Systemic inflammation, circulating immune cell activation, and endothelial cell damage play a critical role in vascular pathogenesis. Flavonoids have shown anti-inflammatory effects. In this study, we investigated the effects of different flavonoids on the production of pro-inflammatory interleukin (IL) 1β, 6, and 8, and tumor necrosis factor α (TNF-α), in peripheral blood cells. Methods: We studied the whole blood from 36 healthy donors. Lipopolysaccharide (LPS)-stimulated (0.5 μg/mL) whole-blood aliquots were incubated in the presence or absence of different concentrations of quercetin, rutin, naringenin, naringin, diosmetin, and diosmin for 6 h. Cultures were centrifuged and the supernatant was collected in order to measure IL-1β, TNF-α, IL-6, and IL-8 production using specific immunoassay techniques. This production was significantly inhibited by quercetin, naringenin, naringin, and diosmetin, but in no case by rutin or diosmin. Flavonoids exert different effects, maybe due to the differences between aglycons and glucosides present in their chemical structures. However, these studies suggest that quercetin, naringenin, naringin, and diosmetin could have a potential therapeutic effect in the inflammatory process of cardiovascular disease. Full article

We used the weighted wavelet method to perform spectral analysis of observed long-term precipitation, streamflow, actual evapotranspiration, and soil water storage at a sub-humid mountain catchment near Tucson, Arizona, USA. Fractal scaling in precipitation and the daily change in soil water storage occurred up to a period of 14 days and corresponded to the typical duration of relatively wet and dry intervals. In contrast, fractal scaling could be observed up to a period of 0.5 years in streamflow and actual evapotranspiration. By considering long-term observations of hydrologic fluxes and storages, we show that, in contrast to previous findings, the phase relationships between water balance components changed with component period and were not perfectly in or out of phase at all periods. Self-averaging behavior was apparent, but the temporal scales over which this behavior was applicable differed among the various water balance components. Conservative tracer analysis showed that this catchment acted as a fractal filter by transforming white noise in the precipitation input signal to a 1/f flicker in the streamflow output signal by means of both spatial and temporal subsurface advection and dispersion processes and soil wetting properties. This study provides an improved understanding of hydrological filtering behavior in mountain critical zones that are critical sources of water and ecosystem services throughout the world. Full article

Green development is an inevitable requirement to build a modern economic system and fundamental solution to pollution problems. Exploring the relationship between environmental regulation and enterprise total factor productivity (TFP) has great significance for realizing the win-win goal of achieving both environmental protection and economic development. Based on a firm-level dataset from 2000-2007, this paper explores the economic effects of the Environmental Target Assessment Policy of Huai River Basin (ETAP, HRB) in 2004, an environmental regulation that clarifies the responsibility of local governments, by identifying changes in the TFP of the clothing industry (CMI). The empirical findings support that the ETAP can significantly promote improvement in the TFP using the difference in differences (DID) method. Robustness tests, such as the triple differences (DDD) and propensity score matching-difference in differences (PSM-DID), are used to address concerns about the DID approach. Analysis of dynamic effects shows that the ETAP has no impact on enterprise TFP in 2004 but significantly improve the TFP on the next three years (2005-2007). The heterogeneity test results indicate that nonstate-owned enterprises are more sensitive to the ETAP, and the coefficient of the average treatment effect is 0.033. In addition, the ETAP has no noteworthy impact on large- and medium-scale enterprises but results in an average increase of 0.037 in small-scale enterprises’ TFP. Full article

The debate on overtourism still lacks conceptual precision in its delineation of the constituent elements and processes. In particular, conflict theory is rarely adopted, even though the social conflict is inscribed into the nature of this phenomenon. This article aims to frame the discussion about (over)tourism within the perspective of social conflict theory by adopting the conflict deconstructing methods in order to diagnose the constructs and intensity of disputes associated with overtourism. In pursuit of this aim, the study addresses the following two research questions: (1) To what extent has the heuristic power of the conflict theory been used in overtourism discourse? and (2) How can overtourism be measured by the nature of the social conflicts referring to urban tourism development? The systematic literature review was conducted to analyze research developments on social conflicts within the overtourism discourse. In the empirical section (the case studies of the Polish cities, Krakow and Poznan), we deconstruct the social conflicts into five functional causes (i.e., values, relationship, data, structural, and interests) to diagnose the nature of the conflicts with respect to urban tourism development. This study shows that value conflicts impact most intensively on the nature and dynamics of the conflicts related to overtourism. Full article

This paper addresses the problem of the optimal location and sizing of photovoltaic (PV) sources in direct current (DC) electrical networks considering time-varying load and renewable generation curves. To represent this problem, a mixed-integer nonlinear programming (MINLP) model is developed. The main idea of including PV sources in the DC grid is minimizing the total greenhouse emissions produced by diesel generators in isolated areas. An artificial neural network is employed for short-term forecasting to deal with uncertainties in the PV power generation. The general algebraic modeling system (GAMS) package is employed to solve the MINLP model by using the CONOPT solver that works with mixed and integer variables. Numerical results demonstrate important reductions of harmful gas emissions to the atmosphere when PV sources are optimally integrated (size and location) to the DC grid. Full article

