SUMMARY
The influence of cooling rate on the intensity of thermoremanent magnetization (TRM) and the necessity to correct archaeo/palaeointensities for this effect have long been recognized. However ...the reliability of the correction is still questioned. We studied 35 bricks baked in two modern kilns (SK and BK) in known experimental conditions and with measurements of the direction and intensity of the geomagnetic field at the site. The smallest kiln (SK, 0.2 m3) cooled in around 12 hr and the biggest kiln (BK, 8 m3) in around 40 hr. Thermomagnetic, hysteresis and backfield curves indicated that the main magnetic carriers were Ti-poor titanomagnetites and Ti-poor titanohematites. The fraction of the TRM carried by Ti-poor titanohematites is the main difference between the two sets of bricks. This fraction is around 5–10 per cent in bricks from BK kiln and up to 40 per cent in those from SK kiln. Intensities of the Earth's magnetic field were determined using the original Thellier-Thellier protocol with correction of TRM anisotropy. The average intensities overestimate the expected field intensity by 5 per cent (SK) and 6 per cent (BK). This result emphasizes the necessity of the cooling rate correction. In order to have a detailed evaluation of the cooling rate effect, we used several slow cooling rates: 0.8, 0.4, 0.2 and 0.1° C min–1. The correction factors obtained with the 0.8° C min–1 cooling ranged between –2 and 21 per cent and were proportional to the TRM fraction carried by Ti-poor titanohematite. The higher proportion of these grains in bricks from SK kiln led to an overestimate of the correction factor and an underestimate of the intensity by 7 per cent. However, the expected intensity is recovered when temperature steps higher than 580 °C (i.e. in the range of Ti-poor titanohematites unblocking temperatures) were excluded from the calculation of archaeointensity and cooling rate correction. In the case of the BK kiln bricks, for which Ti-poor titanohematites does not contribute significantly to the TRM, all tested cooling rates give average intensities close to the expected value. Incorrectly estimating the duration of the archaeological cooling has therefore a low impact on the accuracy of the archaeointensity data on these kinds of material.
GS-5734 is a monophosphate prodrug of an adenosine nucleoside analog that showed therapeutic efficacy in a non-human primate model of Ebola virus infection. It has been administered under ...compassionate use to two Ebola patients, both of whom survived, and is currently in Phase 2 clinical development for treatment of Ebola virus disease. Here we report the antiviral activities of GS-5734 and the parent nucleoside analog across multiple virus families, providing evidence to support new indications for this compound against human viruses of significant public health concern.
The recent Ebola virus (EBOV) outbreak in West Africa was the largest recorded in history with over 28,000 cases, resulting in >11,000 deaths including >500 healthcare workers. A focused screening ...and lead optimization effort identified 4b (GS-5734) with anti-EBOV EC50 = 86 nM in macrophages as the clinical candidate. Structure activity relationships established that the 1′-CN group and C-linked nucleobase were critical for optimal anti-EBOV potency and selectivity against host polymerases. A robust diastereoselective synthesis provided sufficient quantities of 4b to enable preclinical efficacy in a non-human-primate EBOV challenge model. Once-daily 10 mg/kg iv treatment on days 3–14 postinfection had a significant effect on viremia and mortality, resulting in 100% survival of infected treated animals Nature 2016, 531, 381−385 . A phase 2 study (PREVAIL IV) is currently enrolling and will evaluate the effect of 4b on viral shedding from sanctuary sites in EBOV survivors.
Host cell barriers to the early phase of immunodeficiency virus replication explain the current distribution of these viruses among human and non-human primate species. Human immunodeficiency virus ...type 1 (HIV-1), the cause of acquired immunodeficiency syndrome (AIDS) in humans, efficiently enters the cells of Old World monkeys but encounters a block before reverse transcription. This species-specific restriction acts on the incoming HIV-1 capsid and is mediated by a dominant repressive factor. Here we identify TRIM5α, a component of cytoplasmic bodies, as the blocking factor. HIV-1 infection is restricted more efficiently by rhesus monkey TRIM5α than by human TRIM5α. The simian immunodeficiency virus, which naturally infects Old World monkeys, is less susceptible to the TRIM5α-mediated block than is HIV-1, and this difference in susceptibility is due to the viral capsid. The early block to HIV-1 infection in monkey cells is relieved by interference with TRIM5α expression. Our studies identify TRIM5α as a species-specific mediator of innate cellular resistance to HIV-1 and reveal host cell components that modulate the uncoating of a retroviral capsid.
Cannabis use during adolescence is known to increase the risk for schizophrenia in men. Sex differences in the dynamics of brain maturation during adolescence may be of particular importance with ...regard to vulnerability of the male brain to cannabis exposure.
To evaluate whether the association between cannabis use and cortical maturation in adolescents is moderated by a polygenic risk score for schizophrenia.
Observation of 3 population-based samples included initial analysis in 1024 adolescents of both sexes from the Canadian Saguenay Youth Study (SYS) and follow-up in 426 adolescents of both sexes from the IMAGEN Study from 8 European cities and 504 male youth from the Avon Longitudinal Study of Parents and Children (ALSPAC) based in England. A total of 1577 participants (aged 12-21 years; 899 57.0% male) had (1) information about cannabis use; (2) imaging studies of the brain; and (3) a polygenic risk score for schizophrenia across 108 genetic loci identified by the Psychiatric Genomics Consortium. Data analysis was performed from March 1 through December 31, 2014.
