Telomerase expression is sufficient for chromosomal integrity in cells lacking p53 dependent G(1 )checkpoint function

BACKGROUND: Secondary cultures of human fibroblasts display a finite lifespan ending at senescence. Loss of p53 function by mutation or viral oncogene expression bypasses senescence, allowing cell division to continue for an additional 10 – 20 doublings. During this time chromosomal aberrations seen in mitotic cells increase while DNA damage and decatenation checkpoint functions in G(2 )cells decrease. METHODS: To explore this complex interplay between chromosomal instability and checkpoint dysfunction, human fibroblast lines were derived that expressed HPV16E6 oncoprotein or dominant-negative alleles of p53 (A143V and H179Q) with or without the catalytic subunit of telomerase. RESULTS: Cells with normal p53 function displayed 86 – 93% G(1 )arrest after exposure to 1.5 Gy ionizing radiation (IR). Expression of HPV16E6 or p53-H179Q severely attenuated G(1 )checkpoint function (3 – 20% arrest) while p53-A143V expression induced intermediate attenuation (55 – 57% arrest) irrespective of telomerase expression. All cell lines, regardless of telomerase expression or p53 status, exhibited a normal DNA damage G(2 )checkpoint response following exposure to 1.5 Gy IR prior to the senescence checkpoint. As telomerase-negative cells bypassed senescence, the frequencies of chromosomal aberrations increased generally congruent with attenuation of G(2 )checkpoint function. Telomerase expression allowed cells with defective p53 function to grow >175 doublings without chromosomal aberrations or attenuation of G(2 )checkpoint function. CONCLUSION: Thus, chromosomal instability in cells with defective p53 function appears to depend upon telomere erosion not loss of the DNA damage induced G(1 )checkpoint

Local links and learning: Resilience in regional, rural and remote schools. Fostering community ties and harnessing learning opportunities to boost resilience

In recent years, schools in regional, rural and remote NSW have been affected by floods, drought, bushfires, animal plagues and other major disruptions, including COVID-19. It is vital that a school community's local capabilities are leveraged and boosted, so that they are ready to deal with future disruptions. This report focusses on two ways to boost the resilience of regional, rural and remote school communities: improving links between schools and their local communities, and opportunities for contextualised student learning and professional learning of school staff

Improving long-term disaster recovery research in Australia through boosting dataset comparability

Emergencies and disasters are increasing in frequency and complexity in Australia and around the world.1 It is well established that the effects of these events take a long time to recover from. There is strong and growing evidence to show that different segments of society are exposed to disasters in different ways, with people and communities affected in interconnected and compounding ways

Fishmeal supplementation during ovine pregnancy and lactation protects against maternal stress-induced programming of the offspring immune system

Background: Prenatally stressed offspring exhibit increased susceptibility to inflammatory disorders due to in utero programming. Research into the effects of n-3 PUFAs shows promising results for the treatment and prevention of these disorders. The purpose of this study was to investigate whether maternal fishmeal supplementation during pregnancy and lactation protects against programming of the offspring\u27s immune response following simulated maternal infection. Methods: In order to accomplish this, 53 ewes were fed a diet supplemented with fishmeal (FM; rich in n-3 PUFA) or soybean meal (SM; rich in n-6 PUFAs) from day 100 of gestation (gd 100) through lactation. On gd135, half the ewes from each dietary group were challenged with either 1.2 μg/kg Escherichia coli lipopolysaccharide (LPS) endotoxin to simulate a bacterial infection, or saline as the control. At 4.5 months of age the offspring\u27s dermal immune response was assessed by cutaneous hypersensitivity testing with ovalbumin (OVA) and candida albicans (CAA) 21 days after sensitization. Skinfold measurements were taken and serum blood samples were also collected to assess the primary and secondary antibody immune response. Results: Offspring born to SM + LPS mothers had a significantly greater change in skinfold thickness in response to both antigens as well as a greater secondary antibody response to OVA compared to all treatments. Conclusions: Supplementation during pregnancy with FM appears to protect against adverse fetal programming that may occur during maternal infection and this may reduce the risk of atopic disease later in life

Associations of lower-limb atherosclerosis and arteriosclerosis with cardiovascular risk factors and disease in older adults:The Atherosclerosis Risk in Communities (ARIC) study

