The evolutionarily conserved DNA mismatch repair (MMR) system corrects base-substitution and insertion-deletion mutations generated during erroneous replication. The mutation or inactivation of many MMR factors strongly predisposes to cancer, where the resulting tumors often display resistance to standard chemotherapeutics. A new direction to develop targeted therapies is the harnessing of synthetic genetic interactions, where the simultaneous loss of two otherwise non-essential factors leads to reduced cell fitness or death. High-throughput screening in human cells to directly identify such interactors for disease-relevant genes is now widespread, but often requires extensive case-by-case optimization. Here we asked if conserved genetic interactors (CGIs) with MMR genes from two evolutionary distant yeast species (Saccharomyces cerevisiae and Schizosaccharomyzes pombe) can predict orthologous genetic relationships in higher eukaryotes.
High-throughput screening was used to identify genetic interaction profiles for the MutSα and MutSβ heterodimer subunits (msh2Δ, msh3Δ, msh6Δ) of fission yeast. Selected negative interactors with MutSβ (msh2Δ/msh3Δ) were directly analyzed in budding yeast, and the CGI with SUMO-protease Ulp2 further examined after RNA interference/drug treatment in MSH2-deficient and -proficient human cells.
This study identified distinct genetic profiles for MutSα and MutSβ, and supports a role for the latter in recombinatorial DNA repair. Approximately 28% of orthologous genetic interactions with msh2Δ/msh3Δ are conserved in both yeasts, a degree consistent with global trends across these species. Further, the CGI between budding/fission yeast msh2 and SUMO-protease Ulp2 is maintained in human cells (MSH2/SENP6), and enhanced by Olaparib, a PARP inhibitor that induces the accumulation of single-strand DNA breaks. This identifies SENP6 as a promising new target for the treatment of MMR-deficient cancers.
Our findings demonstrate the utility of employing evolutionary distance in tractable lower eukaryotes to predict orthologous genetic relationships in higher eukaryotes. Moreover, we provide novel insights into the genome maintenance functions of a critical DNA repair complex and propose a promising targeted treatment for MMR deficient tumors.
Defective DNA mismatch repair (MMR) is the underlying cause of hereditary non-polyposis colorectal cancer/Lynch syndrome (HNPCC/LS) and a significant proportion of sporadic colorectal cancers (CRCs) ,. The MMR genes most frequently mutated or epigentically silenced in these cancers are MSH2 and MLH1, which respectively function in the coordination of mismatch recognition and excision ,. The characteristic repair steps in MMR are highly conserved in bacteria, yeast, and mammals. In eukaryotes, the efficient recognition of distinct mismatches requires subsets of three different homologs of bacterial mutS: the MutSα heterodimer (MSH2-MSH6) initiates the repair of single-base mispairs and single-base insertion/deletions (IDLs), while MutSβ (MSH2-MSH3) primarily initiates the repair of larger IDLs of two to four bases but also facilitates the restoration of single-base mismatches  (Figure1A). Subsequent to mismatch recognition MutSα or MutSβ interact with MutLα (MLH1-PMS2) in an ATP-dependent manner to initiate excision of the appropriate DNA strand . During this process individual MutS and MutL subunits directly interact with PCNA, RFC, and RPA, indicating that mismatch excision is closely correlated with DNA replication .
Synthetic lethality as a therapeutic strategy for the treatment of MMR-deficient cancers. (A) DNA mismatch repair is a stepwise process. In the schematic the MutSα heterodimer (Msh2-Msh6) recognizes a single-base mispair while MutSβ (Msh2-Msh3) primarily (but not exclusively -) initiates the repair of larger insertions/deletions (IDLs) of two to four bases. Recognition activates the recruitment of MutLα (Mlh1-Pms2) and multiple downstream factors (for example, Exo1, PCNA, RFC, RPA, and DNA pol δ) for repair by lesion excision and strand resynthesis. Each MutS also has roles independent of these downstream effectors of MMR: as an example, MutSα associates with cell cycle regulators at sites of DNA damage to mediate arrest and apoptosis , while MutSβ contributes to the repair of double-strand breaks via recombinatorial single-strand annealing ,. Mutations in many factors from this pathway are associated with cancer. (B) Loss of A (for example, MSH2) is a common initiating event in many colorectal cancers. Candidate screening seeks to identify and exploit negative genetic relationships (synthetic sick/lethal) to selectively kill cells that harbor the MSH2 deficiency, but spare those lacking this cancer-related alteration.
