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Background: Vitamin D deficiency (VDD) may be considered an independent cardiovascular (CV) risk factor, and it is well known that CV risk is higher in males. Our goal was to investigate the pharmacological reactivity and receptor expression of intramural coronary artery segments of male rats in cases of different vitamin D supply. Methods: Four-week-old male Wistar rats were divided into a control group (n = 11) with optimal vitamin D supply (300 IU/kgbw/day) and a VDD group (n = 11, &lt, 0.5 IU/kgbw/day). After 8 weeks of treatment, intramural coronary artery segments were microprepared, their pharmacological reactivity was examined by in vitro microangiometry, and their receptor expression was investigated by immunohistochemistry. Results: Thromboxane A2 (TXA2)-agonist induced reduced vasoconstriction, testosterone (T) and 17-β-estradiol (E2) relaxations were significantly decreased, a significant decrease in thromboxane receptor (TP) expression was shown, and the reduction in estrogen receptor-α (ERα) expression was on the border of significance in the VDD group. Conclusions: VD-deficient male coronary arteries showed deteriorated pharmacological reactivity to TXA2 and sexual steroids (E2, T). Insufficient vasoconstrictor capacity was accompanied by decreased TP receptor expression, and vasodilator impairments were mainly functional. The decrease in vasoconstrictor and vasodilator responses results in narrowed adaptational range of coronaries, causing inadequate coronary perfusion that might contribute to the increased CV risk in VDD.

Activation of the parasympathetic nervous system has been reported to have an antiarrhythmic role during ischemia–reperfusion injury by decreasing the arrhythmia triggers. Furthermore, it was reported that the parasympathetic neurotransmitter acetylcholine is able to modulate the ATP-dependent potassium current (I K-ATP), a crucial current activated during hypoxia. However, the possible significance of this current modulation in the antiarrhythmic mechanism is not fully clarified. Action potentials were measured using the conventional microelectrode technique from canine left ventricular papillary muscle and free-running Purkinje fibers, under normal and hypoxic conditions. Ionic currents were measured using the whole-cell configuration of the patch-clamp method. Acetylcholine at 5 μmol/L did not influence the action potential duration (APD) either in Purkinje fibers or in papillary muscle preparations. In contrast, it significantly lengthened the APD and suppressed the Purkinje–ventricle APD dispersion when it was administered after 5 μmol/L pinacidil application. Carbachol at 3 μmol/L reduced the pinacidil-activated I K-ATP under voltage-clamp conditions. Acetylcholine lengthened the ventricular action potential under simulated ischemia condition. In this study, we found that acetylcholine inhibits the I K-ATP and thus suppresses the ventricle–Purkinje APD dispersion. We conclude that parasympathetic tone may reduce the arrhythmogenic substrate exerting a complex antiarrhythmic mechanism during hypoxic conditions.

Ibuprofen is a widely used nonsteroidal anti-inflammatory drug, which has recently been associated with increased cardiovascular risk, but its electrophysiological effects have not yet been properly studied in isolated cardiac preparations. We studied the effects of ibuprofen on action potential characteristics and several transmembrane ionic currents using the conventional microelectrode technique and the whole-cell configuration of the patch-clamp technique on cardiac preparations and enzymatically isolated ventricular myocytes. In dog (200 µM; n = 6) and rabbit (100 µM; n = 7) papillary muscles, ibuprofen moderately but significantly prolonged repolarization at 1 Hz stimulation frequency. In dog Purkinje fibers, repolarization was abbreviated and maximal rate of depolarization was depressed in a frequency-dependent manner. Levofloxacin (40 µM) alone did not alter repolarization, but augmented the ibuprofen-evoked repolarization lengthening in rabbit preparations (n = 7). In dog myocytes, ibuprofen (250 µM) did not significantly influence IK1, but decreased the amplitude of Ito and IKr potassium currents by 28.2% (60 mV) and 15.2% (20 mV), respectively. Ibuprofen also depressed INaL and ICa currents by 19.9% and 16.4%, respectively. We conclude that ibuprofen seems to be free from effects on action potential parameters at lower concentrations. However, at higher concentrations it may alter repolarization reserve, contributing to the observed proarrhythmic risk in patients.

Transition-metal-catalyzed cross-coupling of organo­halides, ethers, sulfides, amines, and alcohols (and derivatives thereof) with Grignard reagents, known as the Kumada–Tamao–Corriu reaction, can be used to prepare important intermediates in the synthesis of numerous­ biologically active compounds. The most frequently used transition metals are nickel, palladium, and iron, but there are several examples for cross-coupling reactions catalyzed by copper, cobalt, manganese, chromium, etc. salts and complexes. The aim of this review is to summarize the most important transition-metal-catalyzed cross-coupling reactions realized in the period 2000 to 2020.1 Introduction2 Nickel Catalysis3 Palladium Catalysis4 Iron Catalysis5 Catalysis by Other Transition Metals5.1 Cobalt Catalysis5.2 Copper Catalysis5.3 Manganese Catalysis5.4 Chromium Catalysis6 Conclusion

This work considers dust deposition and the heavy metal (HM) content on leaves of urban trees (Acer platanoides L. ‘Globosum,’ Fraxinus excelsior L. ‘Westhof’s Glorie’ and Tilia tomentosa Moench.) in order to estimate the trees’ capacity to remove dust and HM from the air. Leaves were collected from the Buda Arboretum and from different streets of heavy traffic in Budapest, Hungary, during 2015 and 2016. At each site, five trees were sampled by collecting 6 leaves from each tree from the height of 2–3 m. Dust deposits on the leaves were removed by soaking the fresh foliage in distilled water for 20 h and then washed with ultrasound shaking. Afterward, the leaves were dried to constant weight and then they were digested in nitric acid–hydrogen peroxide treatment, and their Pb, Fe, Ni, Zn and Cu contents were measured using an inductively coupled plasma (ICP AS) spectrometer. The removed dust deposit was dried, and after a similar digestion treatment the Pb, Fe, Ni, Zn and Cu contents were measured using an AURORA AI 1200 AAS appliance. The HM deposit was calculated in mg m–2 leaf surface area. In 2015, the amount of foliar dust deposit from spring to autumn increased from 86.3 to 270.2 mg m–2. The most efficient tree species in trapping dust on their leaves was the silver linden (98.5–123.5 mg m−2), followed by the Norway maple (74.2–84.8 mg m−2) and the common ash (62.8–74.6 mg m−2). The deposit of HM elements showed seasonal differences: the quantity of Fe and Pb deposit on autumnal leaves increased five- to tenfold, while other heavy metals did not show accumulation. Silver linden with its pubescent (hairy) leaf surface proved to be most efficient in entrapping and retaining dust and heavy metals. The 60–100% higher Pb and Fe content of autumnal leaves indicate that over the season leaves may absorb Fe and Pb from the foliar dust. Our results confirmed that the foliar dust is a potential indicator for monitoring the HM content in the air. We also show that foliar dust deposits should be considered when estimating the capacity of urban trees to clean the air.

