Modelling the species jump: towards assessing the risk of human infection from novel avian influenzas

The scientific understanding of the driving factors behind zoonotic and pandemic influenzas is hampered by complex interactions between viruses, animal hosts and humans. This complexity makes identifying influenza viruses of high zoonotic or pandemic risk, before they emerge from animal populations, extremely difficult and uncertain. As a first step towards assessing zoonotic risk of Influenza, we demonstrate a risk assessment framework to assess the relative likelihood of influenza A viruses, circulating in animal populations, making the species jump into humans. The intention is that such a risk assessment framework could assist decisionmakers to compare multiple influenza viruses for zoonotic potential and hence to develop appropriate strain-specific control measures. It also provides a first step towards showing proof of principle for an eventual pandemic risk model. We show that the spatial and temporal epidemiology is as important in assessing the risk of an influenza A species jump as understanding the innate molecular capability of the virus.We also demonstrate data deficiencies that need to be addressed in order to consistently combine both epidemiological and molecular virology data into a risk assessment framework

Television, physical activity, diet, and body weight status: the ARIC cohort

<p>Abstract</p> <p>Background</p> <p>Television (TV) watching is the most common leisure activity in the United States. Few studies of adults have described the relationship between TV and health behaviors such as physical activity, diet, and body weight status.</p> <p>Methods</p> <p>Extant data from the Atherosclerosis Risk in Communities (ARIC) Study were analyzed to assess the association of TV with physical activity, diet, and body mass index (BMI) among 15,574 adults at baseline (1986–89) and 12,678 adults six years later. Television, physical activity, and diet were collected with questionnaires and BMI was measured at both time points. Based on baseline TV exposure, adults were categorized into high, medium, and low TV exposure. Linear and logistic regression models were adjusted for gender, age, race-center, smoking, education, and general health.</p> <p>Results</p> <p>Relative to participants who had low TV exposure, those with high TV exposure were more likely to be less physically active and have a poorer dietary profile at baseline and six-years later. Participants with high TV exposure at baseline had a 40% and 31% greater odds of being considered insufficiently active at baseline (1.40, 95% CI 1.26, 1.55), and six years later (1.31, 95% CI 1.18, 1.46). At baseline, high TV exposure was also associated with a 20% to 30% greater odds of being above the median for servings of salty snacks (1.37, 95% CI 1.24, 1.51), sweets (1.26, 95% CI 1.15, 1.38), and sweetened drinks (1.29, 95% CI 1.17, 1.42), and below the median for fruit and vegetable servings (1.36, 95% CI 1.24, 1.50). Higher TV exposure was also cross-sectionally associated with a greater odds for being overweight or obese (1.43, 95% CI 1.29, 1.58). Similar associations were observed between baseline TV exposure and six-year physical activity and diet, but were not observed with BMI after six years follow-up.</p> <p>Conclusion</p> <p>These results support the hypothesis that time spent watching TV is associated with deleterious effects on physical activity, diet, and BMI.</p

Micropatterned Cell–Cell Interactions Enable Functional Encapsulation of Primary Hepatocytes in Hydrogel Microtissues

Drug-induced liver injury is a major cause of drug development failures and postmarket withdrawals. In vitro models that incorporate primary hepatocytes have been shown to be more predictive than model systems which rely on liver microsomes or hepatocellular carcinoma cell lines. Methods to phenotypically stabilize primary hepatocytes ex vivo often rely on mimicry of hepatic microenvironmental cues such as cell–cell interactions and cell–matrix interactions. In this work, we sought to incorporate phenotypically stable hepatocytes into three-dimensional (3D) microtissues, which, in turn, could be deployed in drug-screening platforms such as multiwell plates and diverse organ-on-a-chip devices. We first utilize micropatterning on collagen I to specify cell–cell interactions in two-dimensions, followed by collagenase digestion to produce well-controlled aggregates for 3D encapsulation in polyethylene glycol (PEG) diacrylate. Using this approach, we examined the influence of homotypic hepatocyte interactions and composition of the encapsulating hydrogel, and achieved the maintenance of liver-specific function for over 50 days. Optimally preaggregated structures were subsequently encapsulated using a microfluidic droplet-generator to produce 3D microtissues. Interactions of engineered hepatic microtissues with drugs was characterized by flow cytometry, and yielded both induction of P450 enzymes in response to prototypic small molecules and drug–drug interactions that give rise to hepatotoxicity. Collectively, this study establishes a pipeline for the manufacturing of 3D hepatic microtissues that exhibit stabilized liver-specific functions and can be incorporated into a wide array of emerging drug development platforms.National Institutes of Health (U.S.) (Grant UH2 EB017103)National Institutes of Health (U.S.) (Grant R01 EB008396)National Institutes of Health (U.S.) (Grant R01 DK85713)National Cancer Institute (U.S.) (Koch Institute Support (Core) Grant P30-CA14051)American Gastroenterological Association (Research Scholar Fellowship)National Science Foundation (U.S.). Graduate Research Fellowship (1122374

