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Activation of aldosterone/mineralocorticoid receptors (MR) has been implicated in vascular dysfunction of diabetes. Underlying mechanisms are elusive. Therefore, we investigated the role of Rho kinase (ROCK) in aldosterone/MR signaling and vascular dysfunction in a model of diabetes. Diabetic obese mice (db/db) and control counterparts (db/+) were treated with MR antagonist (MRA, potassium canrenoate, 30 mg/kg/day, 4 weeks) or ROCK inhibitor, fasudil (30 mg/kg/day, 3 weeks). Plasma aldosterone was increased in db/db versus db/+. This was associated with enhanced vascular MR signaling. Norepinephrine (NE)-induced contraction was increased in arteries from db/db mice. These responses were attenuated in mice treated with canrenoate or fasudil. Db/db mice displayed hypertrophic remodeling and increased arterial stiffness, improved by MR blockade. Vascular calcium sensitivity was similar between depolarized arteries from db/+ and db/db. Vascular hypercontractility in db/db mice was associated with increased myosin light chain phosphorylation and reduced expression of PKG-1 alpha. Vascular RhoA/ROCK signaling and expression of pro-inflammatory and pro-fibrotic markers were exaggerated in db/db mice, effects that were attenuated by MRA. Fasudil, but not MRA, improved vascular insulin sensitivity in db/db mice, evidenced by normalization of Irs1 phosphorylation. Our data identify novel pathways involving MR-RhoA/ROCK-PKG-1 that underlie vascular dysfunction and injury in diabetic mice.
One-third of diabetes mellitus patients develop diabetic nephropathy, and with underlying mechanisms unknown it is imperative that diabetic animal models resemble human disease. The present study investigated the susceptibility to develop diabetic nephropathy in four commonly used and commercially available mouse strains with type 1 diabetes to determine the suitability of each strain. Type 1 diabetes was induced in C57Bl/6, NMRI, BALB/c, and 129Sv mice by alloxan, and conscious glomerular filtration rate, proteinuria, and oxidative stress levels were measured in control and diabetic animals at baseline and after 5 and 10 wk. Histological alterations were analyzed using periodic acid-Schiff staining. Diabetic C57Bl/6 displayed increased glomerular filtration rate, i.e., hyperfiltration, whereas all other parameters remained unchanged. Diabetic NMRI developed the most pronounced hyperfiltration as well as increased oxidative stress and proteinuria but without glomerular damage. Diabetic BALB/c did not develop hyperfiltration but presented with pronounced proteinuria, increased oxidative stress, and glomerular damage. Diabetic 129Sv displayed proteinuria and increased oxidative stress without glomerular hyperfiltration or damage. However, all strains displayed intras-train correlation between oxidative stress and proteinuria. In conclusion, diabetic C57Bl/6 and NMRI both developed glomerular hyperfiltration but neither presented with histological damage, although NMRI developed low-degree proteinuria. Thus these strains may be suitable when investigating the mechanism causing hyperfiltration. Neither BALB/c nor 129Sv developed hyperfiltration although both developed pronounced proteinuria. However, only BALB/c developed detectable histological damage. Thus BALB/c may be suitable when studying the roles of proteinuria and histological alterations for the progression of diabetic nephropathy.
AimUncoupling protein-2 (UCP-2) can induce mitochondrial uncoupling in the diabetic kidney. Although mitochondrial uncoupling reduces oxidative stress originating from the mitochondria and can be regarded as a protective mechanism, the increased oxygen consumption occurring secondarily to increased mitochondria uncoupling, that is leak respiration, may contribute to kidney tissue hypoxia. Using UCP-2(-/-) mice, we tested the hypothesis that UCP-2-mediated leak respiration is important for the development of diabetes-induced intrarenal hypoxia and proteinuria. MethodsKidney function, invivo oxygen metabolism, urinary protein leakage and mitochondrial function were determined in wild-type and UCP-2(-/-) mice during normoglycaemia and 2weeks after diabetes induction. ResultsDiabetic wild-type mice displayed mitochondrial leak respiration, pronounced intrarenal hypoxia, proteinuria and increased urinary KIM-1 excretion. However, diabetic UCP-2(-/-) mice did not develop increased mitochondrial leak respiration and presented with normal intrarenal oxygen levels, urinary protein and KIM-1 excretion. ConclusionAlthough functioning as an antioxidant system, mitochondria uncoupling is always in co-occurrence with increased oxygen consumption, that is leak respiration; a potentially detrimental side effect as it can result in kidney tissue hypoxia; an acknowledged unifying pathway to nephropathy. Indeed, this study demonstrates a novel mechanism in which UCP-2-mediated mitochondrial leak respiration is necessary for the development of diabetes-induced intrarenal tissue hypoxia and proteinuria.
Diabetes is closely associated with increased oxidative stress, especially originating from the mitochondria. A mechanism to reduce increased mitochondria superoxide production is to reduce the mitochondria membrane potential by releasing protons across the mitochondria membrane. This phenomenon is referred to as mitochondria uncoupling since oxygen is consumed independently of ATP being produced and can be mediated by Uncoupling Proteins (UCPs). However, increased oxygen consumption is potentially detrimental for the kidney since it can cause tissue hypoxia. Therefore, this thesis aimed to investigate the role of mitochondria uncoupling for development of diabetic nephropathy.
UCP-2 was demonstrated to be the only isoform expressed in the kidney, and localized to tubular segments performing the majority of tubular electrolyte transport. Streptozotocin-induced diabetes in rats increased UCP-2 protein expression and correlated to increased non-transport dependent oxygen consumption in isolated proximal tubular cells. These effects were prevented by intense insulin treatment to the diabetic animals demonstrating a pivotal role of hyperglycemia. Importantly, elevated UCP-2 protein expression increased mitochondria uncoupling in mitochondria isolated from diabetic kidneys. Mitochondria uncoupling and altered morphology was also evident in kidneys from db/db-mice, a model of type-2 diabetes, together with proteinuria and glomerular hyperfiltration which are both clinical manifestations of diabetic nephropathy. Treatment with the antioxidant coenzyme Q10 prevented mitochondria uncoupling as well as morphological and functional alterations in these kidneys. Acute knockdown of UCP-2 paradoxically increased mitochondria uncoupling in a mechanism involving the adenosine nucleotide transporter. Increased uncoupling via adenosine nucleotide transporter decreased mitochondria membrane potential and kidney oxidative stress but did not affect glomerular filtration rate, renal blood flow, total kidney oxygen consumption or intrarenal tissue oxygen tension.
The role of increased mitochondria oxygen consumption was investigated by administering the chemical uncoupler dinitrophenol to healthy rats. Importantly, increased mitochondria oxygen consumption resulted in kidney tissue hypoxia, proteinuria and increased staining of the tubular injury marker vimentin, demonstrating a crucial role of increased oxygen consumption per se and the resulting kidney tissue hypoxia for the development of nephropathy.
Taken together, the data presented in this thesis establishes an important role of mitochondria uncoupling for the development of diabetic nephropathy.
Uncoupling protein (UCP)-2 and -3 are ubiquitously expressed throughout the body but there is currently no information regarding the expression and distribution of the different UCP isoforms in the kidney. Due to the known cross-reactivity of the antibodies presently available for detection of UCP-2 and -3 proteins, we measured the mRNA expression of UCP-1, -2 and -3 in the rat kidney in order to detect the kidney-specific UCP isoforms. Thereafter, we determined the intrarenal distribution of the detected UCP isoforms using immunohistochemistry. Thereafter, we compared the protein levels in control and streptozotocin-induced diabetic rats using Western blot. Expressions of the UCP isoforms were also performed in brown adipose tissue and heart as positive controls for UCP-1 and 3, respectively. UCP-2 mRNA was the only isoform detected in the kidney. UCP-2 protein expression in the kidney cortex was localized to proximal tubular cells, but not glomerulus or distal nephron. In the medulla, UCP-2 was localized to cells of the medullary thick ascending loop of Henle, but not to the vasculature or parts of the nephron located in the inner medulla. Western blot showed that diabetic kidneys have about 2.5-fold higher UCP-2 levels compared to controls. In conclusion, UCP-2 is the only isoform detectable in the kidney and UCP-2 protein can be detected in proximal tubular cells and cells of the medullary thick ascending loop of Henle. Furthermore, diabetic rats have increased UCP-2 levels compared to controls, but the mechanisms underlying this increase and its consequences warrants further studies.
We have previously reported increased O(2) consumption unrelated to active transport by tubular cells and up-regulated mitochondrial uncoupling protein (UCP)-2 expressions in diabetic kidneys. It is presently unknown if the increased UCP-2 levels in the diabetic kidney results in mitochondrial uncoupling and increased O(2) consumption, which we therefore investigated in this study. The presence of UCP-2 in proximal tubular cells was confirmed by immunohistochemistry and found to be increased (western blot) in homogenized tissue and isolated mitochondria from kidney cortex of diabetic rats. Isolated proximal tubular cells had increased total and ouabain-insensitive O(2) consumption compared to controls. Isolated mitochondria from diabetic animals displayed increased glutamate-stimulated O(2) consumption (in the absence of ADP and during inhibition of the ATP-synthase by oligomycin) compared to controls. Guanosine diphosphate, an UCP inhibitor, and bovine serum albumin which removes fatty acids that are essential for UCP-2 uncoupling activity, independently prevented the increased glutamate-stimulated O(2) consumption in mitochondria from diabetic animals. In conclusion, diabetic rats have increased mitochondrial UCP-2 expression in renal proximal tubular cells, which results in mitochondrial uncoupling and increased O(2) consumption. This mechanism may be protective against diabetes-induced oxidative stress, but will increase O(2) usage. The subsequently reduced O(2) availability may contribute to diabetes-induced progressive kidney damage.
Aims/hypothesis: Increased oxygen consumption results in kidney tissue hypoxia, which is proposed to contribute to the development of diabetic nephropathy. Oxidative stress causes increased oxygen consumption in type 1 diabetic kidneys, partly mediated by uncoupling protein-2 (UCP-2)-induced mitochondrial uncoupling. The present study investigates the role of UCP-2 and oxidative stress in mitochondrial oxygen consumption and kidney function in db/db mice as a model of type 2 diabetes.
Methods: Mitochondrial oxygen consumption, glomerular filtration rate and proteinuria were investigated in db/db mice and corresponding controls with and without coenzyme Q10 (CoQ10) treatment.
Results: Untreated db/db mice displayed mitochondrial uncoupling, manifested as glutamate-stimulated oxygen consumption (2.7 +/- 0.1 vs 0.2 +/- 0.1 pmol O-2 s(-1) [mg protein](-1)), glomerular hyperfiltration (502 +/- 26 vs 385 +/- 3 mu l/min), increased proteinuria (21 +/- 2 vs 14 +/- 1, mu g/24 h), mitochondrial fragmentation (fragmentation score 2.4 +/- 0.3 vs 0.7 +/- 0.1) and size (1.6 +/- 0.1 vs 1 +/- 0.0 mu m) compared with untreated controls. All alterations were prevented or reduced by CoQ10 treatment. Mitochondrial uncoupling was partly inhibited by the UCP inhibitor GDP (-1.1 +/- 0.1 pmol O-2 s(-1) [mg protein](-1)). UCP-2 protein levels were similar in untreated control and db/db mice (67 +/- 9 vs 67 +/- 4 optical density; OD) but were reduced in CoQ10 treated groups (43 +/- 2 and 38 +/- 7 OD).
Conclusions/interpretation: db/db mice displayed oxidative stress-mediated activation of UCP-2, which resulted in mitochondrial uncoupling and increased oxygen consumption. CoQ10 prevented altered mitochondrial function and morphology, glomerular hyperfiltration and proteinuria in db/db mice, highlighting the role of mitochondria in the pathogenesis of diabetic nephropathy and the benefits of preventing increased oxidative stress.
Increased O2 metabolism resulting in chronic hypoxia is common in models of endstage renal disease. Mitochondrial uncoupling increases O2 consumption but the ensuing reduction in mitochondrial membrane potential may limit excessive oxidative stress. The present study addressed the hypothesis that mitochondrial uncoupling regulates mitochondria function and oxidative stress in the diabetic kidney. Isolated mitochondria from kidney cortex of control and streptozotocin-induced diabetic rats were studied before and after siRNA knockdown of uncoupling protein-2 (UCP-2). Diabetes resulted in increased UCP-2 protein expression and UCP-2-mediated uncoupling, but normal mitochondria membrane potential. This uncoupling was inhibited by GDP, which also increased the membrane potential. siRNA reduced UCP-2 protein expression in controls and diabetics (−30–50%), but paradoxically further increased uncoupling and markedly reduced the membrane potential. This siRNA mediated uncoupling was unaffected by GDP but was blocked by ADP and carboxyatractylate (CAT). Mitochondria membrane potential after UCP-2 siRNA was unaffected by GDP but increased by CAT. This demonstrated that further increased mitochondria uncoupling after siRNA towards UCP-2 is mediated through the adenine nucleotide transporter (ANT). The increased oxidative stress in the diabetic kidney, manifested as increased thiobarbituric acids, was reduced by knocking down UCP-2 whereas whole-body oxidative stress, manifested as increased circulating malondialdehyde, remained unaffected. All parameters investigated were unaffected by scrambled siRNA. In conclusion, mitochondrial uncoupling via UCP-2 regulates mitochondria membrane potential in diabetes. However, blockade of the diabetes-induced upregulation of UCP- 2 results in excessive uncoupling and reduced oxidative stress in the kidney via activation of ANT.
Kidney uncoupling protein 2 (UCP-2) increases in streptozotocin-induced diabetes, resulting in mitochondria uncoupling, i.e., increased oxygen consumption unrelated to active transport. The present study aimed to investigate the role of UCP-2 for normal and diabetic kidney function utilizing small interference RNA (siRNA) to reduce protein expression. Diabetic animals had increased glomerular filtration rate and kidney oxygen consumption, resulting in decreased oxygen tension and transported sodium per consumed oxygen. UCP-2 protein levels decreased 2 and 50% after UCP-2 siRNA administration in control and diabetic animals respectively. Kidney function was unaffected by in vivo siRNA-mediated gene silencing of UCP-2. The reason for the lack of effect of reducing UCP-2 is presently unknown but may involve compensatory mitochondrial uncoupling by the adenosine nucleotide transporter.
Exaggerated activation of the renin-angiotensin-aldosterone system (RAAS) is a key feature in diseases such as hypertension, diabetes, and chronic kidney disease. Recently, an intracellular RAAS was demonstrated with angiotensin II (ANG II) type 1 (AT1) and type 2 (AT2) receptors expressed in nuclei and mitochondria. Diabetes is associated with both mitochondrial dysfunction and increased intracellular ANG II concentration in the kidney cortex. The present study investigated the role of ANG II signaling in kidney cortex mitochondria isolated from control and streptozotocin-induced diabetic rats. Mitochondrial oxygen consumption was evaluated after addition of ANG II alone or after preincubation with candesartan (AT1 receptor antagonist), PD-123319 (AT2 receptor antagonist), or the two in combination. ANG II binds to only mitochondrial AT2 receptors in control rats and both AT1 receptors and AT2 receptors in diabetic rats. ANG II decreased oxygen consumption in mitochondria from both control and diabetic rats. ANG II response was reversed to increased oxygen consumption by the nitric oxide synthase inhibitor N-nitro-l-arginine methyl ester. AT1 receptor inhibition did not affect the response to ANG II, whereas AT2 receptor inhibition abolished the response in mitochondria from control rats and reversed the response to increased oxygen consumption through superoxide-induced mitochondrial uncoupling in mitochondria from diabetic rats. ANG II decrease mitochondrial respiration via AT2 receptor-mediated nitric oxide release in both control and diabetic rats. AT1 receptors do not regulate mitochondria function in control rats, whereas ANG II via AT1 receptors increase mitochondria leak respiration in diabetic animals.
Intrarenal tissue hypoxia is an acknowledged common pathway to end-stage renal disease in clinically common conditions associated with development of chronic kidney disease, such as diabetes and hypertension. In diabetic kidneys, increased oxygen metabolism mediated by mitochondrial uncoupling results in decreased kidney oxygen tension (PO2) and contributes to the development of diabetic nephropathy. The present study investigated whether increased intrarenal oxygen metabolism per se can cause intrarenal tissue hypoxia and kidney damage, independently of confounding factors such as hyperglycemia and oxidative stress. Male Sprague-Dawley rats were untreated or treated with either triiodothyronine (T3, 10 g/kg bw/day, subcutaneously for 10 days) or the mitochondria uncoupler dinitrophenol (DNP, 30 mg/kg bw/day, oral gavage for 14 days), after which in vivo kidney function was evaluated in terms of glomerular filtration rate (GFR, inulin clearance), renal blood flow (RBF, Transonic, PAH clearance), cortical PO2 (Clark-type electrodes), kidney oxygen consumption (QO2), and proteinuria. Administration of both T3 and DNP increased kidney QO2 and decreased PO2 which resulted in proteinuria. However, GFR and RBF were unaltered by either treatment. The present study demonstrates that increased kidney metabolism per se can cause intrarenal tissue hypoxia which results in proteinuria. Increased kidney QO2 and concomitantly reduced PO2 may therefore be a mechanism for the development of chronic kidney disease and progression to end-stage renal disease.