Evidence has shown for over 20 years that patients residing in rural areas face poorer outcomes for cancer. The inequalities in survival that rural cancer patients face are observed throughout the developed world, yet this issue remains under-examined and unexplained. There is evidence to suggest that rural patients are more likely to be diagnosed as a result of an emergency presentation and that rural patients may take longer to seek help for symptoms. However, research to date has been predominantly epidemiological, providing us with an understanding of what is occurring in these populations, yet failing to explain why. In this paper we outline the problems inherent in current research approaches to rural cancer inequalities, namely how ‘cancer symptoms’ are conceived of and examined, and the propensity towards a reductionist approach to rural environments and populations, which fails to account for their heterogeneity. We advocate for a revised rural cancer inequalities research agenda, built upon in-depth, community-based examinations of rural patients’ experiences across the cancer pathway, which takes into account both the micro and macro factors which exert influence on these experiences, in order to develop meaningful interventions to improve cancer outcomes for rural populations. Full article

Protein import across the endoplasmic reticulum membrane is physiologically regulated in a substrate-selective manner to ensure the protection of stressed ER from the overload of misfolded proteins. However, it is poorly understood how different types of substrates are accurately distinguished and disqualified during translocational regulation. In this study, we found poorly assembled translocon-associated protein (TRAP) complexes in stressed ER. Immunoaffinity purification identified calnexin in the TRAP complex in which poor assembly inhibited membrane insertion of the prion protein (PrP) in a transmembrane sequence-selective manner, through translocational regulation. This reaction was induced selectively by redox perturbation, rather than calcium depletion, in the ER. The liberation of ERp57 from calnexin appeared to be the reason for the redox sensitivity. Stress-independent disruption of the TRAP complex prevented a pathogenic transmembrane form of PrP (ctmPrP) from accumulating in the ER. This study uncovered a previously unappreciated role for calnexin in assisting the redox-sensitive function of the TRAP complex and provided insights into the ER stress-induced reassembly of translocon auxiliary components as a key mechanism by which protein translocation acquires substrate selectivity. Full article

The role of circulating plasma cells (CPCs) and circulating leukemic cells (CLCs) as biomarkers for several blood cancers, such as multiple myeloma and leukemia, respectively, have recently been reported. These markers can be attractive due to the minimally invasive nature of their acquisition through a blood draw (i.e., liquid biopsy), negating the need for painful bone marrow biopsies. CPCs or CLCs can be used for cellular/molecular analyses as well, such as immunophenotyping or fluorescence in situ hybridization (FISH). FISH, which is typically carried out on slides involving complex workflows, becomes problematic when operating on CLCs or CPCs due to their relatively modest numbers. Here, we present a microfluidic device for characterizing CPCs and CLCs using immunofluorescence or FISH that have been enriched from peripheral blood using a different microfluidic device. The microfluidic possessed an array of cross-channels (2-4 µm in depth and width) that interconnected a series of input and output fluidic channels. Placing a cover plate over the device formed microtraps, the size of which was defined by the width and depth of the cross-channels. This microfluidic chip allowed for automation of immunofluorescence and FISH, requiring the use of small volumes of reagents, such as antibodies and probes, as compared to slide-based immunophenotyping and FISH. In addition, the device could secure FISH results in <4 h compared to 2–3 days for conventional FISH. Full article

Targeted therapies of various diseases are nowadays widely studied in many biomedical fields. Photodynamic therapy (PDT) represents a modern treatment of cancer using a locally activated light. TMPyP is an efficient synthetic water-soluble photosensitizer (PS), yet with poor absorption in the visible and the red regions. In this work, we prepared size-selected and colloidally stable graphene oxide (GO) that is appropriate for biomedical use. Thanks to the negative surface charge of GO, TMPyP was easily linked in order to create conjugates of GO/TMPyP by electrostatic force. Due to the strong ionic interactions, charge transfers between GO and TMPyP occur, as comprehensively investigated by steady-state and time-resolved fluorescence spectroscopy. Biocompatibility and an in vitro effect of GO/TMPyP were confirmed by a battery of in vitro tests including MTT, comet assay, reactive oxygen species (ROS) production, and monitoring the cellular uptake. PDT efficiency of GO/TMPyP was tested using 414 and 740 nm photoexcitation. Our newly prepared nanotherapeutics showed a higher PDT effect than in free TMPyP, and is promising for targeted therapy using clinically favorable conditions. Full article

