text:
Valentin A. Pavlov
Northwell Health, United States
P Trayhurn
University of Liverpool, United Kingdom
Jose R. González-Juanatey
Hospital Clínico Universitario de Santiago, Spain
Original Research ARTICLE
Front. Immunol., 19 September 2019 | https://doi.org/10.3389/fimmu.2019.02163
Adipocytes Directly Affect Coronary Artery Disease Pathogenesis via Induction of Adipokine and Cytokine Imbalances
Olga Gruzdeva1,2, Evgenya Uchasova1*, Yulia Dyleva1, Daria Borodkina3, Olga Akbasheva4, Larisa Antonova1, Vera Matveeva1, Ekaterina Belik1, Sergei Ivanov1, Anton Sotnikov1, Kirill Kozyrin1, Natalia Brel1, Maxim Sinitsky1, Victoria Karetnikova1,2, Alexander Kokov1, Evgenya Bychkova2, Tamara Pecherina1 and Olga Barbarash1,2
1Federal State Budgetary Institution, Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo, Russia
2Federal State Budget Educational Institution of Higher Education, Kemerovo State Medical University of the Ministry of Healthcare of the Russian Federation, Kemerovo, Russia
3Regional Center for Diabetes, Autonomous Public Healthcare Institution of the Kemrovo Region, Kemerovo Regional Clinical Hospital Named After S.V. Beliyaev, Kemerovo, Russia
4Federal State Budget Educational Institution of Higher Education, Siberian State Medical University of the Ministry of Healthcare of the Russian Federation, Tomsk, Russia
This study aimed to investigate the adipokine and cytokine profiles of adipocytes from epicardial and subcutaneous adipose tissues in interconnection with the visceral adipose tissue area and the biochemical and clinical characteristics of patients with coronary artery disease. We assessed 84 patients with coronary artery disease (65 men, 19 women) and divided them into two groups based on the presence of visceral obesity. We sampled epicardial and subcutaneous adipose tissues from the patients with visceral obesity. We then cultured the adipocytes and evaluated their adipokine profiles and pro-inflammatory activity. Results show that the mRNA expression of adiponectin in cultures of epicardial adipocytes from patients with and without visceral obesity was lower than that in subcutaneous adipocytes. Moreover, adiponectin mRNA expression in cultures of subcutaneous and epicardial adipocytes from patients with visceral obesity was lower than that in patients without obesity. For leptin, the reverse pattern was observed, with expression higher in cultures of epicardial adipocytes than in subcutaneous adipocytes and higher in epicardial adipocytes from patients with visceral obesity than in those from subjects without visceral obesity. In addition, in epicardial adipocytes, increased expression of proinflammatory cytokine genes (IL6, TNF) was observed compared with that in subcutaneous adipocytes. In contrast, expression of IL10 was higher in cultures of subcutaneous adipocytes than in epicardial adipocytes. The epicardial adipose tissue area was associated with the presence of higher levels of leptin and TNF-α within adipocytes and serum, increased lipid and carbohydrate metabolism. Coronary artery disease, in the context of the status of epicardial adipocytes, can be characterized as "metabolic inflammation," suggesting the direct involvement of adipocytes in pathogenesis through the development of adipokine imbalances and activation of proinflammatory processes.
Cardiovascular disease (CVD) is the leading cause of disability and mortality worldwide (1). In 2013, more than 17.3 million people died from CVD, an increase of 40.8% from 1990 (2). This increase was driven by a change in the number of deaths attributed to the aging population and the negative impact of cardiovascular risk factors, including obesity (3). Total body fat comprises accumulated fat in both the subcutaneous and visceral depots (4). Visceral adipose tissue (VAT) surrounds the internal organs and is associated with cardiometabolic risk factors, regardless of the total fat mass (5, 6).
Previous publications have highlighted associations between ectopic fat deposits and cardiometabolic risks for and clinical manifestations of CVD (7). Epicardial adipose tissue (EAT) is visceral fat deposited around the heart, particularly around epicardial coronary vessels. Because of its proximity to the myocardium and the absence of fascia, epicardial fat may directly affect the coronary arteries and myocardium (8). Several studies have shown that excessive amounts of EAT are accompanied by a reduction in adiponectin synthesis, myocardial hypertrophy, fibrosis, and the apoptosis of cardiomyocytes, leading to ventricular arrhythmias (9). However, epicardial adipocytes under physiological conditions have specific cardioprotective functions that include absorbing excess free fatty acids (FFAs), acting as a source of energy during ischaemia, and synthesizing adiponectin and adrenomedullin, both of which have cardioprotective effects (10). In addition, there is evidence of differences in the expression of the adipokine, leptin, and cytokine genes at the mRNA level in epicardial and subcutaneous adipose tissue (SAT) (11–13).
The present study aimed to investigate the adipokine and cytokine profiles of adipocytes from the EAT and SAT and in the serum, as well as to determine their relationships with the visceral fat area and the biochemical and clinical parameters of patients with coronary artery disease (CAD).
The study protocol was approved by the Local Ethics Committee of the Federal State Budgetary Institution Research Institute for Complex Issues of Cardiovascular Diseases and was developed in accordance with the WMA Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects, 2000 edition, and the GCP Principles in the Russian Federation approved by the Russian Ministry of Health (2003). All patients provided written informed consent.
Study Subjects
Eighty-four patients with CAD, including 65 men and 19 women with a mean age of 61.9 years (range: 53.7–68.5 years) were included in the study (all women were postmenopausal), who underwent coronary artery bypass grafting. Diagnosis of CAD was achieved according to the criteria of the All-Russian Scientific Society of Cardiology (2007) and the European Cardiology Society (2013). Blood samples were taken from patients with and without VO for assessment of serum levels of adipokines, cytokines, and regulators of lipid and carbohydrate metabolism. All patients were administered standard antianginal and antiplatelet therapies.
The control group comprised 30 male patients who did not have CVD and whose mean age was 58.42 years (range: 52.2–71.1 years). The ages of the patients in the control group were comparable with those in the study group (p = 0.64).
Imaging Assessments
Multi-spiral computed tomography (MSCT) was performed on a Siemens Somatom 64 computed tomography scanner (Siemens Healthcare, Erlangen, Germany) for measurement of the visceral fat area and subcutaneous fat area to confirm the presence of visceral obesity (VO). A visceral fat area >130 cm2 and a VAT-to-SAT ratio at the level of the umbilicus of ≥0.4 were used as diagnostic cut-off values for VO (14) (Figure 1). Of the 84 patients, 54 had VO.
Figure 1. Diagnosis of visceral obesity via multi-spiral computed tomography. (A) Patient with obesity, (B) patient without obesity.
Determination of the thickness of EAT was performed by magnetic resonance imaging (MRI) on an Exelart Atlas 1.5-T MR imager (Toshiba, Tokyo, Japan). Measurements were carried out on images oriented along the short axis of the heart. EAT thickness was measured at three points along the anterior wall of the right ventricle, and the average value was then calculated (Figure 2).
Figure 2. Quantitative assessment of the thickness of epicardial adipose tissue along the anterior wall of the right ventricle, as well as the thickness of the epicardial adipose tissue (orange contour) along the posterior wall of the left ventricle via magnetic resonance imaging. (A) Patient without obesity, (B) patient with obesity.
The body weight in kilograms, height in meters, waist circumference (WC) in centimeters, and hip circumference (HC) in centimeters were measured in each subject, and the waist-to-hip ratio (WHR) and body mass index (BMI) in kilograms per square meter were calculated.
Adipocyte Extraction and Culture
From each patient, 3–5 g of SAT and EAT biopsies were collected during coronary artery bypass surgery for isolation of adipocytes from freshly harvested tissues. EAT samples were obtained from fat depots located mainly around the right heart chambers, and SAT samples were obtained from the subcutaneous tissue in the region of the inferior mediastinum. The adipose tissue samples were placed in Hanks' Balanced Salt Solution (Merck KGaA, St. Louis, MO, USA) containing penicillin (100 U/L), streptomycin (100 mg/mL), and gentamicin (50 μg/mL). Adipocytes were isolated from adipose tissues under sterile conditions in a laminar flow hood (BOV-001-AMS MZMO, Millerovo, Russia) using the protocol developed by Carswell et al. (15). Adipose tissue samples (1–2 mm3) were incubated in a collagenase solution (0.5 mg/mL) (Thermo Fisher Scientific, Waltham, MA, USA) containing 200 nM adenosine (Merck KGaA) in a water bath at 37°C for 30 min. Then, the adipocytes were poured through a Falcon™ 100-μm sterile mesh (Thermo Fisher Scientific) and washed with Gibco® M199 culture medium (Thermo Fisher Scientific) containing 1% 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid buffer (Thermo Fisher Scientific), 1% l-glutamine with penicillin and streptomycin (Thermo Fisher Scientific), 0.4% amphotericin B (Thermo Fisher Scientific), and glucose at a final concentration of 5 mmol/L, supplemented with 10% fetal bovine serum (Thermo Fisher Scientific). The volume of the liquid containing the cells was adjusted to 5 mL, and the cells were centrifuged for 2 min at 200 × g. Isolated adipocytes were placed in a separate tube, and the volume was adjusted to 1 mL with culture medium. Adipocytes were counted in a Goryaev's chamber, and cell viability was evaluated as described previously (16). Adipocytes (20 × 105) were seeded into a 24-well-plate (Greiner Bio One International GmbH, Kremsmünster, Austria), and the volume in each well was adjusted to 1 mL with culture medium. Incubated for 24 h at a temperature of (37 ± 1) °C in an atmosphere of 5% CO2 and 10% oxygen. After 24 h, adipokine and cytokine profiles were analyzed.
RNA Extraction
Before RNA extraction, all work surfaces and laboratory equipment were treated with RNaseZap™ RNase Decontamination Solution (Invitrogen, Carlsbad, CA, USA). Total RNA purification from isolated adipocytes was performed using the commercial RNeasy® Plus Universal Mini Kit (Qiagen, Hilden, Germany) according to the manufacturer's protocol with some modifications described previously (17). Briefly, not more than 5 × 105 cells were washed with phosphate-buffered saline (PBS) and homogenized with 750 μL of QIAzol™ Lysis Reagent (Qiagen). Homogenate was centrifuged at 12,000 × g for 10 min at 4°C. The upper fat monolayer was completely discarded and 75 μL of gDNA Eliminator Solution (Qiagen) and 150 μL of chloroform were added to each tube; the samples were then centrifuged at 12,000 × g for 30 min at 4°C. The clean upper aqueous phase was transferred into new tube, admixed with 1.5 volumes of 95% ethanol, and processed for binding, washing, and elution of total RNA according to the protocol. Extracted RNA was stored at −70°C.
The quantity and quality of purified RNA were assessed using a NanoDrop 2000 Spectrophotometer (Thermo Fisher Scientific) by measuring the light absorbance at 280 nm, 260 nm, and 230 nm and calculating the 260/280 (A260/280) and 260/230 (A260/230) ratios. The integrity of the RNA was determined by electrophoresis in agarose gel, followed by visualization using the Gel Doc™ XR+ System (Bio-Rad, Hercules, CA, USA).
Single-stranded cDNA was synthesized using the High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems, Foster City, CA, USA) on a Veriti™ 96-Well Thermal Cycler (Applied Biosystems). Each 20-μL reverse transcription mix contained 2 μL of RT buffer, 0.8 μL of 100 nM dNTP mix, 2 μL of random primers, 1 μL of reverse transcriptase, 1 μL of RNase inhibitor, 3.2 μL of nuclease-free water, and 10 μL of RNA template (50 ng of RNA + nuclease-free water). Reverse transcription was performed using the program suggested by the kit's manufacturer.
The quantity and quality of synthesized cDNA were assessed using a NanoDrop 2000 Spectrophotometer. Samples were stored at −20°C.
