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Why Puppies Hump - How you can Stop a Puppy From Humping and Biting Your Leg
why do dogs hump
It's so embarrassing when your puppy begins madly humping people's legs, you, other animals in your house, and just about everything else that incites your pup into humping. Ever thought about why your dog really wants to hump things such as a couch cushion or perhaps a plush toy? For your benefit, this short article explains why puppies hump and offers you with practical advice on the best way to teach your pup to halt humping and biting your leg.
why do dogs hump people
o Your dog is now a youngster as we say, with surging sexual hormones, which causes your puppy to need to mimic adult dog mating behavior. Admonish a puppy sharply to avoid his humping and biting the moment he begins.
o Neutering your dog at six-months of age or perhaps the age your pets veterinarian recommends, can stop an issue with humping from ever developing initially with very few exceptions.
o Puppies humping behavior is not always sexual as the name indicated. A puppy needing to assert his dominance over those he considers his subordinates may also hump and bite. Reassert yourself as the dominate member of your pack family with command as well as other training and also teaching a puppy to halt humping and biting in that way. A great trick to test is always to possess a noisemaker or small handheld alarm which you activate to make noise to startle a puppy enough he won't desire to hump or bite your leg.
o Engaging your puppy inside a fun activity like fetching a toy as soon as he shows an interest in humping your leg can stop him from humping and biting. It is extremely very easy to draw a puppy's attention away from negative behaviors and direct him towards acceptable behaviors. Undertake it before bad behaviors become permanent habits for the puppy.
A completely anxious puppy may react by humping and biting your leg. Fitting in with strengthen your puppy to relax can help stop this unwanted behavior.


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Mysore-style is the traditional way to learn Ashtanga Yoga. (As taught in Mysore, India, where the practice originated).
Mysore classes allow for students to develop their own self practice, learning and memorising the sequence bit by bit. It is the safest, most effective method of learning ashtanga yoga.
The introduction to Mysore workshop is aimed at complete beginners to ashtanga as well as students who have experience of led classes but would like to transition to morning self-practice. The next workshop will take place on Sunday 19th November with Gem Maryan.
Why you shouldn't feel nervous about starting mysore
Many people feel intimidated by the idea of mysore self practice classes in case they don't remember how to do the sequence or they fear they won't be good enough.
But there's no need to worry – mysore classes are mixed level classes suitable for beginners right through to advanced students.
What you'll learn in the workshop
- Background to the the ashtanga system
- Explanation on how the ashtanga sequence works and how it is designed to be learnt
- Fundamental techniques used throughout the ashtanga sequence
- Sun salutations and finishing postures so you have the essentials of practice to build on
By the end of the workshop you will have a suitable sequence from which to start your own self practice and have the confidence to give Mysore classes a try!
Workshop Costs £25
Location and How to Book
The workshop will take place at PYM Finnieston, 1061 Argyle St ( gate directly opposite Lebowskis)
Workshop Date: Sunday 19th November 2017
Workshop Time: 13.00 – 15.30

subset: commoncrawl


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Enhance your child's reading comprehension skills and ensure success across disciplines with Spectrum® Focus: Reading for Main Ideas and Details in Informational Text for grade. Aligned to state standards, this workbook helps children analyze what they read with targeted practice for in-depth learning.
Reading words is just the first step; help children comprehend the message by summarizing stories, drawing inferences, finding main ideas, supporting answers with evidence, and more using Spectrum Focus: Reading for Main Ideas and Details in Informational Text for grade 4.
Spectrum Focus takes aim at specific areas of study and helps children gain mastery by honing one skill at a time. With skill-specific instruction, this standards-based workbook elevates critical thinking with extensive introductions and explanations, guided and independent practice, comprehensive assessments, and performance tasks—it's the perfect resource to help children meet and exceed expectations.
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You do not need permission from us to place temporary traffic signals:
- on a trunk road in Suffolk - contact Highways England for permission
- on a private road
Before you apply
Your application must include:
- a 1:1000 O.S. based plan showing the length of highways affected, junctions and major access
- a 1:250 (min) O.S. based plan including:
- the location of signal heads, showing the distance of each signal from the centre of the junction, the arrow should point towards approaching traffic
- staging arrangement that clearly relate to the plan
- dimensioned widths of carriageways
- proposed signal timings
- current speed restrictions on affected roads
- working area, longways clearance and safety zone
Application for applying for permission to place temporary traffic signals on the highway (PDF, 845KB)
After you apply
If you get permission you must:
- keep a copy of the approval document on site for the duration of the works
- display a 24 hour emergency phone number on site which connects to a manned fault reporting service


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Equifax Fraud product manager, Rich Huffman, was recently published in Corporate Compliance Insights discussing how Boards of Directors can stay on top of trends in the fraud landscape and ensure C-level executives implement effective measures to detect and mitigate fraud.
Huffman recommends that
Boards also should encourage the executive team to set realistic goals. Companies shouldn't aim to stop 100 percent of fraud, as this is impossible and would harm the experience of legitimate customers. Aiming to stop all fraud will result in high abandonment rates and harm to revenue. Instead, they should aim to find the mix that works best for their operations.
That mix should include a waterfall approach to detecting fraud by looking at a wide variety of information about an applicant. Simple things like validating an identity, which most organizations are already good at doing, start the waterfall. More detailed gates looks at the device the person is using, their presence on social media, and mine information from shared fraud data consortiums within an industry or across industries.
Beyond revenue loss, fraud also affects an organization's reputation when consumers feel it's too hard to do business with that company because of fraud prevention barriers or conversely when regulators begin to scrutinize what they believe are lax fraud protections. Fraud may not always be examined on the same level as revenue and other KPIs that directly impact executive pay and bonuses, but it needs to be tracked to effectively measure the health of the company.
The post Working with the C-Suite to Mitigate Fraud appeared first on Insights.


