The Identification of CELSR3 and Other Potential Cell Surface Targets in Neuroendocrine Prostate Cancer.

UNLABELLED Although recent efforts have led to the development of highly effective androgen receptor (AR)-directed therapies for the treatment of advanced prostate cancer, a significant subset of patients will progress with resistant disease including AR-negative tumors that display neuroendocrine features [neuroendocrine prostate cancer (NEPC)]. On the basis of RNA sequencing (RNA-seq) data from a clinical cohort of tissue from benign prostate, locally advanced prostate cancer, metastatic castration-resistant prostate cancer and NEPC, we developed a multi-step bioinformatics pipeline to identify NEPC-specific, overexpressed gene transcripts that encode cell surface proteins. This included the identification of known NEPC surface protein CEACAM5 as well as other potentially targetable proteins (e.g., HMMR and CESLR3). We further showed that cadherin EGF LAG seven-pass G-type receptor 3 (CELSR3) knockdown results in reduced NEPC tumor cell proliferation and migration in vitro. We provide in vivo data including laser capture microdissection followed by RNA-seq data supporting a causal role of CELSR3 in the development and/or maintenance of the phenotype associated with NEPC. Finally, we provide initial data that suggests CELSR3 is a target for T-cell redirection therapeutics. Further work is now needed to fully evaluate the utility of targeting CELSR3 with T-cell redirection or other similar therapeutics as a potential new strategy for patients with NEPC. SIGNIFICANCE The development of effective treatment for patients with NEPC remains an unmet clinical need. We have identified specific surface proteins, including CELSR3, that may serve as novel biomarkers or therapeutic targets for NEPC

Contrasting Expression of Canonical Wnt Signaling Reporters TOPGAL, BATGAL and Axin2LacZ during Murine Lung Development and Repair

Canonical Wnt signaling plays multiple roles in lung organogenesis and repair by regulating early progenitor cell fates: investigation has been enhanced by canonical Wnt reporter mice, TOPGAL, BATGAL and Axin2LacZ. Although widely used, it remains unclear whether these reporters convey the same information about canonical Wnt signaling. We therefore compared beta-galactosidase expression patterns in canonical Wnt signaling of these reporter mice in whole embryo versus isolated prenatal lungs. To determine if expression varied further during repair, we analyzed comparative pulmonary expression of beta-galactosidase after naphthalene injury. Our data show important differences between reporter mice. While TOPGAL and BATGAL lines demonstrate Wnt signaling well in early lung epithelium, BATGAL expression is markedly reduced in late embryonic and adult lungs. By contrast, Axin2LacZ expression is sustained in embryonic lung mesenchyme as well as epithelium. Three days into repair after naphthalene, BATGAL expression is induced in bronchial epithelium as well as TOPGAL expression (already strongly expressed without injury). Axin2LacZ expression is increased in bronchial epithelium of injured lungs. Interestingly, both TOPGAL and Axin2LacZ are up regulated in parabronchial smooth muscle cells during repair. Therefore the optimal choice of Wnt reporter line depends on whether up- or down-regulation of canonical Wnt signal reporting in either lung epithelium or mesenchyme is being compared

Epidemiology of nasopharyngeal carriage of respiratory bacterial pathogens in children and adults: cross-sectional surveys in a population with high rates of pneumococcal disease

