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Abstract Age-related cognitive decline has become an increasingly relevant public health issue. However, risk and protective factors of cognitive decline have yet to be investigated prospectively taking into account genetic, lifestyle, physical and mental health factors. Population-based data from middle-aged (40 to 59 years; N = 2,764) and older individuals (60 to 80 years; N = 1,254) were drawn from a prospective community cohort study using the Tower of London (TOL) planning task. Assessments were repeated at a 5-year interval to investigate age-related changes in planning performance and to determine the impact of risk and protective factors. Planning performance improved in middle-aged, but declined in older participants over 5 years. SNPs affecting the dopamine system (COMT, DRD2) and APOE polymorphisms differentially predicted cognitive performance in older vs. middle-aged individuals. For older individuals, high alcohol consumption, antidepressant medication and living without a partner had additional negative predictive power on cognition. In contrast, undiagnosed hypertension, no obstructive lung disease, and fewer years of education predicted cognitive decline in the middle-aged group. The results inform screening for individuals particularly vulnerable to cognitive decline and interventions (e.g., focusing on lifestyle factors) to help maintain cognitive performance into old age.

Abstract People with type 2 diabetes mellitus (T2DM) show a high prevalence of steatotic liver disease (SLD), and especially metabolic dysfunction-associated steatotic liver disease (MASLD), with liver fibrosis. Their health-related quality of life (HRQL) is affected by multiple in part overlapping factors and aggravated by metabolic and liver-related comorbidities, including liver fibrosis stage. The aim of this study was to investigate the effect size of advanced fibrosis (AF) on the HRQL in people with T2DM. A total of 149 individuals with T2DM treated at a primary care provider within the German disease management program (DMP) were included in the final analysis. Vibration-controlled transient elastography (VCTE) was used to non-invasively detect steatosis and AF. The EQ-5D-3L questionnaire was used to assess the HRQL. Uni- and multivariable linear regression models were used to identify independent predictors of impaired HRQL. The majority was male (63.1%), and the median age was 67 years (IQR 59; 71). In the entire cohort, the prevalence of MASLD and AF was 70.7% and 19.5%, respectively. People with T2DM and AF had an overall lower HRQL in comparison to those without AF (p

Abstract Preliminary work has shown that portal hypertension plays a key role for the prognosis in patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE). Specifically, the presence of ascites appears to be a strong negative predictor for these patients. However, it remains unclear whether different ascites volumes influence prognosis. Therefore, the aim of this work was to investigate the influence of different ascites volumes on survival for patients with HCC undergoing TACE. A total of 327 treatment-naïve patients with HCC undergoing initial TACE at our tertiary care center between 2010 and 2020 were included. In patients with ascites, the fluid was segmented, and the volume quantified by slice-wise addition using contrast-enhanced CT imaging. Median overall survival (OS) was calculated and univariate and multivariate Cox regression analysis has been performed. Ascites was present in 102 (31.9%) patients. Ascites volume as continuous variable was significantly associated with an increased hazard ratio in univariate analysis (p

Abstract The prevalence of metabolic risk factors and non-alcoholic fatty liver disease (NAFLD) is high among people living with HIV (PLWH). Data on the recently proposed definition of metabolic dysfunction-associated fatty liver disease (MAFLD) in PLWH receiving antiretroviral therapy (ART) remains unknown. A total of 282 PLWH were included in this cross-sectional cohort study. Vibration-controlled transient elastography (VCTE) was used to assess hepatic steatosis and fibrosis. MAFLD and its subgroups (overweight/obese, lean/normal weight, and type 2 diabetes) were defined according to a recently published international consensus statement. The majority of this cohort was male (n = 198, 70.2%), and the median age was 51.5 years. The median BMI was 25 kg/m2, and obesity was prevalent in 16.2% (n = 44). A total of 207 (73.4%) PLWH were classified as non-MAFLD while 75 (26.6%) qualified as MAFLD. The median CAP in the MAFLD group was 320 dB/m. PLWH with MAFLD showed a higher median LSM (p

Background: Soil spatial variability is a major concern when deciding how to collect a representative topsoil sample for laboratory analysis. Sampling design to capture site-specific variability is documented in the agricultural literature, but poorly understood for urban forest soils where soils may be characterized by strong horizontal and vertical variability and large temporal anthropogenic disturbances. Methods: This paper evaluates the spatial variability of selected topsoil properties under urban trees to define a statistically robust sampling design that optimizes the number of samples to reliably characterize basal soil respiration (BSR), a property associated with soil health. To provide a reference on variability, two additional soil properties were measured, unrelated to BSR: electrical conductivity (EC) and bulk density (BD). Thirteen sampling sites comprising both park and street trees (Acer rubrum) were selected in Cambridge, MA, USA. Results: Results indicate street tree topsoil had approximately twice as much variation, requiring more intensive sampling, as did park tree topsoil, even though street trees had smaller soil sampling zones, constricted by tree pits. The variability of BSR was nearly identical to that of EC, and BD results varied least. A large number of samples would be required for acceptable levels of statistical reliability (90% CI - 10% ER) of 44.4, 41.7, and 6.4 for BSR, EC, and BD, respectively, whereas by accepting a lower level of certainty (80% CI - 20% ER) the number of required soil samples was calculated as 6.8, 6.4, and 0.4 for BSR, EC, and BD, respectively. Conclusions: The use of EC testing as a baseline measure to determine spatial variation in the topsoil is proposed, to alleviate the financial implications of more expensive BSR testing. Factors of topsoil disturbance and soil access restrictions at sites with severe root-sidewalk conflicts and the overall generalizability of the results are also discussed.

