Human selenoprotein P and S variant mRNAs with different numbers of SECIS elements and inferences from mutant mice of the roles of multiple SECIS elements

Dynamic redefinition of the 10 UGAs in human and mouse selenoprotein P (Sepp1) mRNAs to specify selenocysteine instead of termination involves two 3′ UTR structural elements (SECIS) and is regulated by selenium availability. In addition to the previously known human Sepp1 mRNA poly(A) addition site just 3′ of SECIS 2, two further sites were identified with one resulting in 10–25% of the mRNA lacking SECIS 2. To address function, mutant mice were generated with either SECIS 1 or SECIS 2 deleted or with the first UGA substituted with a serine codon. They were fed on either high or selenium-deficient diets. The mutants had very different effects on the proportions of shorter and longer product Sepp1 protein isoforms isolated from plasma, and on viability. Spatially and functionally distinctive effects of the two SECIS elements on UGA decoding were inferred. We also bioinformatically identify two selenoprotein S mRNAs with different 5′ sequences predicted to yield products with different N-termini. These results provide insights into SECIS function and mRNA processing in selenoprotein isoform diversity

The synthetic TRPML1 agonist ML-SA1 rescues Alzheimer-related alterations of the endosomal-autophagic-lysosomal system

Abnormalities in the endosomal-autophagic-lysosomal (EAL) system are an early event in Alzheimer's disease (AD) pathogenesis. However, the mechanisms underlying these abnormalities are unclear. The transient receptor potential channel mucolipin 1(TRPML1, also known as MCOLN1), a vital endosomal-lysosomal Ca2+ channel whose loss of function leads to neurodegeneration, has not been investigated with respect to EAL pathogenesis in late-onset AD (LOAD). Here, we identify pathological hallmarks of TRPML1 dysregulation in LOAD neurons, including increased perinuclear clustering and vacuolation of endolysosomes. We reveal that induced pluripotent stem cell (iPSC)-derived human cortical neurons expressing APOE ε4, the strongest genetic risk factor for LOAD, have significantly diminished TRPML1-induced endolysosomal Ca2+ release. Furthermore, we found that blocking TRPML1 function in primary neurons by depleting the TRPML1 agonist PI(3,5)P2 via PIKfyve inhibition, recreated multiple features of EAL neuropathology evident in LOAD. This included increased endolysosomal Ca2+ content, enlargement and perinuclear clustering of endolysosomes, autophagic vesicle accumulation and early endosomal enlargement. Strikingly, these AD-like neuronal EAL defects were rescued by TRPML1 reactivation using its synthetic agonist ML-SA1. These findings implicate defects in TRPML1 in LOAD EAL pathogenesis and present TRPML1 as a potential therapeutic target

PTSD-8: A Short PTSD Inventory

Traumatic events pose great challenges on mental health services in scarcity of specialist trauma clinicians and services. Simple short screening instruments for detecting adverse psychological responses are needed. Several brief screening instruments have been developed. However, some are limited, especially in relation to reflecting the posttraumatic stress disorder (PTSD) diagnosis. Recently, several studies have challenged pre-existing ideas about PTSD’s latent structure. Factor analytic research currently supports two four factor models. One particular model contains a dysphoria factor which has been associated with depression and anxiety. The symptoms in this factor have been hailed as less specific to PTSD. The scope of this article is therefore to present a short screening instrument, based on this research; Posttraumatic Stress Disorder (PTSD) – 8 items. The PTSD-8 is shown to have good psychometric properties in three independent samples of whiplash patients (n=1710), rape victims (n=305), and disaster victims (n=516). Good test-rest reliability is also shown in a pilot study of young adults from families with alcohol problems (n=56)

Cultural geographies of extinction: animal culture amongst Scottish ospreys

This paper explores cultural geographies of extinction. I trace the decline of the Scottish osprey during the nineteenth century, and its enduring, haunting presence in the landscape today. Taking inspiration from the environmental humanities, extinction is framed as an event affecting losses that exceed comprehension in terms merely of biological species numbers and survival rates. Disavowing the ‘species thinking’ of contemporary conservation biopolitics, the osprey’s extinction story pays attention to the worth of ‘animal cultures’. Drawing a hybrid conceptual framework from research in the environmental humanities, ‘speculative’ ethology and more-than-human geographies, I champion an experimental attention to the cultural geographies of animals in terms of historically contingent, communally shared, spatial practices and attachments. In doing so, I propose nonhuman cultural geographies as assemblages that matter, and which are fundamentally at stake in the face of extinction

Unravelling calcium-release channel gating: clues from a 'hot' disease.

Ryanodine receptors (RyRs) are a family of intracellular channels that mediate Ca2+ release from the endoplasmic and sarcoplasmic reticulum. More than 50 distinct point mutations in one member of this family, RyR1, cause malignant hyperthermia, a potentially lethal pharmacogenetic disorder of skeletal muscle. These mutations are not randomly distributed throughout the primary structure of RyR1, but are grouped in three discrete clusters. In this issue of the Biochemical Journal, Kobayashi et al. present evidence that interdomain interactions between two of these mutation-enriched regions play a key role in the gating mechanism of RyR1

Atypical L-type channels are down-regulated in hypoxia

Abstract One type of cellular response to hypoxia is an increase in cytosolic Ca 2+ . Immunofluorescence microscopy shows the approx. 100 kDa protein located within the cell and on the cell surface, while the approx. 150 kDa protein is intracellular with punctate staining. Further analysis revealed that this approx. 150 kDa protein co-localizes with nuclear proteins but not with markers for other intracellular compartments. In addition, these proteins are both down-regulated in DFX-treated and hypoxic cells, suggesting that the mechanism of down-regulation is along the HIF (hypoxia-inducible factor) pathway. This atypical localization of the 150 kDa protein suggests that it might play a role in nuclear calcium signalling in health and disease

Impact of cancer cachexia on respiratory muscle function and the therapeutic potential of exercise

Cancer cachexia is defined as a multi-factorial syndrome characterised by an ongoing loss of skeletal muscle mass and progressive functional impairment, estimated to affect 50–80% of patients and responsible for 20% of cancer deaths. Elevations in the morbidity and mortality rates of cachectic cancer patients has been linked to respiratory failure due to atrophy and dysfunction of the ventilatory muscles. Despite this, there is a distinct scarcity of research investigating the structural and functional condition of the respiratory musculature in cancer, with the majority of studies exclusively focussing on limb muscle. Treatment strategies are largely ineffective in mitigating the cachectic state. It is now widely accepted that an efficacious intervention will likely combine elements of pharmacology, nutrition, and exercise. However, of these approaches, exercise has received comparatively little attention. Therefore, it is unlikely to be implemented optimally, whether in isolation or combination. In consideration of these limitations, the current review describes the mechanistic basis of cancer cachexia, and subsequently explores the available respiratory- and exercise-focussed literature within this context. The molecular basis of cachexia is thoroughly reviewed. The pivotal role of inflammatory mediators is described. Unravelling the mechanisms of exercise-induced support of muscle via antioxidant and anti-inflammatory effects in addition to promoting efficient energy metabolism via increased mitochondrial biogenesis, mitochondrial function, and muscle glucose uptake provide avenues for interventional studies. Currently available pre-clinical mouse models including novel transgenic animals provide a platform for the development of multi-modal therapeutic strategies to protect respiratory muscles in people with cancer