Expression of the adiponectin, leptin and cytokines IL6, TNF, IL10 genes was evaluated by quantitative real-time polymerase chain reaction (qPCR) using TaqMan™ Gene Expression Assays (Applied Biosystems) on a ViiA 7 Real-Time PCR System (Applied Biosystems). Each 20-μL reaction mix contained 10 μL of TaqMan™ Gene Expression Master Mix (Applied Biosystems), 1 μL of TaqMan™ Gene Expression Assay (Applied Biosystems), and 9 μL of cDNA template (100 ng of cDNA + nuclease-free water) and was amplified under the following thermal cycling conditions: 2 min at 50°C, 10 min at 95°C, and 40 cycles of 15 s at 95°C and 1 min at 60°C. As a negative control, we used 20 μL of reaction mix with no cDNA template. For each sample and negative control, three technical replicates were prepared.
Normalization of the PCR results was carried out using three reference genes, ACTB, GAPDH, and HPRT1, in accordance with currently accepted recommendations (18). To assess the effectiveness of PCR, amplification graphs and standard curves were analyzed using QuantStudio™ Real-Time PCR Software v.1.3 (Applied Biosystems). The expression of the studied genes (normalized quantification ratio, NRQ) was calculated by the Pfaffl method and is represented on a logarithmic (log10) scale as the fold change compared to that in control samples. Gene expression experiments were performed in accordance with MIQE Guidelines (19, 20).
Laboratory Assays
Levels of leptin and adiponectin in the culture medium from EAT and SAT adipocytes and in serum samples were measured using commercially available enzyme immunoassay kits (R&D Systems, Minneapolis, MN, USA) according to manufacturer's instructions. Each sample was tested twice, and intra-assay coefficients of variation (CVs) averaged 5.8%, with all standard curve correlation coefficients >0.998. The levels of interleukin (IL)-6, IL-10, and tumor necrosis factor-α (TNF-α) in the culture medium from EAT and SAT adipocytes and in serum samples were measured using commercially available enzyme-linked immunosorbent assays (ELISAs) (Bender MedSystems GmbH, Vienna, Austria) (CV: 7.03–8.99%).
Serum total cholesterol (TC), triglyceride (TG), very low-density lipoprotein cholesterol (VLDL-C), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein (Apo)-A1, Apo-B, FFA, glucose, and glycated hemoglobin (HbA1c) levels were measured using enzymatic methods with end points on an automatic biochemical analyser (Konelab 30i; Thermo Fisher Scientific). Serum insulin and C-reactive peptide levels were measured using commercially available ELISA kits (Monobind, Lake Forest, CA, USA). Insulin sensitivity was evaluated based on insulin and fasting glucose levels using the homeostasis model assessment (HOMA) index, as follows: insulin level × glucose level/22.5. Insulin resistance (IR) was diagnosed when the HOMA-IR index was >2.77 (21).
Statistical analysis was performed using GraphPad Prism 6 (GraphPad Software, La Jolla, CA, USA) and Statistica software, version 6.1 (Dell Software, Inc., Round Rock, TX, USA). The Mann–Whitney U-test was used to compare non-normally distributed independent variables. Spearman's rank correlation coefficients were calculated to identify dependencies between variables. The data are presented as medians and 25th and 75th quartiles. Differences with values of p < 0.05 were considered statistically significant.
Anthropometric and Clinical Data
Demographic and clinical data of the study patients are shown in Table 1. Patients were divided into two groups based on presence of VO: the first group included 54 patients with VO, and the second group included 30 without VO (Table 2). Patients in the two groups were comparable in age, presence of risk factors for CVD (i.e., hypertension, smoking, dyslipoproteinaemia, angina pectoris, and congestive heart failure), and myocardial infarction based on clinical history.
Table 1. Clinical and anamnestic characteristics of the study patients.
Table 2. Baseline clinical characteristics of the study patients, based on the presence of visceral obesity.
Adipokine and Cytokine Expression Levels in the SAT and EAT
The mRNA expression levels of adiponectin, leptin, and cytokines IL6, TNF, IL10 were assessed in adipocyte cultures isolated from EAT and SAT. Expression of adiponectin in cultures of epicardial adipocytes from both patients with VO (p = 0.001) and without VO (p = 0.002) was lower than that in SAT adipocytes (Figure 3).
Figure 3. Expression of adipokine genes in adipocytes from the subcutaneous and epicardial fat depots. The data presented are the medians and the 25th and 75th quartiles. p < 0.05 for comparisons between the study groups.
At the same time, adiponectin mRNA expression in cultures of subcutaneous (p = 0.007) and epicardial (p = 0.002) adipocytes from patients with VO was lower than that in cultures from patients without obesity. For leptin, the reverse pattern was observed: expression was higher in cultures of epicardial adipocytes (p = 0.002, p = 0.009) than in those of subcutaneous adipocytes, and patients with VO (p = 0.002) exhibited higher expression of leptin mRNA in EAT adipocytes than in those without VO (p = 0.0001). In addition, in EAT adipocytes, increased expression of proinflammatory cytokines IL6 and TNF was observed compared with that in SAT adipocytes (Figure 4). Moreover, expression in patients with VO was significantly higher than that in patients without VO, in both SAT and EAT cultures. In contrast, levels of IL10 expression in SAT cultures were higher than those in EAT adipocytes. Between the two study groups, patients with VO were characterized by reduced expression of IL10 (Figure 4).
Figure 4. Expression of cytokine genes in adipocytes from the subcutaneous and epicardial fat depots. The data presented are the medians and the 25th and 75th quartiles. p < 0.05 for comparisons between the study groups.
The concentrations of adipokines and cytokines in the cultures of EAT and SAT adipocytes from patients with CAD are presented in Table 3. The leptin content was not significantly different between the cultures of epicardial and subcutaneous adipocytes. However, levels of leptin in patients with VO were significantly higher than those in patients without VO. Unlike leptin, levels of the protective molecule adiponectin were lower in EAT adipocytes than in SAT adipocytes, both in patients with VO (15% reduction) and without VO (21% reduction). At the same time, in patients without VO, levels of adiponectin in the culture media were significantly higher than those in patients with VO.
Table 3. Adipokine and cytokine levels in the adipocytes culture medium.
Levels of proinflammatory cytokines TNF and IL6 were significantly higher in EAT adipocytes than in SAT adipocytes, whereas concentrations of the protective cytokine IL10 were lower in EAT than in SAT cultures, among both patients with VO (25% reduction) and without VO (30% reduction). Moreover, higher levels of proinflammatory cytokines and lower levels of the anti-inflammatory IL10 were noted in patients with VO compared to levels in patients without VO.
Serum Adipokine and Cytokine Levels
Analysis of the sera from CAD patients with VO (Table 4) showed that serum adiponectin levels in patients with VO were 27.6% lower than those in patients without VO. Additionally, a 1.67-fold increase in leptin levels was observed in patients with VO compared to levels in CAD patients without VO.
Table 4. Adipokine and cytokine levels in the serum of patients with cardiovascular disease with and without visceral obesity.
Serum TNF-α levels were 1.5-fold higher in patients with VO than in those without VO. Levels of IL-6 also increased 2.9 and 2 times in patients with VO and without VO, respectively, indicating higher levels in patients with VO than in those without VO. IL-10 levels were 2-fold lower in patients with VO than in patients without VO. Positive correlations between levels of leptin, TNF-α, and IL-10 in adipocytes and those in sera were evident, with correlation coefficients of 0.43 (p = 0.04), 0.53 (p = 0.02), and 0.50 (p = 0.04), respectively.
Factors Associated With Lipid and Carbohydrate Metabolism
Compared with patients without VO, serum levels of atherogenic factors associated with lipid metabolism, namely, LDL-C, VLDL-C, Apo-B, TGs, and Apo-B/Apo-Al, increased significantly in patients with VO, whereas antiatherogenic fractions, namely, HDL-C and Apo-A1, were lower in patients with VO. Changes in carbohydrate metabolism were more pronounced in CAD patients with VO compared to those in patients without VO. IR was present in CAD patients with VO, who showed a 1.5-fold increase in the HOMA index compared with that in patients without VO. Hyperinsulinaemia was often present in patients with VO, and their C-reactive peptide levels were elevated compared with those in patients without VO. The two groups did not differ significantly with respect to glucose or HbA1c levels (p > 0.05).
Correlations Between Adipose Tissue Area and Adipokine and Cytokine Levels
Some of the patients with VO had normal BMIs. Likewise, some of the patients with high BMIs and class II or III obesity did not have VO. In contrast to the SAT area, the EAT area was positively associated with higher levels of leptin and TNF-α in the adipocytes and serum, along with higher levels of factors associated with lipid and carbohydrate metabolism (Table 5). In contrast, serum adiponectin levels were associated with the SAT area (r = 0.47, p = 0.03).
Table 5. Correlations between the level of adipokines and cytokines in serum, in the adipocytes culture medium and the area of visceral adipose tissue.
Obesity is a leading risk factor associated with CVD, and VO is the factor with the strongest influence on the development of CVD. Cardiovascular risk increases by 2.75-fold for patients who present with VO and whose body weights are normal, and the risk of all-cause mortality increases by 2.08-fold compared with patients who do not have VO (22–26).
VAT is an active endocrine organ that releases adipokines, regulators of lipid and carbohydrate metabolism, and cytokines; hence, it can potentially contribute to atherogenesis. Moreover, VAT has unique metabolic functions. Compared with adipocytes from other fat depots, VAT adipocytes exhibit increases in β3-adrenoreceptor expression and function and a decrease in the number of insulin receptors, leading to an increase in lipid metabolism. Accumulations of FFAs and ceramide non-oxidized metabolites can stimulate the development of lipotoxic disorders, resulting in IR, dyslipidaemia, cardiomyopathy, and higher blood pressure (22). Within the VAT, the EAT may be of particular importance. EAT is a unique fat depot, the thickness, and metabolic activity of which correlate directly with the VAT area (27). The thickness of the EAT correlates directly with the severity of CAD in patients and with the thickness of the left ventricular myocardium (28).
VO is adversely associated with the development of cardiac pathology. We hypothesized that the adipokines and cytokines synthesized by EAT adipocytes from patients with VO and released into the blood were cardiovascular risk factors; hence, this study's primary focus was to investigate adipokine and cytokine profiles in adipocytes and in serum samples from CAD patients with VO. We found that EAT adipocytes had elevated leptin levels and reduced adiponectin levels compared with those in SAT adipocytes. The elevated leptin levels in the EAT and SAT adipocytes correlated directly with elevated concentrations in the serum.