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1Departments of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, USA
2Departments of Ophthalmology, Georgia Regents University, Augusta, USA
3Departments of Neurology, Georgia Regents University, Augusta, USA
4The James and Jean Culver Vision Discovery Institute, Georgia Regents University, Augusta, USA
Received Date: April 04, 2013; Accepted Date: April 27, 2013; Published Date: April 29, 2013
Citation: Martin PM, Gambhir D, Promsote W, Ganapathy V, Moore-Hill D (2013) Expression of the Niacin Receptor GPR109A in Retina: More than Meets the Eye? Clin Exp Pharmacol S3:003. doi: 10.4172/2161-1459.S3-003
Copyright: © 2013 Martin PM, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Visit for more related articles at Journal of Clinical & Experimental Pharmacology
GPR109A was discovered recently as the G-protein coupled receptor for niacin (nicotinic acid), a drug used widely in the treatment of hyperlipidemia. Upon its initial discovery, expression of the receptor was thought to be restricted primarily to adipocytes and immune cells (monocytes/macrophages), a pattern of localization consistent with the known actions of niacin – anti-lipolytic and anti-atherogenic. Of late however, several new reports have arisen detailing expression of the receptor in other cell and tissue types. Interestingly, with the exception of dermal Langerhans cells, the cells responsible for skin flushing, an unwanted side effect of high-dose niacin therapy, the function of the receptor in the additional cell types described is largely anti-inflammatory in nature. The receptor might also have a role in cancer; silencing of the receptor has been reported in colon and breast cancers, and forced expression of the receptor in tumor cells induces apoptosis, thereby suggesting a tumor-suppressive role for the receptor. This supports strongly not only the critical importance of GPR109A expression and activity under normal, basal conditions, but also the strength in impact that therapies capable of augmenting or optimizing its expression and activation may have in thwarting the development and progression of inflammation and cancer. Given the key causative role of inflammation in diabetic retinopathy, and the critical lack of viable strategies for intervening early in this pathology, new therapies, particularly those targeting inflammation, are sorely needed. Herein, we describe preclinical and clinical studies documenting the expression of GPR109A, the pleiotropic effects elicited in response to its activation and the underlying mechanisms to explain these actions. This information we discuss in the context of its relevance to diabetic retina, ultimately providing insight into strategy for future targeting of the receptor and development of new therapies for prevention and treatment of retinopathy in diabetes.
Nicotinic acid; G-protein coupled receptor; GPR109A; Diabetes; Diabetic retinopathy; Retina; RPE
Diabetic retinopathy (DR), one of the most common and feared complications of diabetes, is the leading cause of irreversible vision loss and blindness among adults of working-age in the U.S. and other industrialized countries [1,2]. The incidence of DR is high; nearly all type 1 patients and greater than 60 percent of patients with type 2 diabetes develop DR within the first 1-2 decades of their disease. In fact, at the time of diagnosis, signs of retinopathy are already detectable in many type 2 diabetic patients. Hyperglycemia is a primary factor in DR pathogenesis and while correcting it through maintenance of tight glycemic control (a task that is difficult in many patients) helps, it does not mitigate entirely DR development and progression [1,3]. There are at present treatments for DR (e.g., laser photocoagulation, vitrectomy, intravitreal anti-VEGF therapy); however in addition to being associated with adverse effects, these therapies are applicable only at the late stages of the disease when the signs and symptoms of proliferative microvascular disease present. But unfortunately, at these late stages, DR has already reached a relatively advanced state. Hence, there is a critical need for new, viable strategies for DR prevention and treatment.
Inflammation is implicated as a key causative factor both in the development and progression of DR [3-6]. Indeed, diabetes itself is recognized as a chronic, low-grade inflammatory disease. Congruent with this is a burgeoning literature suggesting strongly that therapies that reduce inflammation in retina may block early cellular and biochemical alterations in this tissue long before they become clinically evident. Thus, strategies to intervene within this "early" time frame have a high likelihood of effectively preventing or slowing progression of DR to advanced stage retinal disease and thereby, preserving vision and quality of life in a large number of persons. We identified recently in retina a new target, the G-protein coupled receptor GPR109A, that when activated therapeutically in diabetes could potentially fit this bill. In this short review, we discuss the clinical and experimental evidence that forms the basis of this rationale.
In 2003, GPR109A, also known as hydroxycarboxylic acid receptor 2 (HCA2) and formerly as HM74A in humans and PUMA-G (Protein Upregulated in MAcrophages by Interferon-γ) in rodents, was identified as the high-affinity receptor for niacin [7-10]. A second receptor with a high degree of homology to HM74A but a much lower affinity for niacin, HM74 (GPR109B), was also reported; however, its exact physiologic role remains unclear. Upon its initial discovery, GPR109A expression was thought to be limited primarily to adipocytes, the cell type in which the anti-lipolytic effects of niacin are most warranted. Niacin has been used widely to treat hyperlipidemia and remains today, five decades following its initial introduction, as one of the most effective agents for lowering low-density lipoprotein (LDL; "bad" cholesterol) and increasing High-Density Lipoprotein (HDL; "good" cholesterol). In contrast, newer therapies such as HMGCoA reductase inhibitors (statins) and fibric acid derivatives are effective only in reducing the LDL cholesterol [11,12]. Congruent with its improvement of lipid/lipoprotein characteristics, niacin is touted also for its ability to reduce vascular inflammation and thrombosis and therefore lower significantly the risk of atherosclerosis, stroke and other cardiovascular events, properties that we now know to be a direct consequence of its interaction with and subsequent activation of the Gi- protein coupled receptor GPR109A [13]. Indeed, the efficacy of niacin in slowing or reversing the progression of atherosclerosis and reducing cardiovascular events and mortality in patients with hyperlipidemia and established cardiovascular disease and the involvement of GPR109A in these actions is unquestionable given the wealth of clinical and experimental evidence that supports it [14].
Along with the identification of GPR109A as the receptor for niacin, came additional studies devoted to characterizing in detail the expression and function of the receptor in various cell and tissue types. Out of these studies came the identification of β-hydroxybutyrate and butyrate as endogenous receptor agonists [15,16], and importantly, the revelation that the benefits of activating the receptor therapeutically extend far beyond the alteration of lipid profiles [17,18]. In immune cells, cells central also to the development and progression of atherosclerotic lesions/cardiovascular disease, GPR109A activation was found to elicit robust anti-inflammatory responses by way of suppressed pro-inflammatory cytokine and chemokine expression and signaling [19]. The same anti-inflammatory effect was described also in adipocytes [20]. Additional studies involving mouse and human endothelial cells demonstrated the potentiation of responses that were both antioxidant and anti-inflammatory in nature in association with GPR109A activation [11,21,22]. Investigations into the role of the receptor under normal physiologic conditions and the consequences of its activation by endogenous ligands (e.g., β-hydroxybutyrate, butyrate), which happen to be intermediates of normal metabolism, led to the discovery of a role for the receptor also in nutrient sensing and energy regulation, and in tumor suppression [17,23,24].
