text:
If you want to see some real sexist stuff in operation you could do worse than follow up on the two idiot commentators who figured the offside rule in soccer was too complicated for a mere woman to understand.
What provoked their ire was a not-offside call by lineswoman Sian Massey. They figured it was offside and she called it wasn't.
They jeered her on-mike and one of them, who was a serial offender, was subsequently sacked by that "gender equality channel" Sky, while the other guy resigned.
Right bloody order.
There is nothing complicated about the offside rule in the first place. It is essentially the same rule as when I started following soccer in the 1960s. It is even the same rule (almost) as applies in the soccer board game Subbuteo, played by both genders of all ages since time immemorial. Further examples here.
While the rule itself is not complicated, implementing it on the field can be. It requires the referee/linesperson to determine whether the intended recipient of the ball is offside at the moment the ball is played by the kicker. No easy task, and angles of view can be very deceptive so the referee-team needs to be way ahead of the actual play.
I wonder if a change in the rule so that it applied to the recipient at the point when he received the ball might not simplify matters without in any way impinging on the game as currently played?
In any event, we're well rid of these pompous sexist pricks. And the rest of them had better watch out.
The only guys offside here were the two idiot commentators.
Full marks, Sian.
Chwarae Teg.


text:
- Research
- Open Access
Effect of tyrosine autophosphorylation on catalytic activity and subcellular localisation of homeodomain-interacting protein kinases (HIPK)
- Jan van der Laden1,
- Ulf Soppa1 and
- Walter Becker1Email author
© van der Laden et al.; licensee BioMed Central. 2015
- Received: 4 June 2014
- Accepted: 30 December 2014
- Published: 29 January 2015
Homeodomain interacting protein kinases (HIPKs) function as modulators of cellular stress responses and regulate cell differentiation, proliferation and apoptosis. The HIPK family includes HIPK1, HIPK2 and HIPK3, which share a similar domain structure, and the more distantly related HIPK4. Although HIPKs phosphorylate their substrates on serine or threonine residues, it was recently reported that HIPK2 depends on the autophosphorylation of a conserved tyrosine in the activation loop to acquire full catalytic activity and correct subcellular localization. In this study we addressed the question whether tyrosine autophosphorylation in the activation loop has a similar function in the other members of the HIPK family.
All HIPKs contained phosphotyrosine when expressed in HeLa cells. Catalytically inactive point mutants were not tyrosine-phosphorylated, indicating that HIPKs are dual-specificity protein kinases that autophosphorylate on tyrosine residues. HIPK point mutants lacking the conserved tyrosine residue in the activation loop showed reduced catalytic activity towards peptide and protein substrates. Analysis of these mutants revealed that HIPK1, HIPK2 and HIPK3 but not HIPK4 are capable of autophosphorylating on other tyrosines. Inhibition of tyrosine phosphatase activity by treatment with vanadate enhanced global phosphotyrosine content of HIPK1, HIPK2 and HIPK3 but did not affect tyrosine phosphorylation in the activation loop. Mutation of the activation-loop tyrosines resulted in a redistribution of HIPK1 and HIPK2 from a speckle-like subnuclear compartment to the cytoplasm, whereas catalytically inactive point mutants showed the same pattern of cellular distribution as the wild type proteins. In contrast, mutation of the activating tyrosine did not increase the low percentage of cells with extranuclear HIPK3. HIPK4 was excluded from the nucleus with no difference between the wild type kinase and the point mutants.
These results show that HIPKs share the mechanism of activation by tyrosine autophosphorylation with the closely related DYRK family (dual-specificity tyrosine phosphorylation regulated kinase). However, members of the HIPK family differ regarding the subcellular localization and its dependence on tyrosine autophosphorylation.
- Protein kinase
- Dual specificity
- Tyrosine autophosphorylation
- Activation loop
- Subcellular localisation
- p27Kip1
Homeodomain-interacting protein kinases (HIPK1, HIPK2, HIPK3) were originally identified as proteins that interact with the homeobox transcription factors NKx-1.2 [1]. HIPK1-3 share about 90% identical amino acids in their kinase domains and are also related in the architecture of the noncatalytic regions. These include a smaller N-terminal part with a conserved sumoylation site and a large C-terminal domain that harbours a homeobox-interaction domain, an autoinhibitory domain, a region rich in proline, glutamic acid, serine and threonine residues (PEST), and a C-terminus rich in short repeats of serines, glutamines and alanines (SQA region, also known as tyrosine/histidine (YH)-rich region) [1,2]. HIPK4 was later identified by its sequence similarity with HIPK1, 2 and 3 and is the most divergent member of the HIPK family [3,4]. HIPK4 is not structurally related with HIPK1-3 outside the catalytic domain [4].
HIPK2, the best-studied member of the HIPK family, is involved in the regulation of various cellular processes including differentiation, proliferation, apoptosis and stress response to DNA damage and hypoxia [5,6]. Perhaps most importantly, HIPK2 promotes apoptosis upon genotoxic stress by phosphorylating the tumor suppressor protein p53 at Ser46 [7-10]. Obviously, the function of HIPK2 as a regulator of cellular life and death must itself be tightly controlled. Accordingly, HIPK2 activity is regulated by several mechanism including degradative ubiquitination, caspase-mediated cleavage of an autoinhibitory domain, sumoylation, acetylation and phosphorylation [11,12]. Most effects of HIPK2 are mediated by transcriptional regulation, as HIPK2 can either activate or repress gene expression by interaction with components of the transcription machinery [13-15].
Whereas more and more putative targets of HIPK2 are being identified [15], enhancing our understanding of its function in cell death and cell survival, much less is known about the other members of the HIPK family. Due to their highly similar primary structures, HIPK1 and HIPK2 are assumed to have at least a certain degree of redundant activity [16]. Whereas HIPK1/2 double knockout mice die at embryonic day 12.5, either HIPK1 or HIPK2-deficient mice develop grossly normal but exhibit differences in apoptosis induction and eye development [17-20]. Although the cellular functions of HIPK1 are not very well defined, available evidence indicates a role in the regulation of apoptosis by interaction with nuclear proteins [16,21]. HIPK3 has been characterized as a regulator of the androgen receptor and Runt-related transcription factor 2 (Runx2) [22,23]. Recently, HIPK3−/− mice were shown to have impaired glucose-induced insulin secretion [24], and HIPK3 has been implicated in the pathogenesis of human type 2 diabetes [25]. Compared to HIPK2, HIPK1 and HIPK3 are less well characterized regarding their molecular and cellular function, and it is unclear to which degree these kinases fulfill redundant or divergent tasks. Almost nothing is known about HIPK4 except for its capacity to phosphorylate p53 at Ser9 [4].
Consistent with their roles in transcriptional regulation, HIPK1, HIPK2 and HIPK3 are predominantly nuclear proteins that are concentrated in subnuclear structures that appear as a punctate pattern [1,21,22,26]. These speckles are distinct from other subnuclear structures and were thus designated HIPK domains [9]. Interestingly, the punctate nuclear distribution of HIPK2 depends on a functional SUMO interaction motif that is also present in HIPK1 and HIPK3 [27]. However, in some cells HIPK2 is localised diffusely in the nucleus and also in the cytoplasm [9]. These findings suggest that the subcellular distribution of HIPK2, and possibly of HIPK1 and HIPK3, is a regulated process relevant for the biological function of these proteins. In contrast to HIPK1-3, HIPK4 lacks an apparent nuclear localization signal and was found to be evenly distributed in the cytoplasm [4].
Although HIPKs phosphorylate substrates on serine or threonine residues, HIPK2 has recently been shown to autophosphorylate at a specific, highly conserved tyrosine residue following the Mg2+-binding DFG motif in the activation loop of the catalytic domain [28,29]. This tyrosine is not only present in all HIPKs but also in other kinases of the CMGC group including the MAPK family, GSK3 and the closely related DYRKs [30]. In the MAPK family, the corresponding tyrosine belongs to a Thr-x-Tyr motif. Dual phosphorylation of this motif by specific upstream kinases serves as a regulatory switch that controls catalytic activity. In contrast, DYRKs and GSK3 autophosphorylate the activation loop-tyrosine already during translation, which induces the constitutive activity of these kinases [31-34]. Similar to the DYRKs, tyrosine autophosphorylation of HIPK2 is necessary for full catalytic activity of the mature kinase [28,29]. We and others have recently shown that DYRK1A and HIPK2 are not only capable of co-translationally phosphorylating the crucial tyrosine in the activation loop, but can also as mature kinases autophosphorylate on tyrosines outside the catalytic domain [29,34]. In contrast to DYRKs, tyrosine phosphorylation of HIPK2 has been reported to be at least partially under the control of upstream kinases [35,36]. Specifically, HIPK2 has been shown to be phosphorylated by the tyrosine kinase Src on numerous residues, including Y361 [36]. Phosphoproteomics screens have provided ample evidence that the activation loop tyrosine is also phosphorylated in HIPK1, HIPK3 and HIPK4 (phosphosite.org). However, it is unknown whether these kinases also autophosphorylate on tyrosine and whether tyrosine phosphorylation is functionally important. The present study aims at a comparative analysis of the role of the activation loop tyrosine in all members of the HIPK family.
Results and discussion
Tyrosine phosphorylation of HIPKs
To further investigate the mechanism of tyrosine phosphorylation in the HIPK family, we created point mutants of all HIPKs. The crucial tyrosine residue in the activation loop was replaced by phenylalanine to reveal whether this was the only phosphorylatable tyrosine. In addition, kinase-deficient mutants were generated by substituting the catalytic aspartate by asparagine [37]. Guided by our previous analysis of DYRK1A autophosphorylation [34], one series of cells was treated with sodium orthovanadate (Na3VO4) to inhibit tyrosine phosphatases that might conceal tyrosine kinase activity of mature HIPKs in living cells.
Compared to the respective wild-type proteins, the kinase-defective mutants HIPK1D315N and HIPK2D324N showed markedly enhanced electrophoretic mobility (Figure 2A-B). This difference most likely reflects extensive autophosphorylation in the wild type proteins that is absent in the kinase dead mutants. Consistently, wild type HIPK1 and HIPK2 migrated more slowly than predicted from their calculated molecular masses (GFP-HIPK1, 158 kDa, GFP-HIPK2 155 kDa) (Figure 2A-B). Interestingly, the Tyr→Phe mutants migrated with similar electrophoretic mobility as wild type HIPK1 and HIPK2, and vanadate-treatment did not alter migration of HIPK1 or HIPK2. Thus, the observed upshift is attributable to the phosphorylation of serine/threonine rather than tyrosine residues. Indeed, migration of HIPK2 was previously shown to strongly be retarded by treatment with the inhibitor of serine/threonine phosphatases, calyculin A [28].
Secondly, HIPK1Y352F and HIPK2Y361F contained substantial amounts of phosphotyrosine (Figure 2A-B), indicating that these kinases autophosphorylate not only the conserved tyrosine in the activation loop. In agreement with our results, Siepi et al. [29] also detected tyrosine phosphorylation of GFP-HIPK2Y361F and identified several phosphorylated tyrosines by mass spectrometry analysis. In contrast, Saul et al. [28] detected no phosphotyrosine in a FLAG tagged version of this mutant. This difference may be due to the use of different phosphotyrosine-specific antibodies and/or due to the use of different epitope tags. In a direct comparison, we found that the basal phosphotyrosine signal was weaker (but detectable) in FLAG-HIPK2Y361F than in the GFP fusion protein (Additional file 1: Figure S1). Nevertheless, vanadate treatment induced a marked tyrosine autophosphorylation of FLAG-HIPK2Y361F.
Treatment with vanadate also revealed that HIPK3Y359F was capable of autophosphorylating tyrosine(s) other than Tyr359, although this reaction was counteracted by tyrosine phosphatases under basal conditions (Figure 2C). In contrast, HIPK4Y175F did not show any phosphotyrosine signal above the background as defined by the catalytically inactive mutant HIPK4D136N (Figure 2D). This difference between HIPK4 and HIPK1-3 may either be due to different enzymatic properties or to the absence of phosphorylatable tyrosines in HIPK4. In particular, HIPK4 lacks the C-terminal tyrosine/histidine-rich domain that harbors 8–10 potentially phosphorylatable tyrosine residues and is conserved in HIPK1-3 (see Figure 1A).