Diabetic nephropathy is strongly associated with both increased oxidative stress and kidney tissue hypoxia. The increased oxidative stress causes increased kidney oxygen consumption resulting in kidney tissue hypoxia. To date, it has been difficult to determine the role of kidney hypoxia, per se, for the development of nephropathy. We tested the hypothesis that kidney hypoxia, without confounding factors such as hyperglycemia or elevated oxidative stress, results in nephropathy. To induce kidney hypoxia, dinitrophenol (30 mg per day per kg bodyweight by gavage), a mitochondrial uncoupler that increases oxygen consumption and causes kidney hypoxia, was administered for 30 consecutive days to rats. Thereafter, glomerular filtration rate, renal blood flow, kidney oxygen consumption, kidney oxygen tension, kidney concentrations of glucose and glycogen, markers of oxidative stress, urinary protein excretion, and histological findings were determined and compared with vehicle-treated controls. Dinitrophenol did not affect arterial blood pressure, renal blood flow, glomerular filtration rate, blood glucose, or markers of oxidative stress but increased kidney oxygen consumption, and reduced cortical and medullary concentrations of glucose and glycogen, and resulted in intrarenal tissue hypoxia. Furthermore, dinitrophenol treatment increased urinary protein excretion, kidney vimentin expression, and infiltration of inflammatory cells. In conclusion, increased mitochondrial oxygen consumption results in kidney hypoxia and subsequent nephropathy. Importantly, these results demonstrate that kidney tissue hypoxia, per se, without confounding hyperglycemia or oxidative stress, may be sufficient to initiate the development of nephropathy and therefore demonstrate a new interventional target for treating kidney disease.
Oxidative stress is closely associated with renal dysfunction following diabetes and hypertension. Angiotensin II (Ang II) can activate the NADPH-oxidase, increasing oxidative stress that is thought to blunt proximal tubular electrolyte transport and thereby oxygen consumption (QO(2)). We investigated the effect of Ang II on QO(2) in immortalized mouse proximal tubular cells over-expressing the NADPH oxidase subunit p22(phox); a model of increased oxidative stress. Cultured cells were exposed to either Ang II or H2O2 for 48 h. QO(2) was determined during baseline (113 mmol/l NaCl; transport-dependent QO(2)) and during sodium-free conditions (transport-independent QO(2)). Ang II reduced transport-dependent QO(2) in wild-types, but not in p22(phox) which also displayed increased QO(2) at baseline. Transport-independent QO(2) was increased in p22(phox) and Ang II had no additional effect, whereas it increased QO(2) in wild-type. Addition of H2O2 reduced transport-dependent QO(2) in wild-types, but not in p22(phox). Transport-independent QO(2) was unaffected by H2O2. The similar effects of Ang II and H2O2 to reduce transport-dependent QO(2) suggest a direct regulatory role of oxidative stress. In accordance, the transport-dependent QO(2) was reduced in p22(phox) already during baseline. The effects of Ang II on transport-independent QO(2) was not replicated by H2O2, indicating direct regulation via Ang II-receptors independently of oxidative stress. However, the Ang II effect was absent in p22(phox), suggesting that oxidative stress also modulates normal Ang II signaling. In conclusion, Ang II affects both transport-dependent and transport-independent QO(2) in proximal tubular cells and may be an important pathway modulating renal QO(2).
Adipose tissue (AT) senescence and mitochondrial dysfunction are associated with obesity. Studies in obese patients and animals demonstrate that the MR (mineralocorticoid receptor) contributes to obesity-associated cardiovascular complications through its specific role in AT. However, underlying mechanisms remain unclear. This study aims to elucidate whether MR regulates mitochondrial function in obesity, resulting in AT premature aging and vascular dysfunction. Obese (db/db) and lean (db/+) mice were treated with an MR antagonist or a specific mitochondria-targeted antioxidant. Mitochondrial and vascular functions were determined by respirometry and myography, respectively. Molecular mechanisms were probed by Western immunoblotting and real-time polymerase chain reaction in visceral AT and arteries and focused on senescence markers and redox-sensitive pathways. db/db mice displayed AT senescence with activation of the p53-p21 pathway and decreased SIRT (sirtuin) levels, as well as mitochondrial dysfunction. Furthermore, the beneficial anticontractile effects of perivascular AT were lost in db/db via ROCK (Rho kinase) activation. MR blockade prevented these effects. Thus, MR activation in obesity induces mitochondrial dysfunction and AT senescence and dysfunction, which consequently increases vascular contractility. In conclusion, our study identifies novel mechanistic insights involving MR, adipose mitochondria, and vascular function that may be of importance to develop new therapeutic strategies to limit obesity-associated cardiovascular complications.
Obesity is a multifaceted, chronic, low-grade inflammation disease characterized by excess accumulation of dysfunctional adipose tissue. It is often associated with the development of cardiovascular (CV) disorders, insulin resistance and diabetes. Under pathological conditions like in obesity, adipose tissue secretes bioactive molecules called 'adipokines', including cytokines, hormones and reactive oxygen species (ROS). There is evidence suggesting that oxidative stress, in particular, the ROS imbalance in adipose tissue, may be the mechanistic link between obesity and its associated CV and metabolic complications. Mitochondria in adipose tissue are an important source of ROS and their dysfunction contributes to the pathogenesis of obesity-related type 2 diabetes. Mitochondrial function is regulated by several factors in order to preserve mitochondria integrity and dynamics. Moreover, the renin-angiotensin-aldosterone system is over-activated in obesity. In this review, we focus on the pathophysiological role of the mineralocorticoid receptor in the adipose tissue and its contribution to obesity-associated metabolic and CV complications. More specifically, we discuss whether dysregulation of the mineralocorticoid system within the adipose tissue may be the upstream mechanism and one of the early events in the development of obesity, via induction of oxidative stress and mitochondrial dysfunction, thus impacting on systemic metabolism and the CV system.
BACKGROUND: Clinical studies have shown that proinsulin C-peptide exerts renoprotective effects in type 1 diabetes, although the underlying mechanisms are poorly understood. As C-peptide has been shown to induce several intracellular events and to localize to nuclei, we aimed to determine whether gene transcription is affected in proximal tubular kidney cells, and if so, whether genes with altered transcription include those related to protective mechanisms. METHODS: The effect of C-peptide incubation (2h) on gene expression was investigated in freshly isolated proximal tubular cells from streptozotocin-diabetic Sprague-Dawley rats using global gene expression profiling and RT-qPCR. Protein expression was assayed using western blotting. Different bioinformatic strategies were employed. RESULTS: Gene transcription profiling demonstrated differential transcription of 492 genes (p<0.01) after 2h of C-peptide exposure, with the majority of these genes repressed (83%). RT-qPCR validation supported a trend of several GPCR's being activated, and certain transcription factors to be repressed. Also, C-peptide repressed the transcription of genes associated with pathways of circulatory and inflammatory diseases. CONCLUSIONS: This study shows that C-peptide exerts early effects on gene transcription in proximal tubular cells. The findings also bring further knowledge to the renoprotective mechanisms of C-peptide in type I diabetes, and supports a transcriptional activity for C-peptide. It is suggested that C-peptide may play a regulatory role in the gene expression of proximal tubular cells.
Hyperglycemia results in increased oxygen consumption and decreased oxygen tension in the kidney. We tested the hypothesis that activation of hypoxia-inducible factors (HIFs) protects against diabetes-induced alterations in oxygen metabolism and kidney function. Experimental groups consisted of control and streptozotocin-induced diabetic rats treated with or without chronic cobalt chloride to activate HIFs. We elucidated the involvement of oxidative stress by studying the effects of acute administration of the superoxide dismutase mimetic tempol. Compared with controls, diabetic rats displayed tissue hypoxia throughout the kidney, glomerular hyperfiltration, increased oxygen consumption, increased total mitochondrial leak respiration, and decreased tubular sodium transport efficiency. Diabetic kidneys showed proteinuria and tubulointerstitial damage. Cobalt chloride activated HIFs, prevented the diabetes-induced alterations in oxygen metabolism, mitochondrial leak respiration, and kidney function, and reduced proteinuria and tubulointerstitial damage. The beneficial effects of tempol were less pronounced after activation of HIFs, indicating improved oxidative stress status. In conclusion, activation of HIFs prevents diabetes-induced alteration in kidney oxygen metabolism by normalizing glomerular filtration, which reduces tubular electrolyte load, preventing mitochondrial leak respiration and improving tubular transport efficiency. These improvements could be related to reduced oxidative stress and account for the reduced proteinuria and tubulointerstitial damage. Thus, pharmacologic activation of the HIF system may prevent development of diabetic nephropathy.
Hypoxia is an acknowledged pathway to renal injury and ischemia-reperfusion (I/R) and is known to reduce renal oxygen tension (PO2). We hypothesized that renal I/R increases oxidative damage and induces mitochondrial uncoupling, resulting in increased oxygen consumption and hence kidney hypoxia. Lewis rats underwent syngenic renal transplantation (TX) and contralateral nephrectomy. Controls were uninephrectomized (1K-CON) or left untreated (2K-CON). After 7 days, urinary excretion of protein and thiobarbituric acid-reactive substances were measured, and after 14 days glomerular filtration rate (GFR), renal blood flow, whole kidney QO(2), cortical PO2, kidney cortex mitochondrial uncoupling, renal oxidative damage, and tubulointerstitial injury were assessed. TX, compared with 1K-CON, resulted in mitochondrial uncoupling mediated via uncoupling protein-2 (16 +/- 3.3 vs. 0.9 +/- 0.4 pmol O-2.s(-1) .mg protein(-1), P < 0.05) and increased whole kidney Q(O2) (55 +/- 16 vs. 33 +/- 10 mu mol O-2/min, P < 0.05). Corticomedullary P-O2 was lower in TX compared with 1K-CON (30 +/- 13 vs. 47 +/- 4 mu M, P < 0.05) whereas no significant difference was observed between 2K-CON and 1K-CON rats. Proteinuria, oxidative damage, and the tubulointerstitial injury score were not significantly different in 1K-CON and TX. Treatment of donors for 5 days with mito-TEMPO reduced mitochondrial uncoupling but did not affect renal hemodynamics, Q(O2), P-O2, or injury. Collectively, our results demonstrate increased mitochondrial uncoupling as an early event after experimental renal transplantation associated with increased oxygen consumption and kidney hypoxia in the absence of increases in markers of damage.
AIM: Diabetic patients are at increased risk for kidney disease. There is presently no clinical treatment available that effectively protects kidney function in diabetics. The present study investigates if chronic stimulation of the adenosine A2a receptor (A2a AR) protects kidney function in insulinopenic diabetic rats.
METHODS: Streptozotocin-induced diabetic rats and corresponding controls were chronically treated with the adenosine A2a AR agonist CGS21680 throughout the four-week diabetes duration. Kidney function was thereafter investigated and urine and plasma samples were collected for analysis of protein, oxidative stress and inflammatory markers.
RESULTS: Glomerular filtration rate, renal blood flow, filtration fraction and diabetes-induced kidney hypoxia were all unaffected by chronic A2a AR stimulation. Furthermore, diabetic rats had increased oxidative stress, which was further increased by chronic A2a AR stimulation. However, the 10-fold increased urinary protein excretion observed in the diabetic rats was completely prevented by chronic A2a AR stimulation. These beneficial effects were accompanied by reduced levels of the pro-inflammatory TNF-α and increased levels of the anti-inflammatory IL-10 as well as decreased infiltration of macrophages, glomerular damage and basement membrane thickness.
CONCLUSION: Chronic A2a AR stimulation prevents proteinuria and glomerular damage in experimental diabetes via an anti-inflammatory mechanism independent of oxidative stress and kidney hypoxia.
The underlying mechanisms in the development of diabetic nephropathy are currently unclear and likely consist of a series of dynamic events from the early to late stages of the disease. Diabetic nephropathy is currently without curative treatments and it is acknowledged that even the earliest clinical manifestation of nephropathy is preceded by an established morphological renal injury that is in turn preceded by functional and metabolic alterations. An early manifestation of the diabetic kidney is the development of kidney hypoxia that has been acknowledged as a common pathway to nephropathy. There have been reports of altered mitochondrial function in the diabetic kidney such as altered mitophagy, mitochondrial dynamics, uncoupling, and cellular signaling through hypoxia inducible factors and AMP-kinase. These factors are also likely to be intertwined in a complex manner. In this review, we discuss how these pathways are connected to mitochondrial production of reactive oxygen species (ROS) and how they may relate to the development of kidney hypoxia in diabetic nephropathy. From available literature, it is evident that early correction and/or prevention of mitochondrial dysfunction may be pivotal in the prevention and treatment of diabetic nephropathy.
An increased kidney oxygen consumption causing tissue hypoxia has been suggested to be a common pathway toward chronic kidney disease. The mammalian target of rapamycin (mTOR) regulates cell proliferation and mitochondrial function. mTOR inhibitors (e.g., rapamycin) are used clinically to prevent graft rejection. mTOR has been identified as a key player in diabetes, which has stimulated the use of mTOR inhibitors to counter diabetic nephropathy. However, the effect of mTOR inhibition on kidney oxygen consumption is unknown. Therefore, we investigated the effects of mTOR inhibition on in vivo kidney function, oxygen homeostasis, and glomerular permeability. Control and streptozotocin-induced diabetic rats were chronically treated with rapamycin, and the functional consequences were studied 14 days thereafter. In both groups, mTOR inhibition induced mitochondrial uncoupling, resulting in increased total kidney oxygen consumption and decreased intrarenal oxygen availability. Concomitantly, mTOR inhibition induced tubular injury, as estimated from urinary excretion of kidney injury molecule-1 (KIM-1) and reduced urinary protein excretion. The latter corresponded to reduced sieving coefficient for large molecules. In conclusion, mTOR inhibition induces mitochondrial dysfunction leading to decreased oxygen availability in normal and diabetic kidneys. which translates into increased KIM-1 in the urine. Reduced proteinuria after mTOR inhibition is an effect of reduced glomerular permeability for large molecules. Since hypoxia has been suggested as a common pathway in the development of chronic kidney disease, mTOR inhibition to patients with preexisting nephropathy should be used with caution, since it may accelerate the progression of the disease.
The mechanisms underlying diabetic nephropathy are not fully understood. However, recent research indicates mitochondria dysfunction as a contributing factor. Mammalian target of rapamycin (mTOR) is a known regulator of mitochondria function and could therefore also be involved in the development of diabetic nephropathy. The present study investigates the role of mTOR for controlling the function of mitochondria isolated from normal and diabetic rat kidneys. Control and streptozotocin-induced diabetic rats were treated with the mTOR inhibitor rapamycin (0.2 mg/day) by oral gavage for 14 days, after which mitochondria function was investigated using high-resolution respirometry. Mitochondrial uncoupling was defined as increased oxygen usage unrelated to ATP production. mTOR inhibition induced mitochondria uncoupling in control rats, but did not affect the already occurring uncoupling in kidney mitochondria from diabetic animals. Inhibition of mTOR using rapamycin induces mitochondria uncoupling in control rats, suggesting a role of mTOR as a moderator of mitochondria efficiency. No effect of mTOR inhibition was observed in mitochondria from diabetic animals, suggesting that there are other pathways in addition to the mTOR pathway regulating mitochondria function in diabetes. The functional significance of the mTOR pathway in regulating mitochondria efficiency warrants further attention.
The content of hyaluronan (HA) in the interstitium of the renal medulla changes in relation to body hydration status. We investigated if hormones of central importance for body fluid homeostasis affect HA production by renomedullary interstitial cells in culture (RMICs). Simultaneous treatment with vasopressin and angiotensin II (Ang II) reduced HA by 69%. No change occurred in the mRNA expressions of hyaluronan synthase 2 (HAS2) or hyaluronidases (Hyals), while Hyal activity in the supernatant increased by 67% and CD44 expression reduced by 42%. The autocoid endothelin (ET-1) at low concentrations (10−10 and 10−8 M) increased HA 3-fold. On the contrary, at a high concentration (10−6 M) ET-1 reduced HA by 47%. The ET-A receptor antagonist BQ123 not only reversed the reducing effect of high ET-1 on HA, but elevated it to the same level as low concentration ET-1, suggesting separate regulating roles for ET-A and ET-B receptors. This was corroborated by the addition of ET-B receptor antagonist BQ788 to low concentration ET-1, which abolished the HA increase. HAS2 and Hyal2 mRNA did not alter, while Hyal1 mRNA was increased at all ET-1 concentrations tested. Hyal activity was elevated the most by high ET-1 concentration, and blockade of ET-A receptors by BQ123 prevented about 30% of this response. The present study demonstrates an important regulatory influence of hormones involved in body fluid balance on HA handling by RMICs, thereby supporting the concept of a dynamic involvement of interstitial HA in renal fluid handling.


