Whether you are a long and lanky seasoned swimmer or short and muscular newbie or any combination of the two at some point, you want to increase your speed in the water. Swimming offers one of the best total body workouts. It’s also an excellent cross training exercise. Because the whole body is involved, however, many techniques offer opportunities to become a faster swimmer.
Commit to Workouts
Olympic swimmer and Masters swim coach Whitney Hedgepeth recommends a minimum of three to four swim workouts each week. Any less and your progress will either plateau or reverse. Alternate early morning workouts with afternoon or evening workouts. See which time feels best for you some people find it difficult to wake up to swim. If working out at the end of the day suits your schedule, don’t jump into a cold pool first thing in the morning. Find the time that suits your schedule so you can commit to regular swim workouts.
Focus on Technique
New research, highlighted in "The New York Times" in July 2012, shows that, contrary to long held beliefs of elite swim coaches and athletes, a deep catch stroke creates more lift and propulsion than the traditional sculling motion. Swimmers typically have been coached to make an S shape with their arms during the underwater, or catch, phase of their freestyle. Scientists now know that this motion actually creates drag and slows forward movement. A single long and deep catch creates the added lift a swimmer needs to increase speed.
Strength Training Out Of The Water
A deep catch stroke requires more arm, back and shoulder strength than a sculling stroke because the arms have more water to move. USA Swimming recommends a total body strength routine two to three times per week, however, to prevent muscle imbalance and avoid overtaxing upper body muscles already so heavily relied upon in the pool. Low weight, high rep circuit workouts are a good option.
Use Your Flip Turns
Don waste valuable seconds on the wall; just flip. Olympian Hedgepeth says flip turns are tantamount to speed. If you don already do flip turns, practice somersaults in the middle of the pool. Focus on tucking your knees to your chest as tight as possible. When you are ready to flip on the wall, swim until you are about one stroke away, tuck, flip and push off. If you already do flip turns, make them faster. Planks and crunches strengthen abdominal muscles. Jump squats and lunges strengthen legs, hips and buttocks. A hardier core and stronger legs mean less time on the walls.
A tight streamline off the flip turn also increases speed. Don let your shoulders sag and your elbows bend. Instead, flip, push off, and be extremely mindful of straightening your arms behind your head, making your body as long as possible, like a bullet. With practice, efficient streamline becomes second nature.
cheap longchamp bags
cheap moncler
the north face outlet uk
cheap ray bans
cheap longchamp
moncler outlet uk
ray ban outlet uk
longchamp outlet uk
ray ban sunglasses uk
cheap michael kors
cheap moncler uk
cheap north face
cheap moncler outlet
cheap moncler jackets
cheap the north face
cheap moncler uk
michael kors outlet uk
moncler outlet online
moncler outlet uk
cheap ray bans uk
cheap longchamp uk
相关的主题文章：
The men, aged 30 and 31, were taken to Napier police station where they were charged with possession for supplying methamphetamine and possession of drug utensils.
Auckland police said the bust has led to numerous leads and more arrests were highly likely as a larger investigation was now underway.
Detective Inspector Ross McKay said the find was a massive win for the communities the drugs were destined for.
"We believe that the supply ring was carrying out its illicit activity between the central and upper North Island, and the methamphetamine was destined for the Hawkes Bay and Tararua areas," he said.
"The supply and dealing of illicit drugs knows no boundaries and this seizure is a major success for these communities."
The 30 year old man appeared in Napier District Court and was remanded in custody. He was due to reappear in Dannevirke District Court on August 21.
Police are continuing to question the 31 year old man. He was remanded on bail and will appear in Napier District Court later this week.
A police spokeswoman said the bust was largest in both the Hawkes Bay and Tararua areas in recent years.
cheap moncler
cheap moncler uk
cheap moncler jackets
cheap ray bans
cheap north face
cheap the north face
cheap longchamp uk
cheap ray bans uk
ray ban sunglasses uk
moncler outlet online
cheap longchamp
cheap moncler uk
michael kors outlet uk
ray ban outlet uk
moncler outlet uk
cheap longchamp bags
moncler outlet uk
the north face outlet uk
cheap moncler outlet
longchamp outlet uk
cheap michael kors
相关的主题文章：
The Chrysler Neon is a car that offers an unusual proposition. Because it doesn’t fit into the pat pigeonholes into which we slot most of our cars, many buyers have been confused as to exactly what they’re getting. On the one hand, the car was initially marketed as an economy car, but the 1999 restyle saw it gain some more upmarket aspirations. What is a Neon and, more importantly, does it cut the mustard as a used proposition?Although it still fails to offer the sophistication of cars like the Ford Focus, the Neon does offer a lot of metal for the money and a degree of exclusivity. Used examples aren’t too thick on the ground, but the plus side is that most have been well looked after. Covered:Neon 1999 to date: 2.0 saloon [SE, LX, R/T]The Neon was first launched on a wave of publicity back in 1996, Chrysler bringing the car to the UK as an aside to their right hand drive push for the Japanese market. The early cars were peppy and enthusiastic but rather unrefined and markedly lacking in sophistication. The cheap and cheerful angle didn’t cut it with British buyers who were used to genuinely cut throat pricing from Korean rivals.The second generation car was a different kettle of fish. Better built, smoother, more luxuriously equipped and with a marketing push that was better tailored to the UK market it seemed to have what it took to succeed. It seems few of you agreed and sales slowed to a trickle. Initially available in SE and LX guises, the entry level SE was deleted in 2001, and a sporty R/T variant was introduced.What You GetThis BMW 3 Series sized saloon is good value in plush LX form, no question and it’s worth stepping up to the LX from the somewhat sparse SE version. For the same kind of money, all you’d get is a pretty ordinary 1.6 litre Vauxhall Astra or Ford Focus. The Neon, on the other hand, comes with a 136bhp 2.0 litre engine, leather trim, twin front airbags, air conditioning, ABS, power steering, alloy wheels, traction control, woodgrain