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Protein tyrosine phosphatase 1B (PTP1B) contributes to leptin resistance by inhibiting intracellular leptin receptor signaling. Mice with whole body or neuron-specific deletion of PTP1B are hypersensitive to leptin and resistant to diet-induced obesity. Here we report a significant increase in PTP1B protein levels in the mediobasal hypothalamus (P = 0.003) and a concomitant reduction in leptin sensitivity following 28 days of high-fat (HF) feeding in rats. A significant increase in PTP1B mRNA levels was also observed in rats chronically infused with leptin (3 μg/day icv) for 14 days (P = 0.01) and in leptin-deficient ob/ob mice infused with leptin (5 μg/day sc for 14 days; P = 0.003). When saline-infused ob/ob mice were placed on a HF diet for 14 days, an increase in hypothalamic PTP1B mRNA expression was detected (P = 0.001) despite the absence of circulating leptin. In addition, although ob/ob mice were much more sensitive to leptin on a low-fat (LF) diet, a reduction in this sensitivity was still observed following exposure to a HF diet. Taken together, these data indicate that hypothalamic PTP1B is specifically increased during HF diet-induced leptin resistance. This increase in PTP1B is due in part to chronic hyperleptinemia, suggesting that hyperleptinemia is one mechanism contributing to the development of leptin resistance. However, these data also indicate that leptin is not required for the increase in hypothalamic PTP1B or the development of leptin resistance. Therefore, additional, leptin-independent mechanisms must exist that increase hypothalamic PTP1B and contribute to leptin resistance.
- high-fat diet
- food intake
- protein tyrosine phosphatase 1B
obesity is associated with increased circulating leptin and resistance to exogenous leptin administration (4, 10, 22, 23). Although the existence of leptin resistance is well accepted, the cellular mechanisms that contribute to changes in leptin sensitivity are not as well characterized (27). Protein tyrosine phosphatase 1B (PTP1B) is a cellular protein implicated in the regulation of cellular insulin and leptin signaling. Initial work focused on PTP1B as a regulator of insulin signaling, since it was shown that PTP1B directly dephosphorylates and inhibits signaling from the insulin receptor (11, 33, 36) in a variety of peripheral tissues (8, 14, 15, 41) and that whole body PTP1B deletion increases insulin sensitivity and protects against diet-induced obesity and insulin resistance (16, 20). A direct link between PTP1B and leptin signaling was subsequently noted, based on evidence that PTP1B dephosphorylates Janus Kinase 2 (Jak2), the initial tyrosine kinase mediating leptin signaling (9, 28, 40) and that mice with whole body PTP1B deletion are hypersensitive to leptin (9, 19, 40).
In addition to being expressed in peripheral tissues, PTP1B is also expressed in the brain, including areas of the hypothalamus (40). Neuron-specific deletion of PTP1B recapitulates many phenotypes of the whole body knockout, including the increased leptin sensitivity and resistance to diet-induced obesity (3). More recent experiments have shown that knockdown of PTP1B within the hypothalamus enhances leptin (and insulin) sensitivity and protects against diet-induced obesity (30). PTP1B levels also appear to be elevated in specific physiological or pathophysiological settings of leptin resistance, since available data indicate that levels of PTP1B mRNA, protein, and activity increase in settings of leptin resistance associated with age, high-fat diet, or acute inflammation (25, 30, 42). The current work provides additional evidence indicating that hypothalamic PTP1B is increased in settings of high-fat diet-induced leptin resistance and tests the hypothesis that chronic hyperleptinemia underlies both the increase in PTP1B and the development of leptin resistance.
All procedures were performed in accordance with the National Institutes of Health guidelines for the care and use of animals and were approved by the Animal Care and Use Committee of Pennington Biomedical Research Center. Unless otherwise noted, ∼10-wk-old male Long Evans rats (Harlan Laboratories, Indianapolis, IN) or 8-wk-old wild-type or leptin-deficient ob/ob mice on the C57BL6 background (Jackson Labs, Bar Harbor, ME) were housed singly and maintained on a 12:12-h light-dark cycle with ad libitum access to standard rat chow and water unless otherwise noted. For third ventricular (icv) cannulation (24, 26), rats were anesthetized and placed in a stereotaxic device. With the use of aseptic techniques, the skull was exposed, head screws were inserted, and a 22-gauge stainless steel cannula was implanted at coordinates −2.2 from bregma and −7.5 from dura (3rd cerebroventricle). After the cannula was anchored and all skull openings were sealed with dental acrylic, the incision was sutured and a 28-gauge obdurator was placed in the cannula. After surgery, animals were treated with analgesics and allowed to recover at least 1 wk before further study.
Experiment 1: Effect of a HF diet on central leptin resistance and hypothalamic PTP1B.
Rats bearing an intracerebroventricular cannula were placed on a high-fat (HF) diet (60% fat diet-D12492; Research Diets, New Brunswick, NJ) or the corresponding control low-fat (LF; 10% fat D12450B) diet for 28 days. On day 28 of HF feeding, rats were randomly assigned to receive an intracerebroventricular injection of either leptin (3 μg; National Hormone and Peptide Program, Dr. A. F. Parlow) or vehicle (saline) ∼2 h before lights off, and 4- and 24-h food intake was recorded. To assess levels of hypothalamic PTP1B, a separate group of uncannulated Long Evans rats was placed on the HF or LF diet as above for 28 days. On day 28, rats were rapidly decapitated, and brains were blocked and frozen on crushed dry ice for subsequent protein extraction and Western Blot analysis.
Experiment 2: Effects of chronic hyperleptinemia on PTP1B expression.
Two studies were conducted. In the first, rats were implanted with indwelling intracerebroventricular cannulas as described above and 1 wk later were implanted with Alzet osmotic minipumps (Durect, Cupertino, CA) delivering leptin (3 μg/day) or saline for 14 days. On day 14, minipumps were disconnected, and rats were allowed to recover for an additional 5 days (day 19). On day 4, day 14, or day 19 (5 days postinfusion), subgroups of rats were killed, and brains were collected and processed for PTP1B mRNA expression. Epididymal and retroperitoneal fat pads were removed and weighed as a measure of body adiposity. In addition to this primary study, an additional study was also conducted that was similar to that described above, except that rats were infused for only 10 days with either saline or leptin (3 μg/day icv) before death.
Experiment 3: Effects of HF diet on PTP1B expression and leptin sensitivity in ob/ob mice.
To test the effects of leptin and diet on PTP1B mRNA expression, 8-wk-old male ob/ob mice and wild-type controls on C57BL6 background were randomly assigned to either a LF or HF diet and consumed the diet for 14 days. At the onset of diet treatments, mice were also implanted with subcutaneous osmotic minipumps delivering either leptin (5 μg/day) or saline. After 14 days of infusion, body weight gain (average daily gain) was determined, mice were killed, and hypothalami were isolated to assess PTP1B mRNA expression via real-time PCR.
To test the effects of HF diet on leptin sensitivity in ob/ob mice, a separate group of wild-type and ob/ob mice was injected with varying doses of leptin to establish doses producing roughly equivalent decreases in food intake following intraperitoneal leptin injection. Once equivalent doses were identified on a LF diet, these mice were placed on a HF diet for 14 days and were then treated with leptin or saline, and 24 h food intake was recorded. On the day of individual study, food was pulled ∼3 h after lights on, injections were made ∼2 h before lights off, food was returned 1 h later, and food intake over the subsequent 24 h was assessed.
RNA extraction and real-time PCR analysis.
PTP1B mRNA expression was measured in wedges of mediobasal hypothalamus, defined caudally by the mammillary bodies, rostrally by the optic chiasm, laterally by the optic tract, and dorsally by the apex of the third ventricle (24, 25). These punches contain principally arcuate nucleus, but we cannot rule out the inclusion of other brain areas and for this reason refer to them as mediobasal hypothalamus. Specifically, it is possible that portions of the ventromedial nucleus, superchiasmatic nucleus, and premammillary areas may also be included. Mediobasal hypothalamic wedges were excised, and total RNA was isolated using Tri-Reagent (Molecular Research Center, Cincinnati, OH) and quantified spectrophotometrically. Confirmation of intact 18S and 28S RNA bands was achieved by ethidium bromide staining after electrophoresis of samples in 1% agarose/formaldehyde gels. mRNA was reversed transcribed into cDNA, and mRNA expression was determined using the SYBR green methodology in optical 384-well plates in an ABI PRISM 7900 sequence detector (Applied Biosystems, Branchburg, NJ). All expression data were normalized to cyclophilin or glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression levels. Primers were designed using the PrimerExpress Software (Applied Biosystems). Primers are as follows: rat Ptp1b (ptpn1), forward: cgagggtgcaaagttcatcat, reverse: ggtcttcatgggaaagctcctt; Mouse PTP1B (ptpn1), forward: gaaggcagagcccagtcaag, reverse: catggatgtggtacggaaggt; rat cyclophilin, forward: ggagatggcacaggaggaaa, reverse: cccatagtgcttcagcttgaagtt; mouse cyclophilin, forward: catggatgtggtacggaaggt, reverse: tgacatccttcagtggcttgtc; rat GAPDH, forward: aacgaccccttcattgac, reverse: tccacgacatactcagcac.
Protein extraction and Western blot.
Frozen brain blocks containing hypothalamus were placed on a cryostat and trimmed on each side to reproducible anatomical points just before and after the hypothalamic arcuate nucleus (∼3 mm thick). A single punch was made over each arcuate nucleus (2 punches/section) using a 0.8-mm-diameter punch in a slightly overlapping pattern along the midline (over the 3rd ventricle). As above, these punches contain principally arcuate nucleus, but we cannot rule out the inclusion of other brain areas and for this reason refer to them as punches of mediobasal hypothalamus. Punches were placed in lysis buffer [1% Triton X-100, 100 mmol/l Tris (pH 7.4), 100 mmol/l sodium pyrophosphate, 100 mmol/l sodium fluoride, 10 mmol/l EDTA, 10 mmol/l sodium vanadate, 2 mmol/l phenylmethylsufonyl fluoride, and 0.1 g/l aprotinin] and snap-frozen using liquid nitrogen. Subsequently, the extracts were sonicated and centrifuged to remove insoluble material. Total protein (50 μg) was electrophoretically separated on an SDS-PAGE and transferred to a nitrocellulose membrane. Blots were blocked in 5% nonfat dry milk or 1% BSA and probed with a commercially available PTP1B antibody (1:1,000; Upstate Biotechnology, Lake Placid, NY). Positive signal was imaged using a chemiluminescent substrate (ECL Reagent; Amersham Biosciences, Piscataway, NJ) and exposure to autoradiograph film, and afterward the blot was stripped and reprobed for levels of β-actin.
Statistical analysis.
Data were analyzed using the SAS software package (SAS V8; SAS Institute, Cary, NC) using a two-tailed t-test or ANOVA using the general linear model procedure. When experiment wide tests were significant, post hoc comparisons were made using the LSMEANS statement with the PDIFF option, and thus represent least-significant difference tests for preplanned comparisons. In some studies, animal numbers were spread across two independent replicates, with replicate included in the statistical model. For Western blot analysis, levels of PTP1B were normalized to β-actin, whereas for PCR levels were normalized to cyclophilin or GAPDH. All data are expressed as means ± SE, with a probability value of <0.05 considered statistically significant.
Experiment 1: HF diets induce central leptin resistance and increase hypothalamic PTP1B.
In response to 28 days of HF feeding, rats exhibited increased body weight, body adiposity, and circulating leptin levels (Fig. 1). In addition, PTP1B protein levels within the mediobasal hypothalamus were significantly higher in HF-fed rats compared with LF-fed rats (P = 0.003; Fig. 2). These increases in body adiposity, circulating leptin, and hypothalamic PTP1B are also associated with the development of central leptin resistance, since animals consuming HF diet for 28 days failed to respond to leptin (P = 0.36; Fig. 3), even though this dose is sufficient to significantly suppress food intake in LF-fed rats (P = 0.03). Consistent with previous observations (25, 30), these data indicate that hypothalamic PTP1B levels are increased in a setting of leptin resistance and likely contribute to the reduction of leptin sensitivity.
Experiment 2: Effects of chronic hyperleptinemia on hypothalamic PTP1B expression.
Because obesity is associated with a chronic elevation of circulating leptin, we tested the hypothesis that chronic hyperleptinemia increases PTP1B. To test this hypothesis, two experiments were conducted to determine whether chronic intracerebroventricular leptin infusion (3 μg/day) is sufficient to increase hypothalamic PTP1B expression. In the first study, leptin was continuously infused for 14 days, and rats were killed on days 4, 14, and 19 to generate groups collected during the maximal effect of leptin on food intake (day 4), when the effects of leptin on food intake were diminished (day 14), and then following the cessation of leptin infusion when body weight is recovering (day 19). As expected, leptin infusion significantly decreased both body weight and food intake (P < 0.01; Fig. 4, A and B), although the effects of leptin on food intake waned over time such that food intake was largely normalized by day 14 (Fig. 4A). Leptin also markedly reduced retroperitoneal and epididymal fat pads in a time-dependent fashion, with retroperitoneal fat pad weights being numerically but not significantly lower on day 4 (1.08 ± 0.1 vs. 0.82 ± 0.2 g; P > 0.26), markedly decreased on day 14 (1.8 ± 0.2 vs. 0.2 ± 0.06 g; P < 0.001), and beginning to normalize by day 19 (1.2 ± 0.2 g vs. 0.55 ± 0.2 g; P < 0.05). Hypothalamic PTP1B mRNA levels were significantly increased on day 14 (P = 0.02; Fig. 4C). However, no effect of leptin on PTP1B mRNA expression was detected on days 4 or 19, indicating that the increase in PTP1B mRNA expression requires chronic leptin exposure and readily normalizes following the cessation of leptin infusion.
In addition to this primary study, an additional group of rats were implanted with indwelling osmotic minipumps and infused with leptin (3 μg/day icv) or saline for 10 days to replicate the observed effect of chronic leptin administration. As before, leptin treatment persistently reduced body weight but only transiently reduced food intake (Fig. 4, D and E). Levels of PTP1B mRNA were significantly increased in leptin-infused rats compared with vehicle-infused controls on day 10 (P = 0.01; Fig. 4F), replicating the previous observation and indicating that hyperleptinemia is sufficient to increase hypothalamic PTP1B, independent of a change in body adiposity or exposure to dietary fat.
Experiment 3: HF diet increases PTP1B and induces leptin resistance in the absence of hyperleptinemia.
The above experiments suggest that leptin is sufficient to increase hypothalamic PTP1B, but they do not test whether hyperleptinemia is necessary for diet-induced increases in PTP1B or the development of leptin resistance. To test the necessity of hyperleptinemia, leptin-deficient ob/ob mice or wild-type controls (C57BL6 background) were placed on a HF or LF diet for 14 days and simultaneously infused with leptin (5 μg/day) via subcutaneous osmotic minipumps. In response to a HF diet, ob/ob mice exhibited a marked increase in their rate of body weight gain compared with wild-type mice, with wild-type mice increasing the rate of body weight gain by 31% on the HF diet but with ob/ob mice increasing weight gain by 737% on the HF diet. Leptin infusion reduced body weight gain by 93% in wild-type mice on a LF diet (P = 0.007; Fig. 5A), but by only 34% in wild-type mice on the HF diet (P = 0.09; Fig. 5A). In ob/ob mice, leptin significantly suppressed weight gain on both the LF and the HF diet (P < 0.01). However, the efficacy of this effect was varied, since leptin infusion suppressed body weight gain by 103% in mice on the LF diet but only by 40% in ob/ob mice on the HF diet. These data are consistent with the possibility that HF diets reduce the efficacy of leptin signaling, even in the absence of leptin.
After 14 days of treatment, mice were killed, and levels of PTP1B in the mediobasal hypothalamus were determined via real-time PCR. In wild-type mice, chronic leptin treatment increased PTP1B mRNA expression (P = 0.048; Fig. 5B), whereas exposure to a HF diet alone also increased hypothalamic PTP1B mRNA expression (P = 0.069; Fig. 5B). In ob/ob mice, chronic leptin infusion also increased hypothalamic PTP1B mRNA expression compared with saline-infused ob/ob mice on a LF diet (P < 0.001; Fig. 5B). In addition, exposure to a HF diet alone also increased PTP1B mRNA levels in ob/ob mice (P < 0.001; Fig. 5B). Although this HF-induced increase in PTP1B replicates our prior observations in rats, this increase cannot be dependent on hyperleptinemia because it occurs in a leptin-deficient background.
If HF diet-induced increases in PTP1B do not depend on hyperleptinemia, then it is possible that the induction of HF diet-induced leptin resistance also does not depend on hyperleptinemia. To directly test this hypothesis, leptin sensitivity was determined in wild-type (C57BL6) and ob/ob mice on a LF or HF diet. There were again marked differences in the effect of HF diet on body weight gain between wild-type and ob/ob mice, with wild-type mice increasing average daily gain by 46% on the HF diet and ob/ob mice increasing average daily gain by 564% (Fig. 6A). On a LF diet, wild-type mice required a substantially larger dose of leptin intraperitoneally to produce an equivalent reduction in food intake compared with ob/ob mice (Fig. 6, B and C), indicating that the absence of leptin markedly enhances the sensitivity to exogenous leptin. However, when placed on a HF diet for 14 days, both ob/ob mice and wild-type mice exhibited a decrease in leptin sensitivity, since doses that significantly suppressed food intake on LF (P < 0.05; Fig. 6, B and C) did not significantly decrease food intake in animals fed a HF diet (P > 0.05). Thus hyperleptinemia is not required for HF diet-induced increases in PTP1B or decreases in leptin sensitivity.
Exposure to a HF diet leads to increased body adiposity and a syndrome of leptin resistance (23, 27). Yet, whether leptin resistance is primarily a cause or a consequence of diet-induced obesity remains a matter of debate (35). Leptin resistance involves at least two separate mechanisms, the first being reduced transport across the blood-brain barrier (2) and the second a reduced capacity for cellular leptin signaling within target neurons (27). This latter resistance is evident in the attenuated response to direct brain leptin injections (which bypass the blood-brain barrier), both in terms of food intake and activation of intracellular signaling.
PTP1B is a phosphatase that binds to and dephosphorylates Jak2, the initial tyrosine kinase mediating leptin receptor signaling (9, 40). Overexpression of PTP1B in vitro dampens leptin receptor signaling (19), and global or neuron-specific deletion of PTP1B produces mice that are lean, hypersensitive to leptin, and resistant to diet-induced obesity (3, 9, 40). The primary objective of the current work was to determine whether PTP1B is a dynamic regulator of leptin signaling, whether increased PTP1B contributes to the acute loss in leptin sensitivity that accompanies a HF diet, and to identify potential mediators of this change.
To test this overall hypothesis, we first determined whether levels of PTP1B were increased within leptin-sensitive brain areas in settings of leptin resistance. The current work demonstrates that resistance to intracerebroventricular leptin is evident within 28 days of feeding a HF diet, and this leptin resistance is associated with a significant increase in PTP1B protein within the mediobasal hypothalamus. These observations are consistent with our prior evidence for increased PTP1B in a model of age-associated leptin resistance (25), since in both cases we detect increased PTP1B protein levels in leptin-resistant animals compared with leptin-sensitive animals. These observations are also consistent with recent publications showing similar increases in PTP1B mRNA or protein in animals consuming a HF diet (30, 42). These publications also suggest that increases in PTP1B protein reflect transcriptional activation and increased PTP1B mRNA (42) and that the increase in PTP1B protein is associated with a complementary increase in PTPT1B activity (30). Therefore, although our data only capture changes in PTP1B mRNA or protein, these and other data suggest a strong correlation between PTP1B activity and mRNA and protein levels (7, 13, 32, 37, 39). Last, considering that mouse genetic models clearly implicate PTP1B in the regulation of leptin signaling (3, 9, 19, 40), these data suggest that PTP1B is not simply a constitutive regulator of leptin signaling but instead that PTP1B contributes to the reduction in leptin sensitivity that occurs following exposure to a HF diet.
If increased PTP1B contributes to the development of leptin resistance, then identifying mechanisms underlying this increase may provide an opportunity to prevent leptin resistance. PTP1B is increased in models of age- and diet-induced obesity, and each of these settings is associated with changes in body adiposity and circulating leptin levels. Therefore, it is possible that increased body adiposity, increased circulating leptin, or both might contribute to the observed increases in PTP1B. To test whether hyperleptinemia is sufficient to increase PTP1B in the absence of obesity, leptin was chronically infused in the third cerebroventricle of normal, chow-fed rats. As expected, leptin persistently suppressed body weight but exerted a biphasic effect on food intake that was marked by an initial decrease in food intake followed by an eventual waning of this effect. This weakening of the feeding response following prolonged leptin infusion has been termed leptin-induced leptin resistance (29, 34). Interestingly, no difference was observed in hypothalamic PTP1B levels at the early time point (day 4), when leptin was maximally suppressing food intake. Similarly, no effect of leptin was detected on day 19, five days following the cessation of leptin infusion. However, a significant increase in PTP1B mRNA was detected at day 14, coincident with the period when leptin's anorectic effects were diminished.
To replicate this effect of chronic leptin treatment, a second study was conducted in which rats were infused chronically with leptin intracerebroventricularly for 10 days. Leptin again exerted a biphasic effect on food intake but a persistent reduction of body weight, and again a significant increase in PTP1B mRNA expression was observed during the period in which leptin's suppression of food intake was diminished (day 10). Thus this second experiment validates the first and suggests that chronic exposure to leptin is sufficient to increase hypothalamic PTP1B. It should be noted that both studies involved intracerebroventricular infusions of leptin at doses that are likely pharmacological. As such, these data do not definitively prove that obesity-induced hyperleptinemia contributes to the observed increases in PTP1B in rats (and mice) on a HF diet. It is also not clear why the increase in PTP1B was only observed following prolonged exposure to leptin, and this delay in the leptin effect suggests that the increase in PTP1B may not be due to a direct effect of leptin. In both studies, the increase in PTP1B was observed only when leptin-dependent suppression of food intake waned, leading to the speculation that the increase in PTP1B might contribute to the observation of leptin-induced leptin resistance. In addition, following removal of this elevated leptin, PTP1B levels normalize in association with normalized leptin sensitivity, as has been demonstrated in animals that are fed a HF diet but then returned to a chow diet (18). In summary, these data suggest that prolonged exposure to high levels of leptin is sufficient to increase PTP1B and that chronic hyperleptinemia may contribute to the effects of HF diet on hypothalamic PTP1B levels.
The above experiments suggest that chronic hyperleptinemia is sufficient to increase hypothalamic PTP1B expression. To determine whether this hyperleptinemia is necessary for the increase in PTP1B following a HF diet, the effects of a HF diet on hypothalamic PTP1B were tested in ob/ob mice, since this approach removes any effect of leptin. In wild-type mice, exposure to a HF diet attenuated the effect of leptin to reduce body weight gain, consistent with the hypothesis that HF diets induce leptin resistance. In addition, exposure of wild-type mice to either chronic leptin infusion or to a HF diet led to increases in hypothalamic PTP1B expression. Thus these observations are consistent with the experiments in rats, and indicate that either chronic hyperleptinemia or a HF diet is sufficient to increase hypothalamic PTP1B expression. In ob/ob mice, chronic leptin infusion again increased PTP1B mRNA expression within the hypothalamus. In addition, hypothalamic PTP1B mRNA was also increased in saline-infused ob/ob mice on a HF diet. Although this observation is consistent with previous experiments, it is also unique considering that the HF diet is increasing PTP1B in the absence of hyperleptinemia. Therefore, while chronic hyperleptinemia appears to be sufficient to increase PTP1B within the hypothalamus, it appears to not be necessary for HF diet-induced increases in PTP1B.
In addition to the observed changes in PTP1B, it should also be noted that ob/ob mice exhibited a marked increase in body weight gain compared with wild-type mice on a HF diet. This effect was observed in both studies, with the HF diet increasing weight gain by 30–40% in wild-type mice but increasing weight gain by 500–700% in ob/ob mice. These data provide compelling evidence that the absence of leptin exacerbates HF diet-induced obesity and by extension are also consistent with the hypothesis that loss of leptin signaling (leptin resistance) similarly exacerbates the response to a HF diet. These observations are consistent with previous work indicating that manipulations which inhibit leptin signaling result in increased weight gain when animals are placed on a HF diet (43). Thus these data collectively support a model in which physiological leptin signaling provides a protection against HF diet-induced weight gain, although this protection is incomplete and insufficient to prevent some weight gain. Yet, because this protection exists, individuals with reduced (leptin resistant) or absent (ob/ob mice) leptin signaling exhibit an exacerbated response to a HF diet.
If levels of PTP1B are increased in HF-fed ob/ob mice, then is it possible that leptin resistance also develops in the absence of hyperleptinemia? To test this hypothesis, we first established doses of leptin that produce equivalent changes in food intake between wild-type and ob/ob mice on a LF diet. On a LF diet, ob/ob mice were substantially more sensitive to intraperitoneal leptin administration, reinforcing the concept that leptin inhibits its own sensitivity. However, despite the high baseline leptin sensitivity, doses of leptin that suppressed food intake in LF-fed ob/ob mice failed to significantly suppress food intake following 14 days on a HF diet. Thus these data not only demonstrate that HF diets reduce leptin sensitivity; they also indicate that hyperleptinemia is not necessary for this loss of sensitivity.
The current work provides evidence for four major conclusions regarding the relationship between HF diets, hyperleptinemia, hypothalamic PTP1B levels, and leptin resistance. The first is that PTP1B levels are dynamically regulated and increased within the mediobasal hypothalamus in settings of leptin resistance, consistent with prior observations (30, 42). The implication therefore is that PTP1B is not simply a static regulator of leptin signaling but instead that alterations in PTP1B levels or activity are positioned to contribute to fluctuations in leptin sensitivity. A second major conclusion of the current work is that chronic exposure to leptin is sufficient to increase PTP1B mRNA levels within the mediobasal hypothalamus. This observation is consistent with evidence supporting the existence of leptin-induced leptin resistance (29, 34) and suggests that periods of chronic hyperleptinemia may induce leptin resistance via an induction of PTP1B. If so, these observations raise the possibility that PTP1B acts as a negative feedback regulator for leptin signaling, similar to Socs3 (5). Socs3 and PTP1B both inhibit leptin receptor signaling, although they impinge on different sites on the leptin receptor. Socs3 binds to specific tyrosine residues of the leptin receptor and attenuates leptin activation of Stat3 and perhaps other signaling systems (1, 6). Contrastingly, PTP1B dephosphorylates Jak2 (9, 40) and thus would be predicted to inhibit all aspects of downstream leptin signaling. It should be noted that, in the two current studies involving chronic leptin infusion, the increase in PTP1B was only detected following an extended period of leptin infusion. This is in contrast to the direct and rapid induction of Socs3 that occurs following leptin treatment (5, 17). Thus it remains unclear whether the increase in PTP1B is directly due to leptin signaling in the hypothalamus or indirectly due to a secondary effect of leptin infusion.
A third major conclusion from the current work is that HF diets also increase PTP1B via a mechanism that is leptin independent. The basis for this conclusion is the observation that PTP1B levels increase in leptin-deficient ob/ob mice following exposure to a HF diet and thus is by definition leptin independent. Currently, the identity of this leptin-independent mechanism is unknown. To date, there is relatively little information regarding cellular mechanisms regulating PTP1B expression, although there is evidence that leptin and other cytokine receptors stimulate PTP1B expression or activity (7, 21). One possibility is insulin, since there is evidence that insulin regulates PTP1B activity (12, 31, 38). However, in the current study, we did not detect a significant difference in insulin levels between HF and LF rats (LF: 5.13 ± 0.93; HF: 5.95 ± 0.92 ng/ml, P = 0.56), despite the increase in PTP1B. In addition to insulin, a very recent publication indicates that inflammation upregulates PTP1B mRNA and protein levels in a variety of tissues, including the hypothalamus (42), primarily via the activation of tumor necrosis factor-α and nuclear factor-κB. Obesity is often associated with an increase in inflammatory markers, and as such it is possible that HF diets increase tumor necrosis factor or some other inflammatory signal, leading to leptin-independent increases in PTP1B.
Last, the fourth major conclusion is that leptin resistance can develop in the absence of hyperleptinemia. This conclusion extends from observations demonstrating that the efficacy of leptin to suppress body weight gain and food intake is attenuated in ob/ob mice consuming a HF diet. Again, because these observations are made in the absence of leptin, the conclusion is that these changes must be leptin independent. In addition, the congruency between hypothalamic PTP1B levels and leptin sensitivity is consistent with a leptin-independent increase in PTP1B contributing to the induction of HF diet-induced leptin resistance in ob/ob mice. These issues of leptin dependence and independence have significant implications for the understanding of leptin resistance and its contribution to the development of obesity. If the development of leptin resistance were to depend on hyperleptinemia and thus require the preexistence of obesity, then leptin resistance would by necessity be primarily a consequence of obesity. As such, the observation that chronic hyperleptinemia is sufficient to induce PTP1B and leptin resistance indicates that at least a portion of the leptin resistance that is observed in obesity is likely a consequence of the excess leptin production. Nevertheless, we also observed increases in PTP1B and the induction of leptin resistance in the absence of hyperleptinemia. These data are therefore also consistent with the possibility that leptin resistance develops before obesity (hyperleptinemia) and as such contributes to its development.
In summary, the data described herein demonstrate that exposure to a HF diet is sufficient to reduce responsiveness to intracerebroventricular leptin administration in rats and that this loss of leptin sensitivity is associated with increases in PTP1B within the mediobasal hypothalamus. The current data also provide support for both a leptin-dependent and leptin-independent mechanism underlying this increase, with the leptin-dependent mechanism illustrated in the increases in PTP1B mRNA levels in response to chronic leptin infusion and the leptin-independent mechanism illustrated by the increased PTP1B and induction of leptin resistance that occurs in ob/ob mice on a HF diet.
This work was supported in part by National Institutes of Health (NIH) Grants NS-051570 and RR-021945 and the Pennington Biomedical Research Foundation to C. D. Morrison, and by the Molecular Mechanisms, Genomics or Cell Biology & Bioimaging core facilities that are supported in part by a Clinical Nutrition Research Unit (NIH 1P30-DK-072476) center grant.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
- Copyright © 2009 the American Physiological Society