Abstract Currently, there are only few data on health literacy in patients with chronic gastrointestinal diseases such as gastrointestinal cancer, inflammatory bowel disease (IBD) and, in particular, liver cirrhosis available. Moreover, head-to-head comparisons between patients with these different diseases are lacking. In this study, 379 patients were enrolled. Of these, 102 patients had gastrointestinal cancer, 86 had IBD, and 191 had cirrhosis. Health literacy was quantified using the Health Literacy Questionnaire (HLQ) developed by Osborne et al. (Swinburne University, Australia) and was compared between these three groups. Patients with cancer had the best health literacy across all nine subscales of the HLQ, while patients with cirrhosis had the poorest. In detail, patients with cirrhosis had significantly poorer health literacy than patients with cancer or IBD in subscales such as “feeling understood and supported by healthcare providers”, “having sufficient information to manage my health”, “appraisal of health information”, “ability to actively engage with healthcare providers” or “understanding health information well enough to know what to do” (p

Differential Optical Absorption Spectroscopy (DOAS) is commonly used to measure gas emissions from volcanoes. DOAS instruments measure the absorption of solar ultraviolet (UV) radiation scattered in the atmosphere by sulfur dioxide (SO2) and other trace gases contained in volcanic plumes. The standard spectral retrieval methods assume that all measured light comes from behind the plume and has passed through the plume along a straight line. However, a fraction of the light that reaches the instrument may have been scattered beneath the plume and thus has passed around it. Since this component does not contain the absorption signatures of gases in the plume, it effectively “dilutes” the measurements and causes underestimation of the gas abundance in the plume. This dilution effect is small for clean-air conditions and short distances between instrument and plume. However, plume measurements made at long distance and/or in conditions with significant atmospheric aerosol, haze, or clouds may be severely affected. Thus, light dilution is regarded as a major error source in DOAS measurements of volcanic degassing. Several attempts have been made to model the phenomena and the physical mechanisms are today relatively well understood. However, these models require knowledge of the local atmospheric aerosol composition and distribution, parameters that are almost always unknown. Thus, a practical algorithm to quantitatively correct for the dilution effect is still lacking. Here, we propose such an algorithm focused specifically on SO2 measurements. The method relies on the fact that light absorption becomes non-linear for high SO2 loads, and that strong and weak SO2 absorption bands are unequally affected by the diluting signal. These differences can be used to identify when dilution is occurring. Moreover, if we assume that the spectral radiance of the diluting light is identical to the spectrum of light measured away from the plume, a measured clean air spectrum can be used to represent the dilution component. A correction can then be implemented by iteratively subtracting fractions of this clean air spectrum from the measured spectrum until the respective absorption signals on strong and weak SO2 absorption bands are consistent with a single overhead SO2 abundance. In this manner, we can quantify the magnitude of light dilution in each individual measurement spectrum as well as obtaining a dilution-corrected value for the SO2 column density along the line of sight of the instrument. This paper first presents the theory behind the method, then discusses validation experiments using a radiative transfer model, as well as applications to field data obtained under different measurement conditions at three different locations; Fagradalsfjall located on the Reykjanaes peninsula in south Island, Manam located off the northeast coast of mainland Papua New Guinea and Holuhraun located in the inland of north east Island.

The function of autophagy and how this affects non-alcoholic fatty liver disease is not fully known. Here the authors show that in mice with a targeted disruption of the autophagy pathway in CD11c+ cells, development of NAFLD is accelerated involving IL-23 and blocking of IL-23 reduces disease.

Abstract The photoluminescence (PL) of metal halide perovskites can recover after light or current‐induced degradation. This self‐healing ability is tested by acting mechanically on MAPbI3 polycrystalline microcrystals by an atomic force microscope tip (applying force, scratching, and cutting) while monitoring the PL. Although strain and crystal damage induce strong PL quenching, the initial balance between radiative and nonradiative processes in the microcrystals is restored within a few minutes. The stepwise quenching–recovery cycles induced by the mechanical action is interpreted as a modulation of the PL blinking behavior. This study proposes that the dynamic equilibrium between active and inactive states of the metastable nonradiative recombination centers causing blinking is perturbed by strain. Reversible stochastic transformation of several nonradiative centers per microcrystal under application/release of the local stress can lead to the observed PL quenching and recovery. Fitting the experimental PL trajectories by a phenomenological model based on viscoelasticity provides a characteristic time of strain relaxation in MAPbI3 on the order of 10–100 s. The key role of metastable defect states in nonradiative losses and in the self‐healing properties of perovskites is suggested.

Abstract Methylglyoxal (MGO) is a highly reactive dicarbonyl species that forms advanced glycation end products (AGEs). The binding of these AGEs to their receptor (RAGE) causes and sustains severe inflammation. Systemic inflammation is postulated to be a major driver in the progression of liver cirrhosis. However, the role of circulating MGO levels in liver cirrhosis remains unknown. In this study, we investigated the serum levels of two dicarbonyl species, MGO and glyoxal (GO) using tandem mass spectrometry (HPLC–MS/MS) and evaluated their association with disease severity. A total of 51 inpatients and outpatients with liver cirrhosis of mixed etiology and different disease stages were included. Elevated MGO levels were seen in an advanced stage of liver cirrhosis (p

The role of the CD200–CD200R axis in regulating pulmonary inflammation is not completely understood. Here the authors show CD200R is expressed on type 2 innate lymphoid cells (ILC2s), and its engagement by CD200 ameliorates airway hyperreactivity and allergic asthma via inhibition of NF-κB signaling.

Abstract The neural encoding of visual features in primary visual cortex (V1) is well understood, with strong correlates to low-level perception, making V1 a strong candidate for vision restoration through neuroprosthetics. However, the functional relevance of neural dynamics evoked through external stimulation directly imposed at the cortical level is poorly understood. Furthermore, protocols for designing cortical stimulation patterns that would induce a naturalistic perception of the encoded stimuli have not yet been established. Here, we demonstrate a proof of concept by solving these issues through a computational model, combining (1) a large-scale spiking neural network model of cat V1 and (2) a virtual prosthetic system transcoding the visual input into tailored light-stimulation patterns which drive in situ the optogenetically modified cortical tissue. Using such virtual experiments, we design a protocol for translating simple Fourier contrasted stimuli (gratings) into activation patterns of the optogenetic matrix stimulator. We then quantify the relationship between spatial configuration of the imposed light pattern and the induced cortical activity. Our simulations in the absence of visual drive (simulated blindness) show that optogenetic stimulation with a spatial resolution as low as 100 $$\upmu$$ μ m, and light intensity as weak as $$10^{16}$$ 10 16 photons/s/cm $$^2$$ 2 is sufficient to evoke activity patterns in V1 close to those evoked by normal vision.

Group 2 innate lymphoid cells (ILC2s) are immune cells present in adipose tissue that contribute to metabolic homeostasis. Here the authors show that Death Receptor 3 (DR3) engagement on ILC2s ameliorates glucose tolerance, protects against insulin-resistance onset and reverses established insulin-resistance.

