Barriers to and Facilitators of Help-Seeking Behavior Among Men Who Experience Sexual Violence

Research on sexual violence and related support services access has mainly focused on female victims; there is still a remarkable lack of research on men who experience sexual violence. Research demonstrates that people who both self-identify as men and are members of sexual-orientation minority populations are at higher risk of sexual violence. They are also less likely to either report or seek support services related to such experiences. The present study is an exploratory one aimed at filling the gap in the literature and better understanding how men, both straight and gay as well as cisgender and transgender, conceptualize, understand, and seek help related to sexual violence. A sample of 32 men was recruited on-line and participated in either a one-on-one in-depth interview (N = 19) or one of two focus group discussions (N = 13). All interviews and groups were audiotaped, professionally transcribed and coded using NVivo 9 qualitative software. The present analysis focused on barriers to and facilitators of support service access. Emergent and cross-cutting themes were identified and presented, with an emphasis on understanding what factors may prevent disclosure of a sexual violence experience and facilitate seeking support services and/or professional help. Through this analysis, the research team aims to add knowledge to inform the development of tools to increase service access and receipt, for use by both researchers and service professionals. Although this study contributes to the understanding of the issue of men’s experiences of sexual violence, more research with diverse populations is needed

UNC2025 , a Potent and Orally Bioavailable MER/FLT3 Dual Inhibitor

We previously reported a potent small molecule Mer tyrosine kinase inhibitor UNC1062. However, its poor PK properties prevented further assessment in vivo. We report here the sequential modification of UNC1062 to address DMPK properties and yield a new potent and highly orally bioavailable Mer inhibitor, 11, capable of inhibiting Mer phosphorylation in vivo, following oral dosing as demonstrated by pharmaco-dynamic (PD) studies examining phospho-Mer in leukemic blasts from mouse bone marrow. Kinome profiling versus more than 300 kinases in vitro and cellular selectivity assessments demonstrate that 11 has similar subnanomolar activity against Flt3, an additional important target in acute myelogenous leukemia (AML), with pharmacologically useful selectivity versus other kinases examined

JWST's PEARLS: dust attenuation and gravitational lensing in the backlit-galaxy system VV 191

We derive the spatial and wavelength behavior of dust attenuation in the multiple-armed spiral galaxy VV191b using backlighting by the superimposed elliptical system VV191a in a pair with an exceptionally favorable geometry for this measurement. Imaging using JWST and HST spans the wavelength range 0.3-4.5 microns with high angular resolution, tracing the dust in detail from 0.6 to 1.5 microns. Distinct dust lanes continue well beyond the bright spiral arms, and trace a complex web, with a very sharp radial cutoff near 1.7 Petrosian radii. We present attenuation profiles and coverage statistics in each band at radii 14-21 kpc. We derive the attenuation law with wavelength; the data both within and between the dust lanes clearly favor a stronger reddening behavior (R ~ 2.0 between 0.6 and 0.9 microns, approaching unity by 1.5 microns) than found for starbursts and star-forming regions of galaxies. Power-law extinction behavior lambda^(-beta) gives beta=2.1 from 0.6-0.9 microns. R decreases at increasing wavelengths (R~1.1 between 0.9 and 1.5 microns), while beta steepens to 2.5. Mixing regions of different column density flattens the wavelength behavior, so these results suggest a different grain population than in our vicinity. The NIRCam images reveal a lens arc and counterimage from a background galaxy at z~1, spanning 90 degrees azimuthally at 2.8" from the foreground elliptical galaxy nucleus, and an additional weakly-lensed galaxy. The lens model and imaging data give a mass/light ratio 7.6 in solar units within the Einstein radius 2.0 kpc.Comment: Accepted by Astron. J. Analysis redone since submission, using updated JWST calibrations. Dust reddening behavior is steeper with wavelength and lensed galaxy redshift lower than we first derive

UNC1062, a new and potent Mer inhibitor

Abnormal activation of Mer kinase has been implicated in the oncogenesis of many human cancers including acute lymphoblastic and myeloid leukemia, non-small cell lung cancer, and glioblastoma. We have discovered a new family of small molecule Mer inhibitors, pyrazolopyrimidine sulfonamides, that potently inhibit the kinase activity of Mer. Importantly, these compounds do not demonstrate significant hERG activity in the PatchXpress assay. Through structure-activity relationship studies, 35 (UNC1062) was identified as a potent (IC50 = 1.1 nM) and selective Mer inhibitor. When applied to live tumor cells, UNC1062 inhibited Mer phosphorylation and colony formation in soft agar. Given the potential of Mer as a therapeutic target, UNC1062 is a promising candidate for further drug development