The autophosphorylation on tyrosines outside the catalytic loop suggests that HIPK1-3 may also be able to phosphorylate tyrosines in exogenous substrates. For DYRK1A, which also autophosphorylates on multiple tyrosines [34], no tyrosine site was identified in extensive peptide array analyses [38,39]. Presently, there is no evidence that any member of the HIPK/DYRK families has tyrosine kinase activity towards other proteins.
Vanadate treatment enhanced the tyrosine phosphorylation of HIPK1, HIPK2 and HIPK3 within 1 h, which is very unlikely to reflect solely the newly synthesized protein. To fully exclude this possibility, we performed experiments in cells that were pretreated with the protein synthesis inhibitor cycloheximide. Again, increased phosphotyrosine was detected after vanadate treatment (Additional file 1: Figure S2). This result corroborates the conclusion that tyrosine kinase activity of HIPK1, HIPK2 and HIPK3 is not limited to a transient translational conformation of the catalytic domain. Also of note, the phosphotyrosine signal of HIPK4 was not enhanced by vanadate treatment. This may be due to the lack of tyrosine phosphorylation sites outside the catalytic domain of HIPK4, if the tyrosine in the activation loop is not subject to dephosphorylation by tyrosine phosphatases [30,32]. Similarly, wild type DYRK1A autophosphorylates on tyrosines outside the activation loop, whereas a deletion construct comprising only the catalytic domain does not [34].
Tyrosine phosphorylation in the activation loop
Reduced catalytic activity of the HIPK Tyr→Phe mutants
Activation loop phosphorylation influences the intracellular localisation of HIPKs
Elimination of the activation loop tyrosine has been reported to alter the subcellular distribution of HIPK2, suggesting that tyrosine autophosphorylation plays a regulatory role in nuclear import or export of HIPK2 [28,29]. To reveal whether this effect was also present in other HIPKs, we compared the subcellular distribution of wild-type and mutant GFP-tagged HIPKs. COS-7 cells were chosen for this analysis because their large, flat cellular shape facilitates microscopic analysis.
As shown in Figure 5A, wild type HIPK1 was also predominantly found in punctate nuclear structures, although the percentage of cells with extranuclear staining was higher than for HIPK2. Interestingly, HIPK1Y352F showed essentially the same pattern of distribution as HIPK2Y361F, with about 38% of cells displaying both nuclear and cytoplasmic fluorescence and about 9% nuclear exclusion of HIPK1Y352F. Again, the kinase-deficient HIPK1D315N mutant behaved like the wild type protein. Hence, mislocalisation of the HIPK1 and HIPK2 Tyr→Phe mutants is not due to reduced catalytic activity but must be considered a gain-of-function effect (Figure 5A, Additional file 1: Figure S3A). One distinctive feature of the Tyr→Phe mutants of HIPK1 and HIPK2 is their altered residue specificity, with a reduced Ser/Thr kinase activity (Figure 4) and enhanced tyrosine kinase activity (Figure 3). Considering that tyrosine autophosphorylation in the activation loop stabilises the active conformation of the catalytic domain in CMGC kinases [34], the more flexible structure of the Tyr→Phe mutants allows for off-target tyrosine autophosphorylation. These phosphotyrosines may then interfere with protein-protein interactions required for nuclear import.
In spite of the conserved domain structure and the close sequence similarity with HIPK1 and HIPK2, HIPK3 showed a distinct pattern of distribution in COS7 cells (Figure 5C). HIPK3 was almost exclusively detected in the nucleus, and only very few cells with a weak cytoplasmic GFP signal were identified. About one quarter of the cells lacked the typical punctate arrangement of nuclear GFP fluorescence but displayed largely homogeneous nuclear staining. In contrast to HIPK1 and HIPK2, the Y359F mutation of HIPK3 did not cause a significant cytoplasmic redistribution of the kinase (Figure 5C, Additional file 1: Figure S3C). Interestingly, the absence of aggresomes in HIPK3Y359F-transfected cells correlates with the observation that this mutant did not contain phosphotyrosine under basal conditions (Figure 3C). However, HIPK3Y359F markedly increased the percentage of cells with homogeneous nuclear fluorescence. This effect was even more pronounced in the catalytically inactive HIPK3D322N. Thus, the association of HIPK3 with an as yet undefined subnuclear speckle-like compartment depends on the catalytic activity of the kinase.
In accordance with previous results [4], HIPK4 was excluded from the nucleus and was homogeneously distributed in the cytoplasm in most cells (Figure 5D). Very few cells showed a punctate distribution throughout the cytoplasm. HIPK4Y175F and HIPK4D136N did not significantly differ from the wild type protein in terms of subcellular appearance (Additional file 1: Figure S3D). The different behaviour of HIPK4 compared to HIPK1-3 correlates with the divergent domain structure and the absence of a canonical nuclear localisation signal (Additional file 1: Figure S3E).
DYRKs have become paradigm examples for their activation mechanism by cis-autophosphorylation of a tyrosine residue in the activation-loop. Here we show that all HIPKs also classify as dual specificity kinases that autophosphorylate on tyrosine residues and depend on the activation loop tyrosine for attaining full catalytic activity. The biochemical and structural similarity of the HIPK and DYRK kinase domains supports the hypothesis that activation by tyrosine autophosphorylation is an ancestral feature of CMGC group kinases [30]. Consistently, tyrosine kinase activity is an intrinsic property of the catalytic domain of HIPK2 and does not depend on the cellular context or the presence of the other domains [29,34]. HIPK1-3 also resemble DYRK1A in being capable to autophosphorylate as mature kinases tyrosines other than that in the activation loop. Furthermore, our observation that all HIPKs phosphorylate CDK inhibitor p27Kip1 on Ser10 highlights the similarity of target recognition by HIPKs with DYRK1A and DYRK1B [43]. Phosphorylation on Ser10 reduces the proteasomal degradation of p27Kip1 and may play a role in the antiapoptotic functions of HIPKs [44].
In contrast to these common properties, HIPKs differ strikingly in the regulatory role of the activation loop tyrosine in subcellular targeting. The increased cytoplasmic localisation of HIPK1Y352F and HIPK2Y361F was not found in the respective mutants of HIPK3 (Figure 5C) or DYRK1A [29]. Interestingly, overexpression of the oncogenic tyrosine kinase Src has recently been reported to enhance tyrosine phosphorylation of HIPK2 and redistribute the kinase to the cytoplasm [36]. Further studies will be necessary to understand how tyrosine phosphorylation affects the tumor-suppressive function of HIPK1 and HIPK2 in human cancers and to reveal the physiological or pathophysiological relevance of tyrosine autophosphorylation in the regulation of the other member of the HIPK family.
Material and methods
The following antibodies were used: mouse monoclonal antibodies against phosphotyrosine (PY99, sc-7020, Santa Cruz Biotechnology, Santa Cruz, CA, USA) and p27Kip1 (BD Transduction laboratories, Heidelberg, Germany), rabbit monoclonal antibodies specific for pS10-p27Kip1 (#ab62364, Abcam, Cambridge, UK) or pTyr361-HIPK2 (#PA5-13045, Thermo Scientific, Rockford, IL, USA) and polyclonal goat antibody against green fluorescent protein (GFP, Rockland Immunochemicals Inc., 600-101-215, Gilbertsville, PA, USA). A rat monoclonal HIPK2 antibody was kindly provided by M. Lienhardt Schmitz (Justus-Liebig-University, Giessen, Germany).
Cell culture and immunoprecipitation of GFP fusion proteins
HeLa cells were cultivated on 100-mm plates in DMEM (Dulbecco's modified eagle medium) containing 10% FCS (fetal calf serum) at 37°C and 5% CO2. Cells were transfected with expression vectors for HIPK fusion proteins using FuGENE HD (Promega, Mannheim, Germany). If indicated, sodium orthovanadate (Na3VO4) was added to the HeLa medium to a final concentration of 100 μM 1 h before cell lysis. After 48 h, cells were washed and lysed in 1 ml of native lysis buffer (50 mM TrisHCl pH 7.5, 150 mM NaCl, 2 mM EDTA, 0.5% NP-40, supplemented with 1 mM Na3VO4, 1 mM phenylmethylsulfonylfluoride and 10 μg/ml each of aprotinin, pepstatin and leupeptin). Samples were cleared off cell debris by centrifugation and incubated with 15 μl GFP-Trap® (ChromoTek, Martinsried, Germany) for 1 h at 4°C in and end-over-end rotator. GFP-Trap® beads were collected using a magnetic rack and washed three times with washing buffer (50 mM TrisHCl pH 7.5, 150 mM NaCl, 2 mM EDTA, 0.1% NP-40). Bound proteins were eluted in 10 μl Laemmli Sample Buffer supplemented with 6 μg/100 μl dithiothreitol at 95°C and resolved by SDS-PAGE.
Immunocomplex kinase assays
To measure the relative catalytic activities of the HIPK Tyr→Phe mutants, GFP-Trap® immunoprecipitates were equilibrated with kinase buffer (25 mM Hepes pH 7.0, 5 mM MgCl2, 0.5 mM dithiothreitol). Non-radioactive assays were performed in a total volume of 20 μL for 30 min at 30°C in the presence of 500 μM ATP and 20 ng/μL of GST-p27, a fusion protein of glutathione S-transferase and human p27Kip1. GST-p27 was produced in Escherichia coli from the plasmid pGEX-5x-3-p27Kip1 (kindly provided by J. Vervoorts-Weber, Institute of Biochemistry, RWTH Aachen University, Germany) and purified by affinity adsorption to glutathione Sepharose. Phosphorylation of Ser10 was detected by western blot analysis, and relative catalytic activity was calculated by normalising the p27(pSer10) signal to the amount of kinase in the reaction, as determined by the intensity of the GFP signal. Radiometric assays were performed in a volume of 30 μL for 15 min at 30°C in the presence of 50 μM myelin basic protein from bovine brain (Sigma) or 200 μM DYRKtide [39] and 10 μM of [γ-32P]ATP. Phosphate incorporation was determined by the phosphocellulose method. Each data point was determined in triplicate, and the linearity of the reactions was verified by measuring incorporation of 32P after 30 min. Activities of wild type HIPK4 exceeded the linear range of the assay and may be underestimated.
Western blotting
Samples were separated by SDS-PAGE using 8% acrylamide gels and blotted onto nitrocellulose membranes. Membranes were blocked with 3% BSA in TBS-T buffer (20 mM Tris–HCl pH 7.6, 137 mM NaCl, 0.2% Tween-20) and incubated with the primary antibodies in a 1:1000 dilution at 4°C overnight. After washing, membranes were incubated with secondary antibodies for 1 h. Chemiluminescence signals were detected with a LAS-3000 CCD imaging system and densitometrically quantitated using the AIDA image analysis software (Raytest, Straubenhardt, Germany).
Fluorescence microscopy
Glass coverslips (15 mm diameter) were transferred into 6-well plates and wells were filled with cell culture medium. Subsequently, COS-7 cells were seeded and grown for 24 h at 37°C in DMEM containing 10% FCS at 5% CO2 before transfection with GFP-HIPK expression vectors using FuGENE HD. After incubation for additional 48 h, cells were carefully washed once with PBS buffer and fixed using 1 ml 4% paraformaldehyde in PBS buffer for 10 minutes. Cells were then washed three times in 50 mM Tris-HCl pH 7.6 and incubated with bisbenzimide (1:4000 dilution in 50 mM TrisHCl pH 7.6) for 10 minutes in darkness in order to stain nuclear DNA. After that, coverslips were mounted onto object slides using Immu-Mount™ (Thermo Fisher Scientific, Waltham, MA). Cells were then analysed using a Axiovert 200 M inverted microscope (Zeiss, Jena, Germany). Only cells with sufficient GFP and bisbenzimide signal as well as vital appearance were counted, aiming to count 100 cells per slide. Due to inadequate transfection or fixation rates only >90 cells could be evaluated in 2 cases. Images were processed using Zeiss AxioVision 4.7 software. One-way ANOVA and Tukey's Multiple Comparison Test were applied to test significant differences between mutants and wild type using the GraphPad Prism 5 software (GraphPad Software Inc, La Jolla, CA, USA).
We thank Simone Bamberg-Lemper for excellent technical assistance and wish to acknowledge that Monika Eipel and Sophie Kaspar contributed to some experiments. We are grateful to M. Lienhardt Schmitz (Justus-Liebig-University of Giessen, Germany), Cheol Yong Choi (Sungkyunkwan University, Suwon, Korea), Jorma Palvimo (University of Eastern Finland, Kuopio, Finland) and Jörg Vervoorts-Weber (Institute of Biochemistry, RWTH Aachen University, Germany) for providing expression plasmids and antibodies. This work was supported by the Deutsche Forschungsgemeinschaft (BE 1967/3-1).
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subset: commoncrawl


