Search

Abstract Habitual consumption of low-calorie sweeteners (LCS) during juvenile-adolescence can lead to greater sugar intake later in life. Here, we investigated if exposure to the LCS Acesulfame Potassium (Ace-K) during this critical period of development reprograms the taste system in a way that would alter hedonic responding for common dietary compounds. Results revealed that early-life LCS intake not only enhanced the avidity for a caloric sugar (fructose) when rats were in a state of caloric need, it increased acceptance of a bitterant (quinine) in Ace-K-exposed rats tested when middle-aged. These behavior shifts, which endured months after the end of Ace-K exposure, were accompanied by widespread changes in the peripheral taste system. The anterior tongue had fewer fungiform taste papillae, and the circumvallate papillae had a reduced anterior to posterior span and diminished expression of genes involved in sweet reception, sweet and bitter intracellular signaling, fructose transport, and cellular progeneration in the Ace-K-exposed rats. Ace-K exposure also led to a significant reduction in dopamine-producing cells of the ventral tegmental area. The collective findings reveal that LCS intake early in life alters the taste-brain axis and the behavioral responsiveness to both positive and negative tastants that are important determinants of dietary preferences.

Abstract Asthma affects approximately 300 million individuals worldwide and the onset predominantly arises in childhood. Children are exposed to multiple environmental irritants, such as viruses and allergens, that are common triggers for asthma onset, whilst their immune systems are developing in early life. Understanding the impact of allergen exposures on the developing immune system and resulting alterations in lung function in early life will help prevent the onset and progression of allergic asthma in children. In this study, we developed an in silico model describing the pulmonary immune response to a common allergen, house dust mite, to investigate its downstream impact on the pathophysiology of asthma, including airway eosinophilic inflammation, remodelling, and lung function. We hypothesised that altered epithelial function following allergen exposure determines the onset of airway remodelling and abnormal lung function, which are irreversible with current asthma therapies. We calibrated the in silico model using age appropriate in vivo data from neonatal and adult mice. We validated the in silico model using in vivo data from mice on the effects of current treatment strategies. The in silico model recapitulates experimental observations and provides an interpretable in silico tool to assess airway pathology and the underlying immune responses upon allergen exposure. The in silico model simulations predict the extent of bronchial epithelial barrier damage observed when allergen sensitisation occurs and demonstrate that epithelial barrier damage and impaired immune maturation are critical determinants of reduced lung function and asthma development. The in silico model demonstrates that both epithelial barrier repair and immune maturation are potential targets for therapeutic intervention to achieve successful asthma prevention.

Abstract Livestock abortion is an important cause of productivity losses worldwide and many infectious causes of abortion are zoonotic pathogens that impact on human health. Little is known about the relative importance of infectious causes of livestock abortion in Africa, including in subsistence farming communities that are critically dependent on livestock for food, income, and wellbeing. We conducted a prospective cohort study of livestock abortion, supported by cross-sectional serosurveillance, to determine aetiologies of livestock abortions in livestock in Tanzania. This approach generated several important findings including detection of a Rift Valley fever virus outbreak in cattle; high prevalence of C. burnetii infection in livestock; and the first report of Neospora caninum, Toxoplasma gondii, and pestiviruses associated with livestock abortion in Tanzania. Our approach provides a model for abortion surveillance in resource-limited settings. Our findings add substantially to current knowledge in sub-Saharan Africa, providing important evidence from which to prioritise disease interventions.

Asthma affects approximately 300 million individuals worldwide and the onset predominantly arises in childhood. Children are exposed to multiple environmental irritants, such as viruses and allergens, that are common triggers for asthma onset, whilst their immune systems are developing in early life. Understanding the impact of allergen exposures on the developing immune system and resulting alterations in lung function in early life will help prevent the onset and progression of allergic asthma in children. In this study, we developed an in silico model describing the pulmonary immune response to a common allergen, house dust mite, to investigate its downstream impact on the pathophysiology of asthma, including airway eosinophilic inflammation, remodelling, and lung function. We hypothesised that altered epithelial function following allergen exposure determines the onset of airway remodelling and abnormal lung function, which are irreversible with current asthma therapies. We calibrated the in silico model using age appropriate in vivo data from neonatal and adult mice. We validated the in silico model using in vivo data from mice on the effects of current treatment strategies. The in silico model recapitulates experimental observations and provides an interpretable in silico tool to assess airway pathology and the underlying immune responses upon allergen exposure. The in silico model simulations predict the extent of bronchial epithelial barrier damage observed when allergen sensitisation occurs and demonstrate that epithelial barrier damage and impaired immune maturation are critical determinants of reduced lung function and asthma development. The in silico model demonstrates that both epithelial barrier repair and immune maturation are potential targets for therapeutic intervention to achieve successful asthma prevention. [ABSTRACT FROM AUTHOR]