As detailed above, the major cellular properties attributed to GPR109A-dependent signaling to date can be described in sum as: lipidmodulatory, anti-inflammatory, anti-oxidative, and energy regulating. The underlying molecular mechanisms to explain these actions include regulation of the activity of lipolytic enzymes (i.e., hormone-sensitive lipase in adipocytes) and cholesterol efflux transport proteins (i.e.; ABCA1 in hepatocytes) [7-10,15,25]; suppression of Nuclear Factor Kappa-B (NF-kB) signaling [16]; Peroxisome Proliferator-Activated Receptor-Gamma (PPAR-γ) activation [26]; and regulation of monocarboxylate transporter expression and functional activity [24]. Alone, each of the aforementioned responses is highly desirable in diabetic retina; however, the discovery of a single receptor with the potential to influence them collectively is extremely significant with respect to developing new, targeted therapies for DR prevention and treatment.
The involvement of inflammation and oxidative stress in DR pathogenesis is undeniable. While there are conflicting opinions as to the existence of a concrete link between atherosclerosis/cardiovascular disease, the pathology for which therapeutic intervention via GPR109A activation is most noted, and DR incidence and severity [27], clinical and experimental evidences support overwhelmingly a definitive correlation between the two [28,29]. Hence, enthusiasm in this regard is in no way diminished. Indeed, altered lipid metabolism and lipoprotein abnormalities are not only well established features of diabetes but more specifically, of diabetic retina. Hypertriglyceridemia is common in type 1 diabetes and even more so in type 2 diabetes, with type 2 patients commonly presenting with reduced HDL-choleserol levels in addition to hypertriglyceridemia [30]. In retina specifically, the size and density of hard exudates in diabetic patients is thought to be reflective directly of the severity of alteration in retinal lipid profiles [31,32]. Additionally, fibrates and statins, well-known antihyperlipidemic agents, have been shown to reduce significantly the risk of advanced DR development and progression both in human patients and experimental models of disease [31-35]. There are an increasing number of new reports citing the benefits of niacin-GPR109A signaling in the treatment of pathologies other than hyperlipidemia (e.g., multiple sclerosis, septic shock, lung inflammation and fibrosis, renal failure, ischemia-induced neovascularization and peripheral vascular dysfunction in diabetes) [36-40]. This coupled with the fact that niacin, the prototypic GPR109A agonist, has proven to be superior to the aforementioned lipid-lowering agents in that it elicits additional, unique actions atop its lipid-lowering effects via its interaction with GPR109A raises the question as to whether similar or added benefit might be attained upon therapeutic targeting of the receptor in DR, a question well worthy of investigation. However, before progress can be made toward addressing this issue, the expression of GPR109A in retinal cell types and intact retina must be characterized fully and its functional significance therein elucidated.
Along these lines, in 2009, we reported for the first time ever, expression of GPR109A in retina [41]. Evaluation of cross sections of mouse retina and transformed human and rodent retinal cell lines revealed the localization of the receptor in Retinal Pigmented Epithelium (RPE) and more specifically, to the basolateral membrane of this cellular layer. This localization is ideally suited for interaction of the receptor with ligands, endogenous or pharmacologic, presenting from the choroidal circulation. Our subsequent inquiry into the functional significance of RPE-specific GPR109A expression led to the discovery of a potent role for the receptor upon its activation by exogenous niacin or β-hydroxybutyrate in the mediation of antiinflammatory signaling not only in cultured RPE cells [42], but also in intact mouse retina as evidenced by the suppressed expression (mRNA and protein) of pro-inflammatory molecules such as Interleukin-1β (IL-1β), Monocyte Chemotactic Protein-1 (MCP-1), Intercellular Adhesion Molecule-1 (ICAM-1) and, the reduction of other notable hallmarks of retinal inflammation such as increased leukostasis (unpublished results). Further investigation into the effects of diabetes on receptor expression led to the revelation that not only does retinal expression of GPR109A persist in diabetes (both type 1 and type 2 diabetes - determined by analysis of receptor expression in postmortem human retina and in rodent models of diabetes) but, that it appears to be upregulated in this condition [42]. While this confirms the presence and availability of the receptor for targeting in diabetic retina, the functional significance of its upregulation remains to be determined. We postulate that it represents a mechanism by which the tissue tries to stop the progression of the damage caused by the disease, one precluded by the absence of an endogenous agonist present at levels sufficient to augment maximally the beneficial effects of GPR109A signaling. In healthy individuals, β-hydroxybutyrate, a principal ketone and physiologic GPR109A agonist, is present in the circulation, but at a relatively low concentration, increasing only slightly during periods of fasting or prolonged exercise. Ketone bodies serve as alternate sources of energy to maintain crucial organs such as the brain, retina, heart, kidney cortex and skeletal muscle when carbohydrates are either in short supply or as is the case in diabetes, cannot be used effectively [43]. Hence, in well-controlled diabetes, significant increases in circulating β-hydroxybutyrate do not occur. Though seemingly protective in moderation, when elevated excessively, as in uncontrolled diabetes, the effects of β-hydroxybutyrate are thought to be largely detrimental (e.g., ketoacidosis). This suggests that despite the presence of both the receptor and the agonist in such conditions, activation of the receptor may not occur at the optimal level and hence the beneficial effects of receptor signaling are lost. It is also plausible, particularly at such high concentrations, that additional, GPR109A-independent mechanisms come in to play. Thus, if receptor activation can be augmented optimally through the use of pharmacological agonists, robust benefits may be reaped in diabetic retina. Support for this line of thought and therefore the therapeutic targeting of GPR109A in diabetic retina can be inferred from the recent report by Poplawski et al. [44] demonstrating pronounced and effective reversal of parameters associated with progression and increased severity of diabetic nephropathy, another major complication of diabetes, through employment of a ketogenic diet, a diet in which β-hydroxybutyrate is the predominant ketone. Additional support can be gathered from a study by Huang et al. [40] in which the authors report niacin-induced improvement of blood flow and peripheral vascular function in a diabetic rodent model of ischemia-reperfusion through mechanisms involving the modification of nitric oxide bioavailability and reduction of oxidative stress, and from clinical and experimental studies of neurodegenerative brain diseases touting the cellular protective effects of β-hydroxybutyrate when employed therapeutically [45].