text: Skulls Skulls Cow Skulls Wild Boar Skull Hog Skull Sheep Skull Wild Boar Skull Female Deer Skull Coyote Skulls Craft Grade Deer Skulls Craft Grade Goat skull Here are some skulls we have.Some are craft grade and others are perfect with all teeth. New skulls available soon. New Coyote,Hog,Deer,and Goat Skulls coming...... « previous | next » Print Photos | View Full-Size Image Cow Skulls $75


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Lovin' the Look of Greece
Lately I've been trying to plan a little girls' trip to Europe in the fall, so I've been obsessed with anything travel related. I've never been, so it's a pretty big deal for me. A friend of mine went to Greece not too long ago, and I seem to be falling madly in love with the pure whites and beautiful blues of the landscapes. The palette is just gorgeous and so relaxing. Everything pops against the bright white. It's a similar look to a favorite local community and oh so pretty!
Simple and beautiful!
Of course, I can't help but think of what I would wear! I think I would live in either version of this dress, or maybe both. The blue is fun, but you can't go wrong with black and white.
Just pack a pair of heels and gladiator sandals — you're good to go!
Photos: DB, Forever 21


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In today's changing and competitive workplace it can be a struggle to keep up with everything that needs to be achieved in the day. Time seems to be against you. Continuous Improvement and Lean practices can help remove some elements from the day-to-day activities that your customers don't value – even some processes that could actually impact on them negatively.
Double handling is pure waste. Chances are that handling in the first instance is probably waste as well - something the customer would not pay money for. You can double-handle many things in a warehouse, including:
Examine your current procedures and brainstorm ideas with your teams to find solutions to reduce the number of times they deal with these double-handling culprits, or even whether you can eliminate them all together. For example, does a team member pick a product and then pass it to another team member to pack it? Instead, can it be picked and packed in the one process?
Having your team members go to a central labelling station to print and collect labels will create a lot of wasted time: time-in-motion to get the labels, waiting-time while team members talk at the printer, as well as potential errors if the wrong label from a pre-printed batch of labels is applied to a picked product.
A simple way to improve this wasted time is to consider mobile label printers and move to labelling just-in-time when you pick the item. The print command can be triggered from a variety of devices, such as an iPod touch or mobile computers.
Cutting out double-handling will save you time, improve the work day and more importantly help your customers.


