New model diagnostics for spatio-temporal systems in epidemiology and ecology

A cardinal challenge in epidemiological and ecological modelling is to develop effective and easily deployed tools for model assessment. The availability of such methods would greatly improve understanding, prediction and management of disease and ecosystems. Conventional Bayesian model assessment tools such as Bayes factors and the deviance information criterion (DIC) are natural candidates but suffer from important limitations because of their sensitivity and complexity. Posterior predictive checks, which use summary statistics of the observed process simulated from competing models, can provide a measure of model fit but appropriate statistics can be difficult to identify. Here, we develop a novel approach for diagnosing mis-specifications of a general spatio-temporal transmission model by embedding classical ideas within a Bayesian analysis. Specifically, by proposing suitably designed non-centred parametrization schemes, we construct latent residuals whose sampling properties are known given the model specification and which can be used to measure overall fit and to elicit evidence of the nature of mis-specifications of spatial and temporal processes included in the model. This model assessment approach can readily be implemented as an addendum to standard estimation algorithms for sampling from the posterior distributions, for example Markov chain Monte Carlo. The proposed methodology is first tested using simulated data and subsequently applied to data describing the spread of Heracleum mantegazzianum (giant hogweed) across Great Britain over a 30-year period. The proposed methods are compared with alternative techniques including posterior predictive checking and the DIC. Results show that the proposed diagnostic tools are effective in assessing competing stochastic spatio-temporal transmission models and may offer improvements in power to detect model mis-specifications. Moreover, the latent-residual framework introduced here extends readily to a broad range of ecological and epidemiological models

Service Region Design for Urban Electric Vehicle Sharing Systems

Emerging collaborative consumption business models have shown promise in terms of both generating business opportunities and enhancing the efficient use of resources. In the transportation domain, car sharing models are being adopted on a mass scale in major metropolitan areas worldwide. This mode of servicized mobility bridges the resource efficiency of public transit and the flexibility of personal transportation. Beyond the significant potential to reduce car ownership, car sharing shows promise in supporting the adoption of fuel- efficient vehicles, such as electric vehicles (EVs), due to these vehicles special cost structure with high purchase but low operating costs. Recently, key players in the car sharing business, such as Autolib, Car2Go and DriveNow, have begun to employ EVs in an operations model that accommodates one-way trips. On the one hand (and particularly in free-floating car sharing), the one-way model results in significant improvements in coverage of travel needs and therefore in adoption potential compared with the conventional round-trip-only model (advocated by ZipCar, for example). On the other hand, this model poses tremendous planning and operational challenges. In this work, we study the planning problem faced by service providers in designing a geographical service region in which to operate the service. This decision entails trade-offs between maximizing customer catchment by covering travel needs and controlling fleet operations costs. We develop a mathematical programming model that incorporates details of both customer adoption behavior and fleet management (including EV repositioning and charging) under imbalanced travel patterns. To address inherent planning uncertainty with regard to adoption patterns, we employ a distributionally robust optimization framework that informs robust decisions to overcome possible ambiguity (or lacking) of data. Mathematically, the problem can be approximated by a mixed integer second-order cone program, which is computationally tractable with practical scale data. Applying this approach to the case of Car2Go’s service with real operations data, we address a number of planning questions and suggest that there is potential for the future development of this service

Regulatory Roles of miRNA in the Human Neural Stem Cell Transformation to Glioma Stem Cells

To investigate the expressional alternation of microRNAs (miRNA) during the malignant transformation and development of human glioma, we measured miRNA expression profile as well as mRNA expression profile in normal human neural stem cells (hNSCs) and human glioma stem cells (hGSCs). We found 116 miRNA up‐regulated and 62 miRNA down‐regulated in GSCs. On the other hand, we identified 1,372 mRNA down‐regulated, and 1,501 mRNA up‐regulated in GSCs compared to those in NSCs. We then analyzed the pathways and the predicted target genes of the miRNAs which differ significantly in expression between GSCs and NSCs using the statistical enrichment methods. These target mRNAs are involved in many cancer‐related signaling pathways, such as cell cycle, axon guidance, glioma development, adhesion junction, MAPK and Wnt signaling. Furthermore, we obtained the differently expressed miRNA‐target relationships according to the θ value which is used to calculate the regulation extent of miRNA‐target and using the databases of miRanda, Targetscans and Pictar. Among the top 10 miRNA‐target relationships, hsa‐miR‐198 and its potential targeted gene DCX and NNAT were selected for validation, and NNAT was found to be the direct target of miR‐198. Finally, the functional roles of miR‐155–5p and miR‐124–3p whose expressions altered significantly between GSCs and NSCs were addressed. Our results provide new clues for the potential mechanisms involved in the origin and development of glioma. Clinically, the altered miRNAs may serve as potential targets and diagnostic tools for novel therapeutic strategies of glioblastoma. J. Cell. Biochem. 115: 1368–1380, 2014. © 2014 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/107550/1/jcb24786.pd

Comparisons of the M1 genome segments and encoded μ2 proteins of different reovirus isolates

