High temperatures reduce growth, infection, and transmission of a naturally occurring fungal plant pathogen.

Climate change is rapidly altering the distribution of suitable habitats for many species as well as their pathogenic microbes. For many pathogens, including vector-borne diseases of humans and agricultural pathogens, climate change is expected to increase transmission and lead to pathogen range expansions. However, if pathogens have a lower heat tolerance than their host, increased warming could generate so-called thermal refugia for hosts. Predicting the outcomes of warming on disease transmission requires detailed knowledge of the thermal tolerances of both the host and the pathogen. Such thermal tolerance studies are generally lacking for fungal pathogens of wild plant populations, despite the fact that plants form the base of all terrestrial communities. Here, we quantified three aspects of the thermal tolerance (growth, infection, and propagule production) of the naturally occurring fungal pathogen Microbotryum lychnidis-dioicae, which causes a sterilizing anther-smut disease on the herbaceous plant Silene latifolia. We also quantified two aspects of host thermal tolerance: seedling survival and flowering rate. We found that temperatures >30°C reduced the ability of anther-smut spores to germinate, grow, and conjugate in vitro. In addition, we found that high temperatures (30°C) during or shortly after the time of inoculation strongly reduced the likelihood of infection in seedlings. Finally, we found that high summer temperatures in the field temporarily cured infected plants, likely reducing transmission. Notably, high temperatures did not reduce survival or flowering of the host plants. Taken together, our results show that the fungus is considerably more sensitive to high temperatures than its host plant. A warming climate could therefore result in reduced disease spread or even local pathogen extirpation, leading to thermal refugia for the host.

Establishing healthy longevity clinics in publicly funded hospitals.

Healthy longevity medicine integrates geroscience and other disciplines into clinical settings, aiming to optimize health throughout one's lifespan. Multiple factors have led to increased consumer engagement, with private clinics currently meeting the demand for guidance to improve healthy longevity. The establishment of healthy longevity clinics in publicly funded hospitals is a significant development, making longevity-focused healthcare more accessible. These clinics rely on multidisciplinary teams of physicians and allied health professionals. Diagnostics involve comprehensive evaluations of medical history, physical examinations, and various clinical tests to detect early signs of age-related functional decline. Interventions in healthy longevity medicine encompass lifestyle modifications, supplements, repurposed drugs, and social and environmental interventions. Collaboration with research institutions and industry partners is crucial for advancing healthy longevity medicine and creating standardized protocols. In this article, we review the process of creating healthy longevity clinics in public hospitals to ensure the best possible care for individuals pursuing healthy longevity.

Risk of falls is associated with 30-day mortality among older adults in the emergency department.

OBJECTIVE: Falls in older adults correlate with heightened morbidity and mortality. Assessing fall risk in the emergency department (ED) not only aids in identifying candidates for prevention interventions but may also offer insights into overall mortality risk. We sought to examine the link between fall risk and 30-day mortality in older ED adults. METHODS: Observational cohort study of adults aged ≥ 75years who presented to an academic ED and who were assessed for fall risk using the Memorial Emergency Department Fall Risk Assessment Tool (MEDFRAT), a validated, ED-specific screening tool. The fall risk was classified as low (0-2 points), moderate (3-4 points), or high (≥5) risk. The primary outcome was 30-day mortality. Hazard ratios (HR) with 95% confidence intervals (CIs) were calculated. RESULTS: A total of 941 patients whose fall risk was assessed in the ED were included in the study. Median age was 83.7 years; 45.6% were male, 75.6% lived in private residences, and 62.7% were admitted. Mortality at 30 days among the high fall risk group was four times that of the low fall risk group (11.8% vs 3.1%; HR 4.00, 95% CI 2.18 to 7.34, p < 0.001). Moderate fall risk individuals had nearly double the mortality rate of the low-risk group (6.0% vs 3.1%), but the difference was not statistically significant (HR 1.98, 95% CI 0.91 to 4.32, p = 0.087). CONCLUSION: ED fall risk assessments are linked to 30-day mortality. Screening may facilitate the stratification of older adults at risk for health deterioration.

