Lysosome-related organelles contain an expansion compartment that mediates delivery of zinc transporters to promote homeostasis.

Zinc is an essential nutrient-it is stored during periods of excess to promote detoxification and released during periods of deficiency to sustain function. Lysosome-related organelles (LROs) are an evolutionarily conserved site of zinc storage, but mechanisms that control the directional zinc flow necessary for homeostasis are not well understood. In Caenorhabditis elegans intestinal cells, the CDF-2 transporter stores zinc in LROs during excess. Here, we identify ZIPT-2.3 as the transporter that releases zinc during deficiency; ZIPT-2.3 transports zinc, localizes to the membrane of LROs in intestinal cells, and is necessary for zinc release from LROs and survival during zinc deficiency. In zinc excess and deficiency, the expression levels of CDF-2 and ZIPT-2.3 are reciprocally regulated at the level of mRNA and protein, establishing a fundamental mechanism for directional flow to promote homeostasis. To elucidate how the ratio of CDF-2 and ZIPT-2.3 is altered, we used super-resolution microscopy to demonstrate that LROs are composed of a spherical acidified compartment and a hemispherical expansion compartment. The expansion compartment increases in volume during zinc excess and deficiency. These results identify the expansion compartment as an unexpected structural feature of LROs that facilitates rapid transitions in the composition of zinc transporters to mediate homeostasis, likely minimizing the disturbance to the acidified compartment.

Exploring Distress and Occupational Participation Among Older Canadians During the COVID-19 Pandemic.

Background. The coronavirus disease 2019 (COVID-19) pandemic disrupted daily life with corresponding implications on levels of distress. Purpose. To describe factors associated with high distress among community-dwelling older adults during the first lockdown and explore how occupational participation was managed. Methods. A mixed methods design whereby multivariate regression analysis of a survey (N = 263) identified factors associated with high distress, as per the Impact of Events of Scale-Revised (IES-R). Follow-up interviews with a sub-sample of those surveyed who reflected a range of IES-R scores were conducted (N = 32). Findings. Those with lower resilience and anxiety/depression had 6.84 and 4.09 greater odds respectively of high distress. From the interviews, the main theme, "Lost and Found," and subthemes (Interruption and Disruption; Surving, not Thriving; Moving Forward, Finding Meaning) highlighted the process and corresponding stages, including adaptive strategies, by which participants navigated changes in their occupational participation. Implications. While the results suggest that many older adults, including those with high distress, were able to manage daily life under lockdown, some experienced ongoing challenges in doing so. Future studies should focus on those who experienced or who are at-higher risk for such challenges to identify supports that mitigate adverse consequences if another event of this magnitude occurs again.

BRG1 HSA domain interactions with BCL7 proteins are critical for remodeling and gene expression.

The SWI/SNF complex remodels chromatin in an ATP-dependent manner through the subunits BRG1 and BRM. Chromatin remodeling alters nucleosome structure to change gene expression; however, aberrant remodeling can result in cancer. We identified BCL7 proteins as critical SWI/SNF members that drive BRG1-dependent gene expression changes. BCL7s have been implicated in B-cell lymphoma, but characterization of their functional role within the SWI/SNF complex has been limited. This study implicates their function alongside BRG1 to drive large-scale changes in gene expression. Mechanistically, the BCL7 proteins bind to the HSA domain of BRG1 and require this domain for binding to chromatin. BRG1 proteins without the HSA domain fail to interact with the BCL7 proteins and have severely reduced chromatin remodeling activity. These results link the HSA domain and the formation of a functional SWI/SNF remodeling complex through the interaction with BCL7 proteins. These data highlight the importance of correct formation of the SWI/SNF complex to drive critical biological functions, as losses of individual accessory members or protein domains can cause loss of complex function.

Chronic stress-driven glucocorticoid receptor activation programs key cell phenotypes and functional epigenomic patterns in human fibroblasts.