BACKGROUND: The reovirus M1 genome segment encodes the μ2 protein, a structurally minor component of the viral core, which has been identified as a transcriptase cofactor, nucleoside and RNA triphosphatase, and microtubule-binding protein. The μ2 protein is the most poorly understood of the reovirus structural proteins. Genome segment sequences have been reported for 9 of the 10 genome segments for the 3 prototypic reoviruses type 1 Lang (T1L), type 2 Jones (T2J), and type 3 Dearing (T3D), but the M1 genome segment sequences for only T1L and T3D have been previously reported. For this study, we determined the M1 nucleotide and deduced μ2 amino acid sequences for T2J, nine other reovirus field isolates, and various T3D plaque-isolated clones from different laboratories. RESULTS: Determination of the T2J M1 sequence completes the analysis of all ten genome segments of that prototype. The T2J M1 sequence contained a 1 base pair deletion in the 3' non-translated region, compared to the T1L and T3D M1 sequences. The T2J M1 gene showed ~80% nucleotide homology, and the encoded μ2 protein showed ~71% amino acid identity, with the T1L and T3D M1 and μ2 sequences, respectively, making the T2J M1 gene and μ2 proteins amongst the most divergent of all reovirus genes and proteins. Comparisons of these newly determined M1 and μ2 sequences with newly determined M1 and μ2 sequences from nine additional field isolates and a variety of laboratory T3D clones identified conserved features and/or regions that provide clues about μ2 structure and function. CONCLUSIONS: The findings suggest a model for the domain organization of μ2 and provide further evidence for a role of μ2 in viral RNA synthesis. The new sequences were also used to explore the basis for M1/μ2-determined differences in the morphology of viral factories in infected cells. The findings confirm the key role of Ser/Pro208 as a prevalent determinant of differences in factory morphology among reovirus isolates and trace the divergence of this residue and its associated phenotype among the different laboratory-specific clones of type 3 Dearing

Targeting the CXCR4 pathway using a novel anti-CXCR4 IgG1 antibody (PF-06747143) in chronic lymphocytic leukemia.

BackgroundThe CXCR4-CXCL12 axis plays an important role in the chronic lymphocytic leukemia (CLL)-microenvironment interaction. Overexpression of CXCR4 has been reported in different hematological malignancies including CLL. Binding of the pro-survival chemokine CXCL12 with its cognate receptor CXCR4 induces cell migration. CXCL12/CXCR4 signaling axis promotes cell survival and proliferation and may contribute to the tropism of leukemia cells towards lymphoid tissues and bone marrow. Therefore, we hypothesized that targeting CXCR4 with an IgG1 antibody, PF-06747143, may constitute an effective therapeutic approach for CLL.MethodsPatient-derived primary CLL-B cells were assessed for cytotoxicity in an in vitro model of CLL microenvironment. PF-06747143 was analyzed for cell death induction and for its potential to interfere with the chemokine CXCL12-induced mechanisms, including migration and F-actin polymerization. PF-06747143 in vivo efficacy was determined in a CLL murine xenograft tumor model.ResultsPF-06747143, a novel-humanized IgG1 CXCR4 antagonist antibody, induced cell death of patient-derived primary CLL-B cells, in presence or absence of stromal cells. Moreover, cell death induction by the antibody was independent of CLL high-risk prognostic markers. The cell death mechanism was dependent on CXCR4 expression, required antibody bivalency, involved reactive oxygen species production, and did not require caspase activation, all characteristics reminiscent of programmed cell death (PCD). PF-06747143 also induced potent B-CLL cytotoxicity via Fc-driven antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity activity (CDC). PF-06747143 had significant combinatorial effect with standard of care (SOC) agents in B-CLL treatment, including rituximab, fludarabine (F-ara-A), ibrutinib, and bendamustine. In a CLL xenograft model, PF-06747143 decreased tumor burden and improved survival as a monotherapy, and in combination with bendamustine.ConclusionsWe show evidence that PF-06747143 has biological activity in CLL primary cells, supporting a rationale for evaluation of PF-06747143 for the treatment of CLL patients

Sustainable clothing: challenges, barriers and interventions for encouraging more sustainable consumer behaviour

Research with consumers has revealed limited awareness of the sustainability impact of clothing (Goworek et al., 2012). Semi-structured interviews conducted with a range of experts in sustainable clothing to increase understanding of the challenges for sustainable clothing revealed that a focus on sustainability alone will not drive the necessary changes in consumers’ clothing purchase, care and disposal behaviour for three reasons: (i) clothing sustainability is too complex; (ii) consumers are too diverse in their ethical concerns; and (iii) clothing is not an altruistic purchase. The findings identify the challenges that need to be addressed and the associated barriers for sustainable clothing. Interventions targeting consumers, suppliers, buyers and retailers are proposed that encourage more sustainable clothing production, purchase, care and disposal behaviour. These interventions range from normalising the design of sustainable clothing and increasing the ease of purchase, to shifting clothes washing norms and increasing upcycling, recycling and repair