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Meet the Interim Provost
Dr. Robert L. Eves serves as Southern Utah University's Interim Provost and Vice President for Academic Affairs.
After completing a BS degree at SUU, he obtained MS and Ph. D. degrees in geology/geochemistry from Washington State University in 1985, and 1991. He joined the faculty at SUU in 1988 and obtained the rank of full professor in 2002.
Dr. Eves has received teaching awards from both Southern Utah University and the Utah State Science Teachers.
Since 1999, he has filled one or more administrative roles, first as Head, Division of Geosciences (six years), and then as Chair of the Department of Physical Science (five years), and most recently as of Dean of the Walter Maxwell Gibson College of Science and Engineering (eleven years).
He assumed the Interim Provost and Vice President position on May 4th, 2019.

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News Release
Perform at Hopkins
Acclaimed violinist Igor Yuzefovich, winner of the 2003-2004 Yale Gordon Concerto Competition at the Peabody Institute, will perform compositions by Franck and Prokofiev at noon on Wednesday, April 7, in Shriver Hall Auditorium on The Johns Hopkins University's Homewood campus, 3400 N. Charles St. in Baltimore.
Yuzefovich has performed at numerous concert venues, from Carnegie Hall to the Cairo Opera House in Egypt. He has also performed in Jordan as part of the Beethoven Violin Concert at King Hussein's birthday celebration.
Born in 1979 in Moscow, Russia, he began to study violin at 5 and enrolled at the Moscow State Gnessin Music School for the Gifted and Talented. His family moved to the United States in 1991, and he began studies at the Catholic University in Washington, D.C. He then went to the Peabody Preparatory program in Baltimore and earned both a bachelor's degree in music and a graduate performance diploma from the Peabody Conservatory. In addition to winning the Gordon Concerto Competition, Yuzefovich took first prize in the Arlington Symphony Competition, the Omega Psi Phi International Talent Hunt, the Fairfax Symphony Competition, the Wolf Trap Foundation Scholarship Competition, and the Marbury Violin Competition at the Peabody Conservatory. A digital image of Yuzefovich is available upon request to firstname.lastname@example.com.
This performance is cosponsored by the Peggy and Yale Gordon Trust and is part of the Wednesday Noon Series presented by The Johns Hopkins University Office of Special Events, now in its 38th season of cultural programming on the Homewood campus. Admission is free. For information, call the Office of Special Events at 443-287-9900.
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Take my advice! Fill out the form below, submitting your proposal advice and you'll automatically be entered to win. A winner will be selected each week with the Adele Diamond grand prize awarded on July 15th to one of the eight weekly winners. Weekly prizes include gift certificates to The Adventure Park at Virginia Aquarium (Family 4-pack), AOC Salon ($100), Todd Jurich's Bistro ($100) & Whole Foods ($100).
This Week's Prize: 4 Pack of tickets to the Adventure Park at Virginia Aquarium
Grand Prize: $500 gift certificate to Adele Diamond
Congrats to Week 7 Winner – Christine from Virginia Beach!
Her great proposal advice won her tickets to the Adventure Park at Virginia Aquarium!


