Regulation and Dynamic Behavior of the Heat Shock Transcription Factor Hsf-1 in C. Elegans

Eukaryotic cells respond to heat stress by activating the transcription factor HSF1. In addition to its role in stress response, HSF1 also functions in protein homeostasis, aging, innate immunity, and cancer. Despite prominent HSF1 involvement in processes pertinent to human health and disease, there are still gaps in our understanding of HSF1. For example, controversy exists regarding the localization of HSF1, the identity of HSF1 regulators, and the function and conservation of heat-induced HSF1 stress granules. Many of the physiological roles for HSF1 have been defined using the model organism Caenorhabditis elegans, yet little is known about how the molecular and biological properties of HSF-1 in C. elegans compare to HSF1 in other organisms, including humans. To address these questions, we generated animals expressing physiological levels of a GFP-tagged C. elegans HSF-1 protein. We studied the localization of HSF-1::GFP in vivo and observed its behavior upon heat shock in C. elegans. Furthermore, we conducted a genome-wide, RNAi-based screen for regulators of an HSF-1-dependent, heat shock-inducible transcriptional reporter. We found that in live C. elegans, HSF-1 localizes predominantly to the nucleus before and after heat shock. Following heat shock, HSF-1 redistributes into subnuclear puncta that share many characteristics with human nuclear stress granules, including rapid formation, reversibility, and colocalization with markers of active transcription. Granule formation in worms was affected by growth temperature, implying physiological regulation of this process. From our RNAi screen, we identified 44 regulators of HSF-1 target gene expression, the majority of which were positive regulators. One RNAi clone, encoding the worm homolog of the post-translational modifier SUMO, resulted in hyper-induction of the HSF-1 target after heat shock. Our findings from the screen suggest that basal repression of HSF-1 under low-temperature conditions may be very strict, and that sumoylation may be involved in downregulation of the activated heat stress response pathway. Our data also support a model of constitutively nuclear C. elegans HSF-1 and present evidence that HSF-1 nuclear stress granule formation may be an evolutionarily conserved phenomenon

Delayed Onset and Reduced Cognitive Deficits through Pre-Conditioning with 3-Nitropropionic Acid is Dependent on Sex and CAG Repeat Length in the R6/2 Mouse Model of Huntington's Disease.

BACKGROUND: Impairments in energy metabolism are implicated in Huntington's disease (HD) pathogenesis. Reduced levels of the mitochondrial enzyme succinate dehydrogenase (SDH), the main element of complex II, are observed post mortem in the brains of HD patients, and energy metabolism defects have been identified in both presymptomatic and symptomatic HD patients. OBJECTIVE: Chemical preconditioning with 3-nitropropionic acid (3-NP), an irreversible inhibitor of SDH, has been shown to increase tolerance against experimental hypoxia in both heart and brain. Here we studied the effect of chronic preconditioning in the R6/2 mouse model of HD using mice carrying CAG repeat lengths of either 250 or 400 repeats. Both are transgenic fragment models, with 250CAG mice having a more rapid disease progression than 400CAG mice. METHODS: Low doses of 3-NP (24 mg/kg) were administered via the drinking water and the effect on phenotype progression and cognition function assessed. RESULTS: After 3-NP treatment there were significant improvements in all aspects of the behavioural phenotype, apart from body weight, with timing and magnitude of improvements dependent on both CAG repeat length and sex. Specifically, a delay in the deterioration of general health (as shown by delayed onset of glycosuria and increased survival) was seen in both male and female 400CAG mice and in female 250CAG mice and was consistent with improved appearance of 3-NP treated R6/2 mice. Male 250CAG mice showed improvements but these were short term, and 3-NP treatment eventually had deleterious effects on their survival rate. When cognitive performance of 250CAG mice was assessed using a two-choice discrimination touchscreen task, we found that female mice showed significant improvements. DISCUSSION: Together, our results support the idea that energy metabolism contributes to the pathogenesis of HD, and suggest that improving energy deficits might be a therapeutically useful target.CHDI Inc.This is the author accepted manuscript. The final version is available from IOS Press via http://dx.doi.org/10.3233/JHD-160189

Beneficial effects of environmental enrichment and food entrainment in the R6/2 mouse model of Huntington's disease.