In the last two decades, considerable attention has been devoted to the use of 4Å molecular sieves (MS 4A) in organic chemical syntheses. Initially, they were applied as drying agents in order to dry gases, solvents and liquid reagents. Nowadays, there is a growing tendency to apply MS 4A as an additive, catalyst, co-catalyst or catalyst support in organic reactions. In this review, we aim to summarize the recent examples of organic syntheses promoted by MS 4A from 1997 to 2020. We hope to provide the reader with an overview of the potential of MS 4A in the field of organic synthesis.1 Introduction2 Application as an Additive3 Application as Catalyst4 Application as Co-catalyst5 Application as Support6 Conclusion

Medium chain fatty acids are candidates of partial sulphur dioxide replacement in wine, as a solution to the growing consumer concerns about chemical additives. In botrytised sweet wine specialties, large amount of sulphur dioxide addition is one of the effective practices to stop alcoholic fermentation. Increasing medium chain fatty acid levels up to 80 mg l-1 was tested as a sole inhibitor on solid agar surface. S. bacillaris seemed to be the most sensitive, S. cerevsisiae and S. bayanus were more tolerant, while Z. bailii showed the highest tolerance. Then, increasing medium chain fatty acid levels up to 40 mg l-1 combined with 100 mg l-1 sulphur dioxide was introduced into a Tokaj Essence under refermentation. After 56 days, the highest dosage had pronounced effect on the yeast population, but the refermentation was not inhibited completely. Medium chain fatty acids have varying inhibitory effect on botrytised wine-related yeasts, moreover, it could be used effectively in media with high ethanol content, unlike Tokaj Essence.

Intercellular gap junction (GJ) contacts formed by the coupling of connexin (Cx) hemichannels (HCs) embedded into the plasma membranes of neighboring cells play significant role in the development, signaling and malfunctions of mammalian tissues. Understanding and targeting GJ functions, however, calls for finding valid Cx subtype-specific inhibitors. We conjecture the lack of information about binding interactions between the GJ interface forming extracellular EL1 and EL2 loops and peptide mimetics designed to specifically inhibit Cx43HC coupling to Cx43GJ. Here, we explore active spots at the GJ interface using known peptide inhibitors that mimic various segments of EL1 and EL2. Binding interactions of these peptide inhibitors and the non-peptide inhibitor quinine has been modelled in combination with the use of blind docking molecular mechanics (MM). The neuron-specific Cx36HC and astrocyte-specific Cx43HC subtypes were modelled with a template derived from the high-resolution structure of Cx26GJ. GJ-coupled and free Cx36HC and Cx43HC models were obtained by dissection of GJs (GJ-coupled) followed by 50 ns molecular dynamics (free). Molecular mechanics (MM) calculations were performed by the docking of inhibitors, explicitly the designed Cx43 EL1 or EL2 loop sequence mimetics (GAP26, P5 or P180–195, GAP27, Peptide5, respectively) and the Cx36 subtype-specific quinine into the model structures. In order to explore specific binding interactions between inhibitors and CxHC subtypes, MM/Generalized Born Surface Area (MM/GBSA) ΔGbind values for representative conformers of peptide mimetics and quinine were evaluated by mapping the binding surface of Cx36HC and Cx43HC for all inhibitors. Quinine specifically contacts Cx36 EL1 residues V54-C55-N56-T57-L58, P60 and N63. Blocking the vestibule by the side of Cx36HC entry, quinine explicitly interacts with the non-conserved V54, L58, N63 residues of Cx36 EL1. In addition, our work challenges the predicted specificity of peptide mimetics, showing that the docking site of peptides is unrelated to the location of the sequence they mimic. Binding features, such as unaffected EL2 residues and the lack of Cx43 subtype-specificity of peptide mimetics, suggest critical roles for peptide stringency and dimension, possibly pertaining to the Cx subtype-specificity of peptide inhibitors.

Eleven samples of registered wheat varieties of bread with diverse technological qualities were used in this study. The samples were devided into two groups. The first group including all the 11 variety were stored for 3 months, while the second group of the samples were stored for 9 months at an ambient temperature. The results of quality evaluation showed that 5 soft wheat varieties (GK Csongrád, GK Garaboly, GK Hattyú, GK Holló, GK Nap) and 6 hard wheat varieties (GK Ati, GK Békés, GK Élet, GK Kalász, GK Petúr, GK Verecke) were involved in the study. Further, the flour yield, the gluten index and the water absorbance capacity has significantly decreased after 9 months storage time when compared to 3 months storage interval.

The present study was conducted to determine the effect of basic agrotechnical factors on the yield and quality of winter wheat. Two experiments were set in 2017/2018 growing season, where we studied the influence of different forecrops, fertilizing treatments and cultivars. 204 samples were measured with Single Kernel Characterization System and NIR grain analyser to determine protein (NIR-P), wet gluten (NIR-WG), Hardness Index (HI), kernel weight (KW) and kernel diameter (KD). Fertilizing had a significant effect on yield, KW, HI, NIR-P and NIR-WG, except KD. N90PK dosage was enough to realize yield potential for 6 out of 9 cultivars, but considering protein content N150PK dosage was needed. The forecrop had no significant influence on yield, KW, KD or HI, however sweet corn as previous crop had significant improving effect on NIR-P and NIR-WG compared to sunflower as forecrop. According to our data of correlation analysis, no negative relationship was found between yield and NIR-P, however HI was in medium positive correlation with NIR-P. The variety Vyckor had the highest yield, but in quality aspect, the highest NIR-P and NIR-WG values belonged to KG Kunhalom variety.

