bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adaptations To Mitochondrial Dysfunction Via Inter‐Organelle Communication
Authors: Haynes Cole M 
Published: November 2023

During metazoan development and cell specification, mitochondrial biogenesis is tailored to match the physiologic requirements of individual cell types. Loss of mitochondrial activity, or mitochondrial dysfunction, is tightly linked with a number of seemingly disparate pathologic scenarios including neurodegeneration, cancer, diabetes and bacterial infection. My laboratory is interested in how cells evaluate mitochondrial function and adapt to survive and ultimately recover from mitochondrial stress. By studying a transcriptional response pathway known as the mitochondrial unfolded protein response (UPRmt), we identified ATFS‐1. Because this unique transcription factor has both a mitochondrial and nuclear localization sequence it can function as a sensor of mitochondrial function to couple defects in mitochondrial protein import efficiency and the activation of a broad mitochondrial protective transcriptional response. I will discuss protective roles for the UPRmt during a variety of physiologic conditions associated with mitochondrial dysfunction including during bacterial infection caused by pathogens that specifically perturb mitochondrial function to promote virulence.Support or Funding InformationThis work was supported by the Ellison Medical Foundation and NIH grants R01AG040061 and R01AG047182.
Are Monthly Food Insecurity Assessments Necessary? A Longitudinal Analysis in Rural Zambia
Authors: Na Muzi , Caswell Bess L. , Talegawkar Sameera A. , Palmer Amanda 
Published: November 2023

In resource‐limited settings, we generally assume that household food insecurity (HFI) status is static over time, ranging from a period of a few months to a few years. Longitudinal HFI measures are required to test the validity of this assumption. We assessed HFI on a monthly basis in the context of an efficacy trial of biofortified maize conducted in rural Zambia from October 2012 to March 2013. This period is mostly characterized as the lean season, which peaks in ~April in this setting. The trial included two intervention arms and a parallel non‐intervened group for the purposes of background dietary and food security measures. A total of 907 households were enrolled at baseline; however, the present analysis includes longitudinal data from 157 households in the non‐intervened arm. At each of the six monthly visits, HFI was assessed using a validated 8‐item perception‐based Likert scale with a one month recall period. We calculated a HFI index by summing scores over the Likert scale (ranging from 0 to 32). The median (IQR) HFI index was 7 (4–11), 8 (5–11), 7 (4–10), 6 (4–9), 6 (4–9) and 7 (4–9) at the six monthly visits, respectively. The correlation between HFI index between visits ranged from 0.3 to 0.4. A random effect model was fit on the index as a function of visit clustered at household level. Results from the model showed that the HFI index decreased on average by 0.25 points per visit. Within and between household variation in the index was 10.6 and 8.8, respectively. Within‐household variability of the HFI index did not show a clear pattern in relation to the household mean score. Because our repeated HFI measurements were conducted in one single season, the small change in mean monthly HFI index suggested that seasonal assessments may be sufficient for population monitoring purposes in similar settings. However, higher variation within some households suggests that household characteristics—as opposed to seasonal impacts on food security—may explain the differences in variation in response to the repeated scale.Support or Funding InformationHarvestPlus (grant 8251) and Sight and Life Global Nutrition Research Institute at Johns Hopkins University
A Folate, Vitamin B12 and Homocysteine‐related dietary pattern and risk of subclinical atherosclerosis: findings from the MRC National Survey of Health and Development (NSHD)
Authors: Maddock Jane , Ambrosini Gina L , Ray Sumantra ,   NSHD Study Team
Published: November 2023

