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We introduce an abstract concept of quantum field theory on categories fibered in groupoids over the category of spacetimes. This provides us with a general and flexible framework to study quantum field theories defined on spacetimes with extra geometric structures such as bundles, connections and spin structures. Using right Kan extensions, we can assign to any such theory an ordinary quantum field theory defined on the category of spacetimes and we shall clarify under which conditions it satisfies the axioms of locally covariant quantum field theory. The same constructions can be performed in a homotopy theoretic framework by using homotopy right Kan extensions, which allows us to obtain first toy-models of homotopical quantum field theories resembling some aspects of gauge theories.
Background
Cells are able to communicate and coordinate their function within tissues via secreted factors. Aberrant secretion by cancer cells can modulate this intercellular communication, in particular in highly organised tissues such as the liver. Hepatocytes, the major cell type of the liver, secrete Dickkopf (Dkk), which inhibits Wnt/ β-catenin signalling in an autocrine and paracrine manner. Consequently, Dkk modulates the expression of Wnt/ β-catenin target genes. We present a mathematical model that describes the autocrine and paracrine regulation of hepatic gene expression by Dkk under wild-type conditions as well as in the presence of mutant cells.
Results
Our spatial model describes the competition of Dkk and Wnt at receptor level, intra-cellular Wnt/ β-catenin signalling, and the regulation of target gene expression for 21 individual hepatocytes. Autocrine and paracrine regulation is mediated through a feedback mechanism via Dkk and Dkk diffusion along the porto-central axis. Along this axis an APC concentration gradient is modelled as experimentally detected in liver. Simulations of mutant cells demonstrate that already a single mutant cell increases overall Dkk concentration. The influence of the mutant cell on gene expression of surrounding wild-type hepatocytes is limited in magnitude and restricted to hepatocytes in close proximity. To explore the underlying molecular mechanisms, we perform a comprehensive analysis of the model parameters such as diffusion coefficient, mutation strength and feedback strength.
Conclusions
Our simulations show that Dkk concentration is elevated in the presence of a mutant cell. However, the impact of these elevated Dkk levels on wild-type hepatocytes is confined in space and magnitude. The combination of inter- and intracellular processes, such as Dkk feedback, diffusion and Wnt/ β-catenin signal transduction, allow wild-type hepatocytes to largely maintain their gene expression.
BACKGROUND: Reduced left ventricular ejection fraction (LVEF) ≤30% is the most powerful prognostic indicator for sudden cardiac death (SCD) in patients after myocardial infarction (MI), but there are little data about long-term changes of LVEF after revascularization and the following implantation of a cardioverter defibrillator (ICD).
METHODS: We performed a retrospective analysis of 277 patients with reduced LVEF at least 1month after MI and complete revascularization. Patients (median time post-MI 23.4months; 74.3% after PCI, 25.7% after CABG were assigned either to group 1 (LVEF<30%) or group 2 (LVEF 30-40%). Biplane echocardiography was redone after a mean follow-up of 441±220days.
RESULTS: LVEF increased significantly in both two groups (group 1: 26.2±4.8% to 32.4±8.5%; p<0.001; group 2: 38.2±2.5% to 44.4±9.6%; p<0.001). However, statistical analysis of first and second LVEF measurement by means of a LOWESS regression and with an appropriate correction of the regression towards the mean effect revealed only a moderate increase of the mean LVEF from 35 to 37% (p<0.001) with a large interindividual variation.
CONCLUSIONS: The impact of early revascularization on LVEF appears to be low in the majority of post-MI heart failure patients. Owing to the high variability, a single measurement may not be reliable enough to justify a decision on ICD indication.
Background
In patients with mild cognitive impairment (MCI), gait instability, particularly in dual-task situations, has been associated with impaired executive function and an increased fall risk. Ginkgo biloba extract (GBE) could be an effective mean to improve gait stability.
Aims
This study investigated the effect of GBE on spatiotemporal gait parameters of MCI patients while walking under single and dual-task conditions.
Methods
Fifty patients aged 50-85 years with MCI and associated dual-task-related gait impairment participated in this randomised, double-blind, placebo-controlled, exploratory phase IV drug trial. Intervention group (IG) patients received GBE (Symfona (R) forte 120 mg) twice-daily for 6 months while control group (CG) patients received placebo capsules. A 6-month open-label phase with identical GBE dosage followed. Gait was quantified at months 0, 3, 6 and 12.
Results
After 6 months, dual-task-related cadence increased in the IG compared to the CG (p = 0.019, d = 0.71). No significant changes, but GBE-associated numerical non-significant trends were found after 6-month treatment for dual-task-related gait velocity and stride time variability.
Discussion
Findings suggest that 120 mg of GBE twice-daily for at least 6 months may improve dual-task-related gait performance in patients with MCI.
Conclusions
The observed gait improvements add to the understanding of the self-reported unspecified improvements among MCI patients when treated with standardised GBE.
