A Crisis of Erasure: Transgender and Gender-Nonconforming Populations Navigating Breast Cancer Health Information

In this paper, we use the topic of breast cancer as an example of health crisis erasure in both informational and institutional contexts, particularly within the transgender and gender-nonconforming population. Breast cancer health information conforms and defaults to conventional cultural associations with femininity, as is the case with pregnancy and other “single-sex” conditions (Surkan, 2015). Many health information and research practices normalize sexualities, pathologize non-normative gender (Drescher et al., 2012; Fish, 2008; Müller, 2018), and fail to recognize gender-nonconforming categories (Frohard‐Dourlent et al., 2017). Because breast cancer health information is sexually normalized, an information boundary exists for the LGBTQ+ community, particularly among transgender and gender-nonconforming adults who are at greater risk of discrimination in healthcare settings (Casey et al., 2019). Transgender and gender-nonconforming people experience unique marginalization and risk with respect to breast cancer. We call upon and propose library and information research, education, and practice opportunities inclusive of the health information needs of transgender and gender-nonconforming populations

A Crisis of Erasure: Transgender and Gender-Nonconforming Populations Navigating Breast Cancer Health Information

In this paper, we use the topic of breast cancer as an example of health crisis erasure in both informational and institutional contexts, particularly within the transgender and gender-nonconforming population. Breast cancer health information conforms and defaults to conventional cultural associations with femininity, as is the case with pregnancy and other “single-sex” conditions (Surkan, 2015). Many health information and research practices normalize sexualities, pathologize non-normative gender (Drescher et al., 2012; Fish, 2008; Müller, 2018), and fail to recognize gender-nonconforming categories (Frohard‐Dourlent et al., 2017). Because breast cancer health information is sexually normalized, an information boundary exists for the LGBTQ+ community, particularly among transgender and gender-nonconforming adults who are at greater risk of discrimination in healthcare settings (Casey et al., 2019). Transgender and gender-nonconforming people experience unique marginalization and risk with respect to breast cancer. We call upon and propose library and information research, education, and practice opportunities inclusive of the health information needs of transgender and gender-nonconforming populations

SlideShare presentations, citations, users and trends: A professional site with academic and educational uses

SlideShare is a free social web site that aims to help users to distribute and find presentations. Owned by LinkedIn since 2012, it targets a professional audience but may give value to scholarship through creating a long term record of the content of talks. This article tests this hypothesis by analysing sets of general and scholarly-related SlideShare documents using content and citation analysis and popularity statistics reported on the site. The results suggest that academics, students and teachers are a minority of SlideShare uploaders, especially since 2010, with most documents not being directly related to scholarship or teaching. About two thirds of uploaded SlideShare documents are presentation slides, with the remainder often being files associated with presentations or video recordings of talks. SlideShare is therefore a presentation-centred site with a predominantly professional user base. Although a minority of the uploaded SlideShare documents are cited by, or cite, academic publications, probably too few articles are cited by SlideShare to consider extracting SlideShare citations for research evaluation. Nevertheless, scholars should consider SlideShare to be a potential source of academic and non-academic information, particularly in library and information science, education and business

Differentially altered Ca2+ regulation and Ca2+ permeability in Cx26 hemichannels formed by the A40V and G45E mutations that cause keratitis ichthyosis deafness syndrome

Mutations in GJB2, which encodes Cx26, are one of the most common causes of inherited deafness in humans. More than 100 mutations have been identified scattered throughout the Cx26 protein, most of which cause nonsyndromic sensorineural deafness. In a subset of mutations, deafness is accompanied by hyperkeratotic skin disorders, which are typically severe and sometimes fatal. Many of these syndromic deafness mutations localize to the amino-terminal and first extracellular loop (E1) domains. Here, we examined two such mutations, A40V and G45E, which are positioned near the TM1/E1 boundary and are associated with keratitis ichthyosis deafness (KID) syndrome. Both of these mutants have been reported to form hemichannels that open aberrantly, leading to “leaky” cell membranes. Here, we quantified the Ca2+ sensitivities and examined the biophysical properties of these mutants at macroscopic and single-channel levels. We find that A40V hemichannels show significantly impaired regulation by extracellular Ca2+, increasing the likelihood of aberrant hemichannel opening as previously suggested. However, G45E hemichannels show only modest impairment in regulation by Ca2+ and instead exhibit a substantial increase in permeability to Ca2+. Using cysteine substitution and examination of accessibility to thiol-modifying reagents, we demonstrate that G45, but not A40, is a pore-lining residue. Both mutants function as cell–cell channels. The data suggest that G45E and A40V are hemichannel gain-of-function mutants that produce similar phenotypes, but by different underlying mechanisms. A40V produces leaky hemichannels, whereas G45E provides a route for excessive entry of Ca2+. These aberrant properties, alone or in combination, can severely compromise cell integrity and lead to increased cell death

Mechanism of inhibition of connexin channels by the quinine derivative N-benzylquininium

