Two HIV-1 Variants Resistant to Small Molecule CCR5 Inhibitors Differ in How They Use CCR5 for Entry

HIV-1 variants resistant to small molecule CCR5 inhibitors recognize the inhibitor-CCR5 complex, while also interacting with free CCR5. The most common genetic route to resistance involves sequence changes in the gp120 V3 region, a pathway followed when the primary isolate CC1/85 was cultured with the AD101 inhibitor in vitro, creating the CC101.19 resistant variant. However, the D1/86.16 escape mutant contains no V3 changes but has three substitutions in the gp41 fusion peptide. By using CCR5 point-mutants and gp120-targeting agents, we have investigated how infectious clonal viruses derived from the parental and both resistant isolates interact with CCR5. We conclude that the V3 sequence changes in CC101.19 cl.7 create a virus with an increased dependency on interactions with the CCR5 N-terminus. Elements of the CCR5 binding site associated with the V3 region and the CD4-induced (CD4i) epitope cluster in the gp120 bridging sheet are more exposed on the native Env complex of CC101.19 cl.7, which is sensitive to neutralization via these epitopes. However, D1/86.16 cl.23 does not have an increased dependency on the CCR5 N-terminus, and its CCR5 binding site has not become more exposed. How this virus interacts with the inhibitor-CCR5 complex remains to be understood

Exposure to Non-Steroidal Anti-Inflammatory Drugs during Pregnancy and the Risk of Selected Birth Defects: A Prospective Cohort Study

Contains fulltext : 97906.pdf (publisher's version ) (Open Access)BACKGROUND: Since use of non-steroidal anti-inflammatory drugs (NSAIDs) during pregnancy is common, small increases in the risk of birth defects may have significant implications for public health. Results of human studies on the teratogenic risks of NSAIDs are inconsistent. Therefore, we evaluated the risk of selected birth defects after prenatal exposure to prescribed and over-the-counter NSAIDs. METHODS AND FINDINGS: We used data on 69,929 women enrolled in the Norwegian Mother and Child Cohort Study between 1999 and 2006. Data on NSAID exposure were available from a self-administered questionnaire completed around gestational week 17. Information on pregnancy outcome was obtained from the Medical Birth Registry of Norway. Only birth defects suspected to be associated with NSAID exposure based upon proposed teratogenic mechanisms and previous studies were included in the multivariable logistic regression analyses. A total of 3,023 women used NSAIDs in gestational weeks 0-12 and 64,074 women did not report NSAID use in early pregnancy. No associations were observed between overall exposure to NSAIDs during pregnancy and the selected birth defects separately or as a group (adjusted odds ratio 0.7, 95% confidence interval 0.4-1.1). Associations between maternal use of specific types of NSAIDs and the selected birth defects were not found either, although an increased risk was seen for septal defects and exposure to multiple NSAIDs based on small numbers (2 exposed cases; crude odds ratio 3.9, 95% confidence interval 0.9-15.7). CONCLUSIONS: Exposure to NSAIDs during the first 12 weeks of gestation does not seem to be associated with an increased risk of the selected birth defects. However, due to the small numbers of NSAID-exposed infants for the individual birth defect categories, increases in the risks of specific birth defects could not be excluded

Novel Allelic Variants in the Canine Cyclooxgenase-2 (Cox-2) Promoter Are Associated with Renal Dysplasia in Dogs

Renal dysplasia (RD) in dogs is a complex disease with a highly variable phenotype and mode of inheritance that does not follow a simple Mendelian pattern. Cox-2 (Cyclooxgenase-2) deficient mice have renal abnormalities and a pathology that has striking similarities to RD in dogs suggesting to us that mutations in the Cox-2 gene could be the cause of RD in dogs. Our data supports this hypothesis. Sequencing of the canine Cox-2 gene was done from clinically affected and normal dogs. Although no changes were detected in the Cox-2 coding region, small insertions and deletions of GC boxes just upstream of the ATG translation start site were found. These sequences are putative SP1 transcription factor binding sites that may represent important cis-acting DNA regulatory elements that govern the expression of Cox-2. A pedigree study of a family of Lhasa apsos revealed an important statistical correlation of these mutant alleles with the disease. We examined an additional 22 clinical cases from various breeds. Regardless of the breed or severity of disease, all of these had one or two copies of the Cox-2 allelic variants. We suggest that the unusual inheritance pattern of RD is due to these alleles, either by changing the pattern of expression of Cox-2 or making Cox-2 levels susceptible to influences of other genes or environmental factors that play an unknown but important role in the development of RD in dogs

Paternal and maternal influences on differences in birth weight between Europeans and Indians born in the UK.