As a consequence of their defective MMR, HNPCC/LS tumors and sporadic CRCs display increased rates of replication errors at short repeat sequences, termed microsatellite instability (MSI). MSI-positive tumors exhibit resistance to DNA damaging agents, and thus respond poorly to conventional chemotherapy ,. Of additional concern, the treatment of these patients with chemotherapeutic agents can induce secondary therapy-related leukemias (for example, acute myeloid leukemia/myelodysplastic syndrome) ,. Indeed it has been suggested that the primary treatment of HNPCC/LS with chemotherapeutics actually selects for hematopoietic precursor cells with MMR-defects . As these cells proliferate they accumulate further mutations and develop increased resistance to anticancer agents. Thus the development of novel therapeutic strategies that efficiently and selectively target the primary MMR-deficient cancer but avoids therapy-induced secondary tumors would be highly desirable.
A promising new direction to develop targeted therapies is the harnessing of synthetic genetic interactions, where the simultaneous loss of two otherwise non-essential factors leads to reduced cell fitness (synthetic sickness (SS)) or cell death (synthetic lethality (SL)) ,. This provides great functional insight: an SS/SL interaction for two alleles often indicates that their gene products are in parallel pathways or impinge on the same essential function. However it can also provide an elegant strategy to selectively eliminate tumor cells that harbor specific cancer-causing mutations. In this manner, the protein products of genes SS/SL to cancer-causing mutations represent potential drug targets (Figure1B). As an example, inhibitors of poly-ADP-ribose polymerase I (PARP; required for the repair of single-stranded DNA breaks) are lethal to cells with deficiencies in BRCA1 or BRCA2 and show promise in the treatment of breast cancer ,.
A range of approaches can be used to search for SS/SL interactions with therapeutic intent, the most direct being RNA interference-based screening by si/shRNA libraries in human cells ,. Although RNAi lends itself to high-throughput, incomplete knockdowns or off-target effects are commonly observed, and the large scale-format precludes single-case optimization. There are additional issues related to cost, that robotic sample handling might limit the type of read-out assay, the requirement for easily transfectable cell-lines, and even the possibility that an SS/SL interaction might be cell-type specific. Despite these potential concerns, various studies describe the successful application of high-throughput RNAi-based approaches to investigate mammalian gene function -. Indeed recent analyses identified the synthetic combinations MSH2/DNA pol β, MLH1/DNA pol γ, and MSH2/dihydrofolate reductase ,. This directly demonstrates the existence of SS/SL interactions for mammalian MMR genes, although both DNA polymerases are essential in knockout mice and contribute to high-fidelity replication in dividing cells ,, which may limit their potential as therapeutic targets.
Genetic interaction screening in tractable model organisms constitutes a powerful alternative approach for candidate identification. Defining the function of a gene product in budding and fission yeasts (Saccharomyces cerevisiae (Sc) and Schizosaccharomyces pombe (Sp), respectively) has proven highly predictive of the role of its metazoan ortholog ,. These yeasts separated approximately 380 million years ago  (by comparison, the last common predecessor of the entire mammalian class existed about 165 mya ), but share substantial gene content, with approximately 75% of Sp genes having one or more Sc orthologs -. This high level of conservation commonly extends to functional units, such that many yeast complexes are reminiscent of their metazoan counterparts ,. High-throughput genetic interaction mapping approaches have been developed for both yeasts to evaluate the genetic interactions of null, hypomorphic, or mutant alleles in a genome-wide manner ,,. These techniques, in combination with the comprehensive deletion libraries available for both species ,, have been used to provide an overview of the functional dependencies within eukaryotic cells, and give insight into both the function of individual genes and the organization of biological systems -. Furthermore, cross species comparison has identified a high conservation (19% to 29%) of SS/SL interactions between orthologous gene pairs in Sc and Sp,,,.