The anti-malarial drug quinine and its quaternary derivative N-benzylquininium (BQ+) have been shown to inhibit gap junction (GJ) channels with specificity for Cx50 over its closely related homologue Cx46. Here, we examined the mechanism of BQ+ action using undocked Cx46 and Cx50 hemichannels, which are more amenable to analyses at the single-channel level. We found that BQ+ (300 µM–1 mM) robustly inhibited Cx50, but not Cx46, hemichannel currents, indicating that the Cx selectivity of BQ+ is preserved in both hemichannel and GJ channel configurations. BQ+ reduced Cx50 hemichannel open probability (Po) without appreciably altering unitary conductance of the fully open state and was effective when added from either extracellular or cytoplasmic sides. The reductions in Po were dependent on BQ+ concentration with a Hill coefficient of 1.8, suggesting binding of at least two BQ+ molecules. Inhibition by BQ+ was voltage dependent, promoted by hyperpolarization from the extracellular side and conversely by depolarization from the cytoplasmic side. These results are consistent with binding of BQ+ in the pore. Substitution of the N-terminal (NT) domain of Cx46 into Cx50 significantly impaired inhibition by BQ+. The NT domain contributes to the formation of the wide cytoplasmic vestibule of the pore and, thus, may contribute to the binding of BQ+. Single-channel analyses showed that BQ+ induced transitions that did not resemble pore block, but rather transitions indistinguishable from the intrinsic gating events ascribed to loop gating, one of two mechanisms that gate Cx channels. Moreover, BQ+ decreased mean open time and increased mean closed time, indicating that inhibition consists of an increase in hemichannel closing rate as well as a stabilization of the closed state. Collectively, these data suggest a mechanism of action for BQ+ that involves modulation loop gating rather than channel block as a result of binding in the NT domain

EKV mutant connexin 31 associated cell death is mediated by ER stress

The epidermis expresses a number of connexin (Cx) proteins that are implicated in gap junction-mediated cell communication. Distinct dominantly inherited mutations in Cx31 cause the skin disease erythrokeratoderma variabilis (EKV) and hearing loss with or without neuropathy. Functional studies reveal tissue-specific effects of these Cx31 disease-associated mutations. The Cx31 mutants (R42P)Cx31, (C86S)Cx31 and (G12D)Cx31 are associated with EKV and the mutant (66delD)Cx31 with peripheral neuropathy and hearing loss, however the mechanisms of pathogenesis remain to be elucidated. Expression of (R42P)Cx31, (C86S)Cx31 and (G12D)Cx31 in vitro, but not (WT)Cx31 or (66delD)Cx31, cause elevated levels of cell-type specific cell death. Previous studies suggest that Cx-associated cell death may be related to abnormal ‘leaky’ hemichannels but we produced direct evidence against that being the major mechanism. Additionally, our immunocytochemistry showed upregulation of components of the unfolded protein response (UPR) in cells expressing the EKV-associated Cx31 mutants but not (WT)Cx31 or (66delD)Cx31. We conclude that the endoplasmic reticulum (ER) stress leading to the UPR is the main mechanism of mutant Cx31-associated cell death. These results indicate that, in vivo, ER stress may lead to abnormal keratinocyte differentiation and hyperproliferation in EKV patient skin

Connexin Mediated Cataract Prevention in Mice

Cataracts, named for any opacity in the ocular lens, remain the leading cause of vision loss in the world. Non-surgical methods for cataract prevention are still elusive. We have genetically tested whether enhanced lens gap junction communication, provided by increased α3 connexin (Cx46) proteins expressed from α8(Kiα3) knock-in alleles in Gja8tm1(Gja3)Tww mice, could prevent nuclear cataracts caused by the γB-crystallin S11R mutation in CrygbS11R/S11R mice. Remarkably, homozygous knock-in α8(Kiα3/Kiα3) mice fully prevented nuclear cataracts, while single knock-in α8(Kiα3/−) allele mice showed variable suppression of nuclear opacities in CrygbS11R/S11R mutant mice. Cataract prevention was correlated with the suppression of many pathological processes, including crystallin degradation and fiber cell degeneration, as well as preservation of normal calcium levels and stable actin filaments in the lens. This work demonstrates that enhanced intercellular gap junction communication can effectively prevent or delay nuclear cataract formation and suggests that small metabolites transported through gap junction channels protect the stability of crystallin proteins and the cytoskeletal structures in the lens core. Thus, the use of an array of small molecules to promote lens homeostasis may become a feasible non-surgical approach for nuclear cataract prevention in the future

Pathogenic Connexin-31 Forms Constitutively Active Hemichannels to Promote Necrotic Cell Death

Mutations in Connexin-31 (Cx31) are associated with multiple human diseases including erythrokeratodermia variabilis (EKV). The molecular action of Cx31 pathogenic mutants remains largely elusive. We report here that expression of EKV pathogenic mutant Cx31R42P induces cell death with necrotic characteristics. Inhibition of hemichannel activity by a connexin hemichannel inhibitor or high extracellular calcium suppresses Cx31R42P-induced cell death. Expression of Cx31R42P induces ER stress resulting in reactive oxygen species (ROS) production, in turn, to regulate gating of Cx31R42P hemichannels and Cx31R42P induced cell death. Moreover, Cx31R42P hemichannels play an important role in mediating ATP release from the cell. In contrast, no hemichannel activity was detected with cells expressing wildtype Cx31. Together, the results suggest that Cx31R42P forms constitutively active hemichannels to promote necrotic cell death. The Cx31R42P active hemichannels are likely resulted by an ER stress mediated ROS overproduction. The study identifies a mechanism of EKV pathogenesis induced by a Cx31 mutant and provides a new avenue for potential treatment strategy of the disease