-5. The zebrafish myf-5 transcripts were first detectable at 7.5 hpf, increased substantially until 16 hpf, and then declined gradually to an undetectable level by 26 hpf. During somitogenesis, zebrafish myf-5 transcripts were distributed mainly in the somites and segmental plates. Prominent signals occurred transiently in adaxial cells in two parallel rows but did not extend beyond the positive-signal somites. Various lengths of upstream region of zebrafish myf-5 fused with EGFP gene were used to carry out transgenic analysis. Results showed that a small, 82 bp (nucleotide positions from -82 to -1), regulatory cassette is sufficient to control the somite- and stage-specific expression of zebrafish myf-5 during early development.

Amino Acid Sequence↗

PubMed2002

The mu-opioid receptor gene polymorphism (A118G) alters HPA axis activation induced by opioid receptor blockade.

An A118G nucleotide exchange in exon 1 of the mu-opioid receptor causes an Asn40Asp substitution polymorphism in the receptor's extracellular domain. In vitro studies show that the Asp40 variant of the mu-opioid receptor binds beta-endorphin three times more avidly than the more common Asn40 variant. Paraventricular corticotropin releasing hormone neurons, which activate the HPA axis, express mu-opioid receptors and are modulated by beta-endorphin neurons. This preliminary study was designed to test the hypothesis that the Asn40Asp substitution polymorphism in the mu-opioid receptor influences HPA axis activation induced by opioid receptor blockade. Thirty-nine healthy men were genotyped (A vs. G) and then underwent opioid receptor blockade with Naloxone. Subjects expressing the A118G receptor variant had greater cortisol responses to opioid receptor blockade. Also, a significant difference in the rate of increase of ACTH (slope) between A/A and A/G was observed between 30-90 minutes as well as a significant difference in the rate of decrease after 90 minutes. Moreover, subjects expressing the variant polymorphism had lower scores on the Conscientiousness Factor and associated subscales of NEO Personality Inventory compared to subjects expressing the common receptor. Because serotonin also modulates the CRF neuron, subjects were genotyped for a functional polymorphism within the serotonin transporter gene. We did not see differences in hormone responses resulting from expression of this functional polymorphism. It is plausible that persons expressing the mu-opioid receptor variant have altered HPA axis dynamics and altered responses to other physiological processes regulated through activation of the mu-opioid receptor.

Adult↗

PubMed2001

Genomic analysis of orthologous mouse and human olfactory receptor loci.

Olfactory receptor (OR) genes represent approximately 1% of genomic coding sequence in mammals, and these genes are clustered on multiple chromosomes in both the mouse and human genomes. We have taken a comparative genomics approach to identify features that may be involved in the dynamic evolution of this gene family and in the transcriptional control that results in a single OR gene expressed per olfactory neuron. We sequenced approximately 350 kb of the murine P2 OR cluster and used synteny, gene linkage, and phylogenetic analysis to identify and sequence approximately 111 kb of an orthologous cluster in the human genome. In total, 18 mouse and 8 human OR genes were identified, including 7 orthologs that appear to be functional in both species. Noncoding homology is evident between orthologs and generally is confined within the transcriptional unit. We find no evidence for common regulatory features shared among paralogs, and promoter regions generally do not contain strong promoter motifs. We discuss these observations, as well as OR clustering, in the context of evolutionary expansion and transcriptional regulation of OR repertoires.

5' Untranslated Regions↗

PubMed2003

Differential hydrophobicity drives self-assembly in Huntington's disease.

Identifying the driving forces and the mechanism of association of huntingtin-exon1, a close marker for the progress of Huntington's disease, is an important prerequisite to finding potential drug targets and, ultimately, a cure. We introduce here a modeling framework based on a key analogy of the physicochemical properties of the exon1 fragment to block copolymers. We use a systematic mesoscale methodology, based on dissipative particle dynamics, which is capable of overcoming kinetic barriers, thus capturing the dynamics of significantly larger systems over longer times than considered before. Our results reveal that the relative hydrophobicity of the poly(glutamine) block as compared with the rest of the (proline-based) exon1 fragment, ignored to date, constitutes a major factor in the initiation of the self-assembly process. We find that the assembly is governed by both the concentration of exon1 and the length of the poly(glutamine) stretch, with a low-length threshold for association, even at the lowest volume fractions we considered. Moreover, this self-association occurs irrespective of whether the glutamine stretch is in random-coil or hairpin configuration, leading to spherical or cylindrical assemblies, respectively. We discuss the implications of these results for reinterpretation of existing research within this context, including that the routes toward aggregation of exon1 may be distinct from those of the widely studied homopolymeric poly(glutamine) peptides.