Starmerella bacillaris (synonym Candida zemplinina) is an important non-Saccharomyces yeast in winemaking with valuable oenological properties, accompanying Saccharomyces species in sweet wine fermentation, and has also been suggested for application as combined starter culture in dry or sweet wines. In this study, the major metabolites and nitrogen utilization of these yeasts are evaluated in the musts with high or extremely high sugar concentration. The change in the metabolic footprint of Saccharomyces cerevisiae, Saccharomyces uvarum and Starmerella bacillaris strains was compared when they were present as pure cultures in chemically defined grape juice medium with 220 and 320 g/L of sugar, to represent a fully matured and an overripe grape. Surprisingly, the extreme sugar concentration did not result in a considerable change in the rate of sugar consumption; only a shift of the sugar consumption curves could be noticed for all species, especially for Starmerella bacillaris. At the extreme sugar concentration, Starmerella bacillaris showed excellent glycerol production, moderate nitrogen demand together with a noticeable proline utilisation. The change in the overall metabolite pattern of Starmerella bacillaris allowed clear discrimination from the change of the Saccharomyces species. In this experiment, the adequacy of this non-Saccharomyces yeast for co-fermentation in juices with high sugar concentration is highlighted. Moreover, the results suggest that Starmerella bacillaris has a more active adaptation mechanism to extremely high sugar concentration.

The migration of various plastic additives (antioxidants: BHT, Ionox 220, Irgafos 168; UV absorber: Uvinul 3039; plasticizers: TBAC and TOTM) from polypropylene and polylactic acid was investigated in a series of experiments conducted over a period of 13 days. As fatty food simulants, both ethanol 95 v/v% and isooctane were used. Non-Fickian behaviour was observed on multiple occasions. The kinetic curves of both migration concentrations and swelling were evaluated using variography, to determine objectively the starting points of long-lasting plateaus as well as short halts in the increase. A strong correlation between migration and swelling was observed: the kinetic curves showed that migration always followed swelling. Also, more intensive swelling results in the increased migration of the additivies. Consequently, migration testing can be improved by considering the swelling of the plastic.

Proteins are prone to aggregate when they are expressed above their solubility limits, a phenomenon termed supersaturation. Aggregation may occur as proteins emerge from the ribosome or after they fold and accumulate in the cell, but the relative importance of these two routes remain poorly known. Here, we systematically probed the solubility limits of each Escherichia coli protein upon overexpression using an image-based screen coupled with machine learning. The analysis suggests that competition between folding and aggregation from the unfolded state governs the two aggregation routes. Remarkably, the majority (70%) of insoluble proteins have low supersaturation risks in their unfolded states and rather aggregate after folding. Furthermore, a substantial fraction (∼35%) of the proteome remain soluble at concentrations much higher than those found naturally, indicating a large margin of safety to tolerate gene expression changes. We show that high disorder content and low surface stickiness are major determinants of high solubility and are favored in abundant bacterial proteins. Overall, our proteome-wide study provides empirical insights into the molecular determinants of protein aggregation routes in a bacterial cell.

The DNA of all organisms is constantly damaged by physiological processes and environmental conditions. Upon persistent damage, plant growth and cell proliferation are reduced. Based on previous findings that RBR1, the only Arabidopsis homolog of the mammalian tumor suppressor gene retinoblastoma, plays a key role in the DNA damage response in plants, we unravel here the network of RBR1 interactors under DNA stress conditions. This led to the identification of homologs of every DREAM component in Arabidopsis, including previously not recognized homologs of LIN52. Interestingly, we also discovered NAC044, a mediator of DNA damage response in plants and close homolog of the major DNA damage regulator SOG1, to directly interact with RBR1 and the DREAM component LIN37B. Consistently, not only mutants in NAC044 but also the double mutant of the two LIN37 homologs and mutants for the DREAM component E2FB showed reduced sensitivities to DNA-damaging conditions. Our work indicates the existence of multiple DREAM complexes that work in conjunction with NAC044 to mediate growth arrest after DNA damage.

Transient receptor potential melastatin 4 (TRPM4) plays an important role in many tissues, including pacemaker and conductive tissues of the heart, but much less is known about its electrophysiological role in ventricular myocytes. Our earlier results showed the lack of selectivity of 9-phenanthrol, so CBA ((4-chloro-2-(2-chlorophenoxy)acetamido) benzoic acid) was chosen as a new, potentially selective inhibitor. Goal: Our aim was to elucidate the effect and selectivity of CBA in canine left ventricular cardiomyocytes and to study the expression of TRPM4 in the canine heart. Experiments were carried out in enzymatically isolated canine left ventricular cardiomyocytes. Ionic currents were recorded with an action potential (AP) voltage-clamp technique in whole-cell configuration at 37 °C. An amount of 10 mM BAPTA was used in the pipette solution to exclude the potential activation of TRPM4 channels. AP was recorded with conventional sharp microelectrodes. CBA was used in 10 µM concentrations. Expression of TRPM4 protein in the heart was studied by Western blot. TRPM4 protein was expressed in the wall of all four chambers of the canine heart as well as in samples prepared from isolated left ventricular cells. CBA induced an approximately 9% reduction in AP duration measured at 75% and 90% of repolarization and decreased the short-term variability of APD90. Moreover, AP amplitude was increased and the maximal rates of phase 0 and 1 were reduced by the drug. In AP clamp measurements, CBA-sensitive current contained a short, early outward and mainly a long, inward current. Transient outward potassium current (Ito) and late sodium current (INa,L) were reduced by approximately 20% and 47%, respectively, in the presence of CBA, while L-type calcium and inward rectifier potassium currents were not affected. These effects of CBA were largely reversible upon washout. Based on our results, the CBA induced reduction of phase-1 slope and the slight increase of AP amplitude could have been due to the inhibition of Ito. The tendency for AP shortening can be explained by the inhibition of inward currents seen in AP-clamp recordings during the plateau phase. This inward current reduced by CBA is possibly INa,L, therefore, CBA is not entirely selective for TRPM4 channels. As a consequence, similarly to 9-phenanthrol, it cannot be used to test the contribution of TRPM4 channels to cardiac electrophysiology in ventricular cells, or at least caution must be applied.

