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The ability of the pathogenic fungus Candida albicans to switch cellular morphologies is important for infection and virulence. Recent studies have revealed that C. albicans yeast cells can switch to filamentous growth under genotoxic stress in a manner dependent on the DNA replication/damage checkpoint. Here, we have investigated the functions of Pph3 (orf19.4378) and Psy2 (orf19.3685), whose orthologues in Saccharomyces cerevisiae mediate the dephosphorylation of the DNA damage checkpoint kinase Rad53 and the histone variant H2AX during recovery from DNA damage. Deleting PPH3 or PSY2 causes hypersensitivity to DNA-damaging agents, including cisplatin, methylmethane sulfonate (MMS), and UV light. In addition, pph3Δ and psy2Δ cells exhibit strong filamentous growth under genotoxic stress. Flow cytometry analysis shows that the mutant cells have lost the ability to adapt to genotoxic stress and remain arrested even after the stress is withdrawn. Furthermore, we show that Pph3 and Psy2 are required for the dephosphorylation of Rad53, but not H2AX, during DNA damage recovery. Taken together, these results show that C. albicans Pph3 and Psy2 have important roles in mediating genotoxin-induced filamentous growth and regulating Rad53 dephosphorylation.
Candida albicans is a pleiomorphic fungal pathogen that causes superficial infections of the skin, vagina, and oral epithelia and life-threatening systemic infections in immunocompromised patients (12, 31, 38). The fungus can exist in three morphological forms, including budding yeast, pseudohyphae, and hyphae (9, 45). The ability to switch between the different growth forms has proved to be important for infection and virulence (22, 30, 52). Many environmental factors can induce hyphal growth, such as appropriate temperature, neutral pH, and serum (19, 45). Several signal transduction pathways regulate the yeast-to-hypha growth transition, among which the cyclic AMP (cAMP) and mitogen-activated protein kinase (MAPK) pathways play central roles. The two pathways target transcription factors Efg1 and Cph1, respectively, to activate the expression of hypha-specific genes, leading to filamentous growth (27, 29, 30, 39, 44).
A series of recent studies reported that perturbing the cell cycle progression by various means causes filamentous growth in a manner independent of the cAMP and MAPK pathways (1–6, 8, 13, 42). For example, C. albicans yeast cells treated with the DNA replication inhibitor hydroxyurea, the DNA-alkylating agent methylmethane sulfonate (MMS), or UV radiation exhibited significant cell elongation (3, 42). Depletion of either the G1 cyclin Cln3 or one of the mitotic cyclins Clb2 and Clb4 also induces constitutive pseudohyphal growth (5, 8, 13), and switching off two cell cycle regulatory genes, CDC4 and CDC5, has similar effects (2, 4). One of the most compelling pieces of evidence for direct involvement of the cell cycle machinery is the identification of the G1 cyclin Hgc1 as a specific regulator of C. albicans hyphal development (52). However, the molecular mechanism by which interference with the cell cycle triggers filamentous growth remains unknown. A rapidly emerging theme of control seems to intimately involve the cell cycle checkpoints, based on a significant body of evidence obtained in studies in both Saccharomyces cerevisiae and Candida albicans. These checkpoints are regulatory pathways that control the order and timing of cell cycle transitions and ensure that critical events, such as bud formation, DNA replication, and chromosome segregation, are completed with high fidelity (24, 34). When these events are impaired, the checkpoints temporarily arrest cell cycle progression to provide time for repairing damage and correcting mistakes. In S. cerevisiae, defective bud construction activates the Swe1-mediated morphogenesis checkpoint to temporarily arrest cell cycle progression, leading to bud elongation (11, 50). Several DNA damage/replication checkpoint proteins, such as Mec1 and Rad53, have been found to be involved in the filamentous growth induced by DNA replication stress (25, 42). In C. albicans, depletion of Rad52 triggers the DNA damage checkpoint, leading to constitutive filamentation (1), and deleting RAD53 completely abolishes the filamentous growth caused by genotoxic stresses (42). Interestingly, the spindle assembly checkpoint is required for the filamentous growth triggered by the disruption of microtubules (6).
Reversible protein phosphorylation is a highly conserved regulatory mechanism involved in many steps of the DNA damage response. While events activated by kinases have been studied rather extensively, little is known about how cells deactivate the damage response once genotoxic stress is overcome or withdrawn. Clearly, inactivation of the cell cycle checkpoints is required for cells to resume cell cycle progression. Previous studies have indicated that the PP2A-like protein phosphatase Pph3 plays an important role in the DNA damage response pathway in S. cerevisiae: deleting PPH3 or PSY2, a gene encoding a regulatory subunit of Pph3, increases sensitivity to cisplatin and MMS (23, 51). One of the earliest events in a eukaryotic cell's response to DNA damage is serine phosphorylation of the histone variant H2AX at the C-terminal SQE motif, leading to assembly of phospho-H2AX (γH2AX)-containing nucleosomes that recruit DNA repair and signaling proteins (20). Work in S. cerevisiae has identified a complex containing Pph3 that regulates the phosphorylation status of γH2AX in vivo and efficiently dephosphorylates γH2AX in vitro (26). Genetic and biochemical evidence is available that Pph3 and Psy2 form a complex (Pph3-Psy2) that binds and dephosphorylates activated Rad53 during adaptation to and recovery from MMS-mediated DNA damage, and in the absence of Pph3-Psy2, Rad53 dephosphorylation and the resumption of DNA synthesis are delayed (35). In addition to Pph3, the PP2C-type phosphatases Ptc2 and Ptc3 also participate in Rad53 deactivation under similar conditions (28, 46, 47).
Although the deactivation of DNA checkpoints has been extensively investigated in S. cerevisiae, it remains totally unknown whether PP2A-related phosphatases have a role in DNA damage recovery and damage-induced filamentous growth in C. albicans. Here, we describe the identification and functional characterization of C. albicans PPH3 (CaPPH3) and PSY2. We found that deletion of PPH3 or PSY2 significantly increased the cell's sensitivity to MMS, cisplatin, and UV. Interestingly, after removing the DNA-damaging agents, both pph3Δ and psy2Δ mutants continued to grow in filamentous form and could not reenter the cell cycle for a long time before losing viability, while wild-type cells switched back to normal yeast growth. In addition, Rad53 dephosphorylation was blocked during recovery from DNA damage in the mutants, suggesting a role for Pph3 and Psy2 in deactivating Rad53. These results provide new insights into the molecular mechanisms underlying the deactivation of the DNA damage checkpoint and filamentous growth in C. albicans response to genotoxic stresses.
Strains and culture conditions.All C. albicans strains used in this study are listed in Table 1. C. albicans was routinely grown at 30°C in YPD medium (2% yeast extract, 1% peptone, and 2% glucose), in GMM (2% glucose and 6.79 g/liter yeast nitrogen base without amino acids), or in GMM supplemented with the required nutrients. For hyphal growth, yeast cells were inoculated into YPD medium containing 20% serum. Solid media contained 2% agar.
C. albicans gene deletion, rescue, and epitope tagging of proteins.C. albicans deletion mutants were constructed by sequentially deleting the two copies of the target gene from BWP17. The deletion cassettes were constructed by flanking a selectable marker gene (ARG4 or HIS1) with the AB and CD fragments, which correspond to the 5′ and 3′ untranslated regions (UTRs) of the target gene, respectively. The first copy was replaced by using the ARG4 cassette, and the second copy was deleted by using the HIS1 cassette. Homozygous deletion mutants were verified by PCR.
For gene rescue, the entire open reading frame (ORF), together with the promoter (∼1,000 bp), was cloned into the CIp10 plasmid at KpnI and ClaI sites, followed by the GAL4 3′ UTR. The construct was linearized by StuI, which is in the RP10 sequence of CIp10, and then introduced into the gene deletion strains.
For C-terminal Myc tagging of Rad53, the DNA fragment for the Myc epitope was ligated in frame to the 3′ end of the target gene in a CIp10 plasmid. After linearizing the plasmid at a unique restriction site within the coding sequence, the plasmid was transformed into strains SJL2 and SJL5, yielding C-terminally Myc-tagged proteins.
Cisplatin, MMS, and UV sensitivity and recovery assays.Tests of sensitivity to DNA-damaging agents on solid and liquid media were carried out as described previously (42). For the damage recovery experiments, cells were grown in YPD medium at 30°C overnight and diluted in fresh YPD medium at a concentration of 5 × 106 cells/ml. After 2 h of growth at 30°C, MMS or cisplatin was added to a final concentration of 0.02% or 1 mM, respectively. After 2 h of drug treatment, cells were harvested, washed twice with distilled water, and resuspended in fresh YPD medium without drugs for further growth.
Protein extraction, Western blotting, and protein dephosphorylation.Cells were harvested by centrifugation, and ∼100 mg of cells was resuspended in 200 μl of ice-cold RIPA buffer (8). After adding an equal volume of acid-washed glass beads (Sigma-Aldrich), the cells were broken by four rounds of 45 s of beating at 5,000 rpm in a MicroSmash MS-100 bead beater (Tomy Medico, Minato-ku, Japan) with 2 min of cooling on ice between rounds. The supernatant was collected after centrifugation of the cell lysate at 13,000 rpm for 20 min at 4°C. The protein concentrations of the supernatant were determined using the bicinchoninic acid (BCA) protein assay (Galen). For Western blots, 30 μg of protein was separated by 8% or 12% SDS-PAGE and transferred to a polyvinylidene difluoride (PVDF) membrane (Millipore). The membrane was immersed in Tris-buffered saline containing 0.1% Tween 20 (TBST) and 5% milk for 1 h at room temperature, followed by 1 h in TBST containing 1% milk and the primary antibody and then in TBST containing 1% milk and the second antibody conjugated with hydrogen peroxidase. The target protein was visualized by using an enhanced-chemiluminescence (ECL) system. The Hta-P antibody was purchased from Upstate Millipore and the anti-Cdc28 (PSTAIRE) antibody from Santa Cruz. Protein dephosphorylation was carried out as described previously (7). Lambda phosphatase was purchased from New England BioLabs (catalog no. P07535).
Identification of CaPPH3 and CaPSY2.The C. albicans genome (http://www.candidagenome.org) contains candidate orthologues of S. cerevisiae PPH3 (ScPPH3) and ScPSY2. CaPPH3 (orf19.4378) encodes a protein of 302 amino acids (aa), which is 6 aa shorter than ScPph3. The two proteins share ∼70% identity (Fig. 1 A), and each contains a highly conserved PP2A-like catalytic domain (Fig. 1B), strongly suggesting that CaPPH3 is orthologous to ScPPH3. CaPSY2 (orf19.3685) encodes a 980-aa protein, which is 122 aa longer than ScPsy2. Although the two proteins share low overall sequence identity, a conserved region with 68% similarity is found in the N termini of the proteins (Fig. 1C).
To investigate the functions of Pph3 and Psy2 in C. albicans, we constructed PPH3 and PSY2 deletion mutants by sequentially replacing the entire coding region of the two copies of the target gene with the selectable markers ARG4 and HIS1. The pph3Δ and psy2Δ mutants grew at rates similar to those of the wild-type strains (SC5314 and BWP17) in both liquid and solid YPD medium under unperturbed conditions (Fig. 2 A and 3). Like wild-type cells, both mutants grew as yeast at 30°C in liquid YPD medium and switched to hyphal growth at 37°C in the presence of serum (Fig. 2B). On solid media, the mutants grew colonies with appearances indistinguishable from those of wild-type colonies (data not shown). However, when grown under embedded conditions, the colonies of the pph3Δ or psy2Δ mutant exhibited less filamentous growth at the edge than wild-type colonies (Fig. 2C), indicating that Pph3 and Psy2 are involved in cell morphology under certain conditions.
CaPPH3 and CaPSY2 are required for resistance to DNA-damaging agents.Recently, PPH3 and PSY2 have been identified in a genome-wide screen of S. cerevisiae genes for hypersensitivity to the DNA-damaging agents cisplatin and oxaliplatin (51). Deletion of PPH3 or PSY2 also led to a moderate increase in sensitivity to MMS (23). Consistently, we found that C. albicans pph3Δ and psy2Δ mutants are more sensitive than wild-type cells to DNA-damaging agents, including cisplatin, MMS, and UV (Fig. 3). When a copy of the wild-type PPH3 or PSY2 gene was reintroduced into the respective gene deletion mutant, sensitivity to genotoxins was fully rescued (Fig. 3). Taken together, these data indicate that the protein phosphatase Pph3 and its regulatory subunit Psy2 play evolutionarily conserved roles in regulating cellular response to DNA damage.
PPH3 and PSY2 have roles in cell cycle arrest and filamentous growth induced by DNA damage.In the past few years, a significant number of publications reported that C. albicans can switch to filamentous growth when treated with genotoxins (3, 42). To investigate the roles of Pph3 and Psy2 in response to DNA damage in C. albicans, we first examined the phenotypes of the pph3Δ and psy2Δ mutants during constant exposure to MMS. We found that when treated with 0.02% MMS, both wild-type and mutant cells switched to a pseudohyphal form of growth. However, the mutant cells were much more elongated than wild-type cells after 4 h (Fig. 4 A), and a similar phenotype was also observed when cells were grown on solid media (data not shown). We measured the lengths of the filaments (n = 30) and found that the average length of pph3Δ and psy2Δ cells was about 25 μm, in contrast to 8 μm for wild-type cells, after exposure to MMS for 8 h (Fig. 4B). Flow cytometry analysis of MMS-treated yeast cells showed that while nearly all the wild-type cells entered G2/M phase at 3 h, a large fraction of pph3Δ and psy2Δ cells were still in S phase (Fig. 4C), indicating that the Pph3 complex is necessary for cells to go through S phase in the presence of MMS. We next examined pph3Δ and psy2Δ cells for morphogenesis and cell cycle progression during recovery from MMS-induced DNA damage. Interestingly, after washing off MMS, wild-type cells reentered the cell cycle and generated round cells from the tips of the filamentous cells, whereas the majority of pph3Δ and psy2Δ cells remained arrested and continued to elongate for at least 8 h (Fig. 4D and E). Methylene blue viability staining of cells at 8 h after washing off MMS did not show a significant increase in positively stained cells in the mutants (data not shown), further indicating that the mutant cells were alive at this time point. However, when we spread the treated cells onto plates without genotoxins, we found that the CFU were dramatically reduced, by ∼90% and ∼95%, for the mutant cells after treatment with 0.02% MMS for 6 h and 8 h, respectively. The results indicate that although the MMS-treated mutant cells remained alive for at least 8 h, the majority of them eventually lost viability and were unable to form visible colonies on plates. In contrast, few wild-type cells lost viability. Moreover, after removing MMS, pph3Δ and psy2Δ cells plated onto YPD solid medium showed strong invasive growth. After 3 days of incubation, we washed the cells off the agar surface and found that, unlike the colonies of wild-type cells, which were easily removed, pph3Δ and psy2Δ cells had grown into the agar, further demonstrating continuous filamentous growth of the mutant cells after the removal of MMS (Fig. 4F). These data indicate that cells lacking PPH3 or PSY2 elicit prolonged S-phase arrest in response to DNA damage by MMS and have great difficulty in resuming DNA synthesis and cell cycle progression even after the removal of the DNA-damaging agent. Together, the results showed that pph3Δ and psy2Δ cells are defective in recovery from the cell cycle arrest and filamentous growth induced by DNA damage. pph3Δ and psy2Δ cells exhibited similar responses when treated with cisplatin (data not shown).
Pph3 and Psy2 are not required for HTA dephosphorylation during recovery from genotoxic stress.Phosphorylation of histone H2AX is one of the earliest events in the response to DNA double-strand breaks (DSB) (40). When cells have adapted to DNA damage or when the damage stress is removed, cells deactivate the DNA damage checkpoint in which γH2AX needs to be dephosphorylated (26). Recently, a Pph3 complex has been implicated as a γH2AX phosphatase in both mammal and yeast (15, 26, 32). To further understand the filamentous growth and the cell cycle defect of pph3Δ and psy2Δ mutants during DNA damage recovery, we sought to determine whether C. albicans Pph3 is also involved in γH2AX dephosphorylation. We first needed to identify the C. albicans histone H2AX, which had not been studied. The C. albicans genome contains candidate orthologues of ScH2AX. CaHta1 (orf19.1051) and CaHta2 (orf19.6924) are two histone H2A subtypes. The amino acid sequences of the two proteins are nearly identical, with only two differences. Both proteins contain the conserved C-terminal SQE motif. Comparison of the CaHta sequences with those of S. cerevisiae showed considerable evolutionary conservation, with 92% identity, suggesting that CaHta is orthologous to ScH2AX. Western blot analysis using an antibody specific for phospho-H2A showed that the amount of phosphorylated CaHta (P-Hta) in wild-type cells increased with increasing concentrations of cisplatin or MMS (Fig. 5 A), indicating that CaHta, like H2AX in mammalian cells and S. cerevisiae, becomes phosphorylated in response to DNA damage. Together, the high sequence conservation and the DNA damage-induced phosphorylation strongly support an orthologous relationship of CaHta and H2AX.
Next, we wished to explore whether Pph3 and Psy2 are required for Hta dephosphorylation during DNA damage recovery. In untreated pph3Δ and psy2Δ cells, we found that P-Hta was barely detectable, as in untreated wild-type cells, and the level of P-Hta increased similarly upon treatment with cisplatin or MMS in both the mutant and wild-type cells. After the genotoxins were washed off, P-Hta levels deceased gradually to near basal levels in ∼4 h at similar rates in wild-type and mutant cells (Fig. 5B and C). Thus, the results indicate that Pph3 and Psy2 are not required for HTA dephosphorylation during DNA damage recovery in C. albicans.
Pph3 and Psy2 are required for Rad53 dephosphorylation during DNA damage recovery.Activation of Rad53 is a critical response to DNA damage that results in the activation of gene transcription, stabilization of stalled replication forks, inhibition of late-origin firing, and delayed entry into mitosis (53). Previous work in S. cerevisiae showed that Pph3 and Psy2 are required for Rad53 deactivation during MMS treatment and recovery from MMS-caused DNA damage (35). Recently, Shi et al. (42) identified Rad53 in C. albicans. We therefore wished to examine whether PPH3 and PSY2 are required for Rad53 dephosphorylation during recovery from DNA damage in C. albicans. Using Myc-tagged Rad53 in Western blot analysis, we detected that wild-type, pph3Δ, and psy2Δ cells all accumulated partially phosphorylated Rad53 after 1 h of MMS or cisplatin treatment and hyperphosphorylated Rad53 at 4 h (Fig. 6 A and B). We next examined the phosphorylation state of Rad53 in cells during recovery from MMS and cisplatin treatment. After removing MMS or cisplatin, Rad53 was completely dephosphorylated at 4 h in wild-type cells, while it remained hyperphosphorylated at that time point in both pph3Δ and psy2Δ cells (Fig. 6C). These data demonstrate that Pph3 and Psy2 are required for Rad53 dephosphorylation during recovery from DNA damage.
CaPPH3 and CaPSY2 are required for resistance to DNA-damaging agents.We have identified the C. albicans PPH3 and PSY2 genes based on sequence identity to their S. cerevisiae homologues. In S. cerevisiae, Pph3 interacts with the regulatory subunits Psy2 and Psy4, and this complex dephosphorylates γH2AX during DNA damage and repair. These three proteins and their interactions are conserved through evolution from yeast to Drosophila to mammals (16). In S. cerevisiae, Pph3 and Psy2 play roles in Rad53 dephosphorylation during recovery from MMS or cisplatin (23, 51), while Psy4 participates only in recovery from cisplatin treatment. In mammalian cells, inhibition of PP4C expression, the orthologue of Pph3, also sensitizes cancer cells to cisplatin treatment (49). Consistently, our data showed that pph3Δ and psy2Δ cells are hypersensitive to DNA-damaging agents, including cisplatin, UV, and MMS. We also found that wild-type cells could adapt to the genotoxins after several hours. Even in the continuous presence of the genotoxins, they were able to exit from the DNA damage-induced S-phase arrest, reenter the cell cycle, and switch from filamentous growth back to yeast growth. In contrast, pph3Δ and psy2Δ cells remained arrested and continued to elongate for a long time before losing viability. This explains why PPH3 or PSY2 deletion increases sensitivity to genotoxins. These data indicate that the evolutionarily conserved protein phosphatase Pph3 complex plays an important role in the DNA damage response.
We searched for the homologue of ScPSY4 in the C. albicans genome database but did not find any significant match. Perhaps C. albicans has only one regulatory subunit for Pph3.
CaPPH3 and CaPSY2 are dispensable for Hta dephosphorylation.In S. cerevisiae, one of the earliest events in cellular response to DNA damage is the phosphorylation of H2AX by the checkpoint kinases Tel1 and Mec1, which are orthologues of the mammalian ATM and ATR, respectively. The phosphorylation occurs at Ser129 in the C-terminal SQE motif, and the phosphorylated H2AX accumulates at the sites of DSB (20, 37, 40). This modification is important for maintaining cell cycle arrest and the repair of DNA damage by recruiting DSB recognition and repair factors to the break site, including DNA damage checkpoint proteins, chromatin remodelers, and cohesins (37, 40). In the C. albicans genome database, we identified candidate genes for the histone H2A variant H2AX. CaHta is highly similar to H2AX in both sequence and domain organization. Our data show that CaHta is also rapidly phosphorylated at the conserved SQE motif upon DNA damage and is dephosphorylated after removing the DNA-damaging agent. In S. cerevisiae, a protein complex containing the phosphatase Pph3 and its regulatory subunits Psy2 and Psy4 has been shown to regulate the H2AX phosphorylation level in vivo and to efficiently dephosphorylate γH2AX in vitro (26). Recently, in mammalian cells, PP4C, the orthologue of S. cerevisiae Pph3, has been reported to dephosphorylate γH2AX (15, 32). Unexpectedly, we found that CaPph3 and CaPsy2 are dispensable for CaHta dephosphorylation during DNA damage recovery. In mammalian cells, PP2A isoforms, the orthologues of S. cerevisiae Pph21 and Pph22, have been reported to directly bind to and dephosphorylate γH2AX (14), and in some cases, other protein phosphatases have redundant functions with Pph3 (10). Therefore, we propose that CaHta dephosphorylation during DNA damage recovery might be dependent on other protein phosphatase(s) in C. albicans.
CaPPH3 and CaPSY2 play important roles in Rad53 dephosphorylation during DNA damage recovery.Activation of the checkpoint kinase Rad53 is an essential event in activating cellular responses when DNA damage occurs (53). Checkpoint activation is crucial to the maintenance of genome integrity in the cell's response to genotoxic insults. Once the damage is repaired, checkpoint deactivation is necessary for the cell cycle to resume. Previous studies in S. cerevisiae found that the PP2C-type phosphatases Ptc2 and Ptc3 were necessary for Rad53 deactivation after the DNA double-strand break was repaired (28). More recently, the phosphatase Pph3 complex was shown to be required for Rad53 dephosphorylation after introduction of a repairable but long-lived double-strand break (35). Here, we demonstrate that CaPph3 and CaPsy2 are required for Rad53 dephosphorylation during DNA damage recovery. Deletion of CaPPH3 or CaPSY2 has little effect on the rate of Rad53 hyperphosphorylation upon exposure to MMS or cisplatin. However, after removing the genotoxins, Rad53 dephosphorylation was complete at 4 h in wild-type cells while Rad53 remained fully phosphorylated in pph3Δ or psy2Δ cells for at least 4 h. In S. cerevisiae, Rad53 plays a crucial role in the stabilization of replication forks in response to DNA damage and in the regulation of DNA replication restart during recovery (46). Our study shows that treatment of pph3Δ or psy2Δ mutants with cisplatin or MMS caused a significantly prolonged S-phase arrest compared with wild-type cells. In addition, the majority of mutant cells did not resume DNA synthesis and cell cycle progression even after the removal of the DNA-damaging agents, although they continued to elongate for hours. Taken together, our data indicate that CaPph3 and CaPsy2 are required for Rad53 dephosphorylation during DNA damage recovery, and Rad53 hyperphosphorylation in pph3Δ and psy2Δ mutants is most likely the reason behind the prolonged S-phase arrest after the removal of genotoxins.
DNA damage checkpoint and pathogen adaptation to host defense.Cell cycle checkpoints are regulatory pathways that control the order and timing of cell cycle transitions (24, 34). When these events are impaired, the checkpoint pathways temporarily arrest cell cycle progression to provide time for cells to repair damage. In the present study, we showed that the Capph3Δ and Capsy2Δ mutants grew normally under unperturbed conditions but exhibited severe defects in their ability to adapt to genotoxic stresses, such as exposure to MMS or cisplatin. The mutant cells failed to resume cell cycle progression even after removing the genotoxins, and many cells eventually lost viability. The observed persistent hyperphosphorylation of Rad53 indicates that the pph3Δ and psy2Δ mutants cannot deactivate the DNA damage checkpoint.
When microbial pathogens are attacked by host defense mechanisms during infection, cell cycle checkpoints may prove to be important for pathogens to repair damage that threatens the integrity of the genome (6). For example, in the case of attacks by reactive oxygen or nitrogen species (33), the DNA damage checkpoint is expected to be activated. Because of the inability of pph3Δ and psy2Δ mutants to deactivate the DNA damage checkpoint, they may not be able to survive in the host. Thus, the Pph3 phosphatase might be targeted in developing antifungal drugs.
Roles of CaPph3 and CaPsy2 in the filamentous growth induced by genotoxic stress.Several recent publications have reported that perturbation of cell cycle progression causes pseudohyphal growth in C. albicans and cell cycle regulatory factors and that checkpoint proteins can influence cell morphogenesis. Deleting RAD53 causes hypersensitivity to genotoxins, failure to arrest the cell cycle, and loss of filamentous growth induced by either DNA damage or DNA replication disruption (42). Furthermore, studies in S. cerevisiae clearly established an essential role for the Mec1/Rad53 checkpoint proteins in the induction of filamentous growth by slowed DNA synthesis (25). Our results showed that Capph3Δ and Capsy2Δ mutants grew highly elongated filaments when DNA damage occurred and failed to revert to yeast growth after the removal of the damaging agents. Flow cytometry data revealed that pph3Δ and psy2Δ mutants were mainly arrested in S phase under genotoxic stress, consistent with a similar result in S. cerevisiae showing cisplatin-induced intra-S-phase delay and constitutive filamentation in a PPH3 deletion mutant (48).
Rad53 activation correlates with its hyperphosphorylation, as does its deactivation with its dephosphorylation (36). The failure of pph3Δ and psy2Δ cells to dephosphorylate Rad53 suggests continuous activation of the DNA damage checkpoint. Rad53 may promote cell elongation in two ways. One is by activating cell cycle arrest, which has been shown to lead to cell elongation in many previous reports (1, 3, 4, 6, 8, 41, 42). Rad53 has also been suggested to have a direct role in C. albicans true hyphal growth (42) and bud morphogenesis in S. cerevisiae (18, 43). Recently, two studies provided evidence suggesting that Rad53 controls cell morphogenesis through interaction with septins in S. cerevisiae (18, 43). Taken together, our data provide further evidence that Rad53 hyperphosphorylation plays an important role in DNA damage-induced filamentous growth.
This work was supported by the National Basic Research Program of China (no. 2007CB914401) and the Fundamental Research Funds for the Central Universities (no. 105566GK).
- Received 21 March 2011.
- Accepted 17 August 2011.
- Accepted manuscript posted online 2 September 2011.
- ↵*Corresponding author. Mailing address for J. L. Sang: College of Life Sciences, Beijing Normal University, Beijing 100875, People's Republic of China. Phone: 86-10-58806226. Fax: 86-10-58809729. E-mail: jlsang{at}bnu.edu.cn. Mailing address for Y. Wang: Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (ASTAR), 61 Biopolis Drive, Singapore 138673, Singapore. Phone: (65) 65869521. Fax: (65) 67791117. E-mail: mcbwangy{at}imcb.a-star.edu.sg.
- Copyright © 2011, American Society for Microbiology. All Rights Reserved.