Here we surmised that complementary genetic analyses of specific MMR genes in the evolutionary distant S. cerevisiae and S. pombe could be used to dissect the function(s) of each individual factor. We further posited that screening against non-essential gene deletions could maximize the potential of identifying SS/SL interactions with potential therapeutic utility. Moreover the identification of Conserved Genetic Interactors (CGIs: SS/SL in both yeasts) could then be tested as candidate drug targets in MSI-positive CRC cell lines. An obvious potential limitation of this approach is the requirement for a high degree of conservation between the yeast and human orthologs. In this regard the MMR factors are particularly well conserved across evolution, which extends to preserving the same repair functions : thus CGIs for each yeast gene might be expected to have strong predictive power for their mammalian orthologs.
Constructs for de novo gene deletion were assembled by PCR megapriming from budding or fission yeast genomic DNA and plasmid templates ,. The resulting products were transformed/targeted by homologous recombination in the desired budding or fission yeast backgrounds and confirmed by sequencing and/or phenotypic analyses as appropriate .
Genetic screening in fission yeast used the PEM-2 approach ,. In brief, NAT-marked (encoding nourseothricin resistance) queries in the PEM-2 background (p392; KFP171) were crossed to a library of 1,955 non-essential gene deletions, with mating, haploid selection, data acquisition, and analysis as previously. Specific interactions of interest were further examined by direct mating, tetrad dissection and spot-testing. Pairwise correlation coefficients (CCs) to examine any relationship between genetic screens were calculated by the CORREL function in Excel.
Many MMR factors participate in meiosis , such that some genetic interactions in fission yeast could be the result of a meiotic defect rather than manifesting during mitotic growth. To avoid this possibility genetic interactions in budding yeast were examined after direct transformation, plasmid shuffling by 5-fluoroorotic acid (5-FOA) selection, and spot-testing. In brief, specific deletions (as KAN cassettes flanked by approximately 500bp of genomic sequence) were amplified from the relevant heterozygous diploid library strain (Open Biosystems), transformed to the appropriate msh2Δ or msh3Δ shuffle strain (with each NAT-marked genomic deletion covered by the relevant wild-type allele on a low-copy URA3 containing plasmid), and homologous-integration events identified by PCR. Replicate clones were successively grown on media containing uracil (to allow loss of the URA3 plasmid) and 5-FOA (converted to a toxic metabolite in the presence of a functional URA pathway, thus isolating double deletion cells). Spot-testing was then performed to evaluate the fitness of the double deletion clones versus their single deletion parents. Any sensitivity to genotoxins was investigated by spotting onto solid media with various concentrations of each agent: camptothecin (CPT) (5, 7.5, and 10µM), methyl methanesulfonate (MMS) (0.005%, 0.075%, and 0.01%), hydroxyurea (HU) (5µmM, 7.5µmM, and 10mM), or 5-fluorouracil (5-FU) (38µM and 76µM). Strains were spotted as 10-fold serial dilutions onto the relevant plates and growth examined at 48, 72, and 96h.
