Background and Aims: While transarterial chemoembolization (TACE) represents a standard of therapy for intermediate-stage hepatocellular carcinoma (HCC) and is also routinely performed in patients with liver metastases, it is still debated which patients represent the ideal candidates for TACE therapy in terms of overall survival. Sarcopenia, the degenerative loss of skeletal muscle mass and strength, has been associated with an adverse outcome for various malignancies, but its role in the context of TACE has largely remained unknown. Here, we evaluated the role of sarcopenia on the outcome of patients undergoing TACE for primary and secondary liver cancer. Methods: The patients’ psoas muscle size was measured on axial computed tomography (CT) scans and normalized for the patients’ height squared. This value was referred to as the psoas muscle index (PMI). The PMI was correlated with clinical and laboratory markers. Results: While pre-interventional sarcopenia had no impact on the direct tumor response to TACE, sarcopenic patients with a pre-interventional PMI below our ideal cut-o value of 13.39 mm/m2 had a significantly impaired long-term outcome with a median overall survival of 491 days compared to 1291 days for patients with a high PMI. This finding was confirmed by uni- and multivariate Cox-regression analyses. Moreover, a progressive rapid decline in muscle mass after TACE was a predictor for an unfavorable prognosis. Conclusion: Our data suggest that sarcopenia represents a previously unrecognized prognostic factor for patients undergoing TACE therapy which might yield important information on the patients’ post-interventional outcome and should therefore be implemented into clinical stratification algorithms.View less
Claudins regulate paracellular permeability in different tissues. The claudin-binding domain of Clostridium perfringens enterotoxin (cCPE) is a known modulator of a claudin subset. However, it does not efficiently bind to claudin-1 (Cldn1). Cldn1 is a pharmacological target since it is (i) an essential co-receptor for hepatitis C virus (HCV) infections and (ii) a key element of the epidermal barrier limiting drug delivery. In this study, we investigated the potential of a Cldn1-binding cCPE mutant (i) to inhibit HCV entry into hepatocytes and (ii) to open the epidermal barrier. Inhibition of HCV infection by blocking of Cldn1 with cCPE variants was analyzed in the Huh7.5 hepatoma cell line. A model of reconstructed human epidermis was used to investigate modulation of the epidermal barrier by cCPE variants. In contrast to cCPEwt, the Cldn1-binding cCPE-S305P/S307R/S313H inhibited infection of Huh7.5 cells with HCV in a dose-dependent manner. In addition, TJ modulation by cCPE variant-mediated targeting of Cldn1 and Cldn4 opened the epidermal barrier in reconstructed human epidermis. cCPE variants are potent claudin modulators. They can be applied for mechanistic in vitro studies and might also be used as biologics for therapeutic claudin targeting including HCV treatment (host-targeting antivirals) and improvement of drug delivery.View less
Gluten-related disorders include distinct disease entities, namely celiac disease, wheat-associated allergy and non-celiac gluten/wheat sensitivity. Despite having in common the contact of the gastrointestinal mucosa with components of wheat and other cereals as a causative factor, these clinical entities have distinct pathophysiological pathways. In celiac disease, a T-cell mediate immune reaction triggered by gluten ingestion is central in the pathogenesis of the enteropathy, while wheat allergy develops as a rapid immunoglobulin E- or non-immunoglobulin E-mediated immune response. In non-celiac wheat sensitivity, classical adaptive immune responses are not involved. Instead, recent research has revealed that an innate immune response to a yet-to-be-defined antigen, as well as the gut microbiota, are pivotal in the development in this disorder. Although impairment of the epithelial barrier has been described in all three clinical conditions, its role as a potential pathogenetic co-factor, specifically in celiac disease and non-celiac wheat sensitivity, is still a matter of investigation. This article gives a short overview of the mucosal barrier of the small intestine, summarizes the aspects of barrier dysfunction observed in all three gluten-related disorders and reviews literature data in favor of a primary involvement of the epithelial barrier in the development of celiac disease and non-celiac wheat sensitivity.View less
