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Premiere Classe Dreux
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... extended family included Christian's mum, three siblings, plus in-laws and nieces who all live close by. It was lovely getting to chat with each of them and learn about their lives. Christian works for a company that sells trailers and it's right near where they live so he set up a trailer at the side of the road, set up some chairs and we watched the race from our very exclusive position, complete with our kangaroo Daisy and our Aussie flags. On Monday morning we bid the ...
... She started building Dreux as the mausoleum for that branch of the family the Orleans. Her son, Louis Phillip became the last king, not king of France, but "King of the French people". He did many good things including restoring Versailles which had been neglected, he finished the Arc de Triumph, he finished Dreux and he had the body of Napoleon brought back to France and interred at the Invalides. ...
Battlefields of World War One
... br>
WE go to the Buffalo Grill restaurant next door. Something light for dinner, because we all ordered a creme brulee for dessert. Came out in a large bowl - and it was delicious. I may go into a diabetic coma but it was worth it completely. The right texture, the right right burnt bit on top, made with vanilla beans. So so good! Great way to end the day.
And now its 10pm, its still light outside, we are watching Jackie Chan, dubbed with French speaking. Nice.
The ANZAC element of our trip
... at the farm) gave us a lovely casserole and glass of red wine before we headed to bed. The temperature in the van was around 5 degrees as we settled in for our first night. The bed never felt sooo good,.. and the doona and sleeping bag (being used as a second blanket) provided a cosy nest for us. What a start!! We both commented that we must be in for a cracker of a trip (working on the 'opposites principle',.. Bad start - Good finish). Monday saw 'a new ...
It's All Uphill
... and accidentally interrupted the beginning of a mass in one of the oldest churches in Paris. It was completely surreal being in the city and seeing everything that I'd only dreamed of or seen on television.
While Paris was awesome, I'd have to say the best part of today was the mini dance party that I had with the family after dinner. Raphaelle, who hasn't been quite sure what she thinks of me, danced with me for a while and loved it so much that she ...


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This review is from: ENCORE ENM232-8VIA 7.1 Channels 24-bit 96KHz PCI Interface Surround Sound Card
Pros: Sounded okay with respect to price for the brief moments I had it installed.
Cons: It always whacked other devices on the PCI bus by disabling at least one of them. Couldn't find a slot swap algorithm that would allow all other PCI devices to work. Something was always disabled. This Encore sound card reminds me of the cheap video capture cards I'd tried in the past that laid the same kinds of IRQ booby traps. Didn't waste more than an hour. It's never going to work.
Other Thoughts: This card's tab is about 3 pins short of filling the PCI slot. I've been building computers for about 15 years and I've never seen this before. At least one other person has posted in this review thread about it being too short. I wonder if they are all like that? Maybe I got a bad one? Not worth trying to exchange. I wll only wind up minimizing my loss by returning this defective thing for a refund but I'm going to return it just the same to make an issue of it. Considering all of the other PCI devices I've installed and configured in the past, I think I'm qualified to say this card was destined to fail installation in many computers from the moment it left the factory. I see many other posts of similar problems for this card.READ FULL REVIEW
This review is from: Hauppauge 1191 WinTV-HVR-955Q TV Tuner Stick/Hybrid Video Recorder with Remote Control
Pros: Receives all of the unscrambled QAM cable stations that are also detected by the digital tv's in my house. It doesn't miss a single station. I've tried many of these TV devices for the computer that claimed to do that. This one really does deliver. Hauppauge WinTV 7 software in Windows 7 Professional is stable and functional. No problems. Windows MediaCenter in Windows 7 is likewise fully functional. I haven't tried over the air reception with this 950Q--only Insight Communications cable signals.
Cons: Can't think of any cons really. I wish digital devices could switch and lock onto stations faster. This HVR-950Q switches channels about as fast as my televisions.
Other Thoughts: My rig is an old P4 3.2GHz HT with a Radeon 4650 graphics card. It's the only graphics card for this old platform that will render hi-def video. (NVidia doesn't offer hi-def support for AGP slots.) Even with this 7 year old computer, using this Hauppauge 950Q, I can watch and record a hi-def 1920x1080 signal without dropping a frame. Windows MediaCenter will only use about 50% CPU doing that. Hauppauge WinTV7 will use about 97% CPU doing that. A standard def signal will only use about 35% CPU in both software packages. So, if I use the built-in Windows MediaCenter, I can easily watch a hi-def station, record it at the same time, and still do eMail, web surfing and other light duty tasks at the same time. I'm sure the Hauppauge software will be much less of a strain on newer multi-core CPU's. I prefer the Hauppauge software because it lays down a more generic *.ts (mpeg2 transport stream) that is more easily converted to other things.READ FULL REVIEW
This review is from: XFX Radeon HD 4650 DirectX 10.1 HD-465X-ZPF2 1GB 128-Bit DDR2 AGP 8X HDCP Ready Video Card
Pros: Had a NewEgg XFX NV 6200 card on the shelf for two years with a "double lifetime warranty." I finally dragged it out and installed it just a couple of months ago. It wouldn't sleep correctly. Sent it to XFX under warranty and they sent me this Radeon instead of another NV. At first I was ticked but I realize now they did me a gigantic favor. Lots of 6200 NV's have sleep problems. Also, it seems NV has abandoned the AGP interface since those 6200's in 2006 and they just don't keep up with today's needs. But, thanks to ATI Radeon, AGP computers have a fighting chance in Windows 7. It supports hi-def video. It supports DirectX 10. It has drivers for WinXP and later. Once I found the Catalyst "hot fix" version of the driver, all is seamless and perfect. I am a Radeon convert.
Cons: I suspect I got into Radeon at the right time. I had driver problems in Windows 7 until I came across the "hotfix" version of the 10.9 Catalyst Control Center driver set. It looks like people really had driver troubles during the first part of 2010--especially with Windows 7. I think it's better now. I ran the installer for the complete Catalyst Control Center but unless I chose the "hotfix" version, the installer only put the "installer manager" on my system. Only the "hotfix" version of the installer would actually put the driver and the control center in this Win7 configuration.
Other Thoughts: This card has two DVI-D Dual-Link monitor connectors. (Try to get dual link capable connectors in order to enjoy full hi-res output.) I have one monitor connected using the all digital connections. Strange, but, if I choose certain resolutions, my screen will only be partially filled. It wasn't until I played around a bit that I discovered that if a resolution choice only partially filled the screen, I could make it fill the screen by trying to change from 32bit color to 16 bit color. Then, the screen would flash, my chosen resolution would now fill the entire screen, and it would revert back to 32bit color anyway. I also discovered that if Windows alerted that a chosen resolution would make some things move off the screen and be unavailable, it would a good idea to just ignore the warning and try it anyway because there were no problems. Even 800 x 600 works on my native 1680x1050 22 inch monitor using the digital connection and the 10.9 hotfix catalyst drivers.READ FULL REVIEW


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Two well characterized signal transduction cascades regulating fungal development and virulence are the MAP kinase and cAMP signaling cascades. Here we review the current state of knowledge on cAMP signaling cascades in fungi. While the processes regulated by cAMP signaling in fungi are as diverse as the fungi themselves, the components involved in signal transduction are remarkably conserved. Fungal cAMP signaling cascades are also quite versatile, which is apparent from the differential regulation of similar biological processes. In this review we compare and contrast cAMP signaling pathways that regulate development in the budding yeast Saccharomyces cerevisiae, the fission yeast Schizosaccharomyces pombe, and differentiation and virulence in the human pathogen Cryptococcus neoformans and the plant pathogen Ustilago maydis. We also present examples of interaction between the cAMP and MAP kinase signaling cascades in the regulation of fungal development and virulence.
The cellular environment plays an important role in growth and differentiation of fungi. Signal transduction cascades mediate communication between environmental signals and the cellular machinery controlling growth and differentiation. In eukaryotic cells, the secondary messenger cyclic adenosine monophosphate (cAMP) is produced in response to extracellular stimuli such as hormones and regulates a variety of physiological processes. The cellular cAMP level is dependent upon relative activities of the biosynthetic enzyme (adenylyl cyclase) and the degradative enzymes (phosphodiesterases). Adenylyl cyclase regulation by heterotrimeric G-proteins is well known [1]. Heterotrimeric G-proteins are composed of α, β, and γ subunits and are regulated by seven transmembrane receptors of the β adrenergic receptor family. Binding of an inducing ligand to the receptor triggers activation of the G-protein involving GDP-to-GTP exchange of the guanine nucleotide bound to the Gα subunit, followed by release of the Gα subunit from the Gβγ dimer [1, 2, 3, 4]. Effectors such as adenylyl cyclase can then be stimulated by either Gα or Gβγ[5, 6].