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Marriage 2 Emma E. SMITH b: 6 NOV 1908 in Daviess County, Indiana/ lived in Wheatland, Indiana most of her life
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Future unknown, Thome remains focused
Free agency looms for prolific slugger after season
By Scott Merkin / MLB.com
Thome currently is playing under a $13 million option that was vested when he reached 1,100 plate appearances over the past two years. But as much as Thome has enjoyed his time in Chicago and has made countless contributions on and off the field, he figures to be a free agent in search of a taker during the upcoming offseason.
Could Cleveland be a potential destination for a slugger with 600 home runs in range over the next two or three years? It was a topic discussed in a USA Today article earlier this season, with Thome taking that never-say-never approach.
The Indians have Travis Hafner under contract through 2012 as the team's designated hitter, with a combination of Victor Martinez and Ryan Garko at first base. But Thome was so embedded in the community and as a part of the organization during his run in Cleveland from 1991-2002 that the chance for him to come back could be intriguing.
As far as Thome is concerned, those sorts of issues can wait until the season is over to thoroughly explore.
"My main focus is to stay healthy and look into now," Thome told MLB.com prior to his scheduled day off on Wednesday. "The bottom line is Cleveland was very special, as have been all the cities I've played.
"Philadelphia was great, and I wouldn't have changed my experience there for the world. Chicago has been tremendous, being able to come back home.
"In this business, you never say never," Thome said. "But focus on the task in front of you. Don't get ahead of yourself and try not to get into 'Is this going to happen?' or 'Is that going to happen?' For me, I try to enjoy every minute of the latter part of my career here."
Following his highly productive stint with the Indians, during which Thome had seven seasons of at least 30 home runs, he signed a six-year, $85 million deal with the Phillies as a free agent. Thome was traded to the White Sox prior to the 2006 season and has not exactly received a warm reception in his yearly returns to Progressive Field.
It's not something that Thome takes personally, not when he continues to hit as he does at the Indians' home ballpark. He has a .300 average, seven home runs and 25 RBIs in 26 games played there as an opponent.
"Coming back is always nice," Thome said. "It's always fun hitting in this park. When I step in the box, it's a good feel.
"This is the issue. Fans are very passionate, and you have to understand as a player, whenever you leave a place where you spent a long time, where fans love you and show passion to you, you have to understand when you leave, there's potentially a negative reaction. They have the right to boo.
"I understand that. You move ahead," Thome said. "You don't regret any decisions, because when you make decisions you have to live by them."
With Thome still a viable option as a hitter, and an even better option as a quality clubhouse presence, there figures to be teams interested in bringing him into their future fold. For now, Thome is a proud member of the White Sox and that's the only point of interest for the 38-year-old potential Hall of Famer.
"You do wonder, you definitely wonder, obviously I want to keep playing," Thome said. "If something would happen where I couldn't return [to Chicago], I have to look out there and say which team would I want to play for. I try not to go there.
"I've had such a great time in Chicago, and I'm so blessed I was able to come back and be a part of this great organization. But out of respect to all parties, you just play baseball. You try as you get older, don't get ahead of yourself. You look what's out there, but you don't disrespect anybody."
Scott Merkin is a reporter for MLB.com. This story was not subject to the approval of Major League Baseball or its clubs.