In contrast to the present study, in the literature, there are several lines of evidence for the absence of a correlation between EAT-secreted cytokines and circulating cytokine levels. Early on, this contradiction was reported only for adiponectin; expression of adiponectin in EAT may or may not correlate with plasma concentrations, which are presumably derived from the SAT and most often decrease in obesity (29). Thus, we found that the expression of the adiponectin gene in cultures of epicardial adipocytes in both patients with and without VO was lower than that in subcutaneous adipocytes. This contradiction can be attributed to the nature of correlation analysis: a correlation between two variables may indicate the existence of a common cause, rather than a direct interaction between the two. After a chronic positive energy balance, the adipocytes in the VAT induce FFA uptake and accumulation. Expansion of VAT triggers the expression of proinflammatory adipokines, oxidative stress, and activation of the renin-angiotensin-aldosterone system. Hypertrophic but not hyperplastic adipocytes are associated with IR (30). Thus, the VAT becomes dysfunctional, dysregulating adipocyte apoptosis and increasing autophagy (30). Nevertheless, the accumulation of fat may saturate VAT capacity. The resultant failure of VAT to store triacylglycerides could result in ectopic deposition of toxic fatty acids species (i.e., diacylglycerol, ceramide) in additional adipose tissue such as the myocardium, leading to an increase in EAT thickness (31). Importantly, the amount of VAT correlates with the volume of the EAT, and thus, significant weight loss in obese patients has been associated with noteworthy reductions in EAT volume (32–34). In obesity, many changes occur, as EAT volumes substantially increase. These changes are often characterized by hypertrophy, failure to store triglycerides, increased lipolysis, and inflammation (35). Dysfunctional adipocytes express high levels of proinflammatory factors (i.e., IFN-γ) that enhance the proinflammatory response of infiltrated immune cells, such as dendritic cells, macrophages, T and B cells, and eosinophils (36). As EAT expands, it becomes hypoxic and dysfunctional (37) and is invaded by an increasing number of macrophages and T lymphocytes, resulting in a shift in its metabolic profile. The result is increased secretion of proinflammatory cytokines such as TNF-α, IL-6, and others that contribute to the inflammatory environment characteristic of atherogenesis (38). Consistent with this, in our study, increased expression of proinflammatory cytokines and decreased expression of an anti-inflammatory cytokine were observed in EAT adipocytes compared with levels in SAT adipocytes. All patients were found to have dyslipidaemia; however, in subjects with VO, levels of TGs, and FFAs were significantly higher than those in subjects without VO. It is possible that TGs act as a pathogenic trigger of adiposopathy in VAT and EAT.
Given the ability of proinflammatory cytokines to modulate the synthesis and secretion of adipokines, activation of inflammation may increase leptin levels and inhibit the protective effects of adiponectin in EAT adipocytes. The activation of inflammation in SAT adipocytes is associated with high levels of IL-10, and elevated leptin levels are accompanied by high adiponectin levels. Thus, analysis of the adipokine and cytokine profiles in this study suggested differences between EAT and SAT adipocytes.
Changes in the levels of leptin, adiponectin, TNF-α, IL-6, and IL-10 in the serum and in EAT adipocytes appeared to show similar patterns; hence, increases in levels of pathogenic factors and reductions in levels of protective factors were observed.
Importantly, the imbalance between disease-promoting and protective adipokines and cytokines in patients with VO was accompanied by more pronounced impairments in lipid and carbohydrate metabolism compared with those observed in patients without VO. Patients with VO showed more pronounced changes in adipokine and cytokine profiles of the serum and adipose tissue. However, changes in metabolism are not dependent on the thickness of the subcutaneous fat layer. The local and systemic imbalances of the adipokine and cytokine profiles in the patients with VO were accompanied by multivessel CAD with stenotic lesions that narrowed the vessels by 30–50%, angina pectoris functional class 2 or 3, increases in atherogenic fractions of serum lipids, and the development of IR. Adipokines and cytokines are apparently released directly into the coronary blood flow owing to the anatomical proximity of the EAT to the coronary arteries, which may have adverse consequences. Administration of TNF-α intra-arterially is accompanied by endothelium-dependent vasodilation and the initiation of inflammation in the vascular wall (39–42). The proatherogenic effects of TNF-α also include the promotion of leucocyte migration to the endothelium, increases in the synthesis of adhesion molecules and chemoattractants, and enhanced vascular permeability (38, 41). Based on the cytokine profiles observed in adipocytes, we conclude that the activation of inflammation in EAT adipocytes in patients with VO may be extremely important in CAD, with increases in TNF-α, IL-1, and IL-6 levels accompanied by decreases in IL-10 levels.
EAT adipocytes in CAD patients with VO may characterize "metabolic inflammation," indicating that adipocytes are directly involved in the pathogenesis of CAD through development of an adipokine imbalance and activation of proinflammatory processes (43).
The datasets analyzed in this manuscript are not publicly available. Requests to access the datasets should be directed to o_gruzdeva@mail.ru.
The Ethics Committee of the Federal State Budgetary Institution, Research Institute for Complex Issues of Cardiovascular Diseases approved this study (Protocol No. 22 from 15.08.2017). All patients provided informed consent.
OG was principal investigator, study co-ordinator and investigator, participated in all stages of recruitment of the patients and in analysis of the data, drafted, and critically reviewed the manuscript. OA and VK were study co-ordinator and investigator, participated in all stages of recruitment of the patients and in analysis of the data, drafted, and critically reviewed the manuscript. EU, AK, TP, EBe, LA, VM, and YD were study investigator, participated in all stages of recruitment of patients and critically reviewed the manuscript. SI, AS, and KK obtained bioptaps of adipose tissue of various localization during coronary bypass surgery. OB was principal investigator. EBy was study investigator, participated in all stages of recruitment of patients and collected the data. All other study investigators conducted the study and collected the data. All authors read and approved the final manuscript.
The work was supported by the Russian Science Foundation [grant number: 17-75-20026].
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20. Bustin SA, Benes V, Garson JA, Hellemans J, Huggett J, Kubista M, et al. The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem. (2009) 55:611–22. doi: 10.1373/clinchem.2008.112797
21. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. (1985) 28:412–9. doi: 10.1007/BF00280883
22. Mahabadi AA, Massaro JM, Rosito GA, Levy D, Murabito JM, Wolf PA, et al. Association of pericardial fat, intrathoracic fat, and visceral abdominal fat with cardiovascular disease burden: the Framingham Heart Study. Eur Heart J. (2009) 30:850–6. doi: 10.1093/eurheartj/ehn573
23. Gruzdeva O, Uchasova E, Dyleva Y, Borodkina D, Akbasheva O, Belik E, et al. Relationships between epicardial adipose tissue thickness and adipo fibrokine indicator profiles post myocardial infarction. Cardiovasc Diabetol. (2018) 17:40. doi: 10.1186/s12933-018-0679-y
24. Björntorp P. Metabolic implications of body fat distribution. Diabetes Care. (1991) 14:1132–43. doi: 10.2337/diacare.14.12.1132
25. Jeong JW, Jeong MH, Yun KH, Oh SK, Park EM, Kim YK, et al. Echocardiographic epicardial fat thickness and coronary artery disease. Circ J. (2007) 71:536–9. doi: 10.1253/circj.71.536
26. Cheng KH, Chu CS, Lee KT, Lin TH, Hsieh CC, Chiu CC, et al. Adipocytokines and proinflammatory mediators from abdominal and epicardial adipose tissue in patients with coronary artery disease. Int J Obes. (2008) 32:268–74. doi: 10.1038/sj.ijo.0803726
27. Könner AC, Brüning JC. Selective insulin and leptin resistance in metabolic disorders. Cell Metab. (2012) 16:144–52. doi: 10.1016/j.cmet.2012.07.004
28. Donoso MA, Muñoz-Calvo MT, Barrios V, Martínez G, Hawkins F, Argente J. Increased leptin/adiponectin ratio and free leptin index are markers of insulin resistance in obese girls during pubertal development. Horm Res Paediatr. (2013) 80:363–70. doi: 10.1159/000356046
29. Margaritis M, Antonopoulos AS, Digby J, Lee R, Reilly S, Coutinho P, et al. Interactions between vascular wall and perivascular adipose tissue reveal novel roles for adiponectin in the regulation of endothelial nitric oxide synthase function in human vessels. Circulation. (2013) 127:2209–21. doi: 10.1161/CIRCULATIONAHA.112.001133
30. Tchernof A, Després JP. Pathophysiology of human visceral obesity: an update. Physiol Rev. (2013) 93:359–404. doi: 10.1152/physrev.00033.2011
31. Fitzgibbons TP, Czech MP. Epicardial and perivascular adipose tissues and their influence on cardiovascular disease: basic mechanisms and clinical associations. J Am Heart Assoc. (2014) 3:e000582. doi: 10.1161/JAHA.113.000582
32. Iacobellis G, Singh N, Wharton S, Sharma AM. Substantial changes in epicardial fat thickness after weight loss in severely obese subjects. Obesity. (2008) 16:1693–97. doi: 10.1038/oby.2008.251
33. Fernández-Trasancos Á, Guerola-Segura R, Paradela-Dobarro B, Álvarez E, García-Acuña JM, et al. Glucose and inflammatory cells decrease adiponectin in epicardial adipose tissue cells: paracrine consequences on vascular endothelium. J Cell Physiol. (2016) 231:1015–23. doi: 10.1002/jcp.25189
34. Harada K, Amano T, Kataoka T, Takeshita M, Harada K, Kunimura A, et al. Impact of abdominal and epicardial fat on the association between plasma adipocytokine levels and coronary atherosclerosis in non-obese patients. Atherosclerosis. (2014) 237:671–76. doi: 10.1016/j.atherosclerosis.2014.10.014
35. Dessouky KM, Sheridah AR, Salah KH. Epicardial adipose tissue thickness as useful marker of metabolic syndrome in adult Egyptian patients. Am J Med Med Sci. (2016) 6:160–5. doi: 10.5923/j.ajmms.20160605.03
36. Henrichot E, Juge-Aubry CE, Pernin A, Pache J-C, Velebit V, Dayer JM, et al. Production of chemokines by perivascular adipose tissue a role in the pathogenesis of atherosclerosis? Arterioscler Thromb Vasc Biol. (2005) 25:2594–9. doi: 10.1161/01.ATV.0000188508.40052.35
37. Greenstein AS, Khavandi K, Withers SB, Sonoyama K, Clancy O, Jeziorska M, et al. Local inflammation and hypoxia abolish the protective anticontractile properties of perivascular fat in obese patients. Circulation. (2009) 119:1661–70. doi: 10.1161/CIRCULATIONAHA.108.821181
38. Mazurek T, Zhang L, Zalewski A, Mannion JD, Diehl JT, Arafat H, et al. Human epicardial adipose tissue is a source of inflammatory mediators. Circulation. (2003) 108:2460–6. doi: 10.1161/01.CIR.0000099542.57313.C5
39. Chia S, Qadan M, Newton R, Ludlam CA, Fox KA, Newby DE. Intra-arterial tumor necrosis factor-alpha impairs endothelium-dependent vasodilatation and stimulates local tissue plasminogen activator release in humans. Arterioscler Thromb Vasc Biol. (2003) 23:695–701. doi: 10.1161/01.ATV.0000065195.22904.FA
40. Lima MM, Pareja JC, Alegre SM, Geloneze SR, Kahn SE, Astiarraga BD, et al. Visceral fat resection in humans: effect on insulin sensitivity, beta-cell function, adipokines, and inflammatory markers. Obesity. (2013) 21:182–9. doi: 10.1002/oby.20030
41. Gaggini M, Gastaldelli A. Brown versus white fat: are they really playing a role in obesity and cardiometabolic risk? Clin Lipidol. (2015) 10:365–8. doi: 10.2217/clp.15.32
42. Gómez-Hernández A, Perdomo L, de las Heras N, Beneit N, Escribano Ó, Otero YF, et al. Antagonistic effect of TNF-alpha and insulin on uncoupling protein 2 (UCP-2) expression and vascular damage. Cardiovasc Diabetol. (2014) 13:108. doi: 10.1186/s12933-014-0108-9
43. Madonna R, Massaro M, Scoditti E, Pescetelli I, De Caterina R. The epicardial adipose tissue and the coronary arteries: dangerous liaisons. Cardiovasc Res. (2019) 115:1013–25. doi: 10.1093/cvr/cvz062
Keywords: visceral obesity, epicardial adipose tissue, insulin resistance, inflammation, cytokine, adipokine
Citation: Gruzdeva O, Uchasova E, Dyleva Y, Borodkina D, Akbasheva O, Antonova L, Matveeva V, Belik E, Ivanov S, Sotnikov A, Kozyrin K, Brel N, Sinitsky M, Karetnikova V, Kokov A, Bychkova E, Pecherina T and Barbarash O (2019) Adipocytes Directly Affect Coronary Artery Disease Pathogenesis via Induction of Adipokine and Cytokine Imbalances. Front. Immunol. 10:2163. doi: 10.3389/fimmu.2019.02163
Received: 18 June 2019; Accepted: 28 August 2019;
Published: 19 September 2019.
Valentin A. Pavlov, Northwell Health, United States
Jose Ramón González-Juanatey, Hospital Clínico Universitario de Santiago, Spain
P. Trayhurn, University of Liverpool, United Kingdom
Copyright © 2019 Gruzdeva, Uchasova, Dyleva, Borodkina, Akbasheva, Antonova, Matveeva, Belik, Ivanov, Sotnikov, Kozyrin, Brel, Sinitsky, Karetnikova, Kokov, Bychkova, Pecherina and Barbarash. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Evgenya Uchasova, evg.uchasova@yandex.ru


