Syndemics and the PrEP Cascade: Results from a Sample of Young Latino Men Who Have Sex with Men.

Young Latino men who have sex with men (MSM) are a highly vulnerable population for HIV infection. Pre-exposure prophylaxis (PrEP) is a novel biomedical HIV prevention tool that may aid in reducing the disparity in HIV incidence among Latino MSM. However, PrEP use is disproportionally low among Latino MSM and, therefore, identifying barriers along the PrEP continuum of care (the "PrEP cascade") would provide insight into how to best deploy PrEP interventions. Syndemics theory is a prominent framework employed in HIV prevention; however, to date, no known studies have applied this theory to PrEP. Thus, the aim of the current study was to explore the association between syndemics and the PrEP cascade, including the degree to which psychosocial and structural syndemic constructs are related to the PrEP cascade. Participants were 151 young Latino MSM (M age = 24 years; SD = 3) residing in San Diego, California, who completed a battery of online self-report measures. Results indicated high levels of syndemic indicators and varying levels of engagement across the PrEP cascade. As syndemic indicators increased, the odds of engagement across the PrEP cascade were significantly lowered. Psychosocial and structural syndemic factors accounted for unique variance in the PrEP cascade. Results highlight the need for combination interventions that address both psychosocial and structural barriers to PrEP use and persistence among young Latino MSM