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Police log - July 24, 2013
The police log was supplied by the Washington County Communications Center.
An arrest is merely an accusation. All suspects should be considered innocent until proven guilty in a court of law.
Total — 29
Treatment — 0
Male section — 15
Female section — 3
Work release — 0
Holding — 0
Special needs – 0
Contract inmates — 11
Traffic accidents
A semi vs. deer accident was reported Wednesday morning at Highway 22 and E Avenue in Kalona. Officers responded. The incident was documented.
Fire calls
A gas leak was reported Tuesday night in the 300 block of West Main Street in Washington. Washington Fire Department and officers responded.
A possible domestic situation was reported Tuesday morning in the 3100 block of Highway 22 in Riverside. The incident was documented.
All other thefts
A wallet was reported missing from a vehicle in the 900 block of East Third Street in Washington Tuesday morning. The incident was documented.
A subject reportedly left a business in the 1500 block of East Washington Street in Washington with tea and cigarettes after his debit card was declined Tuesday afternoon. Officers attempted to locate.
A bicycle was reported stolen Tuesday afternoon from the 100 block of South Sixth Street in Kalona. The incident was documented.
A vehicle with several subjects inside was reported in a parking lot in the 300 block of South Iowa Avenue in Washington Tuesday afternoon. Someone reportedly threw a bottle out the window and it broke.
A subject reportedly scratched the caller's car with her keys Tuesday evening in the 200 block of North Second Avenue in Washington. Officers responded.
Someone reportedly vandalized metal fencing in the 300 block of North B Avenue in Washington Tuesday evening. Officers responded. The incident was documented.
A violation of a no-contact order was reported Tuesday morning in the 1600 block of North Fifth Avenue in Washington. Officers spoke with the caller.
A caller in the 600 block of South Third Avenue in Washington reported harassment from the neighbors. Officers spoke with the caller.
Phone trap
A caller in the 800 block of East 15th Street in Washington reported Tuesday afternoon receiving nuisance phone calls from the last three days. The incident is under investigation.
Animal complaints
A caller reported Tuesday afternoon having to swerve to miss goats in the 2200 block of 170th Street in Washington. Officers responded.
Several cats were reported roaming in a neighborhood in the 500 block of South D Avenue in Washington, a caller reported Tuesday afternoon. Officers responded and spoke with the owner.
A barking dog was reported Tuesday afternoon in the 1300 block of First Avenue in Wellman. Officers responded. A note was left for the owner.
All other offenses
A young girl was reported playing in the fountain in Central Park in Washington Tuesday afternoon. Officers responded. The child was returned to her mother.
An abandoned bicycle was reported in the 300 block of North B Avenue in Washington Tuesday afternoon. The bike was taken to the bike shed.
A caller reported Wednesday morning finding a bicycle by the skate park in Sunset Park in Washington. The bike was taken to the bike shed.
Suspicious activity
A caller in the 500 block of Main Street in Kalona reported Tuesday night being awakened by her cats to the noise of a woman screaming outside. Officers were unable to locate.
Family offense non violent
A loud domestic situation was reported Tuesday night in the 1900 block of 250th Street in Washington. Officers responded.