The ErbB-3 BINDING PROTEIN 1 (EBP1) drives growth, but the mechanism of how it acts in plants is little understood. Here, we show that EBP1 expression and protein abundance in Arabidopsis (Arabidopsis thaliana) are predominantly confined to meristematic cells and are induced by sucrose and partially dependent on TARGET OF RAPAMYCIN (TOR) kinase activity. Consistent with being downstream of TOR, silencing of EBP1 restrains, while overexpression promotes, root growth, mostly under sucrose-limiting conditions. Inducible overexpression of RETINOBLASTOMA RELATED (RBR), a sugar-dependent transcriptional repressor of cell proliferation, depletes meristematic activity and causes precocious differentiation, which is attenuated by EBP1. To understand the molecular mechanism, we searched for EBP1- and RBR-interacting proteins by affinity purification and mass spectrometry. In line with the double-stranded RNA-binding activity of EBP1 in human (Homo sapiens) cells, the overwhelming majority of EBP1 interactors are part of ribonucleoprotein complexes regulating many aspects of protein synthesis, including ribosome biogenesis and mRNA translation. We confirmed that EBP1 associates with ribosomes and that EBP1 silencing hinders ribosomal RNA processing. We revealed that RBR also interacts with a set of EBP1-associated nucleolar proteins as well as factors that function in protein translation. This suggests EBP1 and RBR act antagonistically on common processes that determine the capacity for translation to tune meristematic activity in relation to available resources.

During our experiments in 2017/2018 crop year at Látókép Experimental Farm of University of Debrecen, we examined the effect of different cultivars and increased dosages of artificial fertilizer (control, N90PK, N150PK) on quality of wheat gluten. The gluten quality parameters of winter wheat were significantly influenced by fertilizing and cultivar. N90PK dosage improved significantly the measured parameters, further fertilizer application had no statistically provable effect. Application of artificial fertilizers increased significantly the gluten spread of the samples, compared to the control ones. KG Kunhalom had significantly higher crude protein (CP), wet gluten (WGC), dry gluten, gluten ratio and Zeleny index (ZI) parameters, this means that KG Kunhalom had the best protein and gluten quality potential. Also only KG Kunhalom with N150PK fertilizing treatment complied with the Hungarian premium class. According to Hungarian standard, samples with control treatment and Hybiza with any fertilizing treatment were unfit to bakery use. Using Pearson’s correlation analysis results, CP and ZI were in tight positive; WGC was in medium positive, while gluten index was in loose negative correlation with fertilizing. In the case of growing wheat for baking use, there is a need to put great emphasis on selecting the right cultivar and agrotechnology practices.

Molecular descriptor (2D) and three dimensional (3D) shape based similarity methods are widely used in ligand based virtual drug design. In the present study pairwise structure comparisons among a set of 4858 DTP compounds tested in the NCI60 tumor cell line anticancer drug screen were computed using chemical hashed fingerprints and 3D molecule shapes to calculate 2D and 3D similarities, respectively. Additionally, pairwise biological activity similarities were calculated by correlating the 60 element vectors of pGI50 values corresponding to the cytotoxicity of the compounds across the NCI60 panel. Subsequently, we compared the power of 2D and 3D structural similarity metrics to predict the toxicity pattern of compounds. We found that while the positive predictive value and sensitivity of 3D and molecular descriptor based approaches to predict biological activity are similar, a subset of molecule pairs yielded contradictory results. By simultaneously requiring similarity of biological activities and 3D shapes, and dissimilarity of molecular descriptor based comparisons, we identify pairs of scaffold hopping candidates displaying characteristic core structural changes such as heteroatom/heterocycle change and ring closure. Attempts to discover scaffold hopping candidates of mitoxantrone recovered known Topoisomerase II (Top2) inhibitors, and also predicted new, previously unknown chemotypes possessing in vitro Top2 inhibitory activity.

Bisphosphonate-related osteonecrosis of the jaw is a disease appearing after tooth removal in patients undergoing bisphosphonate treatment for metastasizing cancers and osteoporosis. The complexity of the condition requires a multicellular model to address the net effects of two key risk factors: mechanical trauma (pathologic overload) and inflammation. In this work, a system comprised of a polydimethylsiloxane chip and mechanical loading device is used to expose bisphosphonate-treated osteocytes to mechanical trauma. Specifically, osteocytes are treated with the potent nitrogen-containing bisphosphonate, zoledronic acid, and exposed to short-term pathologic overload via substrate stretch. During bone remodeling, osteocyte apoptosis plays a role in attracting pre-osteoclasts to sites of damage; as such, lactate dehydrogenase activity, cell death and protein expression are evaluated as functions of load. Additionally, the effects of osteocyte soluble factors on osteoclast and osteoblast functional activity are quantified. Osteoclast activity and bone resorption are quantified in the presence and absence of inflammatory components, lipopolysaccharide and interferon gamma. Results suggest that inflammation associated with bacterial infection may hinder bone resorption by osteoclasts. In addition, osteocytes may respond to overload by altering expression of soluble signals that act on osteoblasts to attenuate bone formation. These findings give insight into the multicellular interactions implicated in bisphosphonate-related osteonecrosis of the jaw.

Dantrolene is a ryanodine receptor (RyR) inhibitor, which is used to relax muscles in malignant hyperthermia syndrome. Although dantrolene binds to the RyR protein, its mechanism of action is unknown, mainly because of the controversial data showing that dantrolene inhibited Ca2+-release from intact fibers and sarcoplasmic reticulum (SR) vesicles, but failed to inhibit single ryanodine receptor (RyR) channel currents in bilayers. Accordingly, it was concluded that an important factor for dantrolene`s action was lost during the purification procedure of RyR. Recently, Mg2+ was demonstrated to be the essential factor for dantrolene to inhibit Ca2+- release in skinned muscle fibers. The aim of the present study was to confirm these results in Ca2+ release- and bilayer experiments, using SR vesicles and solubilized channels, respectively. Our Ca2+-release experiments demonstrated that the effect of dantrolene and Mg2+ was cooperative; and that ATP enhanced the inhibiting effect of dantrolene. Namely, 10 µM dantrolene reduced RyR channel open probability by ~50% in the presence of 3 mM free Mg2+ and 1 mM ATP, while channel activity further decreased to ~20% of control when [ATP] was increased to 2 mM. Our data provide important complementary information that support the direct, Mg2+-dependent mechanism of dantrolene9s action and suggest that dantrolene also requires ATP to inhibit RyR. SIGNIFICANCE STATEMENT The muscle relaxant dantrolene acts on ryanodine receptor in the presence of magnesium and ATP, which should be considered in therapy.