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I'm usually not big on breakfast pastries, but I do love a nice cinnamon roll on a cold morning. It's not cold yet, but I was still in the mood for some cinnamon goodness and I decided to brew up a cup of 52Teas' Cinnamon Roll Honeybush.
It's not a bad tea, but I think it's better at room temperature (or maybe even iced). As a hot tea, the cinnamon kind of overpowers any other lingering flavors, and just ends up tasting like a cup of cinnamon tea. Try it out for yourself!


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Email Giulia Sciannandrone, CBT Psychotherapist, EMDR Therapist, BABCP Accredited.
I am a Cognitive Behavioural Psychotherapist and EMDR therapist, I offer therapy in Italian and English in a safe and friendly environment, where together we can explore and understand your difficulties in a confidential and non-judgemental manner.
Please either enable it in your browser and try again, or return to the profile page for Giulia Sciannandrone and select a different method of contact.


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Your support keeps us leaping into the future!
Please scroll down and complete the form below and click on "Submit" to make your tax-deductible donation.
To submit this form, all "*" fields must be filled in.
If you'd like to send a check, please make it payable to Invertigo Dance Theatre and send it to:
Invertigo Dance Theatre
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Los Angeles, CA 90066
If you would like to underwrite an education/outreach project, you can bring dance to communities or schools that may not otherwise have access to it. Costs can range from $3,000 to $10,000 per project and we rely on donor support to off-set them.
Invertigo Dance Theatre is a California non-profit public benefit corporation that is tax exempt under section 501(c)(3) of the Internal Revenue Code. Your contribution will be tax deductible to the extent allowed by law and you will receive a tax receipt.


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Defying the barriers
Expand view
Research summaries, case studies and process documentation from "Inclusive Protection and Empowerment Project for Children with Disabilities (IPEP)" are presented. The aim of the project was to build resilience and capacity among children with disabilities and to create a violence-free community for them. The project ran in five districts of Bangladesh i.e. Sylhet, Dhaka, Barishal, Rangpur and Gaibandha from 2014- 2017.
The research topics were:
- Understanding the Vulnerabilities of Children with Disabilities Living in both Government-run and Private Residential Institutions
- The Vulnerabilities of Children with Disabilities from Low-income Households
- Social Protection Schemes Relevant to Children with Disabilities and their Families


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Freedman Point Pre-Leasing Units
From Hopewell City Government: WODA Workforce Housing Project, known as Freedman Point, is currently pre-leasing units and currently under construction. Freedman Point will feature 12 one-bedroom, 36 two-bedroom and 20 three-bedroom apartments with onsite parking. This $11 million development will offer 68 affordable family rental units and commercial space within Hopewell's Downtown district.
Charlie Dane Assistant City Manager
- June 11, 2019
- Send Email


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Presspop inc.
Hello to the toy junkies around the globe!
DANIEL CLOWES "THE DEATH-RAY 12 "Action Figure
Regular price $0.00
Hello to the toy junkies around the globe!
OAKLAND TOY CORP. was born in Oakland, California, USA.
Little is still known about them except the fact that they are a cool garage company that make super fun limited products, and Presspop is their exclusive distributor.
- Designed by : Daniel Clowes
- Doll height: 12 "(31cm)
- Package size: 12.59″x4.33″x2.55″ (32cm x 11cmx 6.5cm)
- Parts and accessories: body (PVC)/ head,gloves,boots(Soft vinyl)/ gun(Polystone)
- Comes in original art box designed by Daniel Clowes
- Box printing: Hand Silkscreened 4 Color
- Release date: 2011
- Limited 200
- Made in Japan