trim, a six speaker stereo and the option of automatic transmission. You can even get a sporty R/T version with bodykit, alloys and an uprated 150bhp engine.It helps that all the improvements are shrouded in smart bodywork that sets the Neon firmly apart from apparent Korean rivals like Hyundai’s Elantra, Daewoo’s Nubira and Kia’s Shuma. Where these cars continually remind you of the money you’ve saved, the Neon feels a class above. The people who tend to buy this car in the UK (the average ownership age is 53) will love all of this.The cabin is a world away from the cheap plastic fittings that characterised the old one. Soft touch materials are everywhere and most of the switchgear is well placed and easy to find. Criticisms are limited to a steering wheel that adjusts only for rake and not for reach and a rather strangely angled windscreen that can make it slightly awkward to see things like traffic lights when you’re directly below them.There’s a reasonable amount of space too enough to make downsizing into Neon ownership a realistic proposition for owners of larger Mondeo and Vectra sized models. Rear seat passengers get more room for hips, shoulders and heads, plus there’s more space for their luggage, thanks to a 13.1cuft boot accessed through 60/40 split folding rear seats.What You PayRefer to Car Driving for an exact up to date valuation section.What to Look ForNo major areas of concern have surfaced since the Neon has been on sale, so provided the car has been maintained according to the service schedule, all should be well. The interior trim is better than the old cars and there have yet to be any noteworthy issues regarding the reliability of the 2.0 litre engine. Even the R/T model is unlikely to have had its tyres shredded by the largely mature ownership clientele.(Based on a 1999 Neon SE, excl VAT) A full exhaust system will be about Brake pads front and rear are about and a starter motor is about and an alternator around You’ll pay around for a new door mirror, roughly for a radiator and about for a replacement windscreen.On the RoadIn terms of driving dynamics, the Chrysler is still no sports saloon. To be fair, you wouldn’t expect that of a car from the land of freeways and 50mph speed limits. Having said that, the on the road experience is much improved, thanks to anti roll bars on both axles.Rightly however, the engineers spent more of their time trying to improve the ride, stiffening the body by 26% and redesigning the independent suspension set up using techniques borrowed from larger models. As a result, though low speed ride could still be better, at cruising speeds the Neon is much improved, again giving the feeling of a much larger car. If you feel the standard Neon is a touch soft, the R/T corners a little more faithfully, although still not as well as a standard Ford Focus. The R/T is certainly the Neon to go for if you want to make quick progress.Cast into the rocker cover is the legend ‘2.0L High Output’ which may sound like a serious power unit, but the truth is somewhat more prosaic. It’s basically an uprated version of the 2.0 litre engine that powers the standard Neon models, tweaked to produce 150bhp. Whilst not at the forefront of engine technology, this powerplant nevertheless offers a willing level of performance for the money. It’s able to hit 60mph in 9.4 seconds and run on to a top speed of 132mph, so you won’t be able to accuse the Neon R/T of being a sheep in wolf’s clothing.Even the standard 2.0 litre versions are faster than most comparably priced rivals. Rest to sixty takes 10.8s on the way to 124mph. Still, at least you don’t have to pay for the bigger capacity at the pumps: in normal driving, around 35mpg should be possible, rising to 45mpg on the open road.Those figures shouldn’t be too dramatically affected if, like most customers, you take the no cost automatic transmission option, though bear in mind that the gearbox has three, rather than the usual four speeds available from rivals (who all charge extra for the privilege).Braking is much improved over the old model, though curiously, the system you get depends on the trim level you choose. Quick, good looking and well equipped it’s a break from the norm. No, it isn’t the last word in sophisticated engineering but for most buyers driving something that offers a little exclusivity will more than make up for that.
michael kors outlet uk
cheap the north face
ray ban outlet uk
the north face outlet uk
cheap ray bans
cheap longchamp
cheap longchamp uk
ray ban sunglasses uk
cheap moncler uk
cheap michael kors
cheap michael kors uk
cheap ray bans uk
cheap longchamp bags
longchamp outlet uk
moncler outlet uk
cheap north face
相关的主题文章：
The Nedd4 family of E3 ubiquitin ligases: functional diversity within a common modular architecture
Robert J Ingham1, Gerald Gish1 and Tony Pawson1,2Top of pageAbstractNeuronal precursor cell expressed developmentally downregulated 4 (Nedd4) is the prototypical protein in a family of E3 ubiquitin ligases that have a common domain architecture. They are comprised of a catalytic C terminal HECT domain and N terminal C2 domain and WW domains responsible for cellular localization and substrate recognition. These proteins are found throughout eukaryotes and regulate diverse biological processes through the targeted degradation of proteins that generally have a PPxY motif for WW domain recognition, and are found in the nucleus and at the plasma membrane. Whereas the yeast Saccharomyces cerevisiae uses a single protein, Rsp5p, to carry out these functions, evolution has provided higher eukaryotes with several related Nedd4 proteins that appear to have specialized roles. In this review we discuss how knowledge of individual domain function has provided insight into the physiological roles of the Nedd4 proteins and describe recent results that suggest discrete functions for individual family members.
Keywords: ubiquitination, Nedd4, E3 ubiquitin ligase, HECT, WW, C2
Top of pageIntroductionE3 protein ubiquitin ligases have the critical role of selecting specific proteins for conjugation to ubiquitin (Varshavsky, 1997). There are two main classes of such E3 ligases, proteins with a HECT (homologous to E6 AP carboxyl terminus) catalytic domain (Huibregtse et al., 1995) and proteins with a zinc binding RING finger (really interesting novel gene) (Joazeiro and Weissman, 2000) adaptor domain. Three additional E3 ligase domains, the U Box (Hatakeyama et al., 2001; Jiang et al., 2001), PHD (Boname and Stevenson, 2001; Coscoy et al., 2001; Lu et al., 2002) and HUL 1 (Van Sant et al., 2001) sequences have recently been described. Polypeptides of the Nedd4 family belong to the HECT class of E3 ligases (Harvey and Kumar, 1999; Rotin et al., 2000).