Abstract Protease-activated receptor 1 (PAR1) is widely expressed in humans and mice, and is activated by a variety of proteases, including thrombin. Recently, we showed that PAR1 contributes to the innate immune response to viral infection. Mice with a global deficiency of PAR1 expressed lower levels of CXCL10 and had increased Coxsackievirus B3 (CVB3)-induced myocarditis compared with control mice. In this study, we determined the effect of cell type-specific deletion of PAR1 in cardiac myocytes (CMs) and cardiac fibroblasts (CFs) on CVB3-induced myocarditis. Mice lacking PAR1 in either CMs or CFs exhibited increased CVB3 genomes, inflammatory infiltrates, macrophages and inflammatory mediators in the heart and increased CVB3-induced myocarditis compared with wild-type controls. Interestingly, PAR1 enhanced poly I:C induction of CXCL10 in rat CFs but not in rat neonatal CMs. Importantly, activation of PAR1 reduced CVB3 replication in murine embryonic fibroblasts and murine embryonic cardiac myocytes. In addition, we showed that PAR1 reduced autophagy in murine embryonic fibroblasts and rat H9c2 cells, which may explain how PAR1 reduces CVB3 replication. These data suggest that PAR1 on CFs protects against CVB3-induced myocarditis by enhancing the anti-viral response whereas PAR1 on both CMs and fibroblasts inhibits viral replication.

Abstract Preoperative assessment of the proximity of critical structures to the tumors is crucial in avoiding unnecessary damage during prostate cancer treatment. A patient-specific 3D anatomical model of those structures, namely the neurovascular bundles (NVB) and the external urethral sphincters (EUS), can enable physicians to perform such assessments intuitively. As a crucial step to generate a patient-specific anatomical model from preoperative MRI in a clinical routine, we propose a multi-class automatic segmentation based on an anisotropic convolutional network. Our specific challenge is to train the network model on a unique source dataset only available at a single clinical site and deploy it to another target site without sharing the original images or labels. As network models trained on data from a single source suffer from quality loss due to the domain shift, we propose a semi-supervised domain adaptation (DA) method to refine the model’s performance in the target domain. Our DA method combines transfer learning and uncertainty guided self-learning based on deep ensembles. Experiments on the segmentation of the prostate, NVB, and EUS, show significant performance gain with the combination of those techniques compared to pure TL and the combination of TL with simple self-learning ( $${p}

Abstract Understanding major climate risks, adaptation strategies, and factors influencing the choice of those strategies is crucial to reduce farmers’ vulnerability. Employing comprehensive data from 2822 farm households in Ethiopia and Kenya (East Africa; EA) and 1902 farm households in Bangladesh, India, and Nepal (South Asia; SA), this study investigates the main climate risks that farmers faced and the adaptation strategies they used. Among others, excessive rainfall and heightened crop pest/disease incidence are commonly observed climate-induced risks in all study areas, while cyclones and salinity are unique to Bangladesh. Drought is prevalent in Ethiopia, India, Kenya, and Nepal. Farmers in those countries responded with strategies that include change in farming practices, sustainable land management, reduce consumption, sell assets, use savings and borrowings, seek alternative employment and assistance from government or NGO. In general, farmers faced several multiple climate risks simultaneously and they responded with multiple adaptation strategies. Therefore, this study used a multivariate probit (MVP) approach to examine the factors influencing the adoption of adaptation strategies. Unlike other studies, we also tested and corrected for possible endogeneity in model estimation. All the countries mentioned have low adaptive capacity to address climate change, which is further weakened by inadequate governance and inefficient institutions. We observed significant differences in the choice of adaptation strategies between male-headed households (MHHs) and female-headed households (FHHs), as well as across countries. Generally, MHHs are more likely to seek additional employment and change agricultural practices, while FHHs and households headed by older persons tend to reduce consumption and rely on savings and borrowings. Institutional support for adaptation is much less in EA compared to SA. Training on alternative farming practices, enhancing non-farm employment options, better institutional support, and social security for older farmers are crucial for climate change adaptation in both regions.

Abstract Large relative brain size is a defining characteristic of the order Primates. Arguably, this can be attributed to selection for behavioral aptitudes linked to a larger brain size. In order for selection of a trait to occur, the trait must vary, that variation must be heritable, and enhance fitness. In this study, we use a quantitative genetic approach to investigate the production and maintenance of variation in endocranial volume in a population of free-ranging rhesus macaques. We measured the endocranial volume and body mass proxies of 542 rhesus macaques from Cayo Santiago. We investigated variation in endocranial volume within and between sexes. Using a genetic pedigree, we estimated heritability of absolute and relative endocranial volume, and selection gradients of both traits as well as estimated body mass in the sample. Within this population, both absolute and relative endocranial volume display variation and sexual dimorphism. Both absolute and relative endocranial volume are highly heritable, but we found no evidence of selection on absolute or relative endocranial volume. These findings suggest that endocranial volume is not undergoing selection, or that we did not detect it because selection is neither linear nor quadratic, or that we lacked sufficient sample sizes to detect it.