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The nonprofit online education group edX is developing a "MicroBachelors" degree that can be broken down and taken in components, according to EdSurge. edX, which has developed 45 low-cost online MicroMasters degrees, secured a $700,000 grant from the Lumina Foundation to support the MicroBachelors project.
edX CEO Anant Agarwal, while attending a summit, said the company will launch a MicroBachleors in the next couple of years. He added that the project is consistent with the group's vision for higher education, as well as trends in the marketplace.
Arizona State University in 2015 partnered with edX to offer the online Global Freshman Academy as a way for students to complete their first year online at a lower cost than a traditional residential freshman year. ASU officials said the program was a success despite the fact that few students have completed the full set of courses online and then enrolled in a traditional program.
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Educating millions of post-traditional learners is of growing importance to American workforce. And as technology transforms workplaces, experts say workers must be able to retrain and re-skill quickly for the jobs that don't exist yet. Post-traditional learners, who tend to come for disadvantaged backgrounds, can be priced of out the higher education marketplace. A recent nationwide survey by Champlain College Online found that adult learners without college degrees want to go back to school but many believe it is unaffordable.
With its work on MicroBachelors and MicroMasters, edX may be developing education models that can successfully serve this critical market of potential learners. More innovation and collaboration are needed on this front as demographic data predicts a shrinking number of traditional-age college students over the next decade. In particular, smaller private institutions that are heavily reliant on student tuition and facing enrollment declines cannot afford to ignore adult learners who could be critical to their bottom lines.