PD-1 is a checkpoint inhibitory immune receptor that restrains proliferation and effector functions of a variety of cells, including ILC2s. Here the authors present a human PD-1 agonist that limits ILC2-dependent allergic airway disease in humanized mice and provide evidence that PD-1 signaling alters ILC2 function by modulation of cell metabolism.

BackgroundPortal vein thrombosis (PVT) is a rare but severe disease that often leads to portal hypertension-related complications. It is well-known that patients with portal hypertension associated with liver cirrhosis are at increased risk for bone fractures, however data on the impact of PVT on fracture risk are lacking.AimsThis study aimed to explore the impact of PVT on the incidence of bone fractures in a large German primary care cohort.MethodsPatients with PVT were extensively matched to non-PVT individuals in a 1:5 ratio. The primary outcome of the study was the incidence of any bone fracture.ResultsThis study included 596 patients with PVT and 2,980 non-PVT individuals. During five years of follow-up, the cumulative incidence of bone fractures was significantly higher in PVT patients (n = 87, 13.6%) than in those without PVT (n = 186, 6.7%) (pConclusionsPVT is independently associated with a higher incidence of bone fractures. Patients with PVT should be critically evaluated for fracture risk and preventive measures should be considered.

The Chlamydia pneumoniae adhesin LIPP plays a role in host cell entry and infection. Here, the authors find that LIPP binds to the host plasma membrane and mediates phosphatidylserine translocation, enhancing pathogen internalization without induction of apoptosis.

Type-2 innate lymphoid cells (ILC2s) are an immune population secreting Th2 cytokines playing a role in the regulation of adipose metabolic homeostasis. Here the authors show that engagement of GITR, a member of the TNF superfamily, in activated ILC2s is protective against insulin resistance in both a preventive and a therapeutic manner in the context of obesity.

BackgroundADVanced Organ Support (ADVOS) is a novel type of extracorporeal albumin dialysis and holds promise to sustain liver function and recovery of patients with acute-on-chronic liver failure (ACLF). Previously, ADVOS was tested as continuous treatment for intensive care patients with liver failure. Data related to the applicability and safety as discontinuous treatment outside of ICU is not available.AimEvaluation of ADVOS as discontinuous treatment for patients with ACLF outside intensive care unit and comparison with a matched historic cohort.Methods and resultsIn this retrospective study, 26 patients with ACLF and the indication for renal replacement therapy related to HRS-AKI were included. Majority of patients were male (65%) with alcoholic cirrhosis in 88% and infections as a trigger of ACLF in 96%. Liver function was severely compromised reflected by high median MELD and CLIF-C ACLF scores of 37 (IQR 32;40) and 56.5 (IQR 51;60), respectively. Patients were treated discontinuously with ADVOS over a median time of 12 days (IQR 8.25;17) and received 8 (IQR 4.25;9.75) treatment cycles on average. No treatment related adverse events were recorded, and safety laboratory parameters remained constant during the observation time. After 16 h cumulative dialysis therapy, ADVOS significantly reduced protein-bound bilirubin (14%), creatinine (11.8%) and blood urea nitrogen (BUN, 33%). Using a matched cohort with ACLF treated with hemodialysis, ADVOS achieved a stronger decrease in bilirubin (p = 0.01), while detoxification of water-soluble catabolites' including creatinine and BUN was comparable. The 28-days mortality in the ADVOS group was 56% (14/26) and was not inferior to predicted survival (predicted median 28-days mortality was 44%, IQR 30; 59).ConclusionDiscontinuous ADVOS treatment was safe and effective in patients with ACLF outside intensive care and outperformed hemodialysis in reducing protein-bound metabolites.

BackgroundPortal vein tumor thrombosis (PVTT) is a frequent complication of hepatocellular carcinoma (HCC), which leads to classification as advanced stage disease (regardless of the degree of PVTT) according to the Barcelona Clinic Liver Cancer Classification. For such patients, systemic therapy is the standard of care. However, in clinical reality, many patients with PVTT undergo different treatments, such as resection, transarterial chemoembolization (TACE), selective internal radiation therapy (SIRT), or best supportive care (BSC). Here we examined whether patients benefited from such alternative therapies, according to the extent of PVTT.MethodsThis analysis included therapy-naïve patients with HCC and PVTT treated between January 2005 and December 2016. PVTT was classified according to the Liver Cancer study group of Japan as follows: Vp1 = segmental PV invasion; Vp2 = right anterior or posterior PV; Vp3 = right or left PV; Vp4 = main trunk. Overall survival (OS) was analyzed for each treatment subgroup considering the extent of PVTT. We performed Cox regression analysis with adjustment for possible confounders. To further attenuate selection bias, we applied propensity score weighting using the inverse probability of treatment weights.ResultsA total of 278 treatment-naïve patients with HCC and PVTT were included for analysis. The median observed OS in months for each treatment modality (resection, TACE/SIRT, sorafenib, BSC, respectively) was 32.4, 8.1, N/A, and 1.7 for Vp1; 10.7, 6.9, 5.5, and 1.2 for Vp2; 6.6, 7.5, 2.9, and 0.6 for Vp3; and 8.0, 3.6, 5.3, and 0.7 for Vp4. Thus, the median OS in the resection group in case of segmental PVTT (Vp1) was significantly longer compared to any other treatment group (all p values ConclusionsTreatment strategy for HCC with PVTT should not be limited to systemic therapy in general. The extent of PVTT should be considered when deciding on treatment alternatives. In patients with segmental PVTT (Vp1), resection should be evaluated.

BackgroundHealth literacy is a concept that refers to patients' ability to manage their disease and the health system's ability to guarantee access to services. There is evidence that health literacy impacts the health outcomes of patients with chronic diseases, but detailed information on this topic in patients with liver cirrhosis is scarce. It was the aim of this study to identify risk factors for poorer health literacy in patients with liver cirrhosis.Methods89 patients with liver cirrhosis were enrolled in this study and health literacy was measured using the Health Literacy Questionnaire (HLQ). Covert hepatic encephalopathy (CHE) was diagnosed clinically according to the West-Haven Criteria (HE grade 1) and the PHES (minimal HE). Depressive symptoms were assessed using the Hamilton Depression Rating Scale (HDRS). Based on the nine subscales of the HLQ, risk factors for poor health literacy were identified using linear regression models.ResultsNormalized HLQ scores ranged between 65-76%, while appraisal of health information had lowest score (65%) and ability to actively engage with healthcare providers had highest score (76%). Multivariable regression analyses revealed an association of poorer health literacy and liver function as determined by MELD score and complications of liver cirrhosis such as a history of ascites or CHE. Additionally, we identified modifiable or preventable factors such as depressive symptoms, a history of falls, and active smoking as risk factors for poorer health literacy.ConclusionMultiple factors seem to impact on health literacy in patients with liver cirrhosis. Addressing modifiable and preventable factors may improve health literacy.