Nedd4 was originally identified in 1992, in a screen for genes developmentally downregulated in the early embryonic mouse central nervous system (Kumar et al., 1992), and resembles other regulatory proteins in containing multiple, distinct modular domains (Pawson and Nash, 2003). Subsequently, related proteins with similar structures have been characterized. All contain a catalytic HECT domain at the C terminus, and an N terminal region involved in substrate recognition, that includes a C2 domain and a series of WW domains. Although the common modular architecture of the Nedd4 family might suggest a redundant functional role for these proteins, recent work has begun to define specific cellular activities for individual members, and to suggest mechanisms that underlie this specificity. This review will provide an overview of the functional properties of the modular domains comprising the Nedd4 family, and highlight physiological processes regulated by these proteins.
Members of the Nedd4 protein familyNedd4 like proteins are found in eukaryotes from yeast to mammals and are defined by a similar domain organization (Figure 1). In Saccharomyces cerevisiae, a single member, Rsp5p, regulates a number of processes including mitochondrial inheritance (Fisk and Yaffe, 1999), internalization of cell surface receptors (reviewed in Rotin et al., 2000), and transcription (Huibregtse et al., 1997). Furthermore, the function of this protein is critical, as disruption of the rsp5 gene is lethal (Hein et al., 1995). The domain architectures of all known Nedd4 proteins are illustrated and designated by accession number and common name. The relative position of the C2 (green), WW (red), and HECT (blue) domains were obtained by blasting the indicated sequences against the Conserved Domain Database (Marchler Bauer et al., 2002, 2003). In cases where multiple protein products have been reported only the largest protein product is illustrated. Based on analysis from the Conserved Domain Database the C2 domain of murine NEDD4 1 may be truncated. The bar at the top represents 200 amino acids
Full figure and legend (302K)
In Schizosaccharomyces pombe, genetic disruption of any one of the three family members, pub1, pub2, and pub3, results in a viable phenotype (Nefsky and Beach, 1996; Tamai and Shimoda, 2002). However, pub1 and pub3 double mutants are lethal, suggesting that Pub1p and Pub3p may have overlapping functions (Tamai and Shimoda, 2002). In contrast, a mutant deficient in both Pub1p and Pub2p is viable suggesting either that Pub2p is nonessential, or that Pub3p can compensate for essential functions of Pub2p.
Caenorhabditis elegans and Drosophila melanogaster each have three Nedd4 family members. Downregulation by RNA interference of mRNA encoding the C. elegans protein CeWWP1 causes defects in morphogenesis in the developing embryo (Huang et al., 2000a). In Drosophila, dNedd4 is involved in axon guidance by inhibiting signaling through the Robo receptor (Myat et al., 2002) while Suppressor of deltex (Su(dx)) negatively regulates signaling through the Notch receptor (Fostier et al., 1998; Cornell et al., 1999). dSmurf antagonizes the transforming growth factor (TGF ) homolog decapentaplegic (DPP) (Podos et al., 2001), which regulates dorsoventral patterning in the developing embryo.
The Nedd4 family has expanded further in mammals, and the existence of multiple spliced isoforms suggests additional complexity (Chen et al., 2001; Dunn et al., 2002; Flasza et al., 2002; Itani et al., 2003). There are only limited data regarding the functional similarities and differences of the various Nedd4 family proteins and their isoforms. However, mice homozygous for a loss of function mutation in the itch gene develop a variety of inflammatory problems, indicating that the Itch protein has nonredundant functions (Hustad et al., 1995; Perry et al., 1998).
Domain architecture of the Nedd4 proteinsAlthough structural studies have not yet been reported for a full length Nedd4 protein, the individual domains have received considerable attention (Figure 2). The catalytic HECT domain was first revealed as a 40 kDa region of the protein E6 AP, a cellular enzyme recruited by the E6 oncoprotein of the human papillomavirus (HPV) associated with cervical cancers (Huibregtse et al., 1993a, 1993b). In these cancers, downregulation of the tumor suppressor protein p53 is an ubiquitin mediated process originating from the E6 induced association of p53 with E6 AP. Biochemical studies of the E6 AP HECT domain found that this region is necessary and sufficient for ubiquitin transfer and that a cysteine residue played a critical role (Scheffner et al., 1995). The mechanism involves initial binding of an ubiquitin conjugated E2 to the HECT domain with subsequent thiol ester exchange to transfer the ubiquitin moiety from the E2 to the catalytic cysteine in the E3. Transfer of ubiquitin then occurs to either a target protein or to another ubiquitin molecule to promote a polyubiquitin chain. In both cases, the ubiquitin is transferred from the E3 catalytic cysteine to a lysine side chain amino group forming an isopeptide bond (Schwarz et al., 1998; Wang et al., 1999). (a) The two lobes that compose the HECT domain are shown in the E6 AP crystal structure (PDB 1D5F). The E2, UbcH7, binds to the N terminal lobe of the HECT domain in an orientation that would direct a conjugated ubiquitin molecule towards the catalytic cysteine within the E6AP C terminal lobe. (b) WW domains are formed by a three stranded anti parallel sheet as shown for the Nedd4 WW domain (PDB 1I5H). A ligand that contains a PPxY motif, forming a polyproline type II helix, binds primarily to one face of the WW domain sheet. (c) The loop regions of the C2 domain, found at one end of the sandwhich fold, form the binding site for calcium and phospholipids as shown in the Synaptotagmin 1 C2B domain (PDB 1K5W)
Full figure and legend (257K)
Two HECT domain structures, from E6 AP (Lan et al., 1999) and the Nedd4 family member WWP1/AIP5 (Verdecia et al., 2003), have been determined by X ray crystallography. Significant differences exist between the two structures, providing insight into how the catalytic activity of the HECT domain is regulated. In both structures the domain is composed of two lobes linked by a flexible hinge loop (Figure 2a). As the E6 AP HECT domain was cocrystallized with the E2 UbcH7, the structure reveals the E2 binding site within the N terminal lobe. This region is only moderately conserved between different HECT domains, which likely reflects differing specificities for one of the over 30 different E2s (Jentsch, 1992). In particular, E6 AP binds the E2 UbcH7 with high affinity, while the yeast Nedd4 protein Rsp5p prefers UbcH5 (Kumar et al., 1997). All known catalytic residues are located in the C terminal lobe of the HECT domain, including the catalytic cysteine that is the transient acceptor for ubiquitin prior to transfer to the final product.