Functional domains of a ribosome arresting peptide are affected by surrounding nonconserved residues.

Expression of the Escherichia coli tnaCAB operon, responsible for L-tryptophan (L-Trp) transport and catabolism, is regulated by L-Trp-directed translation arrest and the ribosome arresting peptide TnaC. The function of TnaC relies on conserved residues distributed throughout the peptide, which are involved in forming an L-Trp binding site at the ribosome exit tunnel and inhibiting the ribosome function. We aimed to understand whether nonconserved amino acids surrounding these critical conserved residues play a functional role in TnaC-mediated ribosome arrest. We have isolated two intragenic suppressor mutations that restore arrest function of TnaC mutants; one of these mutations is located near the L-Trp binding site, while the other mutation is located near the ribosome active site. We used reporter gene fusions to show that both suppressor mutations have similar effects on TnaC mutants at the conserved residues involved in forming a free L-Trp binding site. However, they diverge in suppressing loss-of-function mutations in a conserved TnaC residue at the ribosome active site. With ribosome toeprinting assays, we determined that both suppressor mutations generate TnaC peptides, which are highly sensitive to L-Trp. Puromycin-challenge assays with isolated arrested ribosomes indicate that both TnaC suppressor mutants are resistant to peptidyl-tRNA cleavage by puromycin in the presence of L-Trp; however, they differ in their resistance to puromycin in the absence of L-Trp. We propose that the TnaC peptide two functionally distinct segments, a sensor domain and a stalling domain, and that the functional versatility of these domains is fine-tuned by the nature of their surrounding nonconserved residues.

Adolescent restraint stress enhances adult nicotine reinforcement in male and female rats.

Adolescent stress is a risk factor for the initiation of nicotine use, but whether adolescent stress can enhance nicotine reinforcement when it is initiated later in adulthood is unknown, and it is unclear whether males and females are equally impacted. Therefore, this study assessed physiological responses (body weight and blood serum corticosterone - CORT) to restraint stress (RS) during adolescence (P28-55) or during adulthood (P70-96) in male and female Sprague-Dawley rats. When all subjects reached adulthood (P69 or 110; 2 weeks after termination of stress exposure), they were tested on sucrose preference and intravenous single-dose nicotine (0.03 mg/kg/infusion) self-administration. It was found that all rats displayed a significant CORT response to RS. Importantly, stress during adolescence, but not during adulthood, enhanced subsequent acquisition of nicotine intake tested in adulthood. Although this effect was observed in both sexes, only males displayed reduced body weight gain and adult sucrose preference. Moreover, regardless of stress exposure, females were more stimulated by nicotine, consumed more nicotine overall, and displayed enhanced nicotine seeking. These results suggest that adolescence is a period of heightened sensitivity to the enhancing effect of repeated stress on the susceptibility to develop nicotine dependence later in life in both sexes.

Biomarkers of cellular senescence and risk of death in humans.

A robust and heterogenous secretory phenotype is a core feature of most senescent cells. In addition to mediators of age-related pathology, components of the senescence associated secretory phenotype (SASP) have been studied as biomarkers of senescent cell burden and, in turn, biological age. Therefore, we hypothesized that circulating concentrations of candidate senescence biomarkers, including chemokines, cytokines, matrix remodeling proteins, and growth factors, could predict mortality in older adults. We assessed associations between plasma levels of 28 SASP proteins and risk of mortality over a median follow-up of 6.3 years in 1923 patients 65 years of age or older with zero or one chronic condition at baseline. Overall, the five senescence biomarkers most strongly associated with an increased risk of death were GDF15, RAGE, VEGFA, PARC, and MMP2, after adjusting for age, sex, race, and the presence of one chronic condition. The combination of biomarkers and clinical and demographic covariates exhibited a significantly higher c-statistic for risk of death (0.79, 95% confidence interval (CI): 0.76-0.82) than the covariates alone (0.70, CI: 0.67-0.74) (p < 0.001). Collectively, these findings lend further support to biomarkers of cellular senescence as informative predictors of clinically important health outcomes in older adults, including death.