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Below are some highlights from the February Rental Statistics from the Tucson Association of Realtors monthly reporting:
Total Active listings for February - 862
Number of properties rented this month - 397
Average monthly rent for Apartments - $558
Average monthly rent for Condominiums - $794
Average monthly rent for Mobile Homes - $692
Average monthly rent for Manufactured Single Family Residence's - $792
Average monthly rent for Plex's - $547
Average monthly rent for Single Family Residence's - $1,176
Average monthly rent for Townhomes - $972
Average Days on Market - 62
Tucson patio homes showed no activity in February.
What are the biggest changes? Mostly drops in rent prices - Tucson condos dropped an average of $27 a month; single family residence rental prices dropped an average of $22 a month. Of the 862 active rental listings - roughly 54 percent did not get rented. Tucson's east side remains the strongest rental area - with a total number of 52 active listings - 43 of them were rented.
Buying or selling Tucson real estate, Mt Lemmon, Tucson bank-owned homes, Tucson rental homes, or Tucson lease option homes? Visit www.KGCPropertiesLLC.com .
This blog is written with my opinions and my opinions are presented with accuracy but not guarantees. Please talk to a professional before making any real estate, financial or agency decisions. Gabrielle Kamahele Rhind - 2014. If you want to reprint parts of this - just email me for my permission: email@example.com .


