The Absolute Age of M92

The \textit{absolute age} of a simple stellar population is of fundamental interest for a wide range of applications but is difficult to measure in practice, as it requires an understanding of the uncertainties in a variety of stellar evolution processes as well as the uncertainty in the distance, reddening and composition. As a result, most studies focus only on the \textit{relative age} by assuming that stellar evolution calculations are accurate and using age determinations techniques that are relatively independent of distance and reddening. Here, we construct $20,000$ sets of theoretical isochrones through Monte Carlo simulation using the Dartmouth Stellar Evolution Program to measure the absolute age of the globular cluster M92. For each model, we vary a range of input physics used in the stellar evolution models, including opacities, nuclear reaction rates, diffusion coefficients, atmospheric boundary conditions, helium abundance, and treatment of convection. We also explore variations in the distance and reddening as well as its overall metallicity and $\alpha$ enhancement. We generate simulated Hess diagrams around the main-sequence turn-off region from each set of isochrones and use a Voronoi binning method to fit the diagrams to HST ACS data. We find the age of M92 to be $13.80 \pm 0.75$ Gyr. The $5.4\%$ error in the absolute age is dominated by the uncertainty in the distance to M92 ($\sim 80\%$ of the error budget); of the remaining parameters, only the total metallicity, $\alpha$ element abundance, and treatment of helium diffusion contribute significantly to the total error.Comment: 15 Pages, 14 Figures, 2 Tables; Accepted for Publication A

Combinations of Griffithsin with Other Carbohydrate-Binding Agents Demonstrate Superior Activity Against HIV Type 1, HIV Type 2, and Selected Carbohydrate-Binding Agent-Resistant HIV Type 1 Strains

Abstract Carbohydrate-binding agents (CBAs) are potential HIV microbicidal agents with a high genetic barrier to resistance. We wanted to evaluate whether two mannose-specific CBAs, recognizing multiple and often distinct glycan structures on the HIV envelope gp120, can interact synergistically against HIV-1, HIV-2, and HIV-1 strains that were selected for resistance against particular CBAs [i.e., 2G12 mAb and microvirin (MVN)]. Paired CBA/CBA combinations mainly showed synergistic activity against both wild-type HIV-1 and HIV-2 but also 2G12 mAb- and MVN-resistant HIV-1 strains as based on the median effect principle with combination indices (CIs) ranging between 0.29 and 0.97. Upon combination, an increase in antiviral potency of griffithsin (GRFT) up to ?12-fold (against HIV-1), ?8-fold (against HIV-2), and ?6-fold (against CBA-resistant HIV-1) was observed. In contrast, HHA/GNA combinations showed additive activity against wild-type HIV-1 and HIV-2 strains, but remarkable synergy with HHA and GNA was observed against 2G12 mAb- and MVN-resistant HIV-1 strains (CI, 0.64 and 0.49, respectively). Overall, combinations of GRFT and other CBAs showed synergistic activity against HIV-1, HIV-2, and even against certain CBA-resistant HIV-1 strains. The CBAs tested appear to have distinct binding patterns on the gp120 envelope and therefore do not necessarily compete with each other's glycan binding sites on gp120. As a result, there might be no steric hindrance between two different CBAs in their competition for glycan binding (except for the HHA/GNA combination). These data are encouraging for the use of paired CBA combinations in topical microbicide applications (e.g., creams, gels, or intravaginal rings) to prevent HIV transmission.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98459/1/aid%2E2012%2E0026.pd

Regulation of Interstate Wine Shipments

Economists argue that there is no clear economic rationale for regulating interstate shipments of wine.

An Interactive Web-Based Lethal Means Safety Decision Aid for Suicidal Adults (Lock to Live): Pilot Randomized Controlled Trial

BACKGROUND: Counseling to reduce access to lethal means such as firearms and medications is recommended for suicidal adults but does not routinely occur. We developed the Web-based Lock to Live (L2L) decision aid to help suicidal adults and their families choose options for safer home storage. OBJECTIVE: This study aimed to test the feasibility and acceptability of L2L among suicidal adults in emergency departments (EDs). METHODS: At 4 EDs, we enrolled participants (English-speaking, community-dwelling, suicidal adults) in a pilot randomized controlled trial. Participants were randomized in a 13:7 ratio to L2L or control (website with general suicide prevention information) groups and received a 1-week follow-up telephone call. RESULTS: Baseline characteristics were similar between the intervention (n=33) and control (n=16) groups. At baseline, many participants reported having access to firearms (33/49, 67%), medications (46/49, 94%), or both (29/49, 59%). Participants viewed L2L for a median of 6 min (IQR 4-10 min). L2L also had very high acceptability; almost all participants reported that they would recommend it to someone in the same situation, that the options felt realistic, and that L2L was respectful of values about firearms. In an exploratory analysis of this pilot trial, more participants in the L2L group reported reduced firearm access at follow-up, although the differences were not statistically significant. CONCLUSIONS: The L2L decision aid appears feasible and acceptable for use among adults with suicide risk and may be a useful adjunct to lethal means counseling and other suicide prevention interventions. Future large-scale studies are needed to determine the effect on home access to lethal means. TRIAL REGISTRATION: ClinicalTrials.gov NCT03478501; https://clinicaltrials.gov/ct2/show/NCT03478501

