Crystal structures of PI3K-C2α PX domain indicate conformational change associated with ligand binding

<p>Abstract</p> <p>Background</p> <p>PX domains have specialized protein structures involved in binding of phosphoinositides (PIs). Through binding to the various PIs PX domains provide site-specific membrane signals to modulate the intracellular localisation and biological activity of effector proteins. Several crystal structures of these domains are now available from a variety of proteins. All PX domains contain a canonical core structure with main differences exhibited within the loop regions forming the phosphoinositide binding pockets. It is within these areas that the molecular basis for ligand specificity originates.</p> <p>Results</p> <p>We now report two new structures of PI3K-C2α PX domain that crystallised in a P3₁21 space group. The two structures, refined to 2.1 Å and 2.5 Å, exhibit significantly different conformations of the phosphoinositide-binding loops. Unexpectedly, in one of the structures, we have detected a putative-ligand trapped in the binding site during the process of protein purification and crystallisation.</p> <p>Conclusion</p> <p>The two structures reported here provide a more complete description of the phosphoinositide binding region compared to the previously reported 2.6 Å crystal structure of human PI3K-C2α PX where this region was highly disordered. The structures enabled us to further analyse PI specificity and to postulate that the observed conformational change could be related to ligand-binding.</p

Prostate Cancer Ambassadors

Prostate cancer is a sizeable threat to the health and well-being of men living in the United States, and African American men suffer at a disproportionately higher rate compared with their Caucasian counterparts (American Cancer Society, 2014). Prostate cancer occurs most frequently in older men, but it occurs at an earlier age in African Americans; the differences in tumor type and disease aggressiveness or progression between Caucasian and African American men may drive the disparity (Powell, Bock, Ruterbusch, & Sakr, 2010; Roberts, 2014). Education is important in bringing people into the cancer care continuum, which begins with prevention and screening. Participatory approaches to educating individuals and communities about prostate cancer and informed decision making (IDM) about screening may be an important step in addressing cancer disparities

Redistribution of Transcription Factor AP-2α in Differentiating Cultured Human Epidermal Cells

Expression of the transcription factor AP-2α was examined in cultured human epidermal cells. Levels of AP-2α mRNA increased substantially after the cultures reached confluence, similar to the expression pattern of the differentiation markers involucrin and keratinocyte transglutaminase. The level of AP-2α protein in nuclear extracts declined markedly after confluence, however, along with its ability to form complexes with oligonucleotides containing the AP-2 response element. In contrast, the levels of AP-2α protein in cytoplasmic extracts increased dramatically after confluence, but these extracts had low DNA binding activity. Supershift experiments with specific antisera detected only AP-2α and not the β or γ isoforms. Examination of its localization by confocal microscopy revealed that AP-2α was primarily in the nucleus of basal cells and largely cytoplasmic in the most superficial cells. Localization was a dynamic phenomenon in that changing the medium resulted in accumulation of this transcription factor in the nucleus after several hours. Overall, the data indicate that AP-2α transcriptional activity is regulated in a differentiation-dependent manner in cultured keratinocytes and that this occurs by relocalization of the protein. Nuclear localization of the AP-2α protein in basal cells permits its accessibility to response elements in gene promoters, whereas sequestration in the cytoplasm as the differentiation program progresses curtails its transcriptional activity. This regulatory scheme may provide keratinocytes with the ability to restore AP-2 transcriptional activity rapidly by redistribution to the nucleus after receiving an appropriate growth signal, such as a medium change

Redistribution of Transcription Factor AP-2α in Differentiating Cultured Human Epidermal Cells

Expression of the transcription factor AP-2α was examined in cultured human epidermal cells. Levels of AP-2α mRNA increased substantially after the cultures reached confluence, similar to the expression pattern of the differentiation markers involucrin and keratinocyte transglutaminase. The level of AP-2α protein in nuclear extracts declined markedly after confluence, however, along with its ability to form complexes with oligonucleotides containing the AP-2 response element. In contrast, the levels of AP-2α protein in cytoplasmic extracts increased dramatically after confluence, but these extracts had low DNA binding activity. Supershift experiments with specific antisera detected only AP-2α and not the β or γ isoforms. Examination of its localization by confocal microscopy revealed that AP-2α was primarily in the nucleus of basal cells and largely cytoplasmic in the most superficial cells. Localization was a dynamic phenomenon in that changing the medium resulted in accumulation of this transcription factor in the nucleus after several hours. Overall, the data indicate that AP-2α transcriptional activity is regulated in a differentiation-dependent manner in cultured keratinocytes and that this occurs by relocalization of the protein. Nuclear localization of the AP-2α protein in basal cells permits its accessibility to response elements in gene promoters, whereas sequestration in the cytoplasm as the differentiation program progresses curtails its transcriptional activity. This regulatory scheme may provide keratinocytes with the ability to restore AP-2 transcriptional activity rapidly by redistribution to the nucleus after receiving an appropriate growth signal, such as a medium change