HCN channel inhibitor induces ketamine-like rapid and sustained antidepressant effects in chronic social defeat stress model.

Repeated, long-term (weeks to months) exposure to standard antidepressant medications is required to achieve treatment efficacy. In contrast, acute ketamine quickly improves mood for an extended time. Recent work implicates that hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are involved in mediating ketamine's antidepressant effects. In this study, we directly targeted HCN channels and achieved ketamine-like rapid and sustained antidepressant efficacy. Our in vitro electrophysiological recordings first showed that HCN inhibitor DK-AH 269 (also called cilobradine) decreased the pathological HCN-mediated current (Ih) and abnormal hyperactivity of ventral tegmental area (VTA) dopamine (DA) neurons in a depressive-like model produced by chronic social defeat stress (CSDS). Our in vivo studies further showed that acute intra-VTA or acute systemic administration of DK-AH 269 normalized social behavior and rescued sucrose preference in CSDS-susceptible mice. The single-dose of DK-AH 269, both by intra-VTA microinfusion and intraperitoneal (ip) approaches, could produce an extended 13-day duration of antidepressant-like efficacy. Animals treated with acute DK-AH 269 spent less time immobile than vehicle-treated mice during forced swim test. A social behavioral reversal lasted up to 13 days following the acute DK-AH 269 ip injection, and this rapid and sustained antidepressant-like response is paralleled with a single-dose treatment of ketamine. This study provides a novel ion channel target for acutely acting, long-lasting antidepressant-like effects.

Braiding Indigenous rights and endangered species law.

Recovery targets fall short of culturally meaningful abundance.

When death comes: linking predator-prey activity patterns to timing of mortality to understand predation risk.

The assumption that activity and foraging are risky for prey underlies many predator-prey theories and has led to the use of predator-prey activity overlap as a proxy of predation risk. However, the simultaneous measures of prey and predator activity along with timing of predation required to test this assumption have not been available. Here, we used accelerometry data on snowshoe hares (Lepus americanus) and Canada lynx (Lynx canadensis) to determine activity patterns of prey and predators and match these to precise timing of predation. Surprisingly we found that lynx kills of hares were as likely to occur during the day when hares were inactive as at night when hares were active. We also found that activity rates of hares were not related to the chance of predation at daily and weekly scales, whereas lynx activity rates positively affected the diel pattern of lynx predation on hares and their weekly kill rates of hares. Our findings suggest that predator-prey diel activity overlap may not always be a good proxy of predation risk, and highlight a need for examining the link between predation and spatio-temporal behaviour of predator and prey to improve our understanding of how predator-prey behavioural interactions drive predation risk.

Exploring the Moderating Role of Ethnic Identity in the Relation Between Peer Stress and Life Satisfaction among Adolescents.

Objective: Ethnic identity is a crucial aspect of identity development during adolescence. This study aimed to examine the potential protective effect of ethnic identity in the relation between peer stress and global life satisfaction among adolescents. Method: Data were collected via self-report measures from 417 adolescents (ages 14 to 18, 63.0% girls; 32.6% African American, 32.1% European American, 15.0% Asian American, 10.5% Hispanic or Latinx, 6.6% Biracial or Multiracial, and 0.7% Other) at one public, urban high school. Results: The first model tested ethnic identity as the single moderator in the entire sample, and the moderation effect was not significant. The second model added ethnicity (African American vs. European American) as another moderator, and moderation effects were significant for both moderators. Furthermore, the negative effect of peer stress on life satisfaction was stronger for African American adolescents than European American counterparts. For both racial groups, the negative effect of peer stress on life satisfaction decreased as ethnic identity increased. The third model tested a three-way interaction across peer stress, ethnicity (African American vs. European American), and ethnic identity, which was not significant. Conclusions: The results supported the buffering effect of ethnic identity in the context of peer stress for both African American and European American adolescents, and such effect appears to be more important for protecting African American adolescents' life satisfaction, though these two moderators appear to work independently, rather than interact with each other and the peer stressor. Implications and future directions are discussed.

