The effects of extended public transport operating hours and venue lockout policies on drinking-related harms in Melbourne, Australia: Results from SimDrink, an agent-based simulation model.

Background: The late-night accessibility of entertainment precincts is a contributing factor to acute drinking-related harms. Using computer simulation we test the effects of improved public transport (PT) and venue lockouts on verbal aggression, consumption-related harms and transport-related harms among a population of young adults engaging in heavy drinking in Melbourne. Methods: Using an agent-based model we implemented: a two-hour PT extension/24-hour PT; 1 am/3 am venue lockouts; and combinations of both. Outcomes determined for outer-urban (OU) and inner-city (IC) residents were: the number of incidents of verbal aggression inside public and private venues; the number of people ejected from public venues for being intoxicated; and the percentage of people experiencing verbal aggression, consumption-related harms and transport-related harms. Results: All-night PT reduced verbal aggression in the model by 21% but displaced some incidents among OU residents from private to public settings. Comparatively, 1 am lockouts reduced verbal aggression in the model by 19% but led to IC residents spending more time in private rather than public venues where their consumption-related harms increased. Extending PT by 2 h had similar outcomes to 24-hour PT except with fewer incidents of verbal aggression displaced. Although 3 am lockouts were inferior to 1 am lockouts, when modelled in combination with any extension of PT both policies were similar. Conclusions: A two-hour extension of PT is likely to be more effective in reducing verbal aggression and consumption-related harms than venue lockouts. Modelling a further extension of PT to 24 h had minimal additional benefits but the potential to displace incidents of verbal aggression among OU residents from private to public venues

Protein-DNA charge transport: Redox activation of a DNA repair protein by guanine radical

DNA charge transport (CT) chemistry provides a route to carry out oxidative DNA damage from a distance in a reaction that is sensitive to DNA mismatches and lesions. Here, DNA-mediated CT also leads to oxidation of a DNA-bound base excision repair enzyme, MutY. DNA-bound Ru(III), generated through a flash/quench technique, is found to promote oxidation of the [4Fe-4S](2+) cluster of MutY to [4Fe-4S](3+) and its decomposition product [3Fe-4S](1+). Flash/quench experiments monitored by EPR spectroscopy reveal spectra with g = 2.08, 2.06, and 2.02, characteristic of the oxidized clusters. Transient absorption spectra of poly(dGC) and [Ru(phen)(2)dppz](3+) (dppz = dipyridophenazine), generated in situ, show an absorption characteristic of the guanine radical that is depleted in the presence of MutY with formation instead of a long-lived species with an absorption at 405 nm; we attribute this absorption also to formation of the oxidized [4Fe-4S](3+) and [3Fe4S](1+) clusters. In ruthenium-tethered DNA assemblies, oxidative damage to the 5'-G of a 5'-GG-3' doublet is generated from a distance but this irreversible damage is inhibited by MutY and instead EPR experiments reveal cluster oxidation. With ruthenium-tethered assemblies containing duplex versus single-stranded regions, MutY oxidation is found to be mediated by the DNA duplex, with guanine radical as an intermediate oxidant; guanine radical formation facilitates MutY oxidation. A model is proposed for the redox activation of DNA repair proteins through DNA CT, with guanine radicals, the first product under oxidative stress, in oxidizing the DNA-bound repair proteins, providing the signal to stimulate DNA repair

Aberrant T cell differentiation in the absence of Dicer

Dicer is an RNaseIII-like enzyme that is required for generating short interfering RNAs and microRNAs. The latter have been implicated in regulating cell fate determination in invertebrates and vertebrates. To test the requirement for Dicer in cell-lineage decisions in a mammalian organism, we have generated a conditional allele of dicer-1 (dcr-1) in the mouse. Specific deletion of dcr-1 in the T cell lineage resulted in impaired T cell development and aberrant T helper cell differentiation and cytokine production. A severe block in peripheral CD8+ T cell development was observed upon dcr-1 deletion in the thymus. However, Dicer-deficient CD4+ T cells, although reduced in numbers, were viable and could be analyzed further. These cells were defective in microRNA processing, and upon stimulation they proliferated poorly and underwent increased apoptosis. Independent of their proliferation defect, Dicer-deficient helper T cells preferentially expressed interferon-γ, the hallmark effector cytokine of the Th1 lineage