Campylobacter jejuni (C. jejuni) is the most common cause of foodborne gastroenteritis worldwide. The bacteria induce diarrhea and inflammation by invading the intestinal epithelium. Curcumin is a natural polyphenol from turmeric rhizome of Curcuma longa, a medical plant, and is commonly used in curry powder. The aim of this study was the investigation of the protective effects of curcumin against immune-induced epithelial barrier dysfunction in C. jejuni infection. The indirect C. jejuni-induced barrier defects and its protection by curcumin were analyzed in co-cultures with HT-29/B6-GR/MR epithelial cells together with differentiated THP-1 immune cells. Electrophysiological measurements revealed a reduction in transepithelial electrical resistance (TER) in infected co-cultures. An increase in fluorescein (332 Da) permeability in co-cultures as well as in the germ-free IL-10-/- mouse model after C. jejuni infection was shown. Curcumin treatment attenuated the C. jejuni-induced increase in fluorescein permeability in both models. Moreover, apoptosis induction, tight junction redistribution, and an increased inflammatory response-represented by TNF-α, IL-1β, and IL-6 secretion-was observed in co-cultures after infection and reversed by curcumin. In conclusion, curcumin protects against indirect C. jejuni-triggered immune-induced barrier defects and might be a therapeutic and protective agent in patients.View less
With increasing population growth, the Harare Metropolitan Province has experienced accelerated land use and land cover (LULC) changes, influencing the city’s growth. This study aims to assess spatiotemporal urban LULC changes, the axis, and patterns of growth as well as drivers influencing urban growth over the past three decades in the Harare Metropolitan Province. The analysis was based on remotely sensed Landsat Thematic Mapper and Operational Land Imager data from 1984–2018, GIS application, and binary logistic regression. Supervised image classification using support vector machines was performed on Landsat 5 TM and Landsat 8 OLI data combined with the soil adjusted vegetation index, enhanced built-up and bareness index and modified difference water index. Statistical modelling was performed using binary logistic regression to identify the influence of the slope and the distance proximity characters as independent variables on urban growth. The overall mapping accuracy for all time periods was over 85%. Built-up areas extended from 279.5 km2 (1984) to 445 km2 (2018) with high-density residential areas growing dramatically from 51.2 km2 (1984) to 218.4 km2 (2018). The results suggest that urban growth was influenced mainly by the presence and density of road networks.View less
Circular RNAs (circRNAs) may act as novel cancer biomarkers. However, a genome-wide evaluation of circRNAs in clear cell renal cell carcinoma (ccRCC) has yet to be conducted. Therefore, the objective of this study was to identify and validate circRNAs in ccRCC tissue with a focus to evaluate their potential as prognostic biomarkers. A genome-wide identification of circRNAs in total RNA extracted from ccRCC tissue samples was performed using microarray analysis. Three relevant differentially expressed circRNAs were selected (circEGLN3, circNOX4, and circRHOBTB3), their circular nature was experimentally confirmed, and their expression-along with that of their linear counterparts-was measured in 99 malignant and 85 adjacent normal tissue samples using specifically established RT-qPCR assays. The capacity of circRNAs to discriminate between malignant and adjacent normal tissue samples and their prognostic potential (with the endpoints cancer-specific, recurrence-free, and overall survival) after surgery were estimated by C-statistics, Kaplan-Meier method, univariate and multivariate Cox regression analysis, decision curve analysis, and Akaike and Bayesian information criteria. CircEGLN3 discriminated malignant from normal tissue with 97% accuracy. We generated a prognostic for the three endpoints by multivariate Cox regression analysis that included circEGLN3, circRHOBT3 and linRHOBTB3. The predictive outcome accuracy of the clinical models based on clinicopathological factors was improved in combination with this circRNA-based signature. Bootstrapping as well as Akaike and Bayesian information criteria confirmed the statistical significance and robustness of the combined models. Limitations of this study include its retrospective nature and the lack of external validation. The study demonstrated the promising potential of circRNAs as diagnostic and particularly prognostic biomarkers in ccRCC patients.View less
We sought to investigate the prevalence of smoking and lung function in the large cohort of elite athletes.