BackgroundLinked color imaging (LCI) has been shown to be effective in multiple randomized controlled trials for enhanced colorectal polyp detection. Recently, artificial intelligence (AI) with deep learning through convolutional neural networks has dramatically improved and is increasingly recognized as a promising new technique for enhancing colorectal polyp detection.AimThis study aims to evaluate a newly developed computer-aided detection (CAD) system in combination with LCI for colorectal polyp detection.MethodsFirst, a convolutional neural network was trained for colorectal polyp detection in combination with the LCI technique using a dataset of anonymized endoscopy videos. For validation, 240 polyps within fully recorded endoscopy videos in LCI mode, covering the entire spectrum of adenomatous histology, were used. Sensitivity (true-positive rate per lesion) and false-positive frames in a full procedure were assessed.ResultsThe new CAD system used in LCI mode could process at least 60 frames per second, allowing for real-time video analysis. Sensitivity (true-positive rate per lesion) was 100%, with no lesion being missed. The calculated false-positive frame rate was 0.001%. Among the 240 polyps, 34 were sessile serrated lesions. The detection rate for sessile serrated lesions with the CAD system used in LCI mode was 100%.ConclusionsThe new CAD system used in LCI mode achieved a 100% sensitivity per lesion and a negligible false-positive frame rate. Note that the new CAD system used in LCI mode also specifically allowed for detection of serrated lesions in all cases. Accordingly, the AI algorithm introduced here for the first time has the potential to dramatically improve the quality of colonoscopy.

Synthetic dyes usages are inevitable, but they are recalcitrant and toxic, hence need treatment before discharge. Lately, phycoremediation of dyes gained more attention due to its value-added benefits, however, it need more investigation of indigenous species for ease. Therefore, the aim of the study was to isolate indigenous microalgae from Elias Tesfaye textile factory runoff, Addis Ababa. The sample was inoculated to Bold’s Basal Medium and incubated for 15 days and the dominant colonies were purified and identified using a microscope. The identified isolate, Oscillatoria sp., which belongs to prokaryotic filamentous cyanobacteria was checked for the dye removal efficiency and biomass production using synthetic dyes of malachite green (MG), methylene blue (MB) and Safranin (SF). The axenic cultures of Oscillatoria sp., was inoculated (0.2 g/L) with various concentrations of dyes (1-5 mg/L) and incubated under Sunlight for 5 days and analyzed the residual color absorbance and biomass production. A maximum of 93% dye color was removed in MG, followed by MB (66%) and SF (52%). Interestingly, the biomass was increased 3.75 times in MB dye (0.75 g/L), while 3.1 and 1.9 times in MG (0.63 g/L) and SF (0.38 g/L), respectively. It seems that the Oscillatoria sp., was decolorizing the dyes by utilizing as nutrients and shown unique potentials on different dyes. Yet, more studies are needed for the exact mechanism of removal and large scale application. This Ethiopian native species of microalgae can be used effectively for the phycoremediation of synthetic dyes locally.

BACKGROUND:External validation of prognostic risk models is essential before they are implemented in clinical practice. This study evaluated the recently developed MEGNA score for survival prediction after resection of intrahepatic cholangiocarcinoma (ICC), with a focus on the direct comparison of its prognostic value to that of the current International Union Against Cancer (UICC)/American Joint Committee on Cancer (AJCC) Cancer staging system. MATERIAL AND METHODS:Between 1997 and 2018, 417 consecutive patients with ICC were referred to our tertiary care centre and were retrospectively identified out of a dedicated clinical database. Of this group, 203 patients underwent surgical resection and met the inclusion criteria. Multivariate analysis was performed to assess the predictors of the recently proposed MEGNA score regarding overall survival (OS). Concordance indices (C-indices) and integrated Brier scores (IBS) were calculated to assess the ability of both the MEGNA score and the current (8th) edition of the UICC/AJCC Cancer staging system to predict individual patient outcome. RESULTS:Stratification according to the MEGNA score resulted in a median OS of 34.5 months, 26.1 months, 21.5 months, and 16.6 months for MEGNA scores 0, 1, 2, and ≥3, respectively (log rank p < 0.001). However, of the five factors that contribute to the MEGNA score, age > 60 years was not a predictor for poor OS in our cohort. The C-index for the MEGNA score was 0.58, the IBS was 0.193. The 8th edition of the UICC/AJCC system performed slightly better, with a C-index of 0.61 and an IBS of 0.186. CONCLUSION:The ability of the MEGNA score to predict individual patient outcome was only moderate in this external validation. Its prognostic value did not reach that of the more widely known and used UICC/AJCC system. However, neither scoring system performed well enough to support clear-cut clinical decisions.

Background and study aimsDespite major technical advancements, endoscopic surveillance for detecting premalignant lesions in Barrett's esophagus is challenging because of their flat appearance with only subtle morphological changes. Molecular endoscopic imaging (MEI) using nanoparticles (NPs), coupled with fluorescently labeled antibody permits visualization of disease-specific molecular alterations. The aim of this ex vivo study was to assess the diagnostic applicability of MEI with NPs to detect Barrett's metaplasia.Patients and methodsSeven patients undergoing endoscopic surveillance of known Barrett's esophagus were recruited. Freshly resected biopsy specimens were incubated with NPs coupled with FITC labeled Muc-2 antibodies and examined with MEI. Fluorescence intensity from Barrett's mucosa and control specimens were compared, followed by histological confirmation.ResultsFluorescence signals, indicating the presence of goblet cells, were noted for traditional MEI using Muc-2 antibodies in Barrett's intestinal metaplasia. Significantly stronger fluorescence signals were achieved with NPs coupled with FITC-conjugated Muc-2 antibodies. The results of MEI with NPs for the prediction of Barrett's metaplasia correlated with the final histopathological examination in all the cases.ConclusionsHighly-specific NPs detected Barrett's metaplasia more efficiently than conventional MEI in this first feasibility study. MEI was as effective as standard histopathology for identifying Muc-2 containing goblet cells for diagnosis of Barrett's metaplasia. (DRKS-ID: DRKS00017747).