text:
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text:
Sunday, September 26, 1999 Published at 01:08 GMT 02:08 UK
Europe in sight of Ryder glory
Sergio Garcia is the toast of his Europe teammates
Overall position: USA 6-10 Europe
Europe took a huge step closer to retaining the Ryder Cup after they clung on to their four-shot lead over the USA at the end of a gripping second day in Boston.
And the draw for the final day threw up an intriguing contest between Tiger Woods and Scot Andrew Coltart, who has yet to play in the competition.
Colin Montgomerie plays US Open champion Payne Stewart, while Lee Westwood opens against Tom Lehman and Sergio Garcia plays the penultimate game against Jim Furyk.
A thrilling rearguard action late on Saturday ensured that the lead Europe had carved out on day one was kept intact.
Inspirational individual performances from Colin Montgomerie, Sergio Garcia and Miguel Angel Jimenez gave Europe two points from the afternoon fourballs - which had looked like slipping away from them after a determined American fightback.
Earlier the foursomes had also been shared two points apiece, as both teams slugged it out on a day of archetypal Ryder Cup drama.
Tension in Boston
At one stage in the fourballs the Americans were up in all four matches on the course - and threatened to claim a whitewash that would have wiped out the European advantage altogether.
And with the home side specialising in singles play, it looked as if James' men were unlikely to earn the cushion they needed going into the third day.
But in the other three matches Europe were not to be denied - even though many of their players were showing signs of tiring after being played virtually unchanged through the first two days.
James chose exactly the same foursomes and fourball pairings for Saturday as he had for Friday - which meant no place for rookies Jean Van de Velde, Andrew Coltart and Jarmo Sandelin, who will all be given their introduction to the competition in the singles.
The captain's selection policy looked like backfiring as players like Westwood, Clarke, Paul Lawrie and Jose Maria Olazabal all struggled with their games in the afternoon.
But the Ryder Cup is about more than just textbook golf - it is about the team ethic at its most intense.
Montgomerie and a flagging Lawrie beat Woods and Steve Pate in a see-saw final match.
And there were half points for Europe's new "dream team" of Garcia and Jesper Parnevik and the all-Spanish pairing of Jimenez and Olazabal.
Nineteen-year-old Garcia showed he is unfazed by the big occasion when he sank a 10ft putt at the 18th to level his match with Davis Love and David Duval.
Jimenez was equally deadly on the greens and his efforts earned another crucial half against Justin Leonard and Hal Sutton.
Foursomes shared
In an equally close-fought morning session, the foursomes spoils were shared in stormy New England conditions.
Westwood and Clarke beat Mark O'Meara and Jim Furyk 3&2, while Parnevik and Garcia saw off the challenge of Payne Stewart and Leonard by the same score.
But the Americans hit back with two narrow victories to keep alive their own chances of a final day comeback.
And then Woods and Pate finally beat Jimenez and Padraig Harrington one-up to take some gloss off the European morning.
Team spirit remains Europe's best hope of success and an emotional Montgomerie, who was subjected to more barracking from the crowds, said: "I've never been part of a team like this before.
"We all want to play, we all want to be there, we all want to win so, so badly for our tour.
"This is fantastic and I really do want to win this thing, I really do."
Saturday's foursomes results:USA first
Saturday's fourball results:USA first
Draw for the concluding singles on Sunday (US first, all times BST)
1538 Tom Lehman v Lee Westwood