Coat color mismatch improves survival of a keystone boreal herbivore: Energetic advantages exceed lost camouflage.

Climate warming is causing asynchronies between animal phenology and environments. Mismatched traits, such as coat color change mismatched with snow, can decrease survival. However, coat change does not serve a singular adaptive benefit of camouflage, and alternate coat change functions may confer advantages that supersede mismatch costs. We found that mismatch reduced, rather than increased, autumn mortality risk of snowshoe hares in Yukon by 86.5% when mismatch occurred. We suggest that the increased coat insulation and lower metabolic rates of winter-acclimatized hares confer energetic advantages to white mismatched hares that reduce their mortality risk. We found that white mismatched hares forage 17-77 min less per day than matched brown hares between 0°C and -10°C, thus lowering their predation risk and increasing survival. We found no effect of mismatch on spring mortality risk, during which mismatch occurred at warmer temperatures, suggesting a potential temperature limit at which the costs of conspicuousness outweigh energetic benefits.

Estrous Cycle Mediates Midbrain Neuron Excitability Altering Social Behavior upon Stress.

The estrous cycle is a potent modulator of neuron physiology. In rodents, in vivo ventral tegmental area (VTA) dopamine (DA) activity has been shown to fluctuate across the estrous cycle. Although the behavioral effect of fluctuating sex steroids on the reward circuit is well studied in response to drugs of abuse, few studies have focused on the molecular adaptations in the context of stress and motivated social behaviors. We hypothesized that estradiol fluctuations across the estrous cycle acts on the dopaminergic activity of the VTA to alter excitability and stress response. We used whole-cell slice electrophysiology of VTA DA neurons in naturally cycling, adult female C57BL/6J mice to characterize the effects of the estrous cycle and the role of 17ß-estradiol on neuronal activity. We show that the estrous phase alters the effect of 17ß-estradiol on excitability in the VTA. Behaviorally, the estrous phase during a series of acute variable social stressors modulates subsequent reward-related behaviors. Pharmacological inhibition of estrogen receptors in the VTA before stress during diestrus mimics the stress susceptibility found during estrus, whereas increased potassium channel activity in the VTA before stress reverses stress susceptibility found during estrus as assessed by social interaction behavior. This study identifies one possible potassium channel mechanism underlying the increased DA activity during estrus and reveals estrogen-dependent changes in neuronal function. Our findings demonstrate that the estrous cycle and estrogen signaling changes the physiology of DA neurons resulting in behavioral differences when the reward circuit is challenged with stress.SIGNIFICANCE STATEMENT The activity of the ventral tegmental area encodes signals of stress and reward. Dopaminergic activity has been found to be regulated by both local synaptic inputs as well as inputs from other brain regions. Here, we provide evidence that cycling sex steroids also play a role in modulating stress sensitivity of dopaminergic reward behavior. Specifically, we reveal a correlation of ionic activity with estrous phase, which influences the behavioral response to stress. These findings shed new light on how estrous cycle may influence dopaminergic activity primarily during times of stress perturbation.

Rescue of deficits by Brwd1 copy number restoration in the Ts65Dn mouse model of Down syndrome.