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Search the Community
Showing results for tags 'justice'.
Found 2 results
Months after (trigger warning)
daughtersmother posted a blog entry in Me now my childIt's been months since my daughter's case was thrown out because her attacker is not competent to stand trial or plea , I'm still mad and I'm still going crazy inside but I think about this was is competent? How can it be ruled hes not competent? He was competent enough to assault my child and enough to continue to look back at the door and make sure no one was coming , he was competent enough to hold his hand over her mouth! I just can't believe he got away with it no counseling nothing at all free to do this to another child free to grow into an adult and continue to do this. In march it will be one year since the assault even though my child is doing much better I can't get past the feeling that hes free to hurt another child . I pray all the time that God makes this right and stops him from claiming another victim. I've thought of going public but again this is where the justice system knows they have you , I don't want my sweet 6 year old daughter to be looked at differently I don't want strangers to judge my child. I hate that I failed my child I should have never left her with the babysitter that day and I should have claimed justice that night with my bare hands I should have ended the cycle . Daily my heart breaks that I failed my daughter and daily it reminds me that I'm not a good mother if I was it wouldn't have happened to her she wouldn't be going through what I went through as a child. I swore that if I ever had children it would never happen to them so I have always been over protective of my children and I still don't understand why it had to happen to my child or any child! I done everything right my child was in her own home for Gods sake! Fuck the justice system fuck rapist and fuck the mothers of rapist that know what their children are and don't end that shit! Fuck you Mary! Fuck the cycle of boys and men hurting children and women!
Enraged Today But Possibly Not Tomorrow
2Siamese posted a blog entry in Random Blips of Light on the Radar of LifeThirty seven years ago I was raped by what I consider a stranger as a teen walking home in the rain... someone I did not know personally nor had I ever spoken to or been in proximity. The place is small and it is a place where telephones aren't necessary for words or rumors to travel. Everybody "knows" everybody or seemingly so is familiar with the names or families. I'd assume this is quite typical in everywhere remote small places. I do not remember details. What I do remember clearly was where I was previously, what I was doing in the arcade was a very normal social activity and that there was no ride home in the rain and I was told to walk. My mother was sick and unable to come get me. Walking is also something that is a normal activity in a very small town. I wasn't doing anything out of the ordinary. There were also no taxis, Uber or Lyft for teens. Bicycles were our only other form of transportation. There were no drugs or alcohol involved. I didn't run in huge social circles and being rather bookish anyway, I wasn't interested in popularity climbs. What I do remember is the luring tactic by the perpetrator who claimed he knew the step-Dad and where I lived. "Hey... need a ride?" seemed to be a kind gesture. That's the lure. An obituary or two clued me in that he'd probably seen me playing in the yard with other kids while he was visiting his uncle on the same block. Yes -- obituaries reveal quite a bit of data that you wouldn't otherwise think would be important. I'm equally as capable of solving my own crime scene -- because I was there. Many months ago, I got up enough wine-induced courage to take that entire PD to task. Yes. Even though the statute of limitations (colorful topic) has passed, I called to re-report the crime on my own accord. Dead parents couldn't back me, but I did it anyway. Dead grandparents weren't there to support me, but I did it anyway. And... the PD hung up on me repeatedly so I kept calling and screamed that they were going to listen to me. Besides... PDs are used to screaming drunks. Might as well temporarily use this to my cathartic advantage. So yes, the 1981 rainy April night was re-reported and that was that. I got my point across that I will not be silenced. After all, telecommunication engineering is in my background. Voila! And wine is not a longterm solution or crutch. I was able to reconstruct decades worth of passwords by loosening up my own cranial archives and getting inside my own head. I'm done with that. Mission accomplished. I figured if it was good for the Ancient Greeks it might work for me, too. Amazing what I was able to piece together that I thought was really permanently blocked... and this time I wrote it down! What I did not know is that a first cousin is related by marriage to both a retired police officer as well as the perpetrator. It's now really no wonder he walked and probably did that over and over as they do. All of these years, she and her mother pretended to act out of concern but at my first hint of "revolt" towards her and not being her technological free support, she turned. She also tried to manipulate me into a fake forgiveness scenario over decades probably out of her own secret guilt. When I told her to stop sending me photos of a truck in a driveway and that it was hurtful, she kept doing it anyway. When she's insecure about her husband sending texts to a woman, she can pay a private eye for the address sleuthing... or actually go find a shrink. As they say, it's actually those closest that do the most longterm damage. I just walked away. I didn't realize that the downstream guilty cling to the victims just as hard as the perpetrators do. In doing so, cutting those ties... I freed myself. This is my healthy decision. And some of that rage subsided.


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CPOE > Canadian CPOE Toolkit > CPOE Request Access
CPOE Request Access
To request access to the Canadian CPOE Toolkit, please enter your details below and you will be contacted by email.
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Vastavam web: Pakistan's new Foreign Minister Shah Mahmood Qureshi today extended the hand of friendship to India soon after taking oath by offering "uninterrupted" dialogue to resolve all the outstanding issues, saying it is the "only wise course" as the two countries cannot afford any "adventurism".
After the swearing-in ceremony at the President House, Qureshi went to Pakistan's Ministry of Foreign Affairs and addressed media. The new foreign minister said Pakistan wants to rebuild ties with eastern and western neighbours and create peace in the region.
He said Pakistan wants to resolve all issues with India through talks. "We need a continued uninterrupted dialogue. It is the only wise course for us," he said. The India-Pakistan ties nose-dived in recent years with no bilateral talks taking place. Qureshi, the vice-president of the Pakistan Tehreek-e-Insaf, today said External Affairs Minister Sushma Swaraj sent a letter yesterday to congratulate Prime Minister Imran Khan and mentioned about talks to resolve issues.
I welcome her letter, he said. I want to say to Indian Foreign Minister that we are not only neighbours but also nuclear powers. We have old issues and we both know what these issues are. We need to address these issues, he said. Qureshi said that the two countries cannot afford any adventurism due to close proximity. He said Kashmir is an issue and both countries know about it.
He said former prime minsiter Atal Bihari Vajpayee visited Lahore and Islamabad and recognised the reality of Pakistan and the issue of Kashmir.
"Whether we wish or not, Kashmir is an issue and both countries have recognised it. In my opinion there is no option other than talks to resolve it, he said. Prime Minister Khan in his maiden address to the nation yesterday said Pakistan will hold talks with all its neighbours to normalise ties as without it peace cannot be brought in the country. "If they take one step towards us, we will take two, but at least (we) need a start," he had said.
Talking about Afghanistan, Qureshi said he will make a phone call to the foreign minister of Afghanistan and also visit Kabul with a "solid message" that both countries have same destiny. There will be no peace in Pakistan without peace in Afghanistan," he said. Talking about relations with the US, he said there is trust deficit between the two countries but Pakistan wants to have good ties based on its interests.
Qureshi said that the foreign policy of the new government will be based on interests of Pakistan and it can be fine-tuned according to the needs of the nation. He said that priority of Pakistan's foreign policy will be how we can change lives of common people through economic diplomacy. He said there are enormous local and regional challenges but we want to make progress on these issues. Some forces have been trying to isolate the country but it will not happen now, he said.He said his government will build national consensus on foreign affairs. I will follow bipartisan approach on the issues of foreign policy.


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Drnicholaswu necesitaba un nuevo diseño de logotipo y lanzó un concurso de diseño en 99designs.
Un ganador ha sido elegido entre 53 diseños de 12 diseñadores freelance.
Kuro Brewing Company
Brew Asian (Japanese) inspired beer.
Kuro means "Black" in japanese.
With the attached files.
We would like a "Stamp" like design as we are going to place it on beer bottles as well.
The word 'Kuro" would be in the "Font" file style, kind of rough looking.
And for the logo , we would like to incorporate the grains on both sides as in the "grain" file.
Our Slogan is "Hand crafted with tradition and courage"
The animal representing the brand is a black stallion.
We would like to have that incorporated as in the "Stamp" file but instead of the king.
Descubre cómo funciona un concurso de diseño u obtén más información sobre nuestros servicios de diseño de logo.


