Sirtuin1 (SIRT1) regulates central metabolic functions such as lipogenesis, protein synthesis, gluconeogenesis, and bile acid (BA) homeostasis through deacetylation. Here we describe that SIRT1 ...tightly controls the regenerative response of the liver. We performed partial hepatectomy (PH) to transgenic mice that overexpress SIRT1 (SIRT). SIRT mice showed increased mortality, impaired hepatocyte proliferation, BA accumulation, and profuse liver injury after surgery. The damaging phenotype in SIRT mice correlated with impaired farnesoid X receptor (FXR) activity due to persistent deacetylation and lower protein expression that led to decreased FXR‐target gene expression; small heterodimer partner (SHP), bile salt export pump (BSEP), and increased Cyp7A1. Next, we show that 24‐norUrsodeoxycholic acid (NorUDCA) attenuates SIRT protein expression, increases the acetylation of FXR and neighboring histones, restores trimethylation of H3K4 and H3K9, and increases miR34a expression, thus reestablishing BA homeostasis. Consequently, NorUDCA restored liver regeneration in SIRT mice, which showed increased survival and hepatocyte proliferation. Furthermore, a leucine‐enriched diet restored mammalian target of rapamycin (mTOR) activation, acetylation of FXR and histones, leading to an overall lower BA production through SHP‐inhibition of Cyp7A1 and higher transport (BSEP) and detoxification (Sult2a1) leading to an improved liver regeneration. Finally, we found that human hepatocellular carcinoma (HCC) samples have increased presence of SIRT1, which correlated with the absence of FXR, suggesting its oncogenic potential. Conclusion: We define SIRT1 as a key regulator of the regenerative response in the liver through posttranscriptional modifications that regulate the activity of FXR, histones, and mTOR. Moreover, our data suggest that SIRT1 contributes to liver tumorigenesis through dysregulation of BA homeostasis by persistent FXR deacetylation. (Hepatology 2014;59:1972–1983)
Abnormally high spiking activity can damage neurons. Signaling systems to protect neurons from the consequences of abnormal discharge activity have been postulated. We generated conditional mutant ...mice that lack expression of the cannabinoid receptor type 1 in principal forebrain neurons but not in adjacent inhibitory intemeurons. In mutant mice, the excitotoxin kainic acid (KA) induced excessive seizures in vivo. The threshold to KA-induced neuronal excitation in vitro was severely reduced in hippocampal pyramidal neurons of mutants. KA administration rapidly raised hippocampal levels of anandamide and induced protective mechanisms in wild-type principal hippocampal neurons. These protective mechanisms could not be triggered in mutant mice. The endogenous cannabinoid system thus provides on-demand protection against acute excitotoxicity in central nervous system neurons.
The outbreak of the COVID-19 pandemic has dramatically shaped higher education and seen the distinct rise of e-learning as a compulsory element of the modern educational landscape. Accordingly, this ...study highlights the factors which have influenced how students perceive their academic performance during this emergency changeover to e-learning. The empirical analysis is performed on a sample of 10,092 higher education students from 10 countries across 4 continents during the pandemic's first wave through an online survey. A structural equation model revealed the quality of e-learning was mainly derived from service quality, the teacher's active role in the process of online education, and the overall system quality, while the students' digital competencies and online interactions with their colleagues and teachers were considered to be slightly less important factors. The impact of e-learning quality on the students' performance was strongly mediated by their satisfaction with e-learning. In general, the model gave quite consistent results across countries, gender, study fields, and levels of study. The findings provide a basis for policy recommendations to support decision-makers incorporate e-learning issues in the current and any new similar circumstances.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cystathionine γ‐lyase (CGL) is a PLP‐dependent enzyme that catalyzes the last step of the reverse transsulfuration route for endogenous cysteine biosynthesis. The canonical CGL‐catalyzed process ...consists of an α,γ‐elimination reaction that breaks down cystathionine into cysteine, α‐ketobutyrate, and ammonia. In some species, the enzyme can alternatively use cysteine as a substrate, resulting in the production of hydrogen sulfide (H2S). Importantly, inhibition of the enzyme and consequently of its H2S production activity, makes multiresistant bacteria considerably more susceptible to antibiotics. Other organisms, such as Toxoplasma gondii, the causative agent of toxoplasmosis, encode a CGL enzyme (TgCGL) that almost exclusively catalyzes the canonical process, with only minor reactivity to cysteine. Interestingly, the substitution of N360 by a serine (the equivalent amino acid residue in the human enzyme) at the active site changes the specificity of TgCGL for the catalysis of cystathionine, resulting in an enzyme that can cleave both the CγS and the CβS bond of cystathionine. Based on these findings and to deepen the molecular basis underlying the enzyme‐substrate specificity, we have elucidated the crystal structures of native TgCGL and the variant TgCGL‐N360S from crystals grown in the presence of cystathionine, cysteine, and the inhibitor d,l‐propargylglycine (PPG). Our structures reveal the binding mode of each molecule within the catalytic cavity and help explain the inhibitory behavior of cysteine and PPG. A specific inhibitory mechanism of TgCGL by PPG is proposed.