TREASUREHUNT: Transients and Variability Discovered with HST in the JWST North Ecliptic Pole Time-domain Field

The James Webb Space Telescope (JWST) North Ecliptic Pole (NEP) Time-domain Field (TDF) is a >14′ diameter field optimized for multiwavelength time-domain science with JWST. It has been observed across the electromagnetic spectrum both from the ground and from space, including with the Hubble Space Telescope (HST). As part of HST observations over three cycles (the “TREASUREHUNT” program), deep images were obtained with the Wide Field Camera on the Advanced Camera for Surveys in F435W and F606W that cover almost the entire JWST NEP TDF. Many of the individual pointings of these programs partially overlap, allowing an initial assessment of the potential of this field for time-domain science with HST and JWST. The cumulative area of overlapping pointings is ∼88 arcmin2, with time intervals between individual epochs that range between 1 day and 4+ yr. To a depth of m AB ≃ 29.5 mag (F606W), we present the discovery of 12 transients and 190 variable candidates. For the variable candidates, we demonstrate that Gaussian statistics are applicable and estimate that ∼80 are false positives. The majority of the transients will be supernovae, although at least two are likely quasars. Most variable candidates are active galactic nuclei (AGNs), where we find 0.42% of the general z ≲ 6 field galaxy population to vary at the ∼3σ level. Based on a 5 yr time frame, this translates into a random supernova areal density of up to ∼0.07 transients arcmin−2 (∼245 deg−2) per epoch and a variable AGN areal density of ∼1.25 variables arcmin−2 (∼4500 deg−2) to these depths

UNC569, a Novel Small-Molecule Mer Inhibitor with Efficacy against Acute Lymphoblastic Leukemia In Vitro and In Vivo

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Although survival rates have improved, patients with certain biological subtypes still have suboptimal outcomes. Current chemotherapeutic regimens are associated with short- and long-term toxicities and novel, less toxic therapeutic strategies are needed. Mer receptor tyrosine kinase is ectopically expressed in ALL patient samples and cell lines. Inhibition of Mer expression reduces pro-survival signaling, increases chemosensitivity, and delays development of leukaemia in vivo suggesting that Mer tyrosine kinase inhibitors are excellent candidates for targeted therapies. Brain and spinal tumors are the second most common malignancies in childhood. Multiple chemotherapy approaches and radiation have been attempted, yet overall survival remains dismal. Mer is also abnormally expressed in atypical teratoid/rhabdoid tumors (ATRT), providing a rationale for targeting Mer as a therapeutic strategy. We have previously described UNC569, the first small molecule Mer inhibitor. This manuscript describes the biochemical and biological effects of UNC569 in ALL and ATRT. UNC569 inhibited Mer activation and downstream signaling through ERK1/2 and AKT, determined by western blot analysis. Treatment with UNC569 reduced proliferation/survival in liquid culture, decreased colony formation in methylcellulose/soft agar, and increased sensitivity to cytotoxic chemotherapies. MYC transgenic zebrafish with T-ALL were treated with UNC569 (4 µM for 2 weeks). Fluorescence was quantified as indicator of the distribution of lymphoblasts, which express Mer and enhanced green fluorescent protein. UNC569 induced >50% reduction in tumor burden compared to vehicle- and mock-treated fish. These data support further development of Mer inhibitors as effective therapies in ALL and ATRT

Discovery of a chemical probe for the L3MBTL3 methyllysine reader domain

We describe the discovery of UNC1215, a potent and selective chemical probe for the methyl-lysine (Kme) reading function of L3MBTL3, a member of the malignant brain tumor (MBT) family of chromatin interacting transcriptional repressors. UNC1215 binds L3MBTL3 with a Kd of 120 nM, competitively displacing mono- or dimethyl-lysine containing peptides, and is greater than 50-fold selective versus other members of the MBT family while also demonstrating selectivity against more than 200 other reader domains examined. X-ray crystallography identified a novel 2:2 polyvalent mode of interaction. In cells, UNC1215 is non-toxic and binds directly to L3MBTL3 via the Kme-binding pocket of the MBT domains. UNC1215 increases the cellular mobility of GFP-L3MBTL3 fusion proteins and point mutants that disrupt the Kme binding function of GFP-L3MBTL3 phenocopy the effects of UNC1215. Finally, UNC1215 demonstrates a novel Kme-dependent interaction of L3MBTL3 with BCLAF1, a protein implicated in DNA damage repair and apoptosis