This cross-sectional study included 804 athletes competing at international level who were consecutively examined from January to December 2017. Elite athletes were classified in four groups of sport disciplines (skill, power, endurance and mixed): skill (n = 141), power (n = 107), endurance (n = 105) and mixed sport disciplines (n = 451). All participants underwent pre-participation screening, including spirometry.
Study included 745 (92.7%) non-smokers, 20 (2.5%) former smokers and 39 (4.8%) active smokers. The percentage of body fat was higher and the percentage of muscle was lower in active smokers than in non-smokers and former smokers. Active smokers were more prevalent among skill and mixed than in power and endurance sports. FEV1 and FVC, as well as FEV1/FVC ratio, were significantly lower in active smokers than in non-smokers. There was no significant difference in PEF assessed in absolute values and in percentages. Forced expiratory flows, evaluated at the usual intervals (25%, 50% and 75% of FVC), were significantly lower in active smokers than in non-smokers. FEV1 and MEF25 were the lowest among active smokers in the skill sport group, whereas FEV1/FVC, MEF50 and MEF25 were the lowest among active smokers in the power sport group. In mixed and endurance disciplines there was no difference in pulmonary function between non-smokers, former smokers and active smokers.
Pulmonary function was reduced in active smokers and these differences were the most prominent in skill and power sports. The percentage of body fat was the highest and percentage of muscle was the lowest in active smokers.View less
Cellular, organ, and whole animal physiology show temporal variation predominantly featuring 24-h (circadian) periodicity. Time-course mRNA gene expression profiling in mouse liver showed two subsets of genes oscillating at the second (12-h) and third (8-h) harmonic of the prime (24-h) frequency. The aim of our study was to identify specific genomic, proteomic, and functional properties of ultradian and circadian subsets. We found hallmarks of the three oscillating gene subsets, including different (i) functional annotation, (ii) proteomic and electrochemical features, and (iii) transcription factor binding motifs in upstream regions of 8-h and 12-h oscillating genes that seemingly allow the link of the ultradian gene sets to a known circadian network. Our multifaceted bioinformatics analysis of circadian and ultradian genes suggests that the different rhythmicity of gene expression impacts physiological outcomes and may be related to transcriptional, translational and post-translational dynamics, as well as to phylogenetic and evolutionary components.View less
We examined the reduced blood pressure (BP) nocturnal fall in patients with obstructive sleep apnea (OSA) by a meta-analysis including studies that provided data on prevalence rates of non-dipping (ND) pattern during 24-h ambulatory blood pressure monitoring (ABPM).
The PubMed, OVID-MEDLINE, and Cochrane CENTRAL literature databases were searched for appropriate articles without temporal restriction up to April 2019 through focused and sensitive search methods. Studies were identified by crossing the search terms as follows: "obstructive sleep apnea", "sleep quality", "non dipping", "reduced nocturnal BP fall", "circadian BP variation", "night-time BP", and "ambulatory blood pressure monitoring".
Meta-analysis included 1562 patients with OSA from different clinical settings and 957 non-OSA controls from 14 studies. ND pattern prevalence in patients with OSA widely varied among studies (36.0-90.0%). This was also the case for non-OSA controls (33.0% to 69.0%). Overall, the ND pattern, assessed as an event rate in the pooled OSA population, was 59.1% (confidence interval (CI): 52.0-65.0%). Meta-analysis of the seven studies comparing the prevalence of ND pattern in participants with OSA and controls showed that OSA entails a significantly increased risk of ND (Odds ratio (OR) = 1.47, CI: 1.07-1.89, p < 0.01). After the exclusion of patients with mild OSA, OR increased to 1.67 (CI: 1.21-2.28, p < 0.001).