Inflammation and reactive oxygen species production are normal physiologic processes. Inflammation is essential to cellular defense, repair and turnover and reactive oxygen species are produced normally as a consequence or byproduct of many normal biologic processes. Therefore, cells, including those of the retina, are naturally equipped to deal with these factors, as they must on a regular basis, in order to maintain tissue homeostasis. In pathologic conditions such as diabetes and DR however, the increased production pro-inflammatory and pro-oxidant factors coupled with the decrease in the cellular defense machinery, influences negatively the delicate balance between proinflammatory/ pro-oxidant and anti-inflammatory/antioxidant factors; this has been documented and described on numerous occasions [4,5,46,47]. Therefore, could it be that when elevated in moderation, β-hydroxybutyrate activates GPR109A expressed by neurons, RPE, and other cell types, thereby conferring protection against inflammation, oxidative stress and other types of cellular insult but, in extreme excess (i.e., ketoacidosis) it tips the scale in the opposite direction, favoring increased inflammation, oxidative stress and cellular damage? The likelihood of an affirmative answer to this question is strengthened by the fact that niacin, when taken at lower doses (< 1 g daily) has proven to be quite effective at improving lipid profiles and reducing the risk of atherosclerosis and cardiovascular disease development and progression in a large number of patients; however, when given at very high doses (3.0 – 4.5 g daily), use of the compound, while still effective in the aforementioned parameters, is associated with three major side effects [11]. The first is flushing, an effect that we now know to be due to the unwanted effects of this compound/GPR109A activation in dermal Langerhans and keratinocytes [48]. The second and third, respectively, are a reversible form of cystoid maculopathy (occurs only in 0.67% of patients), and modest hyperglycemia [11,49]. These undesirable effects have fueled the search for lipid-lowering therapies in lieu of niacin. However, of the alternative therapies discovered and employed, the fact remains that none have proven to be as effective as niacin at raising HDL levels and improving additional parameters consistent with reduced risk of advanced cardiovascular disease; for this primary reason, the clinical use of niacin has continually been revisited. Indeed, the recent introduction of immediate-release and extended-release forms of the niacin brings the compound back to the forefront as the incidence and severity of the adverse effects associated with its use has been reduced significantly even when the agent is employed at very high doses while retaining the benefits attributed to the original compound [11]. Of specific interest and relevance to our present topic, the potential employment of GPR109A agonists for therapeutic management of DR, is the fact that the incidence of ocular side effects (niacin maculopathy), which was already relatively low, appears to have diminished even further as evidenced by the few, rare reports that can be found in the published literature over the past decade. The same is true with respect to niacin-induced deterioration of glycemic control in diabetic patients, which is now reported as being only minor with no evidence of increased incidence of new onset diabetes [11,50]. Furthermore, the avoidance or lessening of the flushing response is important, as it may impact positively patient compliance rates. The discovery by Walters et al. [51] that niacin-induced signaling through beta-arrestin 1 is responsible for flushing but not for the anti-lipolytic effects of the compound suggests that relevant compounds that activate GPR109A in a beta-arrestin-independent fashion could be developed. Hence, targeting GPR109A for therapeutic management of DR, whether by the use of niacin, other newly identified pharmacologic ligands like monomethylfumarate [49,52] or alternately, intake of a ketogenic diet to increase the endogenous agonist β-hydroxybutyrate, remains as a feasible and seemingly viable option that should be explored further. The appeal for such is heightened by the fact that it might be accomplished successfully via the re-purposing of existing compounds or strategies that have already garnered FDA-approval for treatment of other indications and therefore much is known regarding the toxicological and pharmacokinetic properties in humans.
The demonstration of GPR109A expression in RPE and its function there in modulating inflammation is a novel and important finding. RPE facilitates numerous functions that are critically essential to retinal health and visual function normally and in diabetes including the regulation of immunity and inflammation in the outer retina via the expression and secretion of a plethora of cytokines and chemokines, maintenance of outer-blood retinal barrier integrity, phagocytosis of shed photoreceptor discs, cholesterol transport/lipid homeostasis, light absorption, amino acid and nutrient transport, etc. [53,54]. However, it is clear that in DR other retinal cell types are largely affected [55]. There are a number of studies suggesting strongly that processes similar to those that promote and/or potentiate atherosclerogenesis occur also in diabetic retina [56,57]. A role for inflammation and oxidative stress in DR has been established. Atop this are clinical studies demonstrating retinal dysfunction and cellular damage in association with lipid accumulation in this tissue [31,32,58] and experimental studies demonstrating the critical causative role of dyslipidemia in endothelial cell dysfunction and vascular inflammation in retina [59]. Could GPR109A in retina be expressed by retinal cell types in addition to RPE, and upon activation therein contribute to the propagation of multiple, unique responses that are, like the demonstrated actions associated with GPR109A expressed in other organs, overwhelmingly beneficial (i.e., improved retinal lipid profiles, reduced inflammation and oxidative stress, protected and preserved retinal cell viability and vascular integrity/function)? Along these lines, our group has initiated additional studies. Using primary rat microglial cells isolated following the method of Roque and Caldwell [60], a generous gift from the laboratory of Dr. Gregory Liou (Georgia Regents University, Augusta, GA), and our rabbit polyclonal GPR109A antibody [41], we evaluated GPR109A expression by Western blotting techniques per our published method [61] (Figure 1). Protein extracted from primary RPE cells that were isolated from normal mouse retinas as described previously [41] was included as a positive control. Microglia are in essence the resident macrophage cells of the retina; their critical involvement in potentiating inflammation and therefore the development and progression of diabetic retinopathy is well documented [62-64]. Our studies have shown that microglia express GPR109A robustly. Though novel, the finding of GPR109A expression in these cells did not come as a surprise given the original description of the receptor protein as PUMA-G (protein-upregulated in macrophages by interferon-γ) and the well established role of these cells in the mediation of inflammatory processes in retina. However, additional studies to ascertain fully the functional significance of GPR109A expression and activation in this retinal cell type normally and in diabetes are needed. Similar studies are also needed with retinal endothelial cells; our preliminary work in this regard leads us to believe that the consequences of GPR109A activation in these cells will be, as described for peripheral vascular endothelial cells, largely anti-inflammatory.
