Ablation of Calsequestrin-1, Ca2+ unbalance, and susceptibility to heat stroke

Introduction: Ca2+ levels in adult skeletal muscle fibers are mainly controlled by excitation-contraction (EC) coupling, a mechanism that translates action potentials in release of Ca2+ from the sarcoplasmic reticulum (SR) release channels, i.e. the ryanodine receptors type-1 (RyR1). Calsequestrin (Casq) is a protein that binds large amounts of Ca2+ in the lumen of the SR terminal cisternae, near sites of Ca2+ release. There is general agreement that Casq is not only important for the SR ability to store Ca2+, but also for modulating the opening probability of the RyR Ca2+ release channels. The initial studies: About 20 years ago we generated a mouse model lacking Casq1 (Casq1-null mice), the isoform predominantly expressed in adult fast twitch skeletal muscle. While the knockout was not lethal as expected, lack of Casq1 caused a striking remodeling of membranes of SR and of transverse tubules (TTs), and mitochondrial damage. Functionally, CASQ1-knockout resulted in reduced SR Ca2+ content, smaller Ca2+ transients, and severe SR depletion during repetitive stimulation. The myopathic phenotype of Casq1-null mice: After the initial studies, we discovered that Casq1-null mice were prone to sudden death when exposed to halogenated anaesthetics, heat and even strenuous exercise. These syndromes are similar to human malignant hyperthermia susceptibility (MHS) and environmental-exertional heat stroke (HS). We learned that mechanisms underlying these syndromes involved excessive SR Ca2+ leak and excessive production of oxidative species: indeed, mortality and mitochondrial damage were significantly prevented by administration of antioxidants and reduction of oxidative stress. Though, how Casq1-null mice could survive without the most important SR Ca2+ binding protein was a puzzling issue that was not solved. Unravelling the mystery: The mystery was finally solved in 2020, when we discovered that in Casq1-null mice the SR undergoes adaptations that result in constitutively active store-operated Ca2+ entry (SOCE). SOCE is a mechanism that allows skeletal fibers to use external Ca2+ when SR stores are depleted. The post-natal compensatory mechanism that allows Casq1-null mice to survive involves the assembly of new SR-TT junctions (named Ca2+ entry units) containing Stim1 and Orai1, the two proteins that mediate SOCE

Comprehensive analysis of Hox gene expression in the amphipod crustacean Parhyale hawaiensis.

Hox genes play crucial roles in establishing regional identity along the anterior-posterior axis in bilaterian animals, and have been implicated in generating morphological diversity throughout evolution. Here we report the identification, expression, and initial genomic characterization of the complete set of Hox genes from the amphipod crustacean Parhyale hawaiensis. Parhyale is an emerging model system that is amenable to experimental manipulations and evolutionary comparisons among the arthropods. Our analyses indicate that the Parhyale genome contains a single copy of each canonical Hox gene with the exception of fushi tarazu, and preliminary mapping suggests that at least some of these genes are clustered together in the genome. With few exceptions, Parhyale Hox genes exhibit both temporal and spatial colinearity, and expression boundaries correlate with morphological differences between segments and their associated appendages. This work represents the most comprehensive analysis of Hox gene expression in a crustacean to date, and provides a foundation for functional studies aimed at elucidating the role of Hox genes in arthropod development and evolution

Store-Operated Ca 2+ Entry in Skeletal Muscle Contributes to the Increase in Body Temperature during Exertional Stress

