In response to a variety of external signals, the fungal pathogen Candida albicans undergoes a transition between ellipsoidal single cells (blastospores) and filaments composed of elongated cells ...attached end‐to‐end. Here we identify a DNA‐binding protein, Nrg1, that represses filamentous growth in Candida probably by acting through the co‐repressor Tup1. nrg1 mutant cells are predominantly filamentous under non‐filament‐inducing conditions and their colony morphology resembles that of tup1 mutants. We also identify two filament‐specific genes, ECE1 and HWP1, whose transcription is repressed by Nrg1 under non‐inducing conditions. These genes constitute a subset of those under Tup1 control, providing further evidence that Nrg1 acts by recruiting Tup1 to target genes. We show that growth in serum at 37°C, a potent inducer of filamentous growth, causes a reduction of NRG1 mRNA, suggesting that filamentous growth is induced by the down‐regulation of NRG1. Consistent with this idea, expression of NRG1 from a non‐regulated promoter partially blocks the induction of filamentous growth.
This paper presents observations of electromagnetic ion cyclotron (EMIC) waves from multiple data sources during the four Geospace Environment Modeling challenge events in 2013 selected by the ...Geospace Environment Modeling Quantitative Assessment of Radiation Belt Modeling focus group: 17 and 18 March (stormtime enhancement), 31 May to 2 June (stormtime dropout), 19 and 20 September (nonstorm enhancement), and 23–25 September (nonstorm dropout). Observations include EMIC wave data from the Van Allen Probes, Geostationary Operational Environmental Satellite, and Time History of Events and Macroscale Interactions during Substorms spacecraft in the near‐equatorial magnetosphere and from several arrays of ground‐based search coil magnetometers worldwide, as well as localized ring current proton precipitation data from low‐altitude Polar Operational Environmental Satellite spacecraft. Each of these data sets provides only limited spatial coverage, but their combination shows consistent occurrence patterns and reveals some events that would not be identified as significant using near‐equatorial spacecraft alone. Relativistic and ultrarelativistic electron flux observations, phase space density data, and pitch angle distributions based on data from the Relativistic Electron‐Proton Telescope and Magnetic Electron Ion Spectrometer instruments on the Van Allen Probes during these events show two cases during which EMIC waves are likely to have played an important role in causing major flux dropouts of ultrarelativistic electrons, particularly near L* ~4.0. In three other cases, identifiable smaller and more short‐lived dropouts appeared, and in five other cases, these waves evidently had little or no effect.
Key Points
EMIC waves can rapidly deplete fluxes of ultrarelativistic electrons, but their occurrences are limited in both space and time
EMIC wave observations by magnetospheric spacecraft are supplemented by observations from ground‐based magnetometers and POES satellites
Many but not all EMIC wave events correlated with major or minor depletions of ultrarelativistic electrons observed by the Van Allen Probes
Context. Observations from the Solar Dynamics Observatory (SDO) have the potential for allowing the helioseismic study of the formation of hundreds of active regions, which would enable us to perform ...statistical analyses. Aims. Our goal is to collate a uniform data set of emerging active regions observed by the SDO/HMI instrument suitable for helioseismic analysis, where each active region is centred on a 60° × 60° area and can be observed up to seven days before emergence. Methods. We restricted the sample to active regions that were visible in the continuum and emerged into quiet Sun largely avoiding pre-existing magnetic regions. As a reference data set we paired a control region (CR), with the same latitude and distance from central meridian, with each emerging active region (EAR). The control regions do not have any strong emerging flux within 10° of the centre of the map. Each region was tracked at the Carrington rotation rate as it crossed the solar disk, within approximately 65° from the central meridian and up to seven days before, and seven days after, emergence. The mapped and tracked data, consisting of line-of-sight velocity, line-of-sight magnetic field, and intensity as observed by SDO/HMI, are stored in datacubes that are 410 min in duration and spaced 320 min apart. We call this data set, which is currently comprised of 105 emerging active regions observed between May 2010 and November 2012, the SDO Helioseismic Emerging Active Region (SDO/HEAR) survey. Results. To demonstrate the utility of a data set of a large number of emerging active regions, we measure the relative east-west velocity of the leading and trailing polarities from the line-of-sight magnetogram maps during the first day after emergence. The latitudinally averaged line-of-sight magnetic field of all the EARs shows that, on average, the leading (trailing) polarity moves in a prograde (retrograde) direction with a speed of 121 ± 22 m s-1 (−70 ± 13 m s-1) relative to the Carrington rotation rate in the first day. However, relative to the differential rotation of the surface plasma, the east-west velocity is symmetric, with a mean of 95 ± 13 m s-1. Conclusions. The SDO/HEAR data set will not only be useful for helioseismic studies, but will also be useful to study other features such as the surface magnetic field evolution of a large sample of EARs. We intend to extend this survey forwards in time to include more EARs observed by SDO/HMI.
