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Unfolded and misfolded proteins are inherently toxic to cells and have to be quickly and efficiently eliminated before they intoxicate the intracellular environment. This is of particular importance during proteotoxic stress when, as a consequence of intrinsic or extrinsic factors, the levels of misfolded proteins are transiently or persistently elevated. To meet this demand, metazoan cells have developed specific protein quality control mechanisms that allow the identification and proper handling of non-native proteins. An important defence mechanism is the specific destruction of these proteins by the ubiquitin-proteasome system (UPS). A number of studies have shown that various proteotoxic stress conditions can cause functional impairment of the UPS resulting in cellular dysfunction and apoptosis. In this review, we will summarize our current understanding of proteotoxic stress-induced dysfunction of the UPS and some of its implications for human pathologies.
General introduction
The presence of unfolded, misfolded, or otherwise abnormal proteins is a never-ending threat to cells.1 These proteins, which contain non-native structures and have a propensity to form insoluble protein aggregates, are inherently toxic.2 Several sources contribute to the pool of aggregation-prone proteins. First, the structure of proteins can be severely affected by the introduction of non-native modifications. Besides spontaneous denaturation, aberrant modifications such as oxidation, nitrosylation, and isomerization can distort the folding of proteins rendering them prone to aggregation. Secondly, proteins may fail to adopt their native conformation due to the absence of binding partners that are crucial for the formation of a multicomponent complex. Thirdly, proteins may be intrinsically misfolded or structurally unstable due to the presence of mutations, which is a prevalent factor in genetic diseases characterized by the presence of protein aggregates.3 These disorders, which are collectively referred to as 'conformational diseases',3 are a heterogeneous collection of familial and sporadic pathologies, including many neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and prion diseases,4 as well as type II diabetes mellitus5 and cardiac diseases.6
Although one may expect that old and 'worn-out' proteins are overrepresented among misfolded proteins, a number of studies suggest that a major fraction is derived from the pool of newly synthesized proteins.7,8 It has been estimated that as much as one-third of all proteins are destroyed within 10 min after synthesis.9 Although these polypeptides have been coined 'DRiPs' (for Defective Ribosomal Products),10 it is unclear whether they are truly inaccurately synthesized polypeptides or whether they represent a pool of nascent proteins that are degraded before they have been able to adopt their native conformation.11 Alternatively, these short-lived proteins may have been damaged directly after proper synthesis since newly synthesized proteins are particularly sensitive to proteotoxic stress conditions.12
As the generation of misfolded proteins is directly linked to protein synthesis and hence an inevitable part of life, this leaves the cell with little alternative than to cope with their presence and eliminate them in a timely fashion. The potential danger of aggregation-prone proteins can be countered by assisting proteins in their folding, preventing the exposure of non-native structures or by elimination of proteins.1 This process is facilitated by molecular chaperones, which assist in the de novo folding of nascent chains or refolding of damaged proteins.13 A general feature of chaperones is that they bind hydrophobic structures, thereby keeping non-native proteins in a soluble state preventing aggregation.
If a protein fails to fold properly, the only safe way to solve the potential threat permanently is through destruction. For this purpose, cells have developed an elaborate degradation system that can break down almost any polypeptide in a highly specific manner. The ubiquitin-proteasome system (UPS), which resides both in the nucleus and in the cytosol, consists of a large number of proteins that are dedicated to the identification, targeting, and destruction of proteins (Figure 1).14 The fact that this system can hydrolyse almost any polypeptide chain is accomplished through the engagement of three different proteases with complementary activities: chymotrypsin-like, trypsin-like, and caspase-like activities.15 These proteases are embedded in a large barrel-shaped proteolytic complex known as the proteasome. The proteolytic chamber of the 20S core particle of the proteasome can only be accessed through gated entrances on either side of the proteasome.16 It is this compartmentalized structure that safeguards the highly specific nature of the process and prevents non-specific protein degradation.17
Proteins are marked for degradation by the proteasome by the covalent linkage of a chain of ubiquitin proteins (Figure 1, left panel). An enzymatic cascade, involving the ubiquitin activase (E1), one of several ubiquitin conjugases (E2s), and one of the many different ubiquitin ligases (E3s), results in the covalent linkage of the C terminus of the 76 amino acid long ubiquitin polypeptide to the ε-NH2 group of an internal lysine residue of the substrate.18 Since ubiquitin contains seven lysine residues, which can each be targeted for ubiquitin conjugation (i.e. ubiquitylation), successive rounds can result in the formation of long ubiquitin chains. The lysine residue in the ubiquitin that is used for formation of the polyubiquitin chain determines the fate of the protein.19 Although lysine 48-linked polyubiquitin chains are the canonical targeting signal for proteasomal degradation, recent studies revealed that alternative chains can also facilitate ubiquitin-dependent proteasomal degradation.20–22 Polyubiquitylated proteins bind to specific ubiquitin-binding domains (UBDs) that are located in shuttling factors and the proteasome itself.23 Ubiquitylation is a reversible process and the chains can be disassembled to ubiquitin monomers by deubiquitylation enzymes (DUBs),24 a process that also takes place at the proteasome prior to degradation (Figure 1, right panel).25 Finally, the protein has to be unfolded and funnelled through the narrow entrance of the proteasome in order to be hydrolysed.26
The UPS is not only the final destination for proteins that fail the protein quality control in the nucleus and cytosol but also for misfolded proteins residing in the endoplasmic reticulum (ER), a process known as ER-associated degradation (ERAD).27 In addition to its task in protein quality control, which is undoubtedly of vital importance for cell survival, the UPS also plays an essential role in other cellular processes such as intracellular signalling, regulation of the cell cycle, and induction of apoptosis (Figure 2).14 Since the UPS is the only proteolytic machinery that facilitates processive degradation in the nuclear and cytosolic compartments in a swift and tightly regulated manner, it is not surprising that this system has taken a central position in both protein quality control and these regulatory processes. As discussed below, the prioritization of these divergent but essential processes may form an extra challenge under conditions of proteotoxic stress.
Protein quality control and the ubiquitin-proteasome system (UPS)
To ensure that proteins meet the demands for proper functioning, they are subject to a process referred to as protein quality control. One of the most important steps in this process is the recognition of non-native proteins before they encounter other non-native proteins and form insoluble aggregates.13 The potential damage to the cellular homeostasis can only be prevented or minimized by sending the terminally misfolded protein for destruction by the UPS in a timely fashion. At the same time, it is unavoidable that newly synthesized proteins require time to reach their folded state and, during this process, they are likely to expose aggregation-prone structures. Cells must therefore somehow balance the rigorous destruction of misfolded proteins with giving immature proteins sufficient time to reach their final conformation.
The protein quality control machinery has been studied in most detail in the ER.28 An additional challenge for the folding in this compartment is that many of these proteins are secretory and cell surface proteins, which will be exposed to the harsh extracellular milieu.29 Consequently, folding of these proteins is more complicated and different from folding in the cytosol and nucleus. Only properly folded proteins are allowed to reach their final destination, whereas unfolded or misfolded proteins are retained and subjected to additional rounds of folding cycles.28 Failure to fold properly will not only result in retention but eventually target the protein for ERAD starting with dislocating the substrate to the cytosol.27 During this stage, the cytosolic ubiquitylation machinery comes in play and specific ubiquitylation,30 deubiquitylation,31 and UBD-containing proteins32 reside at the ER/cytosol interface to regulate the retro-translocation from the ER to the cytosol and the subsequent degradation of these proteins. The urgent need to avoid excessive production of misfolded proteins in the ER is reflected in the unfolded protein response (UPR), which is an adaptive response triggered by the accumulation of non-native proteins in the ER. The UPR results in inhibition of translation, which reduces the ER load, and up-regulation of chaperones and ERAD components to promote folding and eventually degradation of the terminally misfolded proteins.33 Although less well understood, recent studies suggest that the UPS may also be involved in the degradation of proteins that fail the protein quality control in the matrix and inter-membrane space of the mitochondria, which would require retro-translocation of proteins analogous to ERAD.34
The cytosol is an important place for protein quality control since, together with the ER, it is the primary location for de novo protein synthesis.7,12 Unlike the situation in the ER, where the identification of misfolded proteins takes place in complete isolation of the UPS, components of the UPS can play a direct role in protein quality control in the cytosol and nucleus. Most notably are the interactions between chaperones and components of the ubiquitylation machinery, which can regulate whether unfolded proteins bound to chaperones are targeted for either refolding or degradation. This mechanism of cross-talk between the refolding and degradation machineries has been referred to as the protein triage.35 The co-chaperone CHIP (carboxyl terminus of Hsp70 interacting protein) illustrates the direct link between these systems in the cytosol.36 CHIP is a ubiquitin ligase that interacts with Hsp70 and Hsp90 facilitating ubiquitylation and degradation of non-native proteins bound to these molecular chaperones.37 It has indeed been shown that CHIP stimulates degradation of a diverse set of aggregation-prone proteins implicated in conformational diseases.38,39 Interestingly, CHIP also ubiquitylates Hsp70, in the absence of a non-native cargo protein, establishing a negative feedback loop that adjusts the levels of this chaperone to the amounts of cytosolic non-native proteins.40 Another interesting protein in this respect is BAG-1, which contains an internal ubiquitin-like domain and forms a trimeric complex together with Hsp70 and CHIP. BAG-1 stimulates the release of non-native proteins from Hsp70 leading to their proteasomal degradation.41 It should be noted that in addition to refolding and proteasomal degradation, the cytosolic compartment has at least two additional means to deal with misfolded proteins, namely the transient or permanent storage in intracellular inclusions42 and the degradation in the lysosomes through autophagy.43 These alternative solutions may be particularly important in the case of aggregated proteins that are resistant to proteasomal degradation.44
Little is known about protein quality control in the nucleus. The nuclear ubiquitin ligase San1 has recently been identified in the budding yeast Saccharomyces cerevisiae as a key player in nuclear protein quality control but no orthologs were found in metazoan cells.45
UPS impairment
It has been well documented that deficiencies in one of the two key players, i.e. ubiquitin or the proteasome, are related to proteotoxic stress. These conditions, which we will refer to as 'ubiquitin stress' and 'proteasome stress', respectively, have a great impact on the physiology of the cell and, unless timely corrected, can cause cellular dysfunction or death.