The influence of sea ice on the hydrodynamics, sediment resuspension, and suspended sediment concentration (SSC) in the coastal area of Qinhuangdao was systematically investigated using 45-day in situ measurements at two stations (with ice at station M1 and without ice at station M2) in the Bohai Sea in the winter of 2018. It was found that the daily fluctuations of temperature and salinity at M1 are more significant than those at M2. During a typical seawater icing event on January 28, the temperature and salinity of the bottom water at M1 were decreased by 1.77 °C and increased by 0.4 psu, respectively. Moreover, due to the shielding effect of the sea ice, the residual current was much less affected by the wind at M1 than at M2. For the vertical distribution of current velocity, it changed from a traditional logarithmic type under ice-free conditions to parabolic type under ice-covered conditions due to the larger drag coefficient of the water body on the solid ice surface. For the SSC and turbidity at the bottom layer, the average values were 4.9 μL/L and 8.6 NTU at M1, respectively, approximately half of those at M2. The smaller SSC and turbidity at M1 can be attributed to the lower near-bottom turbulent kinetic energy (TKE). At M2, however, the larger SSC is closely related to the strong wind forcing, which could induce higher TKE without sea ice cover, and hence stronger turbulent resuspension. The seabed sediment analysis results showed that in the study area, fine sand is most likely to resuspend, while cohesive particles would resuspend only under strong hydrodynamic conditions. Full article

Disruption of epithelial junctional complex (EJC), especially tight junctions (TJ), resulting in increased intestinal permeability, is supposed to activate the enhanced immune response to gluten and to induce the development of celiac disease (CD). This study is aimed to present the role of EJC in CD pathogenesis. To analyze differentially expressed genes the next-generation mRNA sequencing data from CD326+ epithelial cells isolated from non-celiac and celiac patients were involved. Ultrastructural studies with morphometry of EJC were done in potential CD, newly recognized active CD, and non-celiac controls. The transcriptional analysis suggested disturbances of epithelium and the most significant gene ontology enriched terms in epithelial cells from CD patients related to the plasma membrane, extracellular exome, extracellular region, and extracellular space. Ultrastructural analyses showed significantly tighter TJ, anomalies in desmosomes, dilatations of intercellular space, and shorter microvilli in potential and active CD compared to controls. Enterocytes of fetal-like type and significantly wider adherence junctions were observed only in active CD. In conclusion, the results do not support the hypothesis that an increased passage of gluten peptides by unsealing TJ precedes CD development. However, increased intestinal permeability due to abnormality of epithelium might play a role in CD onset. Full article

The efficacy of cisplatin-based chemotherapy in ovarian cancer is often limited by the development of drug resistance. In most ovarian cancer cells, cisplatin activates extracellular signal-regulated kinase1/2 (ERK1/2) signalling. Phosphoprotein enriched in astrocytes (PEA-15) is a ubiquitously expressed protein, capable of sequestering ERK1/2 in the cytoplasm and inhibiting cell proliferation. This and other functions of PEA-15 are regulated by its phosphorylation status. In this study, the relevance of PEA-15 phosphorylation state for cisplatin sensitivity of ovarian carcinoma cells was examined. The results of MTT-assays indicated that overexpression of PEA-15AA (a non-phosphorylatable variant) sensitised SKOV-3 cells to cisplatin. Phosphomimetic PEA-15DD did not affect cell sensitivity to the drug. While PEA-15DD facilitates nuclear translocation of activated ERK1/2, PEA-15AA acts to sequester the kinase in the cytoplasm as shown by Western blot. Microarray data indicated deregulation of thirteen genes in PEA-15AA-transfected cells compared to non-transfected or PEA-15DD-transfected variants. Data derived from The Cancer Genome Atlas (TCGA) showed that the expression of seven of these genes including EGR1 (early growth response protein 1) and FLNA (filamin A) significantly correlated with the therapy outcome in cisplatin-treated cancer patients. Further analysis indicated the relevance of nuclear factor erythroid 2related factor 2/antioxidant response element (Nrf2/ARE) signalling for the favourable effect of PEA-15AA on cisplatin sensitivity. The results warrant further evaluation of the PEA-15 phosphorylation status as a potential candidate biomarker of response to cisplatin-based chemotherapy. Full article

Candida albicans is a fungus that is a commensal organism and a member of the normal human microbiota. It has the ability to transition into an opportunistic invasive pathogen. Attributes that support pathogenesis include secretion of virulence-associated proteins, hyphal formation, and biofilm formation. These processes are supported by secretion, as defined in the broad context of membrane trafficking. In this review, we examine the role of secretory pathways in Candida virulence, with a focus on the model opportunistic fungal pathogen, Candida albicans. Full article

New Vinca alkaloid derivatives were synthesized to improve the biological activity of the natural alkaloid vindoline. To this end, experiments were performed to link vindoline with various structural units, such as amino acids, a 1,2,3-triazole derivative, morpholine, piperazine and N-methylpiperazine. The structure of the new compounds was characterized by NMR spectroscopy and mass spectrometry (MS). Several compounds exhibited in vitro antiproliferative activity against human gynecological cancer cell lines with IC₅₀ values in the low micromolar concentration range. Full article

Previous research on bank deregulation has supported the idea that interstate banking deregulation lowered the cost of credit and increased the net farm income. This analysis builds on that base by investigating whether the agricultural loan delinquency volume was also affected. Using a panel data fixed effects approach, deregulation was found to be associated with changes in the volume of delinquencies: interstate banking deregulation reduced the volume of production loan delinquencies, and de novo branching deregulation increased both production and real-estate loan delinquencies. Thus, deregulation’s outcome is not clear cut: interstate banking reduced farm financial stress but de novo deregulation increased it. Full article