Chronic environmental stress can profoundly impact cell and body function. Although the underlying mechanisms are poorly understood, epigenetics has emerged as a key link between environment and health. The genomic effects of stress are thought to be mediated by the action of glucocorticoid stress hormones, primarily cortisol in humans, which act via the glucocorticoid receptor (GR). To dissect how chronic stress-driven GR activation influences epigenetic and cell states, human fibroblasts underwent prolonged exposure to physiological stress levels of cortisol and/or a selective GR antagonist. Cortisol was found to drive robust changes in cell proliferation, migration, and morphology, which were abrogated by concomitant GR blockade. The GR-driven cell phenotypes were accompanied by widespread, yet genomic context-dependent, changes in DNA methylation and mRNA expression, including gene loci with known roles in cell proliferation and migration. These findings provide insights into how chronic stress-driven functional epigenomic patterns become established to shape key cell phenotypes.

Impact of COVID-19 on mobility and participation of older adults living in Hamilton, Ontario, Canada: a multimethod cohort design protocol.

INTRODUCTION: The novel COVID-19 required many countries to impose public health measures that likely impacted the participation and mobility of community-dwelling older adults. This protocol details a multimethod cohort design undertaken to describe short-term and medium-term changes to the mobility and participation of older Canadians living in the community rather than retirement facilities during the COVID-19 pandemic. METHODS AND ANALYSIS: A longitudinal telephone (or online)-administered survey is being conducted with a random sample of older adults living within 20 km of McMaster University, Hamilton, Ontario, Canada, identified from census dissemination areas. Baseline data collection of community-dwelling older adults aged 65 years and over began in May 2020 with follow-ups at 3, 6, 9 and 12 months. The Late-Life Function and Disability Instrument and global rating of change anchors are the primary outcomes of interest. A subsample of respondents will participate in open-ended, semistructured interviews conducted over the telephone or through video-conference, to explore participants' lived experiences with respect to their mobility and participation during the pandemic. Descriptive statistics and quantitative approaches will be used to determine changes in mobility and social and personal participation, and associated personal and environmental factors. For the interviews, qualitative data will be analysed using descriptive phenomenology. ETHICS AND DISSEMINATION: Approval was obtained from the Hamilton Integrated Research Ethics Board of McMaster University (2020-10814-GRA). This study may inform the design of programmes that can support community-dwelling older adults during and after the COVID-19 pandemic. Findings will be disseminated through peer-reviewed publications and conferences focused on ageing.

BAF Complexes and the Glucocorticoid Receptor in Breast Cancers.

Breast cancers are a diverse group of diseases and are often characterized by their expression of receptors for hormones such as estrogen and progesterone. Recently another steroid hormone receptor, the glucocorticoid receptor (GR) has been shown to be a key player in breast cancer progression, metastasis, and treatment. These receptors bind to chromatin to elicit transcriptional changes within cells, which are often inhibited by the structure of chromatin itself. Chromatin remodeling proteins, such as Brahma-related gene 1 (BRG1), function to overcome this physical inhibition of transcription factor function and have been linked to many cancers including breast cancer. Recent efforts to understand the interactions of BRG1 and GR, including genomic and single cell analyses, within breast cancers may give insight into personalized medicine and other potential treatments.

The zinc transporter ZIPT-7.1 regulates sperm activation in nematodes.

Sperm activation is a fascinating example of cell differentiation, in which immotile spermatids undergo a rapid and dramatic transition to become mature, motile sperm. Because the sperm nucleus is transcriptionally silent, this transition does not involve transcriptional changes. Although Caenorhabditis elegans is a leading model for studies of sperm activation, the mechanisms by which signaling pathways induce this transformation remain poorly characterized. Here we show that a conserved transmembrane zinc transporter, ZIPT-7.1, regulates the induction of sperm activation in Caenorhabditis nematodes. The zipt-7.1 mutant hermaphrodites cannot self-fertilize, and males reproduce poorly, because mutant spermatids are defective in responding to activating signals. The zipt-7.1 gene is expressed in the germ line and functions in germ cells to promote sperm activation. When expressed in mammalian cells, ZIPT-7.1 mediates zinc transport with high specificity and is predominantly located on internal membranes. Finally, genetic epistasis places zipt-7.1 at the end of the spe-8 sperm activation pathway, and ZIPT-7.1 binds SPE-4, a presenilin that regulates sperm activation. Based on these results, we propose a new model for sperm activation. In spermatids, inactive ZIPT-7.1 is localized to the membranous organelles, which contain higher levels of zinc than the cytoplasm. When sperm activation is triggered, ZIPT-7.1 activity increases, releasing zinc from internal stores. The resulting increase in cytoplasmic zinc promotes the phenotypic changes characteristic of activation. Thus, zinc signaling is a key step in the signal transduction process that mediates sperm activation, and we have identified a zinc transporter that is central to this activation process.