Patterning Vascular Networks In Vivo for Tissue Engineering Applications

The ultimate design of functionally therapeutic engineered tissues and organs will rely on our ability to engineer vasculature that can meet tissue-specific metabolic needs. We recently introduced an approach for patterning the formation of functional spatially organized vascular architectures within engineered tissues in vivo. Here, we now explore the design parameters of this approach and how they impact the vascularization of an engineered tissue construct after implantation. We used micropatterning techniques to organize endothelial cells (ECs) into geometrically defined “cords,” which in turn acted as a template after implantation for the guided formation of patterned capillaries integrated with the host tissue. We demonstrated that the diameter of the cords before implantation impacts the location and density of the resultant capillary network. Inclusion of mural cells to the vascularization response appears primarily to impact the dynamics of vascularization. We established that clinically relevant endothelial sources such as induced pluripotent stem cell-derived ECs and human microvascular endothelial cells can drive vascularization within this system. Finally, we demonstrated the ability to control the juxtaposition of parenchyma with perfused vasculature by implanting cords containing a mixture of both a parenchymal cell type (hepatocytes) and ECs. These findings define important characteristics that will ultimately impact the design of vasculature structures that meet tissue-specific needs.National Institute of Biomedical Imaging and Bioengineering (U.S.) (Award Number EB000262)National Institute of Biomedical Imaging and Bioengineering (U.S.) (Award Number EB08396)National Institutes of Health (U.S.). National Research Service Awards (1F32DK091007)National Institutes of Health (U.S.). National Research Service Awards (5T32AR007132-35

Why do semi-analytic models predict higher scatter in the stellar mass-halo mass relation than cosmological hydrodynamic simulations?

Semi-analytic models (SAMs) systematically predict higher stellar-mass scatter at a given halo mass than hydrodynamical simulations and most empirical models. Our goal is to investigate the physical origin of this scatter by exploring modifications to the physics in the SAM Dark Sage. We design two black hole formation models that approximate results from the IllustrisTNG 300-1 hydrodynamical simulation. In the first model, we assign a fixed black hole mass of $10^{6}\, \mathrm{M}_{\odot}$ to every halo that reaches $10^{10.5}\, \mathrm{M}_{\odot}$. In the second model, we disregard any black hole growth as implemented in the standard Dark Sage model. Instead, we force all black hole masses to follow the median black hole mass-halo mass relation in IllustrisTNG 300-1 with a fixed scatter. We find that each model on its own does not significantly reduce the scatter in stellar mass. To do this, we replace the native Dark Sage AGN feedback model with a simple model where we turn off cooling for galaxies with black hole masses above $10^{8}\, \mathrm{M}_{\odot}$. With this additional modification, the SMBH seeding and fixed conditional distribution models find a significant reduction in the scatter in stellar mass at halo masses between $10^{11-14}\, \mathrm{M}_{\odot}$. These results suggest that AGN feedback in SAMs acts in a qualitatively different way than feedback implemented in cosmological simulations. Either or both may require substantial modification to match the empirically inferred scatter in the Stellar Mass Halo Mass Relation (SMHMR).Comment: 21 pages, 16 figure

Comparative Study of Multicellular Tumor Spheroid Formation Methods and Implications for Drug Screening

