Elevated levels of circulating asymmetric and symmetric dimethylarginines (ADMA and SDMA) predict and potentially contribute to end organ damage in cardiovascular diseases. Alanine-glyoxylate aminotransferase 2 (AGXT2) regulates systemic levels of ADMA and SDMA, and also of beta-aminoisobutyric acid (BAIB)-a modulator of lipid metabolism. We identified a putative binding site for hepatic nuclear factor 4 α (HNF4α) in AGXT2 promoter sequence. In a luciferase reporter assay we found a 75% decrease in activity of Agxt2 core promoter after disruption of the HNF4α binding site. Direct binding of HNF4α to Agxt2 promoter was confirmed by chromatin immunoprecipitation assay. siRNA-mediated knockdown of Hnf4a led to an almost 50% reduction in Agxt2 mRNA levels in Hepa 1–6 cells. Liver-specific Hnf4a knockout mice exhibited a 90% decrease in liver Agxt2 expression and activity, and elevated plasma levels of ADMA, SDMA and BAIB, compared to wild-type littermates. Thus we identified HNF4α as a major regulator of Agxt2 expression. Considering a strong association between human HNF4A polymorphisms and increased risk of type 2 diabetes our current findings suggest that downregulation of AGXT2 and subsequent impairment in metabolism of dimethylarginines and BAIB caused by HNF4α deficiency might contribute to development of cardiovascular complications in diabetic patients.

Background Pancreatic heterotopia (PH) is defined as ectopic pancreatic tissue outside the normal pancreas and its vasculature and duct system. Most frequently, PH is detected incidentally by histopathological examination. The aim of the present study was to analyze a large single-center series of duodenal PH with respect to the clinical presentation. Methods A prospective pancreatic database was retrospectively analyzed for cases of PH of the duodenum. All pancreatic and duodenal resections performed between January 2000 and October 2015 were included and screened for histopathologically proven duodenal PH. PH was classified according to Heinrich’s classification (Type I acini, ducts, and islet cells; Type II acini and ducts; Type III only ducts). Results A total of 1274 pancreatic and duodenal resections were performed within the study period, and 67 cases of PH (5.3%) were identified. The respective patients were predominantly male (72%) and either underwent pancreatoduodenectomy (n = 60); a limited pancreas resection with partial duodenal resection (n = 4); distal pancreatectomy with partial duodenal resection (n = 1); total pancreatectomy (n = 1); or enucleation (n = 1). Whereas 65 patients (83.5%) were asymptomatic, 11 patients (18.4%) presented with symptoms related to PH (most frequently with abdominal pain [72%] and duodenal obstruction [55%]). Of those, seven patients (63.6%) had chronic pancreatitis in the heterotopic pancreas. The risk of malignant transformation into adenocarcinoma was 2.9%. Conclusions PH is found in approximately 5% of pancreatic or duodenal resections and is generally asymptomatic. Chronic pancreatitis is not uncommon in heterotopic pancreatic tissue, and even there is a risk of malignant transformation. PH should be considered for the differential diagnosis of duodenal lesions and surgery should be considered, especially in symptomatic cases.

There are large overlaps in cognitive deficits occurring in attention deficit disorder (ADD) and neurodevelopmental disorders like neurofibromatosis type 1 (NF1). This overlap is mostly based on clinical measures and not on in-depth analyses of neuronal mechanisms. However, the consideration of such neuronal underpinnings is crucial when aiming to integrate measures that can lead to a better understanding of the underlying mechanisms. Inhibitory control deficits, for example, are a hallmark in ADD, but it is unclear how far there are similar deficits in NF1. We thus compared adolescent ADD and NF1 patients to healthy controls in a Go/Nogo task using behavioural and neurophysiological measures. Clinical measures of ADD-symptoms were not different between ADD and NF1. Only patients with ADD showed increased Nogo errors and reductions in components reflecting response inhibition (i.e. Nogo-P3). Early perceptual processes (P1) were changed in ADD and NF1. Clinically, patients with ADD and NF1 thus show strong similarities. This is not the case in regard to underlying cognitive control processes. This shows that in-depth analyses of neurophysiological processes are needed to determine whether the overlap between ADD and NF1 is as strong as assumed and to develop appropriate treatment strategies.