Amino Acid Sequence↗

PubMed1992

Growth hormone (GH) binding protein and GH interactions in vivo in the guinea pig.

GH binding proteins (GHBPs) are present in the blood of several species and by complexing with circulating GH may alter its clearance and distribution. The actions of human GHBP (hGHBP) have hitherto been studied indirectly via their effects on the clearance of hGH. In the present experiments, recombinant preparations of hGHBP and a shorter variant lacking exon 3 (delta 3hGHBP) were tested in vivo, either alone or after preincubation with recombinant hGH, recombinant 20K methionyl-hGH, or rat GH. Multiple serial blood sampling was performed in conscious chronically cannulated guinea pigs and both GHBP and GH variants monitored in the same samples by specific RIAs, unaffected by endogenous activities in this species. hGHBP, delta 3hGHBP, hGH, and 20K met-hGH (10-40 micrograms) were all cleared rapidly when injected alone (t1/2 = 11-20 min). However, when the same amounts of hGHBP and hGH were incubated together for 60 min and then injected, the clearance of both proteins was greatly prolonged (t1/2 hGHBP = 75-94 min, hGH = 80-137 min). Similar results were obtained for hGH complexed with delta 3hGHBP, and over a range of GH:GHBP ratios from 0.3:1 to 4:1. The effect was specific for 22K hGH; neither rat GH nor 20K met-hGH altered hGHBP clearance, nor were their clearances slowed by preincubation with hGHBP. Rapid complex formation also could be demonstrated in vivo. Injections of hGH 30 min after delta 3hGHBP, or vice versa, altered the established plasma disappearance curve of hGHBP, and hGH clearance was slowed in parallel. During a continuous infusion of hGH to steady state, injections of delta 3hGHBP increased plateau hGH concentrations by forming a delta 3hGHBP/hGH complex in the circulation. These experiments show that the conscious chronically cannulated guinea pig provides a useful model in which the in vivo interaction between hGHBP and hGH can be studied dynamically. The results imply that the location, extent, and rate of complex formation between GHBP and GH may be an important determinant of the passage of GH between the intra- and extravascular compartments, which could affect the pattern of tissue exposure to GH.

Animals↗

PubMed2003

Dynamic regulation of alternative ATP-binding cassette transporter A1 transcripts.

The ATP-binding cassette transporter A1 (ABCA1) gene, a major regulator of high-density lipoprotein (HDL) metabolism, utilizes several transcriptional start sites. The pattern of transcripts among tissues and cells differed significantly. The longest (class 1) transcripts were abundant in adult brain and fetal tissues. Class 2 transcripts predominated in most other tissues. The shortest (class 3) transcripts were present mainly in adult liver and lung. To study the biochemical significance of changes in transcript distribution, two cell models were compared. In primary human fibroblasts, upregulation of mRNA levels by oxysterols and retinoic acid increased the relative proportion of class 2 transcript compared to class 1. Phorbol ester stimulated human macrophage-derived THP-1 cells increased the abundance of class 1 transcripts relative to class 2. In both cell lines class 3 transcript levels were minimal and unchanged. It is shown here for the first time that the regulation of ABCA1 mRNA levels exploits the use of alternative transcription start sites.

ATP Binding Cassette Transporter 1↗

PubMed2003

Dynamic methylation of histone H3 at lysine 4 in transcriptional regulation by the androgen receptor.

The methylation of histone H3 correlates with either gene expression or silencing depending on the residues modified. Methylated lysine 4 (H3-K4) is associated with transcription at active gene loci. Furthermore, it was reported that trimethylated but not dimethylated H3-K4 is exclusively associated with active chromatin in Saccharomyces cerevisiae. In the present study, we investigated the H3-K4 methylation at the human prostate specific antigen (PSA) locus following gene activation and repression via androgen receptor (AR). We show that ligand-induced, AR-mediated transcription was accompanied by rapid decreases in di- and trimethylated H3-K4 at the PSA enhancer and promoter. Moreover, the observed decreases in H3-K4 methylation were reversed when AR was inhibited by a specific AR antagonist, bicalutamide. In contrast to the decreases in methylation at the 5' transcriptional control regions of the PSA gene, H3-K4 methylation in the coding region steadily increased after a lag period of approximately 4 h. The results suggest a novel role of methylated H3-K4 in transcriptional regulation.