Premature Osteoblast Clustering by Enamel Matrix Proteins Induces Osteoblast Differentiation through Up-Regulation of Connexin 43 and N-Cadherin

In recent years, enamel matrix derivative (EMD) has garnered much interest in the dental field for its apparent bioactivity that stimulates regeneration of periodontal tissues including periodontal ligament, cementum and alveolar bone. Despite its widespread use, the underlying cellular mechanisms remain unclear and an understanding of its biological interactions could identify new strategies for tissue engineering. Previous in vitro research has demonstrated that EMD promotes premature osteoblast clustering at early time points. The aim of the present study was to evaluate the influence of cell clustering on vital osteoblast cell-cell communication and adhesion molecules, connexin 43 (cx43) and N-cadherin (N-cad) as assessed by immunofluorescence imaging, real-time PCR and Western blot analysis. In addition, differentiation markers of osteoblasts were quantified using alkaline phosphatase, osteocalcin and von Kossa staining. EMD significantly increased the expression of connexin 43 and N-cadherin at early time points ranging from 2 to 5 days. Protein expression was localized to cell membranes when compared to control groups. Alkaline phosphatase activity was also significantly increased on EMD-coated samples at 3, 5 and 7 days post seeding. Interestingly, higher activity was localized to cell cluster regions. There was a 3 fold increase in osteocalcin and bone sialoprotein mRNA levels for osteoblasts cultured on EMD-coated culture dishes. Moreover, EMD significantly increased extracellular mineral deposition in cell clusters as assessed through von Kossa staining at 5, 7, 10 and 14 days post seeding. We conclude that EMD up-regulates the expression of vital osteoblast cell-cell communication and adhesion molecules, which enhances the differentiation and mineralization activity of osteoblasts. These findings provide further support for the clinical evidence that EMD increases the speed and quality of new bone formation in vivo

Coils, Loops, and Fingers: Functional Motifs in Hantavirus Proteins

New world hantaviruses are a threat as an emerging pathogen with the potential to cause outbreaks in rural regions remote from medical facilities. Medical authorities emphasize the need for preventative education programs and the development of antiviral drug treatments based on an understanding of the viral replication process. The virus is composed of three negative sense RNA genomic segments and four proteins; the RNA-dependent RNA polymerase (RdRP), glycoprotein Gn, glycoprotein Gc, and the nucleocapsid protein (Npro). This dissertation presents the structures of three motifs within hantavirus proteins as part of an effort to identify potential targets for antiviral drugs. 1) The NMR structure of the N-terminal region of Npro is described here to form a helical coiled-coil motif. Three acidic amino acids in this structure significantly contribute to the ability of Npro to self associate, an important process in viral replication. 2) The middle region of Npro is proposed at a low resolution to contain a helix-loop-helix motif which interacts with the cytoskeletal filament, vimentin. The Npro-vimentin interaction contributes to the proper trafficking of Npro through the cytoplasm. 3) The glycoprotein Gn contains an unusually long cytoplasmic tail with a conserved dual CCHC sequence. NMR resolution revealed that this sequence forms a zinc finger motif. The potential for this zinc finger to bind viral RNA was predicted by molecular modeling and molecular dynamic simulations. This interaction is thought to coordinate the packaging of each of the three viral genome segments. The presentation of these three structures contributes a better understanding of the physical properties of proteins involved in viral infections

The Absolute Age of M92

The absolute age of a simple stellar population is of fundamental interest for a wide range of applications but is difficult to measure in practice, as it requires an understanding of the uncertainties in a variety of stellar evolution processes as well as the uncertainty in the distance, reddening, and composition. As a result, most studies focus only on the relative age by assuming that stellar evolution calculations are accurate and using age determinations techniques that are relatively independent of distance and reddening. Here, we construct 20,000 sets of theoretical isochrones through Monte Carlo simulation using the Dartmouth Stellar Evolution Program to measure the absolute age of the globular cluster M92. For each model, we vary a range of input physics used in the stellar evolution models, including opacities, nuclear reaction rates, diffusion coefficients, atmospheric boundary conditions, helium abundance, and treatment of convection. We also explore variations in the distance and reddening as well as its overall metallicity and α enhancement. We generate simulated Hess diagrams around the main-sequence turn-off region from each set of isochrones and use a Voronoi binning method to fit the diagrams to Hubble Space Telescope Advanced Camera for Surveys data. We find the age of M92 to be 13.80 ± 0.75 Gyr. The 5.4% error in the absolute age is dominated by the uncertainty in the distance to M92 (∼80% of the error budget); of the remaining parameters, only the total metallicity, α element abundance, and treatment of helium diffusion contribute significantly to the total error