Association between solar insolation and a history of suicide attempts in bipolar I disorder

In many international studies, rates of completed suicide and suicide attempts have a seasonal pattern that peaks in spring or summer. This exploratory study investigated the association between solar insolation and a history of suicide attempt in patients with bipolar I disorder. Solar insolation is the amount of electromagnetic energy from the Sun striking a surface area on Earth. Data were collected previously from 5536 patients with bipolar I disorder at 50 collection sites in 32 countries at a wide range of latitudes in both hemispheres. Suicide related data were available for 3365 patients from 310 onset locations in 51 countries. 1047 (31.1%) had a history of suicide attempt. There was a significant inverse association between a history of suicide attempt and the ratio of mean winter solar insolation/mean summer solar insolation. This ratio is smallest near the poles where the winter insolation is very small compared to the summer insolation. This ratio is largest near the equator where there is relatively little variation in the insolation over the year. Other variables in the model that were positively associated with suicide attempt were being female, a history of alcohol or substance abuse, and being in a younger birth cohort. Living in a country with a state-sponsored religion decreased the association. (All estimated coefficients p <0.01). In summary, living in locations with large changes in solar insolation between winter and summer may be associated with increased suicide attempts in patients with bipolar disorder. Further investigation of the impacts of solar insolation on the course of bipolar disorder is needed.Peer reviewe

JWST’s PEARLS: A new lens model for ACT-CL J0102−4915, “El Gordo,” and the first red supergiant star at cosmological distances discovered by JWST

The first James Webb Space Telescope (JWST) data on the massive colliding cluster El Gordo allow for 23 known families of multiply lensed images to be confirmed and for eight new members of these families to be identified. Based on these families, which have been confirmed spectroscopically by MUSE, we derived an initial lens model. This model guided the identification of 37 additional families of multiply lensed galaxies, among which 28 are entirely new systems, and nine were previously known. The initial lens model determined geometric redshifts for the 37 new systems. The geometric redshifts agree reasonably well with spectroscopic or photometric redshifts when those are available. The geometric redshifts enable two additional models that include all 60 families of multiply lensed galaxies spanning a redshift range 2  0.8 and has an estimated virial mass close the maximum mass allowed by standard cosmological models. The JWST images also reveal the presence of small-mass perturbers that produce small lensing distortions. The smallest of these is consistent with being a dwarf galaxy at z = 0.87 and has an estimated mass of 3.8 × 109 M⊙, making it the smallest substructure found at z > 0.5. The JWST images also show several candidate caustic-crossing events. One of them is detected at high significance at the expected position of the critical curve and is likely a red supergiant star at z = 2.1878. This would be the first red supergiant found at cosmological distances. The cluster lensing should magnify background objects at z > 6, making more of them visible than in blank fields of a similar size, but there appears to be a deficiency of such objects.J.M.D. acknowledges the support of project PGC2018-101814-B-100 (MCIU/AEI/MINECO/FEDER, UE) Ministerio de Ciencia, Investigación y Universidades. This project was funded by the Agencia Estatal de Investigación, Unidad de Excelencia María de Maeztu, ref. MDM-2017-0765. AZ and AKM acknowledge support by Grant No. 2020750 from the United States-Israel Binational Science Foundation (BSF) and Grant No. 2109066 from the United States National Science Foundation (NSF), and by the Ministry of Science & Technology, Israel. RAW, SHC, and RAJ acknowledge support from NASA JWST Interdisciplinary Scientist grants NAG5-12460, NNX14AN10G and 80NSSC18K0200 from GSFC. EZ acknowledges funding from the Swedish National Space Agency. Work by CJC acknowledges support from the European Research Council (ERC) Advanced Investigator Grant EPOCHS (788113). LD acknowledges the research grant support from the Alfred P. Sloan Foundation (Award Number FG-2021-16495). BLF thanks the Berkeley Center for Theoretical Physics for their hospitality during the writing of this paper. MAM acknowledges the support of a National Research Council of Canada Plaskett Fellowship, and the Australian Research Council Centre of Excellence for All Sky Astrophysics in 3 Dimensions (ASTRO 3D), through project number CE17010001. CNAW acknowledges funding from the JWST/NIRCam contract NASS-0215 to the University of Arizona. GBC acknowledges the Max Planck Society for financial support through the Max Planck Research Group for S. H. Suyu and the academic support from the German Centre for Cosmological Lensing.Peer reviewe