Intranasal immunisation with a 62 kDa proteinase combined with cholera toxin or CpG adjuvant protects against Trichomonas vaginalis genital tract infections in mice

Trichomonosis, caused by the protozoan parasite Trichomonas vaginalis, is one of the most frequent sexually transmitted diseases and is widely spread in all continents. Trichomonas vaginalis as well as other protozoan organisms have high levels of proteolitic activity mainly of the cysteine-proteinase type. This activity is necessary for recognition and adhesion of the parasite to the superficial epithelial cells of the host. In the present study, we show that intranasal immunisation with a 62 kDa cysteine-proteinase purified from T. vaginalis excretion-secretion products in combination with cholera toxin or with synthetic oligodeoxynucleotides (ODN) that contain unmethylated CpG motifs (CpG-ODN) elicits 62kDa specific IgG and IgA in vaginal lavage fluid and specific IgG in serum. This immunisation protocol resulted in enhanced elimination of parasites following intravaginal challenge of BALB/c mice.     

Intersubunit interactions associated with Tyr42 alpha stabilize the quaternary-T tetramer but are not major quaternary constraints in deoxyhemoglobin

Previous mutational studies on Tyr42alpha variants as well as the current studies on the mutant hemoglobin alphaY42A show that the intersubunit interactions associated with Tyr42alpha significantly stabilize the alpha1beta2 interface of the quaternary-T deoxyhemoglobin tetramer. However, crystallographic studies, UV and visible resonance Raman spectroscopy, CO combination kinetic measurements, and oxygen binding measurements on alphaY42A show that the intersubunit interactions formed by Tyr42alpha have only a modest influence on the structural properties and ligand affinity of the deoxyhemoglobin tetramer. Therefore, the alpha1beta2 interface interactions associated with Tyr42alpha do not contribute significantly to the quaternary constraints that are responsible for the low oxygen affinity of deoxyhemoglobin. The slight increase in the ligand affinity of deoxy alphaY42A correlates with small, mutation-induced structural changes that perturb the environment of Trp37beta, a critical region of the quaternary-T alpha1beta2 interface that has been shown to be the major source of quaternary constraint in deoxyhemoglobin.     

Effects of heterotropic allosteric effectors on the equilibrium and kinetics of the reaction of a single ligand molecule with an alpha or beta subunit of deoxygenated HbA

Symmetrical FeZn hybrids of human HbA have been used to measure K(1)(alpha) and K(1)(beta), the dissociation constants for the binding of a single molecule of oxygen to unliganded HbA at an alpha subunit and at a beta subunit, respectively. The kinetic constants, l(1)'(alpha) and l(1)'(beta), for the combination of the first CO molecule to unliganded HbA at an alpha or a beta subunit, respectively, were also measured. Measurements were carried out between pH 6 and pH 8 in the presence and absence of inositol hexaphosphate (IHP). Both equilibrium constants exhibit a significant Bohr effect in the absence of IHP. The addition of IHP to a concentration of 0.1 mM increases both dissociation constants in a pH-dependent manner with the result that both Bohr effects are greatly reduced. These results require a negative thermodynamic linkage between the binding of a single oxygen at either an alpha or a beta subunit and the binding of IHP to the T quaternary structure of HbA. Although the beta hemes are relatively near the IHP binding site, a linkage between that site and the alpha hemes, such that the binding of a single oxygen molecule to the heme of one alpha subunit reduces the affinity of the T state for IHP, requires communication across the molecule. l(1)'(alpha) exhibits a very slight pH dependence, with a maximum variation of 20%, while l(1)'(beta) varies with pH three times as much. IHP has no effect on the pH dependence of either rate constant but reduces l(1)'(alpha) marginally, 20%, and l(1)'(beta) by 2-fold at all pH values.     