BackgroundObesity is often associated with inflammation in adipose tissue (AT) with release of mediators of atherogenesis. We postulated that it would be feasible to collect sufficient abdominal AT to quantify changes in a broad array of adaptive and innate mononuclear white cells in obese non-diabetic adults in response to a dipeptidyl protease inhibitor (DPP4i), known to inhibit activation of immune white cells.MethodsAdults 18-55 years-of-age were screened for abdominal obesity and insulin resistance or impaired glucose tolerance but without known inflammatory conditions. Twenty-one eligible participants consented for study and were randomized 3:1 to receive sitagliptin (DPP4i) at 100mg or matching placebo daily for 28 days. Abdominal AT collected by percutaneous biopsy and peripheral blood mononuclear cell fractions were evaluated before and after treatment; plasma was stored for batch testing.ResultsHighly sensitive C-reactive protein, a global marker of inflammation, was not elevated in the study population. Innate lymphoid cells (ILC) type 3 (ILC-3) in abdominal AT decreased with active treatment compared with placebo (p = 0.04). Other immune white cells in AT and peripheral blood mononuclear cell (PBMC) fractions did not change with treatment compared to placebo (p>0.05); although ILC-2 declined in PBMCs (p = 0.007) in the sitagliptin treatment group. Two circulating biomarkers of atherogenesis, interferon-inducible protein-10 (IP-10) and sCD40L declined in plasma (p = 0.02 and p = 0.07, respectively) in the active treatment group, providing indirect validation of a net reduction in inflammation.ConclusionsIn this pilot study, two cell types of the innate lymphoid system, ILC-3 in AT and ILC-2 PBMCs declined during treatment and as did circulating biomarkers of atherogenesis. Changes in other immune cells were not demonstrable. The study showed that sufficient abdominal AT could be obtained to quantify white cells of both innate and adaptive immunity and to demonstrate changes during therapy with an immune inhibitor.Trial registrationClinicalTrials.gov identifier (NCT number): NCT02576.

Background and study aims Despite major technical advancements, endoscopic surveillance for detecting premalignant lesions in Barrett’s esophagus is challenging because of their flat appearance with only subtle morphological changes. Molecular endoscopic imaging (MEI) using nanoparticles (NPs), coupled with fluorescently labeled antibody permits visualization of disease-specific molecular alterations. The aim of this ex vivo study was to assess the diagnostic applicability of MEI with NPs to detect Barrett’s metaplasia. Patients and methods Seven patients undergoing endoscopic surveillance of known Barrett’s esophagus were recruited. Freshly resected biopsy specimens were incubated with NPs coupled with FITC labeled Muc-2 antibodies and examined with MEI. Fluorescence intensity from Barrett’s mucosa and control specimens were compared, followed by histological confirmation. Results Fluorescence signals, indicating the presence of goblet cells, were noted for traditional MEI using Muc-2 antibodies in Barrett’s intestinal metaplasia. Significantly stronger fluorescence signals were achieved with NPs coupled with FITC-conjugated Muc-2 antibodies. The results of MEI with NPs for the prediction of Barrett’s metaplasia correlated with the final histopathological examination in all the cases. Conclusions Highly-specific NPs detected Barrett’s metaplasia more efficiently than conventional MEI in this first feasibility study. MEI was as effective as standard histopathology for identifying Muc-2 containing goblet cells for diagnosis of Barrett’s metaplasia. (DRKS-ID: DRKS00017747)

In growth and development genomic imprinting is important in regulating gene expression. Here, the authors study loss of imprinting (LOI) in cancer, developing a mixture model to detect monoallelically expressed loci without genotyping data - applying this novel methodology to TCGA breast cancer data they find massive deregulation of imprinting.

Bcl-3 modulates effector T cell responses, but the importance of Bcl-3 in T regulatory cells and autoimmunity is not clear. Here the authors show that Bcl-3 impedes NF-κB DNA binding to alter T regulatory cell development and function, causing spontaneous colitis in mice.

Recent long-term observations of the bromine monoxide (BrO) to sulphur dioxide (SO2) molar ratio in volcanic plumes have suggested a link between changes in the BrO/SO2 ratio and the volcanic activity. Nevertheless, understanding of the mechanisms determining this link is still limited due to the lack of studies on volcanic bromine release from the melt into the atmosphere. We present the results of 10 years (2007–2017) of observations of the BrO/SO2 molar ratio in the volcanic plume of Tungurahua volcano, Ecuador. Following the nearly continuous eruptive activity from 1999 to 2008, Tungurahua showed alternating phases of eruptive activity separated by periods of quiescence between late 2008 and March 2016, after which degassing intensity decreased below detection. By comparing the BrO/SO2 molar ratios collected from 13 eruptive phases to volcanic activity, this study aims to broaden the global observational database investigating their link. For this purpose, we combine three different methods to retrieve the BrO/SO2 molar ratio to analyse variations over different timescales. We identify a cyclic pattern in BrO/SO2 molar ratios for 11 of the 13 eruptive phases. The phases are initialised by low BrO/SO2 molar ratios between 2 and 6 × 10−5 coinciding with vulcanian-type activity followed by a strong increase to ratios ranging between 4 and 17 × 10−5 when eruptive dynamism shifts to strombolian. For five phases, we additionally observe a progressive decrease to the initial values of 2 to 5 × 10−5 toward the end of the phase. This clear pattern indicates a connection between the BrO/SO2 molar ratio and eruptive dynamics. Based on our new data, we propose a conceptual model of the volcanic processes taking place at Tungurahua during the eruptive phases. Our data furthermore indicate that maximal BrO/SO2 molar ratios observed during each phase could be related to the input of volatile-rich magma into the active part of the volcanic system of Tungurahua. This study shows that long-term BrO/SO2 molar ratios can be used as a proxy for the volatile status as well as temporal evolution of the volcanic system.