The two structures differ in the relative orientation of the N and C lobes. In the E6 AP structure, the two lobes display an L shaped architecture, with conserved residues lining a broad catalytic cleft at the junction between the lobes. Consistent with the suggestion that this cleft forms part of the HECT active site, inactivating mutations in E6 AP that cause the neurological disorder Angelman Syndrome are localized to this region (Kishino et al., 1997; Jiang et al., 1999). However, the E6 AP/UbcH7 structure also presented a problem in that the position of the E3 catalytic cysteine is 40 distant from the E2 cysteine conjugate. Clearly, large conformational changes would be required to allow efficient thiol ester exchange to occur. The WWP1/AIP5 structure supported this notion, since the N and C terminal lobes were positioned such that the two cysteines would be closer together (16 Further, molecular modeling showed that this distance could be reduced to 5 if the relative orientation of the lobes were altered by rotation about the hinge loop (Verdecia et al., 2003). The importance of the flexible hinge linking the two lobes was further demonstrated by mutation and deletion analysis, predicted to restrict the relative movement of the lobes, which resulted in inhibited autoubiquitination. The inferred importance of the hinge has led to the proposal that the HECT domain functions as a ratchet to transfer ubiquitin from the E2 to the E3 catalytic cysteine. Motion about the hinge causes separation of the two lobes allowing the C terminal lobe to ubiquitinate the substrate while the N terminal lobe is recharged with an E2 ubiquitin conjugate.
Although these structural data have provided insight into the mechanism of action of the HECT domain, they have not definitively addressed how ubiquitin is transferred to the eventual substrate. It is unclear, for example, whether a polyubiquitin chain is formed by individual transfer of single ubiquitin molecules or whether a polyubiquitin chain is assembled on the E3 ligase and then directly added to the substrate. Recent data suggesting that some HECT domains may control the site of attachment on growing ubiquitin chains further complicates this issue. Proteins designated for proteasomal degradation are modified by attachment of a chain of ubiquitin molecules linked through lysine 48 of ubiquitin (Chan and Hill, 2001). For the HECT domain containing protein KIAA0010, assembly of ubiquitin chains linked through lysine 29 or 48 is possible (You and Pickart, 2001). Furthermore, Rsp5p can promote the formation of polyubiquitin chains linked through lysine 63 (Galan and Haguenauer Tsapis, 1997; Springael et al., 1999; Soetens et al., 2001). In addition, it is not known if the HECT domain plays a direct role in selecting substrates for mono or polyubiquitination.
The C2 domain and multiple WW domains N terminal to the HECT domain regulate cellular localization and substrate selection by the Nedd4 proteins. The WW domain, a small module consisting of approximately 35 amino acids and named for the presence of two conserved tryptophan residues spaced 20 amino acids apart, appears to mediate substrate recognition (reviewed in Zarrinpar and Lim (2000); Macias et al., 2002). Each family member has at least one WW domain with most possessing three or four modules located over a large middle region of the protein to form a substrate recognition scaffold.
WW domains are found in a variety of different proteins and have been shown to bind predominately proline rich motifs, including PPxY (amino acid single letter code; where x is any amino acid) (Chen and Sudol, 1995), PPLP (Bedford et al., 1997), PR (Bedford et al., 1998, 2000) and phosphoserine/threonine (pS/pT) residues that precede a proline residue (Yaffe et al., 1997; Lu et al., 1999). The Nedd4 family WW domains primarily recognize PPxY motifs but they have also been shown to bind to pS/pT residues (Lu et al., 1999) and may interact with other ligands (Qiu et al., 2000; Courbard et al., 2002; Murillas et al., 2002).
Several WW domain structures have been solved and the ligand binding determinants for the PPxY motif characterized (Figure 2b) (Kanelis et al., 1998: Huang et al., 2000b; Verdecia et al., 2000; Kanelis et al., 2001; Pires et al., 2001). WW domains possess a consensus three stranded anti parallel sheet fold that forms a hydrophobic ligand binding groove, together with a conserved binding pocket (termed the XP groove), which is generated by the juxtaposition of two large aromatic residues. The PPxY ligand yields a polyproline type II helix, and the two prolines are packed into the XP groove. The tyrosine makes several important interactions including a hydrogen bond with a conserved histidine residue as seen in the dystrophin WW domain (Huang et al., 2000b). This might explain the requirement for the tyrosine residue seen in biochemical studies (Chen and Sudol, 1995; Chen et al., 1997; Kasanov et al., 2001; Otte et al., 2003). Other interactions between the peptide and WW domain may also be important. For instance, the structure of the third WW domain of rat Nedd4 with a peptide from the ENaC channel shows an extended PPxY motif, PPxYxxL, binds the WW domain, with the leucine making important contacts. Binding studies support this result as a peptide with a leucine to alanine substitution displayed a six fold lower affinity than the wild type peptide (Henry et al., 2003).
The C2 domain was first identified in classical Protein Kinase C isoforms as a Ca2+ dependent phospholipid binding domain (reviewed in Rizo and Sudhof, 1998). It is approximately 120 amino acids and is composed of two four stranded sheets oriented to form an eight stranded sandwich structure (Figure 2c) (Sutton et al., 1995; Grobler et al., 1996; Essen et al., 1997; Perisic et al., 1998). Loop regions between the strands at the ‘top’ of the sandwich contain a number of conserved aspartate residues that are responsible for Ca2+ binding (Sutton et al., 1995; Essen et al., 1996; Shao et al., 1996). C2 domains have been shown to interact with a variety of phospholipids and proteins (Nalefski and Falke, 1996) and are thought to function as membrane recruitment domains involved in protein localization and trafficking. Indeed, the C2 domain is found in many proteins that require association with phospholipids at membrane surfaces for function, such as RasGAP, Synaptotagmin and several phospholipases (Ponting and Parker, 1996).
