ObjectivesNon-alcoholic fatty liver disease (NAFLD) can persist in the stage of simple hepatic steatosis or progress to steatohepatitis (NASH) with an increased risk for cirrhosis and cancer. We ...examined the mechanisms controlling the progression to severe NASH in order to develop future treatment strategies for this disease.DesignNFATc1 activation and regulation was examined in livers from patients with NAFLD, cultured and primary hepatocytes and in transgenic mice with differential hepatocyte-specific expression of the transcription factor (Alb-cre, NFATc1c.a . and NFATc1Δ/Δ ). Animals were fed with high-fat western diet (WD) alone or in combination with tauroursodeoxycholic acid (TUDCA), a candidate drug for NAFLD treatment. NFATc1-dependent ER stress-responses, NLRP3 inflammasome activation and disease progression were assessed both in vitro and in vivo.ResultsNFATc1 expression was weak in healthy livers but strongly induced in advanced NAFLD stages, where it correlates with liver enzyme values as well as hepatic inflammation and fibrosis. Moreover, high-fat WD increased NFATc1 expression, nuclear localisation and activation to promote NAFLD progression, whereas hepatocyte-specific depletion of the transcription factor can prevent mice from disease acceleration. Mechanistically, NFATc1 drives liver cell damage and inflammation through ER stress sensing and activation of the PERK-CHOP unfolded protein response (UPR). Finally, NFATc1-induced disease progression towards NASH can be blocked by TUDCA administration.ConclusionNFATc1 stimulates NAFLD progression through chronic ER stress sensing and subsequent activation of terminal UPR signalling in hepatocytes. Interfering with ER stress-responses, for example, by TUDCA, protects fatty livers from progression towards manifest NASH.
Integrating automated vehicles into mixed traffic entails several challenges. Their driving behavior must be designed such that is understandable for all human road users, and that it ensures an ...efficient and safe traffic system. Previous studies investigated these issues, especially regarding the communication between automated vehicles and pedestrians. These studies used different methods, e.g., videos, virtual reality, or Wizard of Oz vehicles. However, the extent of transferability between these studies is still unknown. Therefore, we replicated the same study design in four different settings: two video, one virtual reality, and one Wizard of Oz setup. In the first video setup, videos from the virtual reality setup were used, while in the second setup, we filmed the Wizard of Oz vehicle. In all studies, participants stood at the roadside in a shared space. An automated vehicle approached from the left, using different driving profiles characterized by changing speed to communicate its intention to let the pedestrians cross the road. Participants were asked to recognize the intention of the automated vehicle and to press a button as soon as they realized this intention. Results revealed differences in the intention recognition time between the four study setups, as well as in the correct intention rate. The results from vehicle–pedestrian interaction studies published in recent years that used different study settings can therefore only be compared to each other to a limited extent.
Due to the short range of the sensor technology used in automated vehicles, we assume that the implemented driving strategies may initially differ from those of human drivers. Nevertheless, automated ...vehicles must be able to move safely through manual road traffic. Initially, they will behave as carefully as human learners do. In the same way that driving-school vehicles tend to be marked in Germany, markings for automated vehicles could also prove advantageous. To this end, a simulation study with 40 participants was conducted. All participants experienced three different highway scenarios, each with and without a marked automated vehicle. One scenario was based around some roadworks, the next scenario was a traffic jam, and the last scenario involved a lane change. Common to all scenarios was that the automated vehicles strictly adhered to German highway regulations, and therefore moved in road traffic somewhat differently to human drivers. After each trial, we asked participants to rate how appropriate and disturbing the automated vehicle’s driving behavior was. We also measured objective data, such as the time of a lane change and the time headway. The results show no differences for the subjective and objective data regarding the marking of an automated vehicle. Reasons for this might be that the driving behavior itself is sufficiently informative for humans to recognize an automated vehicle. In addition, participants experienced the automated vehicle’s driving behavior for the first time, and it is reasonable to assume that an adjustment of the humans’ driving behavior would take place in the event of repeated encounters.
The Hippo pathway is involved in the proliferation of intrafollicular cells and in early embryonic development, mainly because effectors of this pathway are key transcription regulators of genes such ...as CTGF and CYR61, which are involved in cell proliferation. Recent studies by our group found that fibroblast growth factor 18 (FGF18) is present in the fallopian tube during early embryonic development, leading to the hypothesis that FGF18 may have a role during embryonic development. Therefore, the aim of the following study was to determine whether FGF18 modulates the expression of Hippo pathway target genes, CTGF and CYR61, during oocyte maturation and early embryonic development. Three experiments were carried out, with in vitro maturation (IVM) of cumulus-oocyte complexes (COCs) and embryo culture. In experiment one, FGF18 (100 ng/ml) induced an increase (P < 0.05) in CTGF gene expression at 12 h post-exposure. In experiment two, FGF18 (100 ng/ml) induced a reduction (P < 0.05) in CTGF expression at 3 h post-exposure. In the third experiment, day 7 embryos exposed to FGF18 during oocyte IVM expressed greater CTGF mRNA abundance, whereas FGF18 exposure during embryo in vitro embryo culture did not alter CTGF expression in comparison with untreated controls. The preliminary data presented here show that FGF18 modulates CTGF expression in critical periods of oocyte nuclear maturation, cumulus expansion and early embryonic development in cattle.
