Harmless? A hierarchical analysis of poppers use correlates among young gay and bisexual men

© 2019 Australasian Professional Society on Alcohol and other Drugs Introduction and Aims: Poppers (alkyl nitrites) are recreational substances commonly used during sexual activity. The current legal status of poppers is complex and wide-ranging bans are increasingly under discussion. Research has identified disproportionate levels of poppers use in sexual minority men. While research on poppers use among sexual minority men exists, little is known about poppers use patterns and correlations with psychosocial and other factors among gay and bisexual young men. Design and Methods: A cross-sectional survey was conducted with 836 Australian gay and bisexual young men aged 18 to 35 years. Descriptive statistics and hierarchical segmentation analyses were conducted to identify poppers use patterns, and correlates of recent poppers use (past 3 months) with personal characteristics, use of other substances, as well as mental and psychosocial health including minority stress, LGBT-community connectedness and participation. Results: High levels of lifetime (38%, n = 315) and recent (24%, n = 204) poppers use were reported. However, few participants reported dependency symptoms, risky consumption or problems arising from using poppers. The final model included three variables (visiting sex-on-premises venues, licensed LGBT venues, and using other substances) and predicted 85% (n = 174) of recent poppers use. No correlations with other concepts or characteristics could be identified. Conclusion: This analysis further supports the hypothesis that poppers may be substances with a comparably low-risk profile. A regulation of poppers with a harm reduction approach may present a valuable public health intervention

The realities of being young, unemployed and poor in post-industrial Britain

Poverty is a complex cultural phenomenon that is very much in existence in contemporary post-industrial Britain. A young person’s poverty-striken situation, in addition to their marginalised hierarchal position, shapes their repetitive life cycle comprising different but interrelated forms of marginality. The young people in this ethnographic study were found to experience marginalisation in their education, training and work spheres, as well as in their community, family and home. The purpose of this article is to carefully analyse the link between marginalised young people’s (in)ability to participate in key social systems and their (lack of) access to financial, cultural and social resources

Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics

The RPE65 gene encodes the isomerase of the retinoid cycle, the enzymatic pathway that underlies mammalian vision. Mutations in RPE65 disrupt the retinoid cycle and cause a congenital human blindness known as Leber congenital amaurosis (LCA). We used adeno-associated virus-2-based RPE65 gene replacement therapy to treat three young adults with RPE65-LCA and measured their vision before and up to 90 days after the intervention. All three patients showed a statistically significant increase in visual sensitivity at 30 days after treatment localized to retinal areas that had received the vector. There were no changes in the effect between 30 and 90 days. Both cone- and rod-photoreceptor-based vision could be demonstrated in treated areas. For cones, there were increases of up to 1.7 log units (i.e., 50 fold); and for rods, there were gains of up to 4.8 log units (i.e., 63,000 fold). To assess what fraction of full vision potential was restored by gene therapy, we related the degree of light sensitivity to the level of remaining photoreceptors within the treatment area. We found that the intervention could overcome nearly all of the loss of light sensitivity resulting from the biochemical blockade. However, this reconstituted retinoid cycle was not completely normal. Resensitization kinetics of the newly treated rods were remarkably slow and required 8 h or more for the attainment of full sensitivity, compared with \u3c1 h in normal eyes. Cone-sensitivity recovery time was rapid. These results demonstrate\u3edramatic, albeit imperfect, recovery of rod- and cone-photoreceptor-based vision after RPE65 gene therapy

Deciphering the Sox-Oct partner code by quantitative cooperativity measurements

Several Sox-Oct transcription factor (TF) combinations have been shown to cooperate on diverse enhancers to determine cell fates. Here, we developed a method to quantify biochemically the Sox-Oct cooperation and assessed the pairing of the high-mobility group (HMG) domains of 11 Sox TFs with Oct4 on a series of composite DNA elements. This way, we clustered Sox proteins according to their dimerization preferences illustrating that Sox HMG domains evolved different propensities to cooperate with Oct4. Sox2, Sox14, Sox21 and Sox15 strongly cooperate on the canonical element but compete with Oct4 on a recently discovered compressed element. Sry also cooperates on the canonical element but binds additively to the compressed element. In contrast, Sox17 and Sox4 cooperate more strongly on the compressed than on the canonical element. Sox5 and Sox18 show some cooperation on both elements, whereas Sox8 and Sox9 compete on both elements. Testing rationally mutated Sox proteins combined with structural modeling highlights critical amino acids for differential Sox-Oct4 partnerships and demonstrates that the cooperativity correlates with the efficiency in producing induced pluripotent stem cells. Our results suggest selective Sox-Oct partnerships in genome regulation and provide a toolset to study protein cooperation on DNA