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reports for the Milwaukee Journal Sentinel.
"Hillary Clinton voters are disconsolate and appalled by Trump. Trump voters who are happy with Trump are unhappy with Congress and Trump's GOP critics. Trump voters who are critical of Trump — and they're not too hard to find here — display everything from resignation to pique to exasperation with his behavior," Gilbert writes. "Voters of all stripes complain about the political culture, including the media, the parties, and the inability to have a respectful conversation about politics with your political opponents."
Journalists and political interest groups are paying attention to the Driftless Area (which the glaciers somehow missed) because it was a hotbed of rural white voters who tipped the election for Trump. The area is particularly interesting because it defies easy stereotypes about red rural America. It contains the largest cluster of blue and purple counties in rural, white America, and has the largest concentration of counties that flipped from Obama in 2012 to Trump in 2016. So though the Driftless Area is no good as a microcosm of America, "what this swingy slice of the heartland does offer is a window into the trends and tumult of the Trump era," Gilbert reports.
Many of the 30 voters Gilbert interviewed felt ambivalent or pessimistic about both Clinton and Trump, and about both major parties as well. It's difficult to predict how they'll vote in the 2018 midterms or the 2020 presidential election, but the answer for many will depend on whether Trump and the GOP-controlled Congress are able to enact palatable legislation and whether Democrats will offer any better alternatives.


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$ 24.00
$ 0.00
Enrich Daily Face Cleanser
Enrich Daily Facial Cleanser | Pure Luxe Apothecary
This balancing cleanser helps restore skin's natural oil production and keeps it clean, refreshed, and happily hydrated. A trio of ylang ylang, cedarwood, and palmarosa essential oils gently stimulates skin cells while olive, jojoba, and castor oils clear away dirt, pollutants, and makeup with ease. Use in the morning and evening to help balance skin's sebum levels. Unlike standard foaming cleansers that strip skin of its moisture, this cleanser leaves skin soft and supple without an oily shine.
Olive Oil helps soften, hydrate, and clear away extra oil, dirt, and makeup.
Jojoba Oil is deeply moisturizing and anti-inflammatory.
Castor Oil cleanses, softens, and provides detoxifying properties.
Cedarwood Oil and Ylang Ylang Oil help soothe and repair skin as they balance sebum production.
Palmarosa Oil contains hydrating and antiseptic properties, and helps stimulate cell regeneration.


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This was a particularly good speech Newt Gingrich gave Wednesday before the Republican Jewish Coalition. Toward the middle of the speech (about 18:00) is what I consider to be one of the better lines from the former Speaker, with regard to appointing Ambassador John Bolton to e Secretary of State, along with new guidelines for the future State Department to follow.
The final few minutes of the speech where Newt talks about his work with Jack Kemp and the issue of getting people out of poverty was absolutely tremendous.


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Basket ball in the park
At the end of first term 2009 when the Guides were planning out their program a few wanted ball activities. Others wanted to have a BBQ, while still others wanted just to be outside later than normal. Friends were invited.
We ended up going to the Glendonald park ion Churchill. Here there is a net ball and basket ball court. Well half the court is net ball, the other half is basket ball.
After all the glass was swept away we were able to go on with trying to get a leader to throw the basket ball into the hoop. After a while she actually did it. Much to her surprise. But the Guides won the count. Even Debbies 2 year old grandchild helped. We put her on our shoulders then helped her throw the ball into the hoop. We stood under the hoop. She did better than the leaders.
The leaders might need practice gettintg the ball into the hoop but they can still pass the ball with force behind it!
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Pop goes the cake!
After Sky's post yesterday, I was inspired to post about this favorite from our household! They are CoCo Popcakes! You may have seen them popping out of a machine at your local grocery store, we did and my son was instantly transfixed. Of course they had samples out, so we tried them. These have become a staple in our house. Both my son and I love them. He replaced his beloved puff-puffs, with these pop-pops! I love that they are made with simple ingredients, just wheat, rice, corn and sea salt. Each cake is 16 calories, and they are large!
They taste great with just about anything. I have had peanut butter, salsa, and seitan "chicken" salad on them (not all at once!). They are as good to eat, as they are fun to watch being made! The best part is they have a great message on their packaging that clearly says:
Vegan, For the animals, For the environment, For our health". I love that!
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Gardner-Webb University's Counseling Center Provides Help to Students, Faculty and Staff
BOILING SPRINGS, N.C. – A cause and effect relationship exists between many things. For a cut, one applies a bandage. For a headache, one takes an aspirin. An upset stomach might warrant some antacid. Generally, people know what to do when something is not right physically. But what about mental maladies? When does something move from being a manageable problem into something much more intense? What should a person do when they can't get how they feel to line up with what they know?
The counselors at Gardner-Webb University Counseling Services are very concerned about these issues. Because of societal stigmas about mental health, many students, faculty and staff don't take advantage of resources at their fingertips. They miss out on valuable coping strategies that can teach them more about how to handle the pressures of life without developing unhealthy habits.
"Mental health is a very overlooked area in society," said Courtney Watford, a licensed professional counselor at GWU's counseling center. "So often, college students have a hard time adjusting and figuring out 'who do I talk to?' and 'who can I trust?' A lot of times, this is somebody's safe place where they can share what's going on in their life.'"
In an effort to help students and other members of the University family identify factors that could lead to depression, the counseling center will offer a Depression Screening on National Depression Awareness Day. Set for Oct. 11 from 9 a.m. to 2:30 p.m. at Tucker Student Center, the event is held each year to help people who may be suffering from depression.
"We see a wide array of things, a lot of students deal with anxiety, depression, or adjustment issues," said Watford. "We even see students who are struggling with an upcoming test and need help figuring out how to handle the pressure."
Watford said the screening process takes only about 10 minutes from start to finish. Participants fill out a brief questionnaire and their answers are reviewed by GWU counselors. If there are items of concern, the counselor reviews the information with the individual, maintaining complete confidentiality. People are given an opportunity to make an appointment if they want to further discuss the results or perhaps take advantage of coping techniques.
"A huge part of what we do here is provide students with healthier coping skills," Watford shared. "Sometimes that is what helps them get through their tough situation." Examples of positive strategies include deep breathing, moderate exercise, establishing healthy eating habits, and learning what one can and cannot control.
The power of discussion can be another tool to help people sort through various emotions. In a situation where someone isn't necessarily feeling depressed, but they know something isn't quite right, Watford believes the best thing to do is just talk about it. "Talk to somebody," she said. "Even if it's a roommate, a residence advisor, a faculty member, a staff member, somebody. Talk to them. Say 'this is what's going on and I'm feeling this way.' Be intentional. Pay attention to the changes in your life and if it gets bad, then come to the counseling center."
For more information or to set up an appointment, call the center at 704-406-2177.
Located in Boiling Springs, N.C., Gardner-Webb University is home to over 5,000 students. Founded in 1905, GWU provides exceptional educational opportunities within a Christian environment.


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August 20, 2017
After decades of decline and uncertainty, our region's long-awaited economic revival has begun. The evidence can be found across Oneida and Herkimer counties, especially in Downtown Utica's recent and continuing revitalization, summarized in the O-D's August 13 editorial, "Downtown destination."
As the community foundation for Herkimer and Oneida counties, our mission is to build our area's collective wealth, holding it in trust for future generations, and investing it to support not-for-profit projects and initiatives that make people's lives better. Although we are a private organization, we uphold a kind of public trust, on behalf of our many donors, to engage and advocate in our community; to encourage dialogue between and among community partners; and to provide leadership, when appropriate, on issues that demand it.
Manager/Media Specialist


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Submitted by Terrell Jones on
Description of App:
From the App Store:
Court TV brings you live, gavel-to-gavel coverage of our nation's most important trials, all anchored by the most talented and trusted legal journalists in America. Plus, you can catch up with recent coverage and access a library of iconic trials On Demand.
Apple Watch Support:
Not Known
Version 1.2
Free or Paid:
Device(s) App Was Tested On:
iOS Version:
Accessibility Comments:
This app is very accessible out of the box.
VoiceOver Performance:
VoiceOver reads all page elements.
Button Labeling:
All buttons are clearly labeled.
The app is fully accessible with VoiceOver and is easy to navigate and use.
App Store Link:
Developer's Website:
Developer's Twitter Username:
User Options
2 Comments
service provider
Submitted by Kerby on
I assume you have to login using your Comcast credentials or whatever provider you use?
How to Watch
Submitted by Terrell Jones on
Here's how to watch Court TV. Just simply double tap the live tab and the vidio player will load. Double tap the done button to stop. No TV Provider is required.


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Everybody is encouraged to donate blood after they come of age. We even have an article about the benefits of blood donation on our blog. If you have ever donated …Read More »
Tag Archives: tattoo
Health Implications Of Tattoo Removal: Is It Safe?
In today's world, a majority of the population have at least one tattoo on their body. Tattoos seem like a very good idea for people of a certain age. They …Read More »
Tattoos Can Be Awesome But..
These days more and more people are sporting a tattoo to look cool, adventurous or trendy. This has been made all the more popular by the celebrities. Although tattoos may …Read More »


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Top benefits of finding stationery suppliers near you
Parents and teachers both look to have stationery suppliers from time to time. Parents of school kids also need to purchase arts and crafts, for which they need to get in touch with suppliers again. A quick look at the market will help you find many stationery suppliers. Likewise, there is a need to find an art and crafts store in Dubai for you to choose from. Fortunately, you will find many stores across the city. When you do, you must consider finding the type of equipment that you wanted to purchase. As far as schools are concerned, they prefer to keep a stock of arts and craft in store. The need to find a top stationery supplier is always there, and as customers, it is up you to make arrangements for finding the one that suits your needs. For now, it would be better to check the benefits associated with finding a top stationery supplier:
Variety of supplies
Checking the variety of supplies is arguably one of the most important things to consider before shortlisting a supplier in Dubai. You will find that many stationery suppliers provide excellent quality supplies, but they somehow don't have the variety. You should look to get in touch with the one that offers variety. Why focus on the variety you might wonder? Because it will allow you to choose different items according to your preferences from time to time.
Many different categories
Elaborating your need to get in touch with the supplier that has a variety of supplies, it is a must to get in touch with the one that maintains equipment in many different categories. This is important as it will help you find items under different categories, which is something that some stationery services may not have. This will make the stationery service your one-stop solution for fulfilling your need to purchase stationery and school supplies under one roof. It will help save you precious time and money.
The stationary service that is reliable will always take great care of her customers. So much so that the service will facilitate in delivering goods before time, and preferring to get customers to know about a recent product catalog. Also, such companies don't hesitate in taking the equipment if a defect surfaces. Same goes for school furniture suppliers in Dubai. They'll do all they can to meet your needs and will replace the faulty item without arguing with the customer, which makes the supplier more reliable and trustworthy.