The best defined target of cAMP in mammalian cells and the budding yeast Saccharomyces cerevisiae is the cAMP-dependent protein kinase (PKA), which mediates most, if not all, physiological effects of cAMP in fungi and other multicellular eukaryotes (reviewed in [7]). When cAMP levels are low, the PKA holoenzyme is an inactive tetramer comprised of two regulatory and two catalytic subunits. Both subunits of PKA are highly conserved among fungi and other eukaryotes. Fig. 1 shows an alignment of conserved PKA catalytic subunits and Fig. 2 shows an alignment of conserved PKA regulatory subunits from a variety of fungi. When cAMP levels increase, cAMP binds to the regulatory subunits and induces a conformational change that causes dissociation of the tetramer into dimeric regulatory subunits and active monomeric catalytic subunits. Liberated catalytic subunits are enzymatically active to phosphorylate target substrates that include metabolic enzymes and transcription factors.
Components of the cAMP signaling cascade (Fig. 3), identified in a variety of fungi, have been found to be well conserved. This review is a compilation of studies on cAMP regulation of pseudohyphal differentiation in S. cerevisiae, mating and sporulation in the fission yeast Schizosaccharomyces pombe, and differentiation and virulence of the pathogenic fungi, Cryptococcus neoformans and Ustilago maydis, that have revealed useful insights on how this cascade functions in fungi.
Pseudohyphal differentiation in S. cerevisiae
The central role of the cAMP signaling pathway in the budding yeast S. cerevisiae is nutrient sensing and regulation of diverse biological processes including growth, metabolism, stress resistance, and entry into either meiosis or pseudohyphal differentiation. Pseudohyphal differentiation refers to the morphogenesis of S. cerevisiae diploid cells to a nutrient-scavenging filamentous form when subjected to nitrogen source starvation [8, 9]. Both the cAMP and MAP kinase signaling cascades regulate pseudohyphal differentiation in parallel in S. cerevisiae [10–14]. Intracellular cAMP levels in S. cerevisiae are dependent upon the activities of adenylyl cyclase, Cyr1 [15–17], and two cAMP phosphodiesterases, Pde1 and Pde2 [18–20]. Two conditions known to increase intracellular cAMP are intracellular acidification or the addition of a rapidly fermentable sugar such as glucose to stationary phase cells (derepressed) or cells grown on non-fermentable carbon sources ([21, 22], reviewed in [21, 23]). The term 'glucose-induced cAMP signaling' refers to the rapid, transient spike in intracellular cAMP levels occurring upon glucose addition to derepressed cells. There are two models for what transpires following the transient spike in cAMP level. In one model, the cAMP level returns to slightly higher than the pre-stimulus basal level to maintain PKA activity and the fermentative metabolic state [24]. In the second model, a cAMP-independent fermentable-growth medium (FGM)-induced pathway sustains PKA activity during continued growth on glucose following the cAMP spike [21, 25, 26]. Elevated PKA activity results in induction of glycolytic enzymes and promotes cell proliferation, while sporulation and stationary phase processes such as gluconeogenesis, accumulation of reserve carbohydrates (trehalose and glycogen), and stress resistance are inhibited. cAMP depletion or inactivation of cAMP signaling results in cell cycle arrest in the G1 phase and permanent entry into stationary phase, indicating that the cAMP pathway signals nutrient availability to the cell cycle machinery.
Upstream components of the cAMP pathway identified in yeast include the G-protein-coupled receptor (GPCR) Gpr1 and the Gα subunit Gpa2, which stimulate cAMP production by adenylyl cyclase in response to glucose and other fermentable carbon sources (Fig. 3) [10, 22, 27–32]. Activation of cAMP synthesis is also dependent upon uptake and hexokinase-mediated intracellular phosphorylation of glucose, suggesting that glucose is sensed extracellularly by Gpr1 and intracellularly by hexokinase [33, 34]. How hexokinase activity influences cAMP synthesis remains to be established. This dual sensing mechanism may enable the cell to establish that glucose is present in the environment and that the metabolic state of the cell is supporting sufficient glucose transport for growth.
The observations that constitutively active Gpa2 mutants or exogenous cAMP induce pseudohyphal growth at nitrogen concentrations that repress differentiation of wild-type cells, and nitrogen starvation induces expression of GPR1, suggest the intriguing possibility that the Gpr1-Gpa2-regulated pathway is activated not only by carbon source abundance but also regulated by nitrogen starvation [10, 31]. It was recently shown that Plc1, a phospholipase C enzyme, may function together with Gpr1 and Gpa2 to regulate pseudohyphal growth [35]. Plc1 catalyzes the cleavage of phosphatidylinositol-4,5-bisphosphate (PIP2) into the secondary messengers inositol-1,4,5-trisphosphate (IP3) and 1,2-diacylglycerol (DAG). It remains to be determined whether the defect of a plc1 mutant in pseudohyphal growth is due to inactivation of Gpr1-Gpa2-mediated cAMP signaling. In addition to pseudohyphal growth, the Gpr1-Gpa2 pathway also regulates entry of cells into meiosis. In the presence of fermentable carbon sources or nitrogen abundance Gpa2 checks improper entry into meiosis by inhibiting the protein kinase Ime2 required for initiation of meiosis and sporulation [36].
Besides Gpa2, the G-proteins Ras1 and Ras2 also regulate cAMP production by adenylyl cyclase [37]. By stimulating cAMP production, Ras proteins signal environmental changes in nutrient availability and coordinately regulate cell cycle progression [24]. Although neither is essential, ras1 ras2 double mutant strains are inviable and overexpression of the CYR1 adenylyl cyclase gene suppresses the lethal phenotype of ras1 ras2 mutant strains [37–40]. Furthermore, expression of a dominant active RAS2val19 allele results in increased cAMP levels [38]. Additionally, a single amino acid substitution in RAS2C318S prevents the cAMP pulse observed in starved wild-type cells following exposure to glucose [24]. Ras signaling in yeast is complex because Ras2 regulates filamentous growth via both the MAP kinase and cAMP signaling pathways [10, 14, 41].
The target of cAMP in S. cerevisiae is PKA, which consists of a regulatory subunit (Bcy1) and three catalytic subunit isoforms (Tpk1, Tpk2, and Tpk3) [42, 43]. Of the three isoforms, Tpk2 positively regulates pseudohyphal growth, whereas Tpk1 and Tpk3 play negative roles [11, 44]. The distinct functions of the three PKA isoforms are attributable to subtle differences in the conserved PKA catalytic domains suggesting that these enzymes have different targets in S. cerevisiae[11]. Unlike the situation in many fungi, PKA is required for vegetative growth of S. cerevisiae and the three PKA isoforms are largely redundant for viability [43]. In contrast, constitutive activation of the PKA pathway in bcy1 mutants lacking the PKA regulatory subunit, or in cells expressing activated Ras2, prevent cells from entering stationary phase, accumulating glycogen, or acquiring heat-shock resistance, even death, in response to conditions (N-starvation) that promote entry into stationary phase [43, 45].
For a long time following the discovery of PKA the only known targets for PKA were enzymes involved in intermediary metabolism, particularly carbohydrate metabolism. Recently identified targets of PKA include the S. cerevisiae transcription factors Msn2 and Msn4, which are key regulators of stress-responsive gene expression [46–49]. The Rim15 protein kinase is another recently identified PKA target [50] which, in addition to regulating meiotic gene expression [51], is also required for stationary phase-induced gene expression. Interestingly, mutants lacking Rim15, Msn2, Msn4, or both Msn2 and Msn4, have no defect in pseudohyphal growth [11]. Tpk2 regulation of pseudohyphal growth is not dependent on Msn2 and Msn4, or the transcription factors Ste12 and Tec1 required for MAPK cascade regulation, but is dependent on the activation of the transcriptional regulator Flo8, which in turn regulates expression of the cell surface flocculin Flo11 that is involved in cell–cell adhesion [11, 44, 52–54]. The transcription factor Sfl1, proposed to inhibit pseudohyphal growth, is yet another PKA target as demonstrated by two-hybrid interactions with Tpk2. Moreover, sfl1 mutations suppress defects in pseudohyphal growth and Flo11 expression of tpk2 mutant strains [44]. Finally, cAMP synthesis itself is a target of the PKA pathway and, following activation, PKA participates in a negative feedback loop that inhibits cAMP synthesis [18, 22, 55]. The phosphodiesterase Pde1 is a good candidate for a PKA target in this negative feedback loop because it has a single PKA consensus phosphorylation site, phosphorylation in crude extracts leads to modest increases in enzyme activity, and pde1 mutations dramatically enhance cAMP production [20]. Recently, the regulator of G-protein signaling (RGS) homolog Rgs2 was identified as a novel moderator of cAMP synthesis and Rgs2 stimulates the GTPase activity of Gpa2 [56]. rgs2 mutations enhance glucose-induced cAMP production, whereas overexpression of RGS2 attenuates this response.
