Estimating the public health impact of the effect of herpes simplex virus suppressive therapy on plasma HIV-1 viral load.

OBJECTIVE: Trials of herpes simplex virus (HSV) suppressive therapy among HSV-2/HIV-1-infected individuals have reported an impact on plasma HIV-1 viral loads (PVLs). Our aim was to estimate the population-level impact of suppressive therapy on female-to-male HIV-1 sexual transmission. DESIGN AND METHODS: By comparing prerandomization and postrandomization individual-level PVL data from the first two HSV suppressive therapy randomized controlled trials in sub-Saharan Africa, we estimated the effect of treatment on duration of asymptomatic infection and number of HIV-1 transmission events for each trial. RESULTS: Assuming that a reduction in PVL is accompanied by an increased duration of HIV-1 asymptomatic infection, 4-6 years of HSV suppressive therapy produce a 1-year increase in the duration of this stage. To avert one HIV-1 transmission requires 8.8 [95% confidence interval (CI), 5.9-14.9] and 11.4 (95% CI, 7.8-27.5) women to be treated from halfway through their HIV-1 asymptomatic period, using results from Burkina Faso and South African trials, respectively. Regardless of the timing of treatment initiation, 51.6 (95% CI, 30.4-137.0) and 66.5 (95% CI, 36.7-222.6) treatment-years are required to avert one HIV-1 infection. Distributions of set-point PVL values from sub-Saharan African populations suggest that unintended adverse consequences of therapy at the population level (i.e. increased HIV-1 transmission due to increased duration of infection) are unlikely to occur in these settings. CONCLUSION: HSV suppressive therapy may avert relatively few HIV-1 transmission events per person-year of treatment. Its use as a prevention intervention may be limited; however, further research into its effect on rate of CD4 cell count decline and the impact of higher dosing schedules is warranted

Transitions in subduction zone properties align with long-term topographic growth (Cascadia, USA)

Simple mechanical models of the earthquake cycle assume that interseismic elastic deformation is recovered during earthquakes, closing the strain budget of steady and episodic slip on the deep and shallow subduction interfaces, respectively. However, elevated topography in the forearc high requires that some deformation is not recovered over each elastic cycle. Here, we compare constraints on deformation over decadal to million-year timescales to disentangle contributions from elastic (recoverable) and inelastic (unrecoverable) deformation within the Olympic Mountains of the Cascadia Subduction Zone. Over timescales of 103 – 106 yrs, elevated topography, permanent deformation, and denudation (from thermochronometry and cosmogenic nuclide data) accumulate in an area adjacent, but not identical, to the maximum in geodetically observed reduced vertical velocity and surface upwarping over tens of years. The domains of geodetic and geomorphic maximum uplift occur over a 20-60 km wide zone overlying the up-dip limits of the zone of conditional frictional stability at the subduction interface. We attribute geologic-scale orogenesis, accumulation of topography and advection of rocks in the active orogen to unrecoverable deformation as stress is relayed up-dip through parts of the subduction interface and dissipated in the overriding plate

Combinatorial Diversity of Fission Yeast SCF Ubiquitin Ligases by Homo- and Heterooligomeric Assemblies of the F-Box Proteins Pop1p and Pop2p

Background: SCF ubiquitin ligases share the core subunits cullin 1, SKP1, and HRT1/RBX1/ROC1, which associate with different F-box proteins. F-box proteins bind substrates following their phosphorylation upon stimulation of various signaling pathways. Ubiquitin-mediated destruction of the fission yeast cyclin-dependent kinase inhibitor Rum1p depends on two heterooligomerizing F-box proteins, Pop1p and Pop2p. Both proteins interact with the cullin Pcu1p when overexpressed, but it is unknown whether this reflects their co-assembly into bona fide SCF complexes. Results: We have identified Psh1p and Pip1p, the fission yeast homologues of human SKP1 and HRT1/RBX1/ROC1, and show that both associate with Pop1p, Pop2p, and Pcu1p into a ~500 kDa SCFPop1p-Pop2p complex, which supports polyubiquitylation of Rum1p. Only the F-box of Pop1p is required for SCFPop1p-Pop2p function, while Pop2p seems to be attracted into the complex through binding to Pop1p. Since all SCFPop1p-Pop2p subunits, except for Pop1p, which is exclusively nuclear, localize to both the nucleus and the cytoplasm, the F-box of Pop2p may be critical for the assembly of cytoplasmic SCFPop2p complexes. In support of this notion, we demonstrate individual SCFPop1p and SCFPop2p complexes bearing ubiquitin ligase activity. Conclusion: Our data suggest that distinct homo- and heterooligomeric assemblies of Pop1p and Pop2p generate combinatorial diversity of SCFPop function in fission yeast. Whereas a heterooligomeric SCFPop1p-Pop2p complex mediates polyubiquitylation of Rum1p, homooligomeric SCFPop1p and SCFPop2p complexes may target unknown nuclear and cytoplasmic substrates

