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The PRETREE hierarchical choice model is a direct extension of the Elimination by Aspects model which is applied in capturing violations from assumptions pertaining to the Independence of Irrelevant Alternative (IIA). The application of the PRETREE aggregate model and a new modified PRETREE (MP) model for choice/preference modeling literature demonstrated the inferior (n-way) market share predictions of the PRETREE compared to MP. The superior n-way predictions of MP also incorporate more input information and eliminates partial IIA assumptions that are required by the PRETREE.

Choice modeling literature assumes that the decision-maker is aware of a set of alternatives at the beginning of the decision process. The decision-making process splits the awareness set into a consideration set, which contains the more seriously considered alternatives, and a non-consideration set, which contains the casually contemplated alternatives. An information-theoretic algorithm for estimating the consideration set is proposed.

A minimum discrimination information (MDI) scheme was developed to relate the two stages of a decision process. The MDI approach can use proportions as direct input for the approximation of the simultaneous compensatory models. A two-stage, two-decision rule model was subsequently constructed. It has an attribute processing structure in the first stage and a simultaneous compensatory processing structure in the second stage.

The bootstrap method can enhance the predictive capabilities of probabilistic attribute choice models. The models present point estimates of choice-attribute and rate of correct prediction coefficients. Choice-attributes help determine the factors behind consumer choices. The bootstrap method determines measures of accuracy from different statistics of interest and calculates the sampling distribution of the statistic of interest by resampling.

This study estimates the risks of agricultural pesticides on non-target organisms and the environment by combining detailed pesticide application data for 2015 with the Danish risk indicator Pesticide Load. We quantify and map the pesticide load of 59 pesticides on 28 crops and pastures in the EU. Furthermore, we investigate how recent bans on 14 pesticides in the EU could reduce pesticide use and load. Key findings show that the highest pesticide loads per hectare occur in Cyprus and the Netherlands due to high application rates and a high proportion of vegetable production. Chlorpyrifos caused the highest pesticide load per hectare on more than half of the assessed crops before its ban. The ban of 14 pesticides between 2018 and 2023 potentially reduced pesticide loads by 94%, but unobserved substitution effects could offset pesticide load reductions. Although bans on active substances are justified to control certain endpoint risks, our results highlight the potential weaknesses of bans that merely shift risks. These findings contribute to the ongoing scientific and societal discourse on efficiently mitigating pesticides' impacts on non-target organisms and the environment. However, to improve the evaluation of pesticide use, it is vital to enhance the reporting on detailed pesticide use for individual crop-pesticide combinations. [Display omitted] • Quantified pesticide-related risks in the EU with the Pesticide Load • The cultivation of vegetables incurs the highest pesticide load per hectare • Ban of pesticides decreased pesticide load substantially • The substitution of banned pesticides could offset reduction of pesticide load [ABSTRACT FROM AUTHOR]

Extracellular potassium [K+] o elevation during synaptic activity retrogradely modifies presynaptic release and astrocytic uptake of glutamate. Hence, local K+ clearance and replenishment mechanisms are crucial regulators of glutamatergic transmission and plasticity. Based on recordings of astrocytic inward rectifier potassium current I Kir and K+-sensitive electrodes as sensors of [K+] o as well as on in silico modeling, we demonstrate that the neuronal K+-Cl- co-transporter KCC2 clears local perisynaptic [K+] o during synaptic excitation by operating in an activity-dependent reversed mode. In reverse mode, KCC2 replenishes K+ in dendritic spines and complements clearance of [K+] o , therewith attenuating presynaptic glutamate release and shortening LTP. We thus demonstrate a physiological role of KCC2 in neuron-glial interactions and regulation of synaptic signaling and plasticity through the uptake of postsynaptically released K+. [Display omitted] • KCC2 is recruited upon perisynaptic K+ increase due to glutamatergic synaptic activity • In reverse mode, KCC2 transiently transports perisynaptic K+ back intothe spine • KCC2 reversal diminishes perisynaptic K+, especially when astrocytic K+ uptake is impaired • KCC2 reverse mode temporarily restricts presynaptic glutamate release and attenuates LTP Byvaltcev et al. demonstrate a physiological role of KCC2 at dendritic spines by showing KCC2 operation in reverse mode that restricts the perisynaptic potassium increase upon glutamatergic stimulation. They describe KCC2 interactions with other perisynaptic potassium transport mechanisms and the consequences of KCC2 modifications for synaptic signaling. [ABSTRACT FROM AUTHOR]

