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Open AccessReview
Claudin-2: Roles beyond Permeability Functions
Int. J. Mol. Sci. 2019, 20(22), 5655; https://doi.org/10.3390/ijms20225655 (registering DOI) - 12 Nov 2019
Abstract
Claudin-2 is expressed in the tight junctions of leaky epithelia, where it forms cation-selective and water permeable paracellular channels. Its abundance is under fine control by a complex signaling network that affects both its synthesis and turnover in response to various environmental inputs. [...] Read more.
Claudin-2 is expressed in the tight junctions of leaky epithelia, where it forms cation-selective and water permeable paracellular channels. Its abundance is under fine control by a complex signaling network that affects both its synthesis and turnover in response to various environmental inputs. Claudin-2 expression is dysregulated in many pathologies including cancer, inflammation, and fibrosis. Claudin-2 has a key role in energy-efficient ion and water transport in the proximal tubules of the kidneys and in the gut. Importantly, strong evidence now also supports a role for this protein as a modulator of vital cellular events relevant to diseases. Signaling pathways that are overactivated in diseases can alter claudin-2 expression, and a good correlation exists between disease stage and claudin-2 abundance. Further, loss- and gain-of-function studies showed that primary changes in claudin-2 expression impact vital cellular processes such as proliferation, migration, and cell fate determination. These effects appear to be mediated by alterations in key signaling pathways. The specific mechanisms linking claudin-2 to these changes remain poorly understood, but adapters binding to the intracellular portion of claudin-2 may play a key role. Thus, dysregulation of claudin-2 may contribute to the generation, maintenance, and/or progression of diseases through both permeability-dependent and -independent mechanisms. The aim of this review is to provide an overview of the properties, regulation, and functions of claudin-2, with a special emphasis on its signal-modulating effects and possible role in diseases. Full article
(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)
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Open AccessArticle
Combinatory Multifactor Treatment Effects on Primary Nanofiber Oligodendrocyte Cultures
Cells 2019, 8(11), 1422; https://doi.org/10.3390/cells8111422 (registering DOI) - 12 Nov 2019
Abstract
Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system. Neurological deficits are attributed to inflammatory demyelination, which compromises axonal function and survival. These are mitigated in experimental models by rapid and often complete remyelination of affected [...] Read more.
Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system. Neurological deficits are attributed to inflammatory demyelination, which compromises axonal function and survival. These are mitigated in experimental models by rapid and often complete remyelination of affected axons, but in MS this endogenous repair mechanism frequently fails, leaving axons increasingly vulnerable to the detrimental effects of inflammatory and metabolic stress. Understanding the molecular basis of remyelination and remyelination failure is essential to develop improved therapies for this devastating disease. However, recent studies suggest that this is not due to a single dominant mechanism, but rather represents the biological outcome of multiple changes in the lesion microenvironment that combine to disrupt oligodendrocyte differentiation. This identifies a pressing need to develop technical platforms to investigate combinatory and/or synergistic effects of factors differentially expressed in MS lesions on oligodendrocyte proliferation and differentiation. Here we describe protocols using primary oligodendrocyte cultures from Bl6 mice on 384-well nanofiber plates to model changes affecting oligodendrogenesis and differentiation in the complex signaling environment associated with multiple sclerosis lesions. Using platelet-derived growth factor (PDGF–AA), fibroblast growth factor 2 (FGF2), bone morphogenetic protein 2 (BMP2) and bone morphogenetic protein 4 (BMP4) as representative targets, we demonstrate that we can assess their combinatory effects across a wide range of concentrations in a single experiment. This in vitro model is ideal for assessing the combinatory effects of changes in availability of multiple factors, thus more closely modelling the situation in vivo and furthering high-throughput screening possibilities. Full article
(This article belongs to the Special Issue Oligodendrocyte Physiology and Pathology Function)
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Open AccessReview
Metabolic Signature of Hepatic Fibrosis: From Individual Pathways to Systems Biology
Cells 2019, 8(11), 1423; https://doi.org/10.3390/cells8111423 (registering DOI) - 12 Nov 2019
Abstract
Hepatic fibrosis is a major cause of morbidity and mortality worldwide, as it ultimately leads to cirrhosis, which is estimated to affect up to 2% of the global population. Hepatic fibrosis is confirmed by liver biopsy, and the erroneous nature of this technique [...] Read more.