Airway hyperreactivity is driven by type 2 cytokines produced by ILC2 and Th2 cells. Here the authors show that an α7-nicotinic receptor agonist (GTS-21) inhibits ILC2 responses and is therapeutic against Alternaria-induced airway hyperreactivity in a humanized mouse model.

Cells constantly adapt to environmental fluctuations. These physiological changes require time and therefore cause a lag phase during which the cells do not function optimally. Interestingly, past exposure to an environmental condition can shorten the time needed to adapt when the condition re-occurs, even in daughter cells that never directly encountered the initial condition. Here, we use the molecular toolbox of Saccharomyces cerevisiae to systematically unravel the molecular mechanism underlying such history-dependent behavior in transitions between glucose and maltose. In contrast to previous hypotheses, the behavior does not depend on persistence of proteins involved in metabolism of a specific sugar. Instead, presence of glucose induces a gradual decline in the cells’ ability to activate respiration, which is needed to metabolize alternative carbon sources. These results reveal how trans-generational transitions in central carbon metabolism generate history-dependent behavior in yeast, and provide a mechanistic framework for similar phenomena in other cell types.

Ginkgo biloba (EGb761) is a widely used botanical drug. Several reports indicate that EGb761 confers preventive as well as anti-tumorigenic properties in a variety of tumors, including hepatocellular carcinoma (HCC). We here evaluate functional effects and molecular alterations induced by EGb761 in hepatoma cells and non-malignant hepatocytes. Hepatoma cell lines, primary human HCC cells and immortalized human hepatocytes (IH) were exposed to various concentrations (0-1000 μg/ml) of EGb761. Apoptosis and proliferation were evaluated after 72h of EGb761 exposure. Response to oxidative stress, tumorigenic properties and molecular changes were further investigated. While anti-oxidant effects were detected in all cell lines, EGb761 promoted anti-proliferative and pro-apoptotic effects mainly in hepatoma cells. Consistently, EGb761 treatment caused a significant reduction in colony and sphere forming ability in hepatoma cells and no mentionable changes in IH. Transcriptomic changes involved oxidative stress response as well as key oncogenic pathways resembling Nrf2- and mTOR signaling pathway. Taken together, EGb761 induces differential effects in non-transformed and cancer cells. While treatment confers protective effects in non-malignant cells, EGb761 significantly impairs tumorigenic properties in cancer cells by affecting key oncogenic pathways. Results provide the rational for clinical testing of EGb761 in preventive and therapeutic strategies in human liver diseases.

Exoskeletons can influence human gait. A healthy gait is characterized by a certain amount of variability compared to a non-healthy gait that has more inherent variability; however which exoskeleton assistance parameters are necessary to avoid increasing gait variability or to potentially lower gait variability below that of unassisted walking are unknown. This study investigated the interaction effects of exoskeleton timing and power on gait variability. Ten healthy participants walked on a treadmill with bilateral ankle-foot exoskeletons under ten conditions with different timing (varied from 36% to 54% of the stride) and power (varied from 0.2 to 0.5 W∙kg-1) combinations. We used the largest Lyapunov exponent (LyE) and maximum Floquet multiplier (FM) to evaluate the stride-to-stride fluctuations of the kinematic time series. We found the lowest LyE at the ankle and a significant reduction versus powered-off with exoskeleton power (summed for both legs) of 0.45 W∙kg-1 and actuation timing at 48% of the stride cycle. At the knee, a significant positive effect of power and a negative interaction effect of power and timing were found for LyE. We found significant positive interaction effects of the square of timing and power for LyE at the knee and hip joints. In contrast, the FM at the ankle increased with increasing power and later timing. We found a significant negative effect of power and a positive interaction effect of power and timing for FM at the knee and no significant effects of any of the exoskeleton parameters for FM at the hip. The ability of the exoskeleton to reduce the LyE at the ankle joint offers new possibilities in terms of altering gait variability, which could have applications for using exoskeletons as rehabilitation devices. Further efforts could examine if it is possible to simultaneously reduce the LyE and FM at one or more lower limb joints.

The Sahel (a semi-arid fringe south of the Sahara) experienced a long and prolonged drought from the 1970s to the mid-1990s, with a few extremely severe episodes that strongly affected ecosystems and societies. Long-term observations showed that surface runoff increased during this period, despite the rainfall deficit. This paradox stems from the soil degradation that was induced by various factors, either directly linked to the drought (impact on vegetation cover), or, in places, to human practices (land clearing and cropping). Surface runoff is still increasing throughout the region, suggesting that Sahelian ecohydrosystems may have shifted to a new hydrological regime. In order to explore this issue, we have developed a simple system dynamics model incorporating vegetation–hydrology interactions and representing in a lumped way the first order processes occurring at the hillslope scale and the annual timestep. Long term observations on a pilot site in northern Mali were used to constrain the model and define an ensemble of plausible simulations. The model successfully reproduced the vegetation collapse and the runoff increase observed over the last 60 years. Our results confirmed that the system presents two alternative states and that during the drought it shifted from a high-vegetation/low-runoff regime to the alternative low-vegetation/high-runoff one, where it has remained trapped until now. We showed that the mean annual rainfall deficit was sufficient to explain the shift. According to the model, vegetation recovery and runoff reduction are possible in this system, but the conditions in which they could occur remain uncertain as the model was only constrained by observations over the collapse trajectory. The study shows that the system is also sensitive to the interannual and decadal variability of rainfall, and that larger variability leads to higher runoff. Both mean rainfall and rainfall variability may increase in central Sahel under climate change, leading to antagonist effects on the system, which makes its resilience uncertain.

Tissue type plasminogen activator (t-PA) has been implicated in the development of multiple sclerosis (MS) and in rodent models of experimental autoimmune encephalomyelitis (EAE). We show that levels of t-PA mRNA and activity are increased ~4 fold in the spinal cords of wild-type mice that are mice subjected to EAE. This was also accompanied with a significant increase in the levels of pro-matrix metalloproteinase 9 (pro-MMP-9) and an influx of fibrinogen. We next compared EAE severity in wild-type mice, t-PA-/- mice and T4+ transgenic mice that selectively over-express (~14-fold) mouse t-PA in neurons of the central nervous system. Our results confirm that t-PA deficient mice have an earlier onset and more severe form of EAE. T4+ mice, despite expressing higher levels of endogenous t-PA, manifested a similar rate of onset and neurological severity of EAE. Levels of proMMP-9, and extravasated fibrinogen in spinal cord extracts were increased in mice following EAE onset regardless of the absence or over-expression of t-PA wild-type. Interestingly, MMP-2 levels also increased in spinal cord extracts of T4+ mice following EAE, but not in the other genotypes. Hence, while the absence of t-PA confers a more deleterious form of EAE, neuronal over-expression of t-PA does not overtly protect against this condition with regards to symptom onset or severity of EAE.