text: With the assistance of the Daniel Langlois Foundation in 2004, as well as by the New York State Council on the Arts, we are focused presently on early video/media instruments - those tools designed individually or by artists and technologists working collaboratively, as well as innovative commercial devices. This research links associated texts, documentation, technical data, maker biographies and interviews, and tapes produced on these systems. Content derives from our tool and paper archives. We are electronically photographing the devices, and in some cases, creating moving image records of the functioning of the tool. We are scanning associated texts, documentation, and ephemera related to events which include posters, exhibition program notes, exhibition catalogs; and audio and video interviews. The data would be published on the existing History Project Website


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See more jobs in the Mine Jobs category.
Underground Mining Maintenance Planner
- Cannington Project
- 7/7 roster
- FIFO Townsville, Cairns, Brisbane
Operating since 1962, The Redpath Group provides technical and operational expertise to the mining industry globally, with a reputation for providing innovative solutions utilizing modern technology.
About the role
They are seeking an experienced underground Maintenance Planner to join on Cannington project in North QLD. In this role you will be responsible for compiling preventative maintenance plans to ensure equipment condition is safe, reliable and meets the utilization requirements for the project. The role is pivotal in gathering information before and after each maintenance activity and ensuring effective communication.
- Managing maintenance data and databases
- Maintenance scheduling and planning
- Parts control for surface and underground store
- Manage rotatable components
- Failure analysis
Skills & Experience
- Mechanical or electrical trade qualification & an interest in maintenance planning
- Underground mining maintenance experience
- Valid manual Drivers License
- Current First Aid & CPR Certificates
- Excellent planning and organizational skills
- Good communication skills, both verbally and written
- A work ethic in keeping with Redpath's motto Consider it done.
An excellent salary package is on offer for the successful candidate.
Redpath is the type of company where you can sink your teeth into a challenging role, get hands on experience and receive learning & development opportunities with experienced personnel.
NOTE: Did you know that your resume could automatically go into the bin if you don't format it correctly. Recruiters these days use software to scan your resume for keywords they place in the job ad. This software tried to match up the words in the ad to the words in your resume. If there's a mismatch – chances are your application will be ignored.
How to apply
To apply, click on the "Apply Now" prompt quoting the reference number 0203-2545-MPL
This is an excellent opportunity to join a dynamic mining operation that recognizes achievement and offers genuine career opportunities. Submit an application for this position, use the Apply button below. Don't forget you will need the appropriate mine site qualifications such as Standard 11 Induction TrainingApply for Underground Mining Maintenance Planner North QLD


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Let Me In (2010)
|Region: 2
UPC/Barcode: 5051429302201
Released: 14th March 2011
Release type: Rental Only
|No. of Discs: 1
Catalogue No: ICON30220
Category: Feature, Horror
Format: DVD / Normal
Only the main feature on this DVD title has English subtitles. [explanation]
Claimed subtitles: English, English for the hearing impaired
Subtitling reviews:
Submitted by mat on 19th July 2011:
Have you got this DVD title?
Film information
Based on: The novel 'Let the Right One In' by John Ajvide Lindqvist
Story: Matt Reeves writes and directs this vampiric coming-of-age romance based on the Swedish novel 'Let the Right One In' by John Ajvide Lindqvist and Tomas Alfredson's 2008 Swedish-language film adaptation. Kodi Smit-McPhee stars as Owen, a solitary 12-year-old in 1980s New Mexico who is continually tormented by a gang of bullies. When the enigmatic Abby (Chloe Moretz) moves in next door, the two form an unlikely friendship that will change Owen's life forever as it emerges that Abby is a 200-year-old vampire, frozen in childhood and condemned to live on a diet of fresh human blood. With Abby on his side, Owen is finally able to face up to the bullies - but Abby's unquenchable thirst for blood gives rise to a fresh set of problems.
Starring: Chloe Moretz, Kodi Smit-McPhee, Richard Jenkins, Jimmy Pinchak, Sasha Barrese, Chris Browning, Cara Buono, Elias Koteas, Seth Adkins, Rachel Hroncich, Dylan Minnette, V.J. Foster
Cinematographer: Greig Fraser
Directed by: Matt Reeves
Music by: Michael Giacchino
Produced by: Alexander Yves Brunner, Guy East, Donna Gigliotti, Carl Molinder, John Nordling, Simon Oakes, Nigel Sinclair
Written by: Matt Reeves
DVD information
Studio/distributor: Icon Home Entertainment
Other releases of this film
Let Me In (2010) (Blu-ray) (Retail / Rental)
Let Me In (2010) (Retail Only)
DVD Information: Copyright ©2020 Bibliographic Data Services Ltd trading as West 10. For personal non-commercial use only. All rights reserved.
Subtitling Information: Copyright ©2002-2020 dvd-subtitles.com.


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In this two-part series published in The New York Review of Books under the titles "The Epidemic of Mental Illness: Why?" and "The Illusions of Psychiatry," Marcia Angell summarizes three books that strongly criticize the pharmaceutical treatment of psychiatric disorders, and particularly the role the pharmaceutical industry has played in shaping public and medical perception of them. The books she reviews include The Emperor's New Drugs: Exploding the Antidepressant Myth, by Irving Kirsch; Anatomy of an Epidemic: Magic Bullets, Psychiatric Drugs and the Astonishing Rise of Mental Illness in America, by Robert Whitaker; and Unhinged: The Trouble With Psychiatry—A Doctor's Revelations About a Profession in Crisis, by Daniel Carlat.
An early-2000s survey by the National Institute of Mental Health (NIMH) found that 46% of adults had met the criteria established by the American Psychiatric Association (APA) for at least one mental illness at least once in their lives. The majority of psychiatrists today treat patients primarily and often only with drugs. These dual forces have led to a huge share of the population taking psychoactive drugs; for example, 10% of Americans are taking antidepressants, and antipsychotics have replaced statins as the top-selling class of drugs in the U.S.
Angell describes how a variety of changes to our understanding of mental illness drove this shift. In the late 20th century, the widespread medical perception of mental illness shifted from the Freudian view (which considers mental illness as the result of environmental stimuli) toward the view that mental disorders result from chemical imbalances in the brain. The latter view was born shortly after the first psychoactive drugs were introduced in the 1950s. Most of these early psychoactive drugs were not originally developed to treat mental disorders.
During the 1970s, the American Psychiatric Association began to push psychoactive drugs aggressively, leveraging the Diagnostic and Statistical Manual of Mental Disorders (DMS) and influential psychiatrists to broaden the definition of mental illness and establish the need for pharmaceutical treatment. The majority of contributors to the DSM-IV had financial ties to pharmaceutical companies, which benefited from the rapidly increasing number of mental conditions the DSM outlined. These same companies simultaneously promoted campaigns to raise awareness of these conditions, stimulating demand for the drugs.
In an extended analysis of how this period became formative of contemporary practices, Angell writes:
As psychiatry became a drug-intensive specialty, the pharmaceutical industry was quick to see the advantages of forming an alliance with the psychiatric profession. Drug companies began to lavish attention and largesse on psychiatrists, both individually and collectively, directly and indirectly. They showered gifts and free samples on practicing psychiatrists, hired them as consultants and speakers, bought them meals, helped pay for them to attend conferences, and supplied them with "educational" materials. When Minnesota and Vermont implemented "sunshine laws" that require drug companies to report all payments to doctors, psychiatrists were found to receive more money than physicians in any other specialty. The pharmaceutical industry also subsidizes meetings of the APA and other psychiatric conferences. About a fifth of APA funding now comes from drug companies.
Drug companies are particularly eager to win over faculty psychiatrists at prestigious academic medical centers. Called "key opinion leaders" (KOLs) by the industry, these are the people who through their writing and teaching influence how mental illness will be diagnosed and treated. They also publish much of the clinical research on drugs and, most importantly, largely determine the content of the DSM. In a sense, they are the best sales force the industry could have, and are worth every cent spent on them.
Angell also references Carlat's rationale for why psychiatrists consistently take more money from drug companies than specialists in other fields:
Unlike the conditions treated in most other branches of medicine, there are no objective signs or tests for mental illness—no lab data or MRI findings—and the boundaries between normal and abnormal are often unclear. That makes it possible to expand diagnostic boundaries or even create new diagnoses, in ways that would be impossible, say, in a field like cardiology. And drug companies have every interest in inducing psychiatrists to do just that.
More recently, this state of affairs has manifested in a dramatic increase in the diagnosis of mental illness among children, with 10% of 10-year-old boys taking ADHD medication and diagnoses of juvenile bipolar disorder jumping 40-fold from 1993 to 2004. Many of the medications given for these juvenile conditions are prescribed off-label, and pharmaceutical companies have been repeatedly found guilty of illegally promoting off-label use to physicians.
Angell notes multiple fundamental issues with the "chemical imbalance" theory underpinning the pharmaceutical treatment of mental disorders. In most cases, this theory argues mental illness results from an imbalance of neurotransmitters in the brain; that is, too much or too little (or too much or too little uptake or utilization) of the chemicals that carry signals between neurons. These drugs have significant effects on neurotransmitter levels. However, patients with mental illnesses show normal neurotransmitter levels and neurotransmitter function prior to treatment, with many abnormalities emerging only after treatment has been applied.
This theory came to be accepted through selective interpretation of the scientific process. The FDA requires two clinical trials demonstrating benefit for a drug to be approved, regardless of how many negative trials preceded them. Freedom of Information Act requests showed that the majority of trials testing antidepressant drugs approved between 1987 and 1999 (Prozac, Paxil, Zoloft, Celexa, Serzone, and Effexor) were negative, and in sum, placebos were 82% as effective.
Subsequent, more sophisticated analyses further undermined the purported efficacy of these drugs. When psychoactive drugs were compared to active placebos—that is, placebos that, like the drugs, caused some side effects and thus caused patients to believe they were receiving treatment—there was no difference in benefit between antidepressants and placebos. In other words, due to the highly subjective nature of evaluating mental disease progression, the perceived benefits of psychoactive drugs may have been entirely due to a strong placebo effect.
This is particularly grave given the negative side effects of these drugs. Some induce obesity, metabolic disease, and other conditions. Many cause new mental conditions in those who take them, leading patients to take cocktails of drugs to treat a bouquet of diagnosed mental illnesses. The majority, if taken chronically, disrupt the brain's ability to naturally regulate neurotransmitter levels, leading to withdrawal symptoms that are often misdiagnosed as a relapse of the original condition.
Angell concludes:
The books by Irving Kirsch, Robert Whitaker, and Daniel Carlat are powerful indictments of the way psychiatry is now practiced. They document the "frenzy" of diagnosis, the overuse of drugs with sometimes devastating side effects, and widespread conflicts of interest. Critics of these books might argue, as Nancy Andreasen implied in her paper on the loss of brain tissue with long-term antipsychotic treatment, that the side effects are the price that must be paid to relieve the suffering caused by mental illness. If we knew that the benefits of psychoactive drugs outweighed their harms, that would be a strong argument, since there is no doubt that many people suffer grievously from mental illness. But as Kirsch, Whitaker, and Carlat argue convincingly, that expectation may be wrong.
At the very least, we need to stop thinking of psychoactive drugs as the best, and often the only, treatment for mental illness or emotional distress. Both psychotherapy and exercise have been shown to be as effective as drugs for depression, and their effects are longer-lasting, but unfortunately, there is no industry to push these alternatives and Americans have come to believe that pills must be more potent.
Together, these books argue that the current ways we diagnose and treat mental illness in the United States is the result of pharmaceutical industry intervention, not academic or clinical evidence. Both our theoretical understanding of mental illness and the existing research data fail to support the effectiveness of psychoactive drugs.
Cover image: An advertisement for Prozac, from The American Journal of Psychiatry, 1995
Comments on Marcia Angell on Psychiatry and the Pharmaceutical Industry