Elevated homocysteine concentrations have been shown to increase the risk of stroke. However, the relationship between dietary patterns (DP) associated with homocysteine and associated nutrients (i.e. folate and vitamin B12) with subclinical atherosclerosis, an early marker of stroke, remains unknown. This study identifies a DP characterised by plasma homocysteine, dietary folate and vitamin B12, and investigates its association with carotid intima‐media thickness (cIMT).Food consumption in the NSHD, a British birth cohort, was assessed using 5‐day estimated food diaries at 36 years (y), 43y, 53y and 60–64y. High resolution cIMT in the right and/or left common carotid artery was measured amongst 1565 participants at 60–64 years. Reduced rank regression was used to identify DPs based on plasma homocysteine (μmol/L), dietary folate (ug/kcal) and vitamin B12 (ug/kcal) as response variables. Multiple linear regression models examined cross‐sectional and prospective associations between DP z‐scores.The DP explaining the maximum amount of total variation (4.5%) in all response variables was correlated with high intakes of folate (r=0.96) and vitamin B12 (r=0.27) and weakly correlated with homocysteine (r =0.10). The DP was characterised by high intakes of vegetables, fruit and breakfast cereal and low intakes of processed meat, white bread, sugar and preserves. No cross‐sectional association was observed between DP z‐scores and left (0.34% 95% CI −1.09%, 1.79%) or right cIMT (0.07%, 95%CI −1.28% to 1.45%), adjusting for age, gender, dietary misreporting, socioeconomic status, BMI, smoking, physical activity, lipid‐lowering/antihypertensive medication and diabetes. Similarly, there was no association between DP z‐scores measured at the ages of 36y, 43y, 53y and cIMT at 60–63y.No cross‐sectional or prospective associations were observed between cIMT and a DP high in dietary folate and vitamin B12 in this study. However, the observed DP explained only a small amount of variation in response variables and food intake. Further examination of DPs explaining greater amounts of variation in alternative response variables and their relationships with cIMT is warranted.Support or Funding InformationMedical Research and British Medical Association, Josephine Landsell Award
The Early Life Predictors of a Dietary Pattern Linked With Greater Metabolic Risk in Adolescence and Tracking of Its Food Components
Authors: Appannah Geeta , Pot Gerda Karolien , Oddy Wendy Hazel , Jebb Susan Ann , Ambrosini Gina Leslie 
Published: November 2023

BackgroundGrowing evidence suggests that dietary behaviours linked with chronic diseases in adulthood may develop early in life. However, little is known on the tracking of food intakes during adolescence. This study examined predictors and tracking of key food groups in a dietary pattern (DP) associated with greater cardiometabolic risk among adolescents aged between 14 and 17 y in the Western Australian Pregnancy (Raine) Cohort study.MethodsA total of 860 adolescents reported their food consumption using a food frequency questionnaire (FFQ) at 14 and 17 y. Z‐scores for an ‘energy dense, high fat and low fibre’ DP were estimated using reduced rank regression (RRR) at both ages. Information on adolescents’ early life exposures and parental socio‐economic status at 14 and 17 y was collected using a detailed questionnaire. Tracking analysis was performed based on the predictive value (PV) of remaining in the same quartile of the DP z‐score between 14 and 17 y. Associations between the DP z‐scores, early life factors and SES were analysed using multiple linear regression.ResultsThe identified DP was prospectively associated with greater cardiometabolic risk factors, in boys and girls, between 14 and 17 y. Tracking was strongest amongst boys with the lowest consumption of vegetables, fruit, legumes, high‐fibre bread and yoghurt at 14 y. A high DP z‐score and high intake of processed meat, low‐fibre bread, crisps and savoury snack also tracked strongly among boys. Greater maternal education (β=0.09, p=0.002 at 14 y; β=0.14, p<0.001 at 17 y) and age at child birth (β=−0.09, p=0.003 at 14 y; β= −0.11, p=0.004 at 17 y) were consistently associated with a higher DP z‐score. Paternal smoking status during pregnancy was associated with a higher DP z‐score (β=0.10, p=0.049), at 14 y.ConclusionThese findings highlight subgroups of the population who may benefit the most from early interventions to improve dietary behaviors and reduce the risk of later chronic diseases.Support or Funding Information

Medical Research Council, UK (U105960389)
National Health and Medical Research Council of Australia
National Heart Foundation of Australia
Beyond Blue Cardiovascular Disease of Australia
Depression Strategic Research Program of Australia
The Role of miR‐378*, miR‐218 & miR‐351 in Cardiac Hypertrophy
Authors: Sadiq Shahzad , Charchar Fadi J , Crowley Tamsyn , Delbridge Lea , Harrap Stephen , Lewandowski Paul 
Published: November 2023