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<<Back to Latest News Main Page
GB.Net News Archive ~ GB.Net News By Category
Category: Misc./General Career News Posted by: admin To my surprise, Den of Thieves is not quite a straight-up Heat knockoff. If anything, it attempts to be a crime thriller in the style of a more old-fashioned heist caper that has an opening sequence of grim violence tacked on for commercial interests. Without going into details, much of the third act concerns a discreet heist that wouldn't be out of place in the happy-go-lucky Logan Lucky and the final action sequence emphasizes tension over copious carnage. That's not to say it's a particularly good movie, but it's not boring and Gerard Butler chews the scenery (and food found at a crime scene) like the B-level movie star he is.
Box Office: Gerard Butler Is A Movie Star If The Price Is Right
Article Date: January 31, 2018 | Publication: Forbes | Author: Scott Mendelson
Source: Forbes
Yes, in relative terms, Gerard Butler has become something of a low-rent movie star. His last three action movies, Gods of Egypt, Geostorm and Den of Thieves have notched $13 million-$15 million opening weekends sans any IP. And London Has Fallen opened with $22m just under two years ago, which was an understandable step down from the $30m debut of Olympus Has Fallen just under five years ago. Now you'll notice that the hit movies are the ones that didn't cost $120m-$140m to produce. The Has Fallen films cost $70m and $60m respectively while Den of Thieves was a $30m production acquired by STX.
After a post-300 period where Hollywood tried to make Gerard Butler into a macho romantic leading man (Jennifer Aniston's The Bounty Hunter, and Katherine Heigl's The Ugly Truth were hits, but Jessica Biel's Playing for Keeps was not), he embraced his destiny as a grindhouse action star. This is the opposite of what happened with Patrick Swayze, who was huge as a romantic, female gaze-friendly icon in Dirty Dancing and Ghost but got pigeon-holed in B-movie action flicks like Road House and Next of Kin. If Swayze was a lover, not a fighter, then Butler is a fighter who has stopped trying to be a lover.
And in a world without many newer action stars (there's a reason why Stallone can still do his thing in his 70s), and Hollywood less willing to give the likes of Ruby Rose or Lewis Tan their own action movie vehicles, Butler joins the likes of Jason Statham, Denzel Washington and Liam Neeson as a genuine B-movie action star. And when the budget matches the probable box office trajectory, his price is right. There is still a place for modern movie stardom if the budget matches the ambition.
Comedy stars like Kevin Hart, Will Ferrell, Melissa McCarthy and (fingers crossed) Tiffany Haddish can open a movie based on star power and the promise of star-driven laughs sans franchise or IP at least partially because those films tend to be relatively cheap. Warner Bros./Time Warner Inc.'s Get Hard was a $40 million production, so its $33m debut was a big win right out of the gate. New Line and WB's Tammy cost $22m, so its $100m worldwide gross made it a hit. Conversely, Sony's Ghostbusters ($266m) performed on the level of a high-grossing McCarthy vehicle, but it cost $144m to produce, so it was a whiff.
Butler can't justify a mega-budget picture like Warner Bros.' Geostorm (which still grossed $212 million worldwide) or Lionsgate's Gods of Egypt (which earned $150m worldwide) because those movies are too bloody expensive. But in grindhouse fare like Den of Thieves or London Has Fallen, where a $15m-$20m debut is an unqualified win, he is worth his top billing because a $15m debut means more for a $30m picture than a $130m picture. Sure, you can argue that investors were hoping that Butler would be a glorified added-value element in the big-budget fantasy actioners, but that's a dangerous game and one that backfired in an era where every week offers another big-budget CGI-drenched action fantasy.
It's the same story with Chris Hemsworth, whose $30 million 12 Strong is going to be more profitable than any of his other non-Thor vehicles partially because it cost a lot less than Blackhat ($70m) or In the Heart of the Sea ($100m). Whether he "opened" 12 Strong (as opposed to the film's value as a nationalistic post-9/11 war melodrama), Hemsworth's name on the marquee is worthwhile because the budget doesn't demand that he carry a franchise or a megabucks fantasy on his shoulders. Most of the movie stars of old had to open legal thrillers, cop dramas, romantic comedies and grounded action movies.
The mid-1980s/early 1990s movies that made Tom Cruise into a star were $15 million-$45 million multiplex studio programmers. That includes Top Gun which cost just $15m in 1986, or just $5m less than Eddie Murphy's Beverly Hills Cop II in 1987. A $20m action comedy like Mel Gibson and Goldie Hawn's Bird on a Wire was a huge hit at $138m worldwide. When a big budget movie is $40m and you can expect post-debut legs, movie stardom is possible and real. But when your big movies cost $150m, and you have conditioned audiences to want movie stars as marquee characters, well it's not entirely Chris Pine's fault that Walt Disney's The Finest Hours couldn't justify an $80m budget.
Yes, budgets went up in the 1990s to where a big-budget movie cost $60 million-$100 million. But marketing costs were still comparatively kept in check because it wasn't yet all about the opening Fri-Sun frame. Moreover, the upswing in budgets coincided with overseas expansion, a healthy post-theatrical life (the DVD boom was just around the corner) and a domestic expansion that brought surround sound, stadium seating and multiplexes into areas that were accustomed to so-called shoebox theaters. And, of course, before VOD and HDTVs changed viewing habits, folks still went to the movies just to go to the movies, giving more dramas or small-scale vehicles a chance to find an audience.
Gerard Butler is a prototypical movie star for an age when many movies have just gotten too big for star power. It's a concept or brand-first industry, where Captain America is a movie star but Chris Evans is thrilled when Gifted gets to $25 million domestic and where a $10m debut for Christian Bale's Hostiles is a relative win. Butler's movies can be counted upon to open over/under $15m in North America. So the key is making sure that they are cheap enough for that to be an unqualified win. True movie stardom exists either at the right price or when your movie star (like Dwayne Johnson) is merely one key piece of an already compelling package.
Category: Misc./General Career News
Posted by: admin
To my surprise, Den of Thieves is not quite a straight-up Heat knockoff. If anything, it attempts to be a crime thriller in the style of a more old-fashioned heist caper that has an opening sequence of grim violence tacked on for commercial interests. Without going into details, much of the third act concerns a discreet heist that wouldn't be out of place in the happy-go-lucky Logan Lucky and the final action sequence emphasizes tension over copious carnage. That's not to say it's a particularly good movie, but it's not boring and Gerard Butler chews the scenery (and food found at a crime scene) like the B-level movie star he is.


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Newton Frames
Simone Frames
Worbs is the name of the game and it was created to help battle those funky moments in our day when our brain just needs a quick break. The objective of the game is to match like colored marbles that are in a bowl. The writers from Observer and Style said, " Worbs is actually a physics-based game with a major focus on simple graphics which is quite closely with Warby Parker's aesthetic for optics and sunglasses." The game also falls in line with a major goal of Kill Screen which is to link game play to other aspects of culture like art and design. It is a great pick me up and I advise anyone who needs that quick getaway from their cubicle to take a few minutes to play it and jumpstart your productivity for the rest of the day!
Limited-edition Burke Warby Parker x Kill Screen Frames
The Burke frames come in a striking Glacier Gray color that would stand out on any face (yay for popping frames)! They feature a distinct keyhole bridge, straight browline, and an embossed Kill Screen logo that lines the temple just right. The frames also have anti-scratch (and my favorite) anti-reflecting coatings which is perfect for reducing glare from screens! So if you are a gamer or a long time blogger like myself, these new frames are needed to protect your eyes from any damage while you are doing what you love the most.
Finch Frames
Unfortunately seeing as the limited-edition frames are...well limited edition I was not able to have the option of adding them to my Home Try-On experience but I was able to try on five other frames that I loved! Here is how it works.
1. Go to Warby Parker's Home Try-On page
2. Pick your five frames.
3. Try on the demo frames with family and friends (for their opinions of course)!
4. Buy at any time
5. Send the rest back!
Super simple right? I remember a lot of people I talked to about their experience said that the thought of buying glasses offline made them really nervous, which I could understand why. My family and I (we all wear glasses) would take a half a day at least for our yearly appointments at the eye doctor. We would get our eyes checked and spend time figuring out which frames we wanted for the next 365 days. It took a few hours, but Warby Parker takes the stress and hassle out of the eyeglass process.
Kimball Frames
Now I can order frames I am interested in trying, they send them to me and I can show my family and decide in FIVE days which frames I like the most. I have five days to decide guys. Even for someone as indecisive as myself that is plenty enough time to figure out which frames I trust and love to make my face pop the most. Glasses are real accessories that should be taken seriously and Warby Parker helps you do just that. Their customer service is beyond helpful and I loved working with this brand!
Laurel Frames
The five frames I tried on during my Home Try-On can be found here:
1. Newton in Aurelia Tortoise
2. Simone in Tea Rose Fade (my favorite)
3. Finch in Violet Magnolia
4. Kimball in Marzipan Tortoise
5. Laurel in Peacock Green
Don't forget to play the new Worbs game! You will not regret it and your brain will thank you! Let me know which frames you guys loved the most and what you think about the game!
Photography by: Jeff Matthews featured in my Audience of One Post
Subscribe to: Posts (Atom)


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for a one off fee of dry voice over liners
£30 per line
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for a produced package
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for a 30 minute session £395
for 1 hour £695
DJ and Live Band
£395 for a DJ and £895 for live band
Radio Commercials
30 second radio advert
Dry voice only £150
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For Radio commercials there are usage fees to be added to the costs above.
Usage Fees
£40 Local Radio
£150 Networked Stations
£450 National Stations
Home Tech Support
Advice on computing, audio and smart phones
£25 per device
Computer software repairs
Quoted per Job
For more details or a personalized quote just ask!
TV & Radio work is subject to VAT.


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The year is coming to an end soon and you might have almost given up on getting a job, please doesn't give up yet. The festive period is a great time to network, meet new people and also let them know about your intentions of landing a job in 2019.
As a fresh graduate, it is easy to give excuses such as "I do not have the experience" or "I am not qualified enough" but what makes you stand out among several other applicants is your ability to learn quickly, volunteer your skills to gain experience and even look out for some holiday jobs you can do during the Christmas.
On my Instagram page here, I have shared some volunteering opportunities you should apply to gain some work experience in readiness for your dream job.
Some the year closes and companies round off their books, bear in mind that they also look for new talents who have fresh ideas for 2019 and you just could be the one they are searching for. So as you attend that family or school reunion, that get together or meet up you have been invited to, ensure you are networking to meet your career goal for 2019 just as you are having fun.
I truly can't wait for you to share your success story with me.


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Regular price $ 3.99
POW*MIA Sticker
(Prisoner of War Missing in Action)
Length: 3.75 in.
Width: 7.5 in.
Click Here! For more POW*MIA merchandise!
Use this popup to embed a mailing list sign up form. Alternatively use it as a simple call to action with a link to a product or a page.
By clicking enter you are verifying that you are old enough to consume alcohol.