PDB Code(s): 7NL1;8BIS;8BIU;8BIV;8BIW;8BIX;8BIZ
The microneedles technology has found applications in many health-related fields. For example, their application in drugs and vaccines delivery as well, as the determination of biomarkers, has been ...reported. They also have a place in the dermatology and cosmetic areas such as the treatment of wounds from burns, scars, acne, depigmentation, and alopecia will be shown. Microneedles are used in therapeutic applications and are manufactured using materials such as metal (steel, titanium, nickel), polymer (oly-glycolic acid (PGA), poly-lactide-co-glycolide acid (PLGA), poly-L-lactic acid (PLA), chitosan), glass, silicon, ceramic, carbohydrates (trehalose, sucrose, mannitol). Examples of application of microneedles and their advantages and disadvantages are discussed. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
The precise effects of HIV-1 on the gut microbiome are unclear. Initial cross-sectional studies provided contradictory associations between microbial richness and HIV serostatus and suggested shifts ...from Bacteroides to Prevotella predominance following HIV-1 infection, which have not been found in animal models or in studies matched for HIV-1 transmission groups. In two independent cohorts of HIV-1-infected subjects and HIV-1-negative controls in Barcelona (n=156) and Stockholm (n=84), men who have sex with men (MSM) predominantly belonged to the Prevotella-rich enterotype whereas most non-MSM subjects were enriched in Bacteroides, independently of HIV-1 status, and with only a limited contribution of diet effects. Moreover, MSM had a significantly richer and more diverse fecal microbiota than non-MSM individuals. After stratifying for sexual orientation, there was no solid evidence of an HIV-specific dysbiosis. However, HIV-1 infection remained consistently associated with reduced bacterial richness, the lowest bacterial richness being observed in subjects with a virological-immune discordant response to antiretroviral therapy. Our findings indicate that HIV gut microbiome studies must control for HIV risk factors and suggest interventions on gut bacterial richness as possible novel avenues to improve HIV-1-associated immune dysfunction.
•The fecal microbiota of gay men in Europe is systematically richer and has a distinct composition.•HIV-1 infection is independently associated with reduced gut bacterial richness, more so in immune discordant subjects.•Interventions to increase gut bacterial richness might offer novel avenues to improve HIV-1-associated immune dysfunction.
The human intestinal microbiota is essential for human health and well-being and is driven by genetic, lifestyle and environmental factors. Here, we show in two independent cohorts of HIV-1-infected subjects and HIV-1-negative controls in Europe that gay men often have a distinct composition of the human fecal microbiota, with increased microbial richness and diversity and enrichment in the Prevotella enterotype. This is independent of HIV-1 status, and with only a limited contribution of diet effects. After accounting for sexual orientation, however, HIV-1 infection remains associated to reduced bacterial richness, more so in subjects with suboptimal CD4+ T-cell count recovery under antiretroviral therapy. Future studies should evaluate if interventions to increase gut bacterial richness could improve HIV-associated immune dysfunction.
Understanding processes controlling stream nutrient dynamics over time is crucial for implementing effective management strategies to prevent water quality degradation. In this respect, the study of ...the nutrient concentration–discharge (C–Q) relationship during individual runoff events can be a valuable tool for extrapolating the hydrochemical processes controlling nutrient fluxes in streams. This study investigated nitrogen concentration dynamics during events by analyzing and interpreting the nitrogen C–Q relationship in a small Atlantic (NW Iberian Peninsula) rural catchment. To this end, nitrate (NO3-N) and total Kjeldahl nitrogen (TKN) concentrations were monitored at a high temporal resolution during 102 runoff events over a 6-year period. For each of the selected runoff events, C–Q response was examined visually for the presence and direction of hysteresis loops and classified into three types of responses, namely clockwise, counterclockwise, and no hysteresis. Changes in concentration
(ΔC) and the hysteresis direction (ΔR) were used to quantify nitrogen (NO3- and TKN) patterns during the runoff events. The transport mechanisms varied between compounds. The most frequent hysteretic response for NO3- was counterclockwise with enrichment. On the contrary, the main TKN dynamic was enrichment with clockwise hysteresis. Event characteristics, such as rainfall amount, peak discharge (i.e., maximum discharge of the runoff event), and event magnitude relative to the initial baseflow (i.e., the difference between the maximum discharge of the runoff event and the initial baseflow divided by initial baseflow) provided a better explanation for hysteresis direction and magnitude for TKN than antecedent conditions (antecedent precipitation and baseflow at the beginning of the event). For NO3- hysteresis, the role of hydrometeorological conditions was more complex. The NO3- hysteresis magnitude was related to the magnitude of the event relative to the initial baseflow and the time elapsed since a preceding runoff event. These findings could be used as a reference for the development of N mitigation strategy in the region.