Figure 1: GPR109A expression in rat retinal microglia. Western blot analysis of GPR109A expression in primary retinal microglial cells isolated from rat retina. Protein isolated from primary mouse Retinal Pigment Epithelial Cells (RPE) was included as a positive control for GPR109A expression. β-Actin served as the loading control.
Based on existing clinical and experimental evidence and our own published and preliminary findings, we speculate that GPR109A expression in retina is essential to the normal regulation of multiple parameters, both lipid-dependent and lipid-independent (e.g., inflammation, the metabolism and handling of lipids, nutrient sensing and energy regulation). Hence, therapies to target this receptor in diabetes may be effective in preventing or slowing the development and progression of DR (Figure 2). Additionally, there is the promise that such strategies could be of benefit also in the prevention and treatment of other debilitating retinal diseases in which inflammation, oxidative stress and/or altered lipid regulation are majorly involved such as for example, age-related macular degeneration.
Figure 2: Hypothetical model for therapeutic intervention in diabetic retinopathy via augmentation of GPR109A signaling. Hyperglycemia and dyslipidemia are major features of diabetes and are known to potentiate factors that contribute to the increased oxidative stress and inflammation characteristic of the disease. Of those factors, clinical and experimental studies show upregulated Nuclear Factor-kappa B (NF-kB) and reduced Peroxisome Proliferator-Activated Receptor-Gamma (PPAR-γ) activity to be crucial. Studies conducted using non-retinal cells and tissues show GPR109A to be effective at reversing and/or inhibiting these parameters upon its activation by specific agonists. Additionally, GPR109A may elicit other direct effects congruent with reduced inflammation and oxidative stress. In retina, GPR109A is expressed in cells critical to the regulation of tissue immunity and inflammation (e.g., Retinal Pigment Epithelial (RPE) and microglia) and similarly suppresses inflammation and oxidative stress when activated. Thus, therapies to augment this phenomenon in diabetic retina may prevent or delay the development and progression of retinopathy.


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PAUSE IT: What do you see? What is the difference between a good movie and a bad movie, between a guilty and a genuine pleasure? In David A. Prior's Deadly Prey we might ask ourselves just this. What is taste? What makes low-brow popcorn flicks so fun? For better or for (entertaining) worse, we … Continue reading PAUSE IT: Deadly Prey →
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March 23, 2016
PAUSE IT: What do you see? In the opening shot from from Roger Corman's The Trip (1967) two lovers appear to walk on water in the center of the frame. It is a surreal image to say the least. Immediately, it commands the viewer's attention as we suspend our disbelief. An open shot … Continue reading Pause It: The Trip →
March 16, 2016
Here are some films that feature betrayal so treacherous and intrigue so intriguing that they rival the assassination of Caesar! BLACK CAESAR The brutal assault at the hands of a racist cop will inform the life of Tommy Gibbs (Fred Williamson, Hammer), who will grow up to become the reigning head of Harlem's black … Continue reading Beware the Ides of March! And stay in with a movie instead →
March 15, 2016
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March 10, 2016
PAUSE IT: What do you see? In this scene from director James Lapine's Impromptu (1991), actors Emma Thompson and Anton Rodgers sit up in bed clearly having had a recent marital tiff. At first, the mood between the two characters strikes us as perhaps uncomfortable or even adversarial. Yet, we soon realize that the … Continue reading Pause It: Impromptu →
March 9, 2016
Spring is almost here, and Olive Films is celebrating by announcing a great slate of titles that will be available May 24, 2016. We've got some old favorites on the way just for you, with classic actors like George Sanders, Clark Gable, Eleanor Parker, John Wayne, and Sophia Loren. We'll also be releasing some fun … Continue reading Olive Films Announces May 2016 Titles →
March 8, 2016
Olive Films is proud to highlight 24 outstanding female-directed and feminist films found within our catalogue in celebration of National Women's History Month. Join the discussion as we look at the many contributions women and their stories have made to the art of motion pictures. Despite their often limited exposure and notoriety, women have a long and … Continue reading Olive Films Celebrates Women's History Month →
March 3, 2016
PAUSE IT: What do you see? A Frame within a frame. Formalist director Alain Robbe-Grillet, a leading voice of the Nouveau Roman (new novel) movement of the late 1950s and early 1960s, paints a pretty picture. A painting rests on an easel overlooking a shoreline. But where are we exactly? From the sights … Continue reading Pause It: La belle captive →
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Jack Scott, author of Perking the Pansies – Jack and Liam move to Turkey (shares these guidelines for writing memoir…
Within the last fifteen months, I've been mad enough to create a blog, design my own personal website and write a book. For most of my meandering expedition, I had absolutely no idea what I was doing. A combination of trial and error, intuition, gentle encouragement from an inspirational publisher and not so gentle cajoling from my partner, have turned an unplanned and uncoordinated series of chess moves into the production of a well-received book that I am proud to have created. My probation has been illuminating – about writing, plot content and construction, network building, promotion and engagement. The list is endless. If you're thinking of writing a book about your life as I have done, you may find some of these Pansy tips useful:
1. Just write
Okay, there are some amazingly talented writers out there. Every word, every sentence and every nuance is described with perfection and beauty. There's no way you can compete, right? Wrong. Everyone has their own style, and most people have ability. It's a matter of flexing your writing muscles first before finding that creative Nirvana. Just start writing. It doesn't matter if it's imperfect. You have to begin somewhere. The more you write, the better you'll get.
2. Be yourself, be unique
Each of us has our own back story. In theory, this means that we all have the potential to write something unique and interesting enough to engage readers. Putting that theory into practice is a tricky one. Think carefully about what will make your writing stand out from the crowd. How is your message different? What's distinctive about your angle? Who will your writing appeal to? Writing beautifully about a glorious sunset may well get some admiring comments but won't necessarily help you rise above the ordinary. Are you prepared to reveal the real you?