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We ordered a ladies Accurist watch late yesterday morning & it arrived less than 24hrs later....... on a Saturday morning!! Superb service, and the watch was immaculate - just as described. Given this, plus their very competitive pricing & free P & P, how can I do other than say that I'd thoroughly recommend their service. Well Done to the nice people at 'Find Watches'. Many Thanks … Read Full Review
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Very nice friendly manner on the phone efficient and pleased with my purchase… Read Full Review
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The service was brilliant received goods in three days, from order date,saving 50% on purchase prise After a top jeweller had failed to replace the Item despite insurance cover… Read Full Review
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Getting ready for the holidays with kids can be exciting or stressful, depending on how you look at it. As moms, we want the holiday season to be magical for our children—twinkling eyes, cold noses, warm hot chocolate. We have images of snow covered fields filled with green Christmas trees that Daddy's tie on the roof without any fuss. We dream about children in cozy pajamas happily hanging shinny ornaments. The reality is that if we are not careful, we can end up with crying babies, whining children, and frustrated mommy's and daddy's thinking—"When is bedtime?"
If you are like me, then you like to decorate every inch of your house—the front yard, all the rooms–you name it, it gets decorated. I have learned that if you start pulling out boxes of decorations, things get overwhelming quickly. Keep it simple for kids—pick out two or three things that they can help you with (things that are non-breakable) and then let them go to town. If you are particular about how you want your tree to look, consider buying another small tree for another area in your house—let the kids have complete say on this one. We bought a 3 inch tree for the kitchen—it has candy canes on it and all of the decorations that they bring home from school. Then I know that there is a place for these "treasures"—just maybe not on my tree. I also let them each pick out a small tree for their rooms (one pink, one blue, and one green.) We also chose a few decorations for my daughter's doll house, including a miniature tree, which was just an old ornament from our large tree.
As we head into December, I plan to post some more ideas and tips about how to decorate for the Holidays, and maybe even some ideas for a few homemade gifts. For now, just remember to relax and enjoy the magic through the eyes of your children—it truly is such an exciting time of the year!
Guest Writer
Latest posts by Guest Writer (see all)
- 7 Ways Pregnancy is Less than Awesome - November 10, 2015
- Feeding Your Toddler a Balanced Meal - April 29, 2015
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City Capri
USD 68.00InStock
Product Details
Stay cool and comfortable all day long in our lightweight stretch City Capri.
- Straight leg silhouette is not too tight for a flexible fit you can layer over your tights, or wear solo for easy forward motion
- 24" inseam with ribbed knit cuff that allows you to customize the length
- Wide, flattering waistband with external drawcord
- Back zippered storage pocket keeps your essentials secure
- Designed For: Running
- Layer: Base
- Temperature Range: 40F to 65F
- Fit: Straight
- Inseam: 21.5"
- Rise: Medium
- Number of Pockets: 1
- Waterproof: No
- Water Resistant: No
- Windproof: No
- Care Instructions: Machine washable, hang to dry
- Fabric Breakdown: Herringbone Stretch Woven (95% Nylon, 5% Spandex)
Breathing is good, whether you're a human or a piece of running gear. The materials in this product are designed to move moisture away from the skin, to keep you running dry and comfortable.
Sweat can cling to your skin and clothes, making you cold, clammy or just plain uncomfortable. Wicking materials move sweat away from your skin. Problem solved.
Recommended Products
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text:
Evocative, an exhibition of sculpture, ceramics, paintings, photographs, prints and mixed media works was chosen by juror Paul Klein of Klein Artist Works. The exhibition opens on January 7, and features 50 small paper sculptures by Book and Paper alumna Laurie LeBreton.
Detail of LeBreton's work Almost Enough.
Works were submitted by over 80 artists from Illinois, Indiana, Iowa, Michigan, and Ohio. In choosing the 21 works from more than 270 submitted, juror Klein indicated that "I looked for art work gave me a sense of the artist, their purpose, and what they sought to communicate. I looked for sincerity, depth, and truth, as well as things that resonated for me."
The exhibition runs from Exhibiting
January 7–30, 2013, with an artists reception on Thursday, January 10, 4:30–8:00 p.m. For more information on the exhibition and the Christopher Gallery at Prairie State College, click here.


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Wednesday, July 20, 2011
Summer Sandwiches
I pack a lunch every day for work, so I am always looking to switch things up from the basic sandwich or salad (two of the easiest things to pack). A recent favorite that has graced my lunch pail and attracted glances from fellow coworkers has been this recipe which I adapted from a Taste of Home magazine.
Since I like to make things a little healthier and I am always looking for excuses to add some of my favorite ingredients (avocado), my adaptation is . . . well better :)
1-1/2 cups cubed cooked turkey breast (I like to have hubby grill mine)
1/2 cup thinly sliced celery
1/3 cup chopped dried apricots
1/4 cup chopped unsalted cashews
2 green onions, chopped
1/4 cup plain yogurt (I like to use Greek yogurt)
1 squirt of reduced-fat mayonnaise (so squirt is not a technical term, but I never measure the exact amount used)
1/2 an avocado (this can make the mixture have a brownish color the next day, so if the discoloration that occurs from the avocado turns you off and you plan to keep this in the fridge for more than a day, use less or eliminate altogether)
1/8 teaspoon celery salt
1/4 teaspoon pepper
I start out by having hubby grill half a package of Jennie-O turkey breasts. You could also use any boneless chicken - and the way you cook it is up to you.
Next, I mash up my avocado half and mix in the yogurt and mayonnaise squirt. Add the celery salt and pepper to this mixture. Set aside.
Then I chop up the remaining ingredients (turkey, celery, apricots, onions). Leave the cashews for now.
In a larger bowl combine chopped ingredients (except for the cashews) and the avocado mixture. If serving immediately, add the cashews. Since the cashews can get soggy easily, I add them in right before I eat my lunch.
Serve between two slices of delicious bread. (I prefer Ezekiel since it is free of wheat gluten, but it is a personal preference).
For variety, you can substitute dried cranberries or cherries for the apricots (I've tried it and love it). To be even healthier, add some green stuff - spinach works best, but other green-leaf lettuces also work.
Live the moment, love life!
Sunday, July 17, 2011
Pretty on the Inside
I love pencil skirts and think they are perfect for wearing to work on a daily basis. However, I have a slight pear shape, making buying a pencil skirt with an ideal fit a little difficult. I either end up with something that fits well in the waist and is too tight across the hips and rear or something that accommodates my larger "assets" and is a little big in the waist. I usually opt for the second option and just wear it a little lower on the waist and problem solved. Lately, I've wanted a pencil skirt that I can wear at my high waist, so I decided to make one.
When I saw this pattern on Burdastyle, I thought it was perfect. It looked like it already had a great pear shape and could be tailored to my body. I think I came close to achieving what I wanted with this skirt and it had a perfect fit until I added the lining. The lining seemed to make things a little tighter, still a nice skirt, but I think that next time I will add a but more wearing ease to this skirt. Since the pattern did not have a slit, I used Sunni's tutorial to add a back vent in my skirt.
So the name "Pretty on the Inside" comes from two sources. First of all, my favorite part of this skirt is my finishes on the inside. I used french seams along the inside of the lining and serged the edges of the wool. I also added a satin ribbon along the inside facing similar to many of my RTW skirts. Lastly, the skirt is hemmed with a lovely ribbon on the inside. Just looking at this skirt in-side-out makes me happy!
The second inspiration source for the title comes from my desire to get on my blogging soapbox and proclaim that women are pretty from the inside out! I often find myself becoming self-conscious when I go to post pictures of myself on this blog. I typically go through my days without ever wearing makeup, yet when I decide to post a picture of myself wearing one of my recently made garments - I take the time to get all dolled up with makeup. Then upon reviewing my pictures before posting, I find myself focusing on all of my flaws. This is not what we as women need to focus on! Our beauty comes from the inside - who we are and where our heart is.
So, although I did take the time throw on some makeup and fuss over how the camera adds ten pounds, I choose not to be brought down in what I don't like. Instead, I see that my beauty comes from the heart, and hopefully that is what radiates on the outside.
Live the moment, love life!
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Shelby Hentges was really taking this whole moving thing well.
Because it was seriously hot outside.
And her car was seriously stuck on the side of the road in front of her house.
"It's fine," she said Saturday afternoon, sweat pouring from her brow. "It's hot. And sure, my car broke down. But it's fine."
Hentges said that "worse things" happen. But save for a brutal rainstorm, Saturday's weather made for a weekend of moving that couldn't have gotten much worse for many residents.
Temperatures reached 100 degrees Saturday, with more high heat and humidity levels expected today, leaving a litany of off-campus students and others in Lawrence sweating in moving trucks that quickly became makeshift ovens.
Many Lawrence landlords - especially those who cater to students - begin the new year's lease Aug. 1. So this weekend marks the beginning and end of the city's unofficial moving season.
Up and down Lawrence streets, old couches and mattresses lined curbs Saturday. Residents also darted in and out of homes and cars carrying armfuls of boxes and other items.
Jesse Morrison, a KU senior from Leawood, spent most of Saturday with his parents carting boxes to his new rental and cleaning out his old apartment house in the 900 block of Louisiana Street.
"It's hell for now," he said.
Aside from going in and out of the scorching heat all day, the inside knob to the front door of he and his roommates' new rental in the 1000 block of Rhode Island Street broke off during the afternoon move.
They had already stacked boxes in the living room, and Morrison said they would have everything into the house by the end of the day.
But settling in will be a different story.
"I think it will take us about a week to get all of it done," he said as his roommates laughed.
Heat advisory
The National Weather Service will institute a heat advisory from 1 p.m. today to 7 p.m. Tuesday for Douglas County and much of eastern Kansas. Forecasters expect hot temperatures and high humidity levels will push the heat index into the 105-degree to 110-degree range.
Copyright 2017 The Lawrence Journal-World. All rights reserved. This material may not be published, broadcast, rewritten or redistributed. We strive to uphold our values for every story published.