Ixodid ticks are important vectors for zoonotic pathogens, with Ixodes ricinus being the most important in Europe. Rodents are hosts of immature life stages of I. ricinus ticks and are considered ...main reservoirs for tick-borne pathogens, e.g. Borrelia burgdorferi. The aim of this study was to analyse the prevalence as well as genospecies and sequence type (ST) diversity of Borrelia burgdorferi sensu lato in ticks and small mammals from central Germany and to elaborate on the influence of environmental and/or individual host and vector factors on Borrelia prevalence.
After species identification, 1167 small mammal skin samples and 1094 ticks from vegetation were screened by B. burgdorferi sensu lato real-time polymerase chain reaction, and positive samples were characterized by multilocus sequence typing. Generalized linear (mixed) models were used to estimate how seasonality, small mammal species/tick life stage and habitat affect individual infection status.
In total, 10 small mammal species and three tick species, Ixodes ricinus, Ixodes inopinatus (both considered members of the I. ricinus complex) and Dermacentor reticulatus, were investigated. Borrelia DNA was detected in eight host species, i.e. the striped field mouse (Apodemus agrarius), the yellow-necked field mouse (Apodemus flavicollis), the wood mouse (Apodemus sylvaticus), the water vole (Arvicola amphibius), the bank vole (Clethrionomys glareolus), the field vole (Microtus agrestis), the common vole (Microtus arvalis), and the common shrew (Sorex araneus). Two species were Borrelia negative, the greater white-toothed shrew (Crocidura russula) and the pygmy shrew (Sorex minutus). The average prevalence was 6.2%, with two genospecies detected, Borrelia afzelii and Borrelia garinii, and at least three STs that had not been previously reported in small mammals. Borrelia prevalence in small mammals did not differ between seasons. Six genospecies of Borrelia-Borrelia afzelii, Borrelia valaisiana, Borrelia garinii, Borrelia lusitaniae, Borrelia spielmanii, and Borrelia burgdorferi sensu stricto-and 25 STs of Borrelia, of which 12 have not been previously described at all and five have not been previously reported in Germany, were detected in 13% of I. ricinus complex ticks. Prevalence was highest in adult females (25.3%) and lowest in nymphs (11.4%). Prevalence was significantly higher in ticks from grassland (16.8%) compared to forests (11.4%).
The high level of small mammal diversity in this region of Germany seems to be reflected in a wide variety of genospecies and STs of B. burgdorferi.
Leptospirosis is a worldwide zoonotic disease with more than 1 million human cases annually. Infections are associated with direct contact to infected animals or indirect contact to contaminated ...water or soil. As not much is known about the prevalence and host specificity of Leptospira spp. in bank voles (Clethrionomys glareolus), our study aimed to evaluate Leptospira spp. prevalence and genomospecies distribution as well as the influence of season, host abundance and individual characteristics on the Leptospira prevalence. Bank voles, which are abundant and widely distributed in forest habitats, were collected in the years 2018 to 2020 in North-West Germany, covering parts of North Rhine-Westphalia and Lower Saxony. The DNA of 1817 kidney samples was analyzed by real-time PCR targeting the lipl32 gene. Positive samples were further analyzed by targeting the secY gene to determine Leptospira genomospecies and multilocus sequence typing (MLST) to determine the sequence type (ST). The overall prevalence was 7.5% (95% confidence interval: 6.4–8.9). Leptospira interrogans (83.3%), L. kirschneri (11.5%) and L. borgpetersenii (5.2%) were detected in bank voles. Increasing body weight as a proxy for age increased the individual infection probability. Only in years with high bank vole abundance was this probability significantly higher in males than in females. Even if case numbers of human leptospirosis in Germany are low, our study shows that pathogenic Leptospira spp. are present and thus a persisting potential source for human infection.
Coronary artery disease (CAD) is a common finding in patients with severe aortic stenosis undergoing transcatheter aortic valve replacement (TAVR). However, the impact on prognosis of chronic total ...occlusions (CTOs), a drastic expression of CAD, remains unclear.
We retrospectively reviewed 1,487 consecutive TAVR cases performed at a single tertiary care medical center. Pre-TAVR angiograms were analyzed for the presence of a CTO. At the time of TAVR, 11.2% (
= 167) patients had a CTO. There was no significant association between the presence of a CTO and in-hospital or 30-day mortality. There was also no difference in long-term survival. LV ejection fraction and mean aortic gradients were lower in the CTO group.
Our analysis suggests that concomitant CTO lesions in patients undergoing TAVR differ in their risk profile and clinical findings to patients without CTO. CTO lesion
were not associated with increased mortality, nevertheless CTOs which supply non-viable myocardium in TAVR population were associated with increased risk of death. Additional research is needed to evaluate the prognostic significance of CTO lesions in TAVR patients.
Key Clinical Message
First, patients may always develop a second severe illness, even a second cancer. Second, things are not always as they are expected to be. So, careful diagnosis is mandatory. ...Third, morphology is very important, but sometimes misleading. Always be aware of morphological variants!
First, patients may always develop a second severe illness, even a second cancer. Second, things are not always as they are expected to be. So, careful diagnosis is mandatory. Third, morphology is very important, but sometimes misleading. Always be aware of morphological variants!
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