Exciting new advances in oral cancer diagnosis: avenues to early detection

The prognosis for patients with oral squamous cell carcinoma remains poor in spite of advances in therapy of many other malignancies. Early diagnosis and treatment remains the key to improved patient survival. Because the scalpel biopsy for diagnosis is invasive and has potential morbidity, it is reserved for evaluating highly suspicious lesions and not for the majority of oral lesions which are clinically not suspicious. Furthermore, scalpel biopsy has significant interobserver and intraobserver variability in the histologic diagnosis of dysplasia. There is an urgent need to devise critical diagnostic tools for early detection of oral dysplasia and malignancy that are practical, noninvasive and can be easily performed in an out-patient set-up. Diagnostic tests for early detection include brush biopsy, toluidine blue staining, autofluorescence, salivary proteomics, DNA analysis, biomarkers and spectroscopy. This state of the art review critically examines these tests and assesses their value in identifying oral squamous cell carcinoma and its precursor lesions

A ChIP-Seq Benchmark Shows That Sequence Conservation Mainly Improves Detection of Strong Transcription Factor Binding Sites

Transcription factors are important controllers of gene expression and mapping transcription factor binding sites (TFBS) is key to inferring transcription factor regulatory networks. Several methods for predicting TFBS exist, but there are no standard genome-wide datasets on which to assess the performance of these prediction methods. Also, it is believed that information about sequence conservation across different genomes can generally improve accuracy of motif-based predictors, but it is not clear under what circumstances use of conservation is most beneficial.Here we use published ChIP-seq data and an improved peak detection method to create comprehensive benchmark datasets for prediction methods which use known descriptors or binding motifs to detect TFBS in genomic sequences. We use this benchmark to assess the performance of five different prediction methods and find that the methods that use information about sequence conservation generally perform better than simpler motif-scanning methods. The difference is greater on high-affinity peaks and when using short and information-poor motifs. However, if the motifs are specific and information-rich, we find that simple motif-scanning methods can perform better than conservation-based methods.Our benchmark provides a comprehensive test that can be used to rank the relative performance of transcription factor binding site prediction methods. Moreover, our results show that, contrary to previous reports, sequence conservation is better suited for predicting strong than weak transcription factor binding sites

Modeling the Evolution of Regulatory Elements by Simultaneous Detection and Alignment with Phylogenetic Pair HMMs

The computational detection of regulatory elements in DNA is a difficult but important problem impacting our progress in understanding the complex nature of eukaryotic gene regulation. Attempts to utilize cross-species conservation for this task have been hampered both by evolutionary changes of functional sites and poor performance of general-purpose alignment programs when applied to non-coding sequence. We describe a new and flexible framework for modeling binding site evolution in multiple related genomes, based on phylogenetic pair hidden Markov models which explicitly model the gain and loss of binding sites along a phylogeny. We demonstrate the value of this framework for both the alignment of regulatory regions and the inference of precise binding-site locations within those regions. As the underlying formalism is a stochastic, generative model, it can also be used to simulate the evolution of regulatory elements. Our implementation is scalable in terms of numbers of species and sequence lengths and can produce alignments and binding-site predictions with accuracy rivaling or exceeding current systems that specialize in only alignment or only binding-site prediction. We demonstrate the validity and power of various model components on extensive simulations of realistic sequence data and apply a specific model to study Drosophila enhancers in as many as ten related genomes and in the presence of gain and loss of binding sites. Different models and modeling assumptions can be easily specified, thus providing an invaluable tool for the exploration of biological hypotheses that can drive improvements in our understanding of the mechanisms and evolution of gene regulation

Linkage between solid-phase apportionment and bioaccessible arsenic, chromium and lead in soil from Glasgow, Scotland, UK

The chemical composition of soil from the Glasgow (UK) urban area was used to identify the controls on the availability of potentially harmful elements (PHEs) in soil to humans. Total and bioaccessible concentrations of arsenic (As), chromium (Cr) and lead (Pb) in 27 soil samples, collected from different land uses, were coupled to information on their solid-phase partitioning derived from sequential extraction data. The total element concentrations in the soils were in the range <0.1–135mgkg–1 for As; 65–3680mgkg–1 for Cr and 126–2160mgkg–1 for Pb, with bioaccessible concentrations averaging 27, 5 and 27% of the total values, respectively. Land use does not appear to be a predictor of contamination; however, the history of the contamination is critically important. The Chemometric Identification of Substrates and Element Distribution (CISED) sequential chemical extraction and associated self-modelling mixture resolution analysis identified three sample groupings and 16 geochemically distinct phases (substrates). These were related to iron (n=3), aluminium–silicon (Al–Si; n=2), calcium (n=3), phosphorus (n=1), magnesium (Mg; n=3), manganese (n=1) and easily extractable (n=3), which was predominantly made up of sodium and sulphur. As, Cr and Pb were respectively found in 9, 10 and 12 of the identified phases, with bioaccessible As predominantly associated with easily extractable phases, bioaccessible Cr with the Mg-dominated phases and bioaccessible Pb with both the Mg-dominated and Al–Si phases. Using a combination of the Unified Barge Method to measure the bioaccessibility of PHEs and CISED to identify the geochemical sources has allowed a much better understanding of the complexity of PHE mobility in the Glasgow urban environment. This approach can be applied to other urban environments and cases of soil contamination, and made part of land-use planning