Exertional heat stroke (HS) is a hyperthermic crisis triggered by an excessive accumulation of Ca2+ in skeletal muscle fibers. We demonstrated that exercise leads to the formation of calcium entry units (CEUs), which are intracellular junctions that reduce muscle fatigue by promoting the recovery of extracellular Ca2+ via store-operated Ca2+ entry (SOCE). Here, we tested the hypothesis that exercise-induced assembly of CEUs may increase the risk of HS when physical activity is performed in adverse environmental conditions (high temperature and humidity). Adult mice were: (a) first, divided into three experimental groups: control, trained-1 month (voluntary running in wheel cages), and acutely exercised-1 h (incremental treadmill run); and (b) then subjected to an exertional stress (ES) protocol, a treadmill run in an environmental chamber at 34◦C and 40% humidity. The internal temperature of the mice at the end of the ES was higher in both pre-exercised groups. During an ES ex-vivo protocol, extensor digitorum longus(EDL) muscles from the trained-1 month and exercised-1 h mice generated greater basal tension than in the control and were those that contained a greater number of CEUs, assessed by electron microscopy. The data collected suggest that the entry of Ca2+ from extracellular space via CEUs could contribute to exertional HS when exercise is performed in adverse environmental conditions

Call Me Caitlyn: Making and making over the 'authentic' transgender body in Anglo-American popular culture

A conception of transgender identity as an ‘authentic’ gendered core ‘trapped’ within a mismatched corporeality, and made tangible through corporeal transformations, has attained unprecedented legibility in contemporary Anglo-American media. Whilst pop-cultural articulations of this discourse have received some scholarly attention, the question of why this 'wrong body' paradigm has solidified as the normative explanation for gender transition within the popular media remains underexplored. This paper argues that this discourse has attained cultural pre-eminence through its convergence with a broader media and commercial zeitgeist, in which corporeal alteration and maintenance are perceived as means of accessing one’s ‘authentic’ self. I analyse the media representations of two transgender celebrities: Caitlyn Jenner and Nadia Almada, alongside the reality TV show TRANSform Me, exploring how these women’s gender transitions have been discursively aligned with a cultural imperative for all women, cisgender or trans, to display their authentic femininity through bodily work. This demonstrates how established tropes of authenticity-via-bodily transformation, have enabled transgender to become culturally legible through the wrong body trope. Problematically, I argue, this process has worked to demarcate ideals of ‘acceptable’ transgender subjectivity: self-sufficient, normatively feminine, and eager to embrace the possibilities for happiness and social integration provided by the commercial domain

A Novel Brain Stimulation Technology Provides Compatibility with MRI

Clinical electrical stimulation systems — such as pacemakers and deep brain stimulators (DBS) — are an increasingly common therapeutic option to treat a large range of medical conditions. Despite their remarkable success, one of the significant limitations of these medical devices is the limited compatibility with magnetic resonance imaging (MRI), a standard diagnostic tool in medicine. During an MRI exam, the leads used with these devices, implanted in the body of the patient, act as an electric antenna potentially causing a large amount of energy to be absorbed in the tissue, which can lead to serious heat-related injury. This study presents a novel lead design that reduces the antenna effect and allows for decreased tissue heating during MRI. The optimal parameters of the wire design were determined by a combination of computational modeling and experimental measurements. The results of these simulations were used to build a prototype, which was tested in a gel phantom during an MRI scan. Measurement results showed a three-fold decrease in heating when compared to a commercially available DBS lead. Accordingly, the proposed design may allow a significantly increased number of patients with medical implants to have safe access to the diagnostic benefits of MRI

Challenging cisgenderism through trans people's narratives of domestic violence and abuse

By drawing on empirical research that explored trans people’s experiences of domestic violence and abuse (DVA), this paper problematises the ‘gender asymmetry debate' in DVA discourse. It does so by highlighting cisgenderism and a heteronormative bias which have led to the invisibility of a trans perspective. Qualitative data was collected via narrative interviews and this was examined using a voice-centred relational technique. A total of twenty four interviews were undertaken with trans people (n = 15) and domestic abuse practitioners (n = 9). In relation to the presentation and impact of DVA, and in the context of trans and cisgender people's abuse experiences, the research findings report both similarities and differences. Four narratives are presented here to illuminate both. This paper adds new insight and challenges normative and dominant discourses by promoting the need for further theorising about the gendered nature of domestic violence and abuse

Bone Marrow–generated Dendritic Cells Pulsed with Tumor Extracts or Tumor RNA Induce Antitumor Immunity against Central Nervous System Tumors