BACKGROUND: In addition to their cognitive and motor deficits, R6/2 mice show a progressive disintegration in circadian rhythms that mirrors the problems associated with sleep-wake disturbances experienced by patients with Huntington's disease (HD). It has been shown previously that motor and cognitive performance, as well as survival, can be improved in transgenic mouse models of HD through the provision of environmental enrichment. METHODS: We compared the effect of two different overnight entrainment paradigms presented either separately or in combination. The first was environmental enrichment, the second was temporal food-entrainment. Environmental enrichment was provided in the dark period (the natural active period for mice) in the form of access to a Perspex playground containing running wheels, tunnels, climbing frame, ropes and chew blocks. Food entrainment was imposed by allowing access to food only during the dark period. We assessed a number of different aspects of function in the mice, measuring general health (by SHIRPA testing, body temperature and body weight measurements), cognitive performance in the touchscreen and locomotor behavior in the open field. RESULTS: There were no significant differences in cognitive performance between groups on different schedules. Environmental enrichment delayed the onset of general health deterioration, while food entrainment slowed the loss of body weight, aided the maintenance of body temperature and improved locomotor behavior. Effects were limited however, and in combination had deleterious effects on survival. CONCLUSIONS: Our results support previous studies showing that environmental enrichment can be beneficial and might be used to enhance the quality of life of HD patients. However, improvements are selective and 'enrichment' per se is likely to only be useful as an adjunct to a more direct therapy

Twenty-Four-Hour ACTH and Cortisol Pulsatility in Depressed Women

Increased plasma cortisol in patients with major depression is a well documented finding, although it is present in only 25–30% of subjects with major depression. However, ACTH and cortisol are secreted in a pulsatile manner, so it is unclear if increased ACTH secretion occurs in depression and if there are changes in the pulsatile components of ACTH secretion. Ten-minute sampling for ACTH and cortisol was performed for 24 hr in 25 premenopausal depressed women, whose age and menstrual cycle day matched control women. As a group, the depressed women demonstrated a trend to increase cortisol secretion (p=0.089). There was no difference in mean cortisol between thepatient group as a whole (8.36±2.9 mcg/dl) and those patients meeting criteria for atypical depression (8.38±1.9 mcg/dl), but patients meeting criteria for endogenous showed increased cortisol (12.17 ±4 mcgg/dl) Mean ACTH was not significantly different between patients and controls. Pulseanalyses revealed similar number of secretory events and similar amplitudes for cortisol secretory bursts in patients and controls. The baseline component area under the curve of cortisol secretion was increased at a trend level (p=.064) in depressed patients, and the baseline AUC for ACTH was significantly increased in depressed patients (p=.045). No differences were found in pulsatile components of ACTH secretion between patients and matched controls. Harmonic analyses indicated no significant differences between patients and controls on any detected rhythm for ACTH or cortisol. These data suggest that the pulsatile and circadian components of the HPA axis are normal in premenopausal depressed women and that only 24% of depressed women demonstrate hypercortisolemia.NIMH MH 50030Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/49489/2/Young24HACTH.pd

Measurement Matters: A commentary on the state of the science on patient reported outcome measures (PROMs) in autism research

High quality science relies upon psychometrically valid and reliable measurement, yet very few Patient Reported Outcome Measures (PROMs) have been developed or thoroughly validated for use with autistic individuals. The present commentary summarizes the current state of autism PROM science, based on discussion at the Special Interest Group (SIG) at the 2022 International Society for Autism Research (INSAR) Annual Meeting and collective expertise of the authors. First, we identify current issues in autism PROM research including content and construct operationalization, informant-structure, measure accessibility, and measure validation and generalization. We then enumerate barriers to conducting and disseminating this research, such as a lack of guidance, concerns regarding funding and time, lack of accessible training and professionals with psychometric skills, difficulties collecting large representative samples, and challenges with dissemination. Lastly, we offer future priorities and resources to improve PROMs in autism research including a need to continue to evaluate and develop PROMs for autistic people using robust methods, to prioritize diverse and representative samples, to expand the breadth of psychometric properties and techniques, and to consider developing field specific guidelines. We remain extremely optimistic about the future directions of this area of autism research. This work is well positioned to have an immense, positive impact on our scientific understanding of autism and the everyday lives of autistic people and their families