Match Box... This is the election symbol of Prof. Kodandaram's Telangana Jana Samithi. But, if you look at the list of the candidates and the symbols allotted to them, there are 111 candidates, most of them independents, with the symbol of match-box. Everyone knows that the TJS is contesting just four seats out of 119 seats in the Telangana assembly. So, who are the other 107 candidates with match-box symbol?
It turns out that while asking for match-box symbol, Prof Kodandaram told the Election Commission that his party would contest 111 seats and wanted match box symbol to be allotted to his candidates. However, the party is now contesting just four seats. So, the election commission has now decided to allot those symbols to independents who ask for that symbol. So there are many candidates with match box symbol, but do not belong to TJS.
Lack of proper planning, absence of foresight have ensured that the TJS is now reduced to a mere joke. His symbol is now a public property. Now, no one is bothering about Prof. Kodandaram. The Congress has rendered him completely ineffectual.


Oak Creek — A proposed retail marijuana shop received unanimous approval from the Oak Creek Planning Commission on Wednesday night and now is one Town Board approval away from being the first recreational storefront in town.
Oak Creek does have one medical marijuana dispensary operating in town, and the application for another proposed recreational pot shop was tabled six weeks ago by the Town Board.
Stagestop 1 LLC's application got the nod from Planning Commission members Ted Allen, Gerry Greenwood and Kieran O'Halloran in what proved to be a quick vote. The business now is up for Town Board approval at its Dec. 11 meeting.
Stagestop 1 co-manager Dan Simon was present Wednesday. Co-manager Steve Speer wasn't in attendance.
In approving Stagestop 1's application, Greenwood said the fate of a new retail marijuana business is more of a matter for the Town Board to ponder than the Planning Commission.
"This is something for the Town Board to deal with," Greenwood said Wednesday.
A retail store is proposed to open at 100 W. Main St. in downtown Oak Creek in the building that formerly housed the Veterans of Foreign Wars and more recently Dovetail Designs.
Since its 2004 remodel, the building was used as "light industrial land use" with half of it serving as a workshop and the other half as a showroom.
In April 2014, the town of Oak Creek approved a land use change to convert a large chunk of the back part of the building into a marijuana cultivation facility operated by Park Range Recreationals LLC. Stagestop 1 owns the property but does not intend to operate the retail store should it pass. The company instead will enter into a lease with a licensee. Park Range Recreationals takes up the back 80 percent of the building, which is known as Unit B, and Stagestop 1 is eying the remaining 480-square-foot storefront, known as Unit A, to be a recreational pot shop.
Town Administrator Mary Alice Page-Allen said at Wednesday's meeting that when Unit B was approved for a land use change, Unit A was reserved for "some other use," but there were no stipulations in Park Range Recreationals' original approval for what it would be.
The building is located in the town's Performance District 1, where the majority of Oak Creek's retail and commercial establishments are located along Main Street. Current Oak Creek land use code states that marijuana establishments are conditionally permitted to be in Performance Districts 1 and 7.
Only a few of the roughly 20 audience members spoke during Wednesday's meeting. Joe Landry, owner of a property adjacent to Statestop 1's building, said he has no issue with a retail marijuana store opening near his property.
Others, though, weren't as sure.
Audience member Bill Auer said he thought there has been a rush to market recreational marijuana businesses in Oak Creek. Carol Villa, who owns property across the street from the proposed retail marijuana store, suggested that town authorities decide exactly how many marijuana businesses Oak Creek wants.
Stagestop 1's application projects the shop's first-year revenues would be about $350,000 averaging 12 to 15 customers per day.
Because the business would be located on Main Street in a building that once housed a retail business, and because its staff would be very small, the applicants don't think parking will be an issue.
Stagestop 1 agreed to have discreet signage on the front and side of the building. The word "marijuana" wouldn't be on its sign, nor would a pot leaf logo be used.