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The Mets committed three errors which led to a pair of unearned runs that proved to be the difference in their seventh consecutive loss, 6-4, to the Pirates on Monday night at Citi Field.
For a full box score of the game, click here.
Things you should know about tonight's game...
1) Seth Lugo needed 99 pitches to complete five innings and was betrayed by a pair of Luis Guillorme errors that directly led to a pair of unearned runs. The right-hander was charged with three runs -- one earned -- on four hits and three walks with four strikeouts. Lugo (2-3) has lost three consecutive starts.
2) Held to one hit through five innings and trailing, 5-0, the Mets broke through off Jameson Taillon with consecutive doubles by Jose Reyes and Kevin Plawecki to begin the seventh. Guillorme walked against Bucs reliever Tyler Glasnow and Wilmer Flores followed with a pinch-hit three-run homer to cut the Pirates' lead to 5-4. Reyes had two of New York's six hits while Asdrubal Cabrera singled and walked.
3) Tyler Bashlor made his Major League debut in relief of Lugo and allowed a two-run homer to Josh Bell in the sixth. He retired the side in order in the seventh.
Michael Avallone, SNY.tv | Twitter |
We can now add poor defense to the ever-growing list of woes that plague the Mets. Three errors -- two by the defensive-oriented Luis Guillorme -- that led directly to two unearned runs which proved to be the difference in their seventh consecutive loss. For those counting at home, that's New York's second seven-game losing streak in 22 games this month.
There's only so much that can be said about the club at this point and virtually none of it good. With five days left in June, New York finds itself with the fewest wins in the National League and 14 games below .500. Let that sink in for a minute. A team that was 10 games over .500 just 12 games into the 2018 campaign has been bypassed in wins by every other team in the league. In fact, no Mets club in the last 23 years has endured a worst start to a season than Mickey Callaway's group. The 1995 Mets -- who rebounded to finish 69-75 thanks to a strong second half -- were 20-36 on June 25 of that year.
Even the worst teams bust out with a winning stretch of baseball at some point. Chances are the Mets will join that group ... but to be this bad for this long is almost impossible to fathom.
News and notes...
The Mets have dropped seven straight games, one shy of matching their season-high set from May 31-June 9. It's the first time they have endured two losing streaks of seven or more games in the same month since September 2003.
New York is 6-24 in its last 30 games, 4-18 this month and 14 games below .500 (31-45) for the season. They have one win in their last 15 games at Citi Field where they are 13-25.
The Mets have committed 11 errors in their last 10 games while the pitching staff has surrendered nine homers in its last 18 innings.
Lugo fell to 1-2 with a 3.52 ERA in five starts. He has allowed 14 runs -- nine earned -- in his last 13 innings (6.23 ERA) after tossing 10 scoreless frames in his first two starts.
Reyes' two hits represented his second multi-hit game of the season and first since April 21 when he went 3-for-4 against the Braves.
Michael Conforto went 0-for-4 with three strikeouts to snap his seven-game hitting streak.
Robert Gsellman and Bashlor allowed three runs in four innings out of the bullpen. Mets relievers have a 6.43 ERA over their last 30 games since May 25.
The Mets recalled Bashlor from Double-A Binghamton prior to the game and optioned Chris Flexen to Triple-A Las Vegas.
What's next...
The Mets (31-45) try to avoid an eighth straight loss as they face the Pirates (37-41) on Tuesday night at Citi Field at 7:00 p.m. on SNY.
Steven Matz (3-5, 3.68 ERA/5.05 FIP, 63 K, 1.282 WHIP) looks to bounce back after surrendering five runs over 5 2/3 innings against the Rockies last Thursday. All the runs scored against him came in the first two innings. Despite the poor start, Matz has a 3.10 ERA over his last nine starts. The 27-year-old allowed two runs in five innings during his only career start against the Pirates in 2016.
Chad Kuhl (5-5, 4.56 ERA/4.75 FIP, 77 Ks, 1.444 WHIP) gets the ball after surrendering a season-high eight runs over two-plus frames to the Diamondbacks last Thursday. Prior to that start, the 25-year-old right-hander had compiled a 2.89 ERA in his previous eight outings while allowing two or fewer runs five times in that span. Kuhl was charged with five runs over 4 1/3 innings in his only career start against the Mets last season.


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Updated 10/7/2018, working from home doesnt have to be a dream. Youll need a good understanding of the language youre translating so that you can convey the meaning of the first document in the translated document. The job: Listen up, take notes and get paid. Advances in office technology have made this a rather effective solution for many busy individuals. (I highly recommend finding your own clients, which you can read more about in the next section.). Just as you would with other freelance jobs I suggest that you tap into your own personal network forex club pl to find jobs. Heres how you can find clients. You should also keep an eye on The Penny Hoarders Work-From-Home Jobs Portal. Heres what you should know:. Your car must be registered in-state and be covered by in-state insurance. If you think youre a good candidate for a tech support job here are some companies you might want to check out: Search Engine Evaluator, when you search for something in Google the search engine tries to bring you the most accurate results.
A lot of the legitimate work from home jobs in cape town the survey sites will only send you a few surveys per month. Small Business For the sake of this article small business means working more for yourself rather than a company like an employee would or for several clients/companies like a freelancer would. Total hourly pay ranges from 14. Think back to all the times youve called a company for help or typed questions into an online help box. Remote Customer Service Jobs Are Booming There are many work-from-home jobs available in the customer service realm. In general, you must: Be 18 years or older. Peruse the listings to find information about the company, pay and type of employment. You can maximize your earnings by signing up with several different sites.
How to get started: If youre even a teeny bit interested, try. Gigs on Fiverr range from standard data entry and research tasks to the truly out-there. Requirements: vipkid applicants must have a bachelors degree. Search engine evaluators will rate the results that come up in search engines. I have a very detailed post that contains everything you need to know on getting paid to write for blogs: How to Become a Paid Freelance Blogger If Youre Starting From Scratch Copywriter Unlike freelance bloggers and magazine writers. However, Im only human and sometimes I make mistakes. They range from full-time positions to side gigs, and none of them are scams. As a virtual assistant there is a wide array of duties that your client may ask you to complete, depending on what business your client. However a word of caution, many of the aforementioned scams originate on this site, so its important to carefully scrutinize the offers found on cragislist.
Earn 500/Month Listing Your Place on Airbnb The job: Have you got a spare room? Here are some possible freelance jobs you might be interested. Customer Service, some of the easiest home jobs to get are in the customer service fields. You can sell used items online at Facebook Yard Sales, eBay, and Craigslist. You shouldnt expect to make any money blogging until youre about a year. It even shows you how to create a website and how to secure clients. Work for Amazon Without Leaving Home The job: Amazon is a huge company that sometimes hires seasonal or permanent work-from-home customer service associates. Each company requires you to commit to a six-month legitimate work from home jobs in cape town contract.
Average earnings: With most ESL sites, its possible to teach two lessons per hour. Virtual Assistant A virtual assistant is an online personal assistant. I know it can be really hard to separate the real work from home opportunities from the scams, so Ive done the work for you. Bonus: Find Work-From-Home Jobs Through This Site If youre trying to land that perfect work-from-home customer service or virtual assistant job, we recommend starting your search with ZipRecruiter. Here are more than 50 legitimate work from home job opportunities. In fact, work from home bookkeepers earn an average of 40,000/year! Instead of outsourcing customer service jobs large companies now have the option of turning to one of many call centers staffed entirely by home workers.
The pay for this service varies greatly so its hard to come up with a salary range. If youre a good host with a desirable space, you could add hundreds even thousands of dollars to your bank account that way. On any given day, sellers in the Fun Lifestyle section legitimate work from home jobs in cape town are offering thousands of unique services from polishing a Tinder profile to creating a family tree. Pass a background check. Depending on the type of jobs performed web developers can make anywhere between 55,000 175,000 per year. Instead of working for only one employer you may work for several. And because there are different skill sets needed for different types of tech support jobs, the pay can vary greatly.
While you wont get a ton of these job the pay is pretty good from the time commitment (usually around 10 for a 15 minute test.) Here are some places you can sign up with: Get to Work. Average earnings: Rover says sitters can earn as much as 1,000 a month. Try driving with Lyft. Average earnings: Its called Fiverr because every job listed on the website used to cost five bucks. InboxDollars What I like most about Inbox Dollars is the email reading feature. How to get started: Youll create an online sitter profile where youll answer questions about your experience with puppers and your schedule availability. Heres where you can find transcriber/transcriptionist jobs: Document Translator, if you are bilingual you have a skill that is in demand. Props like charts, pictures, posters or stuffed animals. This should start giving you an idea of the kinds of work at home jobs that you can find through our directory and recommended job search sites.
They are merely meant to be ways you can supplement your income from the comfort of your home. These jobs usually pay anywhere from 10 15 dollars per hour. He says to aim for 60 an hour. If you have creativity plus the love for technicality this can be a good career for you. Its important that you take the time to weed through opportunities and find the one thats most likely to be successful. (Rover keeps a small percentage as a service fee.) Dog owners will reach out to you. Here are some options:. Although Ive done my best to make sure all of these companies are legitimate and hiring, things change and I cant keep up with all the websites listed here. Do you have the stick-to-it-iveness needed to finish an online training course? Drivers license, and pass a background check. If you have specific knowledge of a subject or second language then tutoring might be a good fit for you.
Build Your Freelance Career 5 at a Time The job: Have you got skills? Find a Remote Customer Service Job. Likewise, if youve had an awesome experience with a company that hasnt made it on the list let me know in the comments and Ill add. There are a variety of jobs always available in many fields, its always a good idea to start your job search at oDesk. Its important to vet each company to see which one will fit your schedule and income needs. For instance instead of typing in work at home try telecommuting or home shoring instead. Our internet-saturated society keeps creating tens of thousands of ways to work at home that didnt exist just a few years ago. Online Reseller If you have a good eye for legitimate work from home jobs in cape town a bargain you can make money by reselling items. Wir verwenden Cookies, um Inhalte zu personalisieren, Werbeanzeigen maßzuschneidern und zu messen sowie die Sicherheit unserer Nutzer zu erhöhen. Might as well list it with use Airbnb to try to make some money with. BUT you have the potential to earn a lot of money.
Average earnings: 10 to 19 an hour, with an average of about.70, according to PayScale. A data entry worker simply inputs information for companies into certain computer programs or types out audio files. You can currently purchase a paperback copy for.29 on Amazon or the Kindle version which is only.90. But they dont always get it right. The job: Would you like the freedom to work remotely while helping others succeed? A lot of work-from-home gigs are ideal for working part-time or supplementing your main income. Online tutoring enables parents to easily get help for their children in a more flexible way than traditional tutoring has allowed. Requirements: You dont have to have a CPA to be successful in this business. Many internet based companies are hiring tutors to service students of all ages and needs. How to get started: Check out Amazons remote jobs page. Requirements: You should have a high school diploma or equivalent and a year or more of exposure in a service environment. How to get started: Numerous staffing companies work in this field.
However in 2012 the median pay for medical transcriptionists was.36/hour. If youre not ready to find your own clients, but want to try out virtual assistant work, here are some companies that hire. Theyre actually full of errors, so companies need real humans to look at the results and judge them for quality, relevance and usefulness. Thats where search engine evaluators come. (I tried this and charged 15 commission) You then sell the items for your clients and take your cut when theyre sold. They can take a couple hours, and you wont be paid for this time. Heres a sample of the kind of work you can do from home. Freelance blogging is how I earn my income and is a topic Ive extensively covered. Provide Customer Service From Your Couch The job: Large corporations often contract smaller companies to provide phone and online customer care, and these smaller companies specifically hire home workers instead of staffing call centers in an office somewhere. Instead you can look for deals at yard sales, sales at retail outlets, or even consider getting your own private label products made.
Some of the most popular gift cards are the 25 Amazon gift card (which only requires 2200 swagbucks) and the Paypal gift card. Check Out Our Directory of Work at Home Jobs Below: Free Job Search Sites: m, is a hub that connects remote workers with project managers from around the world. Here are a few places you can look for work from home customer service representative jobs: Tech Support Provider, tech support providers cover a wide array of tech related customer service questions for customers. When you work from home the common theme is that you are responsible for paying your own taxes (an employer wont withhold them for you) and providing your own health insurance and retirement plans. Some of the links in this post are from our sponsors.
To give you an idea of whats out there, weve rounded up this list of legitimate work-from-home jobs. Are you tired of the 9-to-5 grind? Test Websites Companies pay everyday internet users to give their opinion on functionality of websites. There are tons of businesses who use mystery shoppers to make sure that employees and branches are operating as they should. I just recently discovered that its possible to start a from-home bookkeeping business. I personally use a couple of these sources to help fund my Christmas shopping. Bookkeeper My very first real job was a bookkeeper. You can choose to offer a variety of services, including dog walking, overnight boarding at your home or theirs, and daycare. Youll also need a quiet house. Heres where you can apply to be a search engine evaluator: Data Entry Worker.
By only using the search engine as you normally would you can rack up quite a few gift card throughout the year. Make an Average 1,000/Month as a Dog Sitter. Ive been a virtual assistant for several years, finding my own clients and making a very strong wage. A high-speed internet connection. I loved it and kept the job for seven years. Start with your friends and family Share your services on social media and ask your friends and family to do the same Put an ad out in the local newspaper Since many people dont like the hassle of selling. Just like Swagbucks you can also search the web, take surveys, and participate in special offers to increase your earnings. In the online money making world youll see the term freelancer a lot. Virtual Assistant, theres a new trend of small and large businesses hiring virtual assistants to provide administrative and secretarial support to their employees. How to get started: Read through our beginners guide to Airbnb before you list your space. If you want to become a magazine writer I highly suggest you purchase a copy of the Writers Market.
However, blogging is something you can easily incorporate in your life with just a few hours per week and could make a nice side job for you. We provide you with accurate, reliable information. Start Your Own Business, start your job search by looking in the mirror. Cutting out the costs of travel and scheduling conflicts legitimate work from home jobs in cape town online tutoring is a simple solution that is beneficial to both tutors and students. Mystery Shop Mystery shopping is basically quality control for customer service. Average earnings: On average, Roth earns 2,000 per month, happily taking jobs when it suits her.
Here are some other places you might be able to find web design jobs. How to get started: Study the website. It only takes a couple seconds to read an email (which is simply just viewing an advertisement) and click the confirm button. But sometimes they get it wrong. I would recommend that you draw up a contract for each client you take. Learn more about how we make money and select our advertising partners. Qkids is more flexible but also prefers a degree. Ive signed up for mystery shopping before but since I live in a small town all the jobs were so far away that the gas money Id spend cancelled out the pay. Theyre in high demand, so requirements to become one are low, especially if you want to teach English abroad. Ill love you forever. Now she works on a contract basis with two companies and puts in about 30 hours a week, transcribing anything from training webinars and audiobooks to radio broadcasts. All you need is a laptop or a phone, a work ethic and internet access.
There are tons of platforms where you can upload and sell your own ebooks and print on demand books. Launch a Side Gig from Home. These things are relatively easy to do and therefore dont pay much. If you know where to look you can find a work at home job in almost any industry. Swagbucks Swagbucks is a program that allows you to earn points (points are called swagbucks) by using their search engine, taking surveys, participating in daily polls, redeeming coupons, and completing special offers. Some people learn web design by trial and error, while others learn web design in college or by taking courses. Special offer: Start a professional blog for as low.95/month. Enter your information into Airbnbs calculator to receive a free income estimate. A little word of warning though : legitimate work from home jobs in cape town theres much more to successfully selling a book than writing it and uploading. Requirements: Depends on the gig use your existing skills!