Standard methods were used to examine any genetic interactions in the MSH2-deficient human endometrial cancer cell line HEC59 (MSH2 − ) and its isogenic chromosome 2-complemented counterpart (MSH2 + ) . Transfections with siRNAs (Dharmacon; sequences in Additional file 1) and the Trans IT-siQUEST (Mirus) reagent were performed in six-well plates by specific optimization of the manufacturer's suggested conditions. Total RNA was isolated by the RNeasy plus kit (Qiagen) 24h after siRNA transfection, cDNA synthesized with random hexamers and the Superscript III reverse transcriptase (Invitrogen), and specific transcript levels measured by qPCR (after pre-amplification if required) . SENP6 protein levels in permeabilized cells 48 h after siRNA transfection were measured by fluorescence cytometry after successive staining with monoclonal mouse anti-human SENP6 (Novus Biologicals) (or an isotype control antibody: eBioscience) and anti-mouse IgG2a-PE (eBioscience) (Additional file 1: Figure S1). Apoptosis in specific populations was quantified by activated caspase 3. In brief, cells were trypsinized, stained with LIVE/DEAD fixable violet (Invitrogen), fixed with 2% paraformaldehyde, and permeabilized with 0.3% saponin. Each sample was then successively stained with rabbit anti-caspase 3 (Cell Signaling Technology) and goat anti-rabbit IgG-Alexa488 (Molecular Probes), and analyzed by fluorescence cytometry. DNA double strand break levels in specific populations was quantified by ƔH2AX. In brief, 72h after siRNA transfection/24h after PARP inhibition (20µM olaparib), cells were permeabilized with Transcription Factor Buffer (BD Pharmingen), successively stained with rabbit anti-γH2AX (Cell Signaling Technologies) and goat anti-rabbit IgG-Alexa488, and analyzed by fluorescence cytometry. To estimate clonogenic survival, cells were re-plated 72h after siRNA transfection/24h after PARP inhibition (5µM olaparib). In brief, cells were collected after each treatment (of triplicate wells), resuspended in the same volume of media, diluted 1/500, and an equal aliquot from each sample re-plated and incubated for 2weeks. Cells were fixed with 2% paraformaldehyde, stained with crystal violet, colonies counted, and the clonogenic potential after each treatment of each population expressed relative to the respective siNT-1 (no drug).
For this study three specific MMR genes involved in mismatch recognition (MSH2, MSH3, and MSH6, comprising subunits of the MutSα and β heterodimers: Figure1A) were chosen for direct analysis. MSH3 mice have late onset intestinal tumors and MSH3-deficiency modifies the tumor spectrum of p53 mutant mice ,. MSH3 mutations are rarely seen in HNPCC/LS, although frame-shifts at repeat sequences within the gene are frequently detected in MSI positive CRCs ,,. MSH2 is frequently mutated in HNPCC/LS, while MSH6 mutations are more rare (although MSH6, like MSH3, is also commonly frame-shifted in MSI positive CRCs ,). Thus the specific genetic interactors of each gene could identify novel therapeutic targets for these conditions. Comprehensive genetic interaction data for all three factors would also be expected to distinguish the relationship of MutSɑ and MutSβ with other repair pathways or biological processes.
Appropriate deletion strains (for example, msh2Δ::NAT) were mated to a library of 1,955 deletions (approximately 52% of the non-essential Sp genome ), and double-mutant haploid daughters selected with the Pombe Epistatic Mapper-2 (PEM-2) approach , (see Methods). We then used colony size (compared in high-throughput by photography and image analysis) as a quantitative readout to derive scores covering each negative genetic interaction (<-2.5: SS/SL) ,. Of note, the deletion of msh3 leads to a modest increase in mutation rates , while msh2Δ or msh6Δ each reduce the fidelity of DNA replication >100-fold in S. pombe, S. cerevisiae and mammals . The resulting accumulation of secondary mutations had the potential to compromise our genetic screening, so multiple independent clones of each deletion were analyzed to obtain a high-quality dataset (Figure2A). To date we have screened 953 query alleles against an array of 1,955 non-essential deletions and comprehensive benchmarking confirms the value of this resource: known SS/SL interactions are reproduced, and protein-protein interactions are accurately predicted ,. Analysis of the msh2Δ, msh3Δ, and msh6Δ replicates confirm these global trends, with their data being highly correlated (Pearson correlation co-efficient (CC) >0.4) indicating that individual SS/SL predictions are highly reproducible (for example, Figure2A and B).
Genetic screening distinguishes the MutSβ complex in actively growing yeast. (A) The specific genetic interactions of fission yeast msh2Δ and msh3Δ are similar and distinct from msh6Δ. NAT-marked deletions (for example, msh2Δ::NAT) were placed in the context of 1,955 non-essential fission yeast gene deletions and relative colony size used to derive scores covering each negative (≤ -2.5) genetic interaction (see Methods). Shown are a representative set of 53 genetic relationships expressed by heat map (key below) and identified by their systematic ID and standard Sp/Sc (if present) gene names. Blue, orthologous relationships also tested in budding yeast (see Figure3). Red, Sp-specific orphans. Given the high rate of replication-errors in MMR-gene mutants ,, multiple queries of each deletion were screened to obtain a high confidence dataset. The independent accumulation of confounding secondary mutations may explain why the specific genetic interactors from this study are not described in the available high-throughput datasets that relied on single deletion clones ,,. (B) Distribution plot of Pearson correlation co-efficients (CCs) comparing the genetic interaction profiles of msh2Δ and msh3Δ within a (953×1,955) dataset. Red dots indicate the CC of each genetic screen to a specific msh2Δ or msh3Δ query clone: shaded area highlights screens that would be classed as significantly correlated (CC ≥0.2).
