This article aims at investigating the impact of financial supports from agricultural policy on farm‐size dynamics. Since not all farms may behave alike, a non‐stationary mixed‐Markov chain modelling ...(M‐MCM) approach is applied to capture unobserved heterogeneity in the movements of farms across economic size (ES) classes. A multinomial logit specification is used for transition probabilities and the parameters are estimated by the maximum likelihood method and the Expectation‐Maximisation (EM) algorithm. An empirical application to an unbalanced panel from 2000 to 2018 shows that French farming consists of ‘almost stayers’, with a high probability of remaining in the same ES class over time, and ‘likely movers’, which present a higher probability of a change in size. The results also show that the impact of subsidies and other economic factors depends greatly on the type that a farm belongs to. These findings confirm that individual characteristics of farmers may be relevant for policy efficiency and more attention should thus be paid to unobserved farm heterogeneity in both policy design and the assessment of their impacts on farm‐size dynamics.
Although antitubulin drugs are used widely to treat human cancer, many patients display intrinsic or acquired drug resistance that imposes major obstacles to successful therapy. Mounting evidence ...argues that cancer cell apoptosis triggered by antitubulin drugs relies upon activation of the cell-cycle kinase Cdk1; however, mechanistic connections of this event to apoptosis remain obscure. In this study, we identified the antiapoptotic protein YAP, a core component of the Hippo signaling pathway implicated in tumorigenesis, as a critical linker coupling Cdk1 activation to apoptosis in the antitubulin drug response. Antitubulin drugs activated Cdk1, which directly phosphorylated YAP on five sites independent of the Hippo pathway. Mutations in these phosphorylation sites on YAP relieved its ability to block antitubulin drug-induced apoptosis, further suggesting that YAP was inactivated by Cdk1 phosphorylation. Notably, we found that YAP was not phosphorylated and inactivated after antitubulin drug treatment in taxol-resistant cancer cells. Our findings suggest YAP and its phosphorylation status as candidate prognostic markers in predicting antitubulin drug response in patients.
Abstract We investigated stroke outcomes in normal weight (body mass index BMI 18.50-24.99 kg/m2 ), overweight (BMI 25.00-29.99 kg/m2 ), and obese (BMI ≥30 kg/m2 ) patients with AF treated with ...rivaroxaban and warfarin. We compared the incidence of stroke and systemic embolic events (SEE) as well as bleeding events in normal weight (n=3289), overweight (n=5535), and obese (n=5206) patients in a post-hoc analysis of the ROCKET AF trial. Stroke and SEE rates per 100 patient-years were 2.93 in the normal weight group (reference group), 2.28 in the overweight group (adjusted hazard ratio HR 0.81, 95% confidence interval CI: 0.66-0.99, p=0.04), and 1.88 in the obese group (adjusted HR 0.69, 95% CI: 0.55-0.86, p<0.001). The risk of stroke was statistically significantly lower for obese patients with BMI ≥35 compared with normal weight patients in both the rivaroxaban and warfarin groups (rivaroxaban: HR 0.62, 95% CI: 0.40-0.96, p=0.033; warfarin: HR 0.48, 95% CI: 0.31-0.74, p<0.001). In conclusion, among patients with AF treated with anticoagulant therapy, increased BMI was associated with decreased stroke risk. Warfarin and the novel anticoagulant rivaroxoban are effective in stroke prevention in all sub-groups of obese patients.
The outbreak of a pandemic influenza H1N1 in 2009 required the rapid generation of high-yielding vaccines against the A/California/7/2009 virus, which were achieved by either addition or deletion of ...a glycosylation site in the influenza proteins hemagglutinin and neuraminidase. In this report, we have systematically evaluated the glycan composition, structural distribution and topology of glycosylation for two high-yield candidate reassortant vaccines (NIBRG-121xp and NYMC-X181A) by combining various enzymatic digestions with high performance liquid chromatography and multiple-stage mass spectrometry. Proteomic data analyses of the full-length protein sequences determined 9 N-glycosylation sites of hemagglutinin, and defined 6 N-glycosylation sites and the glycan structures of low abundance neuraminidase, which were occupied by high-mannose, hybrid and complex-type N-glycans. A total of ~300 glycopeptides were analyzed and manually validated by tandem mass spectrometry. The specific N-glycan structure and topological location of these N-glycans are highly correlated to the spatial protein structure and the residential ligand binding. Interestingly, sulfation, fucosylation and bisecting N-acetylglucosamine of N-glycans were also reliably identified at the specific glycosylation sites of the two influenza proteins that may serve a crucial role in regulating the protein structure and increasing the protein abundance of the influenza virus reassortants.