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Samara The Justicar by MadSpikeWatch
©2012-2017 MadSpike
shes near battling 1000 and still fights like a...well cougar... damn she's been training her whole life
dude this would make an AWESOME poster! i'd get it framed in a SECOND! xD lol
She looks so beautiful. Thanks for putting her so well in Pose.
I love her so much
I love her so much
Life would be WAY to fucking easy if the asari were actually real. :L
Wow. THat is really amazing.
Amazing Alien Amazon Space-MILF <3 Im in love
Man I love ur take on Mass Effect squad pics!!
Very Nice!
Very Nice!
She's the best... I hope you'll create a desktop wallpaper with her
Great job!
Great job!
awesome. Samara has GOT to be one the most unique and interesting characters of Mass Effort lore.
Samara is way too awesome!
Love it.
Really great!
Waw! Awesome!
<3 She's so pretty and awesome. XD Very nice.
Awsome art
Bravo! You really do these characters justice. Bioware need you on their payroll, now.
omg wow!
Best lookin Asari out there.
Really nicely done!
Excellent work. You really captured Samara here.
Beautiful, simply beautiful.
The one thing we can never have!
One of my three favorite Asari ! (with Liara and Aria)
Samara rules!
amazing job, Mad Spike
Samara rules!
amazing job, Mad Spike
Next up: Liara and Ashley.
I'm afraid only after ME3 release )))
Well I can wait. Ashley's model looks very...hot. So having that in a nude model would be worth the wait.
so cool! *___*
Love the Biotic look think you should add it to the thane concept.
Ah, Samara Or, rather, as she's also known, Mass Effect's greatest cock-tease. Frakking BioWare...
That said though, this is absolutely brilliant.
That said though, this is absolutely brilliant.
Awesome work! Samara is a great character
Awesome job! Fav'd without a doubt!


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|[TowerTalk] MARC question
|firstname.lastname@example.com (JC Smith) (JC Smith)
|Fri, 30 May 1997 12:25:38 GMT
Hi Steve, I've been having fun playing with the MARC software, trying all sort of what-if situations. Nice program, thanks (& your check is in the mail). I assume antennas can be added to the database by simply editing the antennas.dat file with any text editor. Is this correct? Second question. I already own a US Tower mast, their # M-20R. You probably already know this, but it is a 20' Galv. steel mast, 2" OD, .120 wall with an insert in the lower half, giving the lower half a .250 wall thickness. Weighs 70 lbs. Any suggestions on fitting this into the results I get from the MARC? I don't see any info. in their catalog on yeild strength, but as it is 2" OD tube with the listed wall thicknesses I would think it is more than just galv. pipe. I have a call in to UST to try to get more info, but perhaps you already know what it is. Where I would like to use it is on top of a rotating tower (MA-550MDP with freestanding rotor base). It would only go approx. one foot into the tower, leaving 19 ft. of useful mast above it. I would like to install a TH-7DX at the mid point of the mast (or higher) and a small antenna at the top, a decent TV antenna so I can tell the cable company to kiss off (any TV antenna recommendations?). Actually, I suspect this should be plenty strong (I'm in a very sheltered location and this tower is motorized so it is down any time the wind is blowing or we are away.) However, what concerns me more is the ability of the mast to support the antennas and itself while it is being tilted up from the horizontal, the ability of the top of the tower to support it (it actually goes less than a foot into the tower) and the ability of the raising fixture (US Tower MAF-550) to support the extra load of the mast and antennas during the raising process. I can help it along for the first few degrees of elevation (where the angle is the worst) but it soon gets out of reach. I'm hoping to avoid the necessity of erecting a temporary tower behind it to use as an assistant raising fixture for the mast. I have a similar question about tilting up another stack, but I'll save that for later. I should also mention that I have an elevation rotor, crossboom and satellite antennas monuted down low on the tower (on the lowest, outermost section of tube). These are quite small, but I mention it because I'm frequently experimenting and playing with them which requires tilting the tower over. I really don't want to have to rent a crane every time I do it. Your (or anyone in the group) advice would be appreciated. 73 - JC,firstname.lastname@example.com -- FAQ on WWW: http://www.contesting.com/towertalkfaq.html Submissions: firstname.lastname@example.com Administrative requests: firstname.lastname@example.com Problems: firstname.lastname@example.com Search: http://www.contesting.com/km9p/search.htm
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text:
"As a teenager, a friends' mother made this for Thanksgiving. She was an old hippie and I loved being in her kitchen which was filled with earthiness and health. I was amazed at how delicious this was and can still remember her telling me everything she put in it as I was intent to make it myself. Surprisingly I haven't made it but wanted to write it down somewhere. Since it was not given to me as a written recipe I am guessing quantities and a couple minor ingredients. I can't wait to make this. Herbamare is a brand of sea salt flavored with herbs that is essential and perfect for this. You will find it in the health food store but can substitute another salt if necessary."
Rice Stuffing W/ Mushrooms & Chestnuts (Gluten Free)
0 recipe photos
READY IN:1hr 35mins
Ingredients Nutrition
- 2 cups cooked basmati rice (white or brown)
- 1 cup cooked wild rice
- 1 cup button mushroom, sliced
- 3 portabella mushroom caps, chopped
- 1 cup oyster mushroom, chopped
- 1 onion, diced
- 4 garlic cloves, minced
- 1 cup celery, chopped
- 2 cups chestnuts, chopped
- 1⁄4 cup fresh sage, minced
- 1 tablespoon dried marjoram
- 2 teaspoons herbamare seasoning salt
- 1⁄2 teaspoon pepper
- 3 tablespoons olive oil
- *Rices should be cooked in vegetable or mushroom broth for optimum flavor.
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Watch on your iPhone, iPad, Apple TV, Roku, or Fire TV.Learn More


text: Police have had to escort the roll-out of the latest phase of Johannesburg's Bus Rapid Transit system while taxi drivers withdrew their services in protest against the system, leaving commuters stranded.According to City of Johannesburg spokesperson Nthatisi Modingoane, the Nancefield depot in Soweto was blocked with rocks and stones.Police had to be sent to the Merafhe station after receiving reports that commuters were being blocked from using the trains as an alternative to the strained BRT system.BRT bus stops were vandalised overnight and on Monday some taxi companies refused to work, overloading the BRT system.Were you affected by this situation? Did you witness the action or take a photo of it? Share your experience with us.Send us you stories and photos and we'll publish them on MyNews24. Follow us on Twitter | Become a fan on Facebook


text:
With a song called "Tik-Tok," nobody should be too surprised about [lastfm link_type="artist_info"]Ke$ha[/lastfm]'s latest business venture. The 24-year-old singer/songwriter has teamed up with Casio to create a new line of watches called Baby-G. Surprisingly, no glitter was involved.
Acting as both the model and designer of the watches, she had a plan all along for the unconventional designs of the watches,
"I wanted everything to look like it was from the seventies, and square, because I hate circles," Ke$ha explained.
Not wearing much in her ads but knee high socks and roller skates, the pop-rocker can be seen in her skivvies and a jean vest rocking watch styles in black, white, blue, and of course, pink! The "Blow" singer just finished her Get $leazy Tour, which featured AMP favorites[lastfm link_type="artist_info"] LMFAO[/lastfm].
You can check out her line at Baby-G.com.
"Tik Tok" by Ke$ha. It's fitting.
[Source: Billboard]
Little Monsters, are you on the edge of your seat for the next Gaga fashion film? Yes! We are too and, good news, she's releasing the 4th installment super soon.
[photogallerylink id=112045 align=left]Gaga's actually showing the full film at Paris Fashion week this Wednesday. But who cares about Paris? We want it now! No worries, though. A special edit of the fashion-film, which is a group effort by Gaga, fashion photographers Inez van Lamsweerde, Vinoodh Matadin under the creative direction of Nicola Formichetti, Gaga's stylist, will hit the internet by Thursday.
Hopefully, this will help hold you over until then! "You and I" by Lady Gaga
[Source: MTV]
Nobody saw this coming, but then again, nobody is complaining either. [lastfm link_type="artist_info"]Snoop Dogg [/lastfm]decided he liked one of [lastfm link_type="artist_info"]Rihanna[/lastfm]'s songs so much that he needed to add his flavor to the love ballad.
[photogallerylink id=91402 align=left]But like any remix, he wanted to make a couple changes. He took Ri Ri's "California King Bed", spliced it with loving, smooth rap verses, like so:
"California dreamin', schemin', you got me gleamin'/ I need you on my team 'n you get my meanin'/ It sound crazy but it's amazing/ Lay down with me so we can make some babies."
Shot a sexy new video with a Kim K look-alike running around in her underwear, and now you have "California King," featuring Rihanna. Ta-Da!
Take a moment to check out the remix and the original, it's a bold change up from the Doggfather, but after taking home a BMI Icon Award you can do almost anything you want. Ta-Da!
"California King" by Snoop Dogg
The Original, "California King Bed" by Rihanna
[Source: Rap-Up]