Ubiquitin stress
The role of ubiquitylation is not limited to the regulation of proteolysis but is also critical for numerous other cellular processes such as endocytosis,46 transcription,47 and DNA repair.48 It is noteworthy that in addition to targeting non-native proteins for proteasomal degradation, ubiquitylation is also involved in the formation of intracellular inclusions,49 as well as the clearance of aggregation-prone proteins through autophagy.50 Thus, ubiquitin appears to be implicated at various levels of the response to misfolded proteins.
The ubiquitin status in cells is highly dynamic since conjugation and de-conjugation are continuously ongoing processes. This means that the pool of free unconjugated ubiquitin is constantly replenished with ubiquitin molecules constitutively being released from substrates or newly synthesized ubiquitin precursors. Although the intracellular ubiquitin levels are relatively high, the pool of free unconjugated ubiquitin is surprisingly small.51 It appears that the vast majority of ubiquitin is either conjugated or in the process of being conjugated, leaving only a limited pool of free ubiquitin. This implies that an increase in the demands of ubiquitin for a specific ubiquitin-dependent process can dramatically change the homeostasis and affect other processes that are also mediated by ubiquitin conjugation. Proteotoxic stress increases the demand on ubiquitylation for the purpose of targeting misfolded proteins for destruction resulting in an accumulation of polyubiquitylated proteins at the expense of the levels of free ubiquitin.51 Accumulation of polyubiquitylated proteins during proteotoxic stress coincides with a reduction in the level of monoubiquitylated histone H2A,52,53 which is an important epigenetic marker for chromatin condensation and transcriptional regulation.54 This correlation appears to be merely a consequence of a direct competition between proteasome substrates and histones for the limited pool of free ubiquitin.51 Interestingly, proteotoxic stress-induced UPS impairment in thermally shocked cells can be directly attributed to a reduction in free ubiquitin levels since increasing the ubiquitin concentration prior to the proteotoxic insult prevents impairment of proteasomal degradation.55 Accordingly, the UPS dysfunction in thermally shocked cells is confined to ubiquitin-dependent substrates, whereas the degradation of substrates that are targeted independent of ubiquitin was not affected, consistent with ubiquitin being the limiting factor.55,56
Given the limited availability of free ubiquitin and the high demands during proteotoxic stress, it is not surprising that synthesis of ubiquitin is strongly induced as part of the heat shock response and that ubiquitin levels steadily increase during or in the aftermath of a proteotoxic insult.57 Besides transcriptional activation, the levels of free ubiquitin can also be increased by accelerating the disassembly of ubiquitin chains.58,59 In budding yeast, two additional mechanisms have been described for maintaining the ubiquitin equilibrium by these means. First, the DUB Ubp6, which associates with the proteasome and rescues ubiquitin by disassembling chains more efficiently prior to protein degradation, is induced during stress conditions.58 The neurological pathology that is observed in mice carrying recessive mutations in the murine ortholog Usp1460 can be rescued by overexpression of ubiquitin,61 which suggests an important role of this enzyme in maintaining the ubiquitin equilibrium also in mammalian cells. Secondly, the DUB inhibitor Rfu1 (Regulator of free ubiquitin chain-1) fine-tunes the generation of free monomeric ubiquitin in yeast through the regulation of DUBs that disassemble unanchored ubiquitin chains.59 The human genome does not contain genes that encode any known Rfu1 orthologs and it is unclear if a similar regulatory mechanism exists in human cells.
A special case regarding the role of ubiquitin in proteotoxic stress is the aberrant ubiquitin UBB+1, which has been found in neurological62 and non-neurological63–65 conformational diseases. The UBB+1 protein is derived from an erroneous transcriptional product from the ubiquitin B gene. It consists of the ubiquitin polypeptide with the last glycine residue substituted for a tyrosine followed by a 19 amino acid long C-terminal extension.62 The UBB+1 is polyubiquitylated and is refractory to DUBs that disassemble polyubiquitin chains.66 At low concentrations, it is degraded by the UPS, but at elevated levels, it resists degradation and causes a general UPS inhibition.67,68 Proteotoxic stress can affect the clearance of UBB+1,69 and it has been speculated that its presence in conformational diseases may be an indication that the affected cells have experienced episodes of dysfunctional UPS.70 The reason for the inefficient clearance of UBB+1 can be attributed to the limited length of the C-terminal extension, which is too short to be handled as an efficient proteasome substrate.71 Although UBB+1 exemplifies that ubiquitin itself can be a cause for UPS impairment, the molecular mechanism is unresolved and it is therefore not clear if UBB+1 causes ubiquitin stress (i.e. ubiquitin deficiency) or affects other events critical for proteasomal degradation.
Proteasome stress
Due to size constraints, unfolding of the substrate prior to translocation through the entrance of the proteasome is an absolute prerequisite for proteasomal degradation.72 The 19S regulatory particle, which docks to the entrance of the proteasome 20S core particle, contains a hexameric ring of AAA-ATPases with unfoldase activity.26 For efficient proteasomal degradation, substrates need a loosely folded initiation site.73 Recent studies suggest that a minimal length of 20–30 amino acids is required for efficient degradation,71,74 which may be needed to cover the physical distance from the folded polyubiquitylated protein to the AAA-ATPase responsible for unwinding the polypeptide chain.75 Although the diverse activities of the proteases residing in the proteasome enables the complex to hydrolyse virtually any polypeptide chain, protein unfolding can still be a major hindrance for efficient degradation. This may be problematic in particular for proteins that form tight non-native interactions as in the case of protein aggregates. Consistently, aggregated proteins can resist degradation by the UPS,44 and preferentially accumulate under conditions of a compromised UPS.55 Since both ubiquitin and proteasomes are present in the intracellular inclusions observed in conformational diseases, it has been proposed that this may be the result of futile attempts of the system to degrade these proteins, which in turn may impair the UPS.4
The presence of aggregation-prone proteins in cellular models can severely inhibit the functionality of the UPS causing a general impairment.76,77 In at least one conformational disorder, the UPS impairment has been directly linked to reduced proteasome activity. Namely, disease-associated prion protein induces the formation of intracellular inclusions,78 inhibits the proteolytic activity of the proteasome, and causes a general inhibition of ubiquitin-mediated degradation in both cellular and animal models for prion pathology.79 This suggests that a direct inhibition of the proteasome may be responsible for the UPS impairment in some conformational diseases. However, the absence of general UPS impairment has been reported for several other conformational diseases, suggesting that this is not a shared property for these disorders.80–83
Proteasome activity appears to be largely excessive during normal cellular conditions since the chymotrypsin-like activity has to be inhibited by as much as 80% before a functional impairment of the UPS occurs.76,84 The surplus activity may reflect the need of the cell to be able to respond instantly to conditions of proteotoxic stress without having to synthesize large amounts of new proteasomes. Cells that are encountering chronic proteotoxic stress conditions appear indeed to be more sensitive to proteasome inhibitors.85 This feature is likely to be a consequence of the fact that these cells utilize a larger proportion of their UPS capacity, which in turn decrease the threshold of the minimal proteasome activity required for cell viability.84
Even though the induction of genes encoding proteasome subunits is probably too slow to generate enough proteolytic capacity to avoid acute protein aggregation, increasing the proteasome pool may eventually help to relieve the burden on the UPS. The mechanism responsible for regulating proteasome levels during proteotoxic stress has been studied in most detail in budding yeast. The transcription factor Rpn4 is not only a general activator of genes encoding proteins involved in the UPS but is also a proteasome substrate.86 An insufficient proteasome capacity will cause a general accumulation of proteasome substrates including Rpn4, which will adjust the capacity of the UPS by a general induction of its components by activating promoters that contain a so-called PACE (Proteasome-Associated Control Element) sequence.87 Although no orthologs of Rpn4 have been found in the human genome, metazoan cells also compensate for reduced proteasome activity by increasing the levels of proteasome subunits.88,89 In addition to increased proteasome synthesis, cells enhance proteasome assembly by increasing the expression of the maturation factor POMP.90
Cells with compromised proteasome activity can restore proteolysis by increasing expression of other proteases, such as the tripeptidyl peptidase-II91,92 and DUBs,93 which by a poorly defined mechanism are able to allow cells to proliferate with minimal levels of proteasome activity. Cells that have activated these compensatory mechanisms displayed an increased resistance to proteasome inhibitor-induced apoptosis.93,94 To our knowledge, the only presently described regulatory system that directly anticipates the increased demand for proteasome activity during proteotoxic stress in mammalian cells is the transcriptional activator Nrf2, which induces expression of proteasome subunits in response to oxidative stress.95 Nrf2 is constitutively ubiquitylated and degraded by the proteasome but stabilized during oxidative stress when its ubiquitin ligase Keap1 is targeted for degradation instead.96 An insufficient capacity of the UPS in mammalian cells triggers a profound stress response through the activation of the heat shock factor 1, which in turn results in the induction of molecular chaperones that can assist the folding or prevent aggregation of non-native proteins.97
Other limiting factors
Besides ubiquitin and the proteasome, a large number of proteins are involved in the regulated destruction of aberrant proteins during proteotoxic stress. Consequently, UPS impairment may be caused by a severe overload or dysfunction of other proteins crucial for a functional UPS. In this respect, it is noteworthy that a recent study mechanistically linked the AAA-ATPase p97Ufd1/Npl4 complex, which is implicated in the degradation of ERAD substrates98,99 as well as some specific cytosolic substrates,100–102 for being a primary cause of aggregation-induced UPS impairment.103
UPS impairment and apoptosis
The involvement of the UPS in various cellular functions, including protein quality control as well as cycle regulation and apoptosis, involves a risk since overloading the UPS with defective proteins, which may occur during proteotoxic stress, can in turn potentially interfere with cell cycle progression and cell viability (Figure 2).104 It is well established that a general inhibition of the UPS causes cell cycle arrest followed by cell death, a feature that is exploited in the usage of proteasome inhibitors for the treatment of some malignancies.105 In cellular models, the presence of aggregation-prone proteins76,106 or other proteotoxic stress conditions55,69 can also cause impairment of the UPS and accumulation of pro-apoptotic proteasome substrates. It seems plausible that the induction of apoptosis under those conditions is, at least partly, caused by impairment of the UPS. However, it should be emphasized that these findings are mostly correlative and do not conclusively show that there is a casual relationship. Since proteotoxic stress has, besides impairment of the UPS, a plethora of additional effects on the physiology of cells, the induction of programmed cell death through stabilization of key regulators may be just one of several mechanisms by which these cells perish.