M1 receptors play a central role in modulating AD-like pathology in transgenic mice

We investigated the therapeutic efficacy of the selective M1 muscarinic agonist AF267B in the 3xTg-AD model of Alzheimer disease. AF267B administration rescued the cognitive deficits in a spatial task but not contextual fear conditioning. The effect of AF267B on cognition predicted the neuropathological outcome, as both the Abeta and tau pathologies were reduced in the hippocampus and cortex, but not in the amygdala. The mechanism underlying the effect on the Abeta pathology was caused by the selective activation of ADAM17, thereby shifting APP processing toward the nonamyloidogenic pathway, whereas the reduction in tau pathology is mediated by decreased GSK3beta activity. We further demonstrate that administration of dicyclomine, an M1 antagonist, exacerbates the Abeta and tau pathologies. In conclusion, AF267B represents a peripherally administered low molecular weight compound to attenuate the major hallmarks of AD and to reverse deficits in cognition. Therefore, selective M1 agonists may be efficacious for the treatment of AD.     

Pregnancy and Infant Outcomes among HIV-Infected Women Taking Long-Term ART with and without Tenofovir in the DART Trial

Background

Few data have described long-term outcomes for infants born to HIV-infected African women taking antiretroviral therapy (ART) in pregnancy. This is particularly true for World Health Organization (WHO)–recommended tenofovir-containing first-line regimens, which are increasingly used and known to cause renal and bone toxicities; concerns have been raised about potential toxicity in babies due to in utero tenofovir exposure.

Methods and Findings

Pregnancy outcome and maternal/infant ART were collected in Ugandan/Zimbabwean HIV-infected women initiating ART during The Development of AntiRetroviral Therapy in Africa (DART) trial, which compared routine laboratory monitoring (CD4; toxicity) versus clinically driven monitoring. Women were followed 15 January 2003 to 28 September 2009. Infant feeding, clinical status, and biochemistry/haematology results were collected in a separate infant study. Effect of in utero ART exposure on infant growth was analysed using random effects models.382 pregnancies occurred in 302/1,867 (16%) women (4.4/100 woman-years [95% CI 4.0–4.9]). 226/390 (58%) outcomes were live-births, 27 (7%) stillbirths (≥22 wk), and 137 (35%) terminations/miscarriages (<22 wk). Of 226 live-births, seven (3%) infants died <2 wk from perinatal causes and there were seven (3%) congenital abnormalities, with no effect of in utero tenofovir exposure (p>0.4). Of 219 surviving infants, 182 (83%) enrolled in the follow-up study; median (interquartile range [IQR]) age at last visit was 25 (12–38) months. From mothers'' ART, 62/9/111 infants had no/20%–89%/≥90% in utero tenofovir exposure; most were also zidovudine/lamivudine exposed. All 172 infants tested were HIV-negative (ten untested). Only 73/182(40%) infants were breast-fed for median 94 (IQR 75–212) days. Overall, 14 infants died at median (IQR) age 9 (3–23) months, giving 5% 12-month mortality; six of 14 were HIV-uninfected; eight untested infants died of respiratory infection (three), sepsis (two), burns (one), measles (one), unknown (one). During follow-up, no bone fractures were reported to have occurred; 12/368 creatinines and seven out of 305 phosphates were grade one (16) or two (three) in 14 children with no effect of in utero tenofovir (p>0.1). There was no evidence that in utero tenofovir affected growth after 2 years (p = 0.38). Attained height- and weight for age were similar to general (HIV-uninfected) Ugandan populations. Study limitations included relatively small size and lack of randomisation to maternal ART regimens.

Conclusions

Overall 1-year 5% infant mortality was similar to the 2%–4% post-neonatal mortality observed in this region. No increase in congenital, renal, or growth abnormalities was observed with in utero tenofovir exposure. Although some infants died untested, absence of recorded HIV infection with combination ART in pregnancy is encouraging. Detailed safety of tenofovir for pre-exposure prophylaxis will need confirmation from longer term follow-up of larger numbers of exposed children.

Trial registration

www.controlled-trials.com ISRCTN13968779 Please see later in the article for the Editors'' Summary     

The Myth of Male Superiority: Rise and Demise

A prolific literature exists concerning the origins and functions of the institutionalization of sex-role differences. However, persistent problems and sharply divergent views remain. This study attempts to circumvent the nature/nurture controversy by utilizing a holistic-evolutionary approach to the problem. The reviews of evidence from ethology, developmental psychology, and cross-cultural investigations lead to a social-exchange model involving differences in the elasticities of male and female labor contributions in social evolution. Assumptions about future technological progress lead to prediction of the demise of the myth of male supremacy. [sex differences in social evolution, ontogeny of human behavior]