Abstract The developmental origins of health and disease hypothesis proposes that an adverse early life environment, including in utero exposure to a maternal obesogenic environment, can lead to an increased long-term risk of obesity and related metabolic complications in offspring. We assessed whether maternal supplementation with conjugated linoleic acid (CLA) could prevent some of these adverse effects in offspring exposed to a maternal high fat diet. Sprague-Dawley dams consumed either a: control (CD), control with CLA (CLA), high fat (HF) or high fat with CLA (HFCLA) diet 10 days prior to mating and throughout pregnancy/lactation. Male offspring were weaned onto a standard chow diet. Body composition was quantified by DXA and oral glucose tolerance tests conducted on adult offspring. Gene/protein expression and histological analysis were conducted in adipose tissue. Offspring from HF dams had increased body weight, body fat deposition, impaired insulin sensitivity and adipocyte hypertrophy; all of which were rescued in HFCLA offspring. Molecular and histological analyses of the adipose tissue suggest that disturbances in adipogenesis may mediate the metabolic dysfunction observed in HF offspring. Therefore, CLA supplementation to a maternal obesogenic diet may be a promising strategy to prevent adverse programming outcomes.

Abstract We examined whether maternal fish oil supplementation during pregnancy could prevent development of insulin resistance in adult male offspring of rat dams fed a high-fat diet. Time-mated Sprague-Dawley rat dams were randomised into four treatment groups: Con-Con, dams fed a control diet (fat: 15% kcal) and administered water by gavage; Con-FO, control diet with unoxidised fish oil by gavage; HF-Con, high-fat diet (fat: 45% kcal) and water by gavage; and HF-FO, high-fat diet and unoxidised fish oil by gavage. Dams were fed the allocated diet ad libitum during pregnancy and lactation, but daily gavage occurred only during pregnancy. After weaning, male offspring consumed a chow diet ad libitum until adulthood. Maternal high-fat diet led to increased food consumption, adiposity, systolic blood pressure, and triglycerides and plasma leptin in adult HF-Con offspring. HF-Con offspring also exhibited lower insulin sensitivity than Con-Con rats. Male offspring from HF-FO group were similar to HF-Con regarding food consumption and most metabolic parameters. However, insulin sensitivity in the HF-FO group was improved relative to the HF-Con offspring. Supplementation with unoxidised n-3 PUFA rich oils in the setting of a maternal obesogenic diet improved insulin sensitivity, but had no impact on body composition of adult male offspring.

Abstract Fetal health is critically dependent on placental function, especially placental transport of oxygen from mother to fetus. When fetal growth is compromised, placental insufficiency must be distinguished from modest genetic growth potential. If placental insufficiency is present, the physician must trade off the risk of prolonged fetal exposure to placental insufficiency against the risks of preterm delivery. Current ultrasound methods to evaluate the placenta are indirect and insensitive. We propose to use Blood-Oxygenation-Level-Dependent (BOLD) MRI with maternal hyperoxia to quantitatively assess mismatch in placental function in seven monozygotic twin pairs naturally matched for genetic growth potential. In-utero BOLD MRI time series were acquired at 29 to 34 weeks gestational age. Maps of oxygen Time-To-Plateau (TTP) were obtained in the placentas by voxel-wise fitting of the time series. Fetal brain and liver volumes were measured based on structural MR images. After delivery, birth weights were obtained and placental pathological evaluations were performed. Mean placental TTP negatively correlated with fetal liver and brain volumes at the time of MRI as well as with birth weights. Mean placental TTP positively correlated with placental pathology. This study demonstrates the potential of BOLD MRI with maternal hyperoxia to quantify regional placental function in vivo.

The pro-inflammatory mediator leukotriene B4 (LTB4) is implicated in the pathologies of an array of diseases and thus represents an attractive therapeutic target. The enzyme leukotriene A4 hydrolase (LTA4H) catalyses the distal step in LTB4 synthesis and hence inhibitors of this enzyme have been actively pursued. Despite potent LTA4H inhibitors entering clinical trials all have failed to show efficacy. We recently identified a secondary anti-inflammatory role for LTA4H in degrading the neutrophil chemoattractant Pro-Gly-Pro (PGP) and rationalized that the failure of conventional LTA4H inhibitors may be that they inadvertently prevented PGP degradation. We demonstrate that these inhibitors do indeed fail to discriminate between the dual activities of LTA4H, and enable PGP accumulation in mice. Accordingly, we have developed novel compounds that potently inhibit LTB4 generation whilst leaving PGP degradation unperturbed. These novel compounds could represent a safer and superior class of LTA4H inhibitors for translation into the clinic. [ABSTRACT FROM AUTHOR]