In the case of ER stress, a condition that also causes UPS dysfunction,69 cells activate the UPR to restore homeostasis, but if left unresolved, a specific pro-apoptotic programme will be triggered to eliminate affected cells.33 The transcriptional activator C/EBP homologous protein (CHOP) is an important regulator of the ER stress-induced apoptosis.107 Strikingly, inhibition of apoptosis by ablation of CHOP can reduce the symptoms in some mouse models for conformational diseases.108,109 Cells appear to have downstream effectors dedicated to the elimination of terminally stressed cells, with caspase 12110 and caspase 4111 being responsible for ER stress-induced apoptosis in murine and human cells, respectively. The presence of specific systems to directly link cellular stress to an apoptotic response underscores the importance to eradicate dysfunctional cells.
The occurrence of stress-induced UPS impairment in the context of human diseases has been generally considered as a negative factor that contributes to the pathology. Accordingly, restoration of UPS function may have a beneficial effect.1,4 It remains, however, possible that the stress-induced UPS impairment fulfils a protective function as a last resort to eliminate aggregation-prone proteins through the organized destruction of cells containing the rogue proteins. Although proliferating cells may be able to get rid of insoluble protein aggregates through asymmetrical division,112 induction of apoptosis may be the only way to eliminate post-mitotic cells that are affected by protein aggregation, a process that may be initiated by stress-induced UPS impairment. Notably, stress-induced UPS impairment may also be relevant for non-pathological processes. It has been proposed that the natural lifespan of activated B lymphocytes may be regulated by proteasome stress caused by the large production of non-native immunoglobulins that gradually overload of the UPS.85
The UPS in cardiac diseases
An increasing body of evidence implicates UPS dysfunction in cardiac diseases. Cardiopathies caused by misfolded proteins display the typical intracellular inclusions composed of amyloid-like deposits similar to those observed in neurodegenerative conformational diseases. A most striking example of the commonalities in conformational neurodegenerative and cardiac diseases is the observation that a mice expressing a prion protein lacking the glycophosphatydylinositol membrane anchor develops a cardiac disease with amyloidogenesis.113 A well-studied example of a conformational disease affecting the heart is the desmin-related myopathies, which are a group of congestive heart failure disorders characterized by the presence of misfolded desmin protein. These diseases can be caused by missense mutations in desmin114 or in the small heat shock protein αB-crystallin, required for proper folding of desmin.6,115 Similar to the situation in other conformational diseases,116,117 the presence of the aggregation-prone proteins causes a general impairment of the UPS, which is accompanied by changes in proteasome activity.118 The UPS dysfunction caused by mutant αB-crystallin could largely be prevented by overexpression of the small heat shock protein Hsp22 or Hsp25, presumably through the inhibition of the formation of toxic oligomers.119 Transgenic mice overexpressing a mutant αB-crystallin that is linked to a familial cardiomyopathy revealed that reductive stress caused by an increase in reductive molecules causes protein aggregation and contributes to the pathology suggesting a pivotal role for protein misfolding in this disease.120 Interestingly, the presence of the aberrant ubiquitin UBB+1, which can inhibit the UPS66,67 and may be an indicator for UPS dysfunction,70 has been reported in desmin-like pathologies.64
Another condition that is directly linked to protein misfolding is ischaemia both of the heart and the brain.121 A number of studies have shown that ischaemia causes a general activation of the UPR, suggesting that the cardiomyocytes are encountering ER stress under hypoxic conditions,122 a condition which is known to compromise the functional status of the UPS.69 It is not clear whether the induction of the UPR in cardiomyocytes contributes to the disease or plays a protective role. Indeed, inducing ER stress in cardiomyocytes prior to a hypoxic stress can have a protective role and improve survival.123 On the other hand, ER stress can result in activation of an apoptotic programme and this, at least in vitro, seems to contribute to cell death under hypoxic conditions.124 Ischaemic conditions result in accumulation of ubiquitylated and oxidized proteins and activate the UPR consistent with the presence of misfolded proteins and proteotoxic stress.125 Thus, it remains to be seen whether the UPR contributes to, or protects from, the molecular pathophysiology in ischaemia of the heart.
The proteasome inhibitor bortezomib (also known as Velcade™) has recently been approved for treatment of multiple myeloma.105 Although it remains unclear why malignant cells display increased sensitivity to proteasome inhibition,89 it appears that in the case of multiple myeloma, major contributing factors are inhibition of NF-κB activation and interference with the UPR.126 Although the side effects of bortezomib are relatively mild, it is noteworthy that congestive heart failure has been reported for several patients.127,128 It has been shown that proteasome inhibition induces ER stress in cardiomyocytes129 and that overexpression of ER chaperones can prevent proteasome inhibitor-induced apoptosis of cardiomyocytes, suggesting that ER stress may be implicated in this phenomenon.129 Moreover, ER stress results in the induction of an apoptotic programme in cardiomyocytes, which has been linked to heart failure.124 It has, however, also been shown that treatment of cardiomyocytes with low doses of proteasome inhibitors can enhance survival of cardiomyocytes under ischaemic conditions.130 This may be mediated through the activation of the heat shock response, which allows the cardiomyocytes to more promptly deal with misfolded proteins during stress conditions.
The possible implication of UPS dysfunction in cardiac diseases is intriguing and relevant for our understanding of the pathophysiology as well as for the development of therapies. In this review, we have discussed only a few examples of the link between proteotoxic stress, the UPS, and cardiac diseases as this topic is covered in other reviews in this issue.131,132 Although the intimate link between the UPS and muscle disease has gained much interest during the last few years, this is a topic that entered the stage two decades ago shortly after the discovery of the UPS. It is noteworthy that the first proteasome inhibitors, of which the first derivative recently found its way to the clinic as an anti-cancer drug, were originally developed with the aim to block muscle wasting (such as the commonly used peptide aldehyde proteasome inhibitor MG132, which stand for MyoGenic 132).133 More recently, the UPS was found to be important also for muscle development.102 Altogether a far more complicated picture is emerging with intracellular protein degradation by the UPS playing a central role in multiple pathways in the cardiomyocyte in health and disease.
The work is supported by the Swedish Research Council (N.P.D. and K.L.), Magn Bergvall's Foundation (K.L.), Karolinska Institutet (K.L.), the Swedish Cancer Society (N.P.D.), the Nordic Center of Excellence Neurodegeneration (N.P.D.), and the EU Network of Excellence Rubicon (N.P.D. and K.L.).
We thank Martijn Luijsterburg and Florian Salomons for critical reading of the manuscript and helpful suggestions.
