Sigma1 Targeting to Suppress Aberrant Androgen Receptor Signaling in Prostate Cancer.

Suppression of androgen receptor (AR) activity in prostate cancer by androgen depletion or direct AR antagonist treatment, although initially effective, leads to incurable castration-resistant prostate cancer (CRPC) via compensatory mechanisms including resurgence of AR and AR splice variant (ARV) signaling. Emerging evidence suggests that Sigma1 (also known as sigma-1 receptor) is a unique chaperone or scaffolding protein that contributes to cellular protein homeostasis. We reported previously that some Sigma1-selective small molecules can be used to pharmacologically modulate protein homeostasis pathways. We hypothesized that these Sigma1-mediated responses could be exploited to suppress AR protein levels and activity. Here we demonstrate that treatment with a small-molecule Sigma1 inhibitor prevented 5α- dihydrotestosterone-mediated nuclear translocation of AR and induced proteasomal degradation of AR and ARV, suppressing the transcriptional activity and protein levels of both full-length and splice-variant AR. Consistent with these data, RNAi knockdown of Sigma1 resulted in decreased AR levels and transcriptional activity. Furthermore, Sigma1 physically associated with ARV7 and A

The role of sand lances (Ammodytes sp.) in the Northwest Atlantic ecosystem: a synthesis of current knowledge with implications for conservation and management

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Staudinger, M. D., Goyert, H., Suca, J. J., Coleman, K., Welch, L., Llopiz, J. K., Wiley, D., Altman, I., Applegate, A., Auster, P., Baumann, H., Beaty, J., Boelke, D., Kaufman, L., Loring, P., Moxley, J., Paton, S., Powers, K., Richardson, D., Robbins, J., Runge, J., Smith, B., Spiegel, C., & Steinmetz, H. The role of sand lances (Ammodytes sp.) in the Northwest Atlantic ecosystem: a synthesis of current knowledge with implications for conservation and management. Fish and Fisheries, 00, (2020): 1-34, doi:10.1111/faf.12445.The American sand lance (Ammodytes americanus, Ammodytidae) and the Northern sand lance (A. dubius, Ammodytidae) are small forage fishes that play an important functional role in the Northwest Atlantic Ocean (NWA). The NWA is a highly dynamic ecosystem currently facing increased risks from climate change, fishing and energy development. We need a better understanding of the biology, population dynamics and ecosystem role of Ammodytes to inform relevant management, climate adaptation and conservation efforts. To meet this need, we synthesized available data on the (a) life history, behaviour and distribution; (b) trophic ecology; (c) threats and vulnerabilities; and (d) ecosystem services role of Ammodytes in the NWA. Overall, 72 regional predators including 45 species of fishes, two squids, 16 seabirds and nine marine mammals were found to consume Ammodytes. Priority research needs identified during this effort include basic information on the patterns and drivers in abundance and distribution of Ammodytes, improved assessments of reproductive biology schedules and investigations of regional sensitivity and resilience to climate change, fishing and habitat disturbance. Food web studies are also needed to evaluate trophic linkages and to assess the consequences of inconsistent zooplankton prey and predator fields on energy flow within the NWA ecosystem. Synthesis results represent the first comprehensive assessment of Ammodytes in the NWA and are intended to inform new research and support regional ecosystem‐based management approaches.This manuscript is the result of follow‐up work stemming from a working group formed at a two‐day multidisciplinary and international workshop held at the Parker River National Wildlife Refuge, Massachusetts in May 2017, which convened 55 experts scientists, natural resource managers and conservation practitioners from 15 state, federal, academic and non‐governmental organizations with interest and expertise in Ammodytes ecology. Support for this effort was provided by USFWS, NOAA Stellwagen Bank National Marine Sanctuary, U.S. Department of the Interior, U.S. Geological Survey, Northeast Climate Adaptation Science Center (Award # G16AC00237), an NSF Graduate Research Fellowship to J.J.S., a CINAR Fellow Award to J.K.L. under Cooperative Agreement NA14OAR4320158, NSF award OCE‐1325451 to J.K.L., NSF award OCE‐1459087 to J.A.R, a Regional Sea Grant award to H.B. (RNE16‐CTHCE‐l), a National Marine Sanctuary Foundation award to P.J.A. (18‐08‐B‐196) and grants from the Mudge Foundation. The contents of this paper are the responsibility of the authors and do not necessarily represent the views of the National Oceanographic and Atmospheric Administration, U.S. Fish and Wildlife Service, New England Fishery Management Council and Mid‐Atlantic Fishery Management Council. This manuscript is submitted for publication with the understanding that the United States Government is authorized to reproduce and distribute reprints for Governmental purposes. Any use of trade, firm or product names is for descriptive purposes only and does not imply endorsement by the U.S. Government

An ecological approach to anomaly detection: the EIA Model.