Complex surface nanostructures were observed in germanium and silicon samples exposed to low energy (24 or 36 eV ion kinetic energy) helium plasma. Pyramidal growth is observed in germanium across the temperature range studied (185 °C to 336 °C), while significant modification in silicon was only observed at 630 °C. Nano-wire growth was observed in both germanium and silicon, and appears to be linked to the strength of the electric field, which in turn determines the implantation energy of the helium ions. Nanostructure formation is proposed to be driven by surface adatom migration which is strongly influenced by an Ehrlich-Schwoebel-type surface instability. The role of helium in this model is to drive germanium interstitial formation by ejecting germanium atoms from lattice sites, leading to germanium interstitial diffusion towards the sample surface and subsequent adatom and surface nanostructure formation.

A series of 9-aryl-hexahydroacridine-1,8-diones are synthetized with good to excellent yields (50–99%) via a one-pot four-component reaction of dimedone, aromatic aldehydes and ammonium acetate in the presence of 4 A molecular sieves modified with iron(III) as an efficient heterogeneous catalyst, in ethanol. The process offers the advantages of high yields, mild reaction conditions and easy work-up procedure. The catalyst can be reused without significant loss of activity.

Context Microscopic measurement of adipocyte size is the gold standard for determining adipose tissue (AT) quality. AT density on CT may also reflect adipocyte quality (lower density = poorer quality). Objective We used abdominal subcutaneous AT (SAT) specimens and CT scans to validate CT SAT density as a marker of SAT quality in adults living with HIV. Setting and Design Secondary data analysis from completed trial of antiretroviral therapy (ART) initiation (ACTG A5224s). CT abdominal SAT density was measured in HU. SAT specimens were digitally scanned for calculation of mean adipocyte area. Participants Participants had SAT biopsy and CT data at baseline (n = 54) and HIV-1 RNA Outcome Measures Spearman correlations and linear regression models adjusting for participant characteristics examined associations between SAT density and adipocyte area. Results Baseline median age was 40 years, CD4+ T lymphocyte count 219 cells per cubic millimeter, and body mass index 26.0 kg/m2; 89% were male and 67% white. Median SAT area and density were 199 cm2 and −100 HU. Over 96 weeks, SAT area increased (+18%) and SAT density decreased (−3%). Mean SAT adipocyte area correlated with SAT density (P < 0.01) off and on ART after adjustment for SAT area, age, race, sex, CD4+ T lymphocyte count, and HIV-1 RNA. Conclusions CT SAT density correlates with biopsy-quantified SAT adipocyte size in adults with HIV on and off ART, suggesting that CT is a useful tool for noninvasive assessment of SAT quality.

Abstract: Inrtoduction: Caveolae are flask shaped with 50–100 nm size, non-clathrin associated invaginations of the plasmamembrane. The main membrane protein of the structures is caveolin-1. Caveolae play an important role in numerous cellular functions including vesicular transport and cell-cycle regulation, and create platforms for classical and alternative signaling pathways. According to international studies, caveolae may influence the physiology and pathology of lens epithelial cells. Aim: The aim of the study was to examine and compare the morphology of caveolae and the immunohistochemical difference of caveolin-1 in control (myopic and hyperopic) lens epithelial cells and human lens epithelial cells affected by cataract. Authors investigated whether caveolae might have a role in cataractogenesis. Method: Anterior lens capsules were obtained by capsulorhexis during surgery of senile cataract and refractive surgery of the clear lens. Ultra-fine sections have been studied by transmission electron microscopy, and semi-fine samples were labelled for immunohistochemistry with polyclonal caveolin-1 and cavin-1 antibodies. Results: By immunohistochemistry, in the control group, significant caveolin-1 label with low cavin-1 signal were measured in the lens epithelial cells. In the cataract group high cavin-1 and caveolin-1 expression was detected. In the control group, caveolae were not observed, but in the lens epithelial cells with cataract, increased number of caveolae have been detected by electron microscopy. Conclusions: For the development and maintenance of the specific caveolae shape, caveolin-1 is needed to be accompanied by cavin-1. Therefore, it is presumable that the increased expression of cavin-1 could explain the higher number of caveolae in the cataract group. These results might suggest that caveolae might play a role in cataractogenesis. Orv Hetil. 2019; 160(8): 300–308.

The reserves and exploitation of conventional, so-called fossil energy resources are limited, therefore the utilisation of renewable energy resources has been becoming more and more important. Present study focuses on the thermal water utilisation possibilities i.e. energy content utilisation, balneological utilisation, irrigation, and the related environmental aspects in North East part of Hungary. Among the environmental effects the total dissolved solid concentration and the methane and carbon dioxide content are examined through the examples of 66 thermal water wells screened into pannonian sensu lato (s.l). succession. Thermal water utilisation may have many various environmental aspects: chemical impacts, gas emission, thermal effects, water quality effects noise effects, landscape change, from which methane and solids dissolved in thermal water emitted by its extraction are highlighted. Considering that the annual thermal water extraction from reservoirs located in the Northern part of the Great Hungarian Plain the annual Total dissolved solid concentration (TDS) and methane production can be estimated as 28,207 tones and 1,671,482 m3, respectively. It must be highlighted that by applying cascade systems, the efficiency of thermal water utilisation can be improved while environmental aspects do not increase considerably.

A one-pot three-component tandem reaction involving a key Pictet-Spengler-like annulation step has been developed, providing an efficient method for the synthesis of 3,4-dihydroquinazolines in moderate to good yields from amides, aldehydes, and amines. The multicomponent triflic anhydride mediated reaction tolerates the installation of numerous functional groups, affording extensive diversity about the heterocyclic scaffold.