text:
While Dallas authorities were providing details about Sunday's fatal police shooting of an unarmed suspect, another man was shot and killed by an officer Monday.
In Monday's case, Jose Manuel Gonzalez, 18, was killed in northwest Dallas after he was believed to have assaulted members of his family and brandished knives while approaching an officer.
The man shot Sunday in north Oak Cliff has been identified as Andrew Scott Gaynier, 26. Police say an officer shot him after he rushed the officer shortly after trying to force his way into a passing vehicle.
"We can assure the public that each of these incidents will be fully investigated for compliance with our policies and state law," Chief David Brown said in a written statement. "But also we accept the scrutiny of our actions while displaying the highest level of professionalism."
He added: "Our hearts go out to the affected families of all involved, as well."
Police said Senior Cpl. Kevin Gladden fatally shot Gonzalez outside his home after the man approached him with a knife Monday morning.
Deputy Chief Gil Garza said neighbors called police after Gonzalez's mother and grandmother fled their home in the 3600 block of Espanola Drive. Gonzalez allegedly had assaulted both women and his father.
The man lived with his parents, grandmother and younger sister in the house, according to neighbors.
When Gladden, an eight-year veteran of the department, arrived at the scene, Gonzalez started walking toward the officer with his hands behind his back, Garza said.
"As the officer was making contact with Gonzalez, the suspect was holding two knives and witnesses were telling the officer, 'He has two knives,'" Garza said.
Gladden walked backward while telling Gonzalez to show his hands and drop the weapons, but Gonzalez kept coming, Garza said. When Gonzalez raised one of the knives, Gladden shot him.
Police said Gonzalez didn't give up one of the knives even after he was shot. Officers had to use a stun gun to control him. He later died.
Garza said police recovered two "kitchen-type" knives from the scene. Investigators are checking whether there is police dashboard camera or private video or audio of the incident.
Police said officers had been called to the home last year, but they declined to provide further details.
The shooting happened about the same time police were providing details about Sunday night's fatal shooting in north Oak Cliff.
A family called 911 about Gaynier, who was in the 100 block of North Windomere Drive, to report "concerning" behavior, said Maj. Jeff Cotner of the crimes against persons division.
Senior Cpl. Antonio Hudson, a seven-year veteran of the department, was working an off-duty neighborhood security patrol job when he spotted Gaynier and followed him down South Rosemont Avenue.
Gaynier tried to get into a passing van near 12th Street, police said. Cotner said privately recorded video showed that Gaynier then rushed the officer, who opened fire.
Cotner said witnesses confirmed that the officer told Gaynier to show his hands before Gaynier charged him.
Gaynier was convicted of family violence assault in Collin County in January, according to court records. He has previous arrests and convictions in Dallas County for assault and theft.
Gaynier's family's attorney Bill Kennedy said his relatives were "shocked and heartbroken by this loss." He also said Gaynier is the father of a 19-month-old.
"This tragic situation is beyond comprehension," he wrote in an email.
Kennedy also reiterated that Gaynier was unarmed.
Hudson's attorney, Lance Wyatt, declined to comment.
Two Dallas police shootings of unarmed men garnered controversy last year. Officer Amy Wilburn shot and wounded a 17-year-old carjacking suspect who a witness said had his hands in the air. Officer Clark Staller fatally shot an unarmed man after a fight when he said the man was choking him until he couldn't breathe.
The consequences were mixed for the officers. Staller kept his job and was cleared by a grand jury; Wilburn was fired and indicted.
The mother of the man who Staller shot has been outspoken on many officer-involved shootings along with local civil rights activists. Some have called for the Justice Department to intervene and investigate Dallas shootings, as federal officials did in Albuquerque, N.M. A spokesperson for the department in Washington did not return a request for comment Monday.
Police avoided a possible third shooting within 24 hours when a man shot at officers and firefighters in Far North Dallas late Monday afternoon. He eventually surrendered and was taken into custody.
Staff writer Stephanie Embree contributed to this report.


text:
I will be in Tuscany in early September, so I am starting my food and wine plans now. This will be my first trip to Tuscany, not to Italy, but I am not real knowledgable on Italian wines.
I think I will spend a few days in Venice first, rent a car, then head to my "home base" in Loro Ciuffenna (Arezzo). I will have a car and will be within an hour of all the terrific cities and towns for great food and wine. We are in a great location.
Any "must see" or "must try" ?
Anyone been tasting on the Chianti Wine Trail recently ...in the past few years?
I am open to experiencing high brow to low brow....we are pretty "laid back" folks and don't like to rush around, are not "fussy", appreciate great views, and prefer wandering around rather than being on a guided tour. However, I am a bit concerned about wine tasting and driving, so I would like to look into a wine tour for "a bigger tasting day" or maybe just hiring a driver if we need to hit more than 2 tasting rooms in a day :/
All advice is welcome!


text:
Director Tony Richardson delves into the complex symbiosis between border guards and illegal aliens on the U.S./Mexican border in a film that's often engrossing, but finally too sprawling and diffuse to be compelling. The film takes a somewhat detached view of both guards and aliens, in laying out an ethnography of tastelessness and obsessive materialism among the Border Patrol that fuels the shady deals that exploit the desperate Mexicans. Jack Nicholson, whose characters have often ridiculed the kind of minor official he plays here, is surprisingly straight as the weary, cynical guard who finally tires of Harvey Keitel's venal boss, and the conflict between them gives the film what energy it has. Less successful is the sketchy character of the Mexican woman played by Elpidia Carillo, who supposedly inspires Nicholson's redemption. Despite the film's limited impact, the documentary aspects of this situation, which seems to have changed little in the intervening years, remains of interest. Valerie Perrine and Warren Oates are typically excellent, and the sweeping camera work of Vilmos Zsigmond and Ric Waite is also worth noting.
The Border (1982)
Directed by Tony RichardsonGenres - Drama, Thriller | Run Time - 107 min. | Countries - USA | MPAA Rating - R
Share on


text:
From the Publisher
The book teaches the principles for Christian missionary work through the lens of the life of Gideon, who was an Old Testament hero. By closely viewing the challenges that came his way, the book reveals how we are to walk with God in a modern day setting. The book illuminates the dark areas of spiritual ignorance that many Christian workers possess when they attempt to work for God and not work with Him.
Published: AuthorHouseBooks on Apr 26, 2012


text:
David Wood
Words - Poem by David Wood
Do words come like a rider less horse
Galloping across green fields, jumping
And running free, kicking the air with
Its hind legs with hoofs kicking up turf.
Do words come like a sail-boat riding the
Waves with a southerly wind blowing
And sea spray from bow waves breaking
In the wind, hitting your face.
Do words come like riding a fast motorbike
Through winding twisty country lanes
In the early morning calm as the sun
Grows large on the horizon.
Or do words come in like a gentle breeze
Kissing your face on a warm summers day,
Words that grace the page with lines
Of thoughts that slowly turn into poems.
Poet's Notes about The Poem
Comments about Words by David Wood
Kevin Halls (5/27/2013 6:56:00 AM)
An enjoyable poem which asks the question where do the thoughts come from to create a poem?
I bet you've been asked that very question many times?
I once read an article by a Poet and writer who said there's no such thing as Writers Block,
it's just the writer being lazy and ignoring the inspiration all around him or her.
He may be right or wrong but there is a lot of stuff out there! (Report) Reply
Farah Ilyas (5/22/2013 1:11:00 PM)
Kissing your face on a warm summers day, wonderfully answersed the question qrised in every mind..i like it (Report) Reply
Shahzia Batool (5/21/2013 5:11:00 AM)
@ Where do the thought that create poems come from:
An Excerpt from The Education Of An Amphibian by Aldous Huxley:
...there is the not-self who inhabits the world from which we derive our insights and inspirations. This is the Not-selfwho spoke to Socrates through his daimon, who dreamed the text of Kubla Khan, who dictated King Lear, and the Agamemnon, and The Tibetan Book Of Dead..., the Not-self who is responsible in all of us for every enhancement of wisdom...every intellectual power... (Report) Reply
Tirupathi Chandrupatla (5/19/2013 4:21:00 PM)
Where do poet's words come from? One always wonders. I think you answered this nicely. (Report) Reply
Valerie Dohren (5/19/2013 8:07:00 AM)
Beautiful David, some lovely metaphors. Love the last verse. (Report) Reply
Somanathan Iyer (5/19/2013 7:39:00 AM)
Gajanan Mishra (5/19/2013 7:23:00 AM)
kissing your face on a warm summers day. Very good David. thanks.
I invite you to read my poems and comment. (Report) Reply
Dave Walker (5/19/2013 7:20:00 AM)
A great poem, I just read A Charmed Life by David Essex.
A fantastic book, I got the idea to write my new poem called,
A Lost And Lonely boy. In the book he talks about his film, Stardust,
I got the idea to write it from that. I not the same story but it's
what gave me the Idea. (Report) Reply
Read this poem in other languages
This poem has not been translated into any other language yet.
I would like to translate this poem »
David Wood's Other Poems
Famous Poems
Phenomenal Woman
Maya Angelou
Still I Rise
Maya Angelou
The Road Not Taken
Robert Frost
If You Forget Me
Pablo Neruda
Langston Hughes
Annabel Lee
Edgar Allan Poe
Caged Bird
Maya Angelou
Rudyard Kipling
Stopping By Woods On A Snowy Evening
Robert Frost
I Do Not Love You Except Because I Love You
Pablo Neruda