The presented work proposes a new approach for anomaly detection. This approach is based on changes in a population of evolving agents under stress. If conditions are appropriate, changes in the population (modeled by the bioindicators) are representative of the alterations to the environment. This approach, based on an ecological view, improves functionally traditional approaches to the detection of anomalies. To verify this assertion, experiments based on Network Intrussion Detection Systems are presented. The results are compared with the behaviour of other bioinspired approaches and machine learning techniques

Roles for H2A.Z and Its Acetylation in GAL1 Transcription and Gene Induction, but Not GAL1-Transcriptional Memory

H2A.Z does not appear to have a role in GAL1 transcriptional memory, but it does have both acetylation-dependent and acetylation-independent roles in GAL1 induction and expression

The LHS 1678 system : two earth-sized transiting planets and an astrometric companion orbiting an M dwarf near the convective boundary at 20 pc

Funding: The MEarth Team gratefully acknowledges funding from the David and Lucile Packard Fellowship for Science and Engineering (awarded to D.C.). This material is based upon work supported by the National Science Foundation under grants AST-0807690, AST-1109468, AST-1004488 (Alan T. Waterman Award), and AST-1616624, and upon work supported by the National Aeronautics and Space Administration under Grant No. 80NSSC18K0476 issued through the XRP Program. This work is made possible by a grant from the John Templeton Foundation. N. A.-D. acknowledges the support of FONDECYT project 3180063. TD acknowledges support from MIT’s Kavli Institute as a Kavli postdoctoral fellow. KH acknowledges support from STFC grant ST/R000824/1. E.A.G. thanks the LSSTC Data Science Fellowship Program, which is funded by LSSTC, NSF Cybertraining Grant #1829740, the Brinson Foundation, and the Moore Foundation; The material is based upon work supported by NASA under award number 80GSFC21M0002. This work was supported by the lead author’s appointment to the NASA Postdoctoral Program at the Goddard Space Flight Center, administered by Universities Space Research Association under contract with NASAWe present the Transiting Exoplanet Survey Satellite (TESS) discovery of the LHS 1678 (TOI-696) exoplanet system, comprised of two approximately Earth-sized transiting planets and a likely astrometric brown dwarf orbiting a bright (VJ = 12.5, Ks = 8.3) M2 dwarf at 19.9 pc. The two TESS-detected planets are of radius 0.70 ± 0.04 R⊕ and 0.98 ± 0.06 R⊕ in 0.86 day and 3.69 day orbits, respectively. Both planets are validated and characterized via ground-based follow-up observations. High Accuracy Radial Velocity Planet Searcher RV monitoring yields 97.7 percentile mass upper limits of 0.35 M⊕ and 1.4 M⊕ for planets b and c, respectively. The astrometric companion detected by the Cerro Tololo Inter-American Observatory/Small and Moderate Aperture Telescope System 0.9 m has an orbital period on the order of decades and is undetected by other means. Additional ground-based observations constrain the companion to being a high-mass brown dwarf or smaller. Each planet is of unique interest; the inner planet has an ultra-short period, and the outer planet is in the Venus zone. Both are promising targets for atmospheric characterization with the James Webb Space Telescope and mass measurements via extreme-precision radial velocity. A third planet candidate of radius 0.9 ± 0.1 R⊕ in a 4.97 day orbit is also identified in multicycle TESS data for validation in future work. The host star is associated with an observed gap in the lower main sequence of the Hertzsprung–Russell diagram. This gap is tied to the transition from partially to fully convective interiors in M dwarfs, and the effect of the associated stellar astrophysics on exoplanet evolution is currently unknown. The culmination of these system properties makes LHS 1678 a unique, compelling playground for comparative exoplanet science and understanding the formation and evolution of small, short-period exoplanets orbiting low-mass stars.Publisher PDFPeer reviewe

The LHS 1678 System: Two Earth-sized Transiting Planets and an Astrometric Companion Orbiting an M Dwarf Near the Convective Boundary at 20 pc

We present the Transiting Exoplanet Survey Satellite (TESS) discovery of the LHS 1678 (TOI-696) exoplanet system, comprised of two approximately Earth-sized transiting planets and a likely astrometric brown dwarf orbiting a bright (V J = 12.5, K s = 8.3) M2 dwarf at 19.9 pc. The two TESS-detected planets are of radius 0.70 ± 0.04 R ⊕ and 0.98 ± 0.06 R ⊕ in 0.86 day and 3.69 day orbits, respectively. Both planets are validated and characterized via ground-based follow-up observations. High Accuracy Radial Velocity Planet Searcher RV monitoring yields 97.7 percentile mass upper limits of 0.35 M ⊕ and 1.4 M ⊕ for planets b and c, respectively. The astrometric companion detected by the Cerro Tololo Inter-American Observatory/Small and Moderate Aperture Telescope System 0.9 m has an orbital period on the order of decades and is undetected by other means. Additional ground-based observations constrain the companion to being a high-mass brown dwarf or smaller. Each planet is of unique interest; the inner planet has an ultra-short period, and the outer planet is in the Venus zone. Both are promising targets for atmospheric characterization with the James Webb Space Telescope and mass measurements via extreme-precision radial velocity. A third planet candidate of radius 0.9 ± 0.1 R ⊕ in a 4.97 day orbit is also identified in multicycle TESS data for validation in future work. The host star is associated with an observed gap in the lower main sequence of the Hertzsprung-Russell diagram. This gap is tied to the transition from partially to fully convective interiors in M dwarfs, and the effect of the associated stellar astrophysics on exoplanet evolution is currently unknown. The culmination of these system properties makes LHS 1678 a unique, compelling playground for comparative exoplanet science and understanding the formation and evolution of small, short-period exoplanets orbiting low-mass stars

