Genome-Wide Linkage Study Meta-Analysis of Male Sexual Orientation.

Male sexual orientation is a scientifically and socially important trait shown by family and twin studies to be influenced by environmental and complex genetic factors. Individual genome-wide linkage studies (GWLS) have been conducted, but not jointly analyzed. Two main datasets account for > 90% of the published GWLS concordant sibling pairs on the trait and are jointly analyzed here: MGSOSO (Molecular Genetic Study of Sexual Orientation; 409 concordant sibling pairs in 384 families, Sanders et al.

Comment on "Large-scale GWAS reveals insights into the genetic architecture of same-sex sexual behavior".

The phenotypic measures used by Ganna (Research Articles, 30 August 2019, p. 882) lump together predominantly heterosexual, bisexual, and homosexual individuals, including those who have experimented with a same-sex partner only once. This may have resulted in misleading associations to personality traits unrelated to understood categories of human sexuality.

Identification of Human Anti-HIV gp160 Monoclonal Antibodies That Make Effective Immunotoxins.

Unlabelled: The envelope (Env) glycoprotein of HIV is the only intact viral protein expressed on the surface of both virions and infected cells. Env is the target of neutralizing antibodies (Abs) and has been the subject of intense study in efforts to produce HIV vaccines. Therapeutic anti-Env Abs can also exert antiviral effects via Fc-mediated effector mechanisms or as cytotoxic immunoconjugates, such as immunotoxins (ITs).

Design and In Vivo Characterization of Immunoconjugates Targeting HIV gp160.

Unlabelled: The envelope (Env) glycoprotein of HIV is expressed on the surface of productively infected cells and can be used as a target for cytotoxic immunoconjugates (ICs), in which cell-killing moieties, including toxins, drugs, or radionuclides, are chemically or genetically linked to monoclonal antibodies (MAbs) or other targeting ligands. Such ICs could be used to eliminate persistent reservoirs of HIV infection. We have found that MAbs which bind to the external loop of gp41, e.

In vivo evaluation of safety and toxicity of a Lactobacillus jensenii producing modified cyanovirin-N in a rhesus macaque vaginal challenge model.

Sexual transmission of human immunodeficiency virus type 1 (HIV-1) across the cervicovaginal mucosa in women is influenced by many factors including the microbiota and the presence of underlying inflammation. It is important that potential HIV preventative agents do not alter the mucosal environment in a way that enhances HIV acquisition. We examined the impact of a "live" microbicide on the vaginal mucosal environment in a rhesus macaque repeated vaginal simian-HIV (SHIVSF162P3) challenge model.

Demonstration of vaginal colonization with GusA-expressing Lactobacillus jensenii following oral delivery in rhesus macaques.

The vaginal microbiome, which harbors beneficial Lactobacillus strains, is believed to be a major host defense mechanism for preventing infections of the urogenital tract. It has been suggested that the gastrointestinal tract serves as a reservoir for lactobacilli that colonize the vagina. Using rhesus macaques, we examined whether oral delivery of human vaginal Lactobacillus jensenii 1153-1646, a GusA-producing strain, would result in colonization of the rectum and the vagina.

Linking gene, brain, and behavior: DRD4, frontal asymmetry, and temperament.

Gene-environment interactions involving exogenous environmental factors are known to shape behavior and personality development. Although gene-environment interactions involving endogenous environmental factors are hypothesized to play an equally important role, this conceptual approach has not been empirically applied in the study of early-developing temperament in humans. Here we report evidence for a gene-endoenvironment (i.

A Chinese rhesus macaque (Macaca mulatta) model for vaginal Lactobacillus colonization and live microbicide development.

Background: We sought to establish a nonhuman primate model of vaginal Lactobacillus colonization suitable for evaluating live microbial microbicide candidates.

Methods: Vaginal and rectal microflora in Chinese rhesus macaques (Macaca mulatta) were analyzed, with cultivable bacteria identified by 16S rRNA gene sequencing. Live lactobacilli were intravaginally administered to evaluate bacterial colonization.

Genome-wide association for nicotine dependence and smoking cessation success in NIH research volunteers.