A pathway for low zinc homeostasis that is conserved in animals and acts in parallel to the pathway for high zinc homeostasis.

The essential element zinc plays critical roles in biology. High zinc homeostasis mechanisms are beginning to be defined in animals, but low zinc homeostasis is poorly characterized. We investigated low zinc homeostasis in Caenorhabditis elegans because the genome encodes 14 evolutionarily conserved Zrt, Irt-like protein (ZIP) zinc transporter family members. Three C. elegans zipt genes were regulated in zinc-deficient conditions; these promoters contained an evolutionarily conserved motif that we named the low zinc activation (LZA) element that was both necessary and sufficient for activation of transcription in response to zinc deficiency. These results demonstrated that the LZA element is a critical part of the low zinc homeostasis pathway. Transcriptional regulation of the LZA element required the transcription factor ELT-2 and mediator complex member MDT-15. We investigated conservation in mammals by analyzing LZA element function in human cultured cells; the LZA element-mediated transcriptional activation in response to zinc deficiency in cells, suggesting a conserved pathway of low zinc homeostasis. We propose that the pathway for low zinc homeostasis, which includes the LZA element and ZIP transporters, acts in parallel to the pathway for high zinc homeostasis, which includes the HZA element, HIZR-1 transcription factor and cation diffusion facilitator transporters.

Insights into zinc and cadmium biology in the nematode Caenorhabditis elegans.

Zinc is an essential metal that is involved in a wide range of biological processes, and aberrant zinc homeostasis is implicated in multiple human diseases. Cadmium is chemically similar to zinc, but it is a nonessential environmental pollutant. Because zinc deficiency and excess are deleterious, animals require homeostatic mechanisms to maintain zinc levels in response to dietary fluctuations. The nematode Caenorhabditis elegans is emerging as a powerful model system to investigate zinc trafficking and homeostasis as well as cadmium toxicity. Here we review genetic and molecular studies that have combined to generate a picture of zinc homeostasis based on the transcriptional control of zinc transporters in intestinal cells. Furthermore, we summarize studies of cadmium toxicity that reveal intriguing parallels with zinc biology.

Angiotensin Converting Enzyme (ACE) Inhibitor Extends Caenorhabditis elegans Life Span.

Animal aging is characterized by progressive, degenerative changes in many organ systems. Because age-related degeneration is a major contributor to disability and death in humans, treatments that delay age-related degeneration are desirable. However, no drugs that delay normal human aging are currently available. To identify drugs that delay age-related degeneration, we used the powerful Caenorhabditis elegans model system to screen for FDA-approved drugs that can extend the adult lifespan of worms. Here we show that captopril extended mean lifespan. Captopril is an angiotensin-converting enzyme (ACE) inhibitor used to treat high blood pressure in humans. To explore the mechanism of captopril, we analyzed the acn-1 gene that encodes the C. elegans homolog of ACE. Reducing the activity of acn-1 extended the mean life span. Furthermore, reducing the activity of acn-1 delayed age-related degenerative changes and increased stress resistance, indicating that acn-1 influences aging. Captopril could not further extend the lifespan of animals with reduced acn-1, suggesting they function in the same pathway; we propose that captopril inhibits acn-1 to extend lifespan. To define the relationship with previously characterized longevity pathways, we analyzed mutant animals. The lifespan extension caused by reducing the activity of acn-1 was additive with caloric restriction and mitochondrial insufficiency, and did not require sir-2.1, hsf-1 or rict-1, suggesting that acn-1 functions by a distinct mechanism. The interactions with the insulin/IGF-1 pathway were complex, since the lifespan extensions caused by captopril and reducing acn-1 activity were additive with daf-2 and age-1 but required daf-16. Captopril treatment and reducing acn-1 activity caused similar effects in a wide range of genetic backgrounds, consistent with the model that they act by the same mechanism. These results identify a new drug and a new gene that can extend the lifespan of worms and suggest new therapeutic strategies for addressing age-related degenerative changes.