Hepatic fibrosis is a major cause of morbidity and mortality worldwide, as it ultimately leads to cirrhosis, which is estimated to affect up to 2% of the global population. Hepatic fibrosis is confirmed by liver biopsy, and the erroneous nature of this technique necessitates the search for noninvasive alternatives. However, current biomarker algorithms for hepatic fibrosis have many limitations. Given that the liver is the largest organ and a major metabolic hub in the body, probing the metabolic signature of hepatic fibrosis holds promise for the discovery of new markers and therapeutic targets. Regarding individual metabolic pathways, accumulating evidence shows that hepatic fibrosis leads to alterations in carbohydrate metabolism, as aerobic glycolysis is aggravated in activated hepatic stellate cells (HSCs) and the whole fibrotic liver; in amino acid metabolism, as Fischer’s ratio (branched-chain amino acids/aromatic amino acids) decreases in patients with hepatic fibrosis; and in lipid metabolism, as HSCs lose vitamin A-containing lipid droplets during transdifferentiation, and cirrhotic patients have decreased serum lipids. The current review also summarizes recent findings of metabolic alterations relevant to hepatic fibrosis based on systems biology approaches, including transcriptomics, proteomics, and metabolomics in vitro, in animal models and in humans. Full article
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Open AccessReview
Viral Infections and Interferons in the Development of Obesity
Biomolecules 2019, 9(11), 726; https://doi.org/10.3390/biom9110726 (registering DOI) - 12 Nov 2019
Abstract
Obesity is now a prevalent disease worldwide and has a multi-factorial etiology. Several viruses or virus-like agents including members of adenoviridae, herpesviridae, slow virus (prion), and hepatitides, have been associated with obesity; meanwhile obese patients are shown to be more susceptible to viral [...] Read more.
Obesity is now a prevalent disease worldwide and has a multi-factorial etiology. Several viruses or virus-like agents including members of adenoviridae, herpesviridae, slow virus (prion), and hepatitides, have been associated with obesity; meanwhile obese patients are shown to be more susceptible to viral infections such as during influenza and dengue epidemics. We examined the co-factorial role of viral infections, particularly of the persistent cases, in synergy with high-fat diet in induction of obesity. Antiviral interferons (IFNs), as key immune regulators against viral infections and in autoimmunity, emerge to be a pivotal player in the regulation of adipogenesis. In this review, we examine the recent evidence indicating that gut microbiota uphold intrinsic IFN signaling, which is extensively involved in the regulation of lipid metabolism. However, the prolonged IFN responses during persistent viral infections and obesogenesis comprise reciprocal causality between virus susceptibility and obesity. Furthermore, some IFN subtypes have shown therapeutic potency in their anti-inflammation and anti-obesity activity. Full article
(This article belongs to the Section Biological Factors)
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Open AccessArticle
Radiation and Stemness Phenotype May Influence Individual Breast Cancer Outcomes: The Crucial Role of MMPs and Microenvironment
Cancers 2019, 11(11), 1781; https://doi.org/10.3390/cancers11111781 (registering DOI) - 12 Nov 2019
Abstract
Breast cancer is the most common cancer in women. Radiotherapy (RT) is one of the mainstay treatments for cancer but in some cases is not effective. Cancer stem cells (CSCs) within the tumor can be responsible for recurrence and metastasis after RT. Matrix [...] Read more.