IntroductionVentricular hypertrophy is an adaptation that is necessary as part of natural growth. It may also occur in response to increased resistance to blood flow (pressure‐overload) as seen in hypertension. The Hypertrophic Heart Rat (HHR) is a model of pressure‐overload cardiac hypertrophy in the absence of hypertension and is thus suitable to study genetic components of pathological increase in cell size without progression to heart failure. Several genes are implicated in the cardiac hypertrophic pathway, which are regulated by microRNAs. The regulatory potential of microRNAs can be exploited to manipulate the expression of target genes. Moreover, microRNAs can also serve as diagnostic/prognostic biomarkers. The study aims to determine microRNAs and their role in cardiac hypertrophy using the HHR.METHODSHeart samples were carefully harvested from rats. A preliminary microRNA microarray analysis was performed. RNA was extracted from the heart samples was reverse transcribed, the cDNA quantified and finally expression levels of microRNAs and cardiac biomarkers measured using qPCR.RESULTSExpression of miR‐378*, miR‐218 & miR‐351 was decreased in adult HHRs compared to the control. Interestingly, transcription of miR‐378* & miR‐351 was higher in 2‐day old HHRs. Moreover, expression of miR‐218 & miR‐351 were higher in 2‐days old HHRs compared to the adults. Significant differences in expression of cardiac biomarkers of hypertrophy were also noted. Further validation of these microRNAs as regulators of cardiac hypertrophy is currently being examined using a myoblast cell line, H9c2(2‐1), treated with Angiotensin II, which is a recognized stimulant for hypertrophy. These cells are being transfected to up and down regulate the expression of the microRNAs under investigation.CONCLUSIONVariable expression of the microRNAs at two important time‐points in life reveals their importance as potential targets for anti‐sense therapy and as biomarkers of cardiac hypertrophy. Apoptosis during fetal life (2 day old) is believed to result in fewer cardiomyocytes at birth with consequential compensatory remodeling during adulthood. Further studies are being done on various cardiac cell lines.Support or Funding InformationSchool of Medicine, Deakin University, Waurn Ponds, Australia
Fenofibrate Induces Cardiac Fibrosis in Mice Lacking the Co‐chaperone and E3‐ubiquitin ligase CHIP
Authors: Ravi Saranya , Willis Monte S , Lockyer Pamela , Patterson Cam , Schisler Jonathan C 
Published: November 2023

ObjectiveTo determine if stimulation of PPARα with fenofibrate can rescue cardiac hypertrophy induced by energy starvation in CHIP−/− mice.Carboxyl Terminus of HSP70 (CHIP) is a co‐chaperone and E3 ubiquitin ligase involved in protein quality control. The genetic depletion of CHIP in mice is associated with cardiac hypertrophy and decreased survival following myocardial infarction. We previously demonstrated that pressure overload‐induced cardiac hypertrophy is a result of energy starvation and lack of AMPK activation. We found that while the rate of fatty acid uptake in isolated adult mouse cardiomyocytes lacking CHIP expression (CHIP−/−) was similar to WT cardiomyocytes, there was a 33% decrease in fatty acid oxidation accompanied by a 98% increase in fatty acid incorporation into cellular lipids in CHIP−/− versus wild‐type cardiomyocytes. This suggested that a decrease in fatty acid oxidation may contribute to the cardiac disease seen in CHIP−/− mice, and activation of fatty acid oxidation may ameliorate the cardiac pathophysiology associated with the loss of CHIP function. To test our hypothesis, we treated mice with 65 mg/g body weight of fenofibrate, a PPARα agonist that increases lipid uptake and oxidation, for six weeks and observed changes in cardiac function via conscious cardiac echocardiography and histological characterization. Much to our surprise, we found that fenofibrate increased cardiac fibrosis in the CHIP−/− mice by 60%, without a change in total heart size or cardiomyocyte cross‐sectional area compared to wild‐type mice. We determined the effectiveness of fenofibrate as a PPARα agonist by measuring PPARα target genes in the liver of mice and observed similar activation of fatty acid gene expression in both CHIP−/− and wild‐type mice. Likewise, candidate PPAR‐responsive genes in whole heart did not reveal any genotype‐specific differences. We suspect that the fibrotic response is due to pathophysiological stimulation of cardiac fibroblasts lacking CHIP expression. We are now studying isolated primary cardiac fibroblasts from wild‐type and CHIP−/− mice in combination with PPAR isoform specific agonists to measure the fibrotic response to PPAR activation. Our findings have important implications for understanding how the loss of CHIP function (CHIPopathy) recently identified as the causal gene in spinocerebellar ataxia autosomal recessive 16, affects cardiac function given the large population of patients taking fibrates to treat hyperlipidemia.
Metabolomic Profile of Serum Retinol Concentrations in the ATBC Study Cohort
Authors: Albanes Demetrius , Panagiotou Orestis , Weinstein Stephanie , Moore Steven , Mondul Alison 
Published: November 2023