Identifying principles of water movement in the shallow subsurface is crucial for adequate process-based hydrological models. Hillslopes are the essential interface for water movement in catchments. The shallow subsurface on slopes typically consists of different layers with varying characteristics. The aim of this study was to draw conclusions about the infiltration behaviour, to identify water flow pathways and derive some general interpretations for the validity of the water movement on a hillslope with periglacial slope deposits (cover beds), where the layers differ in their sedimentological and hydrological properties. Especially the described varying influence of the basal layer (LB) as an impeding layer on the one hand and as a remarkable pathway for rapid subsurface stormflow on the other. We used a time lapse 3-D electrical resistivity tomography (ERT) approach combined with punctual hydrometric data to trace the spreading and the progression of an irrigation plume in layered slope deposits during two irrigation experiments. This multi-technical approach enables us to connect the high spatial resolution of the 3-D ERT with the high temporal resolution of the hydrometric devices. Infiltration through the uppermost layer was dominated by preferential flow, whereas the water flow in the deeper layers was mainly matrix flow. Subsurface stormflow due to impeding characteristic of the underlying layer occurs in form of organic layer interflow and at the interface to the first basal layer (LB1). However, the main driving factor for subsurface stormflow is the formation of a capillary barrier at the interface to the second basal layer (LB2). The capillary barrier prevents water from entering the deeper layer under unsaturated conditions and diverts the seepage water according to the slope inclination. With higher saturation, the capillary barrier breaks down and water reaches the highly conductive deeper layer. This highlights the importance of the capillary barrier effect for the prevention or activation of different flow pathways under variable hydrological conditions.

Glycosaminoglycans are known to bind biological mediators thereby modulating their biological activity. Sulfated hyaluronans (sHA) were reported to strongly interact with transforming growth factor (TGF)-β1 leading to impaired bioactivity in fibroblasts. The underlying mechanism is not fully elucidated yet. Examining the interaction of all components of the TGF-β1:receptor complex with sHA by surface plasmon resonance, we could show that highly sulfated HA (sHA3) blocks binding of TGF-β1 to its TGF-β receptor-I (TβR-I) and -II (TβR-II). However, sequential addition of sHA3 to the TβR-II/TGF-β1 complex led to a significantly stronger recruitment of TβR-I compared to a complex lacking sHA3, indicating that the order of binding events is very important. Molecular modeling suggested a possible molecular mechanism in which sHA3 could potentially favor the association of TβR-I when added sequentially. For the first time bioactivity of TGF-β1 in conjunction with sHA was investigated at the receptor level. TβR-I and, furthermore, Smad2 phosphorylation were decreased in the presence of sHA3 indicating the formation of an inactive signaling complex. The results contribute to an improved understanding of the interference of sHA3 with TGF-β1:receptor complex formation and will help to further improve the design of functional biomaterials that interfere with TGF-β1-driven skin fibrosis.

The clinical diagnostics of olfactory dysfunction in children turns out to be challenging due to low attention span, insufficient linguistic development and lack of odor experiences. Several smell tests have been developed for adults. Most of these examinations take a relatively long time and require a high level of concentration. Therefore, the aim of the current study was to evaluate an odor discrimination and olfactory threshold test using the frequently used “Sniffin’ Sticks” in children and adolescents in a simplified two-alternative-forced-choice version (2AFC) and compare it to the original three-alternative-forced-choice test (3AFC). One-hundred-twenty-one healthy participants aged between 5 and 17 years took part in this study. Within each of the two sessions participants underwent olfactory testing using the modified 2AFC as well as the standard 3AFC method. A better test-retest reliability was achieved using the original 3AFC method compared to the modified 2AFC. This was true for the odor discrimination as well as the olfactory threshold. Age had a significant influence on both tests, which should be considered when testing young children. We discuss these findings with relation to the existing norms and recommend using the 3AFC version due to a better test-retest reliability to measure olfactory function in children.