Palifermin, a recombinant human keratinocyte growth factor, was tested for potential benefits on acute graft-versus-host disease (GVHD) and hematopoietic recovery in allogeneic hematopoietic stem ...cell transplantation (HSCT) recipients. This randomized, double-blind, placebo-controlled, dose-escalation study assessed the safety and tolerability of palifermin (n = 69) as compared with placebo (n = 31) in patients conditioned with cyclophosphamide and fractionated total-body irradiation (Cy/TBI) or busulfan and cyclophosphamide (Bu/Cy) and given methotrexate along with a calcineurin inhibitor (cyclosporine A, tacrolimus) for GVHD prophylaxis. All patients received 3 doses before conditioning and either 3 (cohort 1), 6 (cohort 2), or 9 (cohort 3) doses after HSCT. Palifermin doses were 40 μg/kg per day (cohort 1 only) or 60 μg/kg per day (all cohorts). Six patients (placebo = 2, palifermin = 4) experienced a total of 11 dose-limiting toxicities (most often skin, respiratory, or oral mucositis). The most common adverse events included edema, infection, skin pain, or rash. Times to neutrophil and platelet engraftment were similar. No significant differences in acute GVHD incidence or severity, survival, or day 100 relapse rates were observed between groups. Palifermin was associated with reduced incidence and mean severity of mucositis in patients conditioned with Cy/TBI but not Bu/Cy. We conclude that palifermin was generally safe in allogeneic HSCTs but had no significant effect on engraftment, acute GVHD, or survival in this trial.
Hyperlipidemia (HL) is a condition associated with endothelial dysfunction and inflammatory disorders. Purinergic system ectoenzymes play an important role in modulating the inflammatory and immune ...response. This study investigated whether the preventive treatment with quercetin is able to prevent changes caused by hyperlipidemia in the purinergic system, through the activities of E-NTPDase and E-ADA in lymphocytes, and quantify the nucleotides and nucleoside, and the secretion of anti- and proinflammatory cytokines. Animals were divided into saline/control, saline/quercetin 5 mg/kg, saline/quercetin 25 mg/kg, saline/quercetin 50 mg/kg, saline/simvastatin (0.04 mg/kg), hyperlipidemia, hyperlipidemia/quercetin 5 mg/kg, hyperlipidemia/quercetin 25 mg/kg, hyperlipidemia/quercetin 50 mg/kg, and hyperlipidemia/simvastatin. Animals were pretreated with quercetin for 30 days and hyperlipidemia was subsequently induced by intraperitoneal administration of 500 mg/kg of poloxamer-407. Simvastatin was administered after the induction of hyperlipidemia. Lymphocytes were isolated and E-NTPDase and E-ADA activities were determined. Serum was separated for the cytokines and nucleotide/nucleoside quantification. E-NTPDase and E-ADA activities were increased in lymphocytes from hyperlipidemic rats and pretreatment with quercetin was able to prevent the increase in the activities of these enzymes caused by hyperlipidemia. Hyperlipidemic rats when receiving pretreatment with quercetin and treatment with simvastatin showed decreased levels of ATP and ADP when compared to the untreated hyperlipidemic group. The IFN-γ and IL-4 cytokines were increased in the hyperlipidemic group when compared with control group, and decreased when hyperlipidemic rats received the pretreatment with quercetin. However, pretreatment with quercetin was able to prevent the alterations caused by hyperlipidemia probably by regulating the inflammatory process. We can suggest that the quercetin is a promising compound to be used as an adjuvant in the treatment of hyperlipidemia.
The pathogenic yeast Candida albicans regulates its cellular morphology in response to environmental conditions. Ellipsoidal, single cells (blastospores) predominate in rich media, whereas filaments ...composed of elongated cells that are attached end-to-end form in response to starvation, serum, and other conditions. The TUP1 gene, which encodes a general transcriptional repressor in Saccharomyces cerevisiae, was isolated from C. albicans and disrupted. The resulting tup1 mutant strain of C. albicans grew exclusively as filaments under all conditions tested. TUP1 was epistatic to the transcriptional activator CPH1, previously found to promote filamentous growth. The results suggest a model where TUP1 represses genes responsible for initiating filamentous growth and this repression is lifted under inducing environmental conditions.
