Influence of Prenatal Arsenic Exposure and Newborn Sex on Global Methylation of Cord Blood DNA

Background An emerging body of evidence indicates that early-life arsenic (As) exposure may influence the trajectory of health outcomes later in life. However, the mechanisms underlying these observations are unknown. Objective The objective of this study was to investigate the influence of prenatal As exposure on global methylation of cord blood DNA in a study of mother/newborn pairs in Matlab, Bangladesh. Design Maternal and cord blood DNA were available from a convenience sample of 101 mother/newborn pairs. Measures of As exposure included maternal urinary As (uAs), maternal blood As (mbAs) and cord blood As (cbAs). Several measures of global DNA methylation were assessed, including the [3H]-methyl-incorporation assay and three Pyrosequencing assays: Alu, LINE-1 and LUMA. Results In the total sample, increasing quartiles of maternal uAs were associated with an increase in covariate-adjusted means of newborn global DNA methylation as measured by the [3H]-methyl-incorporation assay (quartile 1 (Q1) and Q2 vs. Q4; p = 0.06 and 0.04, respectively). Sex-specific linear regression analyses, while not reaching significance level of 0.05, indicated that the associations between As exposures and Alu, LINE-1 and LUMA were positive among male newborns (N = 58) but negative among female newborns (N = 43); tests for sex differences were borderline significant for the association of cbAs and mbAs with Alu (p = 0.05 and 0.09, respectively) and for the association between maternal uAs and LINE-1 (p = 0.07). Sex-specific correlations between maternal urinary creatinine and newborn methyl-incorporation, Alu and LINE-1 were also evident (p\u3c0.05). Conclusions These results suggest that prenatal As exposure is associated with global DNA methylation in cord blood DNA, possibly in a sex-specific manner. Arsenic-induced epigenetic modifications in utero may potentially influence disease outcomes later in life. Additional studies are needed to confirm these findings and to examine the persistence of DNA methylation marks over time

Age related decline in female lar gibbon great call performance suggests that call features correlate with physical condition

Background: White-handed gibbons (Hylobates lar) are small Asian apes known for living in stable territories and producing loud, elaborate vocalizations (songs), often in well-coordinated male/female duets. The female great call, the most conspicuous phrase of the repertoire, has been hypothesized to function in intra-sexual territorial defense. We therefore predicted that characteristics of the great call would correlate with a caller’s physical condition, and thus might honestly reflect resource holding potential (RHP). Because measurement of RHP is virtually impossible for wild animals, we used age as a proxy, hypothesizing that great call climaxes are difficult to produce and maintain over time, and that older adults will therefore perform lower quality great calls than young adults. To test this we analyzed the great call climaxes of 15 wild lar gibbon females at Khao Yai National Park, Thailand and 2 captive females at Leo Conservation Center, Greenwich, CT. Results: Findings show that call climaxes correlate with female age, as young animals (n = 8, mean age: 12.9 years) produced climaxes with a higher frequency range (delta F0), maximum F0 frequency and duty cycle than old animals (n = 9, mean age: 29.6 years). A permuted discriminant function analysis also correctly classified calls by age group. During long song bouts the maximum F0 frequency of great call climaxes’ also decreased. Additional data support the hypothesis that short high notes, associated with rapid inhalation as an individual catches its breath, reflect increased caller effort. Older females produced more high notes than younger females, but the difference only approached statistical significance, suggesting that calling effort may be similar across different ages. Finally, for the first time in this species, we measured peak intensity of calls in captive females. They were capable of producing climaxes in excess of 100 dB at close range (2.7 m). Conclusions: Age and within-bout differences in the lar gibbon great call climax suggest that call features correlate with physical condition and thus the call may have evolved as an honest signal in the context of intra-sexual territorial defense and possibly also in male mate choice via sexual selection, although further testing of these hypotheses is necessary. Results: Findings show that call climaxes correlate with female age, as young animals (n = 8, mean age: 12.9 years) produced climaxes with a higher frequency range (delta F0), maximum F0 frequency and duty cycle than old animals (n = 9, mean age: 29.6 years). A permuted discriminant function analysis also correctly classified calls by age group. During long song bouts the maximum F0 frequency of great call climaxes’ also decreased. Additional data support the hypothesis that short high notes, associated with rapid inhalation as an individual catches its breath, reflect increased caller effort. Older females produced more high notes than younger females, but the difference only approached statistical significance, suggesting that calling effort may be similar across different ages. Finally, for the first time in this species, we measured peak intensity of calls in captive females. They were capable of producing climaxes in excess of 100 dB at close range (2.7 m). Conclusions: Age and within-bout differences in the lar gibbon great call climax suggest that call features correlate with physical condition and thus the call may have evolved as an honest signal in the context of intra-sexual territorial defense and possibly also in male mate choice via sexual selection, although further testing of these hypotheses is necessary