Residents of the Kathmandu Valley experience severe particulate and gaseous air pollution throughout most of the year, even during much of the rainy season. The knowledge base for understanding the air pollution in the Kathmandu Valley was previously very limited, but is improving rapidly due to several field measurement studies conducted in the last few years. Thus far, most analyses of observations in the Kathmandu Valley have been limited to short periods of time at single locations. This study extends on the past studies by examining the spatial and temporal characteristics of two important gaseous air pollutant (CO and O3) based on simultaneous observations over a longer period at five locations within the valley and on its rim, including a supersite (at Bode in the valley center, 1345m above sea level) and four satellite sites (at Paknajol, 1380masl in the Kathmandu city center, at Bhimdhunga (1522masl), a mountain pass on the valley's western rim, at Nagarkot (1901masl), another mountain pass on the eastern rim, and Naikhandi, near the valley's only river outlet). CO and O3 mixing ratios were monitored from January to July 2013, along with other gases and aerosol particles by instruments deployed at the Bode supersite during the international air pollution measurement campaign SusKat-ABC (Sustainable Atmosphere for the Kathmandu Valley – endorsed by the Atmospheric Brown Clouds program of UNEP). The O3 monitoring at Bode, Paknajol and Nagarkot as well as the CO monitoring at Bode were extended beyond July 2013 to investigate their variability over a complete annual cycle. Higher CO mixing ratios were found at Bode than at the outskirt sites (Bhimdhunga, Naikhandi and Nagarkot), and all sites except Nagarkot showed distinct diurnal cycles of CO mixing ratio with morning peaks and daytime lows. Seasonally, CO was higher during the pre-monsoon and winter seasons, especially due to the emissions from brick kiln industries, which only operate during this period, as well as increased domestic heating during winter, and regional forest fires and agro-residue burning. It was lower during the monsoon due to rainfall, which reduces open burning activities within the valley and in the surrounding regions, and thus reduces the sources of CO. The meteorology of the valley also played a key role in determining the CO mixing ratios. Furthermore, there was evidence of some influence of pollution from the greater region around the valley. A top-down estimate of the CO emission flux was made by using the CO mixing ratio and mixing layer height (MLH) measured at Bode. The estimated annual CO flux at Bode was 4.92μgm−2s−1, which is 2–14 times higher than that in widely used emission inventory databases (EDGAR HTAP, REAS and INTEX-B). This difference in CO flux between Bode and other emission databases likely arises from large uncertainties in both the top-down and bottom-up approaches to estimating the emission flux. The O3 mixing ratio was found to be highest during the pre-monsoon season at all sites, while the timing of the seasonal minimum varied across the sites. The daily maximum 8 hour average O3 exceeded the WHO recommended guideline of 50ppb on more days at the hilltop station of Nagarkot (159/357 days) than at the urban valley bottom sites of Paknajol (132/354 days) and Bode (102/353 days), presumably due to the influence of free-tropospheric air at the high-altitude site, as well as to titration of O3 by fresh NOx emissions near the urban sites. More than 78% of the exceedance days were during the pre-monsoon period at all sites. This was due to both favorable meteorological conditions as well as contributions of precursors from regional sources such as forest fires and agro-residue burning. The high O3 mixing ratio observed during the pre-monsoon period is of a high concern for human health and ecosystems, including agroecosystems in the Kathmandu Valley and surrounding regions.
Landscape and scale-dependent spatial niches of bats foraging above intensively used arable fields
(2017)
Introduction
Bats are threatened by agricultural intensification, and although bat ecology in agricultural landscapes is in the focus of current research, the effects of interacting spatiotemporal factors on species-specific bat activity above farmland remain understudied. Our aim was to identify spatiotemporal factors and their interactions relevant for the activity of bat species above conventionally managed arable fields.
Methods
We repeatedly monitored relative bat activity above open arable fields in Germany using acoustic monitoring. We used site-related biotic and abiotic factors and landscape characteristics across five spatial scales, their combinations, and interactions to identify those factors which best explain variation in bat activity.
Results
Numerous interactions between landscape characteristics and the insect abundance affected bat activity above fields. For instance, Pipistrellus pipistrellus became more active with increasing insect abundance, but only above fields with a low proportion of woody vegetation cover in the surroundings. Additionally, the level of bat activity in summer depended on landscape characteristics. For example, the activity of Pipistrellus nathusii was relatively low in summer above fields that were surrounded by vegetation patches with a high degree of edge complexity (e.g., hedgerow). However, the activity remained at a relatively high level and did not differ between seasons above fields that were surrounded by vegetation patches with a low degree of edge complexity (e.g., roundly shaped forest patch).
Conclusions
Our results revealed that landscape characteristics and their interactions with insect abundance affected bat activity above conventionally managed fields and highlighted the opportunistic foraging behavior of bats. To improve the conditions for bats in agricultural landscapes, we recommend re-establishing landscape heterogeneity to protect aquatic habitats and to increase arthropod availability.