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Posted on :
1 Sep, 2015
1 Sep, 2015
Established in 1978, Dis-Chem started out as a small pharmacy in Mondeor, South of Johannesburg.
Today the group is still privately owned and run by the original founders.
Dis-Chem has been rated as the country's best pharmacy chain by Professional Management Review, and has also been voted as Best Pharmacy, Best Medical Supply Store and Best Health Store in both The Star Your Choice and Pretoria News Readers Survey, as well as in the Leisure Options Readers Choice Awards.
What makes this so special is that the readers voted for their favourite businesses or establishments.
Our exponential growth can be attributed to strong branding, a good product range that meets our customers' pharmaceutical, health and beauty needs, low prices and valuable customer relationships.
That is not enough though, in order to stay competitive in the future, we are continuing to pioneer by being the first to offer a loyalty programme (within in the pharmaceutical industry) – the Benefit Programme."
Dis-Chem was built on the ethos of old-fashioned family values. However, the concept of the 'trusted local pharmacist that everyone knows' is under pressure from the sheer volume of customer numbers and the increased pace of modern-day living.
Dis-Chem has evolved to the next level of customer service by not only living by their motto, 'take care of the customer and the business will take care of us,' but by taking it a step further in extending that caring attitude to the community at large, which will be delivered through the Benefit Programme."
If you would like to kick-start your career with Dis-Chem Pharmacies
Click here to apply for available positions
Click on "Job Search"


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Court action/deposit
On hand delivering a letter to them advising that I would give them one week to pay or take them to court, I actually met them outside the house.
They mentioned they would pay the rent next week, but also mentioned they would use the deposit to pay the last months rent. However after I told them they never paid a deposit on or after moving in they asserted the opposite.
The tenancy agreement which we all signed clearly shows a blank in the box on page 2 where the deposit amount is to be filled in. However I am concerned they are going to push their word against mine at court and they said they were going to counter-sue me for this.
Is the tenancy agreement robust enough to protect myself or do I need to be aware of anything else to prove my case ?
Want to read more?
This is a members only forum, if you want to read more you need to login to your membership, if you are not a member, click here to join.


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Great Innovations Keep Homes Well Lit
Has anyone ever been dazzled by the wonderful illuminations found in some great places like hotels, banks and up market office blocks? Well, take a closer look and see that sometimes they use some very simple methods to give illuminated 'spots' just where they want the visitor to look. They often do this by using gadgets like cordless picture lights to highlight some great artwork or even photographs of the venue so that they can show the place off to its best advantage. A cordless picture light, as the name implies, can go just about anywhere that the user wants.
Indeed, some seminar venues have a whole array of these gadgets instead of having to have messy wires everywhere. The form or photo that they want to display is often put up on moveable partitions so they would be hard pressed to supple power points exactly where they want them. The permanent walls will have outlets of course, but for those in the center of the room and away from the walls, another innovative idea had to be found.
In clinics and offices belonging to doctors and other professionals, certificates and qualifications should be on display so that the prospective patient can inspect where they went to school and which college they graduated from. Indeed, any doctor or specialist who does not display these should be questioned thoroughly.
To facilitate easy viewing, these gadgets are the best solution. Muted illumination is standard in most places where the public has to go but there is always a need for a bright spot here and there.
In the home, these handy little gadgets also have their place. For example, family photos which are placed all alone a dark hallway, or up a stairwell for example, will often be left in the dark or shadow. However, by adding a few of these innovative gadgets, not only will the photos 'pop' to the eye, the whole place will be lit well enough to find the way too. These can also be used at night if there are visitors in the home who do not really know their way around as well.
In the living area, these really stand out. Wonderful paintings, perhaps by a child or family member, are of great importance. To put them on display where the world can see them is such a compliment. But adding its own illumination source finishes the deal completely.
Of course, there are those varieties which are wired directly into the power supply. Sometimes there are outlets in just the right place, but when this is not so, try using one of these babies until the right place for the artwork has been found. If it is going to be a permanent fixture then the local handyman can come in and dig out the walls and put it in properly.
This work tends to be messy and costly so finding the right place first is very important. Even battery operated varieties, with rechargeable batteries, are a green way of keeping everything looking wonderful.
Stewart Wrighter is an entrepreneur who runs a large group of websites that specialize in high end items such as cordless picture lights. He offers a large selection of lights which include a cordless picture light.


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The ORCHID Skin 디오키드스킨
Moisture TOK TOK Hand Cream
Regular price $7.50
Korea's best-selling hand cream? The answer lies in its unique water-based gel texture which turns into hydrating water droplets when rubbed into your skin. This lightweight texture leaves your skin feeling fresh and hydrated. White Dendrobium Orchid is infused into this hydrating formula that gives your skin a fresh floral scent.
KOREA #01 Bestselling Hand Cream


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Sometime last year the amazing women who run the Declare Conference invited me to teach an online class for their community. And I totally blew it. I was overwhelmed with projects, the end of the year came crashing in, and before I knew it we were rescheduling for "sometime next year." I'm so glad these gals put up with me and gave me a second chance. Next Monday, on July 8th, YOU are invited to join me for a very special online course called "Embracing Failure & Redefining Success." This class is for you if: You've ever struggled to balance sharing your success with staying humbleYou've ever walked into a conference or a meeting and felt the dreaded imposter syndrome ... View the Post
Meant for Full Sun
We wandered through the garden section of our local home improvement store the other weekend - the prize for having to wander through the aisles of paint and hardware earlier in our trip. As we looked at the plants, Madi realized they all had tags on them with little pictures of the sun, and she asked what it meant. I shared with her that some plants are made to thrive in the shade, like the huge hostas we have under our deck, or the ferns my mom has hanging on her porch. Those plants come with tags that don't have much sun showing on them - they need a little light, a few hours a day, but not much more than that. Other plants like an even mix of sun and shade - not too much of one ... View the Post
Don't Miss It!
I decided to spontaneously host a giveaway over on my Instagram account yesterday. Maybe it's because we're in the FINAL countdown of school and summer is getting closer and closer. Maybe it's because I have done absolutely NOTHING to invite people to hang out with me on social media over the past um...year? Whatever the reason, you might be the lucky one who benefits from my random decision making! It's super simple - just head to this post on Instagram, follow me (if you don't already), like the post, tag a friend, and earn an extra entry by sharing it in your IG stories. Side note: in case you don't know how to do that --> click the little arrow shaped thing beside the heart ... View the Post
Not Ashamed
I've always struggled with depression and anxiety. As a kid, I remember never going to sleepovers or camp because I would always become so anxious and emotional that my mom would need to pick me up late at night. In college I remember who seasons when I wouldn't engage with friends. I would stay in my dorm room or apartment by myself, go to class and work, and return right back where I started. I wasn't good at making friends, I'm an introvert by nature, and I didn't understand that seclusion only made me struggle more - and the more I struggled and felt excluded or uninvited, the more I battled with depression. When I was fired from my corporate job I was terrified and spent ... View the Post
Get Off My…Ministry
I'm in the middle of this incredible coaching opportunity for creative leaders at work, but I'm finding it leaking into most of my life. Probably because what I do at work isn't that different from what I do on my own time. Unlike the years where I worked at a bank and then came home to blog or create, I spend most of my days paid to do online, creative communication and then I come home and do the same. I pretty much feel like I'm working 18 hours a day. But the creative leadership coaching has been teaching me to think outside the box, ask for help, and become more confident in asking people to stop stealing my ministry. That seems harsh right? I mean, most of the time people ... View the Post
But Do You Know "Her"?
He asked me how my book was doing, wondering if I was going to write another one. I shared that I'd just found out about "Holy Hustle" going into it's 4th printing, and he immediately asked for numbers. Before I could even answer his second question about a second book, he said "Oh well have you heard about {not including her name because that's not the point.}? She has this AMAZING talk where she shares how HER book has sold over 6 million copies and her business brings in 8 figures a year and she learned how to do it all online and now she's THE BEST public speaker. Have you heard of her?" Of course I had. And as he went on...and on and on...about her wonderful qualities I wondered ... View the Post


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Pick Up a Pumice Stone
Save your soles from months of wearing heavy boots with the help of a pumice stone. Scrub rough patches and calluses to gently soften skin and take your feet into sandal and open-toe-shoe season. Make sure to use your pumice stone after you shower; the hot water will aid in opening up pores and will make it easier to tackle this typically rough body part.