Predation Risk, Elk, and Aspen: Comment

With the exception of humans, gray wolves (Canis lupus) are perhaps the most significant predator of cervids in the northern hemisphere, mainly due to the group-hunting, year-round activity, and widespread geographic distribution (Peterson et al. 2003). Thus, interactions between wolves and large herbivore prey, such as elk (Cervus elaphus) and moose (Alces alces), have long been of interest to biologists (Peterson 1995, Jęodrzejewska et al. 2000, Mech and Boitani 2003). The potential ecological role this apex predator may have, via trophic cascades, has also received attention in recent years by researchers (e.g., Callan et al. 2013, Kuijper et al. 2013, 2014), wildlife management agencies (e.g., state wolf management plans), as well as the general public. Perhaps nowhere in the western United States has a heightened examination of this large predator been more focused than in Yellowstone National Park (YNP; Laundré et al. 2001, Smith et al. 2003, 2013, Fortin et al. 2005). Here, wolves were reintroduced in the mid-1990s, again completing the park\u27s large predator guild after approximately seven decades of absence, thus providing a long-term, landscape-scale, natural experiment (Diamond 1983). The Gallatin winter range is one of two that occur along the northern portion of YNP, the other is the northern ungulate winter range, or “northern range,” located some 25 km or more to the east. Of these, the Gallatin has been less studied. Nevertheless, the Gallatin winter range, like the northern range, experienced high levels of elk herbivory following the extirpation of wolves in the early 1900s. Over a period of approximately seven decades, intensive herbivory by elk led to the long-term decline in aspen (Populus tremuloides) and willow (Salix spp.) recruitment (i.e., growth of young plants above the browse level of elk) in the Gallatin winter range, leaving these plant communities in an impoverished condition (Lovaas 1967, Patten 1968, Kay 2001, Ripple and Beschta 2004, Halofsky and Ripple 2008). Accelerated soil and channel erosion also occurred (Lovaas 1967, Beschta and Ripple 2006). Thus, when wolves were reintroduced into Yellowstone in the mid-1990s, aspen recruitment within the Gallatin elk winter range, had been largely absent for several decades (Kay 2001, Halofsky and Ripple 2008). In 2010, Winnie (2012) sampled 65 aspen stands in the northwestern corner of YNP, within the Gallatin elk winter range, to determine if a behaviorally mediated trophic cascade (BMTC) was occurring. As background information Winnie (2012:2600) included only a single sentence about wolves in the Greater Yellowstone Ecosystem and the remainder of the paragraph briefly discussed elk numbers, with most of the emphasis on elk in YNP\u27s northern range where there has been a pronounced redistribution of elk since the reintroduction of wolves (White et al. 2012). A more complete summary regarding the status and dynamics of wolves and elk over the last 15 years (i.e., 1995–2010) in the Gallatin elk winter range, as well as in the Daly Creek sub-drainage where Winnie\u27s study occurred, would have helped readers better understand the context of his study. Furthermore, information regarding human harvest of elk in the Gallatin winter range since the return of wolves, or whether such hunting has been affecting elk numbers or distribution in recent years was not provided. As part of his 2010 field study, Winnie (2012) characterized the presence or absence of several hypothesized risk factors (independent variables) for each aspen stand, including escape impediments, visual impediments, distance to conifer forest edge, and presence of deadfall trees. For dependent variables, Winnie (2012) recorded the presence or absence of browsing on aspen suckers (ramets \u3c2 m in height) and the number of aspen juveniles (plants \u3e2 m in height but \u3c6 cm in diameter at breast height). A height of 2 m generally represents the upper browse level of elk, and young aspen exceeding this height are considered to have successfully recruited. Such recruitment would represent a major departure from the browsing suppression that occurred in his study area over recent decades (Kay 2001, Halofsky and Ripple 2008) and an indication that a tri-trophic cascade involving wolves, elk, and aspen may be underway. From the results of his analyses, Winnie (2012:2600) concluded that “aspen were not responding to hypothesized fine-scale risk factors in ways consistent with the current BMTC hypothesis.” We respectfully submit that the design and analysis used to support such a conclusion may be deficient for two reasons, the first based on conceptual concerns and the second on statistical concerns. (1) Unfortunately, some aspen stands Winnie (2012) sampled contained juveniles associated with “physical barriers,” barriers that could prevent elk from browsing young aspen. To be scientifically valid, a risk assessment using young aspen as the dependent variable must inherently assure that all evaluated plants were accessible to elk browsing. (2) The inclusion of 10 aspen stands containing some physically protected aspen likely confounded results from his predation risk analyses (i.e., Figs. 5, 6, and 7 in Winnie 2012). While the inclusion of stands with protected aspen may increase the variance associated with his dependent variables (i.e., browsing rate, number of juveniles), the fallacy of doing so is revealed by inspecting these variables for the 85% of his stands (n = 55 stands) that did not have physically protected aspen. Here, a browsing rate of ∼99% and an average of \u3c1 juvenile per stand occurred (back-transformed means from Fig. 8b and a, respectively [Winnie 2012:2609]), indicating a general lack of variance in the dependent variables associated with these stands and little likelihood of a statistically significant outcome. Thus, we suspect that the “statistically significant” results Winnie (2012) found in Figs. 5, 6, and 7, whether contrary to or in support of a BMTC hypothesis, are primarily influenced by the occurrence of risk factors associated with those stands where some of the young aspen were physically protected. A reanalysis by Winnie of browsing rate and number of juveniles vs. his risk factors, using just the 55 stands accessible to elk, could clarify this issue. Because of the above concerns, we would offer that results of Winnie\u27s (2012) analyses of “proportion of sprouts browsed” or “number of juveniles per stand” relative to his hypothesized risk factors may well be spurious. If so, any discussions and conclusions based on those results are in question. A 2004 field study of aspen stands in the Gallatin winter range found aspen recruitment had declined precipitously following the extirpation of wolves in the 1920s and remained essentially absent through the late 1990s (Halofsky and Ripple 2008). Thus, when Winnie (2012) undertook his field study in 2010, a wolf–elk–aspen trophic cascade had not yet been confirmed. While the occurrence of juvenile aspen would be important to the long-term survival of aspen stands, the data for elk-accessible stands continue to show exceptionally high browse rates and little or no recruitment (Winnie 2012). This situation contrasts with YNP\u27s northern range where decreased browsing and increased heights of young aspen in portions of that range have been observed some 6–10 years after the occurrence of increased willow growth, although this recruitment has been spatially patchy (e.g., Ripple and Beschta 2012, Painter 2013; also see northern range photos of aspen recruitment available online).5 It should be noted that decreased browsing and increased heights of willows in the Gallatin winter range (at the base of the Daly Creek watershed) following the return of wolves, and consistent with the occurrence of a trophic cascade, were documented as early as 1999–2000 (Ripple and Beschta 2004), with heights continuing to increase in more recent years (Beschta and Ripple 2010). Also consistent with a trophic cascade, various northern range studies have found increased willow growth/canopy cover, sometimes interacting with climatic fluctuations, following wolf reintroduction (e.g., Groshong 2004, Beschta and Ripple 2007, Beyer et al. 2007, Baril 2009, Tercek et al. 2010, Marshall 2012). The occurrence of 192 juvenile aspen within Winnie\u27s (2012) study area would seem to indicate the beginnings of a tri-trophic cascade, particularly when compared to the lack of juvenile production in the decades immediately before wolf reintroduction (Halofsky and Ripple 2008). However, most of the 192 juveniles were associated with aspen stands characterized as having some degree of physical protection from elk (Fig. 8a in Winnie 2012), making it difficult to confirm if they represent a wolf–elk–aspen trophic cascade involving density and/or behavioral mediation. A trophic cascade involving aspen can be complex and context dependent (e.g., linked to bottom-up factors such as fire [Eisenberg et al. 2013]). Furthermore, undertaking risk assessments associated with large mammalian predators and ungulates in mountainous terrain, where human hunting is also occurring across part of the landscape, can be especially challenging. While we commend Winnie (2012) for attempting such an assessment, without a reanalysis of only those young aspen accessible to elk it would appear that his evaluation may not have been sufficiently rigorous to evaluate the presence or absence of a potential BMTC in the Gallatin winter range