The p400 Complex Is an Essential E1A Transformation Target

AbstractHere, we report the identification of a new E1A binding protein complex that is essential for E1A-mediated transformation. Its core component is a SWI2/SNF2-related, 400 kDa protein (p400). Other components include the myc- and p/CAF-associated cofactor, TRRAP/PAF400, the DNA helicases TAP54α/β, actin-like proteins, and the human homolog of the Drosophila Enhancer of Polycomb protein. An E1A mutant, defective in p400 binding, is also defective in transformation. Certain p400 fragments partially rescued this phenotype, underscoring the role of E1A-p400 complex formation in the E1A transforming process. Furthermore, E1A and c-myc each alter the subunit composition of p400 complexes, implying that physiological p400 complex formation contributes to transformation suppression

Toxicity and pathophysiology of palytoxin congeners after intraperitoneal and aerosol administration in rats

Author Posting. © The Author(s), 2018. This is the author's version of the work. It is posted here under a nonexclusive, irrevocable, paid-up, worldwide license granted to WHOI. It is made available for personal use, not for redistribution. The definitive version was published in Toxicon 150 (2018): 235-250, doi:10.1016/j.toxicon.2018.06.067.Preparations of palytoxin (PLTX, derived from Japanese Palythoa tuberculosa) and the congeners 42-OH-PLTX (from Hawaiian P. toxica) and ovatoxin-a (isolated from a Japanese strain of Ostreopsis ovata), as well as a 50:50 mixture of PLTX and 42-OH-PLTX derived from Hawaiian P. tuberculosa were characterized as to their concentration, composition, in-vitro potency and interaction with an anti-PLTX monoclonal antibody (mAb), after which they were evaluated for lethality and pathophysiological effects by intraperitoneal (IP) and aerosol administration to rats. Once each preparation was characterized as to its toxin composition by LC-HRMS and normalized to a total PLTX/OVTX concentration using HPLC-UV, all four preparations showed similar potency towards mouse erythrocytes in the erythrocyte hemolysis assay and interactions with the anti-PLTX mAb. The IP LD50 values derived from these experiments (1-3 μg/kg for all) were consistent with published values, although some differences from the published literature were seen. The aerosol LD50 values (.03-.06 μg/kg) confirmed the exquisite potency of PLTX suggested by the literature. The pathophysiological effects of the different toxin preparations by IP and aerosol administration were similar, albeit with some differences. Most commonly affected tissues were the lungs, liver, heart, kidneys, salivary glands, and adrenal glands. Despite some differences, these results suggest commonalities in potency and mechanism of action among these PLTX congeners.This work was supported by the Defense Threat Reduction Agency, through the Joint Program Executive Office for Chemical and Biological Defense, Contract number CB10396. Additional support to DMA and DLK was provided by National Science Foundation (Grant OCE-1314642) and National Institutes of Health (NIEHS-1P50-ES021923-01) through the Woods Hole Center for Oceans and Human Health

K2 Discovers a Busy Bee: An Unusual Transiting Neptune Found in the Beehive Cluster

