Lysosomal Ca2+ Signalling and Neurodegeneration: A Global View

Dysfunction of the lysosomal Ca2+ channels TRPML1 and TPC2 has been implicated in neurodegenerative disease. However, there is little information about the involvement of these channels in cell-wide global Ca2+ signalling and it is unknown whether their dysfunction contributes to neurodegeneration by disturbing it. First, by using synthetic compounds, I demonstrate that TRPML1 activation causes global Ca2+ signals. In contrast with the predominant lysosomal localisation of the channel these Ca2+ signals comprised a small lysosomal contribution and a large Ca2+ entry component. Examination of TRPML1-mediated Fe2+ entry posed the possibility that divalent cation entry can occur directly through TRPML1 on the plasma membrane. Second, I identified enlarged and clustered lysosomes in fibroblasts derived from people with sporadic Parkinson’s disease (PD). This was appropriately quantified from microscopy images by creating an automated sequence of image processing functions. By inhibiting TPC expression in fibroblasts I demonstrated their involvement in the propagation of physiological global Ca2+ signals evoked by bradykinin. In sporadic and familial PD patient fibroblasts these TPCdependent Ca2+ signals were subtly modulated. Finally, in a neuronal cell line, reduced TPC expression inhibited the propagation of physiological global Ca2+ signals evoked by carbachol. These Ca2+ signals were also blocked by a recently identified TPC blocker and by putative TPC blockers that were screened by collaborators. In cells expressing the PD-associated mutant, LRRK2 G2019S, these TPC-dependent Ca2+ signals were potentiated. In contrast, bradykinin-evoked Ca2+ signals in this neuronal cell line were not inhibited by TPC blockers, nor were they potentiated in the LRRK2 G2019S cells. Therefore, physiological global Ca2+ signalling in PD may be perturbed by TPC dysfunction, and be a compounding factor in neurodegeneration. Collectively this research suggests that lysosomal Ca2+ signalling through TRPML1 and TPCs plays a role in global Ca2+ signalling and that this may be disturbed in neurodegenerative disease

The psychological impact of the secondary school transition on families of autistic children

© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/The transition from primary to secondary school is a stressful period for autistic individuals. However, less isknown about parental experiences of the school transition, and its impact on the family. This study exploredmothers’perspectives on the psychological impact of the transition to secondary school for their autistic chil-dren and their families. Using Interpretative Phenomenological Analysis, semi-structured interviews were ana-lysed to explore the experiences of eight mothers of autistic children at the end of their child’s first year insecondary school. The analysis revealed two superordinate themes: lack of available support and detrimentalpsychological impact on the family. Mothers reported the negative impact the transition had on themselves,their child, and the wider family. The importance of pre- and ongoing transition support was highlighted toreduce the concerns of children and their parents throughout the transition process. The findings highlightedthe need for autism-specific individualized guidance, as well as considering the potential for transition issuesto impact on siblings.Peer reviewe

Contamination-focussed vignettes as an analogue of infectious pandemics: an experimental validation via state disgust and anxiety responses in OCD

Despite infectious pandemics proving particularly detrimental to those with Obsessive-Compulsive Disorder (OCD), the investigation of analogous experimental paradigms is lacking. To address this gap, we conducted two studies employing vignettes that depicted contamination-related situations commonly experienced during a pandemic (e.g., Coughing into hands and failing to use hand sanitizer). We manipulated the salience of these vignettes across three levels: high contamination, low contamination, and a neutral control condition. Our examination of state anxiety and disgust responses in all participants revealed the successful manipulation of the vignettes’ impact. Specifically, individuals with more severe OCD symptoms reported significantly higher levels of state disgust and anxiety for both high and low contamination vignettes, in contrast to the group with lower symptom severity. No significant differences were observed in the neutral vignette condition between the high- and low-scoring groups. Interestingly, for those with higher OCD symptoms, high salience contamination-focused vignettes resulted in similarly elevated state disgust and anxiety, regardless of whether the vignettes were situated in public (Study 1) or domestic (Study 2) settings. This suggests that the heightened sensitivity to contamination-related scenarios observed in individuals with OCD symptoms in the present study is not confined to a specific context. These findings support the use of contamination-focused vignettes as analogues for studying infectious pandemics and provide valuable insights into OCD models, interventions, and future research