Birth Weight for Gestational Age Norms for a Large Cohort of Infants Born to HIV-Negative Women in Botswana Compared with Norms for U.S.-Born Black Infants

Background: Standard values for birth weight by gestational age are not available for sub-Saharan Africa, but are needed to evaluate incidence and risk factors for intrauterine growth retardation in settings where HIV, antiretrovirals, and other in utero exposures may impact birth outcomes. Methods: Birth weight data were collected from six hospitals in Botswana. Infants born to HIV-negative women between 26-44 weeks gestation were analyzed to construct birth weight for gestational age charts. These data were compared with published norms for black infants in the United States. Results: During a 29 month period from 2007-2010, birth records were reviewed in real-time from 6 hospitals and clinics in Botswana. Of these, 11,753 live infants born to HIV-negative women were included in the analysis. The median gestational age at birth was 39 weeks (1st quartile 38, 3rd quartile 40 weeks), and the median birth weight was 3100 grams (1st quartile 2800, 3rd quartile 3400 grams). We constructed estimated percentile curves for birth weight by gestational age which demonstrate increasing slope during the third trimester and leveling off beyond 40 weeks. Compared with black infants in the United States, Botswana-born infants had lower median birth weight for gestational age from weeks 37 through 42 (p < .02). Conclusions: We present birth weight for gestational age norms for Botswana, which are lower at term than norms for black infants in the United States. These findings suggest the importance of regional birth weight norms to identify and define risk factors for higher risk births. These data serve as a reference for Botswana, may apply to southern Africa, and may help to identify infants at risk for perinatal complications and inform comparisons among infants exposed to HIV and antiretrovirals in utero

Музично-етнографічні польові дослідження (на прикладі обстеження історичної Хотинщини)

The author of the article researches the approaches of musical-ethnographic work, its methods and goals, as well as the choice of the specific territory and its exploration defined by them. The author comments on his intention to examine the area of Khotyn, which now is a part of Chernivtsy region; explains the methods of examining the territory. Pluses and minuses of the existing song collections dedicated to the given district are under consideration in this article. In conclusion short information about Northern Bessarabia and its population is given

Test methods to determine durability of concrete under combined environmental actions and mechanical load: final report of RILEM TC 246-TDC

At present several methods are available to predict the durability of reinforced concrete structures. In most cases, one dominant deterioration process such as carbonation or chloride penetration is taken into consideration. Experimental results as well as observations in practice show that this is not a realistic and certainly not a conservative approach. In order to test more realistically, RILEM TC 246-TDC, founded in 2011, has developed a method to determine the durability of concrete exposed to the combined action of chloride penetration and mechanical load. In this report, a test method is presented which allows determination of realistic diffusion coefficients for chloride ions in concrete under compressive or tensile stress. Comparative test results from five different laboratories showed that the combination of mechanical and environmental loads may be much more severe than a single environmental load without mechanical loading. Modelling and probabilistic analysis also showed that the obvious synergetic effects cannot be neglected in realistic service life prediction

YAP1 withdrawal in hepatoblastoma drives therapeutic differentiation of tumor cells to functional hepatocyte-like cells

BACKGROUND and AIMS: Despite surgical and chemotherapeutic advances, the five-year survival rate for Stage IV Hepatoblastoma (HB), the predominant pediatric liver tumor, remains at 27%. YAP1 and beta-Catenin co-activation occurs in 80% of children\u27s HB; however, a lack of conditional genetic models precludes tumor maintenance exploration. Thus, the need for a targeted therapy remains unmet. Given the predominance of YAP1 and beta-Catenin activation in HB, we sought to evaluate YAP1 as a therapeutic target in HB. APPROACH and RESULTS: We engineered the first conditional HB murine model using hydrodynamic injection to deliver transposon plasmids encoding inducible YAP1(S127A) , constitutive beta-Catenin(DelN90) , and a luciferase reporter to murine liver. Tumor regression was evaluated using bioluminescent imaging, and tumor landscape characterized using RNA and ATAC sequencing, and DNA foot-printing. Here we show that YAP1(S127A) withdrawal mediates \u3e90% tumor regression with survival for 230+ days in mice. YAP1 (S127A) withdrawal promotes apoptosis in a subset of tumor cells and in remaining cells induces a cell fate switch driving therapeutic differentiation of HB tumors into Ki-67 negative hbHep cells with hepatocyte-like morphology and mature hepatocyte gene expression. YAP1 (S127A) withdrawal drives formation of hbHeps by modulating liver differentiation transcription factor (TF) occupancy. Indeed, tumor-derived hbHeps, consistent with their reprogrammed transcriptional landscape, regain partial hepatocyte function and rescue liver damage in mice. CONCLUSIONS: YAP1(S127A) withdrawal, without silencing oncogenic beta-Catenin, significantly regresses hepatoblastoma, providing the first in vivo data to support YAP1 as a therapeutic target for HB. YAP1(S127A) withdrawal alone sufficiently drives long-term regression in hepatoblastoma because it promotes cell death in a subset of tumor cells and modulates transcription factor occupancy to reverse the fate of residual tumor cells to mimic functional hepatocytes