The genetic interaction (GI) profile of a mutant allele comprises its set of interacting partners, or in the case of our quantitative screening, the set of scores for these interactions (for example, Figure2A). GI profiles have been used to predict gene function with high confidence, while the degree of similarity to other mutant profiles can reveal how groups of gene products cooperate in higher-level biological processes ,,,. As an example, Msh2 enters into heterodimeric complexes with Msh3 and Msh6, so it might be expected that the set of genetic interactions for msh2Δ would encompass those observed on deletion of both its partners. Alternatively, since MutSα (Msh2-Msh6) is sufficient for the majority of fission yeast MMR , the genetic interactions for msh2Δ and msh6Δ could have been very similar. To investigate this we compared the profile for each mshΔ within our (953×1,955) dataset , with significant relatedness considered a Pearson CC >0.3 ,,. In this approach msh2Δ had no discernible relationship to msh6Δ, but was instead highly correlated with msh3Δ (Figure2B). We considered that msh2 and msh3 may be genetically related by their loss of function in a process other than MMR. Budding yeast MutSβ also acts with the Rad1-Rad10 nuclease to remove non-complementary tails during DNA DSB repair by homologous recombination  (Figure1A). We thus noted with interest that the GI profiles of msh2 and msh3 were both highly correlated with those of fml1 (Sc Mph1; ATP-dependent 3′ to 5′ DNA helicase, FANCM ortholog), rhp55 and rhp57 (both RecA family ATPases), and rhp51 (Sc Rad51; RecA family recombinase) (Figure2B), all of which regulate DNA double-strand break (DSB) repair by recombination ,. Thus the similar GI profiles of fission yeast msh2Δ and msh3Δ might be due to their shared role in recombinatorial rather than mismatch repair ,,.
Network analyses suggest that the average orthologous gene has significantly more genetic interactions than sequence orphans (that is, genes with no identifiable orthologs in other species) . The MSH genes are highly conserved, yet msh6Δ showed an unexpectedly low percentage of negative GIs relative to all profiles in our (953×1,955) dataset (4.6% msh2Δ; 2.5% msh3Δ; 1.1% msh6Δ vs. 3.8% average ). This distinction from the general trend suggested a limited cross-talk between Msh6 and other pathways: this could be because its protein product acts exclusively in MMR, although such an interpretation is made with caution. In this study genetic interactions were revealed by the specific read-out of altered colony size on rich media. Repeating these analyses in the presence of genomic stress (for example, genotoxin-induced damage) might uncover additional, or an altered spectrum, of synthetic interactions ,, and thus reveal more functional relationships for MutSΔ.
We next sought evolutionarily conserved genetic interactions (CGIs) for fission and budding yeast msh2Δ/msh3Δ to identify orthologous relationships of possible utility in mammalian systems. Twenty-six candidates (25 one-to-one orthologs and the paralogous pair mlp1/mlp2) from the fission yeast SS/SL dataset (for example, Figure2A) were chosen for direct study by satisfying three criteria: synthetic with both msh2Δ and msh3Δ; identifiable Sc and human/mouse orthologs (or a limited group of paralogs); and non-essential in both Sc and human/mouse, thus increasing their potential therapeutic utility. Each mutant combination was created and examined for growth on rich-media and any additional sensitivity to genotoxins, which included 5-fluorouracil (5-FU). This agent is a commonly used chemotherapeutic for colorectal cancer, although MMR-deficient MSI-positive tumors display resistance ,: thus synthetic chemo-sensitization in any double-mutant background would be of particular interest.