Open clusters have been the focus of several exoplanet surveys but only a few planets have so far been discovered. The \emph{Kepler} spacecraft revealed an abundance of small planets around small, cool stars, therefore, such cluster members are prime targets for exoplanet transit searches. Kepler's new mission, K2, is targeting several open clusters and star-forming regions around the ecliptic to search for transiting planets around their low-mass constituents. Here, we report the discovery of the first transiting planet in the intermediate-age (800 Myr) Beehive cluster (Praesepe). K2-95 is a faint ($\mathrm{Kp = 15.5\,mag}$) $\mathrm{M3.0\pm0.5}$ dwarf from K2's Campaign 5 with an effective temperature of $\mathrm{3471 \pm 124\,K}$, approximately solar metallicity and a radius of $\mathrm{0.402 \pm 0.050 \,R_\odot}$. We detected a transiting planet with a radius of $\mathrm{3.47^{+0.78}_{-0.53} \, R_\oplus}$ and an orbital period of 10.134 days. We combined photometry, medium/high-resolution spectroscopy, adaptive optics/speckle imaging and archival survey images to rule out any false positive detection scenarios, validate the planet, and further characterize the system. The planet's radius is very unusual as M-dwarf field stars rarely have Neptune-sized transiting planets. The comparatively large radius of K2-95b is consistent with the other recently discovered cluster planets K2-25b (Hyades) and K2-33b (Upper Scorpius), indicating systematic differences in their evolutionary states or formation. These discoveries from K2 provide a snapshot of planet formation and evolution in cluster environments and thus make excellent laboratories to test differences between field-star and cluster planet populations.Comment: 14 pages, 8 figues. Accepted for publication in A

60 Validated Planets from K2 Campaigns 5-8

We present a uniform analysis of 155 candidates from the second year of NASA's $K2$ mission (Campaigns 5-8), yielding 60 statistically validated planets spanning a range of properties, with median values of $R_p$ = 2.5 $R_\oplus$, $P$ = 7.1 d, $T_\mathrm{eq}$ = 811 K, and $J$ = 11.3 mag. The sample includes 24 planets in 11 multi-planetary systems, as well as 18 false positives, and 77 remaining planet candidates. Of particular interest are 18 planets smaller than 2 $R_\oplus$, five orbiting stars brighter than $J$ = 10 mag, and a system of four small planets orbiting the solar-type star EPIC 212157262. We compute planetary transit parameters and false positive probabilities using a robust statistical framework and present a complete analysis incorporating the results of an intensive campaign of high resolution imaging and spectroscopic observations. This work brings the $K2$ yield to over 360 planets, and by extrapolation we expect that $K2$ will have discovered $\sim$600 planets before the expected depletion of its on-board fuel in late 2018.Comment: 33 pages, 13 figures, 5 tables, accepted for publication in A

BRCA1 haploinsufficiency for replication stress suppression in primary cells

BRCA1—a breast and ovarian cancer suppressor gene—promotes genome integrity. To study the functionality of BRCA1 in the heterozygous state, we established a collection of primary human BRCA1+/+ and BRCA1mut/+ mammary epithelial cells and fibroblasts. Here we report that all BRCA1mut/+ cells exhibited multiple normal BRCA1 functions, including the support of homologous recombination- type double-strand break repair (HR-DSBR), checkpoint functions, centrosome number control, spindle pole formation, Slug expression and satellite RNA suppression. In contrast, the same cells were defective in stalled replication fork repair and/or suppression of fork collapse, that is, replication stress. These defects were rescued by reconstituting BRCA1mut/+ cells with wt BRCA1. In addition, we observed ‘conditional’ haploinsufficiency for HR-DSBR in BRCA1mut/+ cells in the face of replication stress. Given the importance of replication stress in epithelial cancer development and of an HR defect in breast cancer pathogenesis, both defects are candidate contributors to tumorigenesis in BRCA1-deficient mammary tissue

X chromosomal abnormalities in basal-like human breast cancer

SummarySporadic basal-like cancers (BLC) are a distinct class of human breast cancers that are phenotypically similar to BRCA1-associated cancers. Like BRCA1-deficient tumors, most BLC lack markers of a normal inactive X chromosome (Xi). Duplication of the active X chromosome and loss of Xi characterized almost half of BLC cases tested. Others contained biparental but nonheterochromatinized X chromosomes or gains of X chromosomal DNA. These abnormalities did not lead to a global increase in X chromosome transcription but were associated with overexpression of a small subset of X chromosomal genes. Other, equally aneuploid, but non-BLC rarely displayed these X chromosome abnormalities. These results suggest that X chromosome abnormalities contribute to the pathogenesis of BLC, both inherited and sporadic