<p>Abstract</p> <p>Background</p> <p>To determine the prevalence of carriage of respiratory bacterial pathogens, and the risk factors for and serotype distribution of pneumococcal carriage in an Australian Aboriginal population.</p> <p>Methods</p> <p>Surveys of nasopharyngeal carriage of <it>Streptococcus pneumoniae</it>, non-typeable <it>Haemophilus influenzae</it>, and <it>Moraxella catarrhalis </it>were conducted among adults (≥16 years) and children (2 to 15 years) in four rural communities in 2002 and 2004. Infant seven-valent pneumococcal conjugate vaccine (7PCV) with booster 23-valent pneumococcal polysaccharide vaccine was introduced in 2001. Standard microbiological methods were used.</p> <p>Results</p> <p>At the time of the 2002 survey, 94% of eligible children had received catch-up pneumococcal vaccination. 324 adults (538 examinations) and 218 children (350 examinations) were enrolled. Pneumococcal carriage prevalence was 26% (95% CI, 22-30) among adults and 67% (95% CI, 62-72) among children. Carriage of non-typeable <it>H. influenzae </it>among adults and children was 23% (95% CI, 19-27) and 57% (95% CI, 52-63) respectively and for <it>M. catarrhalis</it>, 17% (95% CI, 14-21) and 74% (95% CI, 69-78) respectively. Adult pneumococcal carriage was associated with increasing age (p = 0.0005 test of trend), concurrent carriage of non-typeable <it>H. influenzae </it>(Odds ratio [OR] 6.74; 95% CI, 4.06-11.2) or <it>M. catarrhalis </it>(OR 3.27; 95% CI, 1.97-5.45), male sex (OR 2.21; 95% CI, 1.31-3.73), rhinorrhoea (OR 1.66; 95% CI, 1.05-2.64), and frequent exposure to outside fires (OR 6.89; 95% CI, 1.87-25.4). Among children, pneumococcal carriage was associated with decreasing age (p < 0.0001 test of trend), and carriage of non-typeable <it>H. influenzae </it>(OR 9.34; 95% CI, 4.71-18.5) or <it>M. catarrhalis </it>(OR 2.67; 95% CI, 1.34-5.33). Excluding an outbreak of serotype 1 in children, the percentages of serotypes included in 7, 10, and 13PCV were 23%, 23%, and 29% (adults) and 22%, 24%, and 40% (2-15 years). Dominance of serotype 16F, and persistent 19F and 6B carriage three years after initiation of 7PCV is noteworthy.</p> <p>Conclusions</p> <p>Population-based carriage of <it>S. pneumoniae</it>, non-typeable <it>H. influenzae</it>, and <it>M. catarrhalis </it>was high in this Australian Aboriginal population. Reducing smoke exposure may reduce pneumococcal carriage. The indirect effects of 10 or 13PCV, above those of 7PCV, among adults in this population may be limited.</p

The He-rich core-collapse supernova 2007Y: Observations from X-ray to Radio Wavelengths

A detailed study spanning approximately a year has been conducted on the Type Ib supernova 2007Y. Imaging was obtained from X-ray to radio wavelengths, and a comprehensive set of multi-band (w2m2w1u'g'r'i'UBVYJHKs) light curves and optical spectroscopy is presented. A virtually complete bolometric light curve is derived, from which we infer a (56)Ni-mass of 0.06 M_sun. The early spectrum strongly resembles SN 2005bf and exhibits high-velocity features of CaII and H_alpha; during late epochs the spectrum shows evidence of a ejecta-wind interaction. Nebular emission lines have similar widths and exhibit profiles that indicate a lack of major asymmetry in the ejecta. Late phase spectra are modeled with a non-LTE code, from which we find (56)Ni, O and total-ejecta masses (excluding He) to be 0.06, 0.2 and 0.42 M_sun, respectively, below 4,500 km/s. The (56)Ni mass confirms results obtained from the bolometric light curve. The oxygen abundance suggests the progenitor was most likely a ~3.3 M_sun He core star that evolved from a zero-age-main-sequence mass of 10-13 M_sun. The explosion energy is determined to be ~10^50 erg, and the mass-loss rate of the progenitor is constrained from X-ray and radio observations to be <~10^-6 M_sun/yr. SN 2007Y is among the least energetic normal Type Ib supernovae ever studied.Comment: Corrected error in Tab. 2 & 3. Photometry has not change