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News & events
May 17
Crazy and Ambitious Conference
8th May 2017 - 10th May 2017
Event Name Crazy and Ambitious Conference Start Date 8 May 2017 … Read more
Mar 17
Update 2: Meet the strains. Continental Antarctica is home to a huge variety of organisms. Eight of these are being studied in culture as part of our project. Some of these are plants, some are bacteria, and some have traditionally been treated as both. There are also two species of fungi.
Feb 17
Testing predicted responses of Antarctic plants and microbes to environmental change 1
28 Feb 17 by Phil Novis
Update 1: How modern DNA-based methods can be used to infer the environmental preferences of Antarctic terrestrial species.
Feb 17
Landcare Research has successfully released two insects to tackle a weed threatening the viability of New Zealand farms.
Feb 17
Crazy and Ambitious Conference
21 Feb 17
The National Science Challenge for NZ's Biological Heritage is calling its first meeting at Te Papa, Wellington.
Feb 17
Landcare Research has appointed Holden Hohaia as its new general manager for Māori Development.
Dec 16
Kiwi scientists make breakthrough
16 Dec 16
A group of New Zealand and American scientists have discovered a new way of chemically converting reactive nitrogen common in soil before it turns into a harmful greenhouse gas.
Dec 16
Christmas closure
15 Dec 16
Landcare Research offices are closed from 12:30 p.m. Friday, 23rd December 2016 - Tuesday, 3rd January 2017.
Dec 16
Holiday pay & termination pay arrears
6 Dec 16 by Human Resources
Details and claim form
Dec 16
Landcare Research welcomes the formation of Predator Free New Zealand 2050 Ltd.
1 Dec 16 by Greg Ford
Conservation Minister Maggie Barry announced that Landcare Research chair Jane Taylor has been appointed chair of PF2050 Ltd, the company which will be a key player in achieving New Zealand's Predator Free 2050 ambition.
Suscribe to News
via email


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Membership Dues, Due Date and Service Eligibility
October 01, 2019
A. Over the last several years, it is without a doubt that the Vietnamese Eucharistic Youth Movement (VEYM) has grown at an unprecedent pace with a record high of 140 Chapters nationwide and growing. In reaching its historic 35th anniversary, the VEYM is recognized as the modeled youth ministry across the country in the promotion of faith, discipleship and family. To continue to stay steadfast on course amidst the many challenges facing the youth today, we need resources. As such, now more than ever, membership dues are increasingly vital.
B. In accordance with the Bylaws 2019 (Chapter VIII, Clause 63), making contribution to the VEYM via membership dues is required and is the responsibility of all members. It is also the responsibility of the National Executive Committee (Ban Chấp Hành Trung Ương) and the Finance Committee (Ban Tài Chánh) to present and make available the VEYM's annual financial report to all for transparency and accountability (report was presented to League of Chapters Presidents in May, 2019, and published in TNTT Bi-Weekly).
C. With unanimous consensus and support from League of Chapters Presidents (Liên Đoàn Trưởng) during recent meetings with the National Board of Executive Officers (Ban Thường Vụ Trung Ương) in April and May, 2019, the National Executive Committee (Ban Chấp Hành Trung Ương) will begin to hold accountable all Chapters with regards to membership dues following the deadline date to submit membership dues, which is November 30th, 2019.
D. Chapters not in compliance with membership dues as outlined by the Bylaws will not be eligible to receive VEYM's services (e.g., training resources, Weekly Gospels, promotions and processing, scholarships, campaign initiatives, training camps, IT support and services, online Education Center, registration to Conventions, Congresses, and etc...). Chapters with unique challenges in meeting the membership dues requirements are invited to contact the National Executive Committee at email@example.com for guidance and support.
E. The deadline to submit the $10/member membership dues to Headquarters as stated earlier is November 30th of each year. To submit membership dues to Headquarters, please see addendum attached. To submit the $5/member membership dues to League of Chapters, please contact your League of Chapters Executive Committee directly (Ban Chấp Hành Liên Đoàn).
F. Through the submission process detailed in the attachment, we are closer to a more efficient process, not to mention a more accurate census. All League of Chapters Executive Committees are invited to direct Chapters to follow through accordingly. Chapter Executive Committees are asked to take action accordingly. For questions, please do not hesitate to contact firstname.lastname@example.com.
Thư Niên Liễm - Quý Cha Tuyên Úy 2019
Thư Niên Liễm Gửi Các Cha Tuyên Úy 2017


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ASUS' new ZenFone Max Pro M1 has a Full HD+ 18:9 display, dual rear cameras, and a massive 5,000mAh battery (Updated!)
ASUS' new ZenFone Max Pro M1 looks to challenge the Xiaomi Redmi Note 5 Pro
Note: First published on 29th April 2018, the phone is now available locally and we've updated the local pricing details.
ASUS announced the ZenFone Max Pro M1 smartphone at a launch event in India today. The Max Pro M1 (no affiliation with local telco M1 by the way) is being touted as a competitor to Xiaomi's Redmi Note 5 Pro, and shares quite similar specs.
Like the Redmi Note 5 Pro, the Max Pro M1 has a 5.99-inch Full HD+ 18:9 aspect ratio 2,160 x 1,080 pixels resolution (~403ppi) display. The phone also uses the same Qualcomm Snapdragon 636 processor. Two variants will be available:-
- 3GB RAM and 32GB storage
- 4GB RAM and 64GB storage
One of the key highlights of the Max Pro M1 is that it will be the first ASUS smartphone to ditch ZenFone UI, opting instead for a completely stock Android 8.1 OS.
The phone also has a massive 5,000mAh battery, with ASUS claiming that it can deliver up to 199 hours of music playback, up to 34.1 days of 4G standby and up to 25.3 hours 1080p video playback.
On the rear of the phone, the Max Pro M1 has a dual rear camera setup pairing a 13-megapixel f/2.2 lens with a 5-megapixel lens. On the front of the device, there's an 8-megapixel selfie camera.
The Max Pro M1 is launching in Indonesia on 25th April exclusively on Lazada, and in India on 3rd May exclusively with online retailer Flipkart.
It will also be available in Singapore at a later timeframe, but pricing has not been announced yet.
Updated on 20th July 2018:-
Singapore is getting the 3GB RAM + 32GB internal storage variant of the ZenFone Max Pro (M1) and it is priced at S$348. No word yet on the higher capacity edition, but this update comes at the same time Huawei is pushing its new Nova 3i for S$398 and it could be a better all-rounder. Stay tuned for our review in the near future to figure out where it really stands!


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Color: Silver
Interior: Cloth
Drive Train: 4WD
Transmission: Automatic
Vin: 1C4BJWEG3DL599592
Engine: 3.6L V6
Mileage: 110,115
Stock #: 26210
Fuel Economy: City 0/Hwy 0
Estimated By E.P.A. - Actual Mileage May Vary
Charlie's Used Cars
230 I-45 South
Huntsville, TX 77340
110,115 miles, 4WD, 6 Cyl 3.6L V6
I hereby consent to receive text messages from or on behalf of dealer at the mobile phone number I provided above. I understand that I am opting in to receive text messages from dealer or their employees. I include consent to receive phone calls at the mobile phone number I provided. I understand that message and data rates may apply.


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As we discussed in class, there is an UNUSUALLY HIGH number of missing assignments/scores in AERIES. I imagine some of you didn't do the work in the first place, I know many of you were absent when work was assigned or collected and it has never been checked in, and some errors were my own clerical errors which I did not become aware of until after I passed papers back to you.
As promised, I will not penalize any work as late during the month of February. If there are mistakes or missing work on Aeries, whether it's my fault or yours, I'll work with you and allow full credit as long as it is handled before March.
- If you HAVE the assignments in question, re-submit them for full credit.
- If you DID NOT DO the assignments, you can still do them for full credit.
- If you know for sure that you completed the work, but you have a zero and it doesn't show up when I pass work back to you, please let me know and I'll excuse the assignment.
Turn in Week 21 work (see previous week's post, any item indicated with ">" is due)
> Práctica: DOPs and IOPs
Tues. Feb 3:
Begin learning song for World Language Week: Mal de Amores - Juan Magan
> Copy "Double Object Pronoun Chant" & practice
Wed. Feb 4:
> Identifying DOP and IOP in the story El Osito (Lines 1 - 19)
Worksheet for El Osito
Thurs. Feb 5:
> Complete "El Osito" lines 20 - 29
> Write your own ending, using IOPs & DOPs
Fri. Feb 6:
> Práctica: Working with both DOP and IOP
> Worksheets: DOP+IOP practice p.89 and p.90


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LeBron James Reveals Top 4 Picks for 2018 NBA All-Star Game; Kevin Durant No. 1February 19, 2018
After leading his team to a win at the NBA All-Star Game, LeBron James finally revealed part of his draft order when choosing teams against Stephen Curry.
According to Jeff Zillgitt of USA Today, Kevin Durant was his top choice, followed by Anthony Davis, Kyrie Irving and DeMarcus Cousins.
Curry ended up with Giannis Antetokounmpo, James Harden, DeMar DeRozan and Joel Embiid as starters for his team. Team LeBron edged Team Stephen Sunday night for a 148-145 victory.
James was named the game's Most Valuable Player after totaling 29 points, 10 rebounds and eight assists.
This is the first year with the redesigned All-Star Game, which is usually the Eastern Conference vs. the Western Conference. The league gave the top vote-getters in each conference the chance to serve as captains who pick the teams, although the draft between James and Curry wasn't televised or released besides the final rosters.
With James picking a top positional rival in Durant and a personal rival in Irving after the former teammate requested a trade during the offseason, there were widespread questions about how the draft shook out.
Curry gave away prior to the draft that he would probably take Durant if he had the opportunity.
"I'm pretty sure he would be a pretty solid pick if you had the first pick," the two-time MVP said of Durant, per Mark Medina of the Mercury News. "If LeBron doesn't take him, I probably will for sure."
Picking Durant was probably the best strategy for James, though waiting on Irving was interesting for both sides.
Although Cousins was injured before getting a chance to play, like fellow Team LeBron players Kevin Love, John Wall and Kristaps Porzingis, the remaining squad was still able to pull out the victory.


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Tim Delehaunty
It is with the deepest sadness that we share the news that our friend and Head of School, Tim Delehaunty, died unexpectedly on Wednesday, November 14. We are devastated by the loss of our dear colleague.
Tim Delehaunty joined Tower School in July of 2017; the impact of his 16 months of leadership on our school and community is immeasurable. Tim's quiet and steady ambition for our students—to prepare them for the dynamic challenges of the future while embracing the joy of childhood—informed his work on a daily basis. He laid the groundwork for Tower to accomplish that ambition. Together with our Board of Trustees, he formed a comprehensive strategic plan for Tower and re-directed the school with a defining mission statement. He led the school's evaluation of our curriculum and implemented expansive improvements. Tim was so proud to be leading Tower at such an exciting time for our school.
Most recently, Tim immersed himself in what he affectionately called The Backyard Project. Collaborating directly with families, board members and teachers, Tim's enthusiasm allowed us all to re-imagine how improved outdoor learning and play spaces could impact all areas of Tower's program––specifically, science, athletics, and physical education.
Perhaps most significantly, Tim emphasized the importance of community and instilling a sense of belonging for students and families. Tim's expression, known and needed, describes the impact that each one of us makes on our school; the individual voices and perspectives of our students, parents and teachers are valuable contributions to our community and to student achievement.
Tower is a stronger school and community because of Tim's leadership. We share his enthusiasm for Tower's present and future and will continue to advance our school's priorities and our ambition for our students.
Tim Delehaunty,
Tower School's 9th Head of School
In April of 2019, our Board of Trustees announced Tower's 10th Head of School, Serena Wilkie Gifford. Ms. Gifford will join Tower in January 2020.
To learn more about Tower, we invite you to browse our website. May we suggest the following places to begin:


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The 'B' division women's finals of the Mercantile Basketball League took place last evening at the Henry Pedris Basketball court. MAS Holdings took on Nations Trust Bank in the final with the game ending in favour of Nations Trust Bank.
Pre-match Quotes
MAS Holdings Coach: "We need to block their shots from downtown and force them to drive in and block them under the basket and only allow a shot under pressure since their strong suit is shooting 3's."
NTB Captain: "We played the semi-finals with them and it was a tight game, we managed to catch up with them only in the final part of the game but hopefully this time we can maintain the lead from the start."
Match Report
NTB got first possession from the jump ball but it was MAS that scored first with a shot from downtown. Both teams were quick to move into a zone defense which was quite effective as the teams went neck to neck for the most part of the quarter. The MAS players made some good passes allowing them to penetrate the defense and get inside the D to secure baskets and take a slight lead during the first quarter.
First-Quarter: MAS Holdings-11 NTB- 07
As the teams moved on into the second quarter they struggled to shoot, making it a low scoring quarter. Nations Trust Bank moved into a full court press to stop MAS in their tracks and turned the tables on them as NTB took the lead going into lemons.
Half-time: MAS Holdings- 12 NTB- 13
NTB came into the second half improving their rebounds and switched to attempting 3 pointers to create a gap between the two teams. The NTB players started to intercept passes more and began to dominate the game creating a deficit. MAS, on the other hand, lost possession of the ball due to bad passes and NTB took the first significant lead of the game.
Third-Quarter: MAS Holdings- 17 NTB- 26
MAS started off strong in the final 10 minutes of the game getting in a shot from downtown and moved on to a full court press. NTB lost 2 crucial players due to injuries making it even more difficult for them, given their already weak bench. During the final few minutes of the game, MAS managed to catch up and reduced the gap to 3 points from the free shots they received due to the high number of fouls by NTB. In a nail biting end, NTB managed to secure the win by 2 points.
Full-time: MAS Holdings- 28 NTB- 30
Speaking to the coach of NTB after the match, he shared his thoughts with ThePapare.com: " We had a tough game playing with only 4 players and no remaining bench. We had to use whatever we had and it was definitely a close call. Had we got more free shots in, it would have been easier, but we're glad we were able to win."


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If you're a fan of The Rolling Stones, there's a new exhibit opening at the Rock and Roll Hall of Fame and Museum that's sure to give you some satisfaction.
FOX News Radio's Entertainment Correspondent, Sabrina Sabbagh reports:
The Rolling Stones will take up two floors at the Rock and Roll Hall of Fame and Museum. The "50 Years of Satisfaction" exhibit chronicles the band from its birth in England as a blues cover band to its current "50 and Counting" tour. It includes nearly 300 artifacts, like rare guitars, stage outfits, concert posters, documents and personal items. (music) Fans will be able to check out three iPad based interactive kiosks where they can put on a pair of headphones and hear the band's early blues influences and explore the Jagger-Richards songwriting team.
Sabrina Sabbagh, FOX News Radio.
Watch a behind the scenes video below of the exhibit:
Click HERE to learn more about the exhibit


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Khyber Pakhtunkhwa Government Increased Pays and Pension 15 Percent of Employees in Budget 2013-14
Peshawar (Breaking News / Monday, June 17, 2013) – Provincial Government of Khyber pakhtunkhwa has announced to raise the salaries of public servants 15 percent.
Pension of retired khyber Pakhtunkhwa government employees has been also increased by 15 percent.
Increase in Salaries of employees = 15%
Increased in Pension of Pensioners = 15%
This announcement was made in assembly session in Peshawar today.
KPK Finance Minister Sirajul Haq presented fiscal budget in assembly.


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Contact: Brigitte
Email: email@example.com
Test it and like it !
Really beautiful place !!! We do love the living room and the huge deck. We get married over there ;-)
An unforgettable honeymoon at
the Lounge Cabin
The lounge cabin is even more epic in person than on the website. My wife and I spent our first week of married life together in this majestic, isolated place. I like camping and she likes fancy places, so this place was a perfect compromise, as even when indoors you feel like you are in the woods with windows all around. We formed relationships with hummingbirds and woodpeckers, and down by the lake with bright frogs and little schools of fishies. The small lake is perfect for swimming--very clear, clean, warm water, and the lake bottom is sandy and rocky and NOT muddy. And there is even a rock in the lake you can climb up on and jump off! We swam every day, we did a lot of cooking in the well equipped gourmet kitchen and some occasional grilling on the gigantic deck. Finally, the highlight of the week and perhaps my life was raspberry picking down by the lake (yes there are wild raspberries all around!!) as the sun was going down on the water. We filled up two large bowls of raspberries and had an incredibly indulgent dessert. Our week went by so fast, leaving the lounge cabin was difficult. We must return to this place.
The Lounge Cabin is the perfect getaway. We loved the wrap around large deck over looking the private lake. The lake was amazing, very quite and war. Can't wait to come back!
Stunningly Gorgeous Property
We stayed at the Lounge Cabin for a long weekend in June. It is living in absolute luxury, while enjoying peace and quiet in nature. The view, privacy, huge deck, fantastic bathrooms, well-equipped kitchen, comfortable beds, and tasteful decor made our stay very enjoyable. You are in total peace, while being six minutes away from Magog. Loved it, wish I owned it.


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Parkersburg tight end Brenton Strange has committed to Penn State.
Federal fraud trial for suspended state Supreme Court justice could take several days.
"Overall, the focus is the safety of the campus community," Chedester said.
Collections once again exceed estimates.
Walker was the star witness on the first day of four expected impeachment trials for West Virginia's Supreme Court justices.
The stop was one of three in West Virginia slated for Monday and part of a 48-stop, 23-state tour expected to cover more than 11,300 miles.
Christopher Carlton Metheny, 35, of Kingwood, is charged with harassment and intimidation of several witnesses
Kappa Alpha, Alpha Sigma Phi, Phi Sigma Kappa, Theta Chi, and Sigma Chi declared the formation of a new Independent Fraternity Council
Wheeling Central stayed unbeaten with a 31-14 win over Linsly.
Greg & Joe discuss the top three matchups in Class AAA football for Week 7.
Prosecuting Attorney Harrah says last week's successful sting operation means others will soon fill the void.
Was it good, was it bad, or was is just "meh"?
Congressman calls his unlikely arrival on the bench a process and not a conclusion.
The Gold & Blue Lunch Report digs into key moments of West Virginia climbing to 4-0.
After jumping to a 35-10 halftime lead at Texas Tech, WVU sat back with an attitude bordering on disinterest as the final 30 minutes slowly melted away.
The Red Raiders quarterback was hospitalized after a crunching hit by the Mountaineers blitzers.
When the 2017 high school football season officially ended Saturday night, December 2nd, 2017, over the course of the two day 2017 Super Six weekend,...
City-issued purchasing card used for thousands dollars of personal purchases.
Weather predictions now being compiled in a pair of temporary trailers in the parking lot of offices while mold abatement gets going
Body recovered Sunday.


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Enter your dates to find available activities
Top attractions in Makarska
Duration: 10 - 13 hours
From Makarska: Kravica & Koćuša Waterfalls Tour
Duration: 7 hours
From Makarska Riviera: Full-Day Split & Trogir Tour
Duration: 11 hours
Krka Waterfalls Excursion from Makarska Riviera
Duration: 12 hours
From Makarska Riviera: Day Trip to Mostar
Duration: 10 hours
From Makarska: Half Day Omiš & River Cetina Tour
Duration: 8 hours
From Makarska: Explore Dubrovnik
Duration: 13 hours
Cetina River Rafting Adventure from Makarska
Duration: 7 hours
From Makarska: Krka National Park Excursion
Duration: 10 hours
From Makarska: Two Islands Boat Tour with Fish Picnic
Duration: 9 hours
From Makarska: Full-Day Dubrovnik Tour
Duration: 12 hours
Things to Do in Makarska
Cities in Croatia
Other Sightseeing Options in Makarska
Want to discover all there is to do in Makarska? Click here for a full list.
What people are saying about Makarska
A pleasant trip with very pleasant people!
Me and my wife enjoyed this trip very much, we are in our late 60s and we did not get tired from the whole trip. Visited very much for 1 day trip without any rush and no stress. The guides where extremely polite and helpful, we felt they gave us some kind of special treatment. We highly recommend this trip.
From Makarska: Two Islands Boat Tour with Fish Picnic Reviewed by Habib, 09/05/2017
Top destinations
Popular on GetYourGuide


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Observing that dark spots or poorly lit areas make people more vulnerable to crimes, the Delhi High Court on Thursday directed the North Delhi Municipal Corporation and power distribution company TPDDL to identify such areas and ensure they are well-lit.
New Delhi:
With regard to the other areas in the national capital, a bench of Justices G S Sistani and A J Bhambhani issued notice to Energy Efficient Systems Ltd (EESL) after BSES said the company has worked in the field of conservation of power as well as ensuring lighting of streets.
EESL, a joint venture of various state-owned power generation companies, including National Thermal Power Corporation (NTPC), was asked by the court to depute someone to appear before it on November 29, the next date of hearing.
The bench was hearing a PIL initiated by the court in 2012 after the horrific December 16, 2012 gang rape of a young woman in a moving bus. The woman later succumbed to her injuries.
The court, during the hearing, said crimes of snatching and assault were on the rise and "dark spots make the victims more vulnerable".
Addressing representatives of Delhi Police, it said for the sake of the national capital's "prestige", steps need to be taken to ensure that such crimes do not happen and streets are safe for citizens, especially women and children.
"Mumbai has done it (made streets safer for women). We should be able to do it. It is not that you (Delhi Police) lack resources or manpower," the bench said.
Advocate Meera Bhatia, who is amicus curiae in the matter, told the bench that the court had in 2017 directed the setting up of a committee to monitor and ensure women's safety and sought that the panel be asked to submit a report of the work it has done.
The bench, thereafter, asked the committee to submit a report indicating the steps it has taken to ensure women's safety.
Delhi government standing counsel (criminal) Rahul Mehra and additional standing counsel Anuj Aggarwal told the court that all police stations, except two, in the city have operational CCTV cameras.
The remaining two stations will also get CCTV cameras installed soon, they told the bench.
The court has been from time to time issuing directions with regard to increasing the number of police officers in the city, installation of CCTV cameras in police stations as well as vulnerable or crime prone areas, reducing delay in testing of samples in forensic science laboratories (FSL) and ensuring speedy disbursal of compensation to victims of sexual assault.