Cortical thickness derived from T1-weighted magnetic resonance images. Linear regression tests were used to assess the relationships between cannabis use, cortical thickness, and risk score.
Across the 3 samples of 1574 participants, a negative association was observed between cannabis use in early adolescence and cortical thickness in male participants with a high polygenic risk score. This observation was not the case for low-risk male participants or for the low- or high-risk female participants. Thus, in SYS male participants, cannabis use interacted with risk score vis-à-vis cortical thickness (P = .009); higher scores were associated with lower thickness only in males who used cannabis. Similarly, in the IMAGEN male participants, cannabis use interacted with increased risk score vis-à-vis a change in decreasing cortical thickness from 14.5 to 18.5 years of age (t137 = -2.36; P = .02). Finally, in the ALSPAC high-risk group of male participants, those who used cannabis most frequently (≥61 occasions) had lower cortical thickness than those who never used cannabis (difference in cortical thickness, 0.07 95% CI, 0.01-0.12; P = .02) and those with light use (<5 occasions) (difference in cortical thickness, 0.11 95% CI, 0.03-0.18; P = .004).
Cannabis use in early adolescence moderates the association between the genetic risk for schizophrenia and cortical maturation among male individuals. This finding implicates processes underlying cortical maturation in mediating the link between cannabis use and liability to schizophrenia.
The host restriction factor TRIM5a mediates species-specific, early blocks to retrovirus infection; susceptibility to these blocks is determined by viral capsid sequences. Here we demonstrate that ...TRIM5α variants from Old World monkeys specifically associate with the HIV type 1 (HIV-1) capsid and that this interaction depends on the TRIM5α B30.2 domain. Human and New World monkey TRIM5α proteins associated less efficiently with the HIV-1 capsid, accounting for the lack of restriction in cells of these species. After infection, the expression of a restricting TRIM5α in the target cells correlated with a decrease in the amount of particulate capsid in the cytosol. In some cases, this loss of particulate capsid was accompanied by a detectable increase in soluble capsid protein. Inhibiting the proteasome did not abrogate restriction. Thus, TRIM5α restricts retroviral infection by specifically recognizing the capsid and promoting its rapid, premature disassembly.
The growth of white matter during human adolescence shows a striking sexual dimorphism; the volume of white matter increases with age slightly in girls and steeply in boys. Here, we provide evidence ...supporting the role of androgen receptor (AR) in mediating the effect of testosterone on white matter. In a large sample of typically developing adolescents (n = 408, 204 males), we used magnetic resonance imaging and acquired T1-weighted and magnetization transfer ratio (MTR) images. We also measured plasma levels of testosterone and genotyped a functional polymorphism in the AR gene, namely the number of CAG repeats in exon 1 believed to be inversely proportional to the AR transcriptional activity. We found that the testosterone-related increase of white-matter volume was stronger in male adolescents with the lower versus higher number of CAG repeats in the AR gene, with testosterone explaining, respectively, 26 and 8% of variance in the volume. The MTR results suggest that this growth is not related to myelination; the MTR decreased with age in male adolescents. We speculate that testosterone affects axonal caliber rather than the thickness of the myelin sheath.
Objective To assess body dissatisfaction among children between 9 and 14 years of age and to examine factors (age, sex, body mass index, perceived shape, and self-esteem) associated with wanting a ...thinner or a larger shape. Study design Through at-school questionnaires, 1515 preadolescent children (51.2% girls) were asked to fill out the Culture Free Self-Esteem Inventory and the Contour Drawing Rating Scale (body dissatisfaction). Trained assessors then weighed and measured the students individually. Results Overall, 50.5% of girls wanted a thinner shape compared with 35.9% of boys. More boys wanted a larger shape compared with girls (21.1% vs 7.2%). Most of the preadolescents who were overweight or obese were unsatisfied whereas 58.0% of girls and 41.6% of boys who were underweight were satisfied with their body. Results of a multinomial logistic regression revealed that age, sex, body mass index, perceived shape, and self-esteem were significant correlates of the 4 body dissatisfaction contrasts (wanting a slightly thinner, much thinner, slightly larger, and much larger shape) and explained 50% of the variance. An interaction between sex and perceived shape was found, revealing that girls who perceived themselves as having a larger shape were more likely to desire a thinner shape than boys. Conclusions The high prevalence rate of body dissatisfaction among children suggests that current approaches in our society to prevent problems related to body image must be improved. The different results between girls and boys highlight the need to take into account sex differences when designing prevention programs that aim to decrease body dissatisfaction.
Abstract This study aims at investigating the impact of parental practices on youths' adjustment. In all, 605 adolescents completed questionnaires at ages 14, 16 and 18. Self-esteem, psychological ...distress as well as parental emotional support and coercive control were measured. Analyses based on individual growth models revealed that self-esteem increased with age, but psychological distress remained stable over time. Boys reported higher levels of self-esteem and lower levels of psychological distress than girls. Maternal and paternal emotional support reinforced self-esteem over time. Maternal coercive control undermined self-esteem, but only at ages 16 and 18. Psychological distress decreased with parental emotional support but increased with parental coercive control at ages 14, 16 and 18. Overall, these results indicate that positive parental practices are related to youths' well-being. These findings support the importance of establishing intervention strategies designed to promote best practices among parents of teenagers to help them develop into well-adjusted adults.
PDF
