Examining the mental health impacts of climate change on young people in Canada: a national cross-sectional survey.

BACKGROUND: Climate change poses a substantial threat to the mental wellbeing of young people. Population-level research is urgently needed to help inform policies and interventions to ensure that young people are not burdened by long-term mental health impacts from climate change. We sought to identify the prevalence, distribution, and factors associated with climate change-related mental and emotional health outcomes among young people (aged 13-34 years) in Canada. METHODS: This study is part of a larger cross-sectional survey, which examined mental and emotional health responses to climate change among individuals aged 13 years or older from across Canada. We used a multi-stage, multi-stratified random probability sampling procedure. Participants were randomly recruited through either an addressed letter or a telephone call. Online and telephone questionnaires were used to interview individuals in English, French, or Inuktitut between April 1, 2022, and March 31, 2023. Data were weighted by age and province using population estimates from Statistics Canada and analysed using descriptive statistics, factor analyses, and multivariable regression analyses. FINDINGS: The full survey included 2476 participants, with a subgroup of 409 young people. Of the 401 respondents who provided their gender identity, 215 (54%) identified as cisgender women, 167 (42%) identified as cisgender men, and 19 (5%) identified as non-binary. Preliminary results suggest that young people in Canada experience a wide range of climate-related emotional and mental health outcomes. More than 70% of respondents in the young people subgroup reported having at least mild levels of sadness, anger, worry, anxiety, concern, helplessness, hopelessness, or powerlessness related to climate change. The severity of climate-related emotional responses differed by gender, with non-binary respondents and cisgender women reporting higher average levels of distress than cisgender men. Regional differences were also observed, with northern regions and urban locations reporting more severe reactions. INTERPRETATION: This study builds on the understanding of the burden of climate change on the mental health of young people. If unaddressed, the impact of this burden could have long-standing and wide-reaching public health and related socioeconomic effects. FUNDING: Canadian Institutes of Health Research, ArcticNet, Social Sciences and Humanities Research Council Doctoral Fellowship, Izaak Walton Killam Memorial Scholarship, and Alberta Innovates Graduate Student Scholarship.

Structural basis for allosteric regulation of human phosphofructokinase-1.

Phosphofructokinase-1 (PFK1) catalyzes the rate-limiting step of glycolysis, committing glucose to conversion into cellular energy. PFK1 is highly regulated to respond to the changing energy needs of the cell. In bacteria, the structural basis of PFK1 regulation is a textbook example of allostery; molecular signals of low and high cellular energy promote transition between an active R-state and inactive T-state conformation, respectively Little is known, however, about the structural basis for regulation of eukaryotic PFK1. Here, we determine structures of the human liver isoform of PFK1 (PFKL) in the R- and T-state by cryoEM, providing insight into eukaryotic PFK1 allosteric regulatory mechanisms. The T-state structure reveals conformational differences between the bacterial and eukaryotic enzyme, the mechanisms of allosteric inhibition by ATP binding at multiple sites, and an autoinhibitory role of the C-terminus in stabilizing the T-state. We also determine structures of PFKL filaments that define the mechanism of higher-order assembly and demonstrate that these structures are necessary for higher-order assembly of PFKL in cells.

Systemic and immunotoxicity induced by topical application of perfluorohexane sulfonic acid (PFHxS) in a murine model.

Per- and polyfluoroalkyl substances (PFAS) are a large group of stable synthetic surfactants that are incorporated into numerous products for their water and oil resistance and have been associated with adverse health effects. The present study evaluated the systemic and immunotoxicity of sub-chronic 28- or 10-day dermal exposure of PFHxS (0.625-5% or 15.63-125 mg/kg/dose) in a murine model. Elevated levels of PFHxS were detected in the serum and urine, suggesting that absorption is occurring through the dermal route. Liver weight (% body) significantly increased and spleen weight (% body) significantly decreased with PFHxS exposure, which was supported by histopathological changes. Additionally, PFHxS significantly reduced the humoral immune response and altered immune subsets in the spleen, suggesting immunosuppression. Gene expression changes were observed in the liver, skin, and spleen with genes involved in fatty acid metabolism, necrosis, and inflammation. Immune-cell phenotyping identified significant decreases in B-cells, NK cells, and CD11b+ monocyte/macrophages in the spleen along with increases in CD4+ and CD8+ T-cells, NK cells, and neutrophils in the skin. These findings support dermal PFHxS-induced liver damage and immune suppression. Overall, data support PFHxS absorption through the skin and demonstrate immunotoxicity via this exposure route, suggesting the need for further examination.

Estimating climate change and mental health impacts in Canada: A cross-sectional survey protocol.