Breast cancer is the most common cancer in women. Radiotherapy (RT) is one of the mainstay treatments for cancer but in some cases is not effective. Cancer stem cells (CSCs) within the tumor can be responsible for recurrence and metastasis after RT. Matrix metalloproteases (MMPs), regulated mainly by tissue inhibitors of metalloproteinases (TIMPs) and histone deacetylases (HDACs), may also contribute to tumor development by modifying its activity after RT. The aim of this work was to study the effects of RT on the expression of MMPs, TIMPs and HDACs on different cell subpopulations in MCF-7, MDA-MB-231 and SK-BR-3 cell lines. We assessed the in vitro expression of these genes in different 3D culture models and induced tumors in female NSG mice by orthotopic xenotransplants. Our results showed that gene expression is related to the cell subpopulation studied, the culture model used and the single radiation dose administered. Moreover, the crucial role played by the microenvironment in terms of cell interactions and CSC plasticity in tumor growth and RT outcome is also shown, supporting the use of higher doses (6 Gy) to achieve better control of tumor development. Full article
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Open AccessArticle
Detection of Fusarium Species in Clinical Specimens by Probe-Based Real-Time PCR
J. Fungi 2019, 5(4), 105; https://doi.org/10.3390/jof5040105 (registering DOI) - 12 Nov 2019
Abstract
The mold Fusarium is a ubiquitous fungus causing plant, animal and human infections. In humans, Fusarium spp. are the major cause of eye infections in patients wearing contact lenses or after local trauma. Systemic infections by Fusarium spp. mainly occur in immunosuppressed patients [...] Read more.
The mold Fusarium is a ubiquitous fungus causing plant, animal and human infections. In humans, Fusarium spp. are the major cause of eye infections in patients wearing contact lenses or after local trauma. Systemic infections by Fusarium spp. mainly occur in immunosuppressed patients and can disseminate throughout the human body. Due to high levels of resistance to antifungals a fast identification of the causative agent is an urgent need. By using a probe-based real-time PCR assay specific for the genus Fusarium we analysed several different clinical specimens detecting Fusarium spp. commonly found in clinical samples in Germany. Also, a large collection of lung fluid samples of haematological patients was analysed (n = 243). In these, two samples (0.8%) were reproducibly positive, but only one could be confirmed by sequencing. For this case of probable invasive fungal disease (IFD) culture was positive for Fusarium species. Here we describe a rapid, probe-based real-time PCR assay to specifically detect DNA from a broad range of Fusarium species and its application to clinically relevant specimens. Full article
(This article belongs to the Special Issue Molecular Diagnostics of Fungal Infections)
Open AccessFeature PaperArticle
Techno-Economic Implications of Fed-Batch Enzymatic Hydrolysis
Processes 2019, 7(11), 847; https://doi.org/10.3390/pr7110847 (registering DOI) - 12 Nov 2019
Abstract
Fed-batch enzymatic hydrolysis has the potential to improve the overall process of converting cellulosic biomass into ethanol. This paper utilizes a process simulation approach to identify and quantify techno-economic differences between batch and fed-batch enzymatic hydrolysis in cellulosic ethanol production. The entire process [...] Read more.
Fed-batch enzymatic hydrolysis has the potential to improve the overall process of converting cellulosic biomass into ethanol. This paper utilizes a process simulation approach to identify and quantify techno-economic differences between batch and fed-batch enzymatic hydrolysis in cellulosic ethanol production. The entire process of converting corn stover into ethanol was simulated using SuperPro Designer simulation software. The analysis was conducted for a plant capacity of 2000 metric tons of dry biomass per day. A literature review was used to identify baseline parameters for the process. The sensitivity of the ethanol production cost to changes in sugar conversion efficiency, plant capacity, biomass cost, power cost, labor cost, and enzyme cost was evaluated using the process simulation. For the base scenario, the ethanol unit production cost was approximately $0.10/gallon lower for fed-batch hydrolysis. The greatest differences were seen in facilities costs, labor costs, and capital costs. Using a fed-batch operation decreased facilities costs by 41%, labor costs by 21%, and capital costs by 15%. The sensitivity analysis found that cost of biomass had the greatest effect on ethanol production cost, and in general, the results support the proposition that fed-batch enzymatic hydrolysis does improve the techno-economics of cellulosic ethanol production. Full article
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Open AccessArticle
The Influence of Parasitic Components on LLC Resonant Converter
Energies 2019, 12(22), 4305; https://doi.org/10.3390/en12224305 (registering DOI) - 12 Nov 2019
Abstract
In recent years, the LLC resonant converter has been widely used in DC–DC conversion applications. However, the parasitic components of the LLC resonant converter have a significant impact in practical applications, such as influence on the conduction loss and the soft-switching of power [...] Read more.