Physiological processes mediated by Nedd4 proteinsUbiquitin mediated processes are involved not only in the targeting of proteins for degradation by the 26S proteasome but also in the sorting of proteins at different steps in biosynthetic and endocytic pathways (Hicke, 2001; Bonifacino and Traub, 2003). Proteins at the plasma membrane are tagged with monoubiquitin to direct internalization. Within vesicles the ubiquitinated proteins are then transported to the late endosome and further sorted, in the multivesicular body, for recycling to the plasma membrane or destruction at the lysosome. Ubiquitin mediated protein sorting also occurs at the trans Golgi network where newly synthesized proteins, such as the amino acid permeases, are directed to the cell surface or targeted for destruction in the lysosome. The Nedd4 proteins participate in these processes through ubiquitination of target proteins.
While S. cerevisiae has only a single Nedd4 member, Rsp5p, other eukaryotes have several Nedd4 proteins that appear to have both redundant and specialized functions (Figure 3). Here, we describe one function of Rsp5p in the regulation of cell surface receptors in yeast. As examples of how the Nedd4 proteins function in mammals, we discuss how several Nedd4 proteins appear to operate in the downregulation of the epithelial sodium channel (ENaC) while Smurf1 and 2 have evolved specialized functions in the control of TGF signaling. Finally, we discuss how viruses have co opted the Nedd4 proteins to regulate various aspects of the viral life cycle. In particular, that Epstein virus (EBV) recruits Nedd4 proteins for the maintenance of viral latency in B cells and retroviruses utilize these proteins to bud from the cell. Selected cellular processes regulated by the NEDD4 family of proteins from yeast to higher eukaryotes are shown. Details regarding the specific roles of the NEDD4 family proteins in each of the processes are provided in the text. Current understanding of the role played by individual family members in the regulation of these processes is illustrated, however the involvement of other family members not yet investigated cannot be discounted
Full figure and legend (142K)
Regulation of yeast membrane proteinsRsp5p mediated regulation of cell surface receptors is one mechanism used by S. cerevisiae to adapt to environmental changes. For example, the Gap1p general amino acid permease is upregulated when it is necessary to use amino acids as a nitrogen source (reviewed in Magasanik and Kaiser, 2002). However, when yeast are grown on ammonia, Gap1p is degraded in an ubiquitin mediated manner (Springael and Andr 1998). Similarly, the factor receptor, Ste2p, the uracil permease, Fur4p, and several other cell surface receptors are regulated by ubiquitination in response to different stimuli (reviewed in Rotin et al., 2000).
The ubiquitination, internalization, and degradation of Ste2p, Gap1p, and Fur4p are all dependent on Rsp5p (Hein et al., 1995; Galan et al., 1996; Dunn and Hicke, 2001a). In the case of Ste2p and Fur4p, receptor degradation occurs not through the proteasome but via the lysosome like vacuole (Galan et al., 1996; Hicke and Riezman, 1996). In fact, in frame fusion of a single ubiquitin molecule to the C terminus of Ste2p is sufficient for internalization and degradation of the receptor (Terrell et al., 1998; Shih et al., 2000; Dunn and Hicke, 2001b), and monoubiquitination of Fur4p is also sufficient for internalization (Springael et al., 1999a). Fur4p and Gap1p are also polyubiquitinated (Galan and Haguenauer Tsapis, 1997; Springael et al., 1999a; Soetens et al., 2001). However, the polyubiquitin chains are not linked through lysine 48, which normally targets proteins to the proteasome, but are linked through lysine 63. This is consistent with polyubiquitinated Fur4p and Gap1p not being substrates of the proteasome. Furthermore, Rsp5p has functions in addition to ubiquitination of Ste2p, as the Ste2p/ubiquitin chimera still requires Rsp5p for internalization and degradation (Dunn and Hicke, 2001b).
longchamp outlet uk
cheap longchamp uk
ray ban sunglasses uk
the north face outlet uk
cheap longchamp
cheap longchamp bags
cheap michael kors
cheap ray bans
ray ban outlet uk
michael kors outlet uk
cheap moncler uk
cheap the north face
cheap north face
cheap michael kors uk
moncler outlet uk
cheap ray bans uk
相关的主题文章：
The company also increased its market share in both the heavy and medium commercial vehicle segment during the year, according to the 2007 08 annual report of Tata Motors.The annual report says that Tata Motors subsidiaries have significantly improved their financial performance during 2007 08. Tata Motors acquired Daewoo Commercial Vehicle Company in March 2004 for Rs 495 crore.According to the annual report, Tata Daewoo Commercial Vehicle Co (TDCV) increased sales by 38 per cent to 11,899 units in 2007 08, against 8,588 units sold in the previous year. Consequently, the company increased its market share to 32.3 per cent from 24.3 per cent in the heavy commercial vehicle segment and to 34.8 per cent from 28.2 per cent in the medium commercial vehicle segment.TDCV exported 3,000 units of HCVs (2,715 in the previous year) and continued to be the largest exporter from Korea in this segment.The company sold 7,698 machines during the year against 5,360 machines in 2006 07. is 60 per cent owned by Tata Motors and the balance by Hitachi Construction Machinery Co Ltd, Japan.The annual report shows that Tata Motors has 26 subsidiaries, with some of them having just begun operations. Eleven of the subsidiaries have shown a loss for the year and five of them have declared a dividend for the year.Tata Motors bought a 21 per cent stake for Rs 70 crore in March 2005 and has the option to buy the remaining 79 per cent at a price not exceeding million (about Rs 14 crore).Hispano has two manufacturing units, one in Spain that caters to the European market and the other in Casablanca, which caters to the Moroccan and other North African markets.
cheap michael kors
ray ban sunglasses uk
cheap michael kors uk
cheap longchamp uk
cheap longchamp
michael kors outlet uk
cheap ray bans uk
cheap north face
cheap ray bans
longchamp outlet uk
moncler outlet uk
the north face outlet uk
ray ban outlet uk
cheap moncler uk
cheap longchamp bags
cheap the north face
相关的主题文章：
The thermostat on your Volkswagen helps the engine keep operating at a predetermined temperature for best fuel economy and engine performance. However, the thermostat mechanism wears down after months of use and subsequently fails. If stuck in the closed position, the thermostat will not allow coolant to circulate, causing the engine to heat up dangerously; if stuck in the open position, the engine will never reach proper operating temperature, causing fuel consumption and poor engine performance. In either case, the thermostat must be replaced.