Testing these 26 candidates identified seven orthologous negative interactions, with a genotoxin-aggravating effect on the double mutant observed in most cases (Figure3). This moderate number of CGIs for msh2/msh3 (7/25 or approximately 28%) is consistent with recent studies interrogating the conservation of global genetic interaction trends across both yeasts ,. The large-scale studies had further noted that GIs within functionally related gene pairs (such as those involved in the same pathway or process) are more highly conserved across species than those between seemingly unrelated gene pairs ,. However the specific CGIs for msh2Δ and msh3Δ (Figure3) appear to be involved in quite diverse biological functions. Tco89, for example, is a subunit of the TORC1 complex that regulates growth in response to nutrient availability ; Sch9 is an AGC family protein kinase downstream of TORC1 mediated regulation of ribosome biogenesis, translation initiation and entry into G0 ; Nup60 is a nucleoporin component of the nuclear pore complex  and involved in gene tethering to the nuclear membrane; Arp8 is an actin-related protein and subunit of chromatin remodeling complexes ; and Mrt4 regulates mRNA turnover and ribosome assembly . Although the molecular basis for these genetic interactions is currently unclear, their conservation across such evolutionary distance indicates functional importance and may reflect the diverse pathways involved in genome maintenance. The CGIs between msh2Δ/msh3Δ and tco89Δ, for example, may reflect the sensitivity of MMR-deficient colorectal cancer cells to mTOR inhibition by rapamycin . Likewise the CGIs with nup60Δ may be linked to the role of the (Nup60/Mlp1-2) nuclear pore complex in maintaining SUMO-protease Ulp1 at the nuclear envelope to regulate the sumoylation of several proteins, including DNA repair factors .
Direct testing identifies conserved orthologous relationships with MutSβ in fission and budding yeast. Negative interactions from fission yeast were tested for orthologous conservation and potential synthetic chemo-sensitivity in budding yeast. msh2Δ- or msh3Δ-containing strains were created by plasmid shuffling and spotted as serial 10-fold dilutions onto the indicated medium (see Methods). To facilitate cross-comparison results are expressed by a color-code indicating the growth of each strain on a six-point scale relative to wild-type in each condition (all after incubation at 30C for 72h). rad55Δ is a positive control for genotoxin sensitivity . Hatch-bar, not tested; YPD, non-selective media; CPT (5μM); MMS (0.005%); HU (5mM); 5-FU (L ow dose, 38μM); 5-FU (H igh dose, 76μM).
The group of CGIs common to msh2Δ and msh3Δ contains two additional factors involved in protein sumoylation: Ulp2 (Sc Ulp2) and Rrp1 (Sc Uls1) (Figures2A and 3). The Ulp2 peptidase deconjugates SUMO polychains from proteins and plays a role in the recovery from checkpoint arrest induced by DNA damage or replication defects ,. The Rrp1 ATPase regulates the proteolytic control of sumoylated substrates and the response to replication stress ,. This cluster of CGIs strongly suggested a `cross-talk between MutSβ and the SUMO pathway. The (msh2Δ/ulp2Δ) interaction is synthetic lethal in fission yeast (Figures2 and 4A), synthetic sick and aggravated by 5FU (a commonly used chemotherapeutic agent) in budding yeast (Figure3). We thus chose to perform a more detailed genetic analysis of this specific CGI in fission yeast before further testing the orthologous relationship in mammalian cells.
Increased polysumoylation is lethal in msh2Δ fission yeast. (A) Deletion of the Ulp2 SUMO-protease is synthetic lethal (SL) with msh2Δ. msh2Δ and ulp2Δ strains were mated, sporulated, tetrads dissected and genotypes determined ((ulp2Δ/msh2Δ) is boxed). (B) Schematic depicts the sumoylation pathway. Fission yeast contains one gene encoding SUMO (Smt3), two E3-ligases (Pli1 and Nse2), and two SUMO proteases (Ulp1 and Ulp2). (C) msh2Δ is SL with ulp2Δ but neutral with ulp1Δ. Strains were mated, sporulated, and tetrads dissected. The number of viable spores observed/expected for each genotype is indicated (see also Additional file 1: Figure S2A and B). (D, E) smt3Δ or nse2-SA (catalytic dead), but not pli1Δ, rescue the lethality of (msh2Δ/ulp2Δ). Strains were mated, sporulated, and the indicated number of tetrads dissected (see also Additional file 1: Figure S2C to E). Panel (E) depicts representative tetrads to demonstrate the growth of each mutant combination.