Elevated temperature has significant effect on the mechanical response of metals and alloys. Industrial processes often use high temperature forming to fabricate components of complex shape from ...alloys such as aluminum or magnesium that have low room temperature formability. Accurate forming models to integrate warm forming in computer aided engineering (CAE) in production environment has been hampered by a lack of constitutive relations at elevated temperatures, forcing one to rely on experimental data for such integration. In this paper, a new thermo elasto-viscoplastic (TEV) constitutive relation is developed to model the behavior of face-centred cubic (FCC) polycrystals, especially aluminum alloys, at elevated temperatures. The model takes into account the temperature dependence of the single crystal elastic coefficients, single slip hardening parameters, thermal softening, rate sensitivity, and the total deformation. The TEV framework has been implemented into the commercial finite element code LS-DYNA to study the effects of temperature on metal forming. Uniaxial tension simulations at six different temperatures ranging from 25 °C to 260 °C have been performed and calibrated with published experimental results. Equations for the variation of single-slip hardening parameters with temperature have been developed for the AA5754 aluminum alloy. Shear test simulations at different temperatures have been used to validate the model. The proposed framework for the single slip parameters for uniaxial tension accurately predicts the shear stress-shear strain data without the need for any further fitting parameter. Temperature dependence of texture evolution, single slip hardening and hardening rates, thermal softening, and slip activity in AA5754 sheet alloy during temperatures corresponding to warm forming temperatures are investigated.
•First 3D thermo-elasto-viscoplastic constitutive model for FCC polycrystals.•Temperature dependence of all components of deformation is considered.•The framework is implemented in LS-DYNA to study the effects of temperature.•Equations for the variation of hardening parameters with temperature are developed.•With one fitting parameter set, both uniaxial tension and shear data are predicted.
Abstract
Accounting for spatial interactions between farms is highly relevant for the analysis of agricultural policy impacts. Existing studies, however, only account for homogeneous (average) ...spatial interactions. We develop a mixture modelling framework to account for unobserved heterogeneity, allowing spatial interaction to vary across endogenously defined farm types. We apply this approach to study farmer decisions to exit the farming business using a large panel dataset covering all registered farms in Brittany, France, for the period 2004–2014. While exiting is on average positively correlated with neighbouring farm size, we find substantial variation between farm types, and a negative correlation for a significant proportion of farms. The approach we develop not only enables us to identify different correlations between neighbouring farm size and exits from farming but also yields different results than pooled estimations.
Background
In most pseudostratified epithelia, basal cells represent a multipotent adult stem cell population. These cells generally remain in a quiescent state, until they are stimulated to respond ...to tissue damage by initiating epithelial regeneration. In the epididymis, cell proliferation occurs at a relatively slow rate under normal physiological conditions. Epididymal basal cells have been shown to share common properties with multipotent adult stem cells. The development of organoids from stem cells represents a novel approach for understanding cellular differentiation and characterization of stem cells.
Objective
To review the literature on tissue regeneration in the epididymis and demonstrate the presence of an epididymal stem cell population.
Methods
PubMed database was searched for studies reporting on cell proliferation, regeneration, and stem cells in the epididymis. Three‐dimensional cell culture of epididymal cells was used to determine whether these can develop into organoids in a similar fashion to stem cells from other tissues.
Results
The epididymal epithelium can rapidly regenerate following orchidectomy or efferent duct ligation, in order to maintain epithelial integrity. Studies have isolated a highly purified fraction of rat epididymal basal cells and reported that these cells displayed properties similar to those of multipotent adult stem cells. In two‐dimensional cell culture conditions, these cells differentiated into cells which expressed connexin 26, a marker of columnar cells, and cytokeratin 8. Furthermore, three‐dimensional cell culture of epididymal cells resulted in the formation of organoids, a phenomenon associated with the proliferation and differentiation of stem cells in vitro.