How to Replace a Volkswagen Thermostat
How to Change the Thermostat in a Chevy Silverado. If you notice your Chevy . . View Photos. How to Check Add Engine Oil. Watch Video.
How to Replace a Thermostat on a 2003 VW Jetta
How to Change the Thermostat in a Volkswagen 2.0 Engine; How to Replace a Jetta 1.8T Thermostat; Volkswagen Thermostat Replacement Instructions; Comments.
longchamp outlet uk
cheap longchamp
cheap michael kors
cheap ray bans uk
cheap moncler uk
ray ban sunglasses uk
cheap michael kors uk
cheap longchamp bags
cheap longchamp uk
moncler outlet uk
cheap the north face
michael kors outlet uk
the north face outlet uk
ray ban outlet uk
cheap north face
cheap ray bans
相关的主题文章：
Bodie Shandro is getting ready to paddle through the "channel of bones." Shandro, who lives on Heffley Lake, is working hard to prepare for the Molokai 2 Oahu Race, the unofficial world championship of stand up paddling. The race, scheduled for July 31, will be held in a 32 mile channel liking Molokai and Oahu. So treacherous is the Ka’iwi Channel that it also is known as the Channel of Bones. Shandro and Squamish’s Norm Hann will work as a team, the pair trading turns on the 14 foot board, with the non paddler riding alongside in the required support boat. Shandro figures the men would trade off after 20 or 40 minutes of paddling, but that could change depending on the size of swells and "how intense it’s going to be." You see, not only do the paddlers have to worry about fighting through fatigue and exposure and maybe a few sharks "You need shark repellant on (boat) and on body," Shandro said there also is the matter of swimming to and from the support boat in 20 to 30 foot swells. "We have some rough days on Heffley Lake," Shandro said, "but it isn’t going to compare" to the Pacific Ocean. This will be Shandro’s first try at Molokai 2 Oahu, but he competed in Hawaii last year. His goal is to complete this year’s race in six hours, and also to try it alone in a few years. "I want to do it solo when I’m 50," said the 46 year old Shandro. central coast.
ray ban sunglasses uk
moncler outlet uk
cheap longchamp uk
cheap ray bans
cheap longchamp bags
cheap ray bans uk
cheap moncler uk
cheap the north face
michael kors outlet uk
cheap michael kors uk
cheap north face
cheap michael kors
the north face outlet uk
ray ban outlet uk
cheap longchamp
longchamp outlet uk
相关的主题文章：
Few countries have impacted wine making standards and methods as much as France has. Winemaking in France is as old as the country itself. Over the years, different segments of society have been the primary cultivators of French wine from the peasants who made and drank the wine in the early years to the church that almost completely controlled wine production in France for a period after the 13th century, and finally to the nobility who eventually took over wine production.
Wine making in France hasn’t always been a smooth process. In the early years, a Roman emperor made a decree that forced all vineyards outside of Italy to shut down. Years passed before France could begin planting again. Later, around the year 1800, the entire French wine making industry was almost driven to a complete stop by a series of diseases that attacked the vineyards. Although progress was made in fighting these diseases, it took nearly 80 years to re stabilize vine cultivation. Then, World War I and World War II took their toll on Europe, and again the wine industry was hurt [source: eZine Articles]. Demand for good French wine was at an all time high, and supply was at an all time low. Counterfeit French wines began showing up, poisoning the country’s reputation. France’s status as a leading wine producer was in jeopardy.
The rough conditions of the 19th and early 20th century didn’t ruin France’s wine industry, however. It emerged stronger. The goal of these laws was to define, control and protect the geography and quality of the wines of France [source: Wine Pros]. standards were allowed to call themselves by the name of the region of France in which they were cultivated. restored faith in French wines and allowed the country to reclaim its status as one of the planet’s most trusted sources of fine wine.
cheap moncler uk
michael kors outlet uk
cheap the north face
ray ban outlet uk
longchamp outlet uk
ralph lauren outlet uk
ralph lauren sale uk
cheap longchamp bags
ray ban sunglasses uk
the north face outlet uk
cheap michael kors uk
cheap moncler uk
cheap ralph lauren
cheap ray bans uk
cheap longchamp uk
moncler outlet uk
cheap ray ban
cheap ray bans
cheap michael kors
cheap north face
cheap longchamp
cheap ralph lauren
longchamp outlet
moncler outlet uk
moncler outlet uk
cheap moncler
相关的主题文章：
After the prolonged media coverage of the build up to, and London’s victory in, the 2012 Olympics race, it seems hard to believe that the last time the summer Olympics were held in London, the city was up against no competition whatsoever. After the turmoil caused by the Second World War and two Olympic cancellations, the UK simply volunteered its capital as host city for 1948 and was willingly accepted by the International Olympic Committee. Wembley Stadium was pressed into temporary service as the main venue, and the Games were broadcast on television for the first time, even though very few had TV sets.
Sporting NationsIt was not to be an Olympics of daring innovation. The world was still recovering from the shock of large scale war and many countries were still in depression. The primary aim of the London Olympics was to draw countries together, not to emanate glitz and glamour. Great Britain had not conceded a single goal in their progress to the final, and yet were humbled 4 0. Hockey has remained a national sport in India ever since.
Other nations celebrating in 1948 included Sri Lanka (Ceylon, as it was at the time) and Korea, both of whom took home their first ever Olympic medals; their heroes being Duncan White (400m Hurdles) and Kim Sung Jip (Middleweight Weightlifting) respectively.