Sumoylation is a reversible post-translational modification that controls the localization, function, interaction, and stability of a large number of proteins, including many involved in transcription, replication, and the DNA damage response . Indeed recent studies highlight the importance of a reversible SUMO-response to preserve genome integrity ,. Fission yeast encodes one form of SUMO (Smt3 aka. Pmt3), two SUMO E3-ligases (Pli1 and Nse2), and two SUMO proteases (Ulp1 and Ulp2; Figure4B). Pli1 catalyzes the majority of cellular sumoylation, while Nse2 targets a limited number of substrates during DNA repair ,. For deconjugation, Ulp1 removes single SUMO modifications and is required for efficient cell cycle progression ,. Ulp2, in contrast, edits poly-SUMO chains, desumoylates the majority of factors activated in response to DNA damage or DNA replication defects, and regulates the recovery from checkpoint arrest ,,,.
On direct testing the SL interaction of (msh2Δ/ulp2Δ) is not observed with (msh2Δ/ulp1Δ) (compare Figure4A and C), indicating that the accumulation of specific sumoylated substrates is toxic to fission yeast cells that also lack an Msh2-mediated repair pathway. This may be because Msh2 is absolutely required to resolve lesions that occur at increased levels in the context of ulp2Δ . Alternatively cells lacking Msh2 might accumulate unresolved DNA damage and induce a poly-sumoylated substrate (or substrates) that cannot be metabolized in the absence of Ulp2, blocking cell cycle progression . The identity of such substrates is currently unknown, though many central players in replication and recombination (for example, Rad52, PCNA, RPA) are sumoylated in response to DNA damage, and this is important for their repair function . To investigate this further we tried to create triple mutants containing msh2Δ, ulp2Δ and a mutation in either SUMO itself (pmt3Δ) or one of its E3-ligases (pli1Δ, or the nse2-SA allele that lacks SUMO ligase activity but retains the essential function for Nse2 in chromosome maintenance ). Following tetrad dissection we obtained the triple mutant combinations (msh2Δ/ulp2Δ/pmt3Δ) and (msh2Δ/ulp2Δ/nse2-SA), but not (msh2Δ/ulp2Δ/pli1Δ) (Figure4D and E and Additional file 1: Figure S2). This clearly demonstrates that msh2Δ is lethal in combination with a deletion of Ulp2, the primary protease to desumoylate DNA damage response proteins ,, but this can be rescued by inactivating the primary ligase for sumoylation in response to DNA damage ,.
We next sought to examine if the CGI between budding and fission yeast msh2 and ulp2 predicted an orthologous relationship in human cells. Humans encode four SUMO proteins (SUMO1-4 with relatedness: SUMO1, SUMO2/3, unconjugated SUMO4) and six SUMO-specific cysteine proteases (SENPs). Of these, SENPs 1/2/3/5 are most closely related to Ulp1 and specifically deconjugate single SUMO1/2/3, while SENPs 6/7 resemble Ulp2 and edit polysumo chains with a clear preference for SUMO2/3 -. A limited literature discriminates the distinct roles of mammalian SENP6 and SENP7 -. However both are expressed in a variety of tissues including the colonic epithelium  and thus might be active in MMR-deficient colorectal cancer cells.
To investigate any relationship between human MSH2, SENP6, and SENP7 we used siRNA to efficiently knockdown each SUMO protease in HEC59 cells (an Msh2-deficient endometrial cancer line) and their isogenic chromosome 2-complemented MSH2 proficient counterparts (Figure5A to D). SENP6 knockdown resulted in significantly increased apoptosis in MSH2-deficient relative to MSH2-proficient cells (Figure5E), reproducing the negative genetic interaction identified in budding and fission yeasts (Figures2A and 3). Interestingly SENP7 knockdown had no effect (Figure5E). This SUMO protease was recently shown to interact with chromatin remodelers and contribute to chromatin relaxation during DNA repair by homologous recombination -. However our results indicate that the effect of SENP7 