TUP1 encodes a transcriptional repressor that negatively controls filamentous growth in Candida albicans. Using subtractive hybridization, we identified six genes, termed repressed by TUP1 (RBT), ...whose expression is regulated by TUP1. One of the genes (HWP1) has previously been characterized, and a seventh TUP1-repressed gene (WAP1) was recovered due to its high similarity to RBT5. These genes all encode secreted or cell surface proteins, and four out of the seven (HWP1, RBT1, RBT5, and WAP1) encode putatively GPI-modified cell wall proteins. The remaining three, RBT2, RBT4, and RBT7, encode, respectively, an apparent ferric reductase, a plant pathogenesis-related protein (PR-1), and a putative secreted RNase T2. The expression of RBT1, RBT4, RBT5, HWP1, and WAP1 was induced in wild-type cells during the switch from the yeast form to filamentous growth, indicating the importance of TUP1 in regulating this process and implicating the RBTs in hyphal-specific functions. We produced knockout strains in C. albicans for RBT1, RBT2, RBT4, RBT5, and WAP1 and detected no phenotypes on several laboratory media. However, two animal models for C. albicans infection, a rabbit cornea model and a mouse systemic infection model, revealed that rbt1Delta and rbt4Delta strains had significantly reduced virulence. TUP1 appears, therefore, to regulate many genes in C. albicans, a significant fraction of which are induced during filamentous growth, and some of which participate in pathogenesis.
Abstract Hyperlipidemia is a group of disorders characterized by excessive lipids in the bloodstream. It is associated with the incidence of cardiovascular diseases and recognized as the most ...important factor underlying the occurrence of atherosclerosis. This study was conducted to investigate whether pretreatment with quercetin can protect against possible memory impairment and deterioration of the cholinergic system in hyperlipidemic rats. Animals were divided into ten groups (n = 7): saline/control, saline/quercetin 5 mg/kg, saline/quercetin 25 mg/kg, saline/quercetin 50 mg/kg, saline/simvastatin (0.04 mg/kg), hyperlipidemia, hyperlipidemia/quercetin 5 mg/kg, hyperlipidemia/quercetin 25 mg/kg, hyperlipidemia/quercetin 50 mg/kg and hyperlipidemia/simvastatin. The animals were pretreated with quercetin by oral gavage for a period of 30 days and hyperlipidemia was subsequently induced by intraperitoneal administration of a single dose of 500 mg/kg of poloxamer-407. Simvastatin was administered after the induction of hyperlipidemia. The results demonstrated that hyperlipidemic rats had memory impairment compared with the saline control group ( P < 0.001). However, pretreatment with quercetin and simvastatin treatment attenuated the damage caused by hyperlipidemia compared with the hyperlipidemic group ( P < 0.05). Acetylcholinesterase (AChE) activity in the cerebral hippocampus was significantly ( P < 0.001) reduced in the hyperlipidemic group compared with the control saline group. Pretreatment with quercetin and simvastatin treatment in the hyperlipidemic groups significantly ( P < 0.05) increased AChE activity compared with the hyperlipidemic group. Our results thus suggest that quercetin may prevent memory impairment, alter lipid metabolism, and modulate AChE activity in an experimental model of hyperlipidemia.
Hyperlipidemia causes lipotoxicity which prompts an inflammatory response linked to the development of cardiovascular diseases. Natural compounds have been receiving special attention for its ...potential to treat diseases, inexpensiveness, and safety. Guarana (Paullinia cupana) has demonstrated notable anti-inflammatory and antioxidant effects, which may prevent chronic diseases caused by changes in lipid profile. Thus, this study aims to evaluate the effect of guarana powder (Paullinia cupana) in the purine metabolism and inflammatory profile in lymphocytes and serum of rats with Poloxamer-407-induced hyperlipidemia. Pretreatment with guarana 12.5, 25, and 50 mg/kg/day or caffeine (0.2 mg/kg/day) by gavage was applied to adult male Wistar rats for a period of 30 days. As a comparative standard, we used simvastatin (0.04 mg/kg) post-induction. Hyperlipidemia was acutely induced with intraperitoneally injection of Poloxamer-407 (500 mg/kg). Guarana powder and caffeine increased the activity of the E-NTPDase (ecto-apyrase), and all pretreatments decreased the E-ADA (ecto-adenosine deaminase) activity, reducing the inflammatory process caused by lipotoxicity. In hyperlipidemic rats, ATP levels were increased while adenosine levels were decreased, guarana and caffeine reverted these changes. Guarana powder, caffeine, and simvastatin also prevented the increase in INF-γ and potentiated the increase in IL-4 levels, promoting an anti-inflammatory profile. Guarana promoted a more robust effect than caffeine. Our results show that guarana powder and caffeine have an anti-inflammatory as seen by the shift from a proinflammatory to an anti-inflammatory profile. The effects of guarana were more pronounced, suggesting that guarana powder may be used as a complementary therapy to improve the lipotoxicity-associated inflammation.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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