Sporting LegendsFor many people, the 1948 Olympics belonged to Dutch athlete Fanny Blankers Koen. ‘The Flying Housewife’ was already a very successful athlete in her own right. She had competed in the 1936 Olympics at the age of 18, and at the time of the Olympics held world records for 100m, 200m, 80m hurdles, long jump and high jump. She had given birth to a daughter (also called Fanny) just three months before entering the 1946 European Championships, winning two gold medals there. Sensibly declining to enter the jumping events in London, she took four gold medals home to Amsterdam: 100m, 200m1, hurdles and sprint relay. It is unlikely that this achievement of four golds in a single Games will ever be matched in the world of female athletics.
Another track and field athlete was taking his first steps to becoming a legend, but almost had his glory upset by some incompetent officiating. Emil Ztopek had served with distinction for Czechoslovakia during the war and was still serving at the rank of Lieutenant when he took the trip to London. He set off in the 10,000m final at a rate of knots and became the first man to run that distance under 30 minutes at the Olympics, winning by nearly a lap of the track. He was so far ahead that the steward neglected to ring the bell signifying the final lap. The said steward claimed to be watching the pole vault, and was presumably given a stiff dressing down later. Despite the confusion in the stadium, which later mixed up most of the lower placings in the race, Ztopek knew he had won. He came second in the 5,000m at London but completed an amazing long distance treble four years later in Helsinki, adding the marathon title on the final day to his 5,000m and 10,000m successes.
An established legend in the world of fencing was also present in London. Aladr Gerevich had won medals for Hungary before the War in both 1932 and 1936, and comfortably won gold in London with an undefeated record. Gerevich went on to win seven gold medals up to 1960, when he competed in his last Olympics in Rome at the age of 50.
Another serial winner just starting out was Denmark’s Paul Elvstrm. His gold in yachting’s ‘Finn’ class at the age of 18 was to be the first of four consecutive Olympic titles.
HeroesIt was a very muted games for the home team, their ranks depleted by stringent post war conditions. The British team netted just three gold medals, although they did claim 14 silvers. All the British successes were on the water: in the rowing at Henley, Burnall and Bushell were victorious in the double sculls; Wilson and Laurie (who had served together in Sudan for the previous ten years) won the coxless pairs. On the sea, Stewart Morris and David Bond were the winners in the London to Torbay ‘swallow’ class yachting the only time this class has appeared at the Games.
The hero of Wembley stadium was unanimously the Belgian marathon runner, Etienne Gailly. Gailly had never run a marathon before, but traded the lead with more established names throughout the first 26 miles. He entered the stadium first, shortly ahead of Argentina’s Delfo Cabrera and Britain’s Thomas Richards. Gailly had barely a lap of the track to complete, but the crowd could see his legs wobbling and his path wavering to and fro. Groans rang out around the stadium as he dried up to a walk and was overtaken by Cabrera and Richards. In a shocking reminiscence of Pietro Dorado collapsing within view of the tape 40 years earlier (the last time the Games had been held in London), Gailly fell to his knees on the home straight. But, to a standing ovation, he straightened up and staggered over the finishing line for a bronze.
Inevitably, the War was to produce its own heroes. Many of those competing in London were veterans, and a few were even carrying injuries sustained in combat. None was more remarkable than Hungarian pistol shooter Kroly Takcs. Originally right handed, his shooting hand was shattered and left unusable by a grenade while he was in service. Takcs nevertheless brought himself quickly up to Olympic standard, shooting with his left hand, and he achieved a much acclaimed gold in London. This feat is all the more remarkable when one considers that it often takes over 20 years for a shooter to reach Olympic standard with their leading hand.
The Olympic boxing had seen bad temper and controversy, not least from a belligerent and self important American team, but was home to another remarkable victory through injury. Jlius Torma shattered his knuckles not like Takcs in combat, but on the jaw of an unlucky opponent in the second round. Nevertheless, he spared his left hand through his last four matches and won the Welterweight title literally single handedly.
The Old and the Young; The Tall and the Short; The Rich and the Poor31 years separated Bob Mathias and Terence ‘Tebbs’ Lloyd Johnson, a gap larger than the age of many other participants. American schoolboy Mathias had only taken up the decathlon three months before and possessed the naivety you might expect of a 17 year old. He nearly earned himself disqualifications in the shot and high jump, before going on to complete the second day in semi darkness. His discus throw was longer than anyone expected and the officials lost the marker for his longest throw. Car headlamps had to be used to highlight the foul line for his javelin throw, since conditions were so bad. But Mathias bettered the weather, darkness and red tape to become the youngest ever winner of a track and field gold medal. It is even more remarkable that he did so in one of the most physically demanding events. When asked how he would celebrate, he self deprecatingly shrugged and replied ‘I’ll start shaving, I guess’. He was back to successfully defend his title in 1952.
By contrast, Lloyd Johnson was a 48 year old veteran. His bronze medal in the punishing 50,000m walk made him by far the oldest medallist of all time at track and field. He had also competed in the 1936 Olympics, taking over the British mantle in this long and exhausting discipline from Thomas Green.
Very much fulfilling the ‘short’ category was Bantamweight weightlifter Joe di Pietro of the USA. Boasting an abnormally small frame of well under five feet, with arms that were barely long enough to lift the weights over his head, di Pietro set lasting Olympic and World Records for his weight category, being contested for the very first time.
No Olympics would be without its moments of light hearted heroics. In London, these were mostly provided on the basketball court. The Iraqi team provoked much amusement with its rank incompetence (they lost two matches by over 100 points), but the highlight for many was watching a diminutive Chinese point guard dribbling the ball right through the legs of the mammoth US centre, Bob Kurland. China and Iraq went on to finish 18th and 19th respectively.
Less amusing were the ridiculously antiquated equestrian rules. The dressage events were reduced to farce when it was pointed out that one of the Swedish riders, Gehnll Persson, was riding in a sergeant’s cap. As only commissioned military officers2 were permitted to compete, the Swedish team was disqualified and robbed of the gold medals which should have been rightfully theirs. The incident clearly made a nonsense of the socially elitist world of equestrianism, and the laws were changed soon afterwards.