GRADE equity guidelines 4: guidance on how to assess and address health equity within the evidence to decision process

Objective: The aim of this paper is to provide detailed guidance on how to incorporate health equity within the GRADE (Grading Recommendations Assessment and Development Evidence) evidence to decision process. Study design and setting: We developed this guidance based on the GRADE evidence to decision (EtD) framework, iteratively reviewing and modifying draft documents, in person discussion of project group members and input from other GRADE members. Results: Considering the impact on health equity may be required, both in general guidelines, and guidelines that focus on disadvantaged populations. We suggest two approaches to incorporate equity considerations: 1) assessing the potential impact of interventions on equity and; 2) incorporating equity considerations when judging or weighing each of the evidence to decision criteria. We provide guidance and include illustrative examples. Conclusion: Guideline panels should consider the impact of recommendations on health equity with attention to remote and underserviced settings and disadvantaged populations. Guideline panels may wish to incorporate equity judgments across the evidence to decision framework

Rx for Hunger: Affordable Housing

This report by Children's HealthWatch and the Medical-Legal Partnership | Boston finds that housing plays a significant role in protecting young children from food insecurity and the health risks of being seriously underweight. This report confirms that increased support for subsidized housing must be part of the strategy for ending childhood hunger

Bringing Children in from the Cold: Solutions for Boston's Hidden Homeless

This report describes a population of "hidden homeless" families and new research showing that children in these families are more likely to be hungry and in poor health. Unrecorded by any homeless census, these families move frequently, often into overcrowded apartments, or double up with another family never knowing how long they can stay. The report estimates that there are over 14,800 hidden homeless families in Boston and that this number is likely to grow as the economy declines

Hematopoietic Cell Transplant and Use of Massage for Improved Symptom Management: Results from a Pilot Randomized Control Trial

Background. Pediatric hematopoietic cell transplant (HCT) is a lifesaving treatment that often results in physical and psychological discomfort. An acupressure-massage intervention may improve symptom management in this setting. Methods. This randomized controlled pilot trial compared a combined massage-acupressure intervention to usual care. Children were offered three practitioner-provided sessions per week throughout hospitalization. Parents were trained to provide additional acupressure as needed. Symptoms were assessed using nurses' reports and two questionnaires, the behavioral affective and somatic experiences scale and the Peds quality of life cancer module. Results. We enrolled 23 children, ages 5 to 18. Children receiving the intervention reported fewer days of mucositis (Hedges' g effect size ES = 0.63), lower overall symptom burden (ES = 0.26), feeling less tired and run-down (ES = 0.86), having fewer moderate/severe symptoms of pain, nausea, and fatigue (ES = 0.62), and less pain (ES = 0.42). The intervention group showed trends toward increasing contentness/serenity (ES = +0.50) and decreasing depression (ES = −0.45), but not decreased anxiety (ES = +0.42). Differences were not statistically significant. Discussion. Feasibility of studying massage-acupressure was established in children undergoing HCT. Larger studies are needed to test the efficacy of such interventions in reducing HCT-associated symptoms in children

Massage for Children Undergoing Hematopoietic Cell Transplantation: A Qualitative Report

Background. No in-depth qualitative research exists about the effects of therapeutic massage with children hospitalized to undergo hematopoietic cell transplantation (HCT). The objective of this study is to describe parent caregivers' experience of the effects of massage/acupressure for their children undergoing HCT. Methods. We conducted a qualitative analysis of open-ended interviews with 15 parents of children in the intervention arm of a massage/acupressure trial. Children received both practitioner and parent-provided massage/acupressure. Results. Parents reported that their child experienced relief from pain and nausea, relaxation, and greater ease falling asleep. They also reported increased caregiver competence and closeness with their child as a result of learning and performing massage/acupressure. Parents supported a semistandardized massage protocol. Conclusion. Massage/acupressure may support symptom relief and promote relaxation and sleep among pediatric HCT patients if administered with attention to individual patients' needs and hospital routines and may relieve stress among parents, improve caregiver competence, and enhance the sense of connection between parent and child