An SMC-like protein binds and regulates Caenorhabditis elegans condensins

Structural Maintenance of Chromosomes (SMC) family proteins participate in multisubunit complexes that govern chromosome structure and dynamics. SMC-containing condensin complexes create chromosome topologies essential for mitosis/meiosis, gene expression, recombination, and repair. Many eukaryotes have two condensin complexes (I and II); C. elegans has three (I, II, and the X-chromosome specialized condensin IDC) and their regulation is poorly understood. Here we identify a novel SMC-like protein, SMCL-1, that binds to C. elegans condensin SMC subunits, and modulates condensin functions. Consistent with a possible role as a negative regulator, loss of SMCL-1 partially rescued the lethal and sterile phenotypes of a hypomorphic condensin mutant, while over-expression of SMCL-1 caused lethality, chromosome mis-segregation, and disruption of condensin IDC localization on X chromosomes. Unlike canonical SMC proteins, SMCL-1 lacks hinge and coil domains, and its ATPase domain lacks conserved amino acids required for ATP hydrolysis, leading to the speculation that it may inhibit condensin ATPase activity. SMCL-1 homologs are apparent only in the subset of Caenorhabditis species in which the condensin I and II subunit SMC-4 duplicated to create the condensin IDC- specific subunit DPY-27, suggesting that SMCL-1 helps this lineage cope with the regulatory challenges imposed by evolution of a third condensin complex. Our findings uncover a new regulator of condensins and highlight how the duplication and divergence of SMC complex components in various lineages has created new proteins with diverse functions in chromosome dynamics

Novel aspects of iron homeostasis in pathogenic bloodstream form Trypanosoma brucei

Iron is an essential regulatory signal for virulence factors in many pathogens. Mammals and bloodstream form (BSF) Trypanosoma brucei obtain iron by receptor-mediated endocytosis of transferrin bound to receptors (TfR) but the mechanisms by which T. brucei subsequently handles iron remains enigmatic. Here, we analyse the transcriptome of T. brucei cultured in iron-rich and iron-poor conditions. We show that adaptation to iron-deprivation induces upregulation of TfR, a cohort of parasite-specific genes (ESAG3, PAGS), genes involved in glucose uptake and glycolysis (THT1 and hexokinase), endocytosis (Phosphatidic Acid Phosphatase, PAP2), and most notably a divergent RNA binding protein RBP5, indicative of a non-canonical mechanism for regulating intracellular iron levels. We show that cells depleted of TfR by RNA silencing import free iron as a compensatory survival strategy. The TfR and RBP5 iron response are reversible by genetic complementation, the response kinetics are similar, but the regulatory mechanisms are distinct. Increased TfR protein is due to increased mRNA. Increased RBP5 expression, however, occurs by a post-transcriptional feedback mechanism whereby RBP5 interacts with its own, and with PAP2 mRNAs. Further observations suggest that increased RBP5 expression in iron-deprived cells has a maximum threshold as ectopic overexpression above this threshold disrupts normal cell cycle progression resulting in an accumulation of anucleate cells and cells in G2/M phase. This phenotype is not observed with overexpression of RPB5 containing a point mutation (F61A) in its single RNA Recognition Motif. Our experiments shed new light on how T. brucei BSFs reorganise their transcriptome to deal with iron stress revealing the first iron responsive RNA binding protein that is co-regulated with TfR, is important for cell viability and iron homeostasis; two essential processes for successful proliferation

Lanthanum associated abnormal liver function tests in two patients on dialysis: a case report

Lanthanum (La) is a phosphate binder used in patients on dialysis in the UK. As it has only recently been in use, there are no long-term data about safety of this rare metal in human subjects with renal failure on renal replacement therapy. La has not been previously reported to cause any adverse reactions apart from nausea, sickness, dialysis graft occlusion and abdominal pain. We report here La induced abnormal liver function tests in a male and a female patient of 70 and 44 years old each, on peritoneal dialysis (PD) and haemodialysis (HD) respectively, the first report of such an adverse reaction to this agent

Mechanisms of breast cancer metastasis

Invasive breast cancer tends to metastasize to lymph nodes and systemic sites. The management of metastasis has evolved by focusing on controlling the growth of the disease in the breast/chest wall, and at metastatic sites, initially by surgery alone, then by a combination of surgery with radiation, and later by adding systemic treatments in the form of chemotherapy, hormone manipulation, targeted therapy, immunotherapy and other treatments aimed at inhibiting the proliferation of cancer cells. It would be valuable for us to know how breast cancer metastasizes; such knowledge would likely encourage the development of therapies that focus on mechanisms of metastasis and might even allow us to avoid toxic therapies that are currently used for this disease. For example, if we had a drug that targeted a gene that is critical for metastasis, we might even be able to cure a vast majority of patients with breast cancer. By bringing together scientists with expertise in molecular aspects of breast cancer metastasis, and those with expertise in the mechanical aspects of metastasis, this paper probes interesting aspects of the metastasis cascade, further enlightening us in our efforts to improve the outcome from breast cancer treatments