BACKGROUND & AIMS Atherosclerosis and arteriosclerosis contribute to vascular aging and cardiovascular disease (CVD) risk. Both processes can be assessed simply in the lower-limbs and reflect systemic pathology. However, only atherosclerosis is routinely assessed, typically via ankle-brachial index (ABI). Arteriosclerosis can be assessed using femoral-ankle pulse wave velocity (faPWV), but no studies have identified whether ABI and faPWV similarly associate with overt CVD and risk factors, nor whether faPWV confers additional information. The aims of this study were to, (i) Compare associations of ABI and faPWV with traditional CVD risk factors, including age, sex, systolic blood pressure (SBP), high-density lipoprotein (HDL), total cholesterol (TC), smoking, and diabetes; and, ii) Determine the independent and additive associations of ABI and faPWV with a composite measure of prevalent CVD. METHODS We evaluated ABI and faPWV in 4,330 older-aged (75.3±5.0 years) adults using an oscillometric screening device. Associations between ABI and faPWV with CVD risk factors and CVD were determined using mixed-model linear- and logistic-regression. RESULTS ABI and faPWV were associated with age, HDL, and smoking. ABI was associated with sex, TC, diabetes. faPWV was associated with SBP. Both ABI and faPWV were inversely associated with CVD. Low ABI (≤0.9 vs. >0.9) and low faPWV (≤9.94 vs. >9.94) increased the odds of CVD by 2.41-fold (95% CI:1.85,3.17) and 1.46-fold (95% CI:1.23,1.74), respectively. The inverse association between faPWV and CVD was independent of ABI and CVD risk factors. CONCLUSION ABI and faPWV, measures of lower-limb atherosclerosis and arteriosclerosis, are independently associated with CVD risk factors and prevalent CVD. Assessment of faPWV may confer additional risk information beyond ABI

Association of Over-The-Counter Pharmaceutical Sales with Influenza-Like-Illnesses to Patient Volume in an Urgent Care Setting

We studied the association between OTC pharmaceutical sales and volume of patients with influenza-like-illnesses (ILI) at an urgent care center over one year. OTC pharmaceutical sales explain 36% of the variance in the patient volume, and each standard deviation increase is associated with 4.7 more patient visits to the urgent care center (p<0.0001). Cross-correlation function analysis demonstrated that OTC pharmaceutical sales are significantly associated with patient volume during non-flu season (p<0.0001), but only the sales of cough and cold (p<0.0001) and thermometer (p<0.0001) categories were significant during flu season with a lag of two and one days, respectively. Our study is the first study to demonstrate and measure the relationship between OTC pharmaceutical sales and urgent care center patient volume, and presents strong evidence that OTC sales predict urgent care center patient volume year round. © 2013 Liu et al

Health benefits of supplementing nursery pig diets with microalgae or fish oil

Weaning stress can negatively impact a pig’s performance; dietary supplementation with omega-3 polyunsaturated fatty acids (n-3 PUFA) reduces inflammatory stress and promotes nursery pig’s health and growth. Fish oil (FO) is a major source of n-3 PUFA; however, microalgae (AL) may provide an alternative source of n-3 PUFA. The aim of this study was to assess the health benefits of supplementing a plant protein-based nursery diet with 3.12% AL or 1.25% FO providing equal total n-3 PUFA compared to a control (CON) diet. Seventy-two pigs were fed experimental diets for three weeks (phases 1 and 2), followed by a common standard diet for three weeks (phase 3). Following phase 2, 8 pigs per treatment underwent a lipopolysaccharide (LPS) immune stress challenge to assess the acute-phase response and 8 pigs per treatment were vaccinated with novel antigens to assess acquired immunity. No significant differences in piglets’ growth were observed, despite decreased feed intake in FO piglets compared to AL piglets in phase 3. AL supplementation tended to reduce, and FO supplementation significantly reduced the LPS-induced fever response. The AL pigs had significantly reduced cortisol responses, increased cytokine concentrations, and increased chromogranin A concentrations compared to FO and CON pigs following LPS challenge. Results suggest that AL or FO supplementation in nursery diets differentially modulate the acute-phase response, possibly due to different n-3 PUFA profiles between the two ingredients