With an incidence of ~1 in 800 births, Down syndrome (DS) is the most common chromosomal condition linked to intellectual disability worldwide. While the genetic basis of DS has been identified as a triplication of chromosome 21 (HSA21), the genes encoded from HSA21 that directly contribute to cognitive deficits remain incompletely understood. Here, we found that the HSA21-encoded chromatin effector, BRWD1, was upregulated in neurons derived from iPS cells from an individual with Down syndrome and brain of trisomic mice. We showed that selective copy number restoration of Brwd1 in trisomic animals rescued deficits in hippocampal LTP, cognition and gene expression. We demonstrated that Brwd1 tightly binds the BAF chromatin remodeling complex, and that increased Brwd1 expression promotes BAF genomic mistargeting. Importantly, Brwd1 renormalization rescued aberrant BAF localization, along with associated changes in chromatin accessibility and gene expression. These findings establish BRWD1 as a key epigenomic mediator of normal neurodevelopment and an important contributor to DS-related phenotypes.

Targeting cellular senescence in metabolic disease.

Cellular senescence is a cell fate involving cell cycle arrest, resistance against apoptosis, and the development of a secretome that can be pro-inflammatory. In aging and obesity, senescent cells accumulate in many tissues, including adipose tissue, brain, kidney, pancreas, and liver. These senescent cells and their downstream effects appear to perpetuate inflammation and have been implicated in the pathogenesis of metabolic dysfunction. Senescent cells are cleared in part by the immune system, a process that is diminished in obesity and aging, likely due in part to senescence of immune cells themselves. Targeting senescent cells or their products improves metabolic function in both aging and in animal models of obesity. Novel therapeutics to target senescent cells are on the horizon and are currently being investigated in clinical trials in humans for multiple diseases. Early evidence suggests that senolytic drugs, which transiently disarm the anti-apoptotic defenses of pro-inflammatory senescent cells, are effective in causing depletion of senescent cells in humans. Senescence-targeting therapeutics, including senolytic drugs and strategies to increase immune clearance of senescent cells, hold significant promise for treating metabolic dysfunction in multiple tissues and disease states.

Metabolic changes in aging humans: current evidence and therapeutic strategies.

Aging and metabolism are inextricably linked, and many age-related changes in body composition, including increased central adiposity and sarcopenia, have underpinnings in fundamental aging processes. These age-related changes are further exacerbated by a sedentary lifestyle and can be in part prevented by maintenance of activity with aging. Here we explore the age-related changes seen in individual metabolic tissues - adipose, muscle, and liver - as well as globally in older adults. We also discuss the available evidence for therapeutic interventions such as caloric restriction, resistance training, and senolytic and senomorphic drugs to maintain healthy metabolism with aging, focusing on data from human studies.

Propofol Immersion As a Euthanasia Method for Adult Zebrafish (Danio Rerio).

The exponential rise of the zebrafish (Danio rerio) as a model organism in biomedical research has far outstripped our un- derstanding of basic husbandry and welfare for this species. As a case in point, here we investigate the efficacy and welfare impact of different euthanasia methods for zebrafish. Not only is a humane death central to welfare and the 3Rs, but stress during euthanasia can change scientific outcomes. However, the most frequently used methods of euthanasia have multiple shortcomings with regard to animal welfare and human safety. In this study, we propose the use of propofol for immersion euthanasia of adult zebrafish. Propofol has been known to rapidly induce anesthesia in many species, including zebrafish, but its efficacy as a euthanasia agent for zebrafish has not fully been explored. In this study, adult zebrafish were euthanized by immersion on one of 5 different preparations: ice bath, 250 ppm MS222, 600 ppm lidocaine hydrochloride, 100 ppm propofol, or 150 ppm propofol for 20 or 30 min. Display of aversive behaviors, time to loss of righting reflex, time to cessation of opercular movement, and time to recovery after transfer to clean tank water were assessed and recorded. Propofol at both concentrations induced loss of righting reflex and loss of opercular movement more quickly than did MS222 or lidocaine hydrochloride and caused no display of aversive behaviors as seen with ice bath or lidocaine exposure. However, fish exposed to propofol at either concentration for 20 min sometimes recovered, whereas a 30-min exposure was sufficient for euthanasia of all fish tested. These findings suggest that exposure to propofol for a duration of at least 30 min quickly and effectively euthanizes adult zebrafish without compromising end-of-life welfare.

Midbrain projection to the basolateral amygdala encodes anxiety-like but not depression-like behaviors.