Telomeric heterochromatin boundaries require NuA4-dependent acetylation of histone variant H2A.Z in Saccharomycescerevisiae

SWR1-Com, which is responsible for depositing H2A.Z into chromatin, shares four subunits with the NuA4 histone acetyltransferase complex. This overlap in composition led us to test whether H2A.Z was a substrate of NuA4 in vitro and in vivo. The N-terminal tail of H2A.Z was acetylated in vivo at multiple sites by a combination of NuA4 and SAGA. H2A.Z acetylation was also dependent on SWR1-Com, causing H2A.Z to be efficiently acetylated only when incorporated in chromatin. Unacetylatable H2A.Z mutants were, like wild-type H2A.Z, enriched at heterochromatin boundaries, but were unable to block spreading of heterochromatin. A mutant version of H2A.Z that could not be acetylated, in combination with a mutation in a nonessential gene in the NuA4 complex, caused a pronounced decrease in growth rate. This H2A.Z mutation was lethal in combination with a mutant version of histone H4 that could not be acetylated by NuA4. Taken together, these results show a role for H2A.Z acetylation in restricting silent chromatin, and reveal that acetylation of H2A.Z and H4 can contribute to a common function essential to life

Roles for H2A.Z and its acetylation in GAL1 transcription and gene induction, but not GAL1-transcriptional memory.

H2A.Z is a histone H2A variant conserved from yeast to humans, and is found at 63% of promoters in Saccharomyces cerevisiae. This pattern of localization suggests that H2A.Z is somehow important for gene expression or regulation. H2A.Z can be acetylated at up to four lysine residues on its amino-terminal tail, and acetylated-H2A.Z is enriched in chromatin containing promoters of active genes. We investigated whether H2A.Z's role in GAL1 gene regulation and gene expression depends on H2A.Z acetylation. Our findings suggested that H2A.Z functioned both in gene regulation and in gene expression and that only its role in gene regulation depended upon its acetylation. Our findings provided an alternate explanation for results that were previously interpreted as evidence that H2A.Z plays a role in GAL1 transcriptional memory. Additionally, our findings provided new insights into the phenotypes of htz1Delta mutants: in the absence of H2A.Z, the SWR1 complex, which deposits H2A.Z into chromatin, was deleterious to the cell, and many of the phenotypes of cells lacking H2A.Z were due to the SWR1 complex's activity rather than to the absence of H2A.Z per se. These results highlight the need to reevaluate all studies on the phenotypes of cells lacking H2A.Z

Identification of an endo-β-1,4-d-Xylanase from Magnaporthe grisea by Gene Knockout Analysis, Purification, and Heterologous Expression

Magnaporthe grisea, a destructive ascomycetous pathogen of rice, secretes cell wall-degrading enzymes into a culture medium containing purified rice cell walls as the sole carbon source. From M. grisea grown under the culture conditions described here, we have identified an expressed sequenced tag, XYL-6, a gene that is also expressed in M. grisea-infected rice leaves 24 h postinoculation with conidia. This gene encodes a protein about 65% similar to endo-β-1,4-d-glycanases within glycoside hydrolase family GH10. A M. grisea knockout mutant for XYL-6 was created, and it was shown to be as virulent as the parent strain in infecting the rice host. The proteins secreted by the parent strain and by the xyl-6Δ mutant were each fractionated by liquid chromatography, and the collected fractions were assayed for endo-β-1,4-d-glucanase or endo-β-1,4-d-xylanase activities. Two protein-containing peaks with endo-β-1,4-d-xylanase activity secreted by the parent strain are not detectable in the column eluant of the proteins secreted by the mutant. The two endoxylanases (XYL-6α and XYL-6β) from the parent were each purified to homogeneity. N-terminal amino acid sequencing indicated that XYL-6α is a fragment of XYL-6β and that XYL-6β is identical to the deduced protein sequence encoded by the XYL-6 gene. Finally, XYL-6 was introduced into Pichia pastoris for heterologous expression, which resulted in the purification of a fusion protein, XYL-6H, from the Pichia pastoris culture filtrate. XYL-6H is active in cleaving arabinoxylan. These experiments unequivocally established that the XYL-6 gene encodes a secreted endo-β-1,4-d-xylanase