The Brief Solastalgia Scale: A Psychometric Evaluation and Revision

Witnessing degradation and loss to one’s home environment can cause the negative emotional experience of solastalgia. We review the psychometric properties of the 9-item Solastalgia subscale from the Environmental Distress Scale (Higginbotham et al. (EcoHealth 3:245–254, 2006)). Using data collected from three large, independent, adult samples (N = 4229), who were surveyed soon after the 2019/20 Australian bushfires, factor analyses confirmed the scale’s unidimensionality, while analyses derived from Item Response Theory highlighted the poor psychometric performance and redundant content of specific items. Consequently, we recommend a short-form scale consisting of five items. This Brief Solastalgia Scale (BSS) yielded excellent model fit and internal consistency in both the initial and cross-validation samples. The BSS and its parent version provide very similar patterns of associations with demographic, health, life satisfaction, climate emotion, and nature connectedness variables. Finally, multi-group confirmatory factor analysis demonstrated comparable construct architecture (i.e. configural, metric, and scalar invariance) across validation samples, gender categories, and age. As individuals and communities increasingly confront and cope with climate change and its consequences, understanding related emotional impacts is crucial. The BSS promises to aid researchers, decision makers, and practitioners to understand and support those affected by negative environmental change

Mental health, wellbeing and resilience after the 2019-20 bushfires: The Australian national bushfire health and wellbeing survey - A preliminary report

This report provides an overview of the mental health and wellbeing following Australia’s 2019-20 bushfires, with data recorded 12-18 months after the bushfire season ended. Findings are based on 3,083 adults' responses in an online survey to standard measures of psychological distress (i.e., symptoms of depression, anxiety, stress and posttraumatic stress disorder), loneliness, social connectedness, financial security and psychological resilience (i.e., resilient coping, posttraumatic growth and psychological wellbeing). A novel framework for classifying respondents' severity of bushfire exposure is used based on respondents' range of experiences, rather than their postal code alone. High rates of depression, anxiety and stress were recorded across the whole sample, with severity of bushfire exposure associated with greater severity of distress. For men and women with high bushfire exposure, one in five reported symptoms associated with the clinical cut-off for PTSD. Parents with dependents impacted by bushfire reported more behavioural and emotional challenges in their children than children in communities not impacted by bushfire. Psychological distress among Aboriginal and Torres Strait Islander peoples was especially high among women affected by bushfire, compared to Indigenous men and non-Indigenous people. Markers of psychological resilience across the whole sample included endorsement of resilient coping, personal growth and psychological wellbeing. Notably, bushfire-affected, Indigenous, and parent respondents all reported higher levels of wellbeing and growth. Six key recommendations are put forward to meet the ongoing mental health and wellbeing needs of people affected by bushfire.This research was supported by the Australian Government’s Medical Research Future Fund (MRFF), National Health and Medical Research Council (NHMRC), Stream 2: Mental health impacts of bushfires on affected communities (Grant ID: APP1201732)

PRMT1-dependent regulation of RNA metabolism and DNA damage response sustains pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that has remained clinically challenging to manage. Here we employ an RNAi-based in vivo functional genomics platform to determine epigenetic vulnerabilities across a panel of patient-derived PDAC models. Through this, we identify protein arginine methyltransferase 1 (PRMT1) as a critical dependency required for PDAC maintenance. Genetic and pharmacological studies validate the role of PRMT1 in maintaining PDAC growth. Mechanistically, using proteomic and transcriptomic analyses, we demonstrate that global inhibition of asymmetric arginine methylation impairs RNA metabolism, which includes RNA splicing, alternative polyadenylation, and transcription termination. This triggers a robust downregulation of multiple pathways involved in the DNA damage response, thereby promoting genomic instability and inhibiting tumor growth. Taken together, our data support PRMT1 as a compelling target in PDAC and informs a mechanism-based translational strategy for future therapeutic development. Statement of significance PDAC is a highly lethal cancer with limited therapeutic options. This study identified and characterized PRMT1-dependent regulation of RNA metabolism and coordination of key cellular processes required for PDAC tumor growth, defining a mechanism-based translational hypothesis for PRMT1 inhibitors