Phenotypes related to both nicotine dependence and ability to successfully quit smoking display substantial heritabilities in classical and molecular genetic studies. Twin studies suggest that some genetic components for dependence overlap with genetic components of ability to quit, but that many components do not overlap. Initial genome-wide association (GWA) studies have demonstrated haplotypes that distinguish nicotine-dependent from nondependent smokers.

Short communication: Activating stimuli enhance immunotoxin-mediated killing of HIV-infected macrophages.

Abstract Strategies for purging persistent reservoirs in human immunodeficiency virus (HIV)-infected individuals may be enhanced by including agents that specifically kill virus-expressing cells. Anti-HIV envelope immunotoxins (ITs) represent one class of candidate molecules that could fulfill this function. We have previously utilized an anti-gp120 IT in conjunction with various stimulants to kill latently infected T cells ex vivo.

Whither or wither microbicides?

After disappointing results from all efficacy trials conducted to date, the field of microbicides research now faces substantial challenges. Poor coordination among interested parties and the choice of nonvalidated scientific targets for phase III studies have hampered progress and created mistrust about the use of microbicides as a method to prevent HIV-1 sexual transmission. Although new promising strategies are available, there will need to be serious reappraisals of how decisions are made to advance the next generations of candidates into clinical trials, and the use of appropriate animal models in this process will be critical.

Enhancement of HIV infection by cellulose sulfate.

Cellulose sulfate, a polyanionic compound derived from cotton, has been proposed as a topical microbicide to reduce the sexual transmission of HIV. However, a phase III clinical trial of a vaginal gel formulation of cellulose sulfate (Ushercell) had to be prematurely closed after early data indicated microbicide users had a higher rate of HIV infection than women using a placebo. The unexpected results of the cellulose sulfate trail prompted us to reexamine and attempt to replicate the available preclinical data for this compound and other polyanions.

Evidence for a gene-gene interaction in predicting children's behavior problems: association of serotonin transporter short and dopamine receptor D4 long genotypes with internalizing and externalizing behaviors in typically developing 7-year-olds.

Recent work on the molecular genetics of complex traits in typical and atypical human development has focused primarily on associations of single genes with behavior. Disparate literature suggests that the presence of one or two copies of the short allele of the serotonin transporter (5-HTT) gene and the long allele (7-repeat allele) version of the dopamine receptor D4 (DRD4) gene predicts internalizing- and externalizing-related behaviors, respectively. Apparently for the first time in the extant literature, we report a gene-gene statistical interaction on behavior problems in a group of typically developing children at age 7.

Infection dynamics in HIV-specific CD4 T cells: does a CD4 T cell boost benefit the host or the virus?

Recent experimental data have shown that HIV-specific CD4 T cells provide a very important target for HIV replication. We use mathematical models to explore the effect of specific CD4 T cell infection on the dynamics of virus spread and immune responses. Infected CD4 T cells can provide antigen for their own stimulation.

Engineered vaginal lactobacillus strain for mucosal delivery of the human immunodeficiency virus inhibitor cyanovirin-N.

Women are at significant risk of human immunodeficiency virus (HIV) infection, with the cervicovaginal mucosa serving as a major portal for virus entry. Female-initiated preventatives, including topical microbicides, are urgently needed to help curtail the HIV/AIDS pandemic. Here we report on the development of a novel, live microbicide that employs a natural vaginal strain of Lactobacillus jensenii engineered to deliver the potent HIV inhibitor cyanovirin-N (CV-N).

The association of DNA sequence variation at the MAOA genetic locus with quantitative behavioural traits in normal males.

Monoamine oxidase A (MAOA) catalyses the oxidative deamination of biogenic amines including neurotransmitters, mainly norepinephrine and serotonin in the brain and peripheral tissues. A nonsense mutation in the gene was shown to be involved in a rare X-linked behavioural syndrome, which includes impaired impulse control, aggression and borderline mental retardation (Brunner syndrome). Several recent studies have shown the association of genetic variation of a VNTR in the gene promoter with various pathological behavioural traits.