Current and Future Patterns of Global Marine Mammal Biodiversity

Quantifying the spatial distribution of taxa is an important prerequisite for the preservation of biodiversity, and can provide a baseline against which to measure the impacts of climate change. Here we analyse patterns of marine mammal species richness based on predictions of global distributional ranges for 115 species, including all extant pinnipeds and cetaceans. We used an environmental suitability model specifically designed to address the paucity of distributional data for many marine mammal species. We generated richness patterns by overlaying predicted distributions for all species; these were then validated against sightings data from dedicated long-term surveys in the Eastern Tropical Pacific, the Northeast Atlantic and the Southern Ocean. Model outputs correlated well with empirically observed patterns of biodiversity in all three survey regions. Marine mammal richness was predicted to be highest in temperate waters of both hemispheres with distinct hotspots around New Zealand, Japan, Baja California, the Galapagos Islands, the Southeast Pacific, and the Southern Ocean. We then applied our model to explore potential changes in biodiversity under future perturbations of environmental conditions. Forward projections of biodiversity using an intermediate Intergovernmental Panel for Climate Change (IPCC) temperature scenario predicted that projected ocean warming and changes in sea ice cover until 2050 may have moderate effects on the spatial patterns of marine mammal richness. Increases in cetacean richness were predicted above 40° latitude in both hemispheres, while decreases in both pinniped and cetacean richness were expected at lower latitudes. Our results show how species distribution models can be applied to explore broad patterns of marine biodiversity worldwide for taxa for which limited distributional data are available

A biogeographical appraisal of the threatened South East Africa Montane Archipelago ecoregion

Recent biological surveys of ancient inselbergs in southern Malawi and northern Mozambique have led to the discovery and description of many species new to science, and overlapping centres of endemism across multiple taxa. Combining these endemic taxa with data on geology and climate, we propose the ‘South East Africa Montane Archipelago’ (SEAMA) as a distinct ecoregion of global biological importance. The ecoregion encompasses 30 granitic inselbergs reaching > 1000 m above sea level, hosting the largest (Mt Mabu) and smallest (Mt Lico) mid-elevation rainforests in southern Africa, as well as biologically unique montane grasslands. Endemic taxa include 127 plants, 45 vertebrates (amphibians, reptiles, birds, mammals) and 45 invertebrate species (butterflies, freshwater crabs), and two endemic genera of plants and reptiles. Existing dated phylogenies of endemic animal lineages suggests this endemism arose from divergence events coinciding with repeated isolation of these mountains from the pan-African forests, together with the mountains’ great age and relative climatic stability. Since 2000, the SEAMA has lost 18% of its primary humid forest cover (up to 43% in some sites)—one of the highest deforestation rates in Africa. Urgently rectifying this situation, while addressing the resource needs of local communities, is a global priority for biodiversity conservation

Priorities for synthesis research in ecology and environmental science

ACKNOWLEDGMENTS We thank the National Science Foundation grant #1940692 for financial support for this workshop, and the National Center for Ecological Analysis and Synthesis (NCEAS) and its staff for logistical support.Peer reviewedPublisher PD

Priorities for synthesis research in ecology and environmental science

ACKNOWLEDGMENTS We thank the National Science Foundation grant #1940692 for financial support for this workshop, and the National Center for Ecological Analysis and Synthesis (NCEAS) and its staff for logistical support.Peer reviewedPublisher PD

Open data from the third observing run of LIGO, Virgo, KAGRA and GEO

The global network of gravitational-wave observatories now includes five detectors, namely LIGO Hanford, LIGO Livingston, Virgo, KAGRA, and GEO 600. These detectors collected data during their third observing run, O3, composed of three phases: O3a starting in April of 2019 and lasting six months, O3b starting in November of 2019 and lasting five months, and O3GK starting in April of 2020 and lasting 2 weeks. In this paper we describe these data and various other science products that can be freely accessed through the Gravitational Wave Open Science Center at https://gwosc.org. The main dataset, consisting of the gravitational-wave strain time series that contains the astrophysical signals, is released together with supporting data useful for their analysis and documentation, tutorials, as well as analysis software packages.Comment: 27 pages, 3 figure