There have recently been considerable advances in our understanding of the neuronal mechanisms underlying multitasking, but the role of multimodal integration for this faculty has remained rather unclear. We examined this issue by comparing different modality combinations in a multitasking (stop-change) paradigm. In-depth neurophysiological analyses of event-related potentials (ERPs) were conducted to complement the obtained behavioral data. Specifically, we applied signal decomposition using second order blind identification (SOBI) to the multi-subject ERP data and source localization. We found that both general multimodal information integration and modality-specific aspects (potentially related to task difficulty) modulate behavioral performance and associated neurophysiological correlates. Simultaneous multimodal input generally increased early attentional processing of visual stimuli (i.e. P1 and N1 amplitudes) as well as measures of cognitive effort and conflict (i.e. central P3 amplitudes). Yet, tactile-visual input caused larger impairments in multitasking than audio-visual input. General aspects of multimodal information integration modulated the activity in the premotor cortex (BA 6) as well as different visual association areas concerned with the integration of visual information with input from other modalities (BA 19, BA 21, BA 37). On top of this, differences in the specific combination of modalities also affected performance and measures of conflict/effort originating in prefrontal regions (BA 6).

Longitudinal developmental fMRI studies just recently began to focus on within-subject reliability using the intraclass coefficient (ICC). It remains largely unclear which degree of reliability can be achieved in developmental studies and whether this depends on the type of task used. Therefore, we aimed to systematically investigate the reliability of three well-classified tasks: an emotional attention, a cognitive control, and an intertemporal choice paradigm. We hypothesized to find higher reliability in the cognitive task than in the emotional or reward-related task. 104 healthy mid-adolescents were scanned at age 14 and again at age 16 within M = 1.8 years using the same paradigms, scanner, and scanning protocols. Overall, we found both variability and stability (i.e. poor to excellent ICCs) depending largely on the region of interest (ROI) and task. Contrary to our hypothesis, whole brain reliability was fair for the cognitive control task but good for the emotional attention and intertemporal choice task. Subcortical ROIs (ventral striatum, amygdala) resulted in lower ICCs than visual ROIs. Current results add to the yet sparse overall ICC literature in both developing samples and adults. This study shows that analyses of stability, i.e. reliability, are helpful benchmarks for longitudinal studies and their implications for adolescent development.

Phosphorus (P) export from forest soils is mainly driven by storm events, which induce rapid flow processes by preferential flow bypassing large parts of the soil matrix. However, little is known about the dynamics, magnitude, and driving processes of P exports into surface waters. In this paper, we present the results of a monitoring study in a small forested catchment (21 ha) situated in the low mountain ranges of Saxony, Germany. During the fixed schedule-sampling (weekly to bi-weekly sampling frequency for a three-year period), a mean total-P concentration of 8 μg·L−1 was measured. However, concentrations increased up to 203 μg·L−1 during individual storm flow events. Based on the analyzed concentrations and continuously measured discharge we calculated mean annual export rates of 19 to 44 g·ha−1·a−1 for the weekly sampling frequency with different load calculation methods. If events are included into the annual load calculation, the mean annual export fluxes can be up to 83 g·ha−1·a−1 based on the different load calculation methods. Predictions of total-P export rates based on a sampling strategy which does not consider short-term changes due to factors such as storms will substantially underestimate P exports.

The commonly used drug diclofenac is an important environmental anthropogenic pollutant. Currently, detection of diclofenac is mainly based on chemical and physical methods. Here we describe a yeast biosensor that drives the diclofenac-dependent expression of a recombinant fluorescent protein from the authentic promoter of the PDR5 gene. This key component of the pleiotropic drug response encodes a multidrug transporter that is involved in cellular detoxification. We analyse the effects on diclofenac sensitivity of artificial PDR5 promoter derivatives in wild-type and various yeast mutant strains. This approach enabled us to generate sensor strains with elevated drug sensitivity.