Androgen Receptor Antagonists↗

PubMed1998

Mapping of the natural resistance-associated macrophage protein 1 (NRAMP1) gene to pig chromosome 15.

The natural resistance-associated macrophage protein 1 (NRAMP1) was mapped in the pig for study as a potential candidate gene in controlling pig resistance to Salmonella infection. Primers were designed from the pig cDNA to amplify a 1.6 kb fragment between exons 1 and 3. By using a pig-rodent somatic cell hybrid panel, NRAMP1 was mapped to pig chromosome 15 (SSC15) with 100% probability, and the regional assignment was SSC15q23-26 with 87% concordance. A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) marker was developed by using the HinfI enzyme and three alleles were identified from a population including 11 breeds. Linkage analysis confirmed the physical assignment by using the PiGMaP reference families. Pig NRAMP1 was linked to SSC15 markers S0088, S0149 and S0284 (LOD > 3). A small population study revealed large allele frequency differences among tested breeds. An A allele is only observed in dam (white) lines whereas a similar exclusivity of the C allele was seen in sire (colored) breeds.

Alleles↗

PubMed2005

An autosomal dominant cerebellar ataxia linked to chromosome 16q22.1 is associated with a single-nucleotide substitution in the 5' untranslated region of the gene encoding a protein with spectrin repeat and Rho guanine-nucleotide exchange-factor domains.

Autosomal dominant cerebellar ataxia (ADCA) is a group of heterogeneous neurodegenerative disorders. By positional cloning, we have identified the gene strongly associated with a form of degenerative ataxia (chromosome 16q22.1-linked ADCA) that clinically shows progressive pure cerebellar ataxia. Detailed examination by use of audiogram suggested that sensorineural hearing impairment may be associated with ataxia in our families. After restricting the candidate region in chromosome 16q22.1 by haplotype analysis, we found that all patients from 52 unrelated Japanese families harbor a heterozygous C-->T single-nucleotide substitution, 16 nt upstream of the putative translation initiation site of the gene for a hypothetical protein DKFZP434I216, which we have called "puratrophin-1" (Purkinje cell atrophy associated protein-1). The full-length puratrophin-1 mRNA had an open reading frame of 3,576 nt, predicted to contain important domains, including the spectrin repeat and the guanine-nucleotide exchange factor (GEF) for Rho GTPases, followed by the Dbl-homologous domain, which indicates the role of puratrophin-1 in intracellular signaling and actin dynamics at the Golgi apparatus. Puratrophin-1--normally expressed in a wide range of cells, including epithelial hair cells in the cochlea--was aggregated in Purkinje cells of the chromosome 16q22.1-linked ADCA brains. Consistent with the protein prediction data of puratrophin-1, the Golgi-apparatus membrane protein and spectrin also formed aggregates in Purkinje cells. The present study highlights the importance of the 5' untranslated region (UTR) in identification of genes of human disease, suggests that a single-nucleotide substitution in the 5' UTR could be associated with protein aggregation, and indicates that the GEF protein is associated with cerebellar degeneration in humans.

5' Untranslated Regions↗

PubMed1995

Expression of a mutant human fibrillin allele upon a normal human or murine genetic background recapitulates a Marfan cellular phenotype.

The Marfan syndrome (MFS) is a connective tissue disorder inherited as an autosomal dominant trait and caused by mutations in the gene encoding fibrillin, a 350-kD glycoprotein that multimerizes to form extracellular microfibrils. It has been unclear whether disease results from a relative deficiency of wild-type fibrillin; from a dominant-negative effect, in which mutant fibrillin monomers disrupt the function of the wild-type protein encoded by the normal allele; or from a dynamic and variable interplay between these two pathogenetic mechanisms. We have now addressed this issue in a cell culture system. A mutant fibrillin allele from a patient with severe MFS was expressed in normal human and murine fibroblasts by stable transfection. Immunohistochemical analysis of the resultant cell lines revealed markedly diminished fibrillin deposition and disorganized microfibrillar architecture. Pulse-chase studies demonstrated normal levels of fibrillin synthesis but substantially reduced deposition into the extracellular matrix. These data illustrate that expression of a mutant fibrillin allele, on a background of two normal alleles, is sufficient to disrupt normal microfibrillar assembly and reproduce the MFS cellular phenotype. This underscores the importance of the fibrillin amino-terminus in normal microfibrillar assembly and suggests that expression of the human extreme 5' fibrillin coding sequence may be sufficient, in isolation, to produce an animal model of MFS. Lastly, this substantiation of a dominant-negative effect offers mutant allele knockout as a potential strategy for gene therapy.