Recent studies have shown that the brain is not a barrier to successful active immunotherapy that uses gene-modified autologous tumor cell vaccines. In this study, we compared the efficacy of two types of vaccines for the treatment of tumors within the central nervous system (CNS): dendritic cell (DC)-based vaccines pulsed with either tumor extract or tumor RNA, and cytokine gene–modified tumor vaccines. Using the B16/F10 murine melanoma (B16) as a model for CNS tumor, we show that vaccination with bone marrow–generated DCs, pulsed with either B16 cell extract or B16 total RNA, can induce specific cytotoxic T lymphocytes against B16 tumor cells. Both types of DC vaccines were able to protect animals from tumors located in the CNS. DC-based vaccines also led to prolonged survival in mice with tumors placed before the initiation of vaccine therapy. The DC-based vaccines were at least as effective, if not more so, as vaccines containing B16 tumor cells in which the granulocytic macrophage colony-stimulating factor gene had been modified. These data support the use of DC-based vaccines for the treatment of patients with CNS tumors

Authenticity, validation and sexualisation on Grindr: an analysis of trans women’s accounts

The socio-historic sexualisation of transgender identities is reported to have disaffirming consequences for the broad trans community, and for trans women in particular. Given trans people’s increasing use of socio-sexual ‘hook-up’ apps, this paper looks at trans women’s talk of self/other identifications in relation to their regular use of Grindr. Eight semi-structured in-depth interviews were conducted with London-based women who identified as trans* in some way. A Foucauldian-informed discourse analysis highlights intersecting frames of trans authenticity, validation and sexualisation. Within these frames, trans women can be variously positioned in gendered and sexualised ways. Specifically, a discourse of trans authenticity is seen to involve the marking out of an identificatory truth that is situated in culturally acceptable and hence de-sexualised womanhood, while a competing discourse of trans validation involves an ambiguity and eroticism that can serve to reimagine this truth. Trans subjectivities can thus consist of a desire for authentic (gendered and non-sexualised) selfhood, on the one hand, and self-affirming ambiguity and sexualisation on the other. That trans women can construct ambivalent relationships with trans-sexualisation discourse highlights the limitation of anti-sexualisation advocacy and implications for supporting trans sexualities are considered

Interrogating trans and sexual identities through the conceptual lens of translocational positionality

This article explores the confluence of trans identity and sexuality drawing on the concept of translocational positionality. In this discussion, a broad spectrum of gendered positionalities incorporates trans identity which, in turn, acknowledges normative male and female identities as well as non-binary ones. It is also recognised, however, that trans identity overlaps with other positionalities (pertaining to sexuality, for example) to shape social location. In seeking to understand subject positions, a translocational lens acknowledges the contextuality and temporality of social categories to offer an analysis which recognises the overlaps and differentials of co-existing positionalities. This approach enables an analysis which explores how macro, or structural, contexts shape agency (at the micro-level) and also how both are mediated by trans people's multiple and shifting positionalities. In this framing, positionality represents a meso layer between structure and agency. Four case studies are presented using data from a qualitative study which explored trans people's experiences of family, intimacy and domestic abuse. We offer an original contribution to the emerging knowledge-base on trans sexuality by presenting data from four case studies. We do so whilst innovatively applying the conceptual lens of translocational positionality to an analysis which considers macro, meso and micro levels of influence

Sex wars and (trans) gender panics : identity and body politics in contemporary UK feminism

This article considers how sex and gender – as conceptual categories and as a lived experience – are subject to contestation and renegotiation in the contemporary UK. Exploring gendered shifts through the lenses of identity and embodiment, the article captures key moments where certainties have been undone within feminist and transgender thought and activism. Yet such fissures resound with calls for a return to traditional understandings of the sexed body. The article pays particular attention to debates within feminism around transgender issues, and sketches out a climate of transgender moral panic whereby conservative thinkers and some feminist activists are joining forces with the aim of resurrecting gender binaries