The Alpha‐Tocopherol, Beta‐Carotene Cancer Prevention (ATBC) Study of male smokers found that beta‐carotene supplementation (20 mg/day for 5–8 years) led to an 18% increase in lung cancer incidence, as well as a 5% increase in serum retinol. Higher serum retinol concentrations have also been associated with elevated prostate cancer risk in this and other prospective cohort analyses (AM Mondul et al. Am J Epidemiol 2011;173:813–21, and TJ Key et al. Am J Clin Nutr 2015;102:1142–57). In order to provide biochemical leads regarding how vitamin A status might influence the risk of developing this malignancy, we conducted an agnostic analysis to examine the metabolomic profile of circulating retinol concentrations. The study is based on pre‐randomization fasting serum from 1,282 ATBC Study participants, retinol determined by high‐performance liquid chromatography, and metabolites identified using ultrahigh‐performance liquid chromatography/mass spectroscopy and gas chromatography/mass spectroscopy (Metabolon, Inc., Durham, N.C.). Raw data were extracted, peak‐identified, and quality control processed, and 800 identified compounds were analyzed, with a median metabolite coefficient of variation of 9%. Linear multivariate regression models computed the standardized beta‐coefficient and 95% confidence intervals (CI) of the log‐transformed metabolite‐retinol associations. Using p=0.05/800 (6×10−5) as the significance threshold to adjust for multiple comparisons, 65 metabolites were significantly associated with fasting serum retinol (units: micrograms/liter). The strongest associations (p<10−10), all positive, were for N‐acetyltryptophan (β=0.001), 1‐palmitoleoylglycerophosphocholine (β=0.001), 1‐palmitoylglycerophosphoethanolamine (β=0.0008), 4‐acetamidobutanoate (β=0.0006), myoinositol (β=0.0004), 6‐carbamoylthreonyladenosine (β=0.0004), and urate (β=0.0003). Androgen metabolites were also positively associated with retinol concentration (p=10−9); for example, 5alpha‐androstan‐3beta,17beta‐diol sulfate (β=0.002) and 4‐androsten‐3beta,17beta‐diol monosulfate (β=0.002). How these and other phospholipid, amino acid, and androgen metabolites are related to retinol metabolism, and whether any of them directly influence prostate cancer risk, will require further investigation. Similar metabolomic profiling studies of serum retinol in other populations would be useful.Support or Funding InformationResearch support: Intramural Research Program of the National Cancer Institute, NIH
Reelin Signaling in Cardiovascular Development
Authors: Kim Dongwook , Poles Asha , Gorski Grzegorz , Hatcher Cathy J 
Published: November 2023

The epicardium and coronary vessels are derived from a cell lineage that descends from the primitive proepicardium during cardiovascular development. These structures are formed through developmentally linked processes that are regulated by a network of transcription factors that control cell behavior and molecular genetic expression. Previously, we demonstrated that the Tbx5 transcription factor contributes to cell adhesion during epicardium formation and coronary vasculogenesis. We speculate that this occurs through potential transcriptional regulation of the Reln gene by Tbx5. Reelin, which is encoded by the Reln gene, is a secreted, extracellular matrix glycoprotein that has an established role in neural and lymphatic system development where it regulates cell migration and positioning. However, its role in cardiovascular development has yet to be determined. Our goal is to identify the functional contributions of reelin signaling to the structural formation of the developing heart and embryonic cardiac cell behavior. We used immunofluorescent staining to examine the developing mouse heart for expression of reelin as well as Crk, an adaptor protein which is a downstream mediator of the reelin signaling pathway. Reelin expression is detected in the proepicardium, myocardium and endocardium of the developing mouse heart as early as embryonic day (e) 9.5. At later developmental stages, reelin is expressed in the epicardium as well as specific cell types within the heart, including endothelial cells. Crk expression is detectable as early as e11.5 in the epicardium and myocardium. These findings prompted us to explore the physiological role of reelin at the cellular level. We assessed its contributions to in vitro cell behavior in the human microvascular endothelial cell (HMEC) line that models aspects of coronary vasculogenesis. Primary cultured HMECs were treated with RELN‐specific small interfering RNAs to knock down endogenous reelin expression. Preliminary results indicated that reelin knockdown caused detectable changes in cell behavior. Together, the results of these in vitro and in vivo studies provide insight into how reelin signaling contributes to cellular functions and mechanisms required for cardiovascular development.Support or Funding InformationPCOM Center for Chronic Disorders of Aging
Regulation Of Lipid Metabolism By SREBPs
Authors: Espenshade Peter 
Published: November 2023