Conflict of interest: none declared.


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Delfina delettrez's signature eye motif has become a modern jewellery classic and this 18kt yellow-gold single earring is a statement way to wear it. It features a white pearl stud, a 0.22ct white-diamond embellished curved band and the illustrious eye centred with 0.02ct black diamonds and 0.10ct emeralds. Color: yellow


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Striking Down Scoundrels
Jerry D. Harrison
Smashword Edition, License Notes
This ebook is licensed for your personal enjoyment only. This ebook may not be re-sold or given away to other people. If you would like to share this book with another person, please purchase an additional copy for each recipient. If you're reading this book and did not purchase it, or it was not purchased for your use only, then please return to Smashwords.com and purchase your own copy. Thank you for respecting the hard work of this author.
Striking Down Scoundrels
by Jerry D. Harrison
Published by Jerry D. Harrison at Smashwords
Copyright 2010 by Jerry D. Harrison, all rights reserved.
This story is a work of fiction. All persons and entities except those trade names listed and acknowledged at the back of this book are fictitious, and all thoughts, statements, and actions of characters in this book are products of the author's imagination, including thoughts, statements and actions pertaining to trade names mentioned.


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Scar treatment protocol creates synergism between fractional lasers, corticosteroids
Same-session therapy that incorporates topical/intralesional corticosteroid and multiple-wavelength laser treatment, including the fractional CO2 ablative laser, shows promise as a safe and effective protocol for providing aesthetic and functional improvement for patients with challenging cutaneous scars, says Jill Waibel, M.D.
All scars were treated for a total of three sessions at one-month intervals. Results were graded six months after the last treatment by three blinded observers who used a 0 to 3 quartile scale to rate improvement in four areas: overall, dyschromia, hypertrophy and texture. The mean score for overall improvement was 2.73; all scars received a score of 2 or higher for improvement in texture, and 14 (93 percent) were rated with a score of 2 or higher for improvement in hypertrophy.
"We have come a long way in treating severe cutaneous scars in the past few years, and in my opinion, the fractional ablative laser has emerged not just as the new gold standard for scar resurfacing, but the platinum," Dr. Waibel says. "However, cutaneous scars can present a complex problem, and in that situation, the treatment approach should also be complex.
"Use of a multimodal protocol combining various laser wavelengths and corticosteroid treatment is based on that principle, because it addresses multiple features of the scar while also taking advantage of the variable depth ablation zones created by the fractional ablative laser to assist drug delivery," she adds. "These channels, which reach 500 to 800 microns into the dermis, allow for synergistic efficacy by enabling dermal penetration of the corticosteroid deeper than can be achieved even with intralesional injection, and thereby optimize its efficacy in breaking down scar tissue."
The combination laser and corticosteroid treatment is performed under topical anesthesia using a compounded cream containing benzocaine 20 percent, lidocaine 8 percent and tetracaine 4 percent. The triamcinolone acetonide is applied or injected immediately after the fractional ablative laser treatment is finished with the chosen concentration (10 mg/cc, 20 mg/cc or 40 mg/cc) and method of administration (topical and/or intralesional), based on scar severity and thickness, Dr. Waibel says.
"We know the inflammatory cascade initiated by the laser treatment begins within just two minutes, and by delivering intralesional steroid we can decrease inflammation and simultaneously diminish collagen synthesis. Application of the corticosteroid immediately after the laser treatment aims to maximize inhibition of this process," Dr. Waibel says.


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Expectation + Breast Reconstruction Q&A
My Silicone Gel Implant is Flat in the Nipple Area, Will That Round Out?
I am 5 days post op and this was placed after my expander that was in place post mastectomy. The scar is across the area tha is flat, so I don't... READ MORE
So if the Max on Reconstruction is 800cc What Size is That Comparable Too? Am I Going to Look Like a Freak?
With DIEP Reconstruction, What Can I Expect in Terms of Regaining Strength and Range of Motion?
My yoga practice is very important to me and I want to make a choice that will enable me to get back to my full practice, if possible, and as soon as... READ MORE
I Am Considering Breast Reconstruction Using a Spectrum Implant/expander- What Result Can I Expect?
I had a tissue-sparing mastectomy in April. I had chemo but no radiation. I am a 38B. Is a Spectrum implant/expander reliable and produce a positive... READ MORE
L May Have to Have Bi-lat Skin/nipple Sparing Mastectomy. I Have Chest Wall Implants Now. Results?
I am waiting on BRCA test results. Due to DCIS in 2007. I have saline implants in the chest wall on both sides. I am a D cup. If the BRCA is positive,... READ MORE
Does the Skin Around the Fat Grafting Get Tightened for Reconstructive Breast Procedures?
I have had a bilateral mastectomy, currently have expanders in place and am undergoing radiation. My PS said I would likely have to have fat grafting... READ MORE
What Do I Need to Ask my Surgeon Before my Exchange Surgery?
I had a double mast, I have expanders in now. I have a consult to go over the next surgery to put in the silcone implants. I will discuss size, and... READ MORE
I'm s/p a mastectomy with reconstruction. My implant is not where is should be and I don't have an IMF. (Photo)
My doctor wants to make an incision and remove a piece of skin and then suture it to my ribs to create an IMF. He called it the Ryan Procedure. What... READ MORE
Cosmetic expectations following skin-sparing mastectomy with reconstruction?
Hi there, I suffer from chronic mastitis and fibrocystic breasts. The recommended procedure is skin-sparing mastectomy with reconstruction using gummy... READ MORE
Realistically, what should I expect my reconstruction to look like? (Photo)
I am about to go through prophylactic bilateral mastectomy.I am a BRCA2 +. I am 37 yrs old. 129 pounds. 5.7 tall. slender and active. I have droop... READ MORE
Slight abdominal bulge below the navel after DIEP flap. Does this go away?
I had bilat. prophylactic mastectomy nearly 3 weeks ago. On one said PS did m/s free tram. On the other side he was able to do DIEP. I have a slight... READ MORE
What to expect after explant?
After stage 3, double mastectomy, chemo, radiation and 2 1/2 yrs of discomfort and sore joints I had second reconstruction along with scar and dead... READ MORE
I'm a 36DDD. I'm scheduled to have a bilateral parenchymal mastectomy with expander.
I would like to know what if I will have the same size breast. I'm 5'3' 130lbs . What should I expect when I'm done with the expanders. READ MORE
Surgery on tram flap breast. What are some of the long-term changes I should expect?
I am wondering if it is better to reduce the size of my tram Flap from a DD to a.C? I am wondering about future complications, sagging, weight of the... READ MORE
Breast reconstruction: How is surgical removal of a seroma done?
I developed a seroma after TRAM flap surgery. My plastic surgeon has tried everything to make it heal to no advail. He has decided on surgery. What am... READ MORE
Large gaping wound on right breast. Saw er doc 10 days later sending me to a surgeon ASAP. What should I expect?
Wound is about 5-6 inches long and 2 inches deep so gaping it is about 4 inches wide. I did hit a blood vessel . Since the time and the damage of the... READ MORE
What to expect from a skin sparing bilateral mastectomy with reconstruction?
37yts old and I've have tumors removed for the last there years but the keep growing back, my body rejected tamoxifen and I'm in the 4th year of my... READ MORE


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alleluia and fugue mp3 download free ul5s full file
== Search results for alleluia and fugue mp3 ==
Searched file: alleluia and fugue mp3
*Filename: alleluia and fugue mp3.zip
*Year: 2015
*Total Downloads: 153451
*Uploaded: 02/26/2015 17:31:00
*Type: WinZip
*Supported OS: All
== Searches related to alleluia and fugue mp3: ==
02/26/2015 17:31:00
Current ChoralTech MIDI library Updated 29 Sept 2014. Either scroll through the list to composer you are interested in, or just use the links below to go directly to ...Georg Friedrich Haendel ou Händel (George Frideric Handel en anglais, comme il l'écrivait lui-même) est un compositeur allemand, devenu sujet britannique, né le ...Sheet music list : › Ça, bergers, assemblons-nous - Lead sheet › Ça, bergers, assemblons-nous - Lead sheet › Ave Maria - Soprano voice, String quartet with OrganWelcome to Hyperion Records, an independent British classical label devoted to presenting high-quality recordings of music of all styles and from all periods from the ...Looking for classical mp3 downloads? We index the free-to-download classical mp3s on the internet. ©2014 Classic Cat - the classical mp3 and video directory.11/15/2009 · Pachelbel's celebrated "Canon in D," performed by Voices of Music, overlaid with a scrolling graphical score. FAQ Q: Where can I get the sheet music for ...The Organ Loft Collection Église Notre-Dame-des-Neiges, Trois-Pistoles, Québec St. Anthony of Padua Church Organ, New ...Other places of interest to the midi musician: Choral Public Domain Library; Choirmidi Piet Mennen's home page The Classical MIDI Resource; Ricci Adam's MusicTheory.netDownload, Search and Listen to over 30 million music and mp3 files from the web free at Musicdumper.comMost of the great romantic pianists wrote their own arrangements, lovingly fashioned and fulfilling the aim of all good transcriptions—to show the player and their ...
alleluia and fugue mp3
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- 02-02-2014, 12:12 AM Thread Author #1
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how to roll back from kit kat to jelly bean
I have a Nexus 7 2012 wifi version that I have updated to kit kat. I decided to root it but there's no way, believe me I've spent a lot of time on it. No driver available (or at least nothing works). I need to roll it back to jelly bean, then I should be able to get the correct driver and root it.