Aims Angiogenesis is defined as the sprouting of capillaries from pre-existing vasculature. It is a complex process that includes endothelial proliferation, migration, and tube formation. Previous data have demonstrated a high expression level of manganese-superoxide dismutase (MnSOD) in endothelial cells and suggested an important role of MnSOD in several cardiovascular diseases. In addition, manganese (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP) has been shown to mimic some of the effects of MnSOD in various tissues. However, its effect on the vasculature remains unknown. Methods and results HUVECs were treated with MnTBAP. Migration, tube formation, and capillary sprouting assays were performed to evaluate the pro-angiogenic effect in vitro . Matrigel plug assay was performed to assess capillary ingrowth in vivo . Compared to control, treatment with MnTBAP revealed increased cell migration, tube formation and capillary sprouting along with more capillary ingrowth in the Matrigel plug assay. This effect was mediated through a mitofusin (Mfn)-1-dependent pathway. Expression of Tie-2, Ang-2 and VEGF mRNA was increased in muscle tissues after ligation in MnTBAP treated mice. However, revascularization in the hindlimb ischemia model was not statistically significant at day 10 in MnTBAP treated mice. Conclusion In summary, our data demonstrate a strong pro-angiogenic, but less pro-arteriogenic effect of MnTBAP in HUVECs mediated by Mfn-1. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Telomeres and associated proteins are regulators of cellular survival, regeneration and aging. PPAR-γ agonists may mediate vascular effects in addition to insulin sensitizing. We therefore examined whether pioglitazone regulates vascular telomere biology. Methods and results: C57/Bl6 mice were randomized to treatment with pioglitazone (20mg/kg i.p. daily) or vehicle for 4 weeks (n =6–8 per group). Telomere repeat amplification protocols showed a 2-fold increase of aortic telomerase activity in the pioglitazone group. Telomere repeat-binding factor 2 protein and mRNA levels (236%+172% of vehicle) as well as phosphorylation of protein kinase Akt (479% of vehicle) were up-regulated. Western blots demonstrated reduced aortic expression of senescence markers p16, cell-cycle checkpoint kinase 2 and p53. These regulatory mechanisms were independent of acute changes of telomere length. Similar observations were made in mononuclear cells (MNC) from these mice and in cultivated bovine aortic endothelial cells, human MNC and endothelial progenitor cells (EPC). Telomerase activation by pioglitazone in cultivated cells was prevented by Akt inhibitors. To test the functional relevance of the findings, isolated mononuclear cells (MNC) were exposed to H2O2. MNC from pioglitazone-treated mice exhibited reduced apoptosis (AnnexinV-FACS). In vivo, lipopolysaccharide-induced aortic endothelial apoptosis was potently prevented in pioglitazone-treated animals (hairpin oligonucleotide assay). Both, up-regulation of telomere-regulating proteins and prevention of oxidative stress-induced aortic apoptosis, were absent in telomerase reverse transcriptase (TERT)-deficient mice. Conclusions/interpretation: Pioglitazone treatment up-regulates telomerase activity, telomere-stabilizing proteins and reduces senescence markers in vascular cells. These effects and the reduction of LPS-induced endothelial apoptosis by thiazolidinediones depend on TERT. The findings underscore the important role of telomere-regulating proteins for vascular cell function and survival. [Copyright &y& Elsevier]