3. Think about 'form'
This is one of the biggest lessons I learned when turning my blog into a book. A story, even a real-life story, must have order, pace, plot, a compelling blend of highs and lows and a sense of purpose. I created a story-board for my book (much like creating a film script). It changed everything. I instantly saw the gaps and inconsistencies in the storyline, the flabby narrative and superfluous characters. A straight chronological account of your life may not be absorbing enough. Introduce some dramatic tension. Write as if it's fiction (one of [my publisher] Jo's main messages). Get that reader to turn the page.
4. Think visually
Set the scene and describe your characters and situations colourfully. Help your readers visualise your story in their mind's eye. Use dialogue to break up the narrative and keep the speech realistic. Don't over-egg the pudding with dense, old-fashioned diction. You're not writing Pride and Prejudice.
5. Edit, edit, edit and when you're done, edit again
Be bold and decisive. If something adds nothing to the 'plot' or message, cut it. Unless you are absolutely confident about your writing skills, re-examine long, flowery sentences and make sure the reader doesn't get lost in the prose. I made an early decision to keep my book extremely tight and fast-moving. That involved some painful and dramatic pruning.
6. Share your writing
Sharing something you've just written is a brave thing to do. If you're a new writer, as I was, it's the only real way of getting a real feel for how you are doing and how your written style is being perceived by others. You can start gently by asking those close to you for an opinion, though a critique from somebody completely independent is, in my view, more useful. Ask for feedback. Then take a deep breath. Take the comments on board. Some of them will be rubbish but some of them won't. Try not to take things personally and never spit back.
6. Start a blog
Blogging is a great auditioning process for writing, and the best way to experiment and grow your fan-base. There are many blogging platforms out there (WordPress, Google, Wordpad, etc) and most are easy to set up and use – providing a range of professionally designed templates to select from. For a small consideration, these applications will also set up your own domain name linked to your blog. I use WordPress.com linked to my own domain, perkingthepansies.com.
In the crowded blogosphere, content is king and the best content is fresh, new and frequently updated. My blog became popular because I wrote little and often about a small number of specific themes that quickly found an audience. Break up your words with interesting and relevant images. Keep your blog clean and uncluttered. Fussy, multi-coloured scripts and busy designs can hurt the eyes and discourage the reader from continuing.
8. Think about Search Engine Optimisation
Don't be spooked by this. Search engine optimisation (SEO) is just how a page is ranked on search engines and by this I mostly mean Google. If your blog doesn't appear in the first few pages of Google then you might as well not be on the internet at all. There are many companies that claim they will increase your ranking for a fee. Don't waste your money. Follow these few steps and you'll soon by up there with the pros:
- Engage with your blogging peers with comments and guest posts
- Add share buttons to your posts so your readers can spread the word effortlessly
- Create reciprocal links by listing other similar blogs on your blog
- Join blog directories. Most are free and some specialise (women bloggers, expat bloggers, for example).
9. Get Yourself Interviewed
Online interviews are a great way to increase your profile. For instance, many expat sites are always looking for interesting people to interview. It provides them with content and you with exposure.
10. Exploit Social Networks and Forums to Grow Exposure
Join social networks and make friends. Facebook and Twitter are the most popular and influential. Create a Facebook page for your blog (and for your book when your masterpiece is done and dusted). Autopost your blog posts to both Facebook and Twitter so you don't have to add them manually. Again, this really helps with SEO.
If forums exist for your area of interest, join them and participate meaningfully. For example, I have been active on the Turkish Living Forum for some time. It's the grandmother of all Turkish forums with the largest and most active membership. Engage gently and be careful not to over-promote. People will catch you out.
11. Create a Personal website
Your work of genius is written but unless you want to be stuck with a box full of books propping open a door or languishing unloved and unread in the attic, you need to make sure people know about it. Use your blog to get the message out. Plaster the good news everywhere, particularly your social networks. Create a personal website. This isn't the expensive faff it used to be. There are a number of free or inexpensive website platforms available that require very little expert knowledge. I use Weebly for my site. It's a free service that's easy to use with all the widgets you could want.
And finally…
Exhausted? You will be. This book lark takes hard graft. I know. I've never worked so hard.
Visit Jack's blog here and Jack Scott Books.


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You can contribute to any of the Allied Services programs to support services provided to our patients and their families. You have the option to designate a gift to a particular area of importance to you or allow us to select based on need.
Honorary or Memorial Giving
Do you ever have trouble finding just the right gift? Never seem to know what to give to your mother, father, spouse or best friend? Why not consider the commemorative giving program at Allied Services Foundation.
At the same time, your gift will help Allied Services continue providing outstanding pediatric care, advancing medical rehabilitation services, providing residential environments, and expanding a variety of human service programs.
The next time you need a special gift to celebrate a birthday or anniversary, remember a loved one, or to thank Allied for outstanding, compassionate care, make a contribution.
Ryan's Run
You or your company, co-workers, or school can get involved and help support Ryan's Run. For opportunities and to learn more about Ryan's Run, head to the the Ryan's Run microsite, or contact Charlotte Wright, Business & Corporate Development coordinator at email@example.com or by calling 570-348-1275.
Make an Honorary / Memorial Gift Online
You may use your credit card to make honorary / memorial gifts online. Our technology provides a secure transaction to protect your credit card and other personal information. We will send you an electronic confirmation of your gift within 24 hours, and a formal acknowledgement letter will be mailed to you within the week.
To donate online, you will be asked for your credit card information. This information is used solely by Allied Services for processing your contribution. For your protection, all credit card information is processed through our secure website.
To make your donation by traditional mail, please send it to:
Allied Services Foundation
100 Abington Executive Park
Clarks Summit, PA 18411
Who Can Tell Me More?
If you would like more information about giving to Allied Services Foundation, contact us via the following:
Foundation Staff
Jim Brogna, Vice President- Advancement & Communications
Barb Norton, Director of Corporate & Foundation Relations
Peggy Ford, Asst. Director of Development


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Thursday, 23 February 2017
THINK ABOUT IT #22: Christopher Lasch
The university remains a diffuse, shapeless, and permissive institution that has absorbed the major currents of cultural modernism and reduced them to a watery blend, a mind-emptying ideology of cultural revolution, personal fulfillment, and creative alienation… Not only does higher education destroy the students' minds; it incapacitates them emotionally as well, rendering them incapable of confronting experience without benefit of textbooks, grades, and pre-digested points of view. Far from preparing students to live 'authentically,' the higher learning in America leaves them unable to perform the simplest task –– to prepare a meal or go to a party or get into bed with a member of the opposite sex –– without seeking academic instruction. The only thing it leaves to chance is higher learning.