Globular Cluster Abundances from High-Resolution, Integrated-Light Spectroscopy. III. The Large Magellanic Cloud: Fe and Ages

In this paper we refine our method for the abundance analysis of high resolution spectroscopy of the integrated light of unresolved globular clusters (GCs). This method was previously demonstrated for the analysis of old ($>$10 Gyr) Milky Way GCs. Here we extend the technique to young clusters using a training set of 9 GCs in the Large Magellanic Cloud (LMC). Depending on the signal-to-noise ratio of the data, we use 20-100 Fe lines per cluster to successfully constrain the ages of old clusters to within a $\sim$5 Gyr range, the ages of $\sim$2 Gyr clusters to a 1-2 Gyr range, and the ages of the youngest clusters (0.05-1 Gyr) to a $\sim$200 Myr range. We also demonstrate that we can measure [Fe/H] in clusters with any age less than 12 Gyrs with similar or only slightly larger uncertainties (0.1-0.25 dex) than those obtained for old Milky Way GCs (0.1 dex); the slightly larger uncertainties are due to the rapid evolution in stellar populations at these ages. In this paper, we present only Fe abundances and ages. In the next paper in this series, we present our complete analysis of the $\sim 20$ elements for which we are able to measure abundances. For several of the clusters in this sample, there are no high resolution abundances in the literature from individual member stars; our results are the first detailed chemical abundances available. The spectra used in this paper were obtained at Las Campanas with the echelle on the du Pont Telescope and with the MIKE spectrograph on the Magellan Clay Telescope.Comment: 34 pages, accepted for publication in Ap

Discovery of Precursor LBV Outbursts in Two Recent Optical Transients: The Fitfully Variable Missing Links UGC 2773-OT and SN 2009ip

We present progenitor-star detections, light curves, and optical spectra of SN2009ip and the 2009 optical transient in UGC2773 (U2773-OT), which were not genuine SNe. Precursor variability in the decade before outburst indicates that both of the progenitor stars were LBVs. Their pre-outburst light curves resemble the S Doradus phases that preceded giant eruptions of eta Carinae and SN1954J (V12 in NGC2403), with intermediate progenitor luminosities. HST detections a decade before discovery indicate that the SN2009ip and U2773-OT progenitors were supergiants with likely initial masses of 50-80 Msun and \ga20 Msun, respectively. Both outbursts had spectra befitting known LBVs, although in different physical states. SN 2009ip exhibited a hot LBV spectrum with characteristic speeds of 550 km/s, plus faster material up to 5000 km/s, resembling the slow Homunculus and fast blast wave of eta Carinae. U2773-OT shows a forest of narrow absorption and emission lines comparable to that of S Dor in its cool state, plus [CaII] emission and an IR excess indicative of dust, similar to SN2008S and N300-OT. [CaII] emission is probably tied to a dusty pre-outburst environment, and not the outburst mechanism. SN2009ip and U2773-OT may provide a critical link between historical LBV eruptions, while U2773-OT may provide a link between LBVs and SN2008S and N300-OT. Future searches will uncover more examples of precursor LBV variability of this kind, providing key clues that may help unravel the instability driving LBVs.Comment: 18 pages, 13 Figures, accepted AJ. added significant material while revising after referee repor

Associations of NINJ2 sequence variants with incident ischemic stroke in the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) consortium