Patient‐friendly pathology reports for patients with breast atypias

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146318/1/tbj13061_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146318/2/tbj13061.pd

Increased tRNA modification and gene-specific codon usage regulate cell cycle progression during the DNA damage response

S-phase and DNA damage promote increased ribonucleotide reductase (RNR) activity. Translation of RNR1 has been linked to the wobble uridine modifying enzyme tRNA methyltransferase 9 (Trm9). We predicted that changes in tRNA modification would translationally regulate RNR1 after DNA damage to promote cell cycle progression. In support, we demonstrate that the Trm9-dependent tRNA modification 5-methoxycarbonylmethyluridine (mcm⁵U) is increased in hydroxyurea (HU)-induced S-phase cells, relative to G₁ and G₂, and that mcm⁵U is one of 16 tRNA modifications whose levels oscillate during the cell cycle. Codon-reporter data matches the mcm⁵U increase to Trm9 and the efficient translation of AGA codons and RNR1. Further, we show that in trm9Δ cells reduced Rnr1 protein levels cause delayed transition into S-phase after damage. Codon re-engineering of RNR1 increased the number of trm9Δ cells that have transitioned into S-phase 1 h after DNA damage and that have increased Rnr1 protein levels, similar to that of wild-type cells expressing native RNR1. Our data supports a model in which codon usage and tRNA modification are regulatory components of the DNA damage response, with both playing vital roles in cell cycle progression.National Institute of Environmental Health Sciences (R01 ES015037)National Institute of Environmental Health Sciences (R01 ES017010)National Institute of Environmental Health Sciences (P30 ES002109)Massachusetts Institute of Technology (Westaway Fund)Singapore-MIT Alliance for Research and Technolog

Combining role-play with interactive simulation to motivate informed climate action: Evidence from the World Climate simulation