In recent years, the LLC resonant converter has been widely used in DC–DC conversion applications. However, the parasitic components of the LLC resonant converter have a significant impact in practical applications, such as influence on the conduction loss and the soft-switching of power devices, the voltage oscillation across rectifier diodes, the unregulated output voltage at light load condition and so on. It is hard to analyze the higher-order circuits by the conventional analysis methods. Focusing on the operational principle of the LLC converter with parasitic components, the differential equation model is presented and solved by the numerical method in this paper. The simulation results verify the correctness of the theoretical analysis. The causes of two different frequency oscillations and the voltage spike are clarified. The design considerations and a specific example of the LLC converter are given. The experimental results are consistent with the simulation results, and the soft-switching of primary-side switches can be achieved in the prototype. Full article
(This article belongs to the Section Energy Fundamentals and Conversion)
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Open AccessArticle
Multiple Mycotoxins Determination in Food by LC-MS/MS: An International Collaborative Study
Toxins 2019, 11(11), 658; https://doi.org/10.3390/toxins11110658 (registering DOI) - 12 Nov 2019
Abstract
An intercollaborative study was organized to evaluate the performance characteristics of a liquid chromatography tandem mass spectrometry procedure for the simultaneous determination of 12 mycotoxins in food, which were ochratoxin A, aflatoxins B1, B2, G1, G2, and M1, deoxynivalenol, zearalenone, fumonisins B1 and [...] Read more.
An intercollaborative study was organized to evaluate the performance characteristics of a liquid chromatography tandem mass spectrometry procedure for the simultaneous determination of 12 mycotoxins in food, which were ochratoxin A, aflatoxins B1, B2, G1, G2, and M1, deoxynivalenol, zearalenone, fumonisins B1 and B2, and T-2 and HT-2 toxins. The method combined the simplicity of the QuEChERS (Quick, Easy, Cheap, Efficient, Rugged and Safe) approach with the efficiency of immunoaffinity column cleanup (the step used to enhance sensitivity and sample cleanup for some matrices only). Twenty-three entities were enrolled and were European reference laboratories for mycotoxin analysis, U.S. and European service laboratories, and Nestlé laboratories. Each participant analyzed 28 incurred and/or spiked blind samples composed of spices, nuts, milk powder, dried fruits, cereals, and baby food using the protocol given. Method performances were assessed according to ISO 5725-2. Relative standard deviations of repeatability and reproducibility and trueness values for each of the 115 mycotoxin/sample combinations ranged from 5% to 23%, 7% to 26%, and 85% to 129%, respectively, in line with requirements defined in EC 401/2006. The overall set of data gathered demonstrated that the method offered a unique platform to ensure compliance with EC 1881/2006 and EC 165/2013 regulations setting maximum limits for mycotoxins in food samples, even at low regulated levels for foods intended for infants and young children. The method was applicable regardless of the food, the regulated mycotoxin, and the concentration level, and thus is an excellent candidate for future standardization. Full article
(This article belongs to the Special Issue Application of LC-MS/MS in the Mycotoxins Studies)
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Open AccessArticle
Augmenter of Liver Regeneration Reduces Ischemia Reperfusion Injury by Less Chemokine Expression, Gr-1 Infiltration and Oxidative Stress
Cells 2019, 8(11), 1421; https://doi.org/10.3390/cells8111421 (registering DOI) - 12 Nov 2019
Abstract
Hepatic ischemia reperfusion injury (IRI) is a major complication in liver resection and transplantation. Here, we analyzed the impact of recombinant human augmenter of liver regeneration (rALR), an anti-oxidative and anti-apoptotic protein, on the deleterious process induced by ischemia reperfusion (IR). Application of [...] Read more.