So here's the 64 thousand dollar question:
How can I take a device that's already been updated to kit kat and install jelly bean on it?
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Re: how to roll back from kit kat to jelly bean
You have a Nexus so anything is possible, but it's better to get the driver working than go back to JB, I don't think that will solve the problem. Although knowing how to flash factory image is a good thing also.
Use this driver here: http://forum.xda-developers.com/show....php?t=2513339
If you are using Windows 8, read the instruction in the thread to disable driver signature enforcement. Then make sure you install the driver while in both ADB and Fastboot mode.
To root you have to unlock the bootloader, install custom recovery using fastboot and use it to flash SuperSU package. There are lots of guides out there for it, look here http://forums.androidcentral.com/goo...ng-roms-hacks/
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Pop Art Accessories are the perfect way to complete an outfit. This kit contains everything you need to create a fashionable bracelet and two matching hair clips.
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F5 Offers FIPS Security on Its Big-IP App Delivery Controller
F5 Networks is enhancing the performance and security around SSL-encrypted data to meet the FIPS specifications. The move means that the F5 product is certified for use by government agencies. The FIPS spec also is being embraced by other industries known for encrypting sensitive data, such as health care and financial services, both of which are seeing growing levels of government regulation.F5 Networks is making its application delivery system ready for government agencies and other institutions with highly sensitive data. F5 announced June 15 that its Big-IP 6900 Application Delivery Controller now comes in an edition that supports the FIPS (Federal Information Processing Standard), which provides high performance and greater security around SSL-encrypted application traffic.
The FIPS support means that F5's Big-IP system manages FIPS security, rather than having each individual server do the job. By consolidating that task onto F5's application delivery system, organizations can save as much as 25 percent on compliance costs, according to F5 officials.
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- Learn More
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- 755126
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Product Information for Philips 40PFL3706 40" 1080p LCD TV - 16:9 - HDTV 1080p
Highlights for Philips 40PFL3706 40" 1080p LCD TV - 16:9 - HDTV 1080p
- Screen Size:40"
- Maximum Resolution:1920 x 1080
- Speakers:Yes
Marketing Information
The Philips 40-Inch 1080p LCD HDTV delivers exceptional image quality, crisp sound performance, and broad connectivity. Compatible with 1080p devices, this HDTV allows you to make the most of the latest Blu-ray and game releases. It also boasts Incredible Surround sound technology, energy efficiency, and a versatile collection of inputs and outputs.
1080p Resolution Supports the Latest Media
The Philips 40-Inch 1080p LCD HDTV supports 1080p signals, so you'll be able to enjoy Blu-ray and high- definition games. The TV also features signal processing, which helps keep image quality pristine. The result is a crisp, high-resolution image that is free of pixel gaps, flickers, and other video artifacts.
Exceptional Image Quality with Any Input
The HDTV offers exceptional high-definition video, progressively scanning images to bring you a smooth, flicker-free picture. It uses Pixel Plus HD technology to process each incoming pixel before it reaches your screen, ensuring exceptional image quality regardless of what input you are using. You'll see improved detail, brighter contrast, and more vivid color--even when using older, standard-definition devices.
Connect DVD Players, Computers, USB Drives, and More
You can quickly and easily connect a cable or satellite box, camcorder, game console, Blu-ray disc player, PC, and more with the HDTV's multiple inputs. Three HDMI inputs--two on the back and one on the side--with Philips' EasyLink feature let you control connected devices with the same remote control as the TV. And, all you need to connect your PC is a VGA cable.
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- 40 inch class
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text:
Here is the checklist description of Move Over, which doesn't
match your picture at all:
MOVE OVER (W. Terry Varner, R. 1995) Sdlg. Q-356. MTB, 20" (51 cm), L
Blue purple self; beards white. Velvet Bouquet X N-318 blue self: (Blue
Twinkle x J-311 light blue: (MLD 0-144 light blue x Velvet Bouquet)).
Ohio Gardens 1995.
I'm betting your iris is a mis-named Loreley also...
SF bay area, zone 9
On 7/18/2011 1:59 PM, Donald Eaves wrote:
> '95 intro by Varner. I think not the same as the NOID Adam posted, but I
> really couldnt' be sure just from looking at the photos. In my own photos
> of this one, the standard markings were variable and the bloom form was as
> well.
> Donald Eaves
> firstname.lastname@example.com
> Texas zone 7b (now a dead zone), USA
Statements made on and attachments (including but not limited to photographs
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text:
Frazer Lockhart
It wasn't so long ago that big budget, award-winning films were produced in Colorado. Now, we have a chance to return to that era in the 2012 Colorado Film Incentives Proposal.
This video is designed to help enlighten the wary taxpayer of the incredible impact a single film can have on a local economy.
On February 8th 2012 starting at 7:30am we, as filmmakers, media professionals, content creators, and local businesses, will stand on the steps of the Colorado Capitol to show our support to the legislators the importance of the Colorado Incentives proposal for 2012.


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I Done It... I Done It .... I Done It......
:pickle::pickle:Well today was me going to Spirit Quest Archery for the first time since my surgery in November. I arrived at 11:30am and left there about 2:30pm....
Keeping right along with my old pace at 10, 20 and 30 yards.
My left shoulder feels like I just had a solid hour work out on the pully weights at PT but this was my workout today at 60# draw.
The doctor had told me I probably wouldn't be able to draw a bow after surgery.... am I excited....
Oh I am so excited... heck I'm 52 and I feel like breast feeding baby in a room full of topless women excited.:pickle::pickle:
Man that is good news that at your age you still have that stamina. LOL:lol:
thats great to hear congrats on recovery
That's great news buddy. I'm really glad that your progressing so quickly. I think I can understand how excited you are:confused::lol:
congrats man i know the feeling.when i could finally shoot again i was so happy.just wait till you get a deer you'll be ecstatic.congrats again
:thumbup::thumbup: great news.
Good deal dude!!!
Good news the shoulder is good and so are your dreams!!!:lol:
I agree with Buckshot...
I will be heading back to the indoor range tomorrow, and now mentoring a friend of mines 16 yr old son who wants to get into shooting bow. I am taking Brandon with me tomorrow so he can get measured up for draw length and see what kind of bow he should get.
Glad his mother trust me :coffee:
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In California, we've been getting some awesomely delicious avocados lately. Chalk it up to avocado season, which runs from Spring to Fall. Even if you don't live in the Golden State, chances are that green fruit you're savoring [1] is from here anyway. Ninety percent of the nation's crop comes out of California. From sandwiches and salads to salsas and other tropical-tinged flavor combinations, avocado is surprisingly versatile. Here are 33 of our favorite ways to enjoy it.
— Additional reporting by Nicole Perry, Emily Bibb, and Hilary White
Smoked Salmon Sandwich
If you love sushi, then you'll love this smoked salmon sandwich [4] with avocado and wasabi cream cheese.
Savory Sopaipillas
Top pan-fried sopaipillas [5] with avocado for a savory twist.
Avocado and Red Onion Salad
Creamy slices of avocado are the star in this fresh four-ingredient salad [6].
Tropical Green Smoothie
For a tropical getaway in a cup, blend up this avocado smoothie [7]. It's thick, creamy, and mouth-puckering.
California Sushi Roll
Homemade sushi's not as hard as everyone makes it out to be. Cut your teeth on a California roll [8], which stars cucumbers, imitation crabmeat, and, of course, dreamy avocado.
Bacon Guacamole
Smoky bacon and creamy avocado come together for the ultimate tortilla-chip dip [9].
Vegan Chocolate Cupcakes
These chocolate cupcakes might look ordinary, but they are actually vegan, thanks to an avocado-based "buttercream" frosting [10].
Rainbow Veggie Sandwich
A rainbow of vegetables — tomatoes, cucumbers, radishes, bell peppers, avocado, sprouts, and kale chips — fill this green-goddess-dressed sandwich [11].
Guacamole Mason Jar Salad
Think of this mason jar salad [12] as deconstructed guacamole with a hefty dose of greens.
Cheesy Avocado Quesadilla
So quick and easy, this insanely tasty cheesy avocado quesadilla [13] recipe is a must for weeknight dinners.
Chicken Posole Soup
Chicken posole often requires hours of simmering, but not this quick-fix version [14].
Grilled Pineapple and Coconut Guacamole
Now this is something we can get into. A blend of creamy avocado, coconut flakes, and grilled pineapple completes this tropical guacamole recipe [15].
Avocado Toast Variations
You'll never get bored with avocado toast thanks to these nine variations [16], ranging from supersimple (red pepper flakes, salt, and pepper) to creative (a spin on caprese salad).
Chocolate-Coconut Avocado Soft Serve
Not only is this chocolate-coconut avocado soft serve [17] delicious, but it also doesn't require an ice cream maker.