Climate change communication efforts grounded in the information deficit model have largely failed to close the gap between scientific and public understanding of the risks posed by climate change. In response, simulations have been proposed to enable people to learn for themselves about this complex and politically charged topic. Here we assess the impact of a widely-used simulation, World Climate, which combines a socially and emotionally engaging role-play with interactive exploration of climate change science through the C-ROADS climate simulation model. Participants take on the roles of delegates to the UN climate negotiations and are challenged to create an agreement that meets international climate goals. Their decisions are entered into C-ROADS, which provides immediate feedback about expected global climate impacts, enabling them to learn about climate change while experiencing the social dynamics of negotiations. We assess the impact of World Climate by analyzing pre- and post-survey results from >2,000 participants in 39 sessions in eight nations. We find statistically significant gains in three areas: (i) knowledge of climate change causes, dynamics and impacts; (ii) affective engagement including greater feelings of urgency and hope; and (iii) a desire to learn and do more about climate change. Contrary to the deficit model, gains in urgency were associated with gains in participants’ desire to learn more and intent to act, while gains in climate knowledge were not. Gains were just as strong among American participants who oppose government regulation of free markets–a political ideology that has been linked to climate change denial in the US–suggesting the simulation’s potential to reach across political divides. The results indicate that World Climate offers a climate change communication tool that enables people to learn and feel for themselves, which together have the potential to motivate action informed by science.National Science Foundation (U.S.) (grant DUE-124558)National Science Foundation (U.S.) (grant ICEER-1701062

Mitochondria as a Target of Environmental Toxicants

Enormous strides have recently been made in our understanding of the biology and pathobiology of mitochondria. Many diseases have been identified as caused by mitochondrial dysfunction, and many pharmaceuticals have been identified as previously unrecognized mitochondrial toxicants. A much smaller but growing literature indicates that mitochondria are also targeted by environmental pollutants. We briefly review the importance of mitochondrial function and maintenance for health based on the genetics of mitochondrial diseases and the toxicities resulting from pharmaceutical exposure. We then discuss how the principles of mitochondrial vulnerability illustrated by those fields might apply to environmental contaminants, with particular attention to factors that may modulate vulnerability including genetic differences, epigenetic interactions, tissue characteristics, and developmental stage. Finally, we review the literature related to environmental mitochondrial toxicants, with a particular focus on those toxicants that target mitochondrial DNA. We conclude that the fields of environmental toxicology and environmental health should focus more strongly on mitochondri

Systematic Investigation of the Permeability of Androgen Receptor PROTACs.

Bifunctional molecules known as PROTACs simultaneously bind an E3 ligase and a protein of interest to direct ubiquitination and clearance of that protein, and they have emerged in the past decade as an exciting new paradigm in drug discovery. In order to investigate the permeability and properties of these large molecules, we synthesized two panels of PROTAC molecules, constructed from a range of protein-target ligands, linkers, and E3 ligase ligands. The androgen receptor, which is a well-studied protein in the PROTAC field was used as a model system. The physicochemical properties and permeability of PROTACs are discussed.This work was funded by Alzheimer’s Research UK (grant: ARUK-2015DDI-CAM), with support from the ALBORADA Trust. The ALBORADA Drug Discovery Institute is core funded by Alzheimer’s Research UK (registered charity No. 1077089 and SC042474)

A genome-wide deletion mutant screen identifies pathways affected by nickel sulfate in Saccharomyces cerevisiae

<p>Abstract</p> <p>Background</p> <p>The understanding of the biological function, regulation, and cellular interactions of the yeast genome and proteome, along with the high conservation in gene function found between yeast genes and their human homologues, has allowed for <it>Saccharomyces cerevisiae </it>to be used as a model organism to deduce biological processes in human cells. Here, we have completed a systematic screen of the entire set of 4,733 haploid <it>S. cerevisiae </it>gene deletion strains (the entire set of nonessential genes for this organism) to identify gene products that modulate cellular toxicity to nickel sulfate (NiSO₄).</p> <p>Results</p> <p>We have identified 149 genes whose gene deletion causes sensitivity to NiSO₄and 119 genes whose gene deletion confers resistance. Pathways analysis with proteins whose absence renders cells sensitive and resistant to nickel identified a wide range of cellular processes engaged in the toxicity of <it>S. cerevisiae </it>to NiSO₄. Functional categories overrepresented with proteins whose absence renders cells sensitive to NiSO₄include homeostasis of protons, cation transport, transport ATPases, endocytosis, siderophore-iron transport, homeostasis of metal ions, and the diphthamide biosynthesis pathway. Functional categories overrepresented with proteins whose absence renders cells resistant to nickel include functioning and transport of the vacuole and lysosome, protein targeting, sorting, and translocation, intra-Golgi transport, regulation of C-compound and carbohydrate metabolism, transcriptional repression, and chromosome segregation/division. Interactome analysis mapped seven nickel toxicity modulating and ten nickel-resistance networks. Additionally, we studied the degree of sensitivity or resistance of the 111 nickel-sensitive and 72 -resistant strains whose gene deletion product has a similar protein in human cells.</p> <p>Conclusion</p> <p>We have undertaken a whole genome approach in order to further understand the mechanism(s) regulating the cell's toxicity to nickel compounds. We have used computational methods to integrate the data and generate global models of the yeast's cellular response to NiSO₄. The results of our study shed light on molecular pathways associated with the cellular response of eukaryotic cells to nickel compounds and provide potential implications for further understanding the toxic effects of nickel compounds to human cells.</p