Cellular Growth Kinetics Distinguish a Cyclophilin Inhibitor from an HSP90 Inhibitor as a Selective Inhibitor of Hepatitis C Virus

During antiviral drug discovery, it is critical to distinguish molecules that selectively interrupt viral replication from those that reduce virus replication by adversely affecting host cell viability. In this report we investigate the selectivity of inhibitors of the host chaperone proteins cyclophilin A (CypA) and heat-shock protein 90 (HSP90) which have each been reported to inhibit replication of hepatitis C virus (HCV). By comparing the toxicity of the HSP90 inhibitor, 17-(Allylamino)-17-demethoxygeldanamycin (17-AAG) to two known cytostatic compounds, colchicine and gemcitabine, we provide evidence that 17-AAG exerts its antiviral effects indirectly through slowing cell growth. In contrast, a cyclophilin inhibitor, cyclosporin A (CsA), exhibited selective antiviral activity without slowing cell proliferation. Furthermore, we observed that 17-AAG had little antiviral effect in a non-dividing cell-culture model of HCV replication, while CsA reduced HCV titer by more than two orders of magnitude in the same model. The assays we describe here are useful for discriminating selective antivirals from compounds that indirectly affect virus replication by reducing host cell viability or slowing cell growth

Potential Drug Development Candidates for Human Soil-Transmitted Helminthiases

There are few drugs - none ideal - for the treatment and control of gastrointestinal helminths (soil-transmitted nematodes) which, as chronic infections jeopardize children's growth, learning and ultimately individual, community and country development. Drugs for helminths are not attractive in human medicine, but are lucrative in animal health. Traditionally, investment in veterinary medicines has benefited humans for these diseases. With modern regulations an approved veterinary medicine can be tested in humans with little adaptation, reducing time and cost of development. We searched for products that could easily be transitioned into humans, having the necessary characteristics for use in communities exposed to these infections. A limited number of candidates met the main criteria for selection. We provide here a detailed analysis of two veterinary products, emodepside and monepantel, and nitazoxanide, which is approved for human use. In addition we include a less detailed analysis of all products examined, and the criteria on which the analysis was based. It is clear that the pipeline of easily obtainable human anthelminthics remains extremely limited, and further efforts are needed to find replacements for the inadequate number of products available today

A next-generation liquid xenon observatory for dark matter and neutrino physics

The nature of dark matter and properties of neutrinos are among the most pressing issues in contemporary particle physics. The dual-phase xenon time-projection chamber is the leading technology to cover the available parameter space for weakly interacting massive particles, while featuring extensive sensitivity to many alternative dark matter candidates. These detectors can also study neutrinos through neutrinoless double-beta decay and through a variety of astrophysical sources. A next-generation xenon-based detector will therefore be a true multi-purpose observatory to significantly advance particle physics, nuclear physics, astrophysics, solar physics, and cosmology. This review article presents the science cases for such a detector