The present meta-analysis, extending previous information on the relationship between OSA and impaired BP dipping, based on single studies, suggests that this condition increases by approximately 1.5 times the likelihood of ND, which is a pattern associated with a greater cardiovascular risk than normal BP dipping.View less
Selenium-binding protein 1 (SELENBP1) is an intracellular protein that has been detected in the circulation in response to myocardial infarction. Hypoxia and cardiac surgery affect selenoprotein expression and selenium (Se) status. For this reason, we decided to analyze circulating SELENBP1 concentrations in patients (n = 75) necessitating cardioplegia and a cardiopulmonary bypass (CPB) during the course of the cardiac surgery. Serum samples were collected at seven time-points spanning the full surgical process. SELENBP1 was quantified by a highly sensitive newly developed immunological assay. Serum concentrations of SELENBP1 increased markedly during the intervention and showed a positive association with the duration of ischemia (ρ = 0.6, p < 0.0001). Elevated serum SELENBP1 concentrations at 1 h after arrival at the intensive care unit (post-surgery) were predictive to identify patients at risk of adverse outcome (death, bradycardia or cerebral ischemia, "endpoint 1"; OR 29.9, CI 3.3-268.8, p = 0.00027). Circulating SELENBP1 during intervention (2 min after reperfusion or 15 min after weaning from the CPB) correlated positively with an established marker of myocardial infarction (CK-MB) measured after the intervention (each with ρ = 0.5, p < 0.0001). We concluded that serum concentrations of SELENBP1 were strongly associated with cardiac arrest and the duration of myocardial ischemia already early during surgery, thereby constituting a novel and promising quantitative marker for myocardial hypoxia, with a high potential to improve diagnostics and prediction in combination with the established clinical parameters.View less
Data regarding cardiac remodeling in patients with alcoholic liver cirrhosis are scarce. We sought to investigate right atrial (RA) and right ventricular (RV) structure, function, and mechanics in patients with alcoholic liver cirrhosis.
This retrospective cross-sectional investigation included 67 end-stage cirrhotic patients, who were referred for evaluation for liver transplantation and 36 healthy controls. All participants underwent echocardiographic examination including strain analysis, which was performed offline.
RV basal diameter and RV thickness were significantly higher in patients with cirrhosis. Conventional parameters of the RV systolic function were similar between the observed groups. Global, endocardial, and epicardial RV longitudinal strains were significantly lower in patients with cirrhosis. Active RA function was significantly higher in cirrhotic patients than in controls. The RA reservoir and conduit strains were significantly lower in cirrhotic patients, while there was no difference in the RA contractile strain. Early diastolic and systolic RA strain rates were significantly lower in cirrhotic patients than in controls, whereas there was no difference in the RA late diastolic strain rate between the two groups. Transaminases and bilirubin correlated negatively with RV global longitudinal strain and RV-free wall strain in patients with end-stage liver cirrhosis. The Model for End-stage Liver Disease (MELD) score, predictor of 3-month mortality, correlated with parameters of RV structure and systolic function, and RA active function in patients with end-stage liver cirrhosis.