VS30, slope, H800 and f0
(2017)
The aim of this paper is to investigate the ability of various site-condition proxies (SCPs) to reduce ground-motion aleatory variability and evaluate how SCPs capture nonlinearity site effects. The SCPs used here are time-averaged shear-wave velocity in the top 30 m (VS30), the topographical slope (slope), the fundamental resonance frequency (f0) and the depth beyond which Vs exceeds 800 m/s (H800). We considered first the performance of each SCP taken alone and then the combined performance of the 6 SCP pairs [VS30–f0], [VS30–H800], [f0–slope], [H800–slope], [VS30–slope] and [f0–H800]. This analysis is performed using a neural network approach including a random effect applied on a KiK-net subset for derivation of ground-motion prediction equations setting the relationship between various ground-motion parameters such as peak ground acceleration, peak ground velocity and pseudo-spectral acceleration PSA (T), and Mw, RJB, focal depth and SCPs. While the choice of SCP is found to have almost no impact on the median groundmotion prediction, it does impact the level of aleatory uncertainty. VS30 is found to perform the best of single proxies
at short periods (T < 0.6 s), while f0 and H800 perform better at longer periods; considering SCP pairs leads to significant improvements, with particular emphasis on [VS30–H800] and [f0–slope] pairs. The results also indicate significant nonlinearity on the site terms for soft sites and that the most relevant loading parameter for characterising nonlinear site response is the “stiff” spectral ordinate at the considered period.
Purpose: Comparison of the dissociation kinetics of rapid-acting insulins lispro, aspart, glulisine and human insulin under physiologically relevant conditions.
Methods: Dissociation kinetics after dilution were monitored directly in terms of the average molecular mass using combined static and dynamic light scattering. Changes in tertiary structure were detected by near-UV circular dichroism.
Results: Glulisine forms compact hexamers in formulation even in the absence of Zn2+. Upon severe dilution, these rapidly dissociate into monomers in less than 10 s. In contrast, in formulations of lispro and aspart, the presence of Zn2+ and phenolic compounds is essential for formation of compact R6 hexamers. These slowly dissociate in times ranging from seconds to one hour depending on the concentration of phenolic additives. The disadvantage of the long dissociation times of lispro and aspart can be diminished by a rapid depletion of the concentration of phenolic additives independent of the insulin dilution. This is especially important in conditions similar to those after subcutaneous injection, where only minor dilution of the insulins occurs.
Conclusion: Knowledge of the diverging dissociation mechanisms of lispro and aspart compared to glulisine will be helpful for optimizing formulation conditions of rapid-acting insulins.
The transition from hunting and gathering to farming involved profound cultural and technological changes. In Western and Central Europe, these changes occurred rapidly and synchronously after the arrival of early farmers of Anatolian origin [1-3], who largely replaced the local Mesolithic hunter-gatherers [1, 4-6]. Further east, in the Baltic region, the transition was gradual, with little or no genetic input from incoming farmers [7]. Here we use ancient DNA to investigate the relationship between hunter-gatherers and farmers in the Lower Danube basin, a geographically intermediate area that is characterized by a rapid Neolithic transition but also by the presence of archaeological evidence that points to cultural exchange, and thus possible admixture, between hunter-gatherers and farmers. We recovered four human paleogenomes (1.13 to 4.13 coverage) from Romania spanning a time transect between 8.8 thousand years ago (kya) and 5.4 kya and supplemented them with two Mesolithic genomes (1.73- and 5.33) from Spain to provide further context on the genetic background of Mesolithic Europe. Our results show major Western hunter-gatherer (WHG) ancestry in a Romanian Eneolithic sample with a minor, but sizeable, contribution from Anatolian farmers, suggesting multiple admixture events between hunter-gatherers and farmers. Dietary stableisotope analysis of this sample suggests a mixed terrestrial/ aquatic diet. Our results provide support for complex interactions among hunter-gatherers and farmers in the Danube basin, demonstrating that in some regions, demic and cultural diffusion were not mutually exclusive, but merely the ends of a continuum for the process of Neolithization.
The unusual mix of morphological traits displayed by extinct South American native ungulates (SANUs) confounded both Charles Darwin, who first discovered them, and Richard Owen, who tried to resolve their relationships. Here we report an almost complete mitochondrial genome for the litoptern Macrauchenia. Our dated phylogenetic tree places Macrauchenia as sister to Perissodactyla, but close to the radiation of major lineages within Laurasiatheria. This position is consistent with a divergence estimate of B66Ma (95% credibility interval, 56.64-77.83 Ma) obtained for the split between Macrauchenia and other Panperissodactyla. Combined with their morphological distinctiveness, this evidence supports the positioning of Litopterna (possibly in company with other SANU groups) as a separate order within Laurasiatheria. We also show that, when using strict criteria, extinct taxa marked by deep divergence times and a lack of close living relatives may still be amenable to palaeogenomic analysis through iterative mapping against more distant relatives.