A recent image of the Sirius region shows that a Type III civilisation has been busy over the last few months (well over the last few months some 9 years ago anyway). A Julia-set Dyson sphere made in some unknown material has appeared around our brightest star. Soon Sirius will no longer be our brightest star as the alien civilisation starts extracting the power of this natural fusion reactor for their own purposes.


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Hopefulness: One of the Believers' Characteristics
April 21, 2020Oasis of Faith, Truth SeekerAllah, belief, believer, faith, FEATURED, God, Hopefulness: One of the Believers' Characteristics, monotheism, quranby School Admin
By A. O.
The Qur'an portrays believers as being in a constant spiritual state of hopefulness toward Allah.
The Qur'an states that hopefulness is an important characteristic of believers and, at the same time, an indication of their faith.
People place their hope in Allah according to their degree of faith and will cherish a deep longing to obtain His mercy and infinite bounties because He has promised believers the most beautiful things in this world and in the hereafter.
People will hope to secure these according to their degree of trust in Allah, their closeness to Him, and their submission and sincerity.
Knowing that everything happens according to His will, believers do not fall into despair or become hopeless and pessimistic. And, since believers know that Allah will accept their prayers, they do not doubt, even for a second, that a seemingly terrible event is simply a part of their test and that eventually, it will work out for the best.
Everything that happens comes about through Allah's command of "Be." At every second, everything and scene that appears before us is created through Allah's will. Nothing is left to its own devices, for everything is created for the destiny that Allah has determined for it.
Believers who are aware of this do not lose hope, even when facing the most negative situations or the most distressing events, in Allah's mercy or help. Those who are patient in hardship, do not lose hope, and never compromise Allah's laws have been given glad tidings in both this world and the Hereafter.
The Qur'an portrays believers as being in a constant spiritual state of hopefulness toward Allah. Sincere believers will know and appreciate our Lord as the Qur'an describes Him and, as a result, will realize the mercy and favors that He has bestowed upon them.
They know that He is the believers' friend and helper, that He is infinitely merciful and compassionate toward them, that He has sent glad tidings to His righteous servants of a great reward both in this world and the next, and that He never breaks His word. They see that He wills only what is best and good for them, that He opens the door of mercy and guidance for them, and that He provides endless opportunities to gain rewards.
And so believers who know this are in a constant state of hopefulness toward our Lord, hoping for the best and the good from Him in both this world and the next. Several Qur'anic verses mention how Allah gives believers a good reward and offers them glad tidings of grace, favor, and mercy.
"As for those who believe and do right actions, We will erase their bad actions and recompense them for the best of what they did." (Al-Ankabut, 7)
"He responds to those who believe and do right actions, and gives them increase from His favor. But the unbelievers will have a harsh punishment." (Al-Shura, 26)
"Satan promises you poverty and commands you to avarice. Allah promises you forgiveness and abundance. Allah is All-Encompassing, All-Knowing." (Al-Baqarah, 268)
The believers' prayers and wishes are full of hope. As one verse says, "they call upon their Lord in fear and ardent hope" (Al-Sajdah, 16). Since prayer itself is both a form of worship and an indication of a hopeful attitude toward Allah, believers pray in the hope that our Lord will answer their prayers.
A. O. is a Turkish writer and author.
Understanding Natural Evil
Faith in the Day of Judgement

redpajama_set_name: RedPajamaCommonCrawl


CBPL release – The "Armchair Film Adventures" series at Coos Bay Public Library continues on Tuesday, February 12th at 2:00 p.m. in the Myrtlewood Meeting Room. This month's feature is National Geographic's "CANYONLANDS" Canyonlands is the little-known jewel of the American National Parks. This stark landscape of extraordinary features contains more than 300,000 acres of desert wilderness, towering spires and spectacular canyons. But this rugged terrain is more than a pretty picture–it is a history book of time. Its stories stretch from the geologic forces that created this land, to the beginnings of life on earth and from ancient people, to the cowboys and outlaws of the Old West. enture beyond the tourist hotspots and discover the hidden secrets of Canyonlands National Park. Everyone is welcome at this program sponsored by The Friends of Coos Bay Public Library. No admission is charged and refreshments will be provided. Please call 269-1101 for further information about this program. The library is located at 525 Anderson Avenue in Coos Bay.


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What is a Catastrophic Injury & What to do if You or a Loved One is Injured
A catastrophic injury is "an injury whose direct and proximate consequences permanently prevent an individual from performing any gainful work." (Title 42, US Code § 3796b) Catastrophic injuries may go beyond this definition to also include severe injuries that lead to long-term disability or disfigurement.
Often, catastrophic injuries are identified by the ramifications of the injury and the severity of its outcomes. These injuries have devastating, long-term effects which can cause the victim to lose a hard-sought career, the ability to support him or herself and a family, and years of wages and benefits.
The victim's well-being may also be affected as injuries of this magnitude can prevent him or her from doing any kind of work, from traveling or enjoying personal interests and hobbies. Severe injuries may also increase mental health issues, like anxiety and depression, and possibly require lifelong medical care.
The impact of a severe injury can cause significant stress and grief for the victim's family. From substantial medical bills and management of care to the possibility of required supervision or long-term assistance, catastrophic injuries can be challenging for families to bear alone.
Examples of catastrophic injuries or illnesses include:
Multiple bone fractures
Loss of eyesight or hearing
Any injury that causes serious, permanent damage or disability
The causes of a severe injury can vary, but many are due to car accidents, negligence, failure of another to follow safety rules, dangerous or defective products or drugs, construction accidents, falls, medical mistakes or workplace accidents.
Speaking with an attorney as soon as possible after a serious injury occurs will ensure your best interest is protected. Your attorney should be able to negotiate with insurance carriers to resolve your medical bills, utilize experts to testify about your health and medical needs, obtain greater compensation to cover your long-term costs, and assess your present and future needs.
Catastrophic injury cases are complex and effects of the injury persist long after the accident. Like all personal injury lawsuits, the victim is entitled to compensation for expenses related to his or her injury and medical treatment, but severe injury claims may also encompass the victim's pain and suffering incurred by the injury. Assuming the at-fault party's insurance company will provide the right level of compensation for your current and future needs will likely lead to disappointment and possible financial difficulty down the road.
If you or a loved one are seriously injured, it is imperative to consult an experienced attorney, like those at Lepley, Engelman, Yaw & Wilk, LLC. Our experienced attorneys will be able to identify the important facts about your claim, whether it qualifies as a catastrophic injury, and consider your financial needs to make a successful claim.
Check out other articles by Lepley, Engelman, Yaw & Wilk
/catastrophic-injury


How do I Apply for the LFPP Grant?
The 2019 Grant application period is now open. Applications will be accepted until 11:59 p.m. EST on June 18, 2019. Applications will only be accepted through Grants.gov.
You can find the requirements for submitting an application in the most recently published Request for Applications.
Forms SF-424 and SF-424B can be found with the www.grants.gov website application submission.
Forms AD-3030 and AD-3031 can be found with the www.grants.gov website application submission.
Is there anything else I need to apply?
Please visit www.grants.gov for additional tools, tips and training on how to apply for a grant.
Are there any resources that can help me write an application?
AMS will host two webinars for LFPP Applicants.


