The p14 fusion-associated small transmembrane (FAST) protein effects membrane fusion from a subset of membrane microdomains

The reovirus fusion-associated small transmembrane (FAST) proteins are a unique family of viral membrane fusion proteins. These nonstructural viral proteins induce efficient cell-cell rather than virus-cell membrane fusion. We analyzed the lipid environment in which the reptilian reovirus p14 FAST protein resides to determine the influence of the cell membrane on the fusion activity of the FAST proteins. Topographical mapping of the surface of fusogenic p14-containing liposomes by atomic force microscopy under aqueous conditions revealed that p14 resides almost exclusively in thickened membrane microdomains. In transfected cells, p14 was found in both Lubrol WX-and Triton X-100-resistant membrane complexes. Cholesterol depletion of donor cell membranes led to preferential disruption of p14 association with Lubrol WX (but not Triton X-100)-resistant membranes and decreased cell-cell fusion activity, both of which were reversed upon subsequent cholesterol repletion. Furthermore, co-patching analysis by fluorescence microscopy indicated that p14 did not co-localize with classical lipid-anchored raft markers. These data suggest that the p14 FAST protein associates with heterogeneous membrane microdomains, a distinct subset of which is defined by cholesterol-dependent Lubrol WX resistance and which may be more relevant to the membrane fusion process. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc

A Coordinated X-ray and Optical Campaign of the Nearby Massive Binary δ\delta Orionis Aa: II. X-ray Variability

We present time-resolved and phase-resolved variability studies of an extensive X-ray high-resolution spectral dataset of the $\delta$ Orionis Aa binary system. The four observations, obtained with Chandra ACIS HETGS, have a total exposure time of ~479 ks and provide nearly complete binary phase coverage. Variability of the total X-ray flux in the range 5-25 $\AA$ is confirmed, with maximum amplitude of about +/-15% within a single ~125 ks observation. Periods of 4.76d and 2.04d are found in the total X-ray flux, as well as an apparent overall increase in flux level throughout the 9-day observational campaign. Using 40 ks contiguous spectra derived from the original observations, we investigate variability of emission line parameters and ratios. Several emission lines are shown to be variable, including S XV, Si XIII, and Ne IX. For the first time, variations of the X-ray emission line widths as a function of the binary phase are found in a binary system, with the smallest widths at phase=0.0 when the secondary $\delta$ Orionis Aa2 is at inferior conjunction. Using 3D hydrodynamic modeling of the interacting winds, we relate the emission line width variability to the presence of a wind cavity created by a wind-wind collision, which is effectively void of embedded wind shocks and is carved out of the X-ray-producing primary wind, thus producing phase-locked X-ray variability.Comment: 36 pages, 14 Tables, 19 Figures, accepted by ApJ, one of 4 related papers to be published togethe

Myc dynamically and preferentially relocates to a transcription factory occupied by Igh.

Transcription in mammalian nuclei is highly compartmentalized in RNA polymerase II-enriched nuclear foci known as transcription factories. Genes in cis and trans can share the same factory, suggesting that genes migrate to preassembled transcription sites. We used fluorescent in situ hybridization to investigate the dynamics of gene association with transcription factories during immediate early (IE) gene induction in mouse B lymphocytes. Here, we show that induction involves rapid gene relocation to transcription factories. Importantly, we find that the Myc proto-oncogene on Chromosome 15 is preferentially recruited to the same transcription factory as the highly transcribed Igh gene located on Chromosome 12. Myc and Igh are the most frequent translocation partners in plasmacytoma and Burkitt lymphoma. Our results show that transcriptional activation of IE genes involves rapid relocation to preassembled transcription factories. Furthermore, the data imply a direct link between the nonrandom interchromosomal organization of transcribed genes at transcription factories and the incidence of specific chromosomal translocations

Hate crimes against trans people: assessing emotions, behaviors and attitudes towards criminal justice agencies

Based on a survey of 593 lesbian, gay, bisexual, and transgender (LGBT) people in the United Kingdom, this study shows that direct anti-LGBT hate crimes (measured by direct experiences of victimization) and indirect anti-LGBT hate crimes (measured by personally knowing other victims of hate crime) are highly prolific and frequent experiences for LGBT people. Our findings show that trans people are particularly susceptible to hate crimes, both in terms of prevalence and frequency. This article additionally highlights the negative emotional and (intended) behavioral reactions that were correlated with an imagined hate crime scenario, showing that trans people are more likely to experience heightened levels of threat, vulnerability, and anxiety compared with non-trans LGB people. The study found that trans people are also more likely to feel unsupported by family, friends, and society for being LGBT, which was correlated with the frequency of direct (verbal) abuse they had previously endured. The final part of this study explores trans people’s confidence levels in the Government, the police, and the Crown Prosecution Service (CPS) in relation to addressing hate crime. In general, trans people felt that the police are not effective at policing anti-LGBT hate crime, and they are not respectful toward them as victims; this was especially true where individuals had previous contact with the police. Respondents were also less confident in the CPS to prosecute anti-LGBT hate crimes, though the level of confidence was slightly higher when respondents had direct experience with the CPS. The empirical evidence presented here supports the assertion that all LGBT people, but particularly trans individuals, continue to be denied equal participation in society due to individual, social, and structural experiences of prejudice. The article concludes by arguing for a renewed policy focus that must address this issue as a public health problem

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment