PurposeThis paper aims to analyse the main variables and causal relationships in the system structure of the diversification of non-agricultural activities on agricultural holdings using system ...dynamics (SD) modelling. The SD model aims to simulate depictions of the behaviour of the real system while testing the effects of alternative decisions over time.Design/methodology/approachAn SD methodology was chosen to model diversification in farm tourism.FindingsA system approach increases the authors’ understanding of the transition of agricultural holdings to farm tourism. The results indicate that the transition to farm tourism depends on the level of tourism development in a certain area. The system is influenced by subsidies allocated by authorities to expand primary agricultural activities. The model describes a situation in which the tourism and agricultural industries have been affected by the COVID-19 pandemic.Research limitations/implicationsThe research is limited by the small set of available data due to the limited number of farms in Slovenia. One major problem is the difference in statistical data on the same activity collected from different institutions in Slovenia.Practical implicationsThe paper includes implications for understanding the transition process to farm tourism, allowing policymakers to experiment with subsidies and promotion to explore the efficacy and efficiency of proposed policies.Originality/valueThis study provides a structured, systemic view of the diversification of non-agricultural activities on agricultural holdings, where the simulation results are a reliable reflection of the behaviour of the actual system being modelled.
Clonal dominance arises when the descendants (clones) of one or a few founder cells contribute disproportionally to the final structure during collective growth 1-8. In contexts such as bacterial ...growth, tumorigenesis, and stem cell reprogramming 2-4, this phenomenon is often attributed to pre-existing propensities for dominance, while in stem cell homeostasis, neutral drift dynamics are invoked 5,6. The mechanistic origin of clonal dominance during development, where it is increasingly documented 1,6-8, is less understood. Here, we investigate this phenomenon in the
follicle epithelium, a system in which the joint growth dynamics of cell lineage trees can be reconstructed. We demonstrate that clonal dominance can emerge spontaneously, in the absence of pre-existing biases, as a collective property of evolving excitable networks through coupling of divisions among connected cells. Similar mechanisms have been identified in forest fires and evolving opinion networks 9-11; we show that the spatial coupling of excitable units explains a critical feature of the development of the organism, with implications for tissue organization and dynamics 1,12,13.
Background: Besides visiting the main tourist attractions in Slovenia, many tourists want to spend their free time in the countryside as well, but the number of farming establishments in Slovenia ...diminished distinctly in the last years.
Objectives: This paper aims to develop a system dynamics model, with the goal to analyse dynamics of the diversification of agricultural holdings into farm tourism activities in Slovenia.
Methods/Approach: A system dynamics methodology was chosen to model the diversification in farm tourism. First, we present a basic concept of a system dynamics model with a causal loop diagram. Further, a system dynamics model with different scenarios is presented.
Results: The main feedback loops were identified, and the simulation model was used to analyse different simulation scenarios of the transition of farming establishments into farm tourism facilities.
Conclusions: The model provides the answers to the strategic questions about the dynamics of transfer into tourist farms, using several simulation scenarios. The transition mainly relies on subsidies, promotion of diversification and the growth of rural tourism, which provides a relevant direction for the development of future incentives.
In this paper a system dynamics model for organic farming development to support government decision making is presented. The system incorporates relevant variables which affect organic farming ...development. The user seeks answers to strategic questions related to the level of organic farming development achievable in a long term dynamic horizon. The model’s basic structure is fully described and results are presented which show that the conversion process relies mainly on subsidies and self-organization resources. User can simulate different policy scenarios for organic farming and for assessing their impact on the economic and environmental parameters of organic production at aggregate level. After performing several simulation scenarios we discovered that conversion to organic farming relies on subsidies which provide the main motivation for conversion from conventional farming to organic farming. However, the subsidies are not the only driving force in the system, even more important are activities that promote organic farming, since sufficiently large subsidies could not be provided in order to complete the conversion from conventional to organic farming to the extent desired. Another important feature is food demand, determined by population size, which negatively influences the conversion to organic farming due to the increased demand leading to increased food prices.
Glioblastoma multiforme (GBM) is among the most aggressive cancers with a poor prognosis in spite of a plethora of established diagnostic and prognostic biomarkers and treatment modalities. ...Therefore, the current goal is the detection of novel biomarkers, possibly detectable in the blood of GBM patients that may enable an early diagnosis and are potential therapeutic targets, leading to more efficient interventions.
MicroRNA profiling of 734 human and human-associated viral miRNAs was performed on blood plasma samples from 16 healthy individuals and 16 patients with GBM, using the nCounter miRNA Expression Assay Kits.
We identified 19 miRNAs with significantly different plasma levels in GBM patients, compared to the healthy individuals group with the difference limited by a factor of 2. Additionally, 11 viral miRNAs were found differentially expressed in plasma of GBM patients and 24 miRNA levels significantly correlated with the patients' survival. Moreover, the overlap between the group of candidate miRNAs for diagnostic biomarkers and the group of miRNAs associated with survival, consisted of ten miRNAs, showing both diagnostic and prognostic potential. Among them, hsa miR 592 and hsa miR 514a 3p have not been previously described in GBM and represent novel candidates for selective biomarkers. The possible signalling, induced by the revealed miRNAs is discussed, including those of viral origin, and in particular those related to the impaired immune response in the progression of GBM.
The GBM burden is reflected in the alteration of the plasma miRNAs pattern, including viral miRNAs, representing the potential for future clinical application. Therefore proposed biomarker candidate miRNAs should be validated in a larger study of an independent cohort of patients.
An erythrocytosis is present when the red blood cell mass is increased, demonstrated as elevated hemoglobin and hematocrit in the laboratory evaluation. Congenital predispositions for erythrocytosis ...are rare, with germline variants in several genes involved in oxygen sensing (
VHL
,
EGLN1
, and
EPAS1
), signaling for hematopoietic cell maturation (
EPOR
and
EPO
), and oxygen transfer (
HBB
,
HBA1
,
HBA2
, and
BPGM
) that were already associated with the eight congenital types (ECYT1–8). Screening for variants in known congenital erythrocytosis genes with classical sequencing approach gives a correct diagnosis for only up to one-third of the patients. The genetic background of erythrocytosis is more heterogeneous, and additional genes involved in erythropoiesis and iron metabolism could have a putative effect on the development of erythrocytosis. This study aimed to detect variants in patients with yet unexplained erythrocytosis using the next-generation sequencing (NGS) approach, targeting genes associated with erythrocytosis and increased iron uptake and implementing the diagnostics of congenital erythrocytosis in Slovenia. Selected 25 patients with high hemoglobin, high hematocrit, and no acquired causes were screened for variants in the 39 candidate genes. We identified one pathogenic variant in
EPAS1
gene and three novel variants with yet unknown significance in genes
EPAS1
,
JAK2
, and
SH2B3.
Interestingly, a high proportion of patients were heterozygous carriers for two variants in
HFE
gene, otherwise pathogenic for the condition of iron overload. The association between the
HFE
variants and the development of erythrocytosis is not clearly understood. With a targeted NGS approach, we determined an actual genetic cause for the erythrocytosis in one patient and contributed to better management of the disease for the patient and his family. The effect of variants of unknown significance on the enhanced production of red blood cells needs to be further explored with functional analysis. This study is of great significance for the improvement of diagnosis of Slovenian patients with unexplained erythrocytosis and future research on the etiology of this rare hematological disorder.
Experimental murine models are an essential tool in the field of bone marrow (BM) transplantation research. Therefore, numerous mice are required to obtain a sufficient number of BM cells, which is ...in contrast with the Reduction principle of the 3R principles. The selection of the cell source and the isolation protocol are therefore critical in obtaining a sufficient yield of cells for experiments. Nowadays, the vertebrae are already used as an extra source of BM cells to enrich the number of isolated cells from the long bones and ilia (LBI), when needed. Yet, little is known if BM cells from LBI and vertebrae share the same characteristics and can be pooled together for further analysis. Therefore, in this study, we aimed to compare the quantity and characteristics of haematopoietic and stromal cell lines in the BM from the LBI and vertebrae. To count haematopoietic and mesenchymal stem/stromal progenitors, colony-forming unit assays were performed. To determine the expansion capacity of mesenchymal stem/stromal cells (MSCs), cultivation of MSCs and measurement of the expression of surface markers by flow cytometry was performed. The characterisation and enumeration of immune cell populations was also performed by flow cytometry. Here, we show that the vertebrae are a comparable source of BM cells to the LBI regarding the analysed parameters.
•Solid state compatibility study.•Isolation and characterization of new tacrolimus degradation impurity.•Structural elucidation using NMR and MS.•Degradation pathway of tacrolimus in the presence of ...divalent cations proposed.
Tacrolimus is macrolide drug that is widely used as a potent immunosuppressant. In the present work compatibility testing was conducted on physical mixtures of tacrolimus with excipients and on compatibility mixtures prepared by the simulation of manufacturing process used for the final drug product preparation. Increase in one major degradation product was detected in the presence of magnesium stearate based upon UHPLC analysis. The degradation product was isolated by preparative HPLC and its structure was elucidated by NMR and MS studies. Mechanism of the formation of this degradation product is proposed based on complementary degradation studies in a solution and structural elucidation data. The structure was proven to be alpha-hydroxy acid which is formed from the parent tacrolimus molecule through a benzilic acid type rearrangement reaction in the presence of divalent metallic cations. Degradation is facilitated at higher pH values.
The purpose of this study is to describe the principles of the development of parallel system-dynamics and agent-based models of organic farming for the case of Slovenia. The advantage of agent-based ...modeling is demonstrated by including geospatial information as an agent attribute. The models were compared by the validation, confirming the appropriate level of similarity.
Both system-dynamics and agent-based modeling approaches were applied. Statistical methods were used in the validation.
The results of the validation confirm the appropriateness of the proposed agent-based model. Introducing additional attributes into the agent-based model provides an important advantage over the system-dynamics model, which serves as the paradigmatic example.
A thorough validation and comparison of the results of the system-dynamics and agent-based models indicates the proper approach to combining the methodologies. This approach is promising, because it enables the modeling of the entire agricultural sector, taking each particular farm into account.
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•Hh signaling shows diurnal oscillations in liver and hepatocytes in vitro and in vivo.•Hh signaling feeds-back on the liver clock via GLI transcription factors.•The amplitude of the ...oscillations of the liver clock is decreased in hepatocytes from Smo-knockout mice.•Rhythmicity of many metabolic pathways, including hepatic lipid metabolism, is affected by oscillating Hh signaling.•Diurnal timing of starvation affects the clock-hedgehog module differently.
The mammalian circadian clock controls various aspects of liver metabolism and integrates nutritional signals. Recently, we described Hedgehog (Hh) signaling as a novel regulator of liver lipid metabolism. Herein, we investigated crosstalk between hepatic Hh signaling and circadian rhythm.
Diurnal rhythms of Hh signaling were investigated in liver and hepatocytes from mice with ablation of Smoothened (SAC-KO) and crossbreeds with PER2::LUC reporter mice. By using genome-wide screening, qPCR, immunostaining, ELISA and RNAi experiments in vitro we identified relevant transcriptional regulatory steps. Shotgun lipidomics and metabolic cages were used for analysis of metabolic alterations and behavior.
Hh signaling showed diurnal oscillations in liver and hepatocytes in vitro. Correspondingly, the level of Indian Hh, oscillated in serum. Depletion of the clock gene Bmal1 in hepatocytes resulted in significant alterations in the expression of Hh genes. Conversely, SAC-KO mice showed altered expression of clock genes, confirmed by RNAi against Gli1 and Gli3. Genome-wide screening revealed that SAC-KO hepatocytes showed time-dependent alterations in various genes, particularly those associated with lipid metabolism. The clock/hedgehog module further plays a role in rhythmicity of steatosis, and in the response of the liver to a high-fat diet or to differently timed starvation.
For the first time, Hh signaling in hepatocytes was found to be time-of-day dependent and to feed back on the circadian clock. Our findings suggest an integrative role of Hh signaling, mediated mainly by GLI factors, in maintaining homeostasis of hepatic lipid metabolism by balancing the circadian clock.
The results of our investigation show for the first time that the Hh signaling in hepatocytes is time-of-day dependent, leading to differences not only in transcript levels but also in the amount of Hh ligands in peripheral blood. Conversely, Hh signaling is able to feed back to the circadian clock.
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