Three-dimensional cephalometric superimposition of the nasomaxillary complex.

INTRODUCTION: Two-dimensional maxillary superimposition techniques have been routinely used in clinical practice, but a 3-dimensional plane has yet to be introduced and validated. The purposes of this study were to propose a new plane for regional superimposition of the maxillary complex and then to validate it through clinical data. METHODS: Pretreatment and posttreatment palatal expansion records were used. The magnitudes of the transverse expansion at the levels of the first premolars and the first molars were assessed using the proposed superimposition plane and then were compared with the gold standard plaster model measurements. Descriptive statistics and agreement testing were performed to compare the methods. RESULTS: When comparing the superimposition and plaster measurement methods, the mean errors for intermolar and interpremolar distances were 0.57 and 0.59 mm, respectively. Both the intraclass correlation coefficient and the Bland-Altman plot demonstrated high agreement between the 2 methods (intraclass correlation coefficient greater than 0.9). CONCLUSIONS: The proposed maxillary superimposition plane yields clinically suitable results when compared with the gold standard technique, with a mean error of less than 0.6 mm for typical intra-arch measurements. This new landmark-derived maxillary plane for superimposition is a promising tool for evaluating maxillary dentoalveolar changes after treatment.

Cone beam computed tomography registration for 3-D airway analysis based on anatomic landmarks.

OBJECTIVES: Explore craniofacial landmarks reliability to superimpose cone beam computed tomography (CBCT) images and assess impact of plane reorientation on airway parameters. STUDY DESIGN: 10 CBCTs were marked 3 times at baseline, 3 T1, to test landmark reliability. Measurement errors of new coordinate system were tested using 3 T1, and other 10 paired CBCT images, at T1 and T2. Effect on upper airway was assessed using volume, surface area, and point-based analysis. RESULTS: Tips of nasal bone and clivus and foramina spinosa defined the new coordinate system. Plane reorientation didn't affect landmark identification reliability and significantly reduced interlandmark distances from T1-T2. Airway volume changed by 25.76 ± 24.9%, surface area by 13.85 ± 10.8%, and mean part analysis was 0.43 ± 0.3 mm. Strong correlation (R(2) > 65%) was found between airway analysis and large distances in second and third cervical vertebrae. CONCLUSIONS: Coordinate transformation significantly reduced measurement errors in longitudinal CBCT data; however, it is not designed to correct for large neck flexion.

Mated progeny production is a biomarker of aging in Caenorhabditis elegans.

The relationships between reproduction and aging are important for understanding the mechanisms of aging and evaluating evolutionary theories of aging. To investigate the effects of progeny production on reproductive and somatic aging, we conducted longitudinal studies of Caenorhabditis elegans hermaphrodites. For mated wild-type animals that were not sperm limited and survived past the end of the reproductive period, high levels of cross-progeny production were positively correlated with delayed reproductive and somatic aging. In this group of animals, individuals that generated more cross progeny also reproduced and lived longer than individuals that generated fewer cross progeny. These results indicate that progeny production does not accelerate reproductive or somatic aging. This longitudinal study demonstrated that cumulative cross progeny production through day four is an early-stage biomarker that is a positive predictor of longevity. Furthermore, in mated animals, high levels of early cross progeny production were positively correlated with high levels of late cross progeny production, indicating that early progeny production does not accelerate reproductive aging. The relationships between progeny production and aging were further evaluated by comparing self-fertile hermaphrodites that generated relatively few self progeny with mated hermaphrodites that generated many cross progeny. The timing of age-related somatic degeneration was similar in these groups, suggesting progeny production does not accelerate somatic aging. These studies rigorously define relationships between progeny production, reproductive aging, and somatic aging and identify new biomarkers of C. elegans aging. These results indicate that some mechanisms or pathways control age-related degeneration of both reproductive and somatic tissues in C. elegans.