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Carnival testing technology upgrades
"Beta testing" is the operative phrase for Carnival these days. The cruise line that caters to family and a younger adult demographic is stepping up to the plate with new products that are being tested on its ships.
Carnival has launched a free mobile app that provides passengers on the Breeze with a wealth of information and features. A chat function allows them to exchange messages and keep up to date on all that's going on.
The cost for the entire trip is $5.
The biggest news is that Carnival's testing enhanced Internet access on the Freedom, Breeze and Sunshine. The results will be known soon but what's known is that it dramatically increases bandwidth and speed, and includes a social media package providing unlimited access to Twitter, Facebook, Instagram, Snapchat and other popular sites for $5 per day or $25 per voyage during the testing period.
Explains Gus Antorcha, Carnival's Senior Vice-President of Guest Commerce:
"We recognize the increasingly important role that technology plays in people's daily lives and the launch of this application and new Internet packages provides us with a strong platform for introducing additional innovations and ways to use technology to enhance our guest experience even further."
The plan now being tested on the three ships gives a convenient, flexible and affordable option for updating social media pages during the cruise at one low price.
Cruisers can upgrade to a "value" package that includes unlimited access to the Internet for checking email, sports scores, weather updates and a wide range of other applications. And a "premium" package provides the fastest available connection speed, allowing access to video-calling sites like Skype.
"While we trusted the plans and the app would be well received, we are stunned by how quickly and widely they have been embraced during the pilot period," said Gabriela Gonzalez, Vice-President of Guest Technology and Photo. "We're excited to bring these innovations to more ships over the coming months while we continue to work to make them even better."
The testing will continue on the three ships, with the new products being rolled out in the next 18 to 24 months.
For a weekly newsletter from Ports and Bows with lots of cruise information and the best deals that we can find, click here to sign up: www.canada.com/newsletter.
All for now.
Today at cruisingdoneright.com: Newsy notes and new deals


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Two cars in Great Gonerby accident
Grantham firefighters attended a road accident last night at Great Gonerby.
Two cars were involved in the accident on Newark Hill just before 10.30pm.
The Grantham crew used absorbant granules to mop up a fuel leak caused by the accident.
There was no report of any injuries.
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DNX-2401 With Interferon Gamma (IFN-γ) for Recurrent Glioblastoma or Gliosarcoma Brain Tumors (TARGET-I)
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
|ClinicalTrials.gov Identifier: NCT02197169
Recruitment Status : Completed
First Posted : July 22, 2014
Last Update Posted : July 16, 2018
DNAtrix, Inc.
Information provided by (Responsible Party):
DNAtrix, Inc.
- Study Details
- Tabular View
- No Results Posted
- Disclaimer
- How to Read a Study Record
No Study Results Posted on ClinicalTrials.gov for this Study
|Recruitment Status :
|Actual Primary Completion Date :
|March 15, 2018
|Actual Study Completion Date :
|March 15, 2018


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By Ben Dawes (Ed.)
Read Online or Download Advances in Parasitology, Vol. 6 PDF
Best infectious disease books
Survival analysis: Techniques for censored and truncated data
Utilized statisticians in lots of fields usually research time-to-event information. whereas the statistical instruments offered during this ebook are acceptable to information from drugs, biology, public well-being, epidemiology, engineering, economics and demography, the focal point here's on purposes of the suggestions to biology and medication.
Parasites and the Behavior of Animals (Oxford Series in Ecology and Evolution)
Whilst a parasite invades an ant, does the ant behave like different ants? possibly not-and if it does not, who, if somebody, merits from the altered behaviors? The parasite? The ant? Parasites and the habit of Animals indicates that parasite-induced behavioral changes are extra universal than we'd detect, and it areas those changes in an evolutionary and ecological context.
Infectious Diseases (Colour Guide)
"The color publications" sequence supply a pictorial review of varied specialities. every one quantity offers a few fifty five subject matters as double web page spreads. In every one case the left hand web page supplies a synoptic account of the subject, anywhere attainable utilizing pathogenesis, prognosis medical beneficial properties, therapy, diagnosis. the perfect hand pages offers a set of (largely) medical pictures.
Public Health Medicine for the Tropics
First released in 1973, brief Textbook of Public future health drugs for the Tropics, Fourth version used to be designed to supply scientific scholars and different trainees with an advent to the foundations of public overall healthiness with targeted connection with the placement in constructing nations of the tropics. instead of trying to offer an in depth entire account, the publication keeps the strategy from previous variants that stresses easy ideas illustrated through chosen examples.
- Encyclopedic Reference of Parasitology: Diseases, Treatment, Therapy
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- Tropical and Parasitic Infections in the Intensive Care Unit (Perspectives on Critical Care Infectious Diseases)
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Additional resources for Advances in Parasitology, Vol. 6
Example text
The literature is full of articles on the subject, and it would be odious to quote examples of what might almost be termed "wishful thinking". As a justification for such a clinical picture there evolved the postulate of a diffuse amoebic infiltration of the liver, without abscess formation. However, with the exception of the report by Doxiades et al. , 1959). Powell et al. (1 959) found that dysenteric cases treated with tetracycline and di-iodohydyoxyquinoline (known to be ineffective in the prevention of liver abscess) were relieved of their tender hepatomegaly to the same degree as those who were given emetine or chloroquine in addition.
They refer to typical symptoms (dysentery or diarrhoea), to uncharacteristic symptoms (asyndromic) and to so-called healthy carriers. Amongst the variety of symptoms they quote are "distressing flatulence", "irritability" and "sexual weakness". This article was not specifically selected, but is unfortunately typical. 29 T H E E P I D E M I O L O G Y OF A M O E B I A S I S TABLE V Drug trials in amoebimis reported in 1960 Criteria Author No. Laboratory Place Clinical, etc. Africa El Sheikh Cairo Salem and Morcos Alexandria Marsden Lagos Shaldon Elsdon-Dew Nigerians in London Durban Chatterjee Calcutta Ghosh and Gupta Parekh and Patel Calcutta Bombay 52 28 4 13 10 151 17 4 1 880 v C V ?
It should be reasonable to draw comparisons between observations in the extensive series by Kuntz and his colleagues, and between those by Jones and Eyles, who were co-authors, as were Norman and Brooke. Subject to the usual reservations, it would seem that, in stable populations, E. hartmanni is commoner than E. histolytica. Table I1 also reveals that E. hartmanni is widely distributed. If indeed this organism has been labelled as E. histolytica, and the patient treated by some member of the Promethean school, there must have been a lot of unnecessary therapy, much of it not without danger.