In summary, nutrient sensing by the cAMP signaling pathway plays a key role in regulation of growth and differentiation in S. cerevisiae and serves as a paradigm for cAMP-mediated signal transduction in other fungi (Fig. 3). The cAMP and MAP kinase pathways coordinately regulate pseudohyphal differentiation in S. cerevisiae and crosstalk occurs at several levels. cAMP synthesis itself is tightly regulated by a negative feedback loop that limits cAMP fluctuations in S. cerevisiae. While much is known about glucose sensing by the cAMP pathway, it still remains to be established how glucose phosphorylation regulates cAMP synthesis and how nitrogen levels are sensed. Interestingly, while any one of the three PKA isoforms suffices for vegetative growth, they have distinct and opposing roles in pseudohyphal differentiation. Further insights into the unique roles of PKA isoforms may be provided by ongoing studies on nutritional regulation of cellular localization of PKA subunits [57]. In rapidly growing cells in glucose medium the Bcy1–Tpk1 complex is predominantly nuclear, whereas Tpk1 is exported to the cytoplasm in response to cAMP while Bcy1 remains nuclear. In contrast, both Bcy1 and Tpk1 are distributed in both the nucleus and cytoplasm in stationary phase cells or cells grown on a non-fermentable carbon source. Besides carbon source availability, cytoplasmic localization of Bcy1 is dependent on phosphorylation by the Yak1 kinase and a putative cytoplasmic retention factor Zds1 [58]. YAK1 expression is dependent on the transcription factors Msn2/Msn4 that are in turn negatively regulated by PKA. Subcellular targeting of PKA therefore provides an additional level of regulation of PKA-mediated signaling.
Sexual development in S. pombe
The fission yeast S. pombe employs cAMP signaling and PKA function to regulate sexual development involving mating, followed by meiosis and sporulation (Fig. 3). Exposure to nitrogen starvation results in decreased intracellular cAMP levels and triggers sexual development (reviewed in [59, 60]). Glucose depletion augments sexual development induced by nitrogen starvation by a similar cAMP-dependent mechanism [61]. In addition to regulating sexual development, glucose monitoring also controls other PKA-inhibited processes, including gluconeogenesis, uptake of alternative carbon sources such as gluconate, and entry into stationary phase. Recently, a definitive role for the cAMP signaling pathway in glucose-induced germination of S. pombe spores was demonstrated [62]. Components of the cAMP signaling cascade were identified by employing heterologous gene probes [61, 63], screening for genes conferring sterility when overexpressed [64], or by isolating git mutations (glucose insensitive transcription) that render transcription of fbp1, the gene encoding the gluconeogenic enzyme fructose-1,6-bisphosphatase, insensitive to glucose repression [65]. The cAMP cascade in S. pombe is remarkably similar to the pathway that regulates pseudohyphal differentiation in S. cerevisiae.
Mutations in the 'upstream' genes git1, git3, git5, git7, git8 (gpa2), and git10 were suppressed by multicopy git2 (adenylyl cyclase) indicating that these genes are required for glucose-triggered adenylyl cyclase activation [66, 67]. The G-protein α subunit gpa2/git8 of the heterotrimeric G-protein has been shown to be specifically involved in the cAMP signaling pathway in S. pombe [61, 68, 69]. A gpa2 null mutant mates and sporulates without nitrogen-deprivation and is unable to elevate intracellular cAMP levels in response to glucose stimulation, consistent with a defect in activation of adenylyl cyclase [63, 66, 70, 71]. git5 has been identified as the Gβ subunit involved in adenylyl cyclase activation [72]. Contrary to another report [73], the Gβ subunit git5 was conclusively demonstrated not to regulate the gpa1 Gα subunit involved in pheromone sensing. The same heterotrimeric G-protein has been considered responsible for signaling both nitrogen and glucose availability, but the precise mechanism for this is still unclear [61, 68].
Recently, it was reported that git3 encodes a GPCR that is distantly related to Gpr1 in S. cerevisiae[69]. Loss of git3 function results in phenotypes similar to those conferred by null mutations in other components of the cAMP signaling pathway, including constitutive fbp1 transcription, starvation-independent sexual development, derepression of gluconate uptake, and delay of spore germination [61, 64, 69, 71, 72]. Consistent with a role for git3 as a glucose monitoring receptor, multicopy git3 does not suppress mutations in other upstream git genes. Additionally, git3Δ and pka1Δ mutations do not have an additive effect on delay in spore germination, consistent with the git3 receptor and PKA functioning in the same pathway. It has been proposed that the primary role of the git3 receptor is to activate the G-protein α subunit gpa2/git8 in response to glucose [61, 69]. While this interpretation is consistent with complete suppression of a git3Δ by a constitutively activated gpa2R176H allele, nevertheless it is complicated by the result that git3Δ and gpa2Δ mutations have an additive effect on fbp1 expression. To account for this, Welton and Hoffman propose that a gpa2-independent activity of git3 plays a minor role in glucose-induced cAMP signaling [69]. The constitutively activated gpa2R176H allele also fully suppresses the Gβ requirement in glucose sensing suggesting that the primary role of Gβ is to couple gpa2 Gα to the git3 receptor. Other signaling components identified include cgs2/pde1, a cAMP phosphodiesterase, the git6/pka1 catalytic subunit of PKA [64, 72, 74] and cgs1, the regulatory subunit of PKA [75]. In addition to the fbp1 gene, the regulator of mating-specific genes, ste11, is also negatively regulated by PKA [76].
While the cAMP signaling pathway in S. pombe closely resembles that in S. cerevisiae, several differences are noteworthy. First, the S. pombe ras1 protein does not play a prominent role in adenylyl cyclase activation, but rather functions in the pheromone sensing MAP kinase cascade [77]. Second, loss of either adenylyl cyclase or PKA function is not lethal to S. pombe cells, although they do grow slower than wild-type cells, indicating that PKA does not primarily regulate cell viability [64, 71]. Third, the S. cerevisiae Gpr1 receptor does not associate with a classical heterotrimeric G-protein, whereas the S. pombe git3 receptor does, given the involvement of the gpa2 Gα and the git5 Gβ subunits in glucose-induced activation of cAMP production [69]. Structural differences between the GPCR and Gα proteins in these yeasts may account for the differential requirement of a canonical Gβ subunit for glucose detection.
Glucose and nitrogen sensing not only influence the cAMP signaling pathway, but starvation for these nutrients, like other environmental stresses, activates a highly conserved MAP kinase cascade. The downstream target of the MAP kinase cascade, a bZIP transcriptional regulator, is required to induce fbp1 transcription [78–81]. The MAP kinase cascade also regulates processes that are negatively regulated by PKA, including sexual development, gluconate uptake, and heat-shock tolerance. Analysis of the fbp1 promoter whose transcription is coordinately regulated by the MAP kinase and cAMP signaling pathways revealed antagonistic interactions of these pathways at each of the two identified cis-acting elements, involving different mechanisms at each site [82]. fbp1 regulation by parallel signaling pathways is analogous to the regulation of FLO11 transcription by similar pathways in S. cerevisiae [11, 12, 83].
To summarize, S. pombe employs both the cAMP signaling and MAP kinase cascades to coordinately regulate the processes of sexual development, gluconeogenesis, and stress tolerance. When glucose is plentiful, cAMP levels and PKA activity increase, inhibiting these processes. On the other hand, when starved for glucose (or nitrogen), reduced cAMP signaling and PKA activity induce these processes. The opposing effects of cAMP on development in budding and fission yeasts clearly demonstrate the versatility of the PKA pathway. Interesting areas for future investigations include defining how the cAMP signaling pathway mediates both glucose and nitrogen sensing in S. pombe and how it regulates cell cycle progression.
Mating and virulence in C. neoformans
C. neoformans is an encapsulated, heterothallic, basidiomycetous yeast that is one of the most common fungal pathogens in AIDS and other immunocompromised patients (reviewed in [84]). Virulence factors that have been identified for C. neoformans include an antiphagocytic polysaccharide capsule [85–87], melanin produced in the cell wall as a probable antioxidant [88–90], production of the enzyme urease [91], the ability to grow at 37°C [86, 92], and the MATα mating type locus [93]. C. neoformans exists in two mating types, MATa and MATα, and interestingly mating type is linked to virulence. When congenic strains were compared in a murine tail vein injection model of systemic cryptococcal infection, MATα strains were more virulent than MATa strains [93].
Virulence, mating and filamentation in C. neoformans are regulated by environmental conditions, and specific signals that induce these processes have been identified. Melanin production can be induced by glucose limitation and requires the presence of diphenolic substrates in the growth medium (Fig. 4A) [94–97]. Abundance of the diphenolic compound dopamine and other neurotransmitters in the CNS may explain the tissue tropism of cryptococcal infections. Melanin has been recently shown to be produced in vivo in infected animals and human brain tissue [98–101]. Formation of a polysaccharide capsule is induced by severe iron limitation (Fig. 4B) or CO2/HCO3− exposure, both conditions found in the infected host. [85, 102]. The capsule has been previously shown to protect fungal cells from phagocytosis and is now known to also enhance survival of cryptococci within macrophages [103]. Additionally, capsular antigens are shed into the circulation and may have deleterious effects on the host immune system by inducing suppressor T-cell networks [104, 105], activating complement [106, 107] by suppressing macrophage cytokine production [108], and inhibiting leukocyte migration into sites of infection [109]. Melanin and capsule are important for virulence, and mutants lacking either of these are either attenuated or avirulent in animal models [86, 88, 90, 110]. In addition, virtually all clinical isolates produce both melanin and capsule [84].