The Ammonia Gas Emission Model for Swine (AGEM-S), a nitrogen flow model, was created with the objective of assisting in the reduction of ammonia emissions in the Hungarian pig sector. Regarding the applied technological processes and considering the factors that influence ammonia emissions, the model quantifies the amount of ammonia emissions of pig farming in all stages (feeding, housing technology, manure storage, and application in the field). The aim of the project was to create a system that performs general calculations using the input data used by practicing farmers, without compromising the information content of the output data. Using this system, the input parameters can be entered as simply as possible and in the shortest possible time. In addition to demonstrating the impact of ammonia emission reduction measures to farmers from an integrated N management approach, AGEM-S has the potential to support the transfer of emission reduction technologies and practices at the farm level as a knowledge transfer tool primarily, but also as a decision support tool for technological change.

Mainstream anaerobic ammonium oxidation (anammox) represents one of the most promising energy-efficient mechanisms of fixed nitrogen elimination from wastewaters. However, little is known about the exact processes and drivers of microbial community assembly within the complex microbial biofilms that support anammox in engineered ecosystems. Here, we followed anammox biofilm development on fresh carriers in an established 8m3 mainstream anammox reactor that is exposed to seasonal temperature changes (~25-12°C) and varying NH4+ concentrations (5-25 mg/L). We use fluorescence in situ hybridization and 16S rRNA gene sequencing to show that three distinct stages of biofilm development emerge naturally from microbial community composition and biofilm structure. Neutral modelling and network analysis are employed to elucidate the relative importance of stochastic versus deterministic processes and synergistic and antagonistic interactions in the biofilms during their development. We find that the different phases are characterized by a dynamic succession and an interplay of both stochastic and deterministic processes. The observed growth stages (Colonization, Succession and Maturation) appear to be the prerequisite for the anticipated growth of anammox bacteria and for reaching a biofilm community structure that supports the desired metabolic and functional capacities observed for biofilm carriers already present in the system (~100gNH4-N m3 d−1). We discuss the relevance of this improved understanding of anammox-community ecology and biofilm development in the context of its practical application in the start-up, configuration, and optimization of anammox biofilm reactors., Water Research, 200, ISSN:0043-1354, ISSN:1879-2448

Significance Rock varnish is a prominent feature of desert landscapes and the canvas for many prehistoric petroglyphs. How it forms—and, in particular, the basis for its extremely high manganese content—has been an enduring mystery. The work presented here establishes a biological mechanism for this manganese enrichment, underpinned by an apparent antioxidant strategy that enables microbes to survive in the harsh environments where varnish forms. The understanding that varnish is the residue of life using manganese to thrive in the desert illustrates that, even in extremely stark environments, the imprint of life is omnipresent on the landscape., Desert varnish is a dark rock coating that forms in arid environments worldwide. It is highly and selectively enriched in manganese, the mechanism for which has been a long-standing geological mystery. We collected varnish samples from diverse sites across the western United States, examined them in petrographic thin section using microscale chemical imaging techniques, and investigated the associated microbial communities using 16S amplicon and shotgun metagenomic DNA sequencing. Our analyses described a material governed by sunlight, water, and manganese redox cycling that hosts an unusually aerobic microbial ecosystem characterized by a remarkable abundance of photosynthetic Cyanobacteria in the genus Chroococcidiopsis as the major autotrophic constituent. We then showed that diverse Cyanobacteria, including the relevant Chroococcidiopsis taxon, accumulate extraordinary amounts of intracellular manganese—over two orders of magnitude higher manganese content than other cells. The speciation of this manganese determined by advanced paramagnetic resonance techniques suggested that the Cyanobacteria use it as a catalytic antioxidant—a valuable adaptation for coping with the substantial oxidative stress present in this environment. Taken together, these results indicated that the manganese enrichment in varnish is related to its specific uptake and use by likely founding members of varnish microbial communities.

Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): NEW NATIONAL EXCELLENCE PROGRAM OF THE MINISTRY FOR INNOVATION AND TECHNOLOGY FROM THE SOURCE OF THE NATIONAL RESEARCH, DEVELOPMENT AND INNOVATION FUND. Introduction and purpose Acute β-adrenergic receptor (β-AR) stimulation shortens the ventricular action potential (AP). This effect is mainly regulated by the β- adrenergic stimulation of the cardiac potassium currents. Our aim was to investigate the extent of calcium/calmodulin-dependent protein kinase II (CaMKII) involvement in mediating the effect of β-AR activation on the inward rectifier potassium current – I K1 . Methods We carried out our experiments on isolated cardiomyocytes originating from canine left ventricles. The inward rectifier potassium current – I K1 was measured under a "canonical" AP under action potential voltage clamp conditions. Data were collected in four study groups [1] Control conditions (CTRL) [2] Inhibition of CaMKII with 1 µM KN-93 (KN-93) [3] Inhibition of PKA with 3 µM H-89 (H-89) [4] Acute β-adrenergic stimulation with 10 nM isoproterenol (ISO) [5] β-adrenergic stimulation with CaMKII inhibition (KN-93 + ISO) [6] β-adrenergic stimulation with PKA inhibition (H-89 + ISO) [7] β-adrenergic stimulation with inhibited PKA and CaMKII (KN-93 + H-89 + ISO) Results I K1 current amplitude did not differ among the studied groups, the total carried charge however was significantly, about 30 % larger in the ISO group compared to CTRL, and about 20 % larger compared to KN-93 + ISO. Under beta- adrenergic stimulation, I K1 starts to activate earlier during the AP plateau. I K1 density was about 3 times greater both at +20 mV and at 0 mV membrane potential under the command "canonical" AP in ISO compared to CTRL. Similarly, I K1 density was about 60 % and 90 % larger at +20 mV and at 0 mV, respectively, in KN-93 + ISO compared to KN-93. Similar results have been obtained by conventional voltage-clamp technique. Conclusion Based on the results of our researches the CaMKII activation plays an important role in β -adrenergic stimulation the I K1 potassium current.