RA and RV remodeling is present in patients with end-stage liver cirrhosis even though RV systolic function is preserved. Liver enzymes, bilirubin, and the MELD score correlated with RV and RA remodeling.View less
Thanks to its unmatched specificity, electron spin resonance (ESR) spectroscopy is amongst the most powerful analytical techniques today with applications ranging from the life sciences over material science analysis to food quality control . By measuring the spin of an unpaired electron, ESR spectroscopy is specifically suited to analyze free radicals, which play a major role in many diseases and can also directly be related to premature cell aging.View less
In this paper, we present an integrator-differentiator transimpedance amplifier (TIA) featuring a multielement pseudo-resistor (MEPR) in the DC feedback path for improved noise performance in the presence of non-zero DC input currents. The presented prototype is implemented in a standard 180 nm CMOS technology and achieves an inband transimpedance of 10 MΩ over a 2.7 MHz signal bandwidth. The MEPR resistor in the DC servo loop can be tuned between 700 k Ω and 100 MΩ enabling a precise adjustment of the TIA's lower cutoff frequency. For a DC feedback resistance of 700 k Ω, the TIA provides an input referred noise floor of 180 fA/√Hz at zero input current, which only marginally increases to 220 fA/√Hz for the maximum bias current of 1 μA. The TIA consumes 0.6 mm 2 of chip area and 18.5 mW of power from a 1.8 V supply.View less
In this paper, we present a pseudo-resistor-based transimpedance amplifier (TIA) whose transimpedance value is PVT-independent and continuously tuneable over a wide range. The nonlinearity of the pseudo-resistors is mitigated by connecting a large number of elements in series and the effect of process variations on the pseudo-resistor is canceled by a biasing network based on a pseudo current mirror. The design is also first order temperature compensated exploiting the PTAT behavior of the proposed pseudo-resistor and using a PTAT current reference for its biasing. The proposed architecture is verified using a prototype manufactured in a 0.18 μm CMOS SOI technology. In this prototype, the transimpedance can be adjusted between approximately 1MΩ and 1 GΩ. The achievable bandwidth varies inversely proportional with the transimpedance value from around 7 kHz for a value of 1 GΩ up to an opamp-limited maximum of 2 MHz. In the white region, the input referred noise is equal to that of a TIA using an equivalent ohmic resistor. A minimum value of 5 fA/√Hz is achieved for a transimpedance of 1 GΩ. Over a temperature range from -40 °C to 125 °C, the transimpedance varies less than 10% for 1MΩ. The TIA occupies a chip area of 0.07 mm 2 . At room temperature, the power consumption is 9.5 mW from a single 1.8 V supply of which the pseudo-resistor consumes 0.2 mW.View less
In this paper, we discuss the use of electron spin resonance (ESR) spectroscopy as a tool for future point-of-care diagnostic applications. Additionally, we present a new ESR sensor ASIC with an improved VCO tuning scheme as an extension to our previously presented portable, VCO-based ESR spectrometer. By using two VCO tuning voltages with widely different VCO gains, the proposed tuning scheme greatly relaxes the requirements on the digital-to-analog converter (DAC). This is because in the previous scheme a single DAC had to be used to generate both the tuning signals for the wide frequency sweep and the small frequency modulation signals at the same time. In contrast, in the new scheme two DACs with optimized dynamic ranges can be used, reducing the AM-to-FM-conversion noise in the varactor to optimize the overall system sensitivity.View less
Emerging infectious diseases (EIDs) have contributed significantly to the current biodiversity crisis, leading to widespread epidemics and population loss. Owing to genetic variation in pathogen virulence, a complete understanding of species decline requires the accurate identification and characterization of EIDs. We explore this issue in the Western honeybee, where increasing mortality of populations in the Northern Hemisphere has caused major concern. Specifically, we investigate the importance of genetic identity of the main suspect in mortality, deformed wing virus (DWV), in driving honeybee loss. Using laboratory experiments and a systematic field survey, we demonstrate that an emerging DWV genotype (DWV-B) is more virulent than the established DWV genotype (DWV-A) and is widespread in the landscape. Furthermore, we show in a simple model that colonies infected with DWV-B collapse sooner than colonies infected with DWV-A. We also identify potential for rapid DWV evolution by revealing extensive genome-wide recombination in vivo. The emergence of DWV-B in naive honeybee populations, including via recombination with DWV-A, could be of significant ecological and economic importance. Our findings emphasize that knowledge of pathogen genetic identity and diversity is critical to understanding drivers of species decline.View less