Conclusions
The rapid proliferation and tissue regeneration of the epididymal epithelium to preserve its integrity following tissue damage as well as the ability of cells to differentiate into organoids in vitro support the notion of a resident progenitor/stem cell population in the adult epididymis.
Neurodegeneration has been correlated with mitochondrial DNA (mtDNA) damage and exposure to environmental toxins, but causation is unclear. We investigated the ability of several known environmental ...genotoxins and neurotoxins to cause mtDNA damage, mtDNA depletion, and neurodegeneration in Caenorhabditis elegans. We found that paraquat, cadmium chloride and aflatoxin B1 caused more mitochondrial than nuclear DNA damage, and paraquat and aflatoxin B1 also caused dopaminergic neurodegeneration. 6-hydroxydopamine (6-OHDA) caused similar levels of mitochondrial and nuclear DNA damage. To further test whether the neurodegeneration could be attributed to the observed mtDNA damage, C. elegans were exposed to repeated low-dose ultraviolet C radiation (UVC) that resulted in persistent mtDNA damage; this exposure also resulted in dopaminergic neurodegeneration. Damage to GABAergic neurons and pharyngeal muscle cells was not detected. We also found that fasting at the first larval stage was protective in dopaminergic neurons against 6-OHDA-induced neurodegeneration. Finally, we found that dopaminergic neurons in C. elegans are capable of regeneration after laser surgery. Our findings are consistent with a causal role for mitochondrial DNA damage in neurodegeneration, but also support non mtDNA-mediated mechanisms.
The use of different expression systems to produce the same recombinant human protein can result in expression-dependent chemical modifications (CMs) leading to variability of structure, stability ...and immunogenicity. Of particular interest are recombinant human proteins expressed in plant-based systems, which have shown particularly high CM variability. In studies presented here, recombinant human serum albumins (rHSA) produced in Oryza sativa (Asian rice) (OsrHSA) from a number of suppliers have been extensively characterized and compared to plasma-derived HSA (pHSA) and rHSA expressed in yeast (Pichia pastoris and Saccharomyces cerevisiae). The heterogeneity of each sample was evaluated using size exclusion chromatography (SEC), reversed-phase high-performance liquid chromatography (RP-HPLC) and capillary electrophoresis (CE). Modifications of the samples were identified by liquid chromatography-mass spectrometry (LC-MS). The secondary and tertiary structure of the albumin samples were assessed with far U/V circular dichroism spectropolarimetry (far U/V CD) and fluorescence spectroscopy, respectively. Far U/V CD and fluorescence analyses were also used to assess thermal stability and drug binding. High molecular weight aggregates in OsrHSA samples were detected with SEC and supplier-to-supplier variability and, more critically, lot-to-lot variability in one manufactures supplied products were identified. LC-MS analysis identified a greater number of hexose-glycated arginine and lysine residues on OsrHSA compared to pHSA or rHSA expressed in yeast. This analysis also showed supplier-to-supplier and lot-to-lot variability in the degree of glycation at specific lysine and arginine residues for OsrHSA. Both the number of glycated residues and the degree of glycation correlated positively with the quantity of non-monomeric species and the chromatographic profiles of the samples. Tertiary structural changes were observed for most OsrHSA samples which correlated well with the degree of arginine/lysine glycation. The extensive glycation of OsrHSA from multiple suppliers may have further implications for the use of OsrHSA as a therapeutic product.
The paper investigates whether accounting for unobserved heterogeneity in farms' size transition processes improves the representation of structural change in agriculture. Considering a mixture of ...two types of farm, the mover-stayer model is applied for the first time in an agricultural economics context. The maximum likelihood method and the expectation-maximization algorithm are used to estimate the model's parameters. An empirical application to a panel of French farms from 2000 to 2013 shows that the mover-stayer model outperforms the homogeneous Markov chain model in recovering the transition process and predicting the future distribution of farm sizes.
PDF