A common set of arguments against intelligent design theory is that it, the Discovery Institute, or the motives behind the theory are religious in nature. It is supposed that for this reason, intelligent design theory is not scientific or is not a viable theory. I have previously shown that intelligent design theory is a historical rather than scientific theory. The study of history is distinct from both science and religion. Bearing in mind this clarification, these kinds of objections can be divided into three groups: the fallacy of poisoning the well, the failure to distinguish philosophical argument from historical theory and the failure to distinguish philosophical claims from scientific ones. Since none of groups are sound arguments, these objections against intelligent design theory are all failures.
The first set of objections are based on the fallacy of poisoning the well. This fallacy begins by pointing out the connections between religious belief and intelligent design theorists. The founders of intelligent design theory and the primary organization promoting intelligent design theory (the Discovery Institute) are all connected to religious belief in a variety of ways. Most are Christians or believe that intelligent design lends support to the existence of God. In addition to this, many of these people have promoted Christian moral values, distinctly Christian teachings or even political action. This fallacy completes by claiming that these facts mean that intelligent design theory is either not scientific, not viable or is brought into some kind of doubt. The first set of facts are simply not relevant to intelligent design theory. Kepler believed that his study of planetary motion showed hidden patterns placed there by God. That is of no relevance to the truth of the laws of planetary motion. Similarly, Isaac Newton wrote commentaries on the Bible and believed that he had uncovered the truth buried by ancient conspiracy. But that is also of no relevance to Newtonian mechanics.
The second set of objections confuse historical theory and philosophical claim. The theory of intelligent design is a historical theory. It claims that there is a method irreducible complexity or specified complexity that can determine that some features of the natural world had an intelligent cause. To go any further than that is a philosophical claim. So claims that this cause is divine, guesses as to the purposes of this cause, arguments that this cause designed poorly or was evil are all philosophical claims. All that this historical theory can tell us (if it works) is that there was an intelligent cause. Even if two features both had an intelligent cause, this theory cannot claim that the cause of one feature is the same as the cause of the other feature. In addition to this, intelligent design theory can have plenty of false negatives (by failing to recognize an intelligent cause masquerading as an unintelligent cause). So any argument against intelligent design that relies on the nature, purposes or actions of the designer is attacking a philosophical theory rather than intelligent design. Similarly, any theory attempting to show, prove or support the existence of a designer of any kind is a philosophical theory based off of intelligent design theory.
The third set of objections confuse philosophical claims with scientific ones. This is complicated, especially because a numbers of scientists are deluded enough to believe themselves competent to answer philosophical questions. Intelligent design theorists sometimes claim that any study of causes should permit there to be supernatural causes. They may also claim that intelligent causes can not be ruled out since we already use them in various historical disciplines. These are two separate claims. Since these claims are made in a context that ignores distinctions between science and history, there is no simple answer to them. On the other side, many scientists claim that methodological naturalism rules out supernatural explanations. They also claim that without supernatural explanations, intelligent design offers no theory. Once again, this groups fails to properly distinguish these two different claims or to distinguish between history and science. Nonetheless, the difference between science and history, understanding what good science and good history are, whether or not supernatural or intelligent causes can be permitted as explanations and what place methodological naturalism has are all philosophical issues. None of them are scientific issues. So science has little to say in these kind of discussions either for or against intelligent design theorists.
Any connection between religion and intelligent design theory is simply a distraction from the real issues. The real issue is whether or not the claims of intelligent design theorists are true or false. The real issue is whether or not intelligent design theorists can actually detect design or not. Religion has nothing at all to do with these claims, so it functions as a bogeyman so that the real issues can be avoided.


The Danish Tax Agency, Skattestyrelsen, announced on January 14 via their website, that it will be gathering trader data from 3 digital currency exchanges including localbitcoins to guarantee that clients are fully paying the right taxes. Data about foreign citizens, companies and organizations will be shared with other nations.
The 3 exchanges must now give data about all purchases and sales of digital currency made by their clients during the 24-month period. They will be duty-bound to include identification data like CPR numbers, names, addresses, personal ID numbers provided by the Danish Civil Registration System.
The determination to allow the Skattestyrelsen to amass the information was taken at the previous meeting of the Tax Council that happened in December last year. The tax agency was alerted by Finland's tax authorities about massive Danish nationals trading cryptoassets on a Finnish Bitcoin (BTC) exchange. The tax body of Denmark also considers sharing data about digital currency transactions conducted by foreign users and firms in Denmark with tax authorities in the nations in question.
The tax authority will correct that tax base for every trader before the summer period. Each case will be reassessed and managed individually to ascertain whether a digital currency trade is part of the nonexempt income.
Last month, Skattestyrelsen was tipped off by Finnish tax authorities about 2,700 Danes trading on a digital currency exchange located in Finland. The Danish nationals have traded cryptos worth over 100 million kroner (approx. $15 million USD) between the year 2015 & 2017.
In December 2017, the authority cited a survey carried out by the National Tax Board which discovered that around 450,000 Danes are planning shopping with cryptoasset. The tax agency established a movement to alert taxpayers about their responsibilities and the tax deductions they are qualified for by right according to law.
Since Denmark has not presented a particular tax structure for cryptos, the tax agency has purportedly treated cryptoasset gains similarly to gains on stocks previously.
The news of Denmark's tax authorities crackdown and severely repressive actions co-occurs with an identical crackdown by the tax authority of Bulgaria. Last year but one, Coinbase, US-based cryptoasset exchanges platform battled a similar request from the U.S tax authority, that demanded the trading information of around 500,000 of its clients; in the long run, Coinbase just gave 13,000 crypto trading records.


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Q: NZEC Error in Python in SPOJ I think my algo is right(done very badly) But I get the desired outputs in ideone.com. But in SPOJ it keeps on saying "Runtime Error NZEC". Please suggest a few changes to get this right.
Here is the link to the Question :
http://www.spoj.com/problems/LASTDIG/
Here is my code :
import sys;
a=dict();
c=dict();
a[1]=[1,1,1,1];
a[2]=[2,4,8,6];
a[3]=[3,9,7,1];
a[4]=[4,6,4,6];
a[5]=[5,5,5,5];
a[6]=[6,6,6,6];
a[7]=[7,9,3,1];
a[8]=[8,4,2,6];
a[9]=[9,1,9,1];
a[10]=[0,0,0,0];
inp=sys.stdin.read().strip().split();
t=int(inp[0]);
readat=1;
for i in xrange(t):
    m,n=map(long,inp[readat:readat+2]);
    r=n%4;
    s=m%10;
    c[i]=a[s][r-1];
    readat=readat+2;
for i in xrange(t):
    print c[i];

A: First things first. You are using Python, you DONT have to end the statements with a semi colon ";"! (If you have this habbit from writing a lot of C programs, it's okay!)
Secondly, you shouldn't use 2 for loops when you could do it with just 1. (The print can be executed within the first loop itself, not that this would be the most efficient way though)
The NZEC error as you might know stands for Non Zero Exit Code which is being returned by Python for your code due to a KeyError. Notice how your dictionary a has keys 1 to 10 & not 0? m%10 would be 0 when s is a multiple of 10. Thus a[10] should actually be a[0].