Compatible C. neoformans cells mate in response to both peptide pheromones and conditions of nitrogen starvation, resulting in the production of a dikaryotic mycelium (Fig. 4C), followed by karyogamy, meiosis, and sporulation ([111, 112]; Shen, W.C., Davidson, R.C., and Heitman, J., in preparation). In the absence of a mating partner and under conditions of nitrogen starvation and desiccation, some strains of the MATα mating type can undergo a process called haploid fruiting involving the formation of hyphal filaments and sporulation [113, 114]. Mating and haploid fruiting both produce small spores that could serve as infectious particles.
Both the MAP kinase and cAMP signaling cascades regulate mating and pathogenicity of C. neoformans ([115, 116], reviewed in [117, 118]). The C. neoformans Gα subunit Gpa1 was found to be homologous in sequence to the S. cerevisiae Gα protein Gpa2 involved in nutrient sensing during pseudohyphal differentiation [10, 28, 119]. Gpa1 plays a key role in cAMP signaling and virulence [115]. gpa1 mutant strains are unable to mate, fail to induce melanin and capsule (Fig. 4), and are considerably attenuated for virulence in both rabbit and mouse models of cryptococcal meningitis [115, 116]. Melanin and capsule production in gpa1 mutants was restored by exogenous cAMP, suggesting that Gpa1 regulates cAMP production [115].
There is evidence to indicate that, unlike in S. cerevisiae, C. neoformans Ras1 does not primarily regulate cAMP production [120]. A ras1 mutant strain exhibited no defects in melanin or capsule production, two inducible cAMP-dependent phenotypes [115]. Furthermore, the mating defect of a ras1 mutant strain was only partially rescued by cAMP in contrast to full suppression of gpa1 by cAMP. Nevertheless, it appears that Ras1 may interact with the cellular machinery involved in cAMP production as suggested by the observation that the agar adherence defect of a ras1 mutant strain, tested by ability of cells in a colony to withstand gentle washing, can be suppressed by exogenous cAMP. The primary role of Ras1 instead appears to be regulation of the MAP kinase pathway in C. neoformans, analogous to the role of Ras homologs in S. cerevisiae and S. pombe [14, 41, 77, 121]. The mating defect of the ras1 mutant was fully suppressed by overexpression of GPB1, the gene encoding a MAP kinase-specific G-protein β subunit, and conversely, introduction of the dominant active RAS1Q67L allele into a gpb1 mutant strain did not restore mating competence, suggesting that Ras1 functions upstream of Gpb1 in the mating signaling pathway. The C. neoformans Ras1 protein is required for growth at 37°C and therefore virulence of this pathogen [120]. The temperature-sensitive growth defect of the ras1 mutant strain was not restored by either exogenous cAMP or overexpression of the GPB1[114], suggesting the presence of another, as yet unidentified, Ras-specific signaling cascade in C. neoformans. A second RAS gene, RAS2, was identified in the serotype A strain H99 (A. Alspaugh, unpublished results). Unlike ras1 mutants, ras2 mutants had no defects in mating, filamentation, growth at 37°C, or virulence. However, null mutations in both RAS1 and RAS2 genes resulted in dramatically reduced growth rate similar to the observation of growth arrest in S. cerevisiae when both RAS1 and RAS2 genes are inactivated [38, 39].
Unlike in S. cerevisiae, the C. neoformans PKA Pka1 is not essential for viability. However, PKA is required for both melanin and capsule production, and mating of C. neoformans[116]. Unlike gpa1 mutant strains, exogenous cAMP does not restore mating, melanin or capsule production in pka1 mutant strains, consistent with the model that Gpa1 regulates cAMP production, whereas Pka1 is the target of cAMP activation. pka1 mutant strains were also severely attenuated for virulence in two different animal models. To further analyze PKA function, the gene encoding the PKA regulatory subunit (PKR1) was identified and disrupted, both in wild-type and gpa1 mutant strains [116]. Consistent with the model that Pkr1 functions downstream of Gpa1, pkr1 mutations suppressed defects conferred by gpa1 in melanin production, capsule formation, and mating. This result also confirms that PKA mediates all of the known responses controlled by the Gpa1-regulated cAMP pathway. pkr1 mutants mate like wild-type but differ in their ability to produce capsule and melanin. pkr1 mutant cells produced larger capsules than the corresponding wild-type cells when grown in low-iron medium. Interestingly, the pkr1 gpa1 double mutant had an even larger capsule size and increased cell volume compared to the wild-type and gpa1 mutant strains. Increased capsule size in pkr1 gpa1 mutants is attributable to the elevated level of PKA activity, because high levels of exogenous cAMP are also known to enhance capsule production [115]. That pkr1 gpa1 mutant cells produced larger capsules than pkr1 single mutant cells suggests that Gpa1 may have targets in addition to the PKA pathway which inhibit capsule production. This is analogous to a similar role for the related S. cerevisiae Gα protein Gpa2, which inhibits the Ime2 kinase to prevent entry into meiosis, and also positively regulates cAMP production and pseudohyphal growth [10, 28, 36]. In a whole cell laccase assay, relative to the wild-type strain, pkr1 and pkr1 gpa1 double mutant strains exhibited lower levels of laccase activity as is the case when strains are exposed to high levels of exogenous cAMP, or when PKA1 is overexpressed [116]. This observation could result from an inhibitory function of elevated PKA activity in these strains.
pkr1 mutant strains were found to be hypervirulent by several measures in both rabbit and mouse models [116]. pkr1-infected mice exhibited decreased survival rates and significantly elevated fungal cell burden in the CNS relative to mice infected with wild-type. Additionally, pkr1 mutant strains were found to elaborate significantly larger capsules in the CNS of infected mice. Therefore, both larger capsule size and increased release of immunosuppressive capsular polysaccharides provide a plausible molecular mechanism for hypervirulence of pkr1 mutant strains. Such hypervirulent strains may be the cause of fungal infection in patients with no apparent defects in immune system [122–124]. Virulence was partially restored to the wild-type level in the pkr1 gpa1 double mutant strain, indicating that the virulence defect of the gpa1 mutant strain can be suppressed by constitutive activation of PKA. These findings further support the proposal that Gpa1 regulates virulence via the cAMP signaling cascade.
There is evidence indicating that crosstalk between the cAMP and MAP kinase signaling cascades may also occur in C. neoformans. One level at which this occurs may involve the G-protein Ras1. As mentioned earlier, C. neoformans Ras1 is responsible for activation of the pheromone-inducible MAP kinase cascade and also plays a secondary role in cAMP production. The transcription factor Ste12α is required for haploid fruiting, marginally functions in mating, and is required for melanin and capsule production [125–127]. Besides bearing consensus PKA phosphorylation sites, overproduction of Ste12α rescued the mating defect of a pka1 mutant strain [116]. However, Ste12α overproduction did not restore melanin or capsule production in a pka1 mutant strain, suggesting that Ste12α may represent one of several downstream targets of Pka1.
Overexpression of STE12α induced haploid fruiting in both wild-type and pka1 mutant strains cultured on filamentation agar (FA), indicating that PKA1 is not required for haploid fruiting when STE12α is overexpressed. However, since pka1 results in considerably reduced haploid fruiting in strains bearing the dominant active RAS1Q67L allele, Pka1 appears to play secondary role in haploid fruiting ([120]; D'Souza, C, unpublished results). Additionally, when cultured in filamentation liquid medium pronounced filamentation was observed in wild-type strains overexpressing STE12α, whereas scarce filamentation was observed in pka1 mutant strains overexpressing STE12α, indicating that hyphal formation under these conditions is in part dependent upon Pka1 [116]. Even after prolonged growth in liquid culture, the filaments lacked basidia or basidiospores, suggesting that other signals contribute to the induction of basidia and basidiospore production.
In summary, C. neoformans employs a highly conserved cAMP signaling pathway to regulate mating and virulence (Fig. 3). It remains to be determined how signals that induce melanin and capsule production and mating are integrated by Gpa1 into the cAMP signaling pathway. Unidentified components include the upstream GPCR and targets of PKA. The only Gβ subunit identified in C. neoformans is not coupled to Gpa1 function [114], suggesting that Gpa1 functions as a novel type of solo Gα subunit, or that unusual Gβγ partners or regulatory factors substitute for a canonical Gβγ subunit. Expected targets of PKA include transcription factors and metabolic enzymes. Ste12α is one of several candidate targets of PKA in the regulation of mating but not virulence in serotype A strains of C. neoformans. Rapid advances in the C. neoformans genome and cDNA sequencing projects should provide alternative resources to identify additional components of the cAMP cascade in C. neoformans. The conserved role of Ras proteins in regulating fungal growth and the involvement of cAMP cascade components in virulence presents these proteins as attractive targets for anti-fungal therapy.