The XMM Cluster Survey: Evidence for energy injection at high redshift from evolution of the X-ray luminosity-temperature relation

We measure the evolution of the X-ray luminosity-temperature (L_X-T) relation since z~1.5 using a sample of 211 serendipitously detected galaxy clusters with spectroscopic redshifts drawn from the XMM Cluster Survey first data release (XCS-DR1). This is the first study spanning this redshift range using a single, large, homogeneous cluster sample. Using an orthogonal regression technique, we find no evidence for evolution in the slope or intrinsic scatter of the relation since z~1.5, finding both to be consistent with previous measurements at z~0.1. However, the normalisation is seen to evolve negatively with respect to the self-similar expectation: we find E(z)^{-1} L_X = 10^{44.67 +/- 0.09} (T/5)^{3.04 +/- 0.16} (1+z)^{-1.5 +/- 0.5}, which is within 2 sigma of the zero evolution case. We see milder, but still negative, evolution with respect to self-similar when using a bisector regression technique. We compare our results to numerical simulations, where we fit simulated cluster samples using the same methods used on the XCS data. Our data favour models in which the majority of the excess entropy required to explain the slope of the L_X-T relation is injected at high redshift. Simulations in which AGN feedback is implemented using prescriptions from current semi-analytic galaxy formation models predict positive evolution of the normalisation, and differ from our data at more than 5 sigma. This suggests that more efficient feedback at high redshift may be needed in these models.Comment: Accepted for publication in MNRAS; 12 pages, 6 figures; added references to match published versio

Evolution of compound eye morphology underlies differences in vision between closely related Drosophila species

Background: Insects have evolved complex visual systems and display an astonishing range of adaptations for diverse ecological niches. Species of Drosophila melanogaster subgroup exhibit extensive intra- and interspecific differences in compound eye size. These differences provide an excellent opportunity to better understand variation in insect eye structure and the impact on vision. Here we further explored the difference in eye size between D. mauritiana and its sibling species D. simulans. Results: We confirmed that D. mauritiana have rapidly evolved larger eyes as a result of more and wider ommatidia than D. simulans since they recently diverged approximately 240,000 years ago. The functional impact of eye size, and specifically ommatidia size, is often only estimated based on the rigid surface morphology of the compound eye. Therefore, we used 3D synchrotron radiation tomography to measure optical parameters in 3D, predict optical capacity, and compare the modelled vision to in vivo optomotor responses. Our optical models predicted higher contrast sensitivity for D. mauritiana, which we verified by presenting sinusoidal gratings to tethered flies in a flight arena. Similarly, we confirmed the higher spatial acuity predicted for Drosophila simulans with smaller ommatidia and found evidence for higher temporal resolution. Conclusions: Our study demonstrates that even subtle differences in ommatidia size between closely related Drosophila species can impact the vision of these insects. Therefore, further comparative studies of intra- and interspecific variation in eye morphology and the consequences for vision among other Drosophila species, other dipterans and other insects are needed to better understand compound eye structure–function and how the diversification of eye size, shape, and function has helped insects to adapt to the vast range of ecological niches