Hepatic ischemia reperfusion injury (IRI) is a major complication in liver resection and transplantation. Here, we analyzed the impact of recombinant human augmenter of liver regeneration (rALR), an anti-oxidative and anti-apoptotic protein, on the deleterious process induced by ischemia reperfusion (IR). Application of rALR reduced tissue damage (necrosis), levels of lipid peroxidation (oxidative stress) and expression of anti-oxidative genes in a mouse IRI model. Damage associated molecule pattern (DAMP) and inflammatory cytokines such as HMGB1 and TNFα, were not affected by rALR. Furthermore, we evaluated infiltration of inflammatory cells into liver tissue after IRI and found no change in CD3 or γδTCR positive cells, or expression of IL17/IFNγ by γδTCR cells. The quantity of Gr-1 positive cells (neutrophils), and therefore, myeloperoxidase activity, was lower in rALR-treated mice. Moreover, we found under hypoxic conditions attenuated ROS levels after ALR treatment in RAW264.7 cells and in primary mouse hepatocytes. Application of rALR also led to reduced expression of chemo-attractants like CXCL1, CXCL2 and CCl2 in hepatocytes. In addition, ALR expression was increased in IR mouse livers after 3 h and in biopsies from human liver transplants with minimal signs of tissue damage. Therefore, ALR attenuates IRI through reduced neutrophil tissue infiltration mediated by lower expression of key hepatic chemokines and reduction of ROS generation. Full article
(This article belongs to the Special Issue Recent Advances in Liver Repair Strategies)
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Open AccessReview
C-Fiber Assays in the Cornea vs. Skin
Brain Sci. 2019, 9(11), 320; https://doi.org/10.3390/brainsci9110320 (registering DOI) - 12 Nov 2019
Abstract
C-fibers are unmyelinated nerve fibers that transmit high threshold mechanical, thermal, and chemical signals that are associated with pain sensations. This review examines current literature on measuring altered peripheral nerve morphology and discusses the most relevant aspects of corneal microscopy, especially whether corneal [...] Read more.
C-fibers are unmyelinated nerve fibers that transmit high threshold mechanical, thermal, and chemical signals that are associated with pain sensations. This review examines current literature on measuring altered peripheral nerve morphology and discusses the most relevant aspects of corneal microscopy, especially whether corneal imaging presents significant method advantages over skin biopsy. Given its relative merits, corneal confocal microscopy would seem to be a more practical and patient-centric approach than utilizing skin biopsies. Full article
(This article belongs to the Special Issue Mechanisms Underlying Alleviation of Pain)
Open AccessArticle
Optimization of Physical Activity Recognition for Real-Time Wearable Systems: Effect of Window Length, Sampling Frequency and Number of Features
Appl. Sci. 2019, 9(22), 4833; https://doi.org/10.3390/app9224833 (registering DOI) - 12 Nov 2019
Abstract
The aim of this study was to develop an optimized physical activity classifier for real-time wearable systems with the focus on reducing the requirements on device power consumption and memory buffer. Classification parameters evaluated in this study were the sampling frequency of the [...] Read more.