The Culture of Narcissism (1979)
Click HERE to read a 1991 Civic Arts Review interview with US historian and cultural critic CHRISTOPHER LASCH.
You might also enjoy:
THINK ABOUT IT #2: C Wright Mills
THINK ABOUT IT #15: Noam Chomsky
THINK ABOUT IT #19: John Pilger
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Money is not the most important thing in the world, but love is. However, we all love money. Most of the times, the money we earn is never enough. So, we end up looking for side hustles that can help in making extra money. In search of part-time businesses, network marketing will never go unmentioned. In this business module, an independent agent will serve as a distributor of goods and services. You will be encouraged to build your own sales force through recruiting and training other agents. In this business, you will earn commission from your sells and those of your agents. However, many people never make it in this business. Out of ten people, the only one makes it. So, how do people fail in network marketing? Here is how to fail at network marketing.
Lack of commitment
Having invested some money through joining network marketing, you have to understand that the entry fee is just the initial investment. To make more money in network marketing, you have to give more than just money. To fail in network marketing, don't make time to attend to this business. For such a business to grow fully, full attention from the owner is always needed.
Having urge of making money immediately
This is one of the ways many people fail in network marketing. Most people join network marketing with the aim of making money immediately. Setting your brain purely on monetary gains will automatically ad you to failure. In network marketing, you will only succeed after helping others out. A team should be set first before thinking of money.
Lack of excitement
Motivation is one of the keys to success in network marketing. As a network marketer, you have to be always excited about your goals. You need to remember why you joined the business and always motivated your agents to work harder. When lack enthusiasm and excitement to work as a marketer, you will be leading on the failure road.
Failing to write down goals
Failure to write down goals means you will easily forget them. When joining network marketing, you must have a goal. With the various distractions in life, forgetting your goals would be easy. You, therefore, need to have a dream board strategically placed where you can see them daily and remember the goals of marketing.
Distributor not talking to people
Failing to talk to people who are being recruited or targeted to a product is one of the ways to fail in network marketing. Most distributors build facades of business and never engage conversations and contacts. One who talks about recruitment but remains silent when it comes to recruiting will never make it in network marketing.
Talking to wrong people
Most distributors end up wasting huge amounts of time through talking to and recruiting wrong people. The right people are those who are interested and light up the moment you introduce to them about network marketing. If you a hire a person who complains after three days of recruitment, then you will be destined to fail.
Having the salesman syndrome
If you are a network marketer with a salesman syndrome, then you might end up failing. A salesman is up to sell a product and earns some commission before going to the next product. A network marketer who sells and doesn't focus on signing more agents will end up failing. A network marketer should always duplicate himself whereby you have to both sell and recruit more agents. A customer who can buy your product can also be interested in selling them. So, you have to try and bring them on board.
The fact that very few network marketers fail in network marketing should not discourage you at all. Always avoid the above pitfalls, and you will never regret investing in network marketing.
At Network Marketing Labs we are proud to share the most current and up to date news and information about the direct selling & network marketing industry.
Let us be your guide or maybe you have insight we would be interested in learning about. Reach out to us so we may collaborate together. Contact us here.


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Prosper, TX 75078
MLS# 13779338 - Built by Dunhill Homes - Ready Now! ~ Brand new J-swing plan! This beautiful two-story home offers style and functionality! Enjoy the open layout providing a sun-filled family room complete with a cozy fireplace. The luxury kitchen includes a convenient center island, abundant storage space, stainless steel appliances and corner walk in pantry. Tucked away in the back of the home is a spacious master suite with private master bath and huge walk-in closet with access to the utility room making laundry days a breeze! Upstairs youll find an entertaining game room, media room, and additional bedrooms with a Jack and Jill bathroom..
Ben Caballero with Dunhill Homes Realty
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All information provided is deemed reliable but is not guaranteed and should be independently verified. The information on this page may not be reproduced, may not be redistributed, and is provided exclusively for consumers' personal, non-commercial use and may not be used for any purpose other than to identify prospective properties that consumers may be interested in purchasing.


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Wed Aug 02 12:33:54 EAT 2017
BOTTOM LINE: Costs of Hamad, Lipumba's feud go beyond their party
As fate would have it, it seems the chairman of the Civic United Front (CUF), Prof Ibrahim Lipumba, and his secretary general Seif Sharriff Hamad are hell-bent to destroy the party, and destabilise the opposition in general.
As fate would have it, it seems the chairman of the Civic United Front (CUF), Prof Ibrahim Lipumba, and his secretary general Seif Sharriff Hamad are hell-bent to destroy the party, and destabilise the opposition in general. This is because the duo seems to not understand the CUF crisis, and how it's slowly destroying the party. This isn't only a big blow to the party, but also for democracy in our country. By the look of things, the impasse the CUF has been in for a while is but a suicidal attempt for the party and its leadership.
Considering the resources and time the mix-ups between the duo have already consumed, not to mention the relationship gone sour, there is no way all or any of the two can benefit from the ongoing drama without sitting on the roundtable and iron out their differences. The duo has discretion to accept such advice or go on their suttee. However, surely the only winner is the ruling party.
Due to the hegemonic nature of our politics, it seems that the duo has hijacked the party so as to pointlessly leave the members in the cold. This means CUF has never belonged to the members. Instead, it has always been the private estate of the leaders. This is why the members are not heard, nor are their views accommodated in addressing the problems the party has, for long, faced.
Interestingly, history has the tendency of replicating itself. Those who know how James Mapalala, the founder of CUF, was thrown under the bus, don't wonder to see Hamad suffering the same fate. Live by sword. Die by sword.
So, too, those who wrongly thought that Hamad was using Lipumba now know how the duo was but strange bedfellows. Who was using whom? It isn't easy to tell. More importantly, CUF has always seen to incline to one side of the United Republic of Tanzania. Refer to how Hamad entered into the Government of National Unity (GNU) in Visiwani without bothering to do the same in the Mainland. Strikingly, you wonder how one party can win on one side of the Union and lose on the other. This shows where its priorities are.