The Nitrates Directive aims (a) to protect water quality across Europe from nitrates originating from agricultural sources that pollute ground and surface water, and (b) to promote good farming practices. One of the most controversial measures of the directive is the winter prohibition period of fertilization, which has been extended by a month in two steps in recent years. According to the regulation, it is forbidden to apply nitrogen fertilization in Hungary between 31st October and 15th February, even though the winter climate is gradually becoming milder. Using the fertilization data of nearly half a million parcels of land in the Hungarian Nitrate Database, a crop model-based spatial analysis was carried out. Our aim was to test if a shift in the prohibition period starting date from 31st October to 30th November caused any differences in the nitrate amount leached at a 90 cm depth. Detailed nitrate inputs and soil and weather databases were coupled with the 4M crop model. The yield, plant nitrogen uptake, and nitrate leaching under five major crops were simulated, covering a considerable portion of arable land. Shifting the prohibition period starting date did not result in significant changes in the nitrate leaching. Further runs of the 4M model with different weather scenarios are needed to decide whether the modification of the prohibition period significantly affects the amount of nitrate leached.

Autotrophic nitrogen removal by anaerobic ammonium oxidizing (anammox) bacteria is an energy-efficient nitrogen removal process in wastewater treatment. However, full-scale deployment under mainstream conditions remains challenging for practitioners due to the high stress susceptibility of anammox bacteria towards fluctuations in dissolved oxygen (DO) and temperature. Here, we investigated the response of microbial biofilms with verified anammox activity to DO shocks under 20 °C and 14 °C. While pulse disturbances of 0.3 mg L−1 DO prompted only moderate declines in the NH4+ removal rates, 1.0 mg L−1 DO led to complete but reversible inhibition of the NH4+ removal activity in all reactors. Genome-centric metagenomics and metatranscriptomics were used to investigate the stress response on various biological levels. We show that temperature regime and strength of DO perturbations induced divergent responses from the process level down to the transcriptional profile of individual taxa. Community-wide gene expression differed significantly depending on the temperature regime in all reactors, and we found a noticeable impact of DO disturbances on genes involved in transcription, translation, replication and posttranslational modification at 20 °C but not 14 °C. Genome-centric analysis revealed that different anammox species and other key biofilm taxa differed in their transcriptional responses to distinct temperature regimes and DO disturbances., Communications Biology, 4, ISSN:2399-3642

Patients with chronic kidney disease (CKD) have elevated circulating levels of trimethylamine N-oxide (TMAO), a metabolite derived from gut microbes and associated with cardiovascular diseases. High circulating levels of TMAO and its dietary precursor, choline, predict increased risk for development of CKD in apparently healthy subjects, and studies in mice fed TMAO or choline suggest that TMAO can contribute to kidney impairment and renal fibrosis. Here we examined the interactions between TMAO, kidney disease, and cardiovascular disease in mouse models. We observed that while female hyperlipidemic apoE KO mice fed a 0.2% adenine diet for 14 weeks developed CKD with elevated plasma levels of TMAO, provision of a non-lethal inhibitor of gut microbial trimethylamine (TMA) production, iodomethylcholine (IMC), significantly reduced multiple markers of renal injury (plasma creatinine, cystatin C, FGF23, and TMAO), reduced histopathologic evidence of fibrosis, and markedly attenuated development of microalbuminuria. In addition, while the adenine-induced CKD model significantly increased heart weight, a surrogate marker for myocardial hypertrophy, this was largely prevented by IMC supplementation. Surprisingly, adenine feeding did not increase atherosclerosis and significantly decreased the expression of inflammatory genes in the aorta compared to the control groups, effects unrelated to TMAO levels. Our data demonstrate that inhibition of TMAO production attenuated CKD development and cardiac hypertrophy in mice, suggesting that TMAO reduction may be a novel strategy in treating CKD and its cardiovascular disease complications.

In the medulla of bursal follicle, only the secretory dendritic cell (BSDC) is furnished with secretory machinery. The granular discharge of BSDC appears in membrane-bound and solubilized forms. Movat pentachrome staining proves that the solubilized form is a glycoprotein, which fills up the extracellular space of follicular medulla. The glycoprotein contributes to bursal microenvironment and may be attached to the surface of medullary lymphocytes. The secretory granules of BSDC may be fused, resulting in large, irregular dense bodies, which are the first sign of BSDC transformation to macrophage-like cells (Mal). To determine the effect of infectious bursal disease virus (IBDV) infection on the extracellular glycoprotein and BSDC, SPF chickens were experimentally infected with IBDV. On the surface of BSDC, the secretory substance is in high concentration, which may contribute to primary binding of IBDV to BSDC. The early distribution of IBDV infected cells is in consent with that BSDC. The IBDV infected BSDC rapidly transforms to Mal in which the glycoprotein staining appears. In the dense bodies, the packed virus particles inhibit the virus particles preventing the granular discharge, which may represent the first, early phase of virus replication cycle. The absence of extracellular glycoprotein results in alteration in the medullary microenvironment and subsequently B cell apoptosis. On the surface of medullary B cells, the solubilized secretory substance can be in much lower concentration, which results in secondary binding of IBDV to B cells. In secondary, late phase of virus replication cycle, the virus particles are not packed in electron dense substance which results in cytolytic lymphocytes and presence of virus in extracellular space. The Mal emigrates into the cortex, where induces inflammation, recruiting heterophil granulocyte and monocyte.

Aggregates or oligomeric forms of many intrinsically disordered proteins (IDPs), including α-synuclein, are hallmarks of neurodegenerative diseases, like Parkinson's and Alzheimer's disease, and key contributors to their pathogenesis. Due to their disordered nature and therefore lack of defined drug-binding pockets, IDPs are difficult targets for traditional small molecule drug design and are often referred to as "undruggable". The 20S proteasome is the main protease that targets IDPs for degradation and therefore small molecule 20S proteasome enhancement presents a novel therapeutic strategy by which these undruggable IDPs could be targeted. The concept of 20S activation is still relatively new, with few potent activators having been identified thus far. Herein, we synthesized and evaluated a library of dihydroquinazoline analogues and discovered several promising new 20S proteasome activators. Further testing of top hits revealed that they can enhance 20S mediated degradation of α-synuclein, the IDP associated with Parkinson's disease.