ROCKs are important regulators of the actin cytoskeleton. Because changes in the actin cytoskeleton underlie vascular contractility and remodeling, inflammatory cell recruitment, and cell proliferation, it is likely that the Rho/ROCK pathway will play a central role in mediating vascular function. Indeed, increased ROCK activity is observed in cerebral and coronary vasospasm, hypertension, vascular inflammation, arteriosclerosis, and atherosclerosis. Recent experimental and clinical studies suggest that inhibition of ROCK could be a promising target for the treatment of cardiovascular disease. For example, inhibition of ROCK might be the underlying mechanism by which statins or HMG-CoA reductase inhibitors exert their therapeutic benefits beyond cholesterol reduction. In this review we summarize current understanding of the crucial role of RhoA/ROCK pathway in the regulation of vascular function and discuss its therapeutic potential in the treatment of atherosclerosis and vascular disease. [ABSTRACT FROM AUTHOR]

Abstract: PPAR-γ agonists (thiazolidinediones, TZDs) may improve endothelial function independently of insulin sensitizing. Bone marrow-derived endothelial progenitor cells (EPC) contribute to neoangiogenesis. Mice were treated with pioglitazone, 20mg/kg/day for 10 days. Treatment with TZD upregulated circulating Sca-1/VEGFR-2 positive EPC in the blood (235±60%) and the bone marrow (166±30%), cultured spleen-derived DiLDL/lectin positive EPC increased to 231±21% (n =24 per group). Upregulation of EPC was persistent after 20 days. TZD increased SDF-1-induced migratory capacity per number of EPC by 246±73% and increased expression of telomere repeat-binding factor 2 by 320±50%. In vivo neoangiogenesis was increased two-fold (214±42%, 20 days). The NOS inhibitor l-NAME did not inhibit the TZD-induced upregulation of EPC. EPC from TZD-treated animals showed reduced in vivo apoptosis (65±2.8% of vehicle). In cultured human EPC, pre-treatment with pioglitazone prevented H2O2-induced apoptosis. Inhibition of EPC apoptosis by TZD was abolished in the presence of wortmannin but not by LNMA. In summary, TZD upregulates both number and functional capacity of endothelial progenitor cells. Pioglitazone prevents apoptosis of EPC in mice as well as in human EPC in a PI3K-dependent but NO-independent manner. Reduction of EPC apoptosis by TZD may be a potentially beneficial mechanism for patients with vascular diseases. [Copyright &y& Elsevier]

In smokers' lungs, excessive mucus clogs small airways, impairing respiration and promoting recurrent infection. A breakthrough in understanding this pathology was the realization that smoke could directly stimulate mucin synthesis in lung epithelial cells and that this phenomenon was dependent on the cell surface receptor for epidermal growth factor, EGFR. Distal steps in the smoke-triggered pathway have not yet been determined. We report here that the predominant airway mucin (MUC5AC) undergoes transcriptional up-regulation in response to tobacco smoke; this is mediated by an AP-1-containing response element, which binds JunD and Fra-2. These transcription factors require phosphorylation by upstream kinases JNK and ERK, respectively. Whereas ERK activation results from the upstream activation of EGFR, JNK activation is chiefly EGFR-independent. Our experiments demonstrated that smoke activates JNK via a Src-dependent, EGFRindependent signaling cascade initiated by smoke-induced reactive oxygen species. Taken together with our earlier results, these data indicate that the induction of mucin by smoke is the combined effect of mutually independent, reactive oxygen species activation of both EGFR and JNK. [ABSTRACT FROM AUTHOR]

The absorption and stimulated emission changes in the first 535 ps of the PYP photocycle can be described by four life times of 0.7, 6.3, and 220 ps and long lived. Two intermediates, I0 and I0‡, were identified. We did not obtain indications for a significant excitation wavelength dependent primary photochemistry as found in low temperature absorption spectroscopy. The anisotropy of the primary photoproduct I0 and its successor I0‡ amounts to 0.3 – significantly lower than that of the bleached ground state (0.4). This distinctive change of the transition dipole moment orientation in the product state (24°) reflects changes of the chromophore geometry and electron density distribution caused by the photoisomerisation. [Copyright &y& Elsevier]