BACKGROUND: Ethnic groups differ significantly in adult physique and birth weight. We aimed to improve understanding of maternal versus paternal contributions to ethnic differences in birth weight, by comparing the offspring of same-ethnic versus mixed-ethnic unions amongst Europeans and South Asian Indians in the UK. METHODOLOGY AND PRINCIPAL FINDINGS: We used data from the UK Office for National Statistics Longitudinal Study (LS) and the Chelsea and Westminster Hospital (CWH), London. In the combined sample at all gestational ages, average birth weight of offspring with two European parents was significantly greater than that of offspring with two Indian parents [Δ = 344 (95% CI 329, 360) g]. Compared to offspring of European mothers, the offspring of Indian mothers had lower birth weight, whether the father was European [Δ = -152 (95% CI -92, -212) g] or Indian [Δ = -254 (95% -315, -192) g]. After adjustment for various confounding factors, average birth weight of offspring with European father and Indian mother was greater than that of offspring with two Indian parents [LS: Δ = 249 (95% CI 143, 354) g; CWH: Δ = 236 (95% CI 62, 411) g]. Average birth weight of offspring with Indian father and European mother was significantly less than that of offspring with two European parents [LS: Δ = -117 (95% CI -207, -26) g; CWH: Δ = -83 (-206, 40) g]. CONCLUSIONS/SIGNIFICANCE: Birth weight of offspring with mixed-ethnic parentage was intermediate between that of offspring with two European or two Indian parents, demonstrating a paternal as well as a maternal contribution to ethnic differences in fetal growth. This can be interpreted as demonstrating paternal modulation of maternal investment in offspring. We suggest long-term nutritional experience over generations may drive such ethnic differences through parental co-adaptation

Differential Brain Development with Low and High IQ in Attention-Deficit/Hyperactivity Disorder

Attention-Deficit/Hyperactivity Disorder (ADHD) and intelligence (IQ) are both heritable phenotypes. Overlapping genetic effects have been suggested to influence both, with neuroimaging work suggesting similar overlap in terms of morphometric properties of the brain. Together, this evidence suggests that the brain changes characteristic of ADHD may vary as a function of IQ. This study investigated this hypothesis in a sample of 108 children with ADHD and 106 typically developing controls, who participated in a cross-sectional anatomical MRI study. A subgroup of 64 children also participated in a diffusion tensor imaging scan. Brain volumes, local cortical thickness and average cerebral white matter microstructure were analyzed in relation to diagnostic group and IQ. Dimensional analyses investigated possible group differences in the relationship between anatomical measures and IQ. Second, the groups were split into above and below median IQ subgroups to investigate possible differences in the trajectories of cortical development. Dimensionally, cerebral gray matter volume and cerebral white matter microstructure were positively associated with IQ for controls, but not for ADHD. In the analyses of the below and above median IQ subgroups, we found no differences from controls in cerebral gray matter volume in ADHD with below-median IQ, but a delay of cortical development in a number of regions, including prefrontal areas. Conversely, in ADHD with above-median IQ, there were significant reductions from controls in cerebral gray matter volume, but no local differences in the trajectories of cortical development

Diminished Medial Prefrontal Activity behind Autistic Social Judgments of Incongruent Information

Individuals with autism spectrum disorders (ASD) tend to make inadequate social judgments, particularly when the nonverbal and verbal emotional expressions of other people are incongruent. Although previous behavioral studies have suggested that ASD individuals have difficulty in using nonverbal cues when presented with incongruent verbal-nonverbal information, the neural mechanisms underlying this symptom of ASD remain unclear. In the present functional magnetic resonance imaging study, we compared brain activity in 15 non-medicated adult males with high-functioning ASD to that of 17 age-, parental-background-, socioeconomic-, and intelligence-quotient-matched typically-developed (TD) male participants. Brain activity was measured while each participant made friend or foe judgments of realistic movies in which professional actors spoke with conflicting nonverbal facial expressions and voice prosody. We found that the ASD group made significantly less judgments primarily based on the nonverbal information than the TD group, and they exhibited significantly less brain activity in the right inferior frontal gyrus, bilateral anterior insula, anterior cingulate cortex/ventral medial prefrontal cortex (ACC/vmPFC), and dorsal medial prefrontal cortex (dmPFC) than the TD group. Among these five regions, the ACC/vmPFC and dmPFC were most involved in nonverbal-information-biased judgments in the TD group. Furthermore, the degree of decrease of the brain activity in these two brain regions predicted the severity of autistic communication deficits. The findings indicate that diminished activity in the ACC/vmPFC and dmPFC underlies the impaired abilities of individuals with ASD to use nonverbal content when making judgments regarding other people based on incongruent social information

Consensus Paper: Cerebellum and Social Cognition.

The traditional view on the cerebellum is that it controls motor behavior. Although recent work has revealed that the cerebellum supports also nonmotor functions such as cognition and affect, only during the last 5 years it has become evident that the cerebellum also plays an important social role. This role is evident in social cognition based on interpreting goal-directed actions through the movements of individuals (social "mirroring") which is very close to its original role in motor learning, as well as in social understanding of other individuals' mental state, such as their intentions, beliefs, past behaviors, future aspirations, and personality traits (social "mentalizing"). Most of this mentalizing role is supported by the posterior cerebellum (e.g., Crus I and II). The most dominant hypothesis is that the cerebellum assists in learning and understanding social action sequences, and so facilitates social cognition by supporting optimal predictions about imminent or future social interaction and cooperation. This consensus paper brings together experts from different fields to discuss recent efforts in understanding the role of the cerebellum in social cognition, and the understanding of social behaviors and mental states by others, its effect on clinical impairments such as cerebellar ataxia and autism spectrum disorder, and how the cerebellum can become a potential target for noninvasive brain stimulation as a therapeutic intervention. We report on the most recent empirical findings and techniques for understanding and manipulating cerebellar circuits in humans. Cerebellar circuitry appears now as a key structure to elucidate social interactions