Objective cough frequency, airway inflammation, and disease control in asthma

Background Cough is recognized as an important troublesome symptom in the diagnosis and monitoring of asthma. Asthma control is thought to be determined by the degree of airway inflammation and hyperresponsiveness but how these factors relate to cough frequency is unclear. The goal of this study was to investigate the relationships between objective cough frequency, disease control, airflow obstruction, and airway inflammation in asthma. Methods Participants with asthma underwent 24-h ambulatory cough monitoring and assessment of exhaled nitric oxide, spirometry, methacholine challenge, and sputum induction (cell counts and inflammatory mediator levels). Asthma control was assessed by using the Global Initiative for Asthma (GINA) classification and the Asthma Control Questionnaire (ACQ). The number of cough sounds was manually counted and expressed as coughs per hour (c/h). Results Eighty-nine subjects with asthma (mean ± SD age, 57 ± 12 years; 57% female) were recruited. According to GINA criteria, 18 (20.2%) patients were classified as controlled, 39 (43.8%) partly controlled, and 32 (36%) uncontrolled; the median ACQ score was 1 (range, 0.0-4.4). The 6-item ACQ correlated with 24-h cough frequency (r = 0.40; P < .001), and patients with uncontrolled asthma (per GINA criteria) had higher median 24-h cough frequency (4.2 c/h; range, 0.3-27.6) compared with partially controlled asthma (1.8 c/h; range, 0.2-25.3; P = .01) and controlled asthma (1.7 c/h; range, 0.3-6.7; P = .002). Measures of airway inflammation were not significantly different between GINA categories and were not correlated with ACQ. In multivariate analyses, increasing cough frequency and worsening FEV1 independently predicted measures of asthma control. Conclusions Ambulatory cough frequency monitoring provides an objective assessment of asthma symptoms that correlates with standard measures of asthma control but not airflow obstruction or airway inflammation. Moreover, cough frequency and airflow obstruction represent independent dimensions of asthma control

Promoting Independence in Dementia (PRIDE): protocol for a feasibility randomised controlled trial.

BACKGROUND: Memory services often see people with early stage dementia who are largely independent and able to participate in community activities but who run the risk of reducing activities and social networks. PRIDE is a self-management intervention designed to promote living well and enhance independence for people with mild dementia. This study aims to examine the feasibility of conducting a definitive randomised trial comparing the clinical and cost-effectiveness of the PRIDE intervention offered in addition to usual care or with usual care alone. METHODS/DESIGN: PRIDE is a parallel, two-arm, multicentre, feasibility, randomised controlled trial (RCT). Eligible participants aged 18 or over who have mild dementia (defined as a score of 0.5 or 1 on the Clinical Dementia Rating Scale) who can participate in the intervention and provide informed consent will be randomised (1:1) to treatment with the PRIDE intervention delivered in addition to usual care, or usual care only. Participants will be followed-up at 3 and 6 month's post-randomisation. There will be an option for a supporter to join each participant. Each supporter will be provided with questionnaires at baseline and follow-ups at 3 to 6 months. Embedded qualitative research with both participants and supporters will explore their perspectives on the intervention investigating a range of themes including acceptability and barriers and facilitators to delivery and participation. The feasibility of conducting a full RCT associated with participant recruitment and follow-up of both conditions, intervention delivery including the recruitment, training, retention of PRIDE trained facilitators, clinical outcomes, intervention and resource use costs and the acceptability of the intervention and study related procedures will be examined. DISCUSSION: This study will assess whether a definitive randomised trial comparing the clinical and cost-effectiveness of whether the PRIDE intervention offered in addition to usual care is feasible in comparison to usual care alone, and if so, will provide data to inform the design and conduct of a future trial. TRIAL REGISTRATION: ISRCTN, ISRCTN11288961, registered on 23 October 2019, http://www.isrctn.com/ISRCTN12345678 Protocol V2.1 dated 19 June 2019

Individual variation in hunger, energy intake and ghrelin responses to acute exercise

Purpose: To characterise the immediate and extended impact of acute exercise on hunger, energy intake and circulating acylated ghrelin concentrations using a large dataset of homogenous experimental trials; and to describe the variation in responses between individuals. Methods: Data from 17 of our group’s experimental crossover trials were aggregated yielding a total sample of 192 young, healthy, males. In these studies, single bouts of moderate to high-intensity aerobic exercise (69 ± 5% VO2 peak; mean ± SD) were completed with detailed participant assessments occurring during and for several hours post-exercise. Mean hunger ratings were determined during (n = 178) and after (n = 118) exercise from visual analogue scales completed at 30 min intervals whilst ad libitum energy intake was measured within the first hour after exercise (n = 60) and at multiple meals (n = 128) during the remainder of trials. Venous concentrations of acylated ghrelin were determined at strategic time points during (n = 118) and after (n = 89) exercise. Results: At group-level, exercise transiently suppressed hunger (P < 0.010; Cohen’s d = 0.77) but did not affect energy intake. Acylated ghrelin was suppressed during exercise (P < 0.001; Cohen’s d = 0.10) and remained significantly lower than control (no exercise) afterwards (P < 0.024; Cohen’s d = 0.61). Between participants, there were notable differences in responses however a large proportion of this spread lay within the boundaries of normal variation associated with biological and technical assessment error. Conclusion: In young men, acute exercise suppresses hunger and circulating acylated ghrelin concentrations with notable diversity between individuals. Care must be taken to distinguish true inter-individual variation from random differences within normal limits