text:
Time to get a better O/S
AmigaOS doesn't have any security updates this month.
Hey, I'm just sayin'...
Microsoft has released 13 bulletins, covering 26 vulnerabilities, as part of a bumper Patch Tuesday. All supported versions of Windows will need patching, though Vista and Win 7 (three critical updates) are less exposed than XP and Windows 2000 shops (five critical fixes). Three of the bulletins are particularly severe and …
AmigaOS doesn't have any security updates this month.
Hey, I'm just sayin'...
That hardware windowing using display lists never gives corrupted windows like Windows does...
Wish I still had my amigas...
Neither does RISC OS (which is still being actively developed, hey) - so what's your point?
So is AmigaOS.
Yes, I know AmigaOS is - but you probably didn't know that RISC OS was. I wasn't trying to come over all superior, I didn't honestly think anybody (except the small cliquish sect who actually perform the updates) would have been aware. Ah, RISC OS. A new lease of life on the Beagleboard? Who knows.
They've rewritten TCP/IP? One of the oldest technologies on the Internet? Didn't they have that pretty much finished before?
No wonder Redmond produces such garbage - they keep rewriting it and starting the whole security-hole-fixing process all over again.
If you'd bothered to read the article before engaging commentard mode, you would have seen that as a result of the new TCP/IP stack Win7 and 2008/R2 are not vulnerable to some exploits affecting earlier versions, so perhaps there was some point to the changes after all. And it's not as though TCP/IP has been frozen for the last couple of decades, judging by the rate at which new RFCs are appearing - I'm pretty sure that you'll find most Linux distros incorporate regular enhancements to this software.
And the prize for the most appropriate handle goes to ...
What I find more alarming than the number of patches being released is that there are several patches which replace previous hotfixes. I wonder whether the flaws were present in the original unpatched version of the code and went unnoticed when MS first patched it, or were these new vulnerabilities introduced as a result of the previously-released patches?
Also, I note that in the Microsoft announcements for each patch, they describe those vulnerabilities that were privately reported as being 'responsibly disclosed' - presumably anyone who goes public before the patch is released (not necessarily without having informed the vendor) is being irresponsible according to Microsoft.
Does anyone really believe that the Baddies out there are incapable of finding vulns themselves and that they all sit around waiting for Metasploit to release an exploit before targeting their victims? I seem to remember that Microsoft were aware of the IE6 Google Hack vulnerability 4 months prior to the rest of us (minus the Baddies) being aware of its existence.
Just because your OS's patches aren't publicized, doesn't mean they fix are any less severe.
Most commercial OS publicise their patches.
Most commercial OS are FAR more secure than Winblows and NEED less patches.
Looks like this patch fixes lots of problems but causes another - The Blue Screen Of Death!
I don't recall any blue screens of death on my Amiga!
You may remember "Guru Meditation" - I certainly do from my A1000


text:
|Reviews for Something Serious
| Guest chapter 1 . 3/15/2015
| Bellman chapter 1 . 3/30/2010
Joey is a situation comedy and maybe it could have been a bit funnier and not written so much as a romance novel. Joey is not really mentioned, he is the central character and he would tie the piece together by using some of his clumsy wit.
You did keep true to Alex's character and her infatuation for Joey
| Katie chapter 1 . 9/15/2009
I think that was great. I love you version!


text:
April 4, 2016
Sheffield Wednesday v Blackburn Rovers
BBC coverage
- How to follow:
- Listen on BBC Radio 5 live and BBC local radio; text commentary on the BBC Sport website
Barry Bannan is out for Sheffield Wednesday as he completes his three-match ban for a red card against Nottingham Forest.
Wednesday are still missing Filipe Melo, who has a knee injury, and Modou Sougou, who has a shoulder problem.
Blackburn defender Shane Duffy serves a one-game ban from his sending-off against Preston at the weekend.
Defender Grant Hanley is back after a one-match ban and Jason Lowe (foot) could play his first game since August.
- The Owls have lost only one of their last eight home league games against Blackburn but this was the most recent time they hosted them in March 2015 (W3 D4).
- Blackburn Rovers have kept just one clean sheet in their last eight visits to Hillsborough in the league.
- No team has scored more goals at home than Sheffield Wednesday (36) in the Championship this season.
- Blackburn have scored just five goals across their previous 10 away games in the league – fewer than any other team.


text:
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April 13, 2009 (8:50 a.m. EDT)
No. 97
Construction Contracts Signed During Minister Day's Trade Mission to China
The Honourable Stockwell Day, Minister of International Trade and Minister for the Asia-Pacific Gateway, announced that seven construction contracts between Canadian and Chinese companies were signed today in Beijing.
"Canada and China enjoy a growing commercial relationship, and construction is one sector where we see particularly strong opportunities," said Minister Day. "Canadian expertise in construction-sector goods and services is recognized around the world. Our companies have a stellar record of constructing high-quality buildings with minimal environmental impact, and this trade mission will help create even more opportunities for Canadian business. I was pleased to be a part of these ceremonies to celebrate our successes."
Details of the contracts signed today follow:
- GenesisTP, a division of Genesis Worldwide Inc. of Mississauga, Ontario, will provide its green building products and technologies to China Perfect Machinery Industry Corp., Ltd. for all its six-storey-or-less building projects.
- China National Materials Industry Import and Export Corp. will become the Hebei province distributor for the soft foam insulation and air barrier system manufactured by Icynene Inc. of Mississauga.
- Y+S International Design Ltd., of Markham, Ontario, will provide its ecological, integrated design services to Beijing Haigang Real Estate Development Co., Ltd.
- Soprema, of Drummondville, Quebec, will supply its waterproof membrane building material to Beijing Engrand Technology and Development Co. Ltd.
- MHKW Architects Inc., of Toronto, Ontario, will design a mixed hospitality and residential development in Tianjin for the Tianjin Supply and Marketing Co.
- MHKW Architects will also design the Guangzhou Tian Ze Sheng Royal Hotel.
- ACICC Trading International Co., of Surrey, British Columbia, will supply western red cedar, hemlock and SPF (spruce-pine-fir) lumber to the Longfor Group; Canada Mortgage and Housing Corporation helped facilitate the contract.
"I am pleased that this trade mission is leading to concrete results that will inject millions of dollars into our economies and help create new jobs in Canada and China," said Minister Day.
Minister Day is in China as part of an April 8 to 17 visit to China and Japan to open doors for Canadian businesses and strengthen trade and investment ties.
For further information, consult the following website:Foreign Affairs and International Trade Canada - International Trade: Minister Day visits Japan and China
- 30 -
For further information, and high-resolution pictures of Minister Day's visit to China and Japan, media representatives may contact:
Mélisa Leclerc
Director of Communications
Office of the Minister of International Trade and Minister for the Asia-Pacific Gateway
Trade Media Relations Office
Foreign Affairs and International Trade Canada
- Date Modified:


text:
There are many issues that pop up that really require a user mode dump in order to successfully diagnose root cause. I will occasionally visit the ASP.NET newsgroups, and when I do, I read only those posts with a subject that interests me. I find that I gravitate towards crashes, high memory issues, hangs ….
Year: 2006
Out of memory! Are you nuts!?
I may have said this before (my memory's not what it was prior to decade number 4), but the most common issues I debug are memory issues. These range from high memory issues (categorized as 800MB of more memory in use by the worker process) to OutOfMemory exceptions, or OOM. High memory cases don't usually…


text:
Stabenow Secures Veterans Health Clinic in Alpena
The new clinic will eliminate the long drives northern Michigan's veterans often face to receive basic heath services
WASHINGTON U.S. Senator Debbie Stabenow (D-MI) today announced that the business plans for a U.S. Department of Veteran's Affairs (VA) Community Based Outpatient Clinic in Alpena have been approved for fiscal year 2007. The new Alpena clinic will ease the burden of veterans in Alpena and the surrounding area who regularly make long and often difficult trips to VA hospitals in other parts of the state to receive basic medical services.
"This is great news for our Alpena veterans and families," said Stabenow. "I am extremely happy this health clinic has been approved - it's high time that our Alpena-area veterans who selflessly served our country have access to the health care services they need and deserve."
"There is an old saying that success has many fathers, and this is an example of that," said John A. McVeety, CEO of Alpena Regional Medical Center. "The efforts of Senator Stabenow and the many veterans in our area and the folks here at Alpena Regional Medical Center have made this possible. The availability of a VA clinic will be a major improvement in the lives of those who have given so much for our country."
Stabenow has led the fight to secure this Alpena VA health clinic and strengthen veterans' access to health care in the Alpena region for nearly four years. She has worked with many area veterans and community leaders, as well as the Alpena Regional Medical Center to gain approval for this facility. She also sent numerous letters and a petition that included over 1,000 signatures urging the VA to increase access to veterans' heath care in the Alpena region, and introduced legislation directing the VA to create this clinic.
"Just as we support our troops overseas with the equipment and armor they need, we must do everything we can to meet the needs of veterans when they come home, and this clinic will greatly enhance the health and quality of life of our veterans living in northern Michigan," said Stabenow.
Source: http://www.stabenow.senate.gov/040207StabenowSecuresVeteransHealthClinicinAlpena.htm