Chlamydia pneumoniae is an intracellular Gram-negative bacterium that possesses a type III secretion system (T3SS), which enables the pathogen to deliver, in a single step, effector proteins for modulation of host-cell functions into the human host cell cytosol to establish a unique intracellular niche for replication. The translocon proteins located at the top of the T3SS needle filament are essential for its function, as they form pores in the host-cell membrane. Interestingly, unlike other Gram-negative bacteria, C. pneumoniae has two putative translocon operons, named LcrH_1 and LcrH_2. However, little is known about chlamydial translocon proteins. In this study, we analyzed CPn0809, one of the putative hydrophobic translocators encoded by the LcrH_1 operon, and identified an 'SseC-like family' domain characteristic of T3S translocators. Using bright-field and confocal microscopy, we found that CPn0809 is associated with EBs during early and very late phases of a C. pneumoniae infection. Furthermore, CPn0809 forms oligomers, and interacts with the T3SS chaperone LcrH_1, via its N-terminal segment. Moreover, expression of full-length CPn0809 in the heterologous host Escherichia coli causes a grave cytotoxic effect that leads to cell death. Taken together, our data indicate that CPn0809 likely represents one of the translocon proteins of the C. pneumoniae T3SS, and possibly plays a role in the translocation of effector proteins in the early stages of infection.

Patients with chronic liver disease often suffer from unspecific symptoms and report severe impairment in the quality of life. The underlying mechanisms are multifactorial and include disease-specific but also liver related causes. The current analysis evaluated the association of hepatocellular apoptosis in non-viral chronic liver disease and health-related quality of life (HRQL). Furthermore we examined factors, which influence patient's physical and mental well-being.A total of 150 patients with non-infectious chronic liver disease were included between January 2014 and June 2015. The German version of the Chronic Liver Disease Questionnaire (CLDQ-D), a liver disease specific instrument to assess HRQL, was employed. Hepatocellular apoptosis was determined by measuring Cytokeratin 18 (CK18, M30 Apoptosense ELISA).Female gender (5.24 vs. 5.54, p = 0.04), diabetes mellitus type II (4.75 vs. 5.46, p

The present paper contains faunistical data obtained by the joint research of Babeş-Bolyai and Szeged University. 44 species of 15 families were identified from Lacul Dracului marsh-complex (Harghita Mountains). Meioneta similis (Kulczynski 1926) is new for the Romanian fauna. Furthermore the occurrences of two questionable species [Kaestneria pullata (O.P.-Cambridge, 1863) and Trichoncus saxicola (O.P.- Cambridge, 1861)] are proved.

BackgroundEven though walking can be sustained for great distances, considerable energy is required for plantarflexion around the instant of opposite leg heel contact. Different groups attempted to reduce metabolic cost with exoskeletons but none could achieve a reduction beyond the level of walking without exoskeleton, possibly because there is no consensus on the optimal actuation timing. The main research question of our study was whether it is possible to obtain a higher reduction in metabolic cost by tuning the actuation timing.Methodology/principal findingsWe measured metabolic cost by means of respiratory gas analysis. Test subjects walked with a simple pneumatic exoskeleton that assists plantarflexion with different actuation timings. We found that the exoskeleton can reduce metabolic cost by 0.18±0.06 W kg(-1) or 6±2% (standard error of the mean) (p = 0.019) below the cost of walking without exoskeleton if actuation starts just before opposite leg heel contact.Conclusions/significanceThe optimum timing that we found concurs with the prediction from a mathematical model of walking. While the present exoskeleton was not ambulant, measurements of joint kinetics reveal that the required power could be recycled from knee extension deceleration work that occurs naturally during walking. This demonstrates that it is theoretically possible to build future ambulant exoskeletons that reduce metabolic cost, without power supply restrictions.

The type III secretion system (T3SS) is a complex nanomachine of many pathogenic gram-negative bacteria. It forms a proteinaceous channel that is inserted into the host eukaryotic cell membrane for injection of bacterial proteins that manipulate host cell signaling. However, few studies have focused on the effector-independent functions of the T3SS. Using a murine model of acute lung infection with Pseudomonas aeruginosa, an important human opportunistic pathogen, we compared the pathogenicity of mutant bacteria that lack all of the known effector toxins ( ΔSTY), with mutant bacteria that also lack the major translocator protein PopB (ΔSTY/ΔPopB) and so cannot form a functional T3SS channel in the host cell membrane. Mortality was higher among mice challenged with ΔSTY compared to mice challenged with ΔSTY/ΔPopB mutant bacteria. In addition, mice infected with ΔSTY showed decreased bacterial clearance from the lungs compared to those infected with ΔSTY/ΔPopB. Infection was in both cases associated with substantial killing of lung infiltrating macrophages. However, macrophages from ΔSTY-infected mice died by pro-inflammatory necrosis characterized by membrane permeabilization and caspase-1 mediated IL-1β production, whereas macrophages from ΔSTY/ΔPopB infected mice died by apoptosis, which is characterized by annexin V positive staining of the cell membrane and caspase-3 activation. This was confirmed in macrophages infected in vitro. These results demonstrate a T3SS effector toxin independent role for the T3SS, in particular the T3SS translocator protein PopB, in the pathogenicity of P. aeruginosa during acute lung infection.