Dawn‐Dusk Asymmetry in Energetic (>20 keV) Particles Adjacent to Saturn's Magnetopause

Energetic particles (>∼25 keV) have been observed routinely in the terrestrial magnetosheath, but have not been well studied at the magnetosheaths of the outer planets. Here we analyze energetic electrons and ions (mostly protons) in the vicinity (±1 RS) of Saturn's magnetopause, using particle data acquired with the low‐energy magnetosphere measurements system, one of the three sensors of the magnetosphere imaging instrument on board the Cassini spacecraft, during a period of ∼14 years (2004–2017). It is found that energetic particles, especially ions, are also common in Saturn's magnetosheath. A clear inward (toward Saturn) gradient in the electron differential flux is identified, suggestive of magnetospheric sources. Such an inward gradient does not appear in some of the ion channels. We conclude that Saturn's magnetopause acts as a porous barrier for energetic electrons and, to a lesser extent, for energetic ions. A dawn‐dusk asymmetry in the gradient of particle flux across the magnetopause is also identified, with a gradual decrease at the dawn and a sharp decrease at the dusk magnetopause. It is also found that magnetic reconnection enhanced flux levels just outside of the magnetopause, with evidence suggesting that these particles are from magnetospheric sources. These findings strongly suggest that Saturn's magnetosphere is most likely the main source of energetic particles in Saturn's magnetosheath and magnetosphere leakage is an important process responsible for the presence of the energetic particles in Saturn's magnetosheath

Understanding Autistic Adults' Use of Social Media

Autism is a developmental condition that impacts 1 in 100 people \citeNationalAutisticSociety2021. It affects autistic people's interactional and sensory preferences and behaviours. Autistic people can find interactions difficult in part due to sensory overwhelm. Interacting online can provide a positive alternative that allows for interactions on their own terms. However, most social media platforms are designed by neurotypical standards and can therefore inhibit full participation by autistic users. We demonstrate through the analysis of 34 semi-structured interviews with autistic adults that current social media design is not sufficient for creating an inclusive environment and enabling participation from autistic adults. We identified six themes across the interviews: (1) 'Social Media compared to In-Person Interactions', (2) 'Social Media as Enabling/Overwhelming', (3) 'Perceived Social Norms', (4) 'Keeping Connected and Finding New Communities', (5) 'Keeping Control through Systematic Practices', and (6) 'Being Authentic'. The themes demonstrate the attention that autistic adults give to online interaction, suggesting that online interactions may be just as fraught as in-person interactions have been shown to be. In order to become more inclusive of autistic adults, we recommend that social media platforms expand low-effort participation features, provide increased control over algorithmic content, support expression of intent and tone, aid discovery of interactional norms, and reinforce interest-based sociality

Patient perspectives on molecular tumor profiling: "why wouldn't you?"

© 2019 The Author(s). Aim: This study explored the attitudes of patients with advanced cancer towards MTP and return of results, prior to undergoing genomic testing within a research program. Methods: Participants were recruited as part of the longitudinal PiGeOn (Psychosocial Issues in Genomics in Oncology) study involving patients with advanced/metastatic solid cancer who had exhausted therapeutic options and who were offered MTP in order to identify cognate therapies. Twenty patients, selected by purposive sampling, were interviewed around the time they gave consent to MTP. Interviews were audio recorded, transcribed and analysed using thematic analysis. Themes identified in the transcripts were cross-validated via qualitative responses to the PiGeOn study survey (n = 569; 63%). Results: All interviewed participants gave consent to MTP without reservation. Three themes were identified and further supported via the survey responses: (1) Obvious agreement to participate, primarily because of desire for new treatments and altruism. (2) The black box - while participant knowledge of genomics was generally poor, faith in their oncologists and the scientific process encouraged them to proceed with testing; and (3) Survival is the priority - receiving treatment to prolong life was the priority for all participants, and other issues such as identification of a germline variant were generally seen as ancillary. Conclusion: Having advanced cancer seemed to abrogate any potential concerns about MTP. Participants valued the research for varied reasons, but this was secondary to their priority to survive. While no negative attitudes toward MTP emerged, limitations in understanding of genomics were evident