Demonstrably, the game the duo is playing is very lethal; however, thanks to their personal ambitions, it's much to their own peril. For over a year now, they've been trading insults, bloviating, pontificating, calling each other names and expelling each other in what started as a spat among others. There is no way they can maintain squabbles and meaningfully forge ahead. This is why they are easily played against each other; simply because they are playing in the hands of their enemies. What the duo is doing is like dancing with the devil thinking that there is a way one can get away with it. When two friends do their dirty laundry in public, the shame that comes therefrom affects both equally.
Provided that the fate of the CUF is clear, what can be done to save or salvage it? Firstly, the duo must admit responsibility; and accept that they are part of the problem, but not the solution. Therefore, they should start addressing the problem based on this understanding, instead of the blame game that has been going on for a long time. Knowing and admitting the roles they have played in destabilising the party are key to the resolution of the conflict. In conflict resolution studies, we say that there must be the stage at which the conflict must be allowed so that those ensnared in it can start using different lenses, positive instead of negative ones to view each other based on their needs.
If the first mechanism flops, the members should shun; and thereafter expel the duo so that they can start afresh to either mend fences or tweak their parties.
In sum, Hamad and Lipumba have the solutions to the problems they created. So, too, they have the means to fell the CUF. Destruction is easier than construction. Again, this being obvious, why Hamad and Lipumba are putting their dirty linens on the agora?
Nkwazi Mhango is a Tanzanian writer who is based in Canada


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It has been a few years since we last saw Clementine and The Walking Dead game from Telltale and while in-between we have gotten some amazing games, the hunger for more from The Walking Dead was something that has now been sated.
The story for this new game start off with a missed call to Javier, the new main protagonist, as he fights to rush home, before his father passes away, but he does not make it in time. After being confronted by his older brother, the family soon discovers that the dead don't stay dead and after a brutal moment of taking action, the family makes their way towards the hospital. What makes this even more powerful is that it takes place before the walkers swarm around, people are living their lives, so we get to see what happens to a regular family, as the story moves forward.
Jump ahead several years, Javier, Kate, Mariana and Gabe are travelling down the road in a beat-up van, looking for supplies. While Gabe and Mariana sleep in the back, Javier chats with Kate about the world and the kids, while Kate is their Step Mother, Javier is the Uncle. We don't learn what happened once the family left the house, only that years have passed. Soon after they make their way into a Junkyard to obtain supplies so they can continue their adventure, but not long after they arrive, another group descends upon them, claiming that it their space. Actions are taken and Javier is knocked out and when he comes too, he is in a truck heading to places unknown, but thankfully after some luck, a tree falls upon the road and that is where Javier meets up with Clementine.
From here, your actions will really define the story, but what I found interesting about this is while every choice you made in the first two games, does impact here, Clementine, at least for now, is more of a background character, with Javier and newcomers like Tripp and Paul providing new interaction opportunities. The new town of Prescott has some interesting characters, like Tripp, but it's the New Frontier that prove to be the most engaging, more so once the second episode ends, providing a mystery that players will likely want to discover. That mystery though is pretty much the only one, the other surprises that happen, I was able to predict with little effort, which is a shame. Of course, making different choices could lead to different outcomes, so going back and playing it again is something I am excited to do.
The problem with the rest of the game however is that most of it is still hands off, with only minimal control input required and with long sections where you don't need to do anything, there are times when it feels like you can relax, only for the game to require an action, with no warning. When you are actually able to walk around the world, talking with people, inspecting things and such, the game seems content to deal with tank style controls, something that Resident Evil created back in the 90's, Javier moves around in odd angles, up does not always mean up, but across, depending on the camera angle. Even when you are just exploring a section of the world, Javier moves slow and even holding down the fast walk option, sees almost no increase to the movement speed and given that Telltale have had years to perfect their formula, this is a let down.
The game still also tries to tell you that your options will craft the story, but that is still only on options that you are presented with. There is one section where you meet an unknown man and the game gives you two options, trust him or tie him up, I personally would have liked to have just left him behind and moved on, but the game does not give you that option. While I know it's not possible to account for every single possible choice someone might want to make, with a choice that like one, the game tells you that you need to take this person with you, which removes that your choices define the game mantra that they tell you at the start.
Thankfully, one area that the game does do better than those in the past is that it looks better, they have clearly used the years to work on their engine and it shows. The game still sports its cel shaded look, but rather than being hard lines and clipping items, shadows and such will now play off the characters' action, which in turn moves those lines around. A bad description I know, but when you see it in motion, the game just looks great, in addition they have overhauled their lighting engine, so the various times of day are represented better than ever before, with night now having this extra level of tension added.
The voice work is almost amazing across the board, sadly one character does annoy me to no end and it's not one element that annoys me, it's just the overall vibe that they give off. Javier is grounded, even when things to crap, there is this feeling that he knows that things can get worse and in a zombie world, that is saying something. Kate, David, Tripp and the rest all offer great balance, from some of the more whiny voices and characters, helping to keep the game from entering the campy nature that zombie content can easily go towards. Music is nice and simple, the themes from earlier come back through at times, helping to connect you through to the new characters and their themes.
The Walking Dead A New Frontier is bringing back the series with some strong new characters, the lacklustre gameplay in this video game, still holds it down. Given that this is the third entry in the series, a lot of your mileage will come from having played the first two seasons, so be aware of that going in.
Thanks to Telltale Games for supplying the game for review


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Enjoy a refreshing and rewarding experience at The Inn at Penn, A Hilton Hotel in University City. In a premier location for hotels in Philadelphia, PA, this AAA Four Diamond hotel is situated on the University of Pennsylvania campus. Stay at this hotel and be near medical and business districts, many restaurants and attractions, and just 20 minutes from Philadelphia International Airport (PHL).
Guests at this hotel can walk to the 30th St Amtrak Station, the city center and the best shops and cultural and entertainment venues in Philadelphia. Visit the
Liberty Bell Center. View masterpieces at the Philadelphia Museum of Art or
shop at the King of Prussia mall and enjoy tax-free purchases. Use the iPad and
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Dine at the award-winning Penne Restaurant and Wine Bar, serving authentic Italian cuisine and homemade pasta. Maintain your exercise routine in the fully
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