Overwhelming lines of epidemiological evidence have indicated that persistent infection with hepatitis C virus (HCV) is a major risk for the development of hepatocellular carcinoma (HCC). We have recently shown that HCV core protein mediates functional inactivation of the promyelocytic leukemia (PML) tumor suppressor pathway. However, the role of PML in HCC development yet remains unclear. To clarify the function of PML in liver carcinogenesis and HCV-associated pathogenesis we crossed PML-deficient mice with HCV transgene (HCV-Tg) expressing mice and treated the resulting animals with DEN/Phenobarbital, an established protocol for liver carcinogenesis. Seven months after treatment, livers were examined macroscopically and histologically. Genetic depletion of the tumor suppressor PML coincided with an increase in hepatocyte proliferation, resulting in development of multiple dysplastic nodules in 100% of the PML-deficient livers and of HCCs in 53%, establishing a tumor suppressive function of PML in the liver. In animals expressing the HCV-transgene in PML-deficient background, HCC development occurred even in 73%, while only 7% of their wildtype littermates developed HCC. The neoplastic nature of the tumors was confirmed by histology and expression of the HCC marker glutamine synthetase. Several pro- and antiapoptotic factors were tested for differential expression and liver carcinogenesis was associated with impaired expression of the proapoptotic molecule TRAIL in PML-deficient mice. In conclusion, this study provides first in vivo evidence that the tumor suppressor PML acts as an important barrier in liver carcinogenesis and HCV-dependent liver pathology.

Current genome-wide ChIP-seq experiments on different epigenetic marks aim at unraveling the interplay between their regulation mechanisms. Published evaluation tools, however, allow testing for predefined hypotheses only. Here, we present a novel method for annotation-independent exploration of epigenetic data and their inter-correlation with other genome-wide features. Our method is based on a combinatorial genome segmentation solely using information on combinations of epigenetic marks. It does not require prior knowledge about the data (e.g. gene positions), but allows integrating the data in a straightforward manner. Thereby, it combines compression, clustering and visualization of the data in a single tool. Our method provides intuitive maps of epigenetic patterns across multiple levels of organization, e.g. of the co-occurrence of different epigenetic marks in different cell types. Thus, it facilitates the formulation of new hypotheses on the principles of epigenetic regulation. We apply our method to histone modification data on trimethylation of histone H3 at lysine 4, 9 and 27 in multi-potent and lineage-primed mouse cells, analyzing their combinatorial modification pattern as well as differentiation-related changes of single modifications. We demonstrate that our method is capable of reproducing recent findings of gene centered approaches, e.g. correlations between CpG-density and the analyzed histone modifications. Moreover, combining the clustered epigenetic data with information on the expression status of associated genes we classify differences in epigenetic status of e.g. house-keeping genes versus differentiation-related genes. Visualizing the distribution of modification states on the chromosomes, we discover strong patterns for chromosome X. For example, exclusively H3K9me3 marked segments are enriched, while poised and active states are rare. Hence, our method also provides new insights into chromosome-specific epigenetic patterns, opening up new questions how "epigenetic computation" is distributed over the genome in space and time.

Therapeutic application of mesenchymal stem cells (MSC) requires their extensive in vitro expansion. MSC in culture typically grow to confluence within a few weeks. They show spindle-shaped fibroblastoid morphology and align to each other in characteristic spatial patterns at high cell density. We present an individual cell-based model (IBM) that is able to quantitatively describe the spatio-temporal organization of MSC in culture. Our model substantially improves on previous models by explicitly representing cell podia and their dynamics. It employs podia-generated forces for cell movement and adjusts cell behavior in response to cell density. At the same time, it is simple enough to simulate thousands of cells with reasonable computational effort. Experimental sheep MSC cultures were monitored under standard conditions. Automated image analysis was used to determine the location and orientation of individual cells. Our simulations quantitatively reproduced the observed growth dynamics and cell-cell alignment assuming cell density-dependent proliferation, migration, and morphology. In addition to cell growth on plain substrates our model captured cell alignment on micro-structured surfaces. We propose a specific surface micro-structure that according to our simulations can substantially enlarge cell culture harvest. The 'tool box' of cell migratory behavior newly introduced in this study significantly enhances the bandwidth of IBM. Our approach is capable of accommodating individual cell behavior and collective cell dynamics of a variety of cell types and tissues in computational systems biology.

The innate immune system is of vital importance for protection against infectious pathogens. Inflammasome mediated caspase-1 activation and subsequent release of pro-inflammatory cytokines like IL-1beta and IL-18 is an important arm of the innate immune system. Salmonella enterica subspecies 1 serovar Typhimurium (S. Typhimurium, SL1344) is an enteropathogenic bacterium causing diarrheal diseases. Different reports have shown that in macrophages, S. Typhimurium may activate caspase-1 by at least three different types of stimuli: flagellin, the type III secretion system 1 (T1) and the T1 effector protein SopE. However, the relative importance and interdependence of the different factors in caspase-1 activation is still a matter of debate. Here, we have analyzed their relative contributions to caspase-1 activation in LPS-pretreated RAW264.7 macrophages. Using flagellar mutants (fliGHI, flgK) and centrifugation to mediate pathogen-host cell contact, we show that flagellins account for a small part of the caspase-1 activation in RAW264.7 cells. In addition, functional flagella are of key importance for motility and host cell attachment which is a prerequisite for mediating caspase-1 activation via these three stimuli. Using site directed mutants lacking several T1 effector proteins and flagellin expression, we found that SopE elicits caspase-1 activation even when flagellins are absent. In contrast, disruption of essential genes of the T1 protein injection system (invG, sipB) completely abolished caspase-1 activation. However, a robust level of caspase-1 activation is retained by the T1 system (or unidentified T1 effectors) in the absence of flagellin and SopE. T1-mediated inflammasome activation is in line with recent work by others and suggests that the T1 system itself may represent the basic caspase-1 activating stimulus in RAW264.7 macrophages which is further enhanced independently by SopE and/or flagellin.

The balance between maintenance of the stem cell state and terminal differentiation is influenced by the cellular environment. The switching between these states has long been understood as a transition between attractor states of a molecular network. Herein, stochastic fluctuations are either suppressed or can trigger the transition, but they do not actually determine the attractor states.We present a novel mathematical concept in which stem cell and progenitor population dynamics are described as a probabilistic process that arises from cell proliferation and small fluctuations in the state of differentiation. These state fluctuations reflect random transitions between different activation patterns of the underlying regulatory network. Importantly, the associated noise amplitudes are state-dependent and set by the environment. Their variability determines the attractor states, and thus actually governs population dynamics. This model quantitatively reproduces the observed dynamics of differentiation and dedifferentiation in promyelocytic precursor cells.Consequently, state-specific noise modulation by external signals can be instrumental in controlling stem cell and progenitor population dynamics. We propose follow-up experiments for quantifying the imprinting influence of the environment on cellular noise regulation.