Dimorphic transition and pathogenicity in U. maydis
The heterothallic, basidiomycete U. maydis is a maize pathogen that employs cAMP signaling to regulate dimorphic transitions during its life cycle (Fig. 3) (reviewed in [128–130]. Asexual haploid cells called sporidia have a yeast-like morphology and proliferate by budding. Mating between compatible partners results in cell fusion followed by a transition from the yeast form to an infectious dikaryotic mycelium. Hyphal proliferation within the plant tissue induces gall formation, followed by production of masses of diploid teliospores that germinate to initiate a new cycle. Establishment of the infectious dikaryon is regulated by two unlinked mating-type loci: a and b. The a locus encodes pheromones and pheromone receptors and controls cell–cell recognition and fusion [131]. The b locus encodes two homeodomain proteins, bE and bW, which dimerize when they are derived from different alleles to form a transcriptional regulator required for the production of stable infectious dikaryons [132–134].
Besides mating, additional factors influence cellular morphology of Ustilago species. In the presence of an abundant supply of glucose Ustilago cells exist in the sporidial form, whereas nutrient limitation, air exposure, or growth at acidic pH promotes filamentous growth in haploid cells [135–137]. Given the influence of glucose sensing on differentiation in budding and fission yeasts, it is tempting to speculate that a similar cAMP signaling mechanism may mediate glucose-regulated morphogenesis in U. maydis. Involvement of cAMP signaling in regulation of morphogenesis and virulence in U. maydis was indicated by the constitutive filamentous growth and avirulence phenotypes of an uac1 (Ustilago adenylyl cyclase) mutant [136, 138]. Exogenous cAMP restores budding growth in uac1 mutants and causes clustering of cells and multiple lateral budding even in wild-type strains, implicating cAMP regulation of both sexual development and cell cycle progression [136]. This is in contrast to S. cerevisiae cells in which high cAMP levels promote pseudohyphal growth. uac1 mutants cannot activate expression of pheromone-inducible genes indicating crosstalk between the cAMP and MAP kinase signaling pathways [139].
Another indication of crosstalk between the cAMP and MAP kinase signaling pathways was the identification of several components of the MAP kinase cascade as suppressors of uac1 [136, 140–142]. This genetic screen also led to the identification of ubc1 (Ustilago bypass of cyclase), which encodes the regulatory subunit of PKA [136]. ubc1 mutants exhibit a multiple budding growth pattern similar to cells treated with high concentrations of cAMP. Additionally, mating compatible ubc1 mutants are unable to form the dikaryotic mycelium both in vitro and in planta, and are compromised for virulence. Although colonization of the plant tissue and initial disease symptoms develop, tumor development is not initiated indicating that increased PKA activity promotes initial plant infection, whereas reduced PKA activity induces tumors [143]. Homozygous ubc1Δ diploids are also attenuated for virulence indicating that PKA regulates post-fusion events [143, 144]. Expression of pheromone-inducible genes in ubc1Δ mutants is increased to levels similar to that in cells treated with exogenous cAMP, or expressing a constitutively activated adenylyl cyclase [139].
Two genes, adr1 (aromatic dicarboximide resistance) and uka1 (Ustilago kinase A), that encode isoforms of the PKA catalytic subunit have been identified [144]. Disruption of adr1 causes constitutive filamentation in haploid cells similar to that of adenylyl cyclase mutants, and impairment of virulence in planta either in crosses or as diploid strains. No obvious phenotype was observed for the uka1 mutant, consistent with the assignment of Adr1 as the major PKA activity in U. maydis cells. adr1 uka1 double mutants were viable, suggesting that PKA activity is dispensable for growth of U. maydis, as is the case with many fungi with the exception of S. cerevisiae. adr1 uka1 double mutants were less filamentous than adr1 single mutants, revealing a minor role for Uka1 in filamentation. In contrast to inactivation of the cAMP cascade, moderate activation of the cAMP pathway by the constitutively active gpa3Q206L Gα subunit allele or a partial loss-of-function mutation in the regulatory subunit of PKA still induces tumors, but fungal proliferation and development in these tumors is arrested [145]. Thus, precise regulation of the cAMP pathway is necessary for fungal proliferation and development but not for tumor induction in planta. Interestingly, activation of the cAMP pathway in U. maydis results in coating of cells with an unidentified fibrillar material much like the capsule of C. neoformans. However, while the Cryptococcus capsule is regarded as a virulence factor, it remains to be established that aberrant tumor formation caused by gpa3Q206L strains is linked to formation of this capsule-like material.
Evidence originally suggested that the Gpa3 Gα subunit might be directly involved in pheromone sensing in U. maydis[146]. This was based on the observations that gpa3 mutants are sterile and fail to induce expression of mfa1 and the b genes in response to pheromone, whereas a constitutively active gpa3Q206L mutant allele caused overexpression of these genes. However, the evidence for specific involvement of Gpa3 in cAMP signaling is now unambiguous [139]. First, gpa3 mutants are avirulent and filamentous like uac1 mutants, and exogenous cAMP restores budding growth. Second, exogenous cAMP also restores mating and pheromone gene expression in gpa3 mutants to similar levels obtained upon pheromone stimulation. Third, the uac1 adenylyl cyclase mutation diminishes mfa1 gene expression in a gpa3Q206L mutant, indicating that Gpa3 functions upstream of adenylyl cyclase. Addition of higher amounts of cAMP results in decreased pheromone gene expression indicating that the level of PKA activity may normally be tightly regulated. Gpa3 shares a high level of sequence identity with the nutrient sensing Gα proteins of budding and fission yeasts, and C. neoformans (Gpa2, gpa2, Gpa1), suggesting that the U. maydis Gpa3 Gα protein will be coupled to a homolog of the S. cerevisiae Gpr1 and S. pombe git3 glucose receptors.
As with gpa3, uac1, and adr1 mutants of U. maydis, a fil1 mutant of its close relative Ustilago hordei, is also constitutively filamentous and is restored to budding growth by exogenous cAMP [147, 148]. Fil1 shares a high degree of sequence identity to the Gα subunit Gpa1 from the basidiomycete C. neoformans, required for virulence of this human pathogen [115, 119]. Like cAMP, overexpression of FIL1 also suppressed the filamentous growth of starved haploid wild-type strains, suggesting that Fil1 functions to activate adenylyl cyclase [148]. Interestingly, like C. neoformans Gpa1, Fil1 regulates production of a melanin-like pigment in teliospores produced on susceptible barley cultivars. cAMP and overexpression of FIL1 transiently repressed pigment formation, whereas the cAMP phosphodiesterase inhibitor isobutyryl-3-methyl xanthine (IBMX) completely repressed pigment formation [149]. Consistent with this, pigment formation was not observed in cells expressing the constitutively active mutant allele fil1Q206R.
Coordinate regulation of mating and pathogenicity in U. maydis by the cAMP and MAP kinase signaling pathways is mediated by Prf1, an HMG-box domain transcriptional regulator and a common target of both pathways [150]. Prf1 is necessary for mating-type gene expression and pathogenicity of this fungus [151]. Analysis of the prf1 promoter defined a cis-acting element which mediates both transcriptional activation by carbon sources, such as glucose and fructose, as well as repression by high levels of cAMP [151]. It has been proposed that divergent cAMP pathways regulate Prf1 activity and pathogenicity as observed in the rice blast fungus Magnaporthe grisea[152]. The positive effect of cAMP may be mediated by the Adr1 kinase, while transcriptional repression could be mediated by either another PKA catalytic subunit or by a PKA-independent mechanism.
In summary, the cAMP cascade regulates mating-type gene expression and pathogenicity of U. maydis (Fig. 3). Several lines of evidence indicate that signaling by the cAMP and MAP kinase pathways is coordinated, similar to the situation in S. cerevisiae, S. pombe, and C. neoformans. However, while the cAMP cascade positively regulates pseudohyphal differentiation in S. cerevisiae, it negatively influences filamentous growth in U. maydis. Crosstalk between the cAMP and MAP kinase pathways in U. maydis has been shown to be mediated by the transcriptional regulator Prf1, and divergent cAMP pathways have been proposed to regulate Prf1 activity and pathogenicity. It remains to be investigated how environmental signals regulate dimorphism of U. maydis in the absence of pheromone stimulation. Additionally, it would be interesting to identify other levels at which the cAMP pathway crosstalks with the MAP kinase pathway, and additional targets of PKA in this organism. The possible involvement of divergent cAMP pathways also opens new avenues for future studies on cAMP signaling in U. maydis. Here we have highlighted interesting parallels between the two basidiomycetes, U. maydis and C. neoformans, with respect to regulation of virulence by the cAMP cascade in these fungi. Further studies to identify new components and targets of this cascade can take advantage of similarities in cAMP signaling cascades between these fungi.