The aim of this study was to develop an optimized physical activity classifier for real-time wearable systems with the focus on reducing the requirements on device power consumption and memory buffer. Classification parameters evaluated in this study were the sampling frequency of the acceleration signal, window length of the classification fragment, and the number of classification features, found with different feature selection methods. For parameter evaluation, a decision tree classifier was created based on the acceleration signals recorded during tests, where 25 healthy test subjects performed various physical activities. Overall average F1-score achieved in this study was about 0.90. Similar F1-scores were achieved with the evaluated window lengths of 5 s (0.92 ± 0.02) and 3 s (0.91 ± 0.02), while classification performance with 1 s were lower (0.87 ± 0.02). Tested sampling frequencies of 50 Hz, 25 Hz, and 13 Hz had similar results with most classified activity types, with an exception of outdoor cycling, where differences were significant. Using forward sequential feature selection enabled the decreasing of the number of features from initial 110 features to about 12 features without lowering the classification performance. The results of this study have been used for developing more efficient real-time physical activity classifiers. Full article
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Open AccessArticle
Synthesis, Characterization, Antimicrobial Activity, and Genotoxicity Assessment of Two Heterocyclic Compounds Containing 1,2,3-Selena- or 1,2,3-Thiadiazole Rings
Molecules 2019, 24(22), 4082; https://doi.org/10.3390/molecules24224082 (registering DOI) - 12 Nov 2019
Abstract
New 1,2,3-thiadiazole and 1,2,3-selenadiazole derivatives, (4-[4-((4-bromobenzyl)oxy)-phenyl]-1,2,3-thiadiazole (5a), 4-[4-((4-chlorobenzyl)oxy)-phenyl]-1,2,3-thiadiazole (5b)), (4-[4-((4-bromobenzyl)oxy)-phenyl]-1,2,3-selenadiazole (6a), and 4-[4-((4-chlorobenzyl)oxy)-phenyl]-1,2,3-selenadiazole (6b)), were prepared and screened in vitro for their antimicrobial activity against various pathogenic microbes. In addition, two compounds (5a and 6a) [...] Read more.
New 1,2,3-thiadiazole and 1,2,3-selenadiazole derivatives, (4-[4-((4-bromobenzyl)oxy)-phenyl]-1,2,3-thiadiazole (5a), 4-[4-((4-chlorobenzyl)oxy)-phenyl]-1,2,3-thiadiazole (5b)), (4-[4-((4-bromobenzyl)oxy)-phenyl]-1,2,3-selenadiazole (6a), and 4-[4-((4-chlorobenzyl)oxy)-phenyl]-1,2,3-selenadiazole (6b)), were prepared and screened in vitro for their antimicrobial activity against various pathogenic microbes. In addition, two compounds (5a and 6a) were examined for their in vivo genotoxicity using rats and an 8-hydroxy-2′-deoxyguanosine (8-OHdG) assay. Compounds 5a and 5b were found to be highly active against Gram-positive and Gram-negative bacteria. In addition, a significant inhibition of urinary 8-OHdG level (50.2%) was observed upon treatment of animals with 500 mg/kg body weight (b.w.) of compound 6a (p < 0.0001). However, compound 5a increased urinary 8-OHdG levels. The lethal dose (LD50) values for compounds 5a and 6a were determined by an up-and-down procedure (OECD 425; OECD 1998), which showed that these compounds are safe, since the LD50 was >5000 mg/kg b.w. Thus, the tested compounds might have the potential for use as antibiotics, since they have low genotoxicity and strong antimicrobial activity. Full article
(This article belongs to the Special Issue Selected Papers from the Joint Symposia of MESMAP-5 & ISPBS-5)
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Open AccessArticle
Hypergraph Contextuality
Entropy 2019, 21(11), 1107; https://doi.org/10.3390/e21111107 (registering DOI) - 12 Nov 2019
Abstract
Quantum contextuality is a source of quantum computational power and a theoretical delimiter between classical and quantum structures. It has been substantiated by numerous experiments and prompted generation of state independent contextual sets, that is, sets of quantum observables capable of revealing quantum [...] Read more.
Quantum contextuality is a source of quantum computational power and a theoretical delimiter between classical and quantum structures. It has been substantiated by numerous experiments and prompted generation of state independent contextual sets, that is, sets of quantum observables capable of revealing quantum contextuality for any quantum state of a given dimension. There are two major classes of state-independent contextual sets—the Kochen-Specker ones and the operator-based ones. In this paper, we present a third, hypergraph-based class of contextual sets. Hypergraph inequalities serve as a measure of contextuality. We limit ourselves to qutrits and obtain thousands of 3-dim contextual sets. The simplest of them involves only 5 quantum observables, thus enabling a straightforward implementation. They also enable establishing new entropic contextualities. Full article
(This article belongs to the Special Issue Entropy in Foundations of Quantum Physics)
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