Equestrianism, though, was just one of many sports to be dragged into the modern era by the London Olympics. Although the Games were hastily organised and often substandardly run, they played an essential part in rekindling the spirit of competition and the likes of Blankers Koen, of Zatopek and of Mathias played a vital part in promoting and inspiring sporting excellence into the second half of the 20th Century.
1Blankers Koen won the 200m on its first Olympic appearance, by a margin of over seven metres and by nearly a second, a distance unmatched ever since.2ie, those of ranks of lieutenant and above.
Write an Entry "The Hitchhiker’s Guide to the Galaxy is a wholly remarkable book. It has been compiled and recompiled many times and under many different editorships. It contains contributions from countless numbers of travellers and researchers."
Write an entry
Read more
Most Recent Entries
The Benefits of Post Test Training Advanced Riding’How I Met Your Mother’ the TV ShowThe Hanging Gardens of BabylonStar Trek Characters: Harry MuddThe Great South RunDoctor Who and the Terror of the TitlesDrinking Your Way Through the Apocalypse: The DIY Fallout Shelter Snack BarThe Ultimate Disney Classic Animated Film Guide: 1980 1989Wrestling Jacob: Smash Hit of 1742Great Kissing Places: Botanical Garden, Rio de Janeiro, Brazil
cheap longchamp bags
cheap ralph lauren
cheap ray bans
longchamp outlet uk
michael kors outlet uk
ray ban sunglasses uk
cheap moncler
cheap the north face
cheap michael kors uk
longchamp outlet
cheap ray ban
cheap longchamp uk
cheap ray bans uk
cheap moncler uk
the north face outlet uk
moncler outlet uk
cheap longchamp
cheap ralph lauren
cheap north face
moncler outlet uk
ralph lauren outlet uk
cheap michael kors
moncler outlet uk
ray ban outlet uk
cheap moncler uk
ralph lauren sale uk
相关的主题文章：
If I say the word what comes up for you?
For some, it brings images of property, money, men or women in suits or graphs. For others, it could be words such as risk, loss gain, strategy, growth or numbers.
When you decide to build up your dream, you may do so swiftly and effectively while still working full time at your current job. That when the word will take a whole new meaning for you. During this transition time to setting up your own business or job or career change, you will need the appropriate investment portfolio. In my book Passion Pays, I refer to four specific types of investments that you will need to manage. I am laying them out to you, each in one article. In this article, let view the first investment. Are you ready?
Not so fast. Just like any journey, before we set off, let check that you are fully equipped:
Belief in your dream? Check.
Awareness of your emotional reason, your Check.
Willing AND ready to commit? Check.
Now, we ready. So, the first of the four investments.
While you are at your current job, your aim is to gather the right inner and outer resources to carry out successfully your future job. Investments aim to maximize the value of assets. What your most valuable asset? You are. Therefore you are your Number One and biggest investment.
Investing in yourself is the only investment that no one will ever be able to take away from you. What you need to do right now is identify what missing to fill the gap between where you are and where you want to be: is there training to follow that you must transform into skill?
Information to acquire that you must transform into knowledge? Personality traits that you must transform into strength of character? Juggling your full time work and nurturing your dream at the same time can set you off on an emotional, physical, mental or spiritual rollercoaster. Your skills and character will take you to the highs and get you through the lows.
Undoubtedly, the primary skill that you must develop is the skill of learning. If you great at learning, you can be great at a n y t h i n g. So first and foremost, develop the skill of learning. How can you learn?
You can learn by attending a course/workshop/seminar. Yes.
You can learn by watching documentaries. Sure.
You can learn by reading articles. Why not.
You can learn by having a mentor/coach. Certainly.
You can learn by following a tutorial. Definitely.
You can learn by reading [Your subject] for Dummies. True.
You can learn by studying people who have succeeded. Not bad.
You can learn by introspecting and contemplating. Good.
You can learn by watching TV. Maybe not.
These usual ways are in fact only learning environments with loads of information. To build your true expertise, you will need more than information. You will need to convert these opportunities and possibilities to learn into actual learning and skill. The best way to learn is through making mistakes. The best way to improve your skills is to practice, play and test. And before you know it, your confidence will grow stronger and stronger.
If you want to become a graphics designer, for example, now is the time to investigate the options available for you get the technical skills of graphics design. I know, this isn rocket science. But here is the part that will make you meditate: do not be concerned with getting the qualification itself but rather with acquiring the skills and the knowledge of designing beautifully. A qualification is a means to invest in yourself, not just in a career. Any qualification you undertake goes beyond the evolving technical skills of your craft. So while learning what graphic designers do, you can enjoy the opportunities to develop problem solving, time management, self sufficiency or people skills; instrumental in eventually being successful. Training becomes a choice based on joy, not on scores.
Take time to digest and plan your first investment. In my next article, I will take you through investment no.2. If you want more inspiration to build your dream, go ahead and download a free sample from my book Passion Pays, on which this article is based and where I go into much more detail.
Did you learn something here? If so, please rate my articles, and it done! It will make me feel good too.
Let change the world of work. My mission is to transform the sleep walkers and the living dead at work into the talented, purposeful creators of the world they really are. Do you know anyone in the media, business, career or humanitarian fields who feels the same? They may want to hear from me and I love to hear from them. If that you, even better. Please get in touch.
My name is Genevieve de Lacaze. I’m just a regular girl. changing the world. one passion at a time. I love passionate conversations and ventures. Here are some labels and links if you want to learn more:.
cheap moncler
cheap ray ban
cheap michael kors
moncler outlet uk
ralph lauren sale uk
ray ban outlet uk
cheap longchamp uk
longchamp outlet
moncler outlet uk
cheap moncler uk
cheap north face
cheap the north face
moncler outlet uk
cheap longchamp bags
cheap michael kors uk
cheap longchamp
ralph lauren outlet uk
longchamp outlet uk
ray ban sunglasses uk
michael kors outlet uk
cheap ralph lauren
cheap ray bans
cheap ray bans uk
the north face outlet uk
cheap moncler uk
cheap ralph lauren
相关的主题文章：