Conclusions and perspectives
It is apparent from the above discussion that cAMP signaling cascades are remarkably conserved in divergent fungi. Differential control of related biological processes in fungi and other eukaryotes is achieved by alterations in the mechanisms by which PKA targets are regulated. Thus, PKA either activates or inhibits transcriptional activators or repressors to achieve specificity. The wealth of information derived from studies of the cAMP signaling pathway in model yeasts like S. cerevisiae and fungi described here can now serve as reference material for excursions into, as yet uninvestigated, cAMP signaling pathways in other fungi, or even to revise current models for regulation by cAMP signaling. Superimposed on the framework of this cascade, depending on the organism, are interactions with the MAP kinase cascade. Given the complexity of signal transduction networks in cells, it will not be surprising to find similar interactions with other existing signal transduction pathways. With significant technological innovations in the areas of functional genomics and bioinformatics, it is only a matter of time before these signal transduction pathways will reveal their secrets.
We thank Carlos Gancedo for the invitation to prepare this review and Tina Jeffries for assistance with preparation of this manuscript. Our work is supported by NIAID R01 Grants AI39115 and AI42159 (to J.H.) and P01 award AI44975 from NIAID to the Duke University Mycology Research Unit. J.H. is a Burroughs Wellcome Scholar in Molecular Pathogenic Mycology and an associate investigator of the Howard Hughes Medical Institute.


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The Nürburgring, Germany's legendary Formula One racing circuit, faces the prospect of bankruptcy and possible closure next week, because the private operating company which runs it has failed to meet debts estimated to be €500m (£390m).
The 25km (15.5m) circuit, which opened in 1927, rates as one of the world's most famous. Every two years it hosts tens of thousands of spectators who descend on the motorsports complex in the village of Nürburg near Koblenz to watch Formula One. But last week the state of Rhineland-Palatinate, which owns the complex, announced that it would ask the operating company, Nürburgring GmbH, to file for insolvency. Bankruptcy proceedings could begin next week.
Kurt Beck, the state's prime minister, has blamed the European Commission for the impending insolvency, claiming that its failure to approve a €13m state-aid package in time for a payment deadline at the end of July has put the future of the 'Ring in jeopardy. He said that "insufficient liquidity" meant that insolvency was "highly probable".
The circuit has operated at a loss for years. But its most serious problems began in 2004 when it started building an amusement park and hotel complex; both have failed to attract sufficient visitors. A new track was built in 1984 to accommodate Formula One racing, which has alternated between Nürburg and the nearby Hockenheimring since 2007.
Media reports suggest that Nürburgring has debts of €496m and that the company is no longer able to pay interest on a €330m loan provided by a state-owned bank. The EU has already backed the provision of millions in funding in an attempt to salvage the track, and officials have recently signalled their reluctance to approve further payments. Last-minute approval of the €13m package could still save the Nürburgring from insolvency.
- More about:
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- Financial Difficulties
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Research Topics
Mark Linzer
Affiliation: Hennepin County Medical Center
Country: USA
Research Grants
Detail Information
- A Cluster Randomized Trial of Interventions to Improve Work Conditions and Clinician Burnout in Primary Care: Results from the Healthy Work Place (HWP) StudyMark Linzer
Division of General Internal Medicine, Hennepin County Medical Center, Minneapolis, MN, USA
J Gen Intern Med 30:1105-11. 2015..Work conditions in primary care are associated with physician burnout and lower quality of care...
- Part-time careers in academic internal medicine: a report from the association of specialty professors part-time careers task force on behalf of the alliance for academic internal medicineMark Linzer
Section of General Internal Medicine Scholars, Department of Medicine, University of Wisconsin Madison, Madison, Wisconsin, USA
Acad Med 84:1395-400. 2009....
- Separate and unequal: clinics where minority and nonminority patients receive primary careAnita B Varkey
Department of Medicine, Loyola University Medical Center, 2160 S First Avenue, Maywood, IL 60153, USA
Arch Intern Med 169:243-50. 2009..We compared 96 primary care clinics in New York, New York, and in the upper Midwest serving various proportions of minority patients to determine differences in workplace organizational characteristics...
- Working conditions in primary care: physician reactions and care qualityMark Linzer
University of Wisconsin School of Medicine and Public Health, and Medical College of Wisconsin, Madison, Wisconsin 53705, USA
Ann Intern Med 151:28-36, W6-9. 2009..Adverse primary care work conditions could lead to a reduction in the primary care workforce and lower-quality patient care...
- Respecting the lifecycle: rational workforce planning for a section of general internal medicineMark Linzer
Department of Medicine, University of Wisconsin Medical School, Madison, Wisconsin 53705, USA
Am J Med 113:443-8. 2002
- Shared decision making in the safety net: where do we go from here?Angelique B Bouma
The Department of Medicine, the Minneapolis Medical Research Foundation, and the Division of General Internal Medicine, Hennepin County Medical Center, Minneapolis, MN the Department of Sociology and Anthropology, University of Lumière, Lyon, France the Department of International Health, CAPHRI School for Public Health and Primary Care, Maastricht University, Maastricht, Netherlands Knowledge and Evaluation Research Unit, Department of Health Sciences Research, Mayo Clinic, Rochester, MN and the Department of Medicine, University of Minnesota, Minneapolis, MN
J Am Board Fam Med 27:292-4. 2014..Clinics serving safety net patients face special challenges, including fewer resources and more challenging work environments. The use of SDM within safety net institutions has not been well studied...
- Physician perspectives on quality and error in the outpatient settingLinda Baier Manwell
Section of General Internal Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
WMJ 108:139-44. 2009..Little is known about the influence of the primary care workplace on patient care. Assessing physician opinion through focus groups can elucidate factors related to safety and error in this setting...
- Exploring the generalist-subspecialist interface in internal medicineMark Linzer
Section of General Internal Medicine, University of Wisconsin, Madison, WI 53705, USA
Am J Med 119:528-37. 2006
- Worklife and satisfaction of general internistsTosha B Wetterneck
Department of Medicine, University of Wisconsin Hospital and Clinics, 600 W Highland Ave, J5 214 Clinical Science Center, MC 2454, Madison, WI 53792 2454, USA
Arch Intern Med 162:649-56. 2002..Prior studies have reported relatively low job satisfaction for general internists. We used data from a large US physician survey to assess correlates of satisfaction of general internists...
Research Grants1
- Minimizing Error, Maximizing Outcome (MEMO): The Physic*Mark Linzer; Fiscal Year: 2003..We also anticipate being able to answer questions about women and minority physicians, groups that are typically underrepresented in physician-centered research. ..


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I have read a lot of articles and rants here and there over the internet. I got to say it just shows the community and the interest in a game still talked about 2 years after its initial release on PC back in 2012.
I purchased Diablo 3 day one of it's release. I was so excited to play it since I had been keeping up with the 'talk of the day' ever since it was first spoken about over 10 years ago. I loved it, I was excited as any fan boy would be to play another in a loved franchise.
After a few months to half a year I started to become a little dissatisfied with the end game result. I think I can speak for everyone out there that it was nothing special, just another "PAY TO WIN" title. Which is partly a fair and unfair statement at best. The game was made for old and new players. Blizzard are a business just like any other, they need to make money. That said, there must always be that spark of post game interest (especially for the hardcore fanbase). This turned out to be not the case, as even the hardcore fanbase were the proprietors of the downfall of this title. Saddening to say the least.
After a year or so, I heard about a console version in production. I was excited but also concerned that I just spent my money on a PC version loved but hated by many who bought into it. Only to find myself purchasing yet again for the Xbox 360.
I mainly bought the console port to play on the couch with my pals while we sipped bear and flung bits of food on plates in the air from shear excitement of every elite, boss pack we found outselves struggling against.
For the most part, we enjoyed our time with Diablo 3 on the console. After a few months again, it grew a tad stale as the multiplayer community started dwindling yet again and found ourselves running around wondering what to do next.
Enter Reaper of Souls announcement... Boy was I excited to hear about a new crusader class, adventure mode and a complete overhaul of the loot system. When I heard about this I immediately jumped back on the PC version to see what changes were made and was surprised that the new system was in place.
Ive got to say, its a blast from the past. (I know corny as hell...) but you'll understand why I say the past.
This game now reminds me of my youth with Diablo 2 and when Lord of Destruction first hit the shelves in game stores all over the world. I dont think I need to say just how much I enjoyed that game to compare it to Reaper of Souls. But I will definitely say that the new Diablo 3 as a whole on the PC is just what everyone was expection day 1 launch back in 2012.
Now I'm sitting here wondering, which version do I prefer...
I have a casual version of the game for when my friends come over and want nothing better to do than eat, drink and slaughter monsters and who am I to deny them?
Or, I have what I would consider a much more updated and hardcore version of Diablo 3. Even without the expansion alone, the game is incredible. I love every change Blizzard have made, and I am so glad that the RMAH (Real Money Auction House) was removed entirely from the game before the release of Reaper of Souls on PC.
What now concerns me about these two version is, I consider the PC version far superior in every way compared to the Console version for a number of reasons.