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Wednesday, December 19, 2012
Abigail Disney to keynote March 4, 2013-producer of "Pray the Devil Back to Hell" and "Women, War & Peace" for YWCA Luncheon
YWCA of Rockford will host Abigail Disney, producer of Pray the Devil Back to Hell and Women, War & Peace http://video.pbs.org/video/2155873888/ , as keynote speaker for Leader Luncheon XXXIII: Women of Achievement, March 4, 2013.
Disney is a filmmaker and philanthropist. Her passion for women's issues and peace-building culminated in her first film, Pray the Devil Back to Hell, about the Liberian women who peacefully ended their country's 14-year civil war. The film premiered in 2008 at the Tribeca Film Festival, where it won the honor of Best Documentary.
Disney is executive producer of the groundbreaking PBS mini-series Women, War & Peace, a global media initiative about the role of women in peace and conflict. The series' awards include a Television Academy Honor, two Overseas Press Club Awards, two Gracie Awards and a Silver Gavel Award from the American Bar Association.
Disney co-founded the Daphne Foundation, which works with low-income communities in the five boroughs of New York City. She also founded Peace is Loud, which amplifies women's voices for peace-building using the power of media.
Disney serves as a board member for a number of organizations, including the Global Fund for Women and the Peace Research Endowment. Her work has been recognized through numerous awards, including the International Advocate for Peace (IAP) Award from the Cardozo Law School's Cardozo Journal of Conflict Resolution.
In addition, Disney holds degrees from Yale, Stanford and Columbia. She has been a judge at the Tribeca Film Festival, and sits on the advisory board of ITVS's initiative, Women and Girls Lead. She travels around the country and internationally to speak in diverse locations, such as The Hague, Davos, the United States Institute of Peace (USIP), universities and community centers. She is a member of the Writers Guild of America.
Read More: http://rockrivertimes.com/2012/12/19/abigail-disney-to-keynote-ywca%E2%80%99s-leader-luncheon-xxxiii-march-4-2013/
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Posted April 27th, 2011
If you would like to view the 172nd/190th roadway alignment concepts from previous rounds of public involvement, here is a reminder that you can access them via the "Previous Virtual Workshops" section of the project website http://172nd.com. To view the three remaining roadway alignment alternatives, there is a link just below Technical Memorandum 7.2 in the "Project Documents" section, or you can click here.
Posted April 26th, 2011
The project team thanks all participants in the 172nd/190th Corridor Planning Workshop #4 and Virtual Workshop #4! The Project Management Team (PMT), made up of engineering and planning representatives of local municipalities, has used your input from the workshops and the Project Advisory Committee to select 3 roadway alignment concepts (AT2, AT6 and AS10a) for a more detailed engineering evaluation. You can access the memorandum entitled, "Technical Memorandum 7.2 - Most Promising Alternatives" on the project website http://172nd.com in the "Project Documents" section to review the concepts approved by the PMT for further analysis. The project design team will now perform a more detailed engineering analysis of the 3 alignment alternatives and will recommend a preferred alignment at an Open House on July 20th, 6 PM at Scouters Mountain Elementary School. Please visit the website in the meanwhile for updates on the project.
Posted April 11th, 2011
Virtual Workshop #4 was closed on Friday, April 8th, and the project team is now processing the 105 comments received. Please mark your calendars for Wednesday, July 13th, at Scouters Mountain Elementary School where the project team will provide their preliminary recommendation of the preferred roadway alignment. You can add an appointment to your Outlook calendar by clicking on the "Meetings" tab at http://172nd.com.
Posted April 7th, 2011
If you have not yet provided your input on the remaining 5 roadway alignments, please do so via the Virtual Workshop at http://vw4.project.kittelson.com/ by tomorrow, Friday April 8th, to ensure your vote is counted. Thank you very much for your participation!
Posted April 4th, 2011
The PowerPoint presentation from 172nd Avenue Workshops 1-4 have all been posted on the project website http://172nd.com. Click on the "Public Meeting Presentations" link on the lower left of the screen. If you were not able to attend any of these workshops you can flip through to see what information you might have missed.
Posted April 4th, 2011
Public Workshop #4 was held last week with over 80 citizens in attendance! If you attended and have not yet provided your feedback, we need to receive it by this Friday, April 8th. Please send the Score Card page today to Alisha Dishaw at the address below or submit your feedback via the Virtual Workshop at http://172nd.com to ensure we receive your thoughts by Friday's deadline. Thank you very much for your participation!
813 SW Alder Street, Suite 320, Portland, OR 97205
fax 503-225-0224 or scan/email firstname.lastname@example.com
Posted March 28th, 2011
Come and share your ideas on the 5 remaining 172nd/190th corridor alignment alternatives! Public Workshop #4 will be held tomorrow, March 30th from 6 to 9 p.m. at Scouters Mountain Elementary School. Your input will help to determine which 3 concepts will be considered for the final round of evaluation. For more information, visit http://172nd.com, or click here. We look forward to seeing you there!
Posted March 24th, 2011
The deadline for submitting feedback using Virtual Workshop #4 has been extended through Friday, April 8th. As a reminder, you can access the virtual workshop using a link on http://172nd.com. If you are not able to attend the Workshop scheduled from 6-9 pm at Scouters Elementary School on Wednesday, March 30th, this virtual workshop will give you the opportunity to provide the project team with feedback on the 5 roadway alignments currently being considered. Based on your feedback, the Project Management Team will choose 3 alignments for a final round of evaluation before the preferred alignment is chosen. Thank you for participating with us!
Posted March 18th, 2011
172nd Avenue Newsletter #4 is on its way to you. In case you are not on the mailing list, you can access a copy here. Among other features, the newsletter provides information regarding the 5 current roadway alignment alternatives, as well as a brief recap of public meetings and a summary of next steps.
Posted March 18th, 2011
Come and share your ideas on the remaining 5 corridor alignment alternatives! Public Workshop #4 will be held Wednesday, March 30th from 6 to 9 p.m. at Scouters Mountain Elementary School. Your input will help to determine which 3 concepts will be considered for the final round of evaluation. We look forward to seeing you there!


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"One small way of expressing our gratitude to our customers is through giving," said Kelly Szwed, marketing and promotions coordinator at Williams Trading. "The customers are the lifeblood of our business and we want to thank them by donating in their names."
According to the company, both causes hold true to Williams Trading Co. Vice President Bob Pyne Jr.
"Both breast cancer and stroke have affected the Pyne family in the past, therefore, the causes are quite literally near and dear to my heart," Pyne said. "We take the fight against breast cancer and stroke prevention very seriously."
Every year breast cancer claims more than 40,000 American women's lives according to statistics, the company said, adding that stroke is the number-three cause of death and the leading cause of adult disability in the U.S., behind diseases of the heart and cancer.
"We are proud to support both of these causes in an effort to find a cure," Pyne said.
Williams Trading has made donations for five years running and continues to do so until a cure is found, the company said.


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Dictionary Definition
1 the process whereby heat changes something from a solid to a liquid; "the power failure caused a refrigerator melt that was a disaster"; "the thawing of a frozen turkey takes several hours" [syn: melt, thawing, melting]
2 warm weather following a freeze; snow and ice melt; "they welcomed the spring thaw" [syn: thawing, warming]
3 a relaxation or slackening of tensions or reserve; becoming less hostile; "the thaw between the United States and Russia has led to increased cooperation in world affairs" v : become or cause to become soft or liquid; "The sun melted the ice"; "the ice thawed"; "the ice cream melted"; "The heat melted the wax"; "The giant iceberg dissolved over the years during the global warming phase"; "dethaw the meat" [syn: dissolve, unfreeze, unthaw, dethaw, melt]
User Contributed Dictionary
- /θɔː/
- To melt, dissolve, or become fluid; to soften; — said of that which is frozen; as, the ice thaws. Specifically by gradual warming
- To become so warm as to melt ice and snow; — said in reference to the weather, and used impersonally.
- In the context of "intransitive|figuratively": To grow gentle or genial.
- To cause (frozen things, as earth, snow, ice) to melt, soften, or dissolve. Specifically by gradual warming.
to melt, dissolve, or become fluid
- Czech: tát
- Dutch: dooien
- Finnish: sulaa
- German: tauen
- Italian: fondersi, scongelarsi
- Lithuanian: ištirpti
- Portuguese: fundir, descongelar, derreter
- Romanian: decongelare
- Slovenian: stopiti se
to cause frozen things to melt, soften, or dissolve
the melting of ice, snow or other congealed matter
- French: dégel
a warmth of weather
- French: dégel
- ttbc Dutch: dooi
- ttbc Italian: fusione , scongelamento
- ttbc Portuguese: descongelamento
Extensive Definition
Thaw may refer to:
- For ice and snow to melt: often used of the weather.
- Gomułka thaw
- Khrushchev Thaw, period in Soviet history
- Thaw (album), studio album by Foetus Interruptus
- "The Thaw" (Voyager episode), second-season episode of Star Trek: Voyager
- Tony Hawk's American Wasteland, video game that has been released for the PS2, Xbox, Xbox 360, Nintendo GameCube and PC
- John Thaw, an English actor
See also
thaw in German: Tauwetter (Begriffsklärung)
thaw in Russian: Оттепель
Synonyms, Antonyms and Related Words
bend, colliquate, cut, decoagulate, decoct, defrost, deliquesce, dissolve, fluidify, fluidize, flux, forbear, forgive, fuse, fusibility, fusion, give quarter, have mercy upon, have pity, heat up, hold in solution, infuse, leach, let up on, liquation, liquefy, liquesce, liquidize, lixiviate, melt, melt down, melting, pardon, percolate, refine, relax, relent, render, reprieve, run, running, smelt, soften, solubilize, solve, spare, take pity on, thawing, thermoplasticity, thin, unbend, unclot, unfreeze, warm, warm up, yield


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Chloe everton hot
Although I must take full credit for also eating up to 3, calories a day. People say your life flashes before your eyes when you drown, but this was much, much worse because my mind went blank. Applying the slap for Siobhan's audition Image: And on one afternoon when we went to the races I scored particularly highly on the activity tracker when trotting up and down the stairs to the bar. Polite claps followed, although I think the applause mostly came from Tim, my photographer. Tim Anderson After my live audition, it was time to see how the real professionals do it in a different studio.