Ovarian cancer(OC) is a serious threat to women worldwide. Peritoneal dissemination, ascites and omental metastasis are typical features for disease progression, which occurs in a micro-environment ...that is rich in high-energy lipids. OC cells require high amounts of lipids for survival and growth. Not only do they import lipids from the host, they also produce lipids
. Inhibitors of fatty acid(FA) synthase(FASN) - the rate-limiting enzyme of endogenous FA synthesis that is overexpressed in OC - induce growth-arrest and apoptosis, rendering them promising candidates for cancer drug development. However, cancer researchers have long hypothesized that the lipid deficiency caused by FASN inhibition can be circumvented by increasing the uptake of exogenous lipids from the host, which would confer resistance to FASN inhibitors. In contrast to a very recent report in colorectal cancer, we demonstrate in OC cells (A2780, OVCAR3, SKOV3) that neither FASN inhibitors (G28UCM, Fasnall) nor FASN-specific siRNAs can stimulate a relief pathway leading to enhanced uptake of extrinsic FAs or low density lipoproteins (LDLs). Instead, we observed that the growth-arrest due to FASN inhibition or FASN knock-down was associated with significant dose- and time-dependent reduction in the uptake of fluorescently labeled FAs and LDLs. Western blotting showed that the expression of the FA receptor CD36, the LDL receptor(LDLR) and the lipid transport proteins fatty acid binding proteins 1-9 (FABP1-9) was not affected by the treatment. Next, we compared experimental blockade of endogenous lipid production with physiologic depletion of exogenous lipids. Lipid-free media, similar to FASN inhibitors, caused growth-arrest. Although lipid-depleted cells have diminished amounts of CD36, LDLR and FABPs, they can still activate a restorative pathway that causes enhanced import of fluorophore-labeled FAs and LDLs. Overall, our data show that OC cells are strictly lipid-depend and exquisitely sensitive to FASN inhibitors, providing a strong rationale for developing anti-FASN strategies for clinical use against OC.
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•PCL-based sensors were developed by a new environmentally friendly approach.•Proper electrical conductivity was achieved by coating with PEDOT:PSS.•The gas dissolution foaming ...approach proved to improve the sensoring performance.•The foaming process allows an enhanced distribution of PEDOT:PSS within the fibers.•Optimized sensors with a reproducible and stable response were achieved.
A new procedure to enhance the performance of polymer-based electrochemical sensors is proposed in this work. Polycaprolactone (PCL) electrospun fiber mats with tunable fiber morphology are functionalized with a conductive polymer (PEDOT:PSS) by a facile dip-coting process, providing them the necessary electrical conductivity to work as sensors. The modification of the fiber morphology is achieved by an enhanced gas dissolution foaming procedure, an environmentally friendly procedure that employs CO2 as blowing agent and takes advantage of recent advances that allowed extending such procedure to polymeric microfibers. Thus, the enhanced gas dissolution foaming approach was employed both before and after the coating of the fiber mats with PEDOT:PSS, producing in both cases hollow fibers with enhanced surface porosity and area, as well as increased diameter regarding the initial solid PCL fibers. The addition of PEDOT:PSS, both in solid and foamed PCL fibers, allows their use as sensors, as proved by cyclic voltammetry in a KCl solution, as well as calibrated with catechol solutions. Remarkable influence of the foaming procedure on the performance of the sensors have been found, proving by a detailed characterization that the foaming procedure applied after the PEDOT:PSS coating provides an enhanced sensoring response (i.e., increased signal, optimal linearity, decreased LOD) due to their superior surface area and optimal PEDOT:PSS distribution along the fiber mats, not only covering the external surface of the fibers but infusing into the inner regions.
In this work, we report the synthesis of Cu, Pt and Pd doped SnO₂ powders and a comparative study of their CO gas sensing performance. Dopants were incorporated into SnO₂ nanostructures using ...chemical and impregnation methods by using urea and ammonia as precipitation agents. The synthesized samples were characterized using X-ray diffraction (XRD), Raman spectroscopy, scanning electron microscopy (SEM) and high resolution transmission electron microscopy (HR-TEM). The presence of dopants within the SnO₂ nanostructures was evidenced from the HR-TEM results. Powders doped utilizing chemical methods with urea as precipitation agent presented higher sensing responses compared to the other forms, which is due to the formation of uniform and homogeneous particles resulting from the temperature-assisted synthesis. The particle sizes of doped SnO₂ nanostructures were in the range of 40-100 nm. An enhanced sensing response around 1783 was achieved with Cu-doped SnO₂ when compared with two other dopants i.e., Pt (1200) and Pd:SnO₂ (502). The high sensing response of Cu:SnO₂ is due to formation of CuO and its excellent association and dissociation with adsorbed atmospheric oxygen in the presence of CO at the sensor operation temperature, which results in high conductance. Cu:SnO₂ may thus be an alternative and cost effective sensor for industrial applications.
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