Anxiety disorders are complex diseases, and often co-occur with depression. It is as yet unclear if a common neural circuit controls anxiety-related behaviors in both anxiety-alone and comorbid conditions. Here, utilizing the chronic social defeat stress (CSDS) paradigm that induces singular or combined anxiety- and depressive-like phenotypes in mice, we show that a ventral tegmental area (VTA) dopamine circuit projecting to the basolateral amygdala (BLA) selectively controls anxiety- but not depression-like behaviors. Using circuit-dissecting ex vivo electrophysiology and in vivo fiber photometry approaches, we establish that expression of anxiety-like, but not depressive-like, phenotypes are negatively correlated with VTA → BLA dopamine neuron activity. Further, our optogenetic studies demonstrate a causal link between such neuronal activity and anxiety-like behaviors. Overall, these data establish a functional role for VTA → BLA dopamine neurons in bi-directionally controlling anxiety-related behaviors not only in anxiety-alone, but also in anxiety-depressive comorbid conditions in mice.

Orally-active, clinically-translatable senolytics restore α-Klotho in mice and humans.

BACKGROUND: α-Klotho is a geroprotective protein that can attenuate or alleviate deleterious changes with ageing and disease. Declines in α-Klotho play a role in the pathophysiology of multiple diseases and age-related phenotypes. Pre-clinical evidence suggests that boosting α-Klotho holds therapeutic potential. However, readily clinically-translatable, practical strategies for increasing α-Klotho are not at hand. Here, we report that orally-active, clinically-translatable senolytics can increase α-Klotho in mice and humans. METHODS: We examined α-Klotho expression in three different human primary cell types co-cultured with conditioned medium (CM) from senescent or non-senescent cells with or without neutralizing antibodies. We assessed α-Klotho expression in aged, obese, and senescent cell-transplanted mice treated with vehicle or senolytics. We assayed urinary α-Klotho in patients with idiopathic pulmonary fibrosis (IPF) who were treated with the senolytic drug combination, Dasatinib plus Quercetin (D+Q). FINDINGS: We found exposure to the senescent cell secretome reduces α-Klotho in multiple nonsenescent human cell types. This was partially prevented by neutralizing antibodies against the senescence-associated secretory phenotype (SASP) factors, activin A and Interleukin 1α (IL-1α). Consistent with senescent cells' being a cause of decreased α-Klotho, transplanting senescent cells into younger mice reduced brain and urine α-Klotho. Selectively removing senescent cells genetically or pharmacologically increased α-Klotho in urine, kidney, and brain of mice with increased senescent cell burden, including naturally-aged, diet-induced obese (DIO), or senescent cell-transplanted mice. D+Q increased α-Klotho in urine of patients with IPF, a disease linked to cellular senescence. INTERPRETATION: Senescent cells cause reduced α-Klotho, partially due to their production of activin A and IL-1α. Targeting senescent cells boosts α-Klotho in mice and humans. Thus, clearing senescent cells restores α-Klotho, potentially opening a novel, translationally-feasible avenue for developing orally-active small molecule, α-Klotho-enhancing clinical interventions. Furthermore, urinary α-Klotho may prove to be a useful test for following treatments in senolytic clinical trials. FUNDING: This work was supported by National Institute of Health grants AG013925 (J.L.K.), AG062413 (J.L.K., S.K.), AG044271 (N.M.), AG013319 (N.M.), and the Translational Geroscience Network (AG061456: J.L.K., T.T., N.M., S.B.K., S.K.), Robert and Arlene Kogod (J.L.K.), the Connor Group (J.L.K.), Robert J. and Theresa W. Ryan (J.L.K.), and the Noaber Foundation (J.L.K.). The previous IPF clinical trial was supported by the Claude D. Pepper Older Americans Independence Centers at WFSM (AG021332: J.N.J., S.B.K.), UTHSCA (AG044271: A.M.N.), and the Translational Geroscience Network.