Such as:
The new 2.0.1 loot system put in place for the launch of Reaper of Souls, far outweighs the loot system on the console version.
In spite of the new system being put in place for the release of the expansion, the entire game plays and feels completely different to console, and I'm not just saying control wise either. Difficulty levels have been changed and improved so as to stop replaying the entire story four times over to get to the max level.
I won't list every reason, we all know what they are, and you're welcome to add and critique on any of mine or eachothers opinions in the comments below.
As for now, I want to know whether these changes pre expansion will be patched to the console versions.
There is no reason it cannot be done, unless Blizzard are unfocused on the PS3/Xbox360 version as its been released and essentially done with. But considering that these two consoles may not EVER see a release of Reaper of Souls. Would it not at least be fair to update the game to the current version it's in on the PC pre expansion?
Who knows, maybe they might even have the PS3 and Xbox 360 versions available on launch when the PS4 and Xbox One versions release some time this year. It's all speculative as of now.
Please comment below and give your thoughts on this. I apologise in advance if this has been covered many times in the past. I haven't really found a discussion regarding the two versions without a rant on PC over console superiority breaks out.
Thanks and Happy Gaming


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Thor Clsup-3 Large Button 6/pk
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Embellish your superhero-themed collection of clothes and accessories with the charming and bold C&D Visionary Marvel Comics Large Button Pack. This pack contains six identical 3-inch round metal buttons. Simply decorate your jackets, sweaters, jeans, bags, fashion accessories and more with these metal buttons. Choose from a wide range of themes and designs that are available to suit your needs.
- Brand: C&D Visionary
- Theme: Thor Close-Up
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Lot 224: Antique Painted Metal Figural Lock Makers Sign
"Mantiques" Auction - October 2016
by Terri Peters & Associates
October 28, 2016
Syracuse, NY, USALive Auction
Looking for the realized and estimated price?
Description: Antique Painted Metal Figural Lock Makers Sign, in the form of a giant padlock, late 19th early 20th century, remains in very good original condition with repainted surface, scatered paint loss, minor loss to metal,
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Real Estate in Hydesville, CA
Hydesville is located in California. Hydesville, California has a population of 1,250. Hydesville is less family-centric than the surrounding county with 23.08% of the households containing married families with children. The county average for households married with children is 27.31%.
The median household income in Hydesville, California is $54,493. The median household income for the surrounding county is $40,830 compared to the national median of $53,046. The median age of people living in Hydesville is 43.2 years.
Hydesville Environment
The average high temperature in July is 69 degrees, with an average low temperature in January of 40.1 degrees. The average rainfall is approximately 48.5 inches per year, with 0.4 inches of snow per year.
Hydesville Map
Hydesville Real Estate offices
Real Estate near Hydesville
Nearby Cities
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Nearby Cities Homes for Sale


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1. Preheat the oven at 200 degrees C or 400 F.
2. Heat a pan on medium flame and add oil into it.
3. Add 1 or 2 onions and check if you hear crackling sound.
4. Then add the onions and stir until brownish in color.
5. Add garlic and cook for 3-4 minutes until soft.
6. Add 2 tablespoon honey and ketchup, chili sauce and soy sauce and mix well.
7. Keep mixing until a nice texture is attained remove from stove and let it cool.
8. Line a baking tray with foil and spray oil over it.
9. Dust the chicken with flour, dip it generously in the cooked sauce and arrange on the prepared baking tray.
10. Roast in the oven for 30 minutes.
11. Remove from the oven and check for doneness using a fork.
12. Place on a serving plate and serve with garnish of cilantro, tomatoes and onions.
Serving size Per servingComplete recipe
Calories 357 Calories from Fat 90
% Daily Value*
Total Fat 10 g15.4%
Saturated Fat 2.1 g10.5%
Trans Fat 0 g
Cholesterol 140 mg46.7%
Sodium 341.9 mg14.2%
Total Carbohydrates 19 g6.4%
Dietary Fiber 0.77 g3.1%
Sugars 11 g
Protein 44 g88%
Vitamin A 2.3%
Vitamin C 11.7%
Calcium 3.3%
Iron 12.6%
*Based on a 2000 Calorie diet


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Category Archives: British Royals← Older posts Newer posts →
Queen Elizabeth Presents New Colours to The Royal Welsh
Queen Elizabeth II travelled to Cardiff, Wales today for the presentation of The Royal Welsh's new colours. The ceremony took place at Millennium Stadium, where the Queen entered in an open-top Range Rover ahead of inspecting the 600 troops gathered for the event (they had marched from Cardiff Castle to the Stadium earlier in the morning). The formal presentation officially marks the 2006 merger of three Welsh regiments into The … Continue readingPosted in British Royals | Tagged Elizabeth II of the United Kingdom, Military, Wales | Leave a comment
Charles and Camilla Host Tea For World War Two Veterans
The Prince of Wales and the Duchess of Cornwall hosted an intimate tea at Clarence House this afternoon for veterans from the Battle of Britain Fighter Association. Prince Charles and Duchess Camilla were joined by seven veterans and members of their families for sandwiches, scones and tea. The couple had lengthy chats with the former pilots and aircrew, discussing a number of topics including the changes in helicopters over the decades … Continue readingPosted in British Royals | Tagged Battle of Britain, Patronage, Princess Charlotte of Cambridge, The Duchess of Cornwall, The Prince of Wales, Veterans, World War II | 2 Comments
See You in 100 Days! Prince Harry Launches Rugby Cup Tour
As the Honorary President of England Rugby 2015, Prince Harry was today present at the launch of the 2015 Rugby World Cup Trophy Tour at Twickenham Stadium. The Prince was joined by rugby legends Jonny Wilkinson and Will Greenwood for the launch. Harry gave a speech during the event, saying that "Rugby is a game built on values – respect, pride, team work and discipline. In 100 days' time, England … Continue readingPosted in British Royals | Tagged Patronage, Prince Harry of Wales, Sport | 1 Comment
British Royals Attend Gurkha Anniversary Pageant
Queen Elizabeth II, the Duke of Edinburgh, the Prince of Wales and Prince Harry attended a pageant at the Royal Hospital Chelsea today to celebrate 200 years of Gurkha service to the British Crown. They were joined by the Sultan of Brunei, Hassanal Bolkiah, for the event. View image | gettyimages.com A large display of battle reenactments and Nepalese cultural displays honoured the Gurkhas, Nepalese soldiers who have served in the … Continue readingPosted in British Royals, Brunei Royals | Tagged Anniversary, Elizabeth II of the United Kingdom, Military, Prince Harry of Wales, Sultan Hassanal Bolkiah of Brunei, The Duke of Edinburgh, The Prince of Wales | Leave a comment
The Duchess of Cornwall Unveils Winston Churchill Memorials
The Duchess of Cornwall headed west to Oxfordshire today to unveil new memorials to Britain's wartime Prime Minister, Sir Winston Churchill. She first unveiled a stained glass window designed by Emma Blount at St Martin's Church in Bladon that bares images associated with Churchill. The Duchess also laid a small bouquet of flowers on the grave of Churchill and his wife Clementine in the church's graveyard. View image | gettyimages.com Afterwards, Camilla travelled to nearby … Continue readingPosted in British Royals | Tagged Memorial, Prime Minister Churchill of the United Kingdom, The Duchess of Cornwall, The Duke of Marlborough | 1 Comment
First The Queen, Now Prince Harry! Lady Gaga Continues Completing Her Royal Collection
She met Queen Elizabeth at the Royal Variety Performance in 2009, and now Lady Gaga has met Prince Harry. The duo were introduced at the Royal Albert Hall this evening, where the American singer gave a jazz concert alongside the legendary Tony Bennett. The concert was held in aid of WellChild, one of the Prince's charities. "We think you are fantastic," Lady Gaga said to Harry as they posed for … Continue readingPosted in British Royals | Tagged Celebrities, Concert, Music, Patronage, Prince Harry of Wales | 1 Comment
Princess Anne Reopens Lincoln Castle
The Princess Royal today reopened Lincoln Castle in Lincolnshire and viewed their exhibition on the Magna Carta. A crowd of around 2,500 were invited to attend the event, where the Princess unveiled a plaque to commemorate the reopening in the castle's East Wing. Princess Anne then was shown around the castle walls – which had been restored meaning the public can now access more of the castle than before – and toured … Continue readingPosted in British Royals | Tagged The Princess Royal | Leave a comment
Kensington Palace Release First Photos Of Princess Charlotte
On June 6, the first official photos were released of Princess Charlotte of Cambridge by Kensington Palace via their Twitter account. Princess Charlotte is pictured, in an adorable set of four photos, with her brother Prince George at their Norfolk home, Anmer Hall. The photos were taken by their mother, the Duchess of Cambridge, in mid-May. View image | gettyimages.com Princess Charlotte Elizabeth Diana of Cambridge was born on May … Continue readingPosted in British Royals | Tagged Portraits, Prince George of Cambridge, Princess Charlotte of Cambridge | 1 Comment