Stigma Management Strategies of Autistic Social Media Users

Background: Research on stigma management strategies in autism relies on questionnaires or experiments, leading to a gap in understanding of how to identify the strategies in naturalistic interactions. The identification of individual (adapting minority group characteristics) and collective (positively redeveloping the in-group) stigma management strategies in online communication is important for understanding how to improve the quality of social media experiences for autistic users. Methods: Using linguistic analysis and engaging with ethnographic perspectives on relationship management, this article develops a novel approach to the identification of individual and collective stigma management strategies of autistic social media users. We combine online observation and interviews with 34 autistic social media users with a corpus-assisted analysis of their posts, divided into two groups according to regular or limited mentions of autism. Results: We show that posts in the first group focus on information provision and exchange and include markers of shared understanding and community building as part of a collective strategy. Interviews with the authors reveal a strong sense of autistic identity and highlight the importance of staying true to one's specific communicative preferences. Posts in the second group are characterized by tentative language (e.g., “seem” and “not sure”) as a way of avoiding social threats by users who report uncertainty and anxiety about misinterpretation of their messages. Conclusions: We show that autistic social media users have specific preferences in how they communicate and express connection online. However, due to negative experiences of social interactions some do not follow these preferences and instead select linguistic and visual resources that can reduce perceived risks of misunderstanding. We question the claims that the internet is inherently enabling for autistic users and call for further research and policy effort to ensure autistic sociality rights in all digital environments. Community brief Why is this an important issue? Autistic people often change their behavior to fit in with nonautistic social environment (thereby “camouflaging” their differences), in person and online. The internet is also a place where autistic people interact with each other and build community. However, research on these online behaviors is mostly focused on conscious actions people can recall when answering survey questions. What was the purpose of this study, and what did the researchers do? We wanted to find out whether it is possible to identify both community building strategies and camouflaging from the language used on social media, as some behaviors may happen without people realizing it. This article uses a method called digital linguistic ethnography to study how 34 autistic adult social media users managed the way they are seen online. The method involved observing where and how participants posted messages and comparing the frequency of word use between participants who regularly mentioned autism in their posts and those who did not. We also interviewed participants about their social media experiences and motivations. What were the results of the study? The results show that participants who mentioned autism used language in specific ways to raise awareness and connect with others. Participants who did not mention autism used more tentative language (e.g., “might,” “seem,” and “not sure”) and worried about being misunderstood. What do these findings add to what was already known? The findings are important as they show that autistic people have specific preferences in how they communicate and express connection on social media. The findings also show that some autistic adults may feel unable to follow these preferences when interacting online, which contradicts previous assumptions that autistic people do not need to mask in online environments. What are the potential weaknesses of the study? Although our participants exhibited a range of internet skills, they may represent a subgroup that is particularly inclined toward social media usage and interaction. This means that our findings may not apply for autistic adults with learning difficulties, for example. Our sample also includes only speaking individuals without the history of intellectual disabilities, which means that that the experiences of nonspeaking autistic people are not represented. How will these findings help autistic adults now or in the future? The findings inform our understanding of what kinds of social media situations make autistic people feel like they fit in or feel uncomfortable. This is important for designing online environments that are inclusive of autistic communicative preferences and have the potential to improve the quality of online social experiences for autistic people

Systematic review of studies generating individual participant data on the efficacy of drugs for treating soil-transmitted helminthiases and the case for data-sharing

Preventive chemotherapy and transmission control (PCT) by mass drug administration is the cornerstone of the World Health Organization (WHO)’s policy to control soil-transmitted helminthiases (STHs) caused by Ascaris lumbricoides (roundworm), Trichuris trichiura (whipworm) and hookworm species (Necator americanus and Ancylostama duodenale) which affect over 1 billion people globally. Despite consensus that drug efficacies should be monitored for signs of decline that could jeopardise the effectiveness of PCT, systematic monitoring and evaluation is seldom implemented. Drug trials mostly report aggregate efficacies in groups of participants, but heterogeneities in design complicate classical meta-analyses of these data. Individual participant data (IPD) permit more detailed analysis of drug efficacies, offering increased sensitivity to identify atypical responses potentially caused by emerging drug resistance