In carbonate‐forming environments, authigenic minerals can cement surface sediments into centimeter‐sized intraclasts that are later reworked into “flat‐pebble” or “edgewise” conglomerates. Flat‐pebble conglomerates comprise only a small portion of facies in modern marine environments but are common in ancient strata, implying that seafloor cements were more widespread in the past. Flat‐pebble conglomerates nearly disappeared after the Ordovician radiation, yet it is unclear if this decline was due to changing seawater chemistry or if increased infaunalization and bioturbation simply worked to break down nascent clasts. We discovered a process analog that produces flat‐pebble conglomerates around the Great Salt Lake, Utah, USA—and studied these facies using field observations, wave models, satellite imagery, petrography, and microanalytic chemical data. Clasts were sourced from wave‐rippled grainstone that cemented in situ in offshore environments. Lake floor cements formed under aragonite saturation states that are lower than modern marine settings, suggesting that physical processes are at least as important as chemical ones. Results from our wave models showed that coarse sediments near the field site experience quiescent periods of up to six months between suspension events, allowing isopachous cements to form. Using a simple mathematical framework, we show that the main difference between Great Salt Lake and modern, low‐energy marine settings is that the latter has enough bioturbating organisms to break up clasts. Observations from Great Salt Lake demonstrate how geologic trends in flat‐pebble abundance could largely reflect changes in total infaunal biomass and ecology without requiring regional‐to‐global changes in seawater chemistry.

Understanding mechanisms, rates, and drivers of past carbonate formation provides insight into the chemical evolution of Earth’s oceans and atmosphere. We paired geological observations with elemental and isotope geochemistry to test potential proxies for calcium‐to‐alkalinity ratios (Ca:ALK). Across diverse carbonate facies from Pleistocene closed‐basin lakes in Owens Valley, CA, we observed less δ^(44/40)Ca variation than theoretically predicted (>0.75‰) for the very low Ca:ALK in these systems. Carbonate clumped isotope disequilibria implied rapid carbonate growth—kinetic isotope effects, combined with the diverse carbonate minerals present, complicated the interpretation of δ^(44/40)Ca as a paleo‐alkalinity proxy. In contrast, we observed that the high phosphate concentrations are recorded by shoreline and lake bottom carbonates formed in eleven Pleistocene lakes at orders of magnitude greater concentrations than in marine carbonates. Because the maximum phosphate content of water depends on Ca:ALK, we propose that carbonate P/Ca can inform phosphate levels and thereby Ca:ALK of aqueous environments in the carbonate record.

Background: Several reports prove interconnection between vitamin D (VD) deficiency and increased cardiovascular risk. Our aim was to investigate the effects of VD status on biomechanical and oxidative&ndash, nitrative (O&ndash, N) stress parameters of coronary arterioles in rats. Methods: 4-week-old male Wistar rats were divided into a control group (11 animals) with optimal VD supply (300 IU/kgbw/day) and a VD-deficient group (11 animals, &lt, 5 IU/kg/day). After 8 weeks, coronary arteriole segments were prepared. Geometrical, elastic, and biomechanical characteristics were measured by in vitro arteriography. O&ndash, N stress markers were investigated by immunohistochemistry. Results: Inner radius decreased, wall thickness and wall-thickness/lumen diameter ratio increased, tangential wall stress and elastic modulus were reduced in VD-deficient group. No difference could be found in wall-cross-sectional area, intima-media area %. While the elastic elements of the vessel wall decreased, the &alpha, smooth muscle actin (&alpha, SMA) immunostaining intensity showed no changes. Significant elevation was found in the lipid peroxidation marker of 4-hidroxy-2-nonenal (HNE), while other O&ndash, N stress markers staining intensity (poly(ADP)ribose, 3-nitrotyrosine) did not change. Conclusions: Inward eutrophic remodeling has developed. The potential background of these impairments may involve the initial change in oxidative damage markers (HNE). These mechanisms can contribute to the increased incidence of the cardiovascular diseases in VD deficiency.

Organic anion-transporting polypeptide 3A1 (OATP3A1) is a membrane transporter mediating the cellular uptake of various hormones such as estrone-3-sulfate, prostaglandins E1 and E2 and thyroxine. OATP3A1 is widely expressed in the human body and its presence in tissue-blood barriers, neurons and muscle cells marks it as a potential pharmacological target. Herein we demonstrate that an otherwise membrane impermeant, zwitterionic fluorescent coumarin probe, bearing a sulfonate function is a potent substrate of human OATP3A1, thus readily transported into HEK-293-OATP3A1 cells allowing functional investigation and the screen of drug interactions of the OATP3A1 transporter. At the same time, dyes lacking either the sulfonate motif or the coumarin scaffold showed a dramatic decrease in affinity or even a complete loss of transport. Furthermore, we observed a distinct inhibition/activation pattern in the OATP3A1-mediated uptake of closely related fluorescent coumarin derivatives differing only in the presence of the sulfonate moiety. Additionally, we detected a synergistic effect between one of the probes tested and the endogenous OATP substrate estrone-3-sulfate. These data, together with docking results indicate the presence of at least two cooperative substrate binding sites in OATP3A1. Besides providing the first sensitive probe for testing OATP3A1 substrate/inhibitor interactions, our results also help to understand substrate recognition and transport mechanism of the poorly characterized OATP3A1. Moreover, coumarins are good candidates for OATP3A1-targeted drug delivery and as pharmacological modulators of OATP3A1.

Complex microbial biofilms orchestrating mainstream anaerobic ammonium oxidation (anammox) represent one of the most promising energy-efficient mechanisms of fixed nitrogen elimination from anthropogenic waste waters. However, little is known about the ecological processes that are driving microbial community assembly leading to functional anammox biofilms in engineered ecosystems. Here, we use fluorescence in situ hybridization and 16S rRNA sequencing combined with network modelling to elucidate the contribution of stochastic and deterministic processes during anammox biofilm development from first colonization to maturation in a carrier-based anammox reactor. We find that distinct stages of biofilm development emerge naturally in terms of structure and community composition. These stages are characterized by dynamic succession and an interplay of stochastic and deterministic processes. The staged process of biofilm establishment appears to be the prerequisite for the anticipated growth of anammox bacteria and for reaching a biofilm community structure with the desired metabolic capacities. We discuss the relevance of this improved understanding of anammox community ecology and biofilm development concerning its practical application in the start-up and configuration of anammox biofilm reactors.