Breakfast Nachos
Nachos, including this breakfast version, aren't really nachos without a generous dose of avocado [18].
Cucumber Avocado Tuna Hand Rolls
Spiralized cucumber noodles take the place of rice in these tuna-avocado hand rolls [19].
Chicken Cobb Salad Wrap
Wraps aren't only for lunch; case in point, this filling take on chicken Cobb salad [20].
Pineapple Avocado Salsa
It's time to take your salsa inspiration to the tropics with this pineapple salsa [21]. The sweet, acidic, and spicy flavors go great on grilled fish tacos and tortilla chips alike!
Green Goddess Dressing
This lighter, greener spin on iconic green goddess dressing [22] swaps avocado and Greek yogurt for mayo and sour cream.
Spicy Avocado Margarita
Avocado sounds like a strange addition to a cocktail [23], until you consider that margaritas are often paired with guacamole and that the fruit itself is mild in flavor.
Vegetarian Burrito
Give leftovers an exciting new life [24] in burrito form. (Don't forget a generous dose of guac!)
His and Hers Guacamole
Why have guacamole only one way? Make and serve two different types of guac [25]: one spicy and smooth with the addition of serrano peppers and olive oil, and a milder guac with crumbled feta.
Cucumber Avocado Caprese Salad
Give classic caprese a summery spin with the addition of cubed avocado and cucumber [26].
Breakfast Tostadas
Fully loaded breakfast tostadas [27] are the ultimate hangover cure.
Shrimp-Ceviche-Stuffed Avocados
Halved avocados are the perfect edible vessel for tangy shrimp ceviche [28].
Creamy Avocado Dressing
Avocado replaces mayo and dairy for a creamy vegan dressing [29].
Crisped Prosciutto and Avocado Crostini
These crisped prosciutto and avocado crostini [30] are incredibly easy, and the resulting bite is sure to be a hit with guests.
Vegan Burrito Bowl
This vegan burrito bowl [31] doesn't skimp on flavor: it's topped with spiced roasted sweet potatoes, black bean corn salsa, and plenty of avocado.
Tropical Fruit Salad With Arugula and Pickled Shallots
For an unexpected salad [32], mix tropical fruit with avocado, peppery arugula, and other savory ingredients.
Classic Guacamole
Creamy guac [33] doesn't need any added frills — it holds its own when paired simply with tortilla chips and topped with a splash of lime.
Avocado Soup
Cool down with a creamy avocado and corn soup [34] topped with tomato, scallions, and briny crab.
Avocado Coconut Popsicle
Try dabbling in avocado desserts with these easy-to-make avocado and coconut milk popsicles [35].
Simple Green Salad
Keep things simple with a zesty green salad topped with onions and avocado [36].


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Seven Sixteen Woodwind Trio is made up of a flautist, clarinetist, and bassoonist.…
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text:
Terrence Malick Speaks
When news hit that Darren Aronofsky's frequent collaborator Clint Mansell would be lending his talents to the score Park Chan-wook's Hollywood debut Stoker, we all assumed that Philip Glass — who was previously rumored — had exited. Thankfully, that's not the case as Entertainment Weekly has an update, as well as an original song for the film.
We've gotten a couple trailers for the film that tells the story of some creepy family drama between Nicole Kidman, Mia Wasikowska, Matthew Goode and Jacki Weaver — and now Fox Searchlight have delivering a fitting cut from the soundtrack. After confirming Mansell's score, along with some original pieces by Glass, EW have shared a song by Emily Wells titled Becomes the Color. The musician was actually hand picked by the director and since no embed is available, check out the impressive song by clicking the player below, along with more details over on the site.
Stoker hits theaters on March 1st.
Since any New York City cinephile has a nearly suffocating wealth of theatrical options, we figured it'd be best to compile some of the more worthwhile repertory showings into one handy list. Displayed below are a few of the city's most reliable theaters and links to screenings of their weekend offerings — films you're not […]
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Bombay Dyeing presents this 3-piece, peach coloured bed sheet set, which will add a touch of quirkiness and vibrancy to your home decor. Made of poly cotton, this bed sheet set is easily washable and long lasting as well. Any item shown in the image, apart from the product/package content is for display purpose only.
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StartUpHire is the place to find Mobile jobs in and near Santa Rosa. Review the list of Mobile Santa Rosa career opportunities to the left. These Mobile jobs represent some of the most rewarding careers available.
You can refine your job search for Mobile career opportunities in Santa Rosa by adding a job title, company name, or keyword to the search box above … or click the "Advanced Search" link for more options.
Don't see the employment opportunity you're looking for? Check back soon for more Mobile jobs in Santa Rosa, or sign up for an email alert (link below) to receive periodic updates on new Mobile jobs in Santa Rosa, CA.
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Telltale Games is looking for Mobile Producer to join an exciting new mobile game initiative.San Rafael, CA Save This Job
Want to own our upcoming next-gen ports Telltale Games is seeking an enthusiastic Mobile Engineer to help us build out our next-generation platform technology for upcoming IPs and our award-winning titlesSan Rafael, CA Save This Job
at Twilio (View all jobs) San Francisco, CA We are looking for an experienced mobile engineer to lead the development of plugins and wrappers to expose Twilio mobile SDKs to mobile cross-platform frameworks like Xamarin and React Native. Twilio SDKs power the next generation of2/21/2017 San Francisco, CA Save This Job
The engineers of Stride Health are in search of a vital new team member? a collaborative, sharp-as-a-tack, self-starter that's ready to own our mobile technical strategy. You'll be the first of your kind, a true pioneer tasked with ensuring that Stride is well-positioned to1/9/2017 San Francisco, CA Save This Job
All times are in India Standard Time. ID 2016-2475 Job Location US-WA-Seattle Posted Date 8/27/2016 More information about this job: Overview: At Accolade, we?re transforming the way people experience healthcare. We believe that conventional approaches are failing American11/5/2016 Seattle, WA Save This Job
Job ID #:14037Location:US-CA-San Francisco Functional Area:Technology-R&DDepartment:TripIt Position Type:US Full TimeEducation Required:Bachelors Degree Experience Required:5 - 7 YearsRelocation Provided: Share: Share on Facebook! Facebook Share on LinkedIn! LinkedIn Share on1/1/2017 San Francisco, CA Save This Job
Telltale Games is seeking an enthusiastic Quality Assurance professional to be part of our QA group dedicated to compliance and certification for our upcoming IPs and current award-winning titles This is a senior group that will work closely with producerSan Rafael, CA Save This Job
Senior Software Engineer (Mobile Development)Apply Here What you?ll be responsible for Participates in development and maintenance of the OpenTok SDK code base Engages in all aspects of the software development life-cycle, including research-oriented exploratory programming,1/25/2017 San Francisco, CA Save This Job
You're a brilliant, hardworking mobile software developer. You?ll be developing our flagship iOS app alongside amazing mobile developers, and collaborating with our product team and backend API team to build something that would make people happy. Requirements: 3+ years12/27/2016 San Francisco, CA Save This Job
This isnât your typical UX design gig; youâll be working with a talented and energetic team that is passionately creating a next generation mobile game. Youâll draw upon your deep-seated UX knowledge to develop creative methods for presenting complex systems in anSan Francisco, CA Save This Job
If you live and breathe mobile games, love working as a team and thrive in creative environments, GREE has a great opportunity for you. As a Level Designer, youâll be working on a cutting-edge new mobile game and will be involved in early stages of concept, design,San Francisco, CA Save This Job
We have a unique opportunity for a Senior Director to lead our Media strategy, planning and buying capability at Gree. Our internal UA, BI and creative teams are already known for pioneering work across mobile media formats, analytics, and franchise excellence. Â Currently weSan Francisco, CA Save This Job
About the roleWe're looking for an experienced Product Manager to manage the development and optimisation of a mobile free-to-play game through all key phases of the product lifecycle! Youâll work with an incredible production team to drive for answers to business questionsSan Francisco, CA Save This Job
We are looking for a passionate Mobile User Acquisition expert to drive growth efforts across our portfolio of games. This person is responsible for buying media worldwide while exceeding ROI goals. The successful candidate is a deeply analytical thinker that has experienceSan Francisco, CA Save This Job
The GREE Design team is looking for an experienced Senior UX/UI Designer to our fun, brilliant and diverse team. You will work primarily with the Game UX Design team, helping to define player facing aspects of our games. You will also work with an incredibly talented group ofSan Francisco, CA Save This Job
San Francisco Hipmunk is looking for someone to join the Product Design team. We are looking for a talented, highly passionate designer with a strong foundation in visual design as well as a solid understanding of user experience, interaction and product design. You will have the1/14/2017 San Francisco, CA Save This Job
GREE International Entertainment creates top quality games that push the boundaries of mobile entertainment. As a company, we have over a decade of experience at delivering quality gaming experiences such as Crime City, Kingdom Age, Modern War, and Knights & Dragons. As partSan Francisco, CA Save This Job
We are looking for a highly quantitative and results-oriented Senior Business Intelligence Data Analyst to dive into our social data ocean and find valuable insights for informing decisions and making our games the best they can be. GREE's business runs on data so you will haveSan Francisco, CA Save This Job
Do you get excited about building high performance services? Do you know what data structures to use, elegant design patterns, clever algorithms, and how to optimize SQL? Great, so do we! Come join one of the largest mobile social gaming companies in the world. What you get toSan Francisco, CA Save This Job