Pathogens may gain a fitness advantage through manipulation of the behaviour of their hosts. Likewise, host behavioural changes can be a defence mechanism, counteracting the impact of pathogens on host fitness. We apply harmonic radar technology to characterize the impact of an emerging pathogen - Nosema ceranae (Microsporidia) - on honeybee (Apis mellifera) flight and orientation performance in the field. Honeybees are the most important commercial pollinators. Emerging diseases have been proposed to play a prominent role in colony decline, partly through sub-lethal behavioural manipulation of their hosts. We found that homing success was significantly reduced in diseased (65.8%) versus healthy foragers (92.5%). Although lost bees had significantly reduced continuous flight times and prolonged resting times, other flight characteristics and navigational abilities showed no significant difference between infected and non-infected bees. Our results suggest that infected bees express normal flight characteristics but are constrained in their homing ability, potentially compromising the colony by reducing its resource inputs, but also counteracting the intra-colony spread of infection. We provide the first high-resolution analysis of sub-lethal effects of an emerging disease on insect flight behaviour. The potential causes and the implications for both host and parasite are discussed.View less
Virologists. You might know a couple of them, but unless you are a virologist yourself, the probability that you have collaborated with one in the past is low. The community is relatively small, but they pack a heavy punch and are expected to play a leading role in the research into pathogens that lies ahead. You may ask why we think virologists are our future. Suffice it to say that it is not just because they have invented technologies that belong to the space age, including use of viruses as vehicles to shuttle genes into cells, organic nanoparticles with specific tools attached to their surfaces to get inside target cells, and using genetically modified viruses as therapies to fight against cancer. Did you know that virologists currently only know of about 3,200 viral species but that more than 320,000 mammal-associated viruses are thought to await discovery? Just think about the viruses hidden in the Arctic ice or in the insects and other animals from once cut-off regions in the world, which now face ever-increasing human exposure. But a heroic (as well as an apocalyptic) role for virologists may also be on the horizon, as the adoption of phage therapy may, in the future, be used to control harmful bacteria when antibiotics fail.View less
Despite the recognized excellence of virology and bioinformatics, these two communities have interacted surprisingly sporadically, aside from some pioneering work on HIV-1 and influenza. Bringing together the expertise of bioinformaticians and virologists is crucial, since very specific but fundamental computational approaches are required for virus research, particularly in an era of big data. Collaboration between virologists and bioinformaticians is necessary to improve existing analytical tools, cloud-based systems, computational resources, data sharing approaches, new diagnostic tools, and bioinformatic training. Here, we highlight current progress and discuss potential avenues for future developments in this promising era of virus bioinformatics. We end by presenting an overview of current technologies, and by outlining some of the major challenges and advantages that bioinformatics will bring to the field of virology.View less
Boom‐bust dynamics – the rise of a population to outbreak levels, followed by a dramatic decline – have been associated with biological invasions and offered as a reason not to manage troublesome invaders. However, boom‐bust dynamics rarely have been critically defined, analyzed, or interpreted. Here, we define boom‐bust dynamics and provide specific suggestions for improving the application of the boom‐bust concept. Boom‐bust dynamics can arise from many causes, some closely associated with invasions, but others occurring across a wide range of ecological settings, especially when environmental conditions are changing rapidly. As a result, it is difficult to infer cause or predict future trajectories merely by observing the dynamic. We use tests with simulated data to show that a common metric for detecting and describing boom‐bust dynamics, decline from an observed peak to a subsequent trough, tends to severely overestimate the frequency and severity of busts, and should be used cautiously if at all. We review and test other metrics that are better suited to describe boom‐bust dynamics. Understanding the frequency and importance of boom‐bust dynamics requires empirical studies of large, representative, long‐term data sets that use clear definitions of boom‐bust, appropriate analytical methods, and careful interpretations.View less