redpajama_set_name: RedPajamaStackExchange


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The Ultimate Doors
Sat · November 19th, 2022
Doors: 7:00 pm / Show: 8:00 pm
$15-$29 | Plus fees and taxes
The Ultimate Doors was formed with the intention of preserving The Doors' music and performances as well as bringing an authentic experience to the old and the new generations of Doors fans.
With great attention to detail, The Ultimate Doors provide their audiences with an authentic looking and sounding tribute to Jim Morrison & The Doors. From Jim Morrison's leather outfits all the way down to the color of the microphone cable, The Ultimate Doors leaves no stone unturned in bringing an authentic Doors tribute show to the stage.
Front and center, taking on the role of Jim Morrison is Nash Stover. Nash doesn't take his job of being Jim lightly. He studies Jim daily. From Jim's vocals and stage persona, to every detail of Jim's ever-changing fashion sense. Jim Morrison was a complex man and Nash deeply respects every part of Jim's legacy which shows true night after night on stage.
On the Gibson SG and playing the role of Robby Krieger is Todd Huffman. Todd has been a Doors fan his entire life and has always considered Robby Krieger to be the most underrated guitar player of all time. Todd puts in countless hours not only practicing Robby's guitar licks, but also keeping every detail of Robby's rig fine tuned. Robby Krieger is a hard role to play, but Todd nails it.
It takes a man with two brains to pull off playing the part of Ray Manzarek. Manning the Gibson G-101 organ while keeping the low end going on the Fender Rhodes piano bass is Nate Shaw. Maintaining the thumping bass with his left hand and the snarling organ with his right, Nate really appreciates every ounce of talent that Ray Manzarek had.
On the Mod Orange Ludwig Downbeat kit, taking on the role of John Densmore is Jordyn Huffman. Jordyn learned to play drums to Doors albums when he was a teenager and has considered John Densmore to be the best drummer of all time ever since. John's style on and off the drums was unlike that of any other and Jordyn loves that challenge.
Temple Live
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Q: Translation as product of reflections I am facing the following problem, given the translation in the euclidean affine space of dimension 4
$
\tau_v=
  \begin{bmatrix}
    1 & 0 & 0 & 0 \\
    0 & 1 & 0 & 0 \\
    \frac{3}{2} & 0 & 1 & 0 \\
    0 & 0 & 0 & 1
  \end{bmatrix}
$
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Tag: i've been deader
I've Been Deader by Adam Sifre: A Review
"About as interesting as slugs and moaned so much that, were Fred alive, he'd be sporting a hell of a migraine." – on zombies.
I've Been Deader by Adam Sifre is a zombie novel. You may groan audibly at the prospect of yet more zombies but it's actually a breath of fresh air. Pitched as a comedy horror by its creator, the humour is black, though I found it much more serious than I'd expected, especially following the halfway point.
It took me a little while to get into the book, I felt the opening was more slapstick than the rest of the story – I thought it was going to be some sort of bizarre "good" zombie love story at the outset, but boy was I wrong.
Adam establishes the rules of his undead horde quickly – they are much like all the other zombies we know and love, but there's some brilliant, gory description to prop them up. There's also Fred, one of the primary protagonists who, as it happens, is a zombie himself.
The difference between Fred, (45, pot belly and limp, bitten by clerk), is that he's a thinking zombie who remembers his past life. He also learns he can control other zombies. The problems, though, are evident. He has no hang-ups over eating brains like his brothers, he enjoys them as much as your next zombie. He's also falling apart and to top it off, he thinks he's fallen in love with Aleta, a "breather" (human, not zombie), with amazing eyes. Also, "breathers" are fewer and farther between so he's hungry and of late they appear to be fighting back; it's almost as if they're going to win the war.
I enjoyed reading about the initial spread of the virus immensely – George Potts the overly-friendly zombie postman and also scenes like Janet and the severely hen-pecked Stanley and the penis incident. I did feel we were, at times, learning about slightly throwaway characters when we perhaps should have been concentrating more on the main players, but this changed as the story progressed and on the whole I thought the descent into madness and anarchy in the world of zombies was well played.
We are also notably treated to Jon Tanner's evil descent (a truly mad bastard) and Timmy, a kid heading for what could possibly send the dead back to the grave and a reunion with his dad, who just happens to be a zombie.
Overall I've Been Deader is a great, snappy read and suitably different from an at times, tired genre. I look forward to what Adam Sifre cooks up next – by the looks of it, a prequel.
Buy the book here.
Posted on July 18, 2012 February 8, 2019 by Ed	0
I've Been Deader: Opening
Friday the 13th is International Zombie Day. When it comes to shamblers, there's no dead
like Fred. Author Adam Sifre a/k/a Splinker, is quite insistent about that. I'm posting the first
chapter of "I've Been Deader," a near perfect blend of horror and comedy. Enjoy!
Fred's ruined face stared back at him from a fractured, mold-spotted mirror. There was no
denying that he'd seen better days. The remains of breakfast pooled around his feet and a pair of
lace panties clung to his shoe, glued there by God knew what. Bits of flesh were stuck between
his yellow teeth, along with the sodden remains of a "hand wash only" label. Being a zombie
was no picnic.
He wiped his gore-stained hands on a filthy shirt, not sure if was cleaning the hands or
the shirt. He felt compelled to pause and take stock of himself. His right eye, now more crater
than ball, looked like a crushed egg yolk. His left leg was broken in at least two places. A large
splinter of bone poked through the skin above his thigh, fine dark lines etched across the surface
like a bad piece of scrimshaw. The open wound on his neck had started leaking again, but at least
the fluid was mostly clear now.
No use dwelling on negatives. Time to get to work. He turned away from his reflection
and limped out of the men's room of the Vince Lombardi rest area.
An overly bright morning sun assaulted him as he stepped outside. Fred gave a mental
wince, wishing again that he could blink. Sunlight had no adverse effect on the undead, but
he had never been a morning person. Today he had to shamble over to Terminal C of Newark
Airport, where eight breathers were making their last stand. Zombies were lone hunters and
rarely worked together. Every so often, however, a kind of collective broadcast signal went out
over the undead grapevine, announcing the newest brain buffet — in a shopping mall, a church,
or an airport – with satisfyingly predictable results.
Dozens were already making their way down the New Jersey turnpike. By their
mindless, "movie" slow pace, he knew they hadn't fed. Zombies weren't exactly Jesse Owens on
the best of days, but they tended to move a lot faster with a little brain in the old furnace.
If Fred could breathe, he would have sighed. It looked like hundreds of zombies would
be fighting over eight brains and assorted bits. Assuming the breathers were able to take out 10
to 20% of the attacking hoard before being overwhelmed, that still left about ten zombies per
breather. With luck, however, he would still be the brainiac of the pack by the time he got there.
Having one's wits about it gave a zombie an edge in the hunt. Depending on the specific virus
strain or whatever it was that put the mojo in their mortified flesh, some undead could reason and
even remember who they were as breathers. So far Fred hadn't come across any other "thinkers,"
as he called himself, but he couldn't imagine he was the only one.
By mid-afternoon, he found himself actually enjoying his walk down the turnpike. Most
of the fires had burned themselves out and although the air still reeked of burning gasoline, the
skies were relatively smoke-free. Even a walking corpse could appreciate a warm, spring day
like this one. Fred pulled his lips up in what should have been a grin.
Death, ruin and destruction improved the New Jersey Turnpike.
Not that there wasn't a black lining to be found around his own little rainbow of a life.
Most of the zombies were a few hundred yards down the road, but two lesser undead doggedly
tagged alongside of Fred, putting a bit of a damper on things. The virus left them as nothing
more than, well, nothing more than zombies. They were about as interesting as slugs and moaned
so much that, were Fred alive, he'd be sporting a hell of a migraine.
All in all, however, the day was turning out quite well. He could almost convince himself
being undead wasn't so bad. Sure, it was bad luck that he was 45 years old with a rather large
potbelly when he had been bitten by that damned clerk. Being cursed to wander the earth in
search of brains was bad enough, but why couldn't it have happened when he was twenty years
younger and thirty pounds lighter?
He was imagining wandering the earth in search of fresh brains as a slimmer, sleeker and
younger Fred, when the head of the zombie on his left exploded.
Shit. He limped over to an abandoned Ford Explorer and crouched down, scanning
the area for the source of the ambush. The other walking corpse stopped and stared vacantly,
a low "Braaaaiiiinnnnsss?" emitting from its drooling mouth. Fred felt a sense of relief when a
bullet took the second one through its right eye. Those two had just about gotten on his last dead
nerve.
A glint of light in the tall grass by a pond off the side of the road revealed the breather's
position. It looked like there was only the one.
The lone gunman on the grassy shoal, Fred thought, mentally smiling.
He stood up from behind the Explorer, pointed at the area where the gunman was hidden,
made the undead scream of discovery – then ducked back down behind the SUV and waited.
Several zombies with lesser survival instincts turned off the road and converged on the field. A
bullet dropped another one and Fred saw a figure pop up from the tall grass and start running. A
collective moan escaped from the zombies and they began to shuffle a little faster. But unless the
breather tripped, broke both legs and fell asleep, he'd be fine — for now.
Fred got up and started limping toward Exit 14. It would be another hour or so before he
reached the airport. Most of the zombies were still on the road. After taking into account the ones
that had left to chase the gunman and Fred's two undead groupies – now just dead — he figured
there would be plenty of brains for everyone when they got there. Fred was… well, he was — I'm
happy! As he shambled down the turnpike, he began humming a song that was popular before
he was turned. In his mind, it was a happy, catchy tune. But when he hummed it, it sounded a lot
like "Braaiinnss . . ."
SO ENDETH CHAPTER ONE
If you like what you read or just have some spare change lying around, you can
download "I've Been Deader" here: http://tinyurl.com/Shambler
2.8 Hours Later
As I'm currently reading and later reviewing a book entitled "I've Been Deader" and I'm getting reading for International Zombie Day tomorrow to celebrate, I thought I'd post a few vids about city-wide tag-game 2.8 Hours Later. I'm still debating taking part in this. It looks pretty epic.
Visit the 2.8 Hours Later website here.
Stop Press: International Zombie Day!
I'd just like to point out that this Friday the 13th (coming) is International Zombie Day. Join the group here (http://on.fb.me/OvnJzC).
"Lets face it. Zombies are hot at the moment. Well hot in a cold, dead kind of way. To celebrate the launch of 'I've Been Deader' by Adam Sifre, Kings of Kindle is declaring an International Zombie Day and we want you to join us… well actually… host us! What better day to meme about zombies than Friday the thirteenth? We're looking for bloggers to go all zombie on us and write anything they fancy about brain eating corpses."
Sounds good, huh? Join the group. I'll be reviewing "I've Been Deader" soon!
Posted on July 10, 2012 July 10, 2012 by Ed	0


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However the scene's integrity is a bit undermined by Monika putting on sunglasses, but I don't know if that was something she did on her own or a producer asked her to. I did connect with the 5 women from LA more than the 3 from Atlanta. I am acutely aware of how much a producer and editing team can influence what we all see on television (I am a reality television producer by day) and I have no reason to believe that they are not the nicest women in the world on the show, but they were not shown to be that way because reality tv loves to have a villain, and Monika made a great villain. To be able to get the scene where she is yelling at her mom is wonderful.
Overall one of the nice parts of the show was that the cast was genuine. They all loved the things they dressed as and loved dressing up. I found it to be educational, I figured out how to do some of the things I was having trouble with on my costumes. Just for that fact alone I would watch the next season. I would like a couple more guys added to the main cast, specifically ones that did armor pieces more often. I really loved Jesse's Assassin's Creed outfit, but it would have been super awesome to see armor being made by people who know way more than me about what they are doing when it comes to fabrication.