Software Engineer - Android Game ClientWe're looking for Android engineers to join our game studios You'll work on new gameplay features, optimizations and improvements, and more for our live titles Many of our games have been in the App Store&rsquoSan Francisco, CA Save This Job


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at Tremor Video (View all jobs) New York, New York, United States OUR MISSION IS TO BRING THE CERTAINTY OF SCIENCE TO THE ART OF BRAND MARKETING. At Tremor Video, we help make every advertising moment more relevant for consumers, and more valuable for advertisers and publishers.2/14/2017 New York, NY Save This Job
Los Angeles, CA Boingo helps the world stay connected. Our vast footprint of Wi-Fi and cellular networks covers more than a million locations and reaches over a billion consumers annually ? in places as varied as airports, stadiums, universities, and military bases. The Product2/14/2017 Los Angeles, CA Save This Job
Share Trion Worlds, Inc. is seeking an Associate Product Manager (Market Research) in its Redwood City, California location. POSITION RESPONSIBILITIES: On behalf of global online developer of Massively Multiplayer Online (MMO) electronic games and interactive entertainment,2/10/2017 REDWOOD SHORES, CA Save This Job
United States - Houston ? Job ID 1758 Job Summary We are continuing to expand our team and are looking for a Senior Product Manager to join some of the industry?s brightest minds that are dedicated to providing our customers and partners with security value and outcomes. This2/9/2017 Houston, TX Save This Job
Business Technology Austin , Texas APPLY Description: We're looking for a smart, creative, and resourceful Technology Product Manager to help in planning, designing, building, and managing our business systems. As a Technology Product Manager, you will be a driving force2/3/2017 Austin, TX Save This Job
EDUCATION: Bachelor of Science or equivalent degree in Computer Science, Computer Engineering, Electrical Engineering, Engineering or an equivalent field. MBA a plus. EXPERIENCE: Minimum of five years of experience as a Product Manager, Technical Program Manager, or2/2/2017 Redwood City, CA Save This Job
Boston Are you a data scientist ready to make an impact on the data science world? The Junior Technical Product Manager will steer the creation of a machine learning product used by thousands of data scientists. We are looking for a talented product manager to join our fast2/1/2017 Boston, MA Save This Job
Description Title: Senior Product Manager Location: San Francisco, CA Clarivate Analytics accelerates the pace of innovation by providing trusted insights and analytics to customers around the world, enabling them to discover, protect and commercialize new ideas faster.1/31/2017 San Francisco, CA Save This Job
The Product Manager is responsible for the development and execution of Opus?s Data Solutions product roadmap. Opus?s Data Solutions business provides entity identifier mapping, entity monitoring and cleansing and de-duplicating services to financial institutions, global1/26/2017 New York, NY Save This Job
Overview Reporting to the VP of Product Management, the Senior Product Manager for Digital Lumens Software Applications is responsible for managing Digital Lumens? building intelligence SW platform and applications including but not limited to Lighting Control, Environmental1/25/2017 Boston, MA Save This JobApplied To
Product Management Campbell, California APPLY Description Position at Campanja 247 is redefining the way that companies interact with consumers. The company?s customer engagement platform assists several hundred million visitors across all channels, and engages in 1.5 billion1/24/2017 Campbell, CA Save This Job
Date Posted: August 31, 2016 We are an equal-opportunity employer. If you are interested in applying for a position, please send your resume to email@example.com. Quantum Secure, now part of HID Global, is the leading provider of enterprise software to manage and1/21/2017 San Jose, CA Save This Job
REMOTE - USPRODUCTFULL-TIME APPLY FOR THIS JOB Job Purpose: We?re looking for a bright, creative, and self-motivated individual to take on an active role in the product management activities for our Procure-to-Pay product line. This is a key position within the Products1/18/2017 Oakland, CA Save This Job
Location:Audubon, PA Job Code:APMKP0117 Description The Product Manager will be responsible for supporting the product development team with a wide range of marketing activities. This position will also be the primary liaison between each product development group and sales1/17/2017 Audubon, PA Save This Job
Location:Audubon, PA Job Code:PM0316 Description The Product Manager will be responsible for supporting the product development team with a wide range of marketing activities. This position will also be the primary liaison between each product development group and sales1/17/2017 Audubon, PA Save This Job
Location: Redwood City, CA OPPORTUNITY Today?s communications landscape is dynamic and increasingly complex. Actiance allows companies to use email, enterprise social software, unified communication, instant messaging, and social media in a way that allows them to improve1/15/2017 Redwood City, CA Save This Job
AnchorFree?s mission is to provide secure and private access to the world?s information for every person on the planet. AnchorFree?s Hotspot Shield app is the world?s most popular freedom and privacy platform. Hotspot Shield is the starting point, for mobile and Web access,1/14/2017 Menlo Park, CA Save This Job
Array Networks (www.arraynetworks.com), a pioneer in converged networking and security, is looking for a successful Senior Product Manager to join our team. The Senior Product Manager will be responsible for guiding the development of the company?s new Converged Networking1/10/2017 Milpitas, CA Save This Job
United States - Austin ? Job ID 1703 Job Summary We are continuing to expand our team and are looking for a Senior Commercial Product Manager to join some of the industry?s brightest minds that are dedicated to providing our customers and partners with security value and1/10/2017 Houston, TX Save This Job
NYC The Product Manager is responsible for helping define, direct, and launch our software products. We are looking for an unique individual who can synthesize information from our current customers, our employees, the market, and the competitive landscape to conceive and build1/8/2017 New York, NY Save This Job


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Report Finds 34 Pesticides in Tea From India
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Try Dilmah which is privately owned and operated by a local community. Or you can try my favorite tea by Mighty Leaf.
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Ross Whetten
Department of Forestry and Environmental Resources
Jordan Hall Addition 5231
Area(s) of Expertise
Biochemistry and Molecular Biology
Research website
B.S., Arizona State University (1981)
Ph.D., Vanderbilt University (1988)
Research Interests
Applications of molecular biology methods to solve practical problems in management of natural or planted populations of forest trees, with an emphasis on conifer species native to the southeastern USA. Massively-parallel or "next-generation" DNA sequencing technologies provide new opportunities to detect and analyze genetic variation in forest tree populations, and my research is focused on development and application of both new laboratory methods to generate data and new analytical methods to understand how genetic variation is related to variation in traits of ecological or economic importance.
FOR 350 – Ethics in Natural Resource Management
FOR 411 – Forest Biology and Genetics
FOR 725 – Advanced Forest Genetics
BIT815 – Analysis of Deep Sequencing Data
- Quantitative trait loci influencing forking defects in an outbred pedigree of loblolly pine (2016)
- Genetic variability and heritability of chlorophyll a fluorescence parameters in Scots pine (Pinus sylvestris L.) (2016)
- Modeling climate change effects on the height growth of loblolly pine (2015)
- Decoding the massive genome of loblolly pine using haploid DNA and novel assembly strategies (2014)
- Genetics of stem forking and ramicorn branches in a cloned loblolly pine family (2014)
- Genetic analysis of diallel progeny test data using factor analytic linear mixed models (2014)
- Potential for evolutionary responses to climate change evidence from tree populations (2013)
- SNP markers trace familial linkages in a cloned population of Pinus taeda - prospects for genomic selection (2012)
- Interactions of Fr genes and mixed-pathogen inocula in the loblolly pine-fusiform rust pathosystem (2012)
- Comparison between tracheary element lignin formation and extracellular lignin-like substance formation during the culture of isolated Zinnia elegans mesophyll cells (2011)


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- 04-05-2014, 03:37 AM Thread Author #1
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LG audio problem during phonecalls using bluetooth
Hi all,
I have a new problem using my car (hyundai i30) bluetooth for calls (in/ougoingt).
when I make or receive calls I can't be heard on the BTspeaker even though I can hear the person I am talking to on the carspeakers (with the BT), so I know the BT is working OK. I have tried another phone using the same device and it doesnt have the same problem, so obviously the issue is to do with the G2 and not the BT itself (or the car's installed microphone).
also, Uptill now I have talked on the phone using the car's BT with no problem at all. I have tried unsuccessfully to find a setting that maybe interferes with this but have not found anything! I have no idea what changed...
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Hotfrog Singapore provides information regarding Marvin Chew in Singapore. Marvin Chew is located at Black Earth Art Museum 352 Joo Chiat Road, Singapore 427599 and provides Art services. Contact them on 65 81132851 or by visiting them on their website http://www.marvinchew.com.
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Ghostwriting Erotica Novella Series
- Status Closed
- Budget $30 - $250 USD
- Total Bids 8
Project Description
Required is a writer for a 3-part hardcore adult erotica novella series.
This is a ghost-writing position and a signed writer release will be required.
Just like the countless billionaire erotica series that have been written, for this series, the story is to be written about a powerful "Trillionaire" male and a heterosexual women.