Background<p></p> Stroke, the leading neurologic cause of death and disability, has a substantial genetic component. We previously conducted a genome-wide association study (GWAS) in four prospective studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and demonstrated that sequence variants near the NINJ2 gene are associated with incident ischemic stroke. Here, we sought to fine-map functional variants in the region and evaluate the contribution of rare variants to ischemic stroke risk.<p></p> Methods and Results<p></p> We sequenced 196 kb around NINJ2 on chromosome 12p13 among 3,986 European ancestry participants, including 475 ischemic stroke cases, from the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, and Framingham Heart Study. Meta-analyses of single-variant tests for 425 common variants (minor allele frequency [MAF] ≥ 1%) confirmed the original GWAS results and identified an independent intronic variant, rs34166160 (MAF = 0.012), most significantly associated with incident ischemic stroke (HR = 1.80, p = 0.0003). Aggregating 278 putatively-functional variants with MAF≤ 1% using count statistics, we observed a nominally statistically significant association, with the burden of rare NINJ2 variants contributing to decreased ischemic stroke incidence (HR = 0.81; p = 0.026).<p></p> Conclusion<p></p> Common and rare variants in the NINJ2 region were nominally associated with incident ischemic stroke among a subset of CHARGE participants. Allelic heterogeneity at this locus, caused by multiple rare, low frequency, and common variants with disparate effects on risk, may explain the difficulties in replicating the original GWAS results. Additional studies that take into account the complex allelic architecture at this locus are needed to confirm these findings

Tributes to Rick Edwards upon His Retirement

I understand that you will be retiring from UNL in August. I wanted to express my sadness that you will be leaving the Center for Great Plains Studies, but am glad that you will now be able to perhaps enjoy life even more without having to do the administrative tasks that go with being the director of any organization. (RFD

A Randomized Trial of a Prenatal Genetic Testing Interactive Computerized Information Aid

To determine whether an interactive computer program could improve patient knowledge regarding genetic screening and diagnostic concepts

Host‐derived population genomics data provides insights into bacterial and diatom composition of the killer whale skin

Recent exploration into the interactions and relationship between hosts and their microbiota has revealed a connection between many aspects of the host's biology, health and associated micro-organisms. Whereas amplicon sequencing has traditionally been used to characterize the microbiome, the increasing number of published population genomics data sets offers an underexploited opportunity to study microbial profiles from the host shotgun sequencing data. Here, we use sequence data originally generated from killer whale Orcinus orca skin biopsies for population genomics, to characterize the skin microbiome and investigate how host social and geographical factors influence the microbial community composition. Having identified 845 microbial taxa from 2.4 million reads that did not map to the killer whale reference genome, we found that both ecotypic and geographical factors influence community composition of killer whale skin microbiomes. Furthermore, we uncovered key taxa that drive the microbiome community composition and showed that they are embedded in unique networks, one of which is tentatively linked to diatom presence and poor skin condition. Community composition differed between Antarctic killer whales with and without diatom coverage, suggesting that the previously reported episodic migrations of Antarctic killer whales to warmer waters associated with skin turnover may control the effects of potentially pathogenic bacteria such as Tenacibaculum dicentrarchi. Our work demonstrates the feasibility of microbiome studies from host shotgun sequencing data and highlights the importance of metagenomics in understanding the relationship between host and microbial ecology

Mutational profiles of persistent/recurrent laryngeal squamous cell carcinoma

BackgroundWe sought to describe targeted DNA sequencing data of persistent/recurrent laryngeal squamous cell carcinoma (LSCC) and to compare gene‐specific alteration frequencies with that of primary, untreated LSCC specimens from The Cancer Genome Atlas (TCGA).MethodsThe tumors of 21 patients with persistent/recurrent LSCC were subjected to targeted DNA sequencing using the Ion AmpliSeq Comprehensive Cancer Panel. Gene‐specific alteration frequencies were compared (Chi‐Square test) to primary, untreated LSCC sequencing data from TCGA using the cBioPortal platform.ResultsPersistent/recurrent LSCC was characterized by a high rate of inactivating alterations in TP53 (38.1%) and CDKN2A (33%), amplification events of CCND1 (19.1%), and ERBB2 (14.3%), and NOTCH1 (19.1%) mutations. Comparison of primary vs persistent/recurrent LSCC revealed significant differences in alteration frequencies of eight critical genes: BAP1, CDKN2A, DCUN1D1, MSH2, MTOR, PIK3CA, TET2, and TP53.ConclusionsOur results provide preliminary support for a distinct mutational profile of persistent/recurrent LSCC that requires validation in larger cohorts.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147873/1/hed25444.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147873/2/hed25444_am.pd