Extreme skewing of X chromosome inactivation in mothers of homosexual men.

Human sexual preference is a sexually dimorphic trait with a substantial genetic component. Linkage of male sexual orientation to markers on the X chromosome has been reported in some families. Here, we measured X chromosome inactivation ratios in 97 mothers of homosexual men and 103 age-matched control women without gay sons.

Evidence for a gene-environment interaction in predicting behavioral inhibition in middle childhood.

Gene-environment interactions are presumed to shape human behavior during early development. However, no human research has demonstrated that such interactions lead to stable individual differences in fear responses. We tested this possibility by focusing on a polymorphism in the promoter region of the gene for the serotonin transporter (5-HTT).

Interfacial metal and antibody recognition.

The unique ligation properties of metal ions are widely exploited by proteins, with approximately one-third of all proteins estimated to be metalloproteins. Although antibodies use various mechanisms for recognition, to our knowledge, none has ever been characterized that uses an interfacial metal. We previously described a family of CD4-reactive antibodies, the archetype being Q425.

Lack of effect of D2 dopamine receptor TaqI A polymorphism on smoking cessation.

One previous report (Cinciripini et al., [2004] Nicotine & Tobacco Research, 6, 229-239) found that the D2 dopamine receptor (DRD2) TaqI A polymorphism was associated with smoking cessation: Carriers of the A1 allele were less likely to quit than were those who were not carriers. If confirmed, this finding would allow one to use precessation genotyping to predict the likelihood of successful quitting.

Toward a live microbial microbicide for HIV: commensal bacteria secreting an HIV fusion inhibitor peptide.

Most HIV transmission occurs on the mucosal surfaces of the gastrointestinal and cervicovaginal tracts, both of which are normally coated by a biofilm of nonpathogenic commensal bacteria. We propose to genetically engineer such naturally occurring bacteria to protect against HIV infection by secreting antiviral peptides. Here we describe the development and characterization of Nissle 1917, a highly colonizing probiotic strain of Escherichia coli, secreting HIV-gp41-hemolysin A hybrid peptides that block HIV fusion and entry into target cells.

Depression vulnerability, cigarette smoking, and the serotonin transporter gene.

People with current or past depression are more likely to have been smokers at some point in their lives. Smokers with depression histories are also less likely to quit. Attempts to understand this relationship are important insofar as they can help treatment efficacy for this group of smokers.

A genomewide scan of male sexual orientation.

This is the first report of a full genome scan of sexual orientation in men. A sample of 456 individuals from 146 families with two or more gay brothers was genotyped with 403 microsatellite markers at 10-cM intervals. Given that previously reported evidence of maternal loading of transmission of sexual orientation could indicate epigenetic factors acting on autosomal genes, maximum likelihood estimations (mlod) scores were calculated separated for maternal, paternal, and combined transmission.

Expression of latent HAART-persistent HIV type 1 induced by novel cellular activating agents.

The novel antitumor-promoting phorbol ester, prostratin, was evaluated for its ability to induce the expression of latent, highly active antiretroviral therapy (HAART)-persistent human immunodeficiency virus type I (HIV-1) from specific subsets of patients' peripheral blood cells. This evaluation was performed relative to the use of other cellular activating agents, such as OKT3, a monoclonal antibody against the human T cell receptor, interleukin-2 (IL-2), phytohemagglutinin (PHA), p24 antigen (HIV-1-specific capsid protein), and a molecular relative of prostratin, 12-deoxyphorbol 13-phenylacetate (DPP). Prostratin performed as efficiently as the other cellular activators at inducing the expression of latent HIV-1 from cells of patients on virally suppressive HAART.

Can HIV be Cured? Mechanisms of HIV persistence and strategies to combat it.

Stable remission is the ultimate goal of HIV therapy. A review of recent studies on the ability of HIV to persist despite highly active antiretroviral therapy (HAART) and immune stimulation suggests that achieving this goal will require four developments in basic and clinical science. First, more effective antiretroviral therapies, targeted at proteins other than reverse transcriptase and protease, in order to eliminate the cryptic replication that continues despite best available HAART.