-Payment will be a total of $[url removed, login to view] for this project. Don't bother applying unless you are happy with this fixed price.
-I will not pay until I am satisfied with the level of the content, and If there is mistakes, you are required to fix them or I will not pay.
-No incest, rape, or assault. All characters over 18 years old.
-Each novella must be a minimum of 10000 words, so the series will be a minimum of 30,000 words.
-Each story should be completed within 10 days of each other (Part 1 after 10 days, part 2 after another 10 days, part 3 after another 10 days)
-Each short story requires a title for each, including which part of the series it is (example being "The Trillionaire (A erotica novella, part 2)").
-Required are good story lines and XXX sexual content.
-All 3 stories must be written for heterosexual women
[url removed, login to view] file format
Explicit hardcore sexual descriptions and some foul language are required.
This work takes a special kind of writer, and previous experience in erotic writing will be preferred. Please attach samples of your work.
******* Also only apply if you are willing to write for me for a long time after this, for at-least a year, don't bother applying unless you are willing to stick it out that long. If you happen to write the series well and continue writing for me, I will pay you 150 words per dollar AFTER this series, for every new book you write*******
All work must be original, I will check. I only use the milestone payment system, full payment will be sent after I approve all work and a signed release is received. When replying to this posting you must put the sentence "I'm looking for a long term partnership with you Brad" in your reply, anywhere. I can not consider anyone who does not follow this step.
Goodluck and Cheers,
BradGet free quotes for a project like this
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Eukanuba® Large Breed Puppy Food - Chicken
As your puppy grows, Eukanuba Large Breed Puppy Food will provide him with the nutrients he needs. This delicious tasting dry food helps to build immunity and promotes healthy brain and vision development. Your dog will love the great chicken flavor, and you'll love feeding it to him.
Features: 100% High Quality Nutrition, 0% Fillers, With DHA for Healthy brain and vision development, Gentle digestion, Helps build immunity, Optimal large breed joint and bone growth
Food Type: Dry Food
Food Consistency: Kibble
Life Stage: Puppy
Flavor: Chicken
Primary Ingredient: Chicken
Package Weight: 16 lb
Chicken, Corn Meal, Chicken By-Product Meal (Source Of Chondroitin Sulfate And Glucosamine), Ground Whole Grain Sorghum, Brewers Rice, Dried Beet Pulp, Natural Flavor, Dried Egg Product, Fish Oil (Preserved With Mixed Tocopherols, A Source Of Vitamin E), Brewers Dried Yeast, Fish Meal (Source Of Fish Oil), Potassium Chloride, Chicken Fat (Preserved With Mixed Tocopherols, A Source Of Vitamin E), Salt, Calcium Carbonate, Choline Chloride, Fructooligosaccharides, Minerals (Ferrous Sulfate, Zinc Oxide, Manganese Sulfate, Copper Sulfate, Manganous Oxide, Potassium Iodide), DL-Methionine, Vitamins (Ascorbic Acid, Vitamin A Acetate, Calcium Pantothenate, Biotin, Thiamine Mononitrate (Source Of Vitamin B1), Vitamin B12 Supplement, Niacin, Riboflavin Supplement (Source Of Vitamin B2), Inositol, Pyridoxine Hydrochloride (Source Of Vitamin B6), Vitamin D3 Supplement, Folic Acid), Vitamin E Supplement, Beta-Carotene, Rosemary Extract
Guaranteed Analysis:
Crude Protein (min) 26.00%
Crude Fat (min) 14.00%
Crude Fiber (max) 5.00%
Moisture (max) 10.00%
Calcium (min) 0.65%
Phosphorus (min) 0.55%
Vitamin E (min) 140 IU/kg
Docosahexaenoic Acid (min) 0.10 %*
Omega-6 Fatty Acids (min) 1.93 %*
Omega-3 Fatty Acids (min) 0.39 %*
Glucosamine (min) 375 mg/kg*
Chondroitin Sulfate (min) 35 mg/kg*
*Not recognized as an essential nutrient by the AAFCO Dog Food Nutrient Profiles.
Caloric Content: Cals (ME)/cup: 337.4 kcal/kg
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Vivaldi knew a thing or two about making art accessible, so it's hardly surprising that his set of fiddle concertos known as The Four Seasons is the call-waiting music of every other high-street bank. For the same reason, it was an obvious choice for the Orchestra of the Age of Enlightenment's groovy new venture The Night Shift, presenting classical and baroque music in a relaxed, late-evening setting complete with drink-in-hand policy, chats with the performers, and an MC compelled to say "woo!" with each round of applause.
The OAE's string players and their guest soloist Kati Debretzeni (who also functioned as conductor) superbly rose to the challenge of keeping the ensemble tight while Debretzeni took her violin on walkabout downstage, the better for the audience to witness her powerhouse technique, as Vivaldi tasks the soloist with summoning the very sight and feel of summer rain, the pressing of grapes, icicles in winter and so on.
Job done, given that Vivaldi himself provided programme notes in the form of four sonnets whose imagery tracks the music. But no, as foreground to this performance, we have six dancers in vests and knickers and choreography by Henri Oguike. This has the perverse effect of obscuring Vivaldi's pictorial detail and adding a layer of abstraction.
It also erects a barrier between audience and orchestra, whose show this ought to be. That said, Oguike's contribution certainly matches the music's oomph. For Spring, he invents a rutting canter, the dancers charging across the stage only to turn on each other and box like hares. In Spring's slow movement, the goatherd and faithful dog of Vivaldi's poem are replaced by an entwining couple, who all but nuzzle the scroll of Debretzeni's instrument as she woos them like a gypsy in a restaurant. It's not a new idea to bring dance and music-making up close (Balanchine did it 40 years ago in Duo Concertant), but it's an intimacy worth pursuing. Perhaps Oguike's Four Seasons will make more sense when it takes its place in a programme of dance. As an adjunct to a concert, it gilds the lily.
As selling points go, the industrial past of The Print Room, in London's Bayswater, has served it well as a venue for drama with a stripped-down aesthetic. Its audience pressed against the walls, it offers an intimate, in-the-square experience, so close, the actors could sit in your lap. With FLOW, it extends the remit to dance, although you could say this exploration of H2O is the ultimate in immersive theatre: spectators are handed waterproof ponchos at the door and, boy, do we need them. By the end, sprinklers have turned the performing space into a sizeable pond in which the five dancers frolic, stamp and loll, making fearsome waves as they scoot across the floor on their stomachs.
At the start, though, the mood is cool to the point of frigid. A glistening translucent cube (design by Tom Dixon) encases a slow-moving male dancer who provides his own chiaroscuro lighting by way of a hand-held LED stick. It seems to slice the textures of Peter Gregson's glacial music, as well as the gloom.
As the watery theme evolves by way of mist and rain, Hubert Essakow's choreography squeezes multiple possibilities from his fine small cast, sending ripples along limbs and between bodies, or massing them in broiling oceanic storms. In a highly charged duet between Sonya Cullingford and Thomasin Gulgec, it's hard not to think of the human turmoil wrought by floods.
Spoken anecdotes (including the disarming confession from one dancer that he sweats a lot) feel slightly tacked on, and a projected list of water-related facts might have come straight from an Oxfam campaign (they just needed following up). Overall, though, FLOW is a model of saying quite a lot with quite a little, and beautifully.
Les Ballets Trockadero de Monte Carlo, aka the New York drag troupe The Trocks, are no strangers to these shores, but it was apt that they should open in the blue-rinse heartland of Kent the day the Commons voted for gay marriage. To a sold-out house, the 17-strong all-male company brought nothing but pleasure, delivering a programme of 19th-century classics with both gusto and technical aplomb. A generation reared on Lily Savage and Dame Edna "gets" The Trocks very quickly, and the jokes in Swan Lake Act II brought the house down. Impressive, too, how the company keeps the comedy fresh: many of the gags were new to me, though I still enjoyed seeing Prince Siegfried find swan poop on his shoe, and the swan-maiden two rows back felled by Odile's grand battement. Oh yes, and the renegade cygnet in the famous arms-linked pas de quatre, who's never quite in step with the other three.
The comic timing is immaculate, but even cleverer is the way the material appeals on multiple levels. Know-nothings adore the slapstick. Balletomanes lap up the history (where else can you see La Vivandière of 1844?), and the sending up of ballet manners (only a tad exaggerated). And everyone loves the living proof that gender needn't be destiny.
Oguike Dance returns in May. 'FLOW': to 23 Feb (020-7221 6036). The Trocks: Bradford Alhambra (01274 432000) Tue & Wed; Brighton Dome (01273 709709) Fri & Sat; and touring
Next Week
Jenny Gilbert fully inhales Two Cigarettes, by Pina Bausch
Critic's choice
The Royal Ballet marks the 25th anniversary of the death of its founding choreographer Frederick Ashton with a bill of five short works. These range from the swooning La Valse (set to music by Ravel) to the space-age abstraction of Monotones (Erik Satie). Then there's full-throttle passion in Marguerite and Armand, which meshes the entirety of Lizst's storming B minor piano sonata with the story of La Dame aux Camélias. At London's Royal Opera House (Tue to 23 Feb).
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