Lipid synthesis requires molecular oxygen. Consequently, maintenance of cell growth under hypoxic conditions requires adaptive mechanisms that control lipid homeostasis. In mammalian cells, sterol regulatory element‐binding protein (SREBP) transcription factors are central regulators of cellular lipid homeostasis. Our studies in fungi demonstrate that SREBPs are oxygen‐responsive transcription factors required for adaptation to low oxygen and for host infection by pathogenic fungi. In fission yeast, proteolytic release of SREBP in response to low oxygen requires the Golgi membrane‐anchored Dsc E3 ligase complex, but no SREBP protease has yet been identified. Recently, we identified an uncharacterized protease required for SREBP proteolytic processing, and we will present our results on how this protease functions in SREBP activation. In addition, fission yeast SREBP does not activate all lipid synthesis genes under low oxygen, for example, those required for unsaturated fatty acid synthesis. We will present data demonstrating that the transcription factor Mga2 is also oxygen‐responsive and functions as an SREBP‐like transcription factor during hypoxic adaptation. Collectively, these two pathways control lipid homeostasis in response to low oxygen in fission yeast.Support or Funding InformationStudies were supported by the National Institutes of Health (HL‐077588).
Utilizing Smartphone Technology To Monitor Improvements In The Healthiness Of The Food Supply
Authors: Dunford Elizabeth , Crino Michelle , Neal Bruce 
Published: November 2023

PurposeTo date, there has been little success in efforts to stem the tide of diet‐related ill health attributable to increased availability of highly processed foods providing high levels of saturated fat, sugar and salt. Central to the challenge faced by policy makers in addressing this is the absence of current data to properly define, understand or respond to the problem.MethodsThe Food Monitoring Group was established in 2010 with the objective of collecting data describing the nutritional composition of the global packaged food supply. The Group harnessed smartphone technology to develop a database that contains brand‐specific information on the nutritional composition of >250,000 foods globally. The “Data Collector App” is made available to all countries around the world to enable simple, low‐cost collection of food composition data on the packaged food supply.ResultsData have been used to monitor the global food supply. E.g. data from Australia were used to monitor the implementation of government sodium reduction targets. Comparisons of sodium levels over time exposed the limited progress in achieving the targets, with data presented at the individual company level. Data from India highlighted the incompleteness of nutritional labelling as another key issue in the field and was used to push government to better enforce existing labelling standards in the country. Data are also being used to fuel the FoodSwitch smartphone application, which allows consumers in Australia, NZ, the UK, China, India and South Africa to scan the barcodes of food items in‐store and be directed to healthier brands of similar products. If a product is missing from the database, app users are prompted to take 3 photos of the missing item. This alone has resulted in more than 700,000 photos being sent in by users to date, and a minimum of 300 new photos being submitted daily. These crowd‐sourced data are also used to help drive improvements in national food supplies. The app already has more than 760,000 downloads in Australia, NZ and the UK alone, with launches in the USA, Canada, Hong Kong and Switzerland planned for 2016.ConclusionSmartphone technology has helped collect large amounts of information about the healthiness of the global food supply. These data have been used for both monitoring of the nutritional content of foods, government initiatives to improve the food supply, and existing labelling initiatives. The data have also been used to educate consumers through the FoodSwitch smartphone application, which in turn helps crowd‐source additional data on the food supply, thus allowing for low‐cost, real‐time tracking of the healthiness of the global food supply.Support or Funding InformationE Dunford is supported by a NHMRC Early Career Fellowship.