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Succeeding in Academic Essay Writing
They refuse to admit making any changes that would affect order execution. Theoretical studies show that the graviton should be massless. Durable goods will prove to be how to choose stock for intraday trading market mover only at the how to choose stock for intraday trading deviation.
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- Research. First up, you need to research your topic and make yourself an expert. There are a lot of resources you can refer to, including the internet, the library, and the academic databases. You need to immerse yourself in the great words while taking notes.
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- Thesis. Brainstorm yourself and think of your insights for the essay. Now you need to pick one idea as your best, and it will be the main point. Make sure you sum it up in a concise sentence, so the readers will know the direction you are going.
- Outline. Make a sketch of your essay before you write it out straight away. Use brief words to describe each paragraph and use bullet points for what you are about to put in each paragraph. Play with the structure of the essay and the orders of the contents.
- Introduction, paragraphs, and conclusion. Now you sit down and write the academic essay. You need to grab readers' attention in the introduction. You also want to set up the issue and lead your readers into your thesis. Each paragraph needs to focus on a single idea supporting your thesis. You should begin a paragraph with a topic sentence and support the assertions with evidence. Use the most sensible and clearest way you can to expound your ideas. At the end, make a graceful exit by using a wrap-up sentence and some memorable thoughts. Maybe use an interesting twist of logic, or a quotation to leave your readers in deep thoughts.
- Formatting and proofreading. Format your academic assay following the correct citation. MLA style is what's commonly used. After formatting the essay, it's time for you to polish your language and correct any mistakes.


text:
This weekend I went through the numbers available (6/30/99) again. We don't know how bad the 9/30 numbers will actually be, but I don't think there's much downside at a price of $24. The question is whether management can get their act together. Even mediocre management should be able to build a pretty good return over the next couple of years, but IMHO it going to take a few quarters before the investment community starts to trust this stock again.My prediction is that we'll see a little bump when the third quarter numbers come out (cuz I think the market overreacted to last week's news). Then we'll see little movement until we're a couple of quarters through FY2000.--David
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Directors of Volunteer Services
Outlined here are some ways Pet Therapy Advisors can assist in expanding animal assisted activity services at your facility through strategic planning, operational consulting and fundraising support.
Pet Therapy Adviser clients generally have existing handler programs that provide successful animal therapy services for its populations, but not all shifts and days are covered, or populations served.
For example, a hospital might have its acute care facility covered but not its ambulatory operations. Or a hospital located on a university campus may want to provide animal therapy handlers for students experiencing stress during final exams, or provide extended services to the community at its outpatient facilities as part of its overall marketing strategies.
For clients wanting to expand their animal therapy services, Pet Therapy Advisers would help them achieve outcomes such as the following:
- Significantly expand the number of animal handling teams in order to provide hundreds of additional service hours on an annual basis.
- Design animal assisted activity services addressing the needs of populations not currently being served.
- Benchmark and implement operational best practices by assessing your program with others in the country,
- Extend your services to targeted community populations through partnerships with well-recognized, non-profit agencies.
- Formalize your existing program to ensure effective risk management policies,
- Develop marketing and recruiting strategies to significantly increase the number of qualified handlers in order to meet the needs of your organization,
- Identify and secure funding to pay for additional costs associated with expanding your program.
Pet Therapy Advisers' consulting services generally start with these first steps, but intervention can be customized around each facility's particular needs:
- Develop a survey to determine management's level of interest and support for a new program, or to expand an existing one.
- Provide a detailed first year budget and seed money requirement to start or expand a program.
- Present a Business Plan to management for feedback, modification and approval,
- Support the implementation of the Plan under management's leadership,
- In partnership with Development and other stakeholders, design and implement fundraising strategies.
Richard Katz, Founder and CEO, Pet Therapy Advisers
Community Colleges
In 2014 Richard Katz launched Pet Therapy Advisers after retiring from a 35-year career as a corporate HR executive, management consultant, and entrepreneur.
As a registered therapy dog handler for the UCLA Health System, Richard was constantly asked by hospital staff, patients and their families, as I made my rounds with my standard poodle, Rudy, how one could become a qualified animal therapy handler.
Market research led me to the conclusion that the general public would benefit by taking a neutral, introductory course called, Rudy on Rounds: How to Become a Qualified Animal Therapy Handler.
The number of colleges offering this introductory course has grown from Orange Coast College, in 2015, to 8 community colleges.
Course Description
Introductory: How to Become a Certified Therapy Dog Handler (One Day, 3-Hours)
This 3-hour class is for adults, 16+, that want to learn the most expedient and least-cost way to become registered with well-respected and recognized local, regional and national dog therapy agencies.
Anyone who has felt a connection with a pet and experienced that joy of unconditional love, understanding, and acceptance, knows the value of a pet's companionship. These qualities make animals, particularly dogs, ideal therapeutic visitors that bring smiles to patients in hospitals, calm travelers at airports, help children on witnesses stands during court proceedings, make good listeners for children learning to read, help victims of natural and man-made disasters, and other newer emerging applications.
In this one-day, 3-hour class, you'll not only see a real-life therapy dog demonstration, but also learn about what it takes to become a therapy dog handler and how you can determine if you're a good fit for this type of service. Course includes an in-depth explanation of the entire registration process, strategies to help you choose a facility, examples of written and live dog handling testing, and post-class support. Please do not bring your dog to class.
Learning Outcomes
- Find out if therapy service is right for you and your dog.
- Learn the precise steps and resources necessary to qualify as a therapy dog handler.
- Master the essentials of learning the most efficient, least cost and quickest way to become qualified.
- Gain an insider's understanding into the types of facilities where you and your dog may qualify.
- Experience a demonstration of a therapy dog handler test.
- Welcome
- Presenters
- Pet Therapy Advisers Mission
- Teaching Schedule
- Today's Agenda
- Learning Outcomes
- Student Sharing
- Three Types of "Working" Dogs
- Emotional Support Dogs
- Service Dogs
- Therapy Dogs
- What Therapy Dog Breeds Qualify and Breed Prejudice
- Therapy Dog Demand
- Therapy Dog Culture
- Therapy Dog Industry and Culture
- Facilities Served
- Populations Served
- The Science Behind Therapy Dog Services
- A Day In The Life of a Therapy Dog
- Handler Qualifications
- Handler Benefits
- Handler Disadvantages
- Handler Expenses
- Dog Benefits
- Class Break
- Basic Therapy Dog Qualifications
- Therapy Dog Temperament And Aggression
- Selecting a Therapy Puppy
- Canine Behavioral Training
- The Process Overview
- National and Local Registering Agencies
- Choosing a Registering Agency
- Sample Dog Handler Evaluation Video
- Advanced Course: Prepping for the Tests
- Jobs and Careers Working with Dogs
- Local Healthcare Facilities
- Therapy Dog Resources
- General Dog Resources
- Post-Class Resources
- Free Rudy on Rounds Newsletter
- Summary
- Student Class Evaluation
- Questions and Answers and Summary
Two More Therapy Dog Courses Now Available
Advanced : Preparing for the Therapy Dog Handler Evaluation (One Day, 3-Hours)
This 3-hour class is for adults, 16+, that fully understand the cost, time commitment and qualifications necessary to become a therapy dog handler and are ready to move forward with training, testing and evaluation.
Do you want to know precisely how to prepare for your therapy dog written test and live dog handling evaluation for your chosen facility and situation? Therapy dog handler evaluations have two parts, or as we say, "two ends of the leash." One part tests the handler's control and treatment of their dog and interpersonal skills; the other part tests the dog's ability to effectively and reliably provide comfort to people, under adverse conditions, in a variety of facilities and situations.
This three-hour class combines lecture, live demonstrations and videos of several therapy dog evaluations used by different registering agencies, as well as review and preparation of the handler's written portion of the certification process. Post class support will also be provided. Please do not bring your dog to class.
Careers Working With Animals: Do What You Love
This class is for teenagers and young adults looking for a part or full-time job working with animals, in particular dogs, directly or indirectly. The class also provides career, educational guidance and job search skills in the field of animal sciences.
How cool would it be to have a career working with dogs and other animals? In this engaging and interactive three-hour class, you'll be amazed to learn about the variety of jobs available using nontraditional sources. It used to be that a career working with dogs was limited to such professions as a veterinarian, veterinary technician, groomer, or dog walker/sitter. Today, while those professions are more viable than ever, there are also a new host of careers, all involving dogs and other animals in some capacity. Come learn how to turn your love of animals into meaningful and profitable employment! Using the latest social-media and Internet-based job search and hiring technologies, you'll learn how to identify the "hidden job market" in your area; increase response from hiring managers; and, improve your interviewing skills. Note: Please do not bring your pet animal to class.
Class Marketing Support
Pet Therapy Advisers supports each class with an extensive digital and print marketing programs to ensure enrollment satisfies the school's investment in listing the class. They include:
- Proprietary email contact list of thousands including, therapy animal associations, therapy animal vendors, health care facilities, targeted community college administrators, non-profit community based agencies, college alumni contacts, HR managers and executives, healthcare workers and clinicians living in the school's target service area.
- PR releases,
- Dog park and pet store signage, where allowed,
- Course website,
- Social media sites include LinkedIn, Facebook Twitter, Instagram, G+,
- Eye-catching and unique teaser graphics for your printed catalog to draw readers into your school's course catalog and marketing communication.
Teaching Insurance
Pet Therapy Advisers carries a multi-million dollar general liability insurance policy and Richard Katz and his registered Pet Therapy dog, Rudy, carries a $2 million insurance policy.
Request a Teaching Proposal
Contact Richard Katz at email@example.com or call (310) 867-4011
Pet Service Providers
As a pet service provider, you will want to consider reaching our audience– an audience of dog owners desiring to prepare their dog to pass the therapy dog registration process.
You have several options to reach our population through website advertising, email and newsletter advertising and as a guest speaker at one of our three-hour classes taught at various colleges in selected areas of the country. The class is called Rudy On Rounds: How To Become a Qualified Therapy Dog Handler.
Rudy on Rounds offers the public an unbiased and objective education on the qualifications and resource options available to become a handler. To our knowledge, there is no class that provides this objective and simpliied understanding of the field of pet therapy, nor incorporates a unique marketing strategy that reaches thousands of people in the community that have thought about animal therapy volunteering but have not taken the next step
Students attending this class typically need various services, such as those offered by your organization, including but not limited to,
- Securing dog through a rescue agency,
- Finding a suitable dog breeder,
- Obedience training,
- Veterinarian services
- Therapy animal training and registering agency,
- Therapy animal agency specializing in serving a specific population such as children, inmates, airport travelers, veterans, college students, healthcare providers, hospitals, and long-term care residents.
- Advocates for related animal-assisted therapy services such as organizations focused on providing service dogs.
If your organization is interested in advertising on our website, emails, and e-newsletter, please provide us with information that might distinguish your organization from the many others that provide similar services. In some situations, we may allow a representative from your organization to participate as a guest speaker.
Please submit information about your business, and/or questions to email@example.com and indicate in the subject line,"Pet Service Collaborator."