Alleles↗

PubMed2004

Single nucleotide polymorphisms in the proximal promoter region of the adiponectin (APM1) gene are associated with type 2 diabetes in Swedish caucasians.

Adiponectin (APM1) is an adipocyte-derived peptide. The APM1 gene is located on chromosome 3q27 and linked to type 2 diabetes. In patients with type 2 diabetes, the adiponectin level in plasma is decreased in comparison to healthy subjects. To identify genetic defects of the APM1 gene that contribute to the development of type 2 diabetes, we genotyped 13 single nucleotide polymorphisms (SNPs) in 106 patients with type 2 diabetes, 325 patients with impaired glucose tolerance (IGT), and 497 nondiabetic control subjects in Swedish Caucasians by using dynamic allele-specific hybridization (DASH). We found that SNPs -11426(A/G) and -11377(G/C) in the proximal promoter region had significant differences of allele frequencies between type 2 diabetic patients and nondiabetic control subjects (P = 0.02 and P = 0.04, respectively). SNP-11426(A/G) was significantly associated with fasting plasma glucose in type 2 diabetic patients (P = 0.02) and in IGT subjects (P = 0.04), while the patients carrying CC and CG genotypes for SNP-11377(G/C) had a higher BMI than the patients with the GG genotype (P = 0.03). Haplotype analysis of 13 SNPs in the APM1 gene showed that estimates of haplotype frequencies in Swedish Caucasians are similar to those estimated in French Caucasians. However, no significant association of haplotypes with type 2 diabetes and IGT was detected in our study. The present study provides additional evidence that SNPs in the proximal promoter region of the APM1 gene contribute to the development of type 2 diabetes.

Adiponectin↗

PubMed1995

[Neurologic diseases due to alterations in oncogenes and tumor suppressing genes].

Tumor growth is a dynamic combination of cell changes that confer a selective advantage for growth in vivo, implying the deregulation of processes that control cell proliferation along with the genesis of increasingly aggressive tumoral forms capable of invasion and metastasis. Such highly malignant tumors are the result of several alterations in genetic material, particularly in 2 types of genes: oncogenes and tumor suppressant genes that involve the activation and loss, respectively, of cell growth regulatory functions. Neurogenic tumors present either in the context of familial syndromes that predispose to cancer or sporadically, in individuals with no previous family history of neoplasia. The identification and description of some of the genes responsible for these syndromes has demonstrated that they generally are tumor suppressors that also participate actively in the genesis of sporadic forms of the same histological classes of tumor. We summarize recently acquired molecular understanding of syndromes that predispose to the development of neural tumors and review the available data on the sequence of molecular changes that contribute to neoplastic transformation and tumor progression toward aggressive forms in gliomas and meningiomas.

Brain↗

PubMed1995

Altered cytokine expression in T lymphocytes from human immunodeficiency virus Tat transgenic mice.

Examination of the interaction between human immunodeficiency virus (HIV) regulatory gene products and the host immune system is fundamental to understanding the pathogenesis of HIV and could reveal possible targets for therapeutic intervention in the treatment of AIDS. The HIV Tat gene is a potential candidate for this type of strategy. Transgenic mice can be used to investigate the in vivo effects of Tat on the developing and dynamic immune system and on cellular gene expression. Thus, we have generated transgenic mice that harbor the HIV type 1 Tat gene under the transcriptional control of the human CD2 gene regulatory elements. This expression cassette results in high-level, tissue-specific transcription of the transgene within the T-cell compartment. In this report, we demonstrate the effects of Tat on the in vivo immune system. CD2-Tat transgenic mice show no signs of aberrant thymic development and have normal levels of T-cell subsets in the thymus and peripheral lymphoid organs. However, activated T cells from transgenic mice contain increased levels of tumor necrosis factor beta mRNA as well as biologically active tumor necrosis factor protein and express elevated levels of transforming growth factor beta and interleukin-4 receptor mRNA. These increased cytokine levels do not appear to alter mitogen- or antigen-stimulated responses or induce the formation of dermal lesions in ageing mice. Such investigations should provide insight into the combination of host immune factors mediating pathogenesis in HIV infection.

Aging↗