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Rob Littlejohn Lands Lead Editorial Role on Charlie Sloth's Iconic 'Fire In The Booth'
Highly respected BBC radio editor Rob Littlejohn is leaving the corporation after 15 years to head up production on the highly influential Fire in the Booth as well as the Charlie Sloth Rap Show.
Starting in August, this appointment marks the beginning of a new chapter for Fire in the Booth as Charlie Sloth aims to bring this culturally significant platform to fans on a more global scale, following their first international edition in June which featured German rapper Luciano and was released exclusively in Germany, Austria and Switzerland. Since its launch ten years ago, Fire in the Booth has become the world's biggest freestyle platform, with more than a billion views to date and is hosted alongside the Rap Show globally on Apple Music. Known for championing the hottest rising talent here in the UK, it also regularly features the rap scene's biggest artists such Drake, Giggs, Lil Baby, Stormzy, Pop Smoke, Wretch 32 and Megan Thee Stallion.
"Hip-Hop Radio is in my DNA and it's a privilege to join Charlie Sloth and his team. After an amazing journey with the BBC, I am proud to be joining what I consider to be the world's leading platform for the MC and Hip-Hop culture." – Rob Littlejohn
"I worked with Rob for almost 10 years at the BBC so I know how passionate and thorough he is when it comes to the culture we love. Rob was someone who had always really championed me so us coming back together on this journey is incredible for me." – Charlie Sloth
Congratulations to Rob!
Charlie Sloth
Fire in the booth
Rob Littlejohn


Dharamsala is a heavenly town with vibrant shades of calm, purity, and elegance, making it perfect for a Dharamsala yoga retreat. Experience the pleasure of living in this yoga training India destination filled with mountain lanes with crepuscular lights. Find yourself engulfed in the beauty of deodar forests, mesmerizing Kangra Valley, gushing water streams, and a holy majesty that truly stirs the soul, prepping your body and spirit for any great Dharamsala yoga retreat or outdoor exploring. Dharamsala speaks volumes of untouched beauty, pleasant climate, tranquility, spiritual heritage, and nature trekking adventures that sum up the ideal definition of a yoga training India destination.
The abode of His Holiness—The Dalai Lama—this scenic hill station situated in the mighty Himalayas is a dream place of several wanderers, spiritual seekers, and adventure souls waiting to explore every inch and charm of the yoga training India destination of Dharamsala, India. We've prepared a list of ways to enjoy Dharamsala, from a Dharmsala yoga retreat to adventures, spiritual centers, scenic places, and so much more. Come, live, and feel this yoga training India destination of Dharamsala with us!
7 What yoga training India destination is at the top of your list?
Rugged terrains, hilly mountains, and dense jungles give an adrenaline rush to the adventurers and the town of Dharamsala offers all three on a platter. From nerve -wrecking sports to pleasing nature walks, this is the place to satiate your lust for adventure and India's natural beauty. These activities are geared towards the adventurous type—if you're planning on visiting with your family, we recommend checking out these tips for traveling to India with kids.
Triund and Indrahar Treks to Bhagsu Falls are famous among national and international travelers. Dotted with the forests of pine and oak, enchanting waterfalls, and occasional glaciers, the mesmerizing view makes Dharamsala a primary choice of trekkers.
Nayagroeon, located in the remote Himalayas in Dharamsala, it is the most popular trail for rock climbing. Climbing steep rocks is both physically and spiritually stimulating for many adventure enthusiasts.
Feel the cool soothing breezes kicking in as the pulley carries you from one hill rock to another. Feed the brave within as you take on the long kilometer ride amidst the thick lush green forests of Dharamsala.
With Dhauladhar ranges in the background and beautiful covering of deodar forests, Dharamsala is a picturesque location alluring the travelers to its holy lap. The place boasts of sparkling waterfalls, colorful temples, and vintage ruins ensuring a fascinating time for the visitors.
Visit this serene spot in this scenic location and transport into the world of magnificence. The spell-binding setting and the surrounding peace make it an ideal destination to let go off all the tensions and to live moments of calmness. The lake is decked with snow-capped mountains and verdant grounds enhancing its beauty to greater heights.
One of the most popular sightseeing locations in Dharamsala, the cascading milky waterfall– Bhagsu falls in enclosed in pristine beauty refreshing the souls of the travelers. Enjoy the flowing saga along with tasty munchings at the cafe nearby.
Unfold the historical tales and awe-inspiring heritage at the Kangra Fort. It's a fort as magnificent as the popular forts of the pink city of Jaipur, but with a very different style. A marvelous ancient work in the Himalayas, Kangra Fort was once the royal abode of Kangra Family– the Katoch Dynasty. This royal specimen offers eye-opening views of the rivers: Manjhi and Banganga and the Maharaja Sansar Chand Katoch Museum.
Looking for another yoga training India destination? Try a yoga retreat in Rishikesh, India!
The Spiritual sanctuary of India, Dharamsala, it is the thriving land of monasteries and temples. It is a place that provides an insight into the Buddhist and Indian culture and offers the perfect ambiance and resources to indulge in spiritual practices. Steal away long-cherished moments of divinity by visiting the alluring temples, Buddhist monasteries, etc.
A beautiful monastery dipped in sunshine and exotic greenery. It is the sacred residence of Karmapa—the head of Kagyu Tibetan Buddhism. Reflecting serenity in its decor and ambiance, the Gyuto Monastery offers a glimpse into the Tantric World.
Regalia of Dalai Lama's first visit to India in 1959, it is the place comprising the Dalai Lama's abode and monasteries. The Dalai Lama's sessions and numerous Tibetan dance and music performances are also held in this complex which is surely not-to-be missed.
The religious attraction of the Dharamshala, Bhagsunag is Lord Shiva's temple. The temple is nestled in the lofty hills and windy trails and is swarmed by numerous pilgrims every year.
The beauty and blissful aura of the yoga training Indian destination of Dharamsala make it an ideal place for undertaking the practices of Yoga and Meditation. The pleasant vibes, simplistic nature of habitats create a suitable atmosphere for embracing health and wellness for any Dharamsala yoga retreat.
Dhamma Sikhara is a Vipassana Meditation center located adjacent to Dharamkot village in Dharamsala, Himachal Pradesh, India. It is the center of study and practicing the art of Vipassana meditation from the traditions, making it perfect for a Dharamsala yoga retreat.
Dharamsala—the seat in exile of his holiness Dalai Lama and the wonderful world of nature and beauty is a treat to explore for the mind, body, and soul. Visit this yoga training India destination for a unique look into the beauty of this amazing place, and immerse yourself in a Dharamsala yoga retreat or outdoor exploring! If you enjoy Dharamsala, you may want to go off-the-beaten path and explore the Chanshal Pass in Himachal Pradesh, India!
What yoga training India destination is at the top of your list?


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Mold Terminator IncBlogGeneralMold That Produced A Cure
March 7, 2016 No Comments By admin General Alexander Fleming, black mold, Memphis mold remediation, Memphis mold removal, Mold Terminator, penicillin
Mold That Produced A Cure
In September of 1928, Dr. Alexander Fleming returned to St. Mary's Hospital in London. He had been vacationing in Scotland, and was likely frustrated to find a very messy lab bench awaiting him.
Dr. Fleming noticed that a mold called Penicillium notatum had contaminated his Petri dishes. As he examined this under a microscope, he was surprised to see that this mold prevented the growth of the more common mold called Staphylococcus aureus. Over the next few weeks, he allowed the mold to grow further, and he was able to confirm these findings. He determined that perhaps this might be used to combat infections in humans.
Regarding the experience, he later stated: "When I woke up just after dawn on September 28, 1928, I certainly didn't plan to revolutionize all medicine by discovering the world's first antibiotic, or bacteria killer. But I guess that was exactly what I did."
In 1938, Dr. Howard Florey, the Director of the Sir William Dunn School of Pathology at Oxford University, came across Fleming's paper on the topic. He and his colleagues decided to unravel the science behind Fleming's discovery. During the summer of 1940, they tested penicillin on mice, and eventually concluded that they had enough promising information to test it on humans. It took 2000 liters of mold culture fluid to obtain enough pure penicillin to treat one human sepsis case.
The first test case was an Oxford police constable named Albert Alexander. He had nicked his face while working in his rose garden. The area had become very infected and then spread to his eyes and scalp. After five days of injections, he began to recover. However, they could not produce enough penicillin to continue treatments, and he ultimately died.
In 1941, the British scientists began working with American scientists in Peoria, IL, to develop ways to produce the product on a more massive scale. During the first five months of 1942, 400 million units of pure penicillin were produced. It was used heavily during WWII with a very high success rate.
Mold Terminator, Inc. is proud to salute those who worked so hard and tirelessly to develop an unwanted item into a cure for thousands.
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Source: PBS. www.pbs.org. 3 March 2016
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Tiger Woods could take another significant step in the world rankings this week at Torrey Pines, writes yahoosports.com.
If he were to capture an eighth career title at the Farmers Insurance Open, Woods, now ranked 13th, could move as high as number sixth in the world, according to Golf Channel's OWGR guru Alan Robison.
Woods is making his first PGA Tour start since his victory last September at the Tour Championship.
With a runner-up finish, Woods could rise as high as No. 8, while a third-place showing – and perhaps even a 10th-place finish – could put him back in the top 10 in the world for the first time since August 2014. If he finishes 25th, he could be as high as 11th.
There figures to be plenty of volatility in the rankings, as 13 of the top 17 in the world are playing across the globe this week.
One ranking that won't change: world No. 1. No matter how Justin Rose finishes this week at Torrey Pines, he won't lose his top spot to Brooks Koepka.
Meanwhile, Woods hopes to get his year off to a strong start at this week's Farmers Insurance Open.
The event is held at Torrey Pines, a place Tiger Woods has "owned" throughout his entire career, picking up eight wins, including his last major title at the 2008 U.S. Open.


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On Saturday, May 14, 2016, the Washita County Sheriff's Office went to 12 businesses within the county to attempt to purchase alcohol with an individual who was under the age of 21. Clerks at eight businesses did sell alcohol to the individual. The money used to purchase the alcohol was recovered from each purchase, and the clerk who sold the alcohol was issued a summons to come to court.


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Um fotino é uma partícula subatômica hipotética, o férmion WIMP superparceiro do fóton previsto por supersimetria. É um exemplo de gaugino. Embora nenhum fotino tenha sido observado até agora, ele é um dos candidatos à partícula supersimétrica mais leve do universo.

Partículas elementares hipotéticas

redpajama_set_name: RedPajamaWikipedia


Posted on April 27, 2016 at 9:23 am.
Graduating from the Ultimate Acting Programme, Marcus Massey has worked 650 days as an actor over a three-year period. He has appeared in various TV, Film and Theatre projects. His testimonial video above was recorded in Business Class on a flight to Thailand to appear in a feature film.