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Katt feel big cock of her husband to slap her leg organizing blogs for moms . Ted looked sharp shooting sensation deep in his groin. Willingly, Sandor sucked her taut nipples.


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Top tips for sun safety
The sun is out and the weather is hot - and it looks like temperatures are set to rise further across Shropshire over the next day or two.
Below please find some top ways for staying safe when the heat arrives:
- look out for others, especially older people, young children and babies and those with underlying health conditions
- close curtains on rooms that face the sun to keep indoor spaces cooler and remember it may be cooler outdoors than indoors
- drink plenty of water as sugary, alcoholic and caffeinated drinks can make you more dehydrated
- never leave anyone in a closed, parked vehicle, especially infants, young children or animals
- try to keep out of the sun between 11am to 3pm
- walk in the shade, apply sunscreen and wear a hat, if you have to go out in the heat
- avoid physical exertion in the hottest parts of the day
- wear light, loose fitting cotton clothes
- make sure you take water with you if you are travelling
Where to get medical help and advice for sunburn
Remember you don't always need to visit a GP for sunburn - a Pharmacist can offer over-the-counter treatments and free advice for mild sunburn (such as aftersun products, calamine lotion, and painkillers, such as paracetamol or ibuprofen, to help ease the pain/reduce inflammation caused by sunburn).
However do seek medical help if you feel unwell or the skin swells badly or blisters. Stay out of the sun until all signs of redness have gone.
The self-care area of our website contains a 'Sunburn, Sunscreen, and Sun safety' section with useful information on sunburn (including advice on self-care treatments and when to seek medical help), general details about sun safety for children and adults, plus handy links to advice on choosing the right sunscreen.
Visit the 'Sunburn, Sunscreen, and Sun safety' page for more information.


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Beer, Salmon, Bovril and Easyjet (yes, it's the latest Be-IT recruit!)
Posted on 16th April 2018
You know what it's like when someone new starts in the office. You put the face to the name, they seem quite normal, you gradually find out more about them - and then you discover that they have been a model, a comedian and a world champion. Admittedly a UFC world champion. No, we didn't know either, but apparently it's ….a bit of a porky. Apart from the comedian bit. However, we've forgiven him and anyone who is obsessive about retro football kit can't be all that bad, so welcome to Scott Bentley, the latest recruit to the ranks of the recruiters at Be-IT.
Name: Scott Bentley
Job title: Recruitment Resourcer
What other jobs have you done apart from working in recruitment?
Bar and nightclub manager, car rental, model, comedian, UFC two-weight world champion.
What it your biggest disaster at work (anywhere)?
Delivering a car to a customer heading down to London and leaving my phone in the glove box.
What makes a good recruiter?
Confidence, attention to detail and consistency.
Favourite food and drink and where in the world would you like to be when you are having them?
Watermelon and a Pina Colada on Copacabana beach with a floral shirt on.
If you had to choose only one, which would it be?
Facebook or Twitter: Facebook
Steak or Salmon: Salmon
Beer or Wine: Beer
Pie or Bovril: Bovril
Easyjet or Ryanair: Easyjet
As a new boy, what was your first impression of Be-IT after your first day in the office?
Good laughs, good people and a good place to work.
Favourite (non work) website and why?
Classic football shirts.com , I'm an obsessive hoarder of retro football tops.
Favourite (work) website?
Favourite techie gadget?
Google Home and Sonos
Posted in Interviews, Recruitment News
.. Back to Blog


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Feasibility & Market Studies
We Provide Feasibility ReportsStarting a new business? We provide feasibility reports to help you better understand the market
Virtual CFO
Virtual CFO Services AvailableWe offer virtual CFO services to our esteemed clients to help them stay on top of their business activities
Due Diligence
Due Diligence Is Our SpecialityWe do the Due Diligence on your behalf to keep you away from pitfalls and traps in the corporate world
Our Other Services
It is a process and a set of procedures used to estimate the economic value of an owner's interest in a business. Valuation is used by financial market participants to determine the price they are willing to pay or receive to affect a sale of a business.
Before the value of a business can be measured, the valuation assignment must specify the reason for and circumstances surrounding the business valuation.
- Fair market value – a value of a business enterprise determined between a willing buyer and a willing seller both in full knowledge of all the relevant facts and neither compelled to conclude a transaction.
- Investment value – a value the company has to a particular investor. Note that the effect of synergy is included in valuation under the investment standard of value.
- Intrinsic value – the measure of business value that reflects the investor's in-depth understanding of the company's economic potential.
We have done valuation of various companies engaged in the business of real estate agencies, facility management companies, life style retailing, different food formats, etc. using one or more of these techniques. We do understand the operational issues in valuing the businesses as we have people who have worked for the target companies. We have worked for buyer's as well as seller's side and understand the typical businessmen approach towards the transaction.
It is a job of an entrepreneur to start, run and grow his/her business. It is our business to write his books and show him his accurate financial position in timely manner.
We possess not only accounting knowledge but also business knowledge. We know exactly what a businessman wants to know about his business. Hence we are in a better position to prepare a monthly MIS and discuss with him to give him insight of his business.
Time is the essence. Hence we take utmost care and pride in providing the MIS in timely manner consistently.
We have in house resources to maintain books of accounts of all enterprises using various accounting platforms.
Give me six hours to chop down a tree and I will spend the first four sharpening the axe – Abraham Lincoln
Mr. Lincoln's statement is so true even 150 years after his death and in the profession which didn't exist in his time.
ERP is Enterprise Resource Planning but for most of the companies it is a big headache and waste of money. There are various reasons for this situation. To give few examples; lack of planning and documentation, improper implementation, partial usage, lack of trained manpower, etc
We have implemented and reviewed ERPs in various sectors and have hands on experience in running the same. We start with writing/reviewing the policies of the organization and understand the business and the business requirements before even touching the ERP.
The job is only begun when you implement the ERP. Getting desired reports in the desired format and in time, is another challenge. We assist organization in both these stages.
Why Choose Us
- Over 10 years of expereince in the field makes us the experts
- Qualified, expereinced and professional team of management experts
- More than 1,000 companies set up by us in the United Arab Emirates
- Recruitment, placement and training provided by our in-house management
- We offer free support because we care about your site as much as you do.
What Client's Say
It's a click! We approached the team with least expectations and now they read our mind, they know what our requirements could be. We are glad that we got connected in no time.
Once our company was incorporated, we knew we did not have to wander around for other service as the team has a full support system providing their unique way of handling most of our enquiries. Great Job!!
A positive start is an initiative from the team. We had a very good experience with the team and we depend on them for the development of our business. Happy to be connected with them.
We couldn't have advised our clients better about having a business by incorporating an International Company in the UAE. The process, timeline, documentation requirement everything had been well informed to us. They know the final touch up and have been able to live up to their clients' expectations.
In terms of complete payroll management & solution, it has been a great experience working with the team for half a decade and we are looking forward for more years
Running through the WPS process and then initialising it, making it a monthly practise was much simpler than we thought it could ever be. Thanks to the team for channelizing it in a right way!