Improved in vitro models are needed to better understand cancer progression and bridge the gap between in vitro proof-of-concept studies, in vivo validation, and clinical application. Multicellular tumor spheroids (MCTS) are a popular method for three-dimensional (3D) cell culture, because they capture some aspects of the dimensionality, cell–cell contact, and cell–matrix interactions seen in vivo. Many approaches exist to create MCTS from cell lines, and they have been used to study tumor cell invasion, growth, and how cells respond to drugs in physiologically relevant 3D microenvironments. However, there are several discrepancies in the observations made of cell behaviors when comparing between MCTS formation methods. To resolve these inconsistencies, we created and compared the behavior of breast, prostate, and ovarian cancer cells across three MCTS formation methods: in polyNIPAAM gels, in microwells, or in suspension culture. These methods formed MCTS via proliferation from single cells or passive aggregation, and therefore showed differential reliance on genes important for cell–cell or cell–matrix interactions. We also found that the MCTS formation method dictated drug sensitivity, where MCTS formed over longer periods of time via clonal growth were more resistant to treatment. Toward clinical application, we compared an ovarian cancer cell line MCTS formed in polyNIPAAM with cells from patient-derived malignant ascites. The method that relied on clonal growth (PolyNIPAAM gel) was more time and cost intensive, but yielded MCTS that were uniformly spherical, and exhibited the most reproducible drug responses. Conversely, MCTS methods that relied on aggregation were faster, but yielded MCTS with grape-like, lobular structures. These three MCTS formation methods differed in culture time requirements and complexity, and had distinct drug response profiles, suggesting the choice of MCTS formation method should be carefully chosen based on the application required

Fetal Organophosphate Pesticide Exposure and Child Adiposity Measures at 10 Years of Age in the General Dutch Population

BACKGROUND: Fetal exposure to organophosphate (OP) pesticides might lead to fetal metabolic adaptations, predisposing individuals to adverse metabolic profiles in later life. OBJECTIVE: We examined the association of maternal urinary OP pesticide metabolite concentrations in pregnancy with offspring body mass index (BMI) and fat measures at 10 years of age. METHODS: Between 2002 and 2006, we included 642 mother–child pairs from the Generation R Study, a population-based prospective cohort study in Rotterdam, the Netherlands. We measured maternal urinary concentrations of OP pesticide metabolites, namely, dialkyl phosphates, including three dimethyl and three diethyl phosphates in early-, mid-and late-pregnancy. At 10 years of age, child total and regional body fat and lean mass were measured through dual energy X-ray absorptiometry, and abdominal and organ fat through magnetic resonance imaging. RESULTS: Higher maternal urinary pregnancy-average or trimester-specific dialkyl, dimethyl, or diethyl phosphate concentrations were not associated with childhood BMI and the risk of overweight. In addition, we did not observe any association of dialkyl, dimethyl, or diethyl phosphate concentrations with total and regional body fat, abdominal visceral fat, liver fat, or pericardial fat at child age of 10 y. CONCLUSION: We observed no associations of maternal urinary dialkyl concentrations during pregnancy with childhood adiposity measures at 10 years of age. Whether these associations develop at older ages should be further studied.</p

Geometric control of vascular networks to enhance engineered tissue integration and function

Tissue vascularization and integration with host circulation remains a key barrier to the translation of engineered tissues into clinically relevant therapies. Here, we used a microtissue molding approach to demonstrate that constructs containing highly aligned “cords” of endothelial cells triggered the formation of new capillaries along the length of the patterned cords. These vessels became perfused with host blood as early as 3 d post implantation and became progressively more mature through 28 d. Immunohistochemical analysis showed that the neovessels were composed of human and mouse endothelial cells and exhibited a mature phenotype, as indicated by the presence of alpha-smooth muscle actin–positive pericytes. Implantation of cords with a prescribed geometry demonstrated that they provided a template that defined the neovascular architecture in vivo. To explore the utility of this geometric control, we implanted primary rat and human hepatocyte constructs containing randomly organized endothelial networks vs. ordered cords. We found substantially enhanced hepatic survival and function in the constructs containing ordered cords following transplantation in mice. These findings demonstrate the importance of multicellular architecture in tissue integration and function, and our approach provides a unique strategy to engineer vascular architecture.National Institutes of Health (U.S.) (Grant EB08396)National Institutes of Health (U.S.) (Grant EB00262)National Institutes of Health (U.S.) (National Research Service Award 1F32DK091007