Royals Head To Isle of Wight For Royal Yacht Squadron Bicentenary
A number of royals descended on the Isle of Wight today, to attend events marking the bicentenary of the Royal Yacht Squadron. The Duke of Edinburgh led the British contingent consisting of the Earl and Countess of Wessex, the Princess Royal and Vice Admiral Sir Timothy Laurence, and Prince Michael of Kent. They were joined by Norwegian King Harald V (on board the Norge), Prince Albert II of Monaco, Denmark's Prince … Continue readingPosted in British Royals, Danish Royals, Greek Royals, Monaco Royals, Norwegian Royals | Tagged Albert II of Monaco, Anniversary, Constantine II of Greece, Crown Prince Pavlos of Greece, Crown Princess Pavlos of Greece, Harald V of Norway, Prince Henrik the Prince Consort, Prince Michael of Kent, Queen Anne-Marie of Greece, Sailing, Sport, The Countess of Wessex, The Duke of Edinburgh, The Earl of Wessex, The Princess Royal, Vice Admiral Sir Timothy Laurence, Yachts | 1 Comment
Princess Charlotte To Be Christened On July 5
Kensington Palace has confirmed that Princess Charlotte, the daughter of the Duke and Duchess of Cambridge, will be christened on July 5. The christening will take place at the St Mary Magdalene Church in Sandringham, and will be performed by the Archbishop of Canterbury, Justin Welby. View image | gettyimages.com Princess Charlotte was born on May 2 at St Mary's Hospital and is fourth in line to the throne.Posted in British Royals | Tagged Christening, Princess Charlotte of Cambridge | 3 Comments
Prince Harry Appointed to the Royal Victorian Order
Queen Elizabeth II has appointed her grandson, Prince Harry, a Knight Commander of the Royal Victorian Order, Buckingham Palace announced this afternoon. The presentation took place privately at Buckingham Palace today. The Royal Victorian Order, founded by Queen Victoria in April 1896, is given to people who have "served the Queen or the Monarchy in a personal way." It is the first royal order that Prince Harry has received. View image | … Continue readingPosted in British Royals | Tagged Elizabeth II of the United Kingdom, Prince Harry of Wales, Royal Orders, Royal Victorian Order | 2 Comments
Sophie Wessex Hosts Garden Party for Blind Veterans UK
After attending the Women's Institute Centenary Meeting in the morning, the Countess of Wessex hosted a garden party at Buckingham Palace to mark the 100th anniversary of another organisation, Blind Veterans UK. Sophie, in an aquamarine blue dress and matching bolero jacket, met with a number of veterans from all areas of the armed forces that have been helped by the charity. Over 2,000 guests attended the garden party. View … Continue readingPosted in British Royals | Tagged Anniversary, Garden Party, Health, Military, The Countess of Wessex | Leave a comment
The Duke of York Attends Founder's Day Parade at RHC
Prince Andrew, Duke of York was present at the Founder's Day Parade at the Royal Hospital Chelsea this morning, where he took the salute from veterans during the parade. The Duke also delivered a speech, in which he called the Chelsea Pensioners – the veterans who live at the Royal Hospital Chelsea – "epitomes of what we would classify as service to the crown." View image | gettyimages.com "The lifelong service … Continue readingPosted in British Royals | Tagged Ambassador, France, Military, The Duke of York, World War II | Leave a comment
Queen Elizabeth Celebrates Women's Institute Centenary
Queen Elizabeth II was joined by the Princess Royal and the Countess of Wessex this morning at the Annual General Meeting of the Women's Institute at the Royal Albert Hall to mark the organisation's 100th anniversary. The royal trio – who are all members of their local WIs – were welcomed on stage at the Hall by 5,000 members of the WI from around the country. The Queen delivered a … Continue readingPosted in British Royals | Tagged Anniversary, Elizabeth II of the United Kingdom, The Countess of Wessex, The Princess Royal | Leave a comment
On This Day: Birth of George V of the United Kingdom
June 3, 2015 marks the 150th anniversary of the birth of King George V of the United Kingdom. George Frederick Ernest Albert was born at Marlborough House in London as the second son of the then Prince of Wales, Albert Edward, and his wife Alexandra of Denmark. He had five siblings: Prince Albert Victor, Princess Louise, Princess Victoria, Princess Maud and Prince Alexander John. The Prince was educated with his elder brother, … Continue readingPosted in British Royals, Historical Royals | Tagged Anniversary, Birth, George V of the United Kingdom | 1 Comment
The Duchess of Cornwall Attends Royal Academy of Arts Annual Dinner
The Duchess of Cornwall tonight attended the annual dinner of the Royal Academy of Arts at Burlington House in London. Among the attendees enjoying a preview of the Academy's 247th Summer Exhibition alongside the Duchess were Joan Collins and Grayson Perry. View image | gettyimages.com The Duchess wore a white evening gown paired with the diamond Cubitt Shand Tiara and the sash and badge of the Royal Victorian Order. The … Continue readingPosted in British Royals | Tagged The Arts, The Duchess of Cornwall | Leave a comment
British Royal Ladies At Garden Party For Women's Institute
Today, several of the ladies of the British Royal Family were present at a Buckingham Palace garden party to honour the 100th anniversary of the Women's Institute (WI). The Duchess of Cornwall hosted the event which was attended by the Countess of Wessex, the Duchess of Gloucester and Princess Alexandra of Kent. The ladies met with a number of members of the WI, one of the largest women's volunteer organisation … Continue readingPosted in British Royals | Tagged Garden Party, Princess Alexandra Lady Ogilvy, The Countess of Wessex, The Duchess of Cornwall, The Duchess of Gloucester | 2 Comments
Prince Charles on Private Visit to Romania
The Prince of Wales is currently on a private visit to Romania, where he has launched a new foundation, The Prince of Wales' Foundation Romania. The aim of the foundation is to "support heritage preservation, agriculture and sustainable development in Romania", as well as education, and will be based in the village of Viscri, located in Brașov County where the Prince has two 18th century houses. The house will be renovated into a … Continue readingPosted in British Royals, Romanian Royals | Tagged Crown Princess Margareta of Romania, Patronage, President Iohannis of Romania, Prince Radu of Romania, The Prince of Wales | 1 Comment
William and Harry's Polo Sunday at Audi Polo Challenge
Princes William and Harry today took to the polo field at Coworth Park in Berkshire, participating in the second day of the Audi Polo Challenge. The two brothers played in aid of three of the charities they are patrons of: WellChild, CentrePoint and Child Bereavement UK. During the trophy presentation, Prince William was given a pair of pink gumboots for Princess Charlotte. View image | gettyimages.com After the match, William and Harry spent … Continue readingPosted in British Royals | Tagged Celebrities, Polo, Prince Harry of Wales, Sport, The Duke of Cambridge | Leave a comment
Prince William Attends FA Cup Final
Prince William attended the FA Cup Final today at Wembley Stadium between Arsenal and Aston Villa, which happens to be the team the Prince follows. Arsenal took home the trophy in a convincing 4-0 win, William – as President of the Football Association – presented the trophy to the winning team's captain at the end of the match. View image | gettyimages.com Earlier in the day, Prince William called on … Continue readingPosted in British Royals | Tagged Football, Patronage, Sport, The Duke of Cambridge | Leave a comment


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Combo MesterPick and mix any elements you can find from the list on the top of the screen together for unlocking many new elements! Iron plus fire equals to metal.
Jigsaw City TripPiece together beautiful city views in this jigsaw puzzle game. Connect the pieces to explore different cities in the world.
Piece Of PieCollide identical pieces and combine them to a new tile. Keep combining until you make a pie! A new and fresh way to play the classic, addicting 2048 game!!
Daily MahjongComplete the game by removing all mahjong tiles. Stay zen and enjoy this classic game with daily challenges!
Trans BlockiesTransform the poly, rectangle and oval figures to remove the purple baddies.This addictive physics puzzle game gets harder through more than 60 levels.
Grand Dot 2048
Classic 2048 game where numbered tiles are designed as dices. Use strategy and puzzle solving skills to get your highscore!


text:
Lightning Storm LWP!
by: Access Lane, Inc. • 34
All Android applications categories
All Android games categories
by: Access Lane, Inc. • 34
Create the perfect lightning storm for your phone with this live wallpaper. Watch the lightning strike, clouds roll by and rain drench your screen.
Includes settings for:
- Screen Orientation
- Enable Touch To Stop
- Number of Clouds
- Rain Amount
- Cloud Speed
- Rain Speed
- Lightning Strike Frequency
- Cloud, cloud light up & lightning strike color
TO USE: Home -> Menu -> Wallpaper -> Live Wallpapers
Live Wallpapers are NOT SUPPORTED on all phones, please check for the Live Wallpapers menu on your phone (see the TO USE section regarding how to check for this menu).
Tags: lightning storm , lightning storm lwp\! , lightning storm lwp , lightning storm lwp .apk , lightning storm lwp apk , lightning storm 1.3 , lightning storm wallpaper hd
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