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This week's BEARcast – WrestleCast is filled with fun and anticipation for Sunday's Extreme Rules PPV. So much to cover that Fred and I had to get Dustin "Tha Doc-ta" on the phone to get his hot takes. We go over the World's Greatest RAW Power Rankings for 4/28/2014, the fun of having Magneto vs Wolverine at a wrestling show and preview Extreme Rules. All of this while The BEAR is under the weather. We don't do this for us, it's for you, the people!
Thank You and enjoy,
Willie Kinoshita
Tweet me at @wkbear or Fred at @FreddyD15
If you'd like to contribute or have any ideas for the show, email the show at firstname.lastname@example.com or click on CONTACT US.
Podcast: Play in new window | Download | Embed


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我叫Felicia Ong,我已经做了两年的自由认证护士助理,最近加入了CaregiverAsia平台。虽然医疗培训课程使我具备了在诊所提供专业服务的相关护理技术和知识,但我还是不确定自由护士助理的工作到底指的是什么。我既没有信心向客户推销自己,也不知道在家庭护理环境中应该如何表现。
Hey guys, my name's Ricky and I'm a freelance nurse who's recently signed up with CaregiverAsia Pte Ltd. As a freelancer, I'm not confined to tight schedules and having to ask my my colleagues to swap shifts when I need to go on leave, because, as a freelance nurse, it's simply based on my own time and availability.
My name is Felicia Ong and I have been working as a certified freelance nurse aide for two years and recently joined the CaregiverAsia platform. While the healthcare training courses have armed me with the relevant nursing techniques and knowledge to provide professional services in clinics, I didn't understand what it meant to work as a freelance nurse aide. Neither did I have the confidence to advertise myself to clients, as well as how I should act in a home care setting.
Having a nurse around to tend to your loved one at home is exactly what you need to ensure they're taken care of. Even though you have a domestic helper at home, it is often a better option to have someone who's confident and experienced in caring for the elderly. Should I hire a nurse for my parent? – a question that we'll have to contend with at some point in our lives. If you are at this crossroad, we'd like to share our careseekers' experiences of engaging a home nurse for their elderly loved ones.
Experiencing joint pains or muscles aches? Try seeking help from a chiropractor. You don't necessarily have to be injured for you to seek chiropractic help. In fact, seeking help from a chiropractor is a great way to protect your body from injuries. Through chiropractic therapy, you can give your body the right treatment it deserves.
A confinement nanny is someone you would definitely want to have by your side during your confinement period. After giving birth, your mind and body will be exhausted and you will need the rest to fully recover. Having someone with years of experience and knowledge about confinement and the best ways to handle, feed, and take care of your child is exactly what you need during this period.
Hypnotherapy may be an unknown territory for many. For John (not his real name), this therapy that involves a form of hypnosis technique has helped him control his emotions, namely anger and pride, and brought him out of the darkness.
She engaged a confinement nanny again when she had her second baby so she could get more rest. "Every mother needs a confinement nanny so they can recuperate and rest well after pregnancy."
There's a common notion that confinement nannies are more beneficial to new moms than experienced ones. Some say moms who are experienced do not need to engage confinement nannies because they're already knowledgeable in handling and breastfeeding newborns. Brenda Lee begs to differ.
Valerie Lim needed day and night nurses to watch over her mother, who was terminally ill.
Like many families who are looking for urgent help at home, the housewife searched and scanned the internet for nurses to care for her elderly mother. "She was already under home hospice care with the Assisi team, but I needed help to bathe her, administer injections, and watch her through the night," Valerie said.


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I don't think this feature is in the game but I think it would be cool to be able to romance, say, the commander. Actually, I am mostly just asking about adding the feature to woo the commander. Can we have it?
I think this goes against the canon plot. Everyone knows the captain's true soulmate is chief viscosity officer Wymdoo.
It's unlocked after you agree to be a dinner guest of the Phamysht.
Why do I feel like you are trolling me?
I understand why the team chose to go "truly" alien with all the aliens.... but it would be sorta neat to see a few tropeish "space elf" "Space fairy" "Space nymph" type races... even if they are just minor way station races...
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Jimmy's sister Renisha, said the family hasn't been able to get closure. After a year of trying to get justice was stifled by the National Prosecuting Authority which declined to prosecute, the Jimmys are now pinning their hopes on an inquest granted by a Western Cape magistrate last week.
Reshall died after his Ford Kuga allegedly burst into flames in December 2015. Several other Kugas ignited on South African roads, leading to public outrage. In February 2017 Ford recalled 4556 1.6-litre Kugas built between December 2012 and February 2014.
Renisha said the family was still fighting to get justice for her brother:
"We have in the past week received confirmation that a magistrate has reviewed Reshall's docket, and that everything has been handed in," she said. "We've been given an inquest number to trace and we're at the final stage of getting a date. We are hoping to get a date for January."
Approached for comment, Ford spokesperson Minesh Bhagaloo said Ford recognised how devastating Reshall's death has been for the Jimmys.
"Given the sensitive and unique circumstances of the case relating to the death of Mr Jimmy," he said, "and the possibility of ongoing legal proceedings, we have nothing further to add on this matter at this time."
In August, it emerged that the NPA had declined to prosecute due to the lack of evidence to secure a successful outcome. Western Cape NPA spokesperson Eric Ntabazalila confirmed that the case had been referred for an inquest, but said he was unable to provide more information.
The Star


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Afternoon News Headlines (October 19, 2017)
– Odisha Governor S C Jamir complains of chest pain, admitted to Apollo Hospital in Bhubaneswar.
– Bijay Kumar Patnaik quits as Vedanta Group's University President.
– Death toll due to explosion at cracker unit in Balasore dist rises to 10.
– Girls of Nagrashola Girls High School walk 25 km to meet Mayurbhanj collector over hostel problems.
– J&K: PM Modi celebrates Diwali with jawans of Indian Army and BSF in Gurez Valley.
– Massive fire breaks out in LIC building in Kolkata; 10 fire tenders at the spot.
– Attack on Afghanistan military base kills at least 43 soldiers.
– Pakistan: NAB probe team reaches UK to probe Nawaz Sharif's assets.


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By Todd Cohen
As nonprofits think more about using technology strategically, they also are adjusting to a shift in the way technology is delivered.
The past five years, for example, have seen big expansion in the number of "application service providers," or ASPs, that provide a broad array of leased services to nonprofits, says Joe Baker, executive director of the San Francisco-based Nonprofit Technology Enterprise Network, or NTEN.
The growth of the ASP marketplace, offering services that range from email, fundraising and advocacy to client-tracking and outcomes-measurement, also has changed the way nonprofits treat the cost of technology, he says.
Five years ago, technology typically was seen as an up-front cost for which nonprofits might be able to secure funding by integrating it into the cost of a particular project or program.
But with ASP services now widely available, technology has become an ongoing cost of doing business, precisely the kind of operating cost that funders traditionally have been reluctant to cover, Baker says.
NpowerNY, which in the past provided support by scheduling its consultants to make periodic visits to its nonprofit clients, now is introducing "NPower Basic," delivering routine maintenance over the internet for tasks such as downloading anti-virus measures, backing up data, creating new users and deleting old users.
The tech-assistance provider also is expanding NPower Basic to deliver software applications for tasks such as fundraising, accounting and even some client services.
Hosting applications on a server and maintaining a tech staff can be a "really expensive and inefficient way to do back-office support" for a nonprofit, especially small organizations, says Barbara Chang, executive director of NpowerNY, a tech-assistance provider in New York City. "You should have peace of mind that when you have limited resources, technology should enable, not be a barrier."
Other stories in the series:
Part 1 — Nonprofits face tech hurdles.
Part 2 — Nonprofits making more strategic use of technology.
Part 4 — Nonprofits face funding gap for technology.
Part 5 — Nonprofits find it tough to find tech support.
Part 6 — Nonprofits work to bridge gap in constituents' tech access.


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I saw it on her Instagram. She looks so pretty..
1. [+161][-7] This is Hanlim's skirt uniform size 44, it's originally this short.. It looks shorter on her because she's tall..
2. [+145][-107] Her skirt is so freaking short..
3. [+94][-148] Somi wasn't this type of kid back in middle school.. She shortened her skirt way too much..
4. [+61][-4] Hanlim's skirt uniforms are originally that short, and it looks way much shorter on Somi because she's tall.. Shut your mouth if you don't know anything about that.. You guys are so ridiculous..
5. [+41][-3] Somi got interviewed when she first enrolled to Hanlim and in that interview she said, 'The skirt here is really short.' 'Why is the skirt so short?'. I bet you guys didn't even bother to watch the video before judging her. And on top of that, Somi is tall, she has a really long legs. People with short legs absolutely can't relate to that. Get your facts right first without judging, you guys are pathetic.


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From best-selling author Nick Earls, William Robinson: A new perspective chronicles the life and career of renowned artist William Robinson.
The unique non-fiction novella provides a new perspective on both author and artist. From cringing over his first solo exhibition in the 1960s, to juggling family life, teaching and goat farming alongside his art practice, William Robinson's career trajectory unfolds throughout the book with Earl's knack for observational humour making each page a delight to read.
"As one of our most significant living artists, William Robinson's work has been the subject of numerous insightful essays and books by art experts," said author Nick Earls.
"With no such expertise to offer, but an eye and an ear for a story, I had a chance to do something different. It was a real privilege to sit down with the artist himself for hours of discussion that brought his story to the surface. I hope that, from that, I'll have joined a few dots that no one's joined before, and created something that gives an insight into how he became the artist he is."