Climate change has severe and sweeping impacts on mental health. Although research is burgeoning on mental health impacts following climate and weather extremes, less is known about how common these impacts are outside of extreme events. Existing research exploring the prevalence of psychosocial responses to climate change primarily examines university students and uses non-random sampling methods. Herein, our protocol outlines an approach to data collection, processing, and analysis to estimate the population prevalence, magnitude, and distribution of mental health responses to climate change in Canada. A cross-sectional survey of youth and adults aged 13 years and older in Canada will be administered over the course of one year. The questionnaire will take approximately 10 minutes to complete orally and will be administered in English, French, and Inuktitut. The survey will consist of six sections: (1) self-reported past experiences of climate change; (2) self-reported climate-related emotions; (3) self-reported past and current impacts, anticipatory impacts, and vicarious experiences; (4) self-reported subclinical outcomes; (5) self-reported behavioural responses; and (6) demographics. A multi-stage, multi-stratified random probability sampling method will be used to obtain a sample representative of the Canadian population. We will use two different modes of recruitment: an addressed letter sent by postal mail or a telephone call (landlines and cellular). Population-weighted descriptive statistics, principal component analysis, and weighted multivariable regression will be used to analyse the data. The results of this survey will provide the first national prevalence estimates of subclinical mental health responses to climate change outcomes of people living in Canada.

Cancer-associated somatic mutations in human phosphofructokinase-1 reveal a critical electrostatic interaction for allosteric regulation of enzyme activity.

Metabolic reprogramming, including increased glucose uptake and lactic acid excretion, is a hallmark of cancer. The glycolytic 'gatekeeper' enzyme phosphofructokinase-1 (PFK1), which catalyzes the step committing glucose to breakdown, is dysregulated in cancers. While altered PFK1 activity and expression in tumors have been demonstrated, little is known about the effects of cancer-associated somatic mutations. Somatic mutations in PFK1 inform our understanding of allosteric regulation by identifying key amino acid residues involved in the regulation of enzyme activity. Here, we characterized mutations disrupting an evolutionarily conserved salt bridge between aspartic acid and arginine in human platelet (PFKP) and liver (PFKL) isoforms. Using purified recombinant proteins, we showed that disruption of the Asp-Arg pair in two PFK1 isoforms decreased enzyme activity and altered allosteric regulation. We determined the crystal structure of PFK1 to 3.6 Šresolution and used molecular dynamic simulations to understand molecular mechanisms of altered allosteric regulation. We showed that PFKP-D564N had a decreased total system energy and changes in the electrostatic surface potential of the effector site. Cells expressing PFKP-D564N demonstrated a decreased rate of glycolysis, while their ability to induce glycolytic flux under conditions of low cellular energy was enhanced compared with cells expressing wild-type PFKP. Taken together, these results suggest that mutations in Arg-Asp pair at the interface of the catalytic-regulatory domains stabilizes the t-state and presents novel mechanistic insight for therapeutic development in cancer.

An analysis of American physician professional statements about gun violence against children.

BACKGROUND: We examine the content of physician professional association statements and assess the extent to which these statements kept gun violence-especially against children-on policymakers' agendas. METHODS: After constructing a list of U.S. physician professional associations, we located position statements by consulting association websites, conducting a PubMed search, and reviewing the citations of identified statements. Once unique statements were identified (N = 32), two reviewers independently coded content such as major events, pediatric focus, firearm type, and policy recommendations. RESULTS: Recent statements appear to be timed following mass casualty events such as the Sandy Hook and Parkland school shootings. Associations have increasingly adopted public health framing over time. Nine statements focused on the pediatric population, while an additional 13 made reference to the pediatric population. The most common recommendations include increased gun violence research or research funding (84%), freedom of physician counseling (75%), mandatory background checks (72%), and safe storage (72%). CONCLUSION: Based on this analysis, recent statement volume appears to be tied to current events rather than keeping daily gun violence against children continuously on the agenda. Mentions of "gun control" have receded over time and have been replaced by public health framing that places advocacy for firearm injury prevention in the physician's domain. LEVEL OF EVIDENCE: III/IV.

Selective activation of PFKL suppresses the phagocytic oxidative burst.

In neutrophils, nicotinamide adenine dinucleotide phosphate (NADPH) generated via the pentose phosphate pathway fuels NADPH oxidase NOX2 to produce reactive oxygen species for killing invading pathogens. However, excessive NOX2 activity can exacerbate inflammation, as in acute respiratory distress syndrome (ARDS). Here, we use two unbiased chemical proteomic strategies to show that small-molecule LDC7559, or a more potent designed analog NA-11, inhibits the NOX2-dependent oxidative burst in neutrophils by activating the glycolytic enzyme phosphofructokinase-1 liver type (PFKL) and dampening flux through the pentose phosphate pathway. Accordingly, neutrophils treated with NA-11 had reduced NOX2-dependent outputs, including neutrophil cell death (NETosis) and tissue damage. A high-resolution structure of PFKL confirmed binding of NA-11 to the AMP/ADP allosteric activation site and explained why NA-11 failed to agonize phosphofructokinase-1 platelet type (PFKP) or muscle type (PFKM). Thus, NA-11 represents a tool for selective activation of PFKL, the main phosphofructokinase-1 isoform expressed in immune cells.