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Baylor Football Title IX Lawsuit Alleges Women Were Drugged, Gang-Raped on VideoMay 17, 2017
A former Baylor volleyball player who said she was gang-raped by Baylor football players filed a Title IX lawsuit against the school Wednesday.
According to ESPN.com's Mark Schlabach, the woman said she was raped by at least four and as many as eight Baylor football players.
Per Jim Vertuno of the Associated Press, the latest Title IX lawsuit against Baylor alleges that football players made a 21-second gang rape video and staged dog fights.
According to KXXV-TV in Waco, Texas, the alleged rape occurred in February 2012.
The lawsuit states that Baylor "permitted a campus condition rife with sexual assault and completely lacking the basic standards of support for victims as required by federal and state law."
It is alleged in the lawsuit that football players engaged in gang rapes as bonding experiences after drugging women, and that there is at least one video of two female students being gang-raped by football players.
Baylor released a statement Wednesday in response to the lawsuit, as provided by Phillip Ericksen of the Waco Tribune-Herald:
The plaintiff's lawyer, Muhammad Aziz, also commented on the decision to file the suit, per Ericksen:
"These girls affected by this are seeking their day in court. We thought about this a lot, and me and my client thought about it and discussed it. Eventually, we decided to proceed. Really, what we are seeking to enforce is just a safe education environment for the girls at the school."
Schlabach added that Baylor is facing seven Title IX lawsuits involving 15 women.
Reporter Bruce Feldman cited a source who said the latest allegations "were well known around the BU athletic [department] at the time and among BU female athletes."
In November, Schlabach and Paula Lavigne reported that Baylor issued a statement regarding an alleged gang rape, reportedly involving a volleyball player.
According to the statement, some athletic department officials and coaches were told about the allegation but didn't report it to judicial affairs, though the coaches refuted this.
Baylor head football coach Art Briles was fired in the wake of the sexual assault allegations against football players last year, while school president Ken Starr and athletic director Ian McCaw left their positions as well.


text: Offering an outdoor pool and a restaurant, Charlie House Pin Klao is located in Bangkok. Free WiFi access is available.The accommodation here will provide you with air conditioning, a seating area and a refrigerator. Featuring a shower, private bathroom also comes with free toiletries. Some units have a dining area.At Charlie House Pin Klao you will find a garden. Other facilities offered at the property include luggage storage. Airport shuttle service can be arranged upon request.The hotel is 2.8 km from Khao San Road, 3.2 km from Temple of the Emerald Buddha and 3.2 km from Bangkok City Pillar. Suvarnabhumi Airport is 31 km away.


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Company Name: Heartland Radio Net
Address: Minnesota, United States
Website: http://www.heartlandradionetwork.com
2003-2005: Heartland Radio Network was created but then shut down when I took a job in Missouri. At the time it was
started we were one of the top Southern Gospel Radio Networks on the internet! My good friend Rob Patz with Southern
Styles had the leading Internet Station. He gave me alot of pointers to starting an internet station.
Christian Country Folk SouthernGospel Holiday
Last Login 09/26/2019
Total Artists Review'd 430
% Artists Approved 31.40%
Listeners & Subscribers


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Our Story
Esyvte is a brand for young women who seek to build a career for themselves. We want to create the kind of stylish and comfortable clothing that makes it effortless to put on in the morning and go to work without worrying too much what to wear, because you know you have the kind of pieces that just fit and look good.
Our products are designed to be unique stylish, comfortable through performance fabrics and extremely useful with extra attached pockets. For some items we offer tailoring and individual customizations such as embroidery. We make them in our own workshop and partner factories in the Ukraine, where we have a team of motivated women tailoring experts creating exceptional quality. We are dedicated to sustainability working and repurposing dead-stock fabric and sustainable fabric suppliers from Italy and Germany.
We also designed a styling and shopping service for those of us that do not really like to shop. We have online stylists and stylists at our pop up that give unique tailored recommendations to find the right clothing for you and then send it to you in a box, you only keep what you like and send the rest back to us.
Building a career for oneself is a tough endeavor and we all have many questions and would like to know how other women got there, we decided to collect stories from women in our blog and also try to answer some of the questions we have/had that could be useful for other women to learn from our experience.


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Why Invest in a Holiday Home Abroad?
It's something many of us dream of. We've all watched Home and Away and thought about how wonderful it would be to have a home away from home in the sun. But is it achievable, is it affordable, and are there any pitfalls?
Getting a deposit
Buying a second home is not always easy. It's a huge investment, and of course you'll need a lump sum in order to buy. But there are ways of doing it:
- Release some equity on your current home to purchase a new By remortgaging your home, you can release some of the equity and get the money back to purchase a second home.
- Likewise, you could look into selling your home and renting it back to get the deposit you need. Websites such as readysteadysell are a quick and effective way of doing this, and will provide you with all of the information you
- If you have any investments, you can use them to purchase another property, for example, stocks and shares.
- And if you're lucky enough, you might be gifted the money. Whether you're left with some inheritance, or a family member decides to help you out, or even if you just have savings, putting these towards a second property abroad is sensible if it's what you desire
What Are The Positives?
A lot of things worth having don't come easy, or cheaply, and holiday homes abroad absolutely fit into this category. Yes they're harder to achieve, but they absolutely have plenty of positives, both financially and personally.
- Property investment is actually fairly low risk in comparison to other
- As well as enjoying it yourself, you can let out your property to other holiday An average of 30 weeks a year can produce an extremely healthy return on your investment. Reports have suggested that UK holiday home owners who rent them out make an average of over £12,000 in gross annual income per unit, with their total expenditures costing half of that at just £6,000. It'll involve hard work and marketing your property in the correct way, but with a 100% gross profit, it's surely worth it.
- The tax relief is considerably better in comparison to other buy-to-lets. With your
average buy-to-let, there is a restriction on on mortgage-interest tax relief nowadays. However, these negative changes in tax relief on buy-to-lets will not affect a fully furnished holiday let. With this you can still offset the full mortgage interest against rental income, just as before. There are certainly attractive tax advantages to being a holiday let investor.
- You're your own boss! Not only can you choose if and when you want to visit your holiday home (where all you have to pay for are flights), but you also get to choose how much money you want to make on it, and when. You can pick the most desirable months of the year, and the more you rent it out, the more you'll make. So in the initial year or so if you're looking to make some money back, this is a good way of doing
- The rise of business travellers choosing to let accommodation on their business trips also makes for a more worthy investment. With the rise of Airbnbs, individual travellers are more likely to want to stay in a home-like environment to work in, rather than a hotel, and this is where your holiday home comes in to
- And of course, on top of the financial benefits, not forgetting that you'll own your own home in the sun, to share with friends and family and make memories in for years to come. You'll get to know the locals, and other people who holiday there, and it's great for socialising away from
Are There Any Negatives?
As with anything, there are less appealing notions to consider when buying a holiday home too.
To make money back on it, it is a lot of hard work. Statistically, if you own and rent out a holiday property, you're likely to spend an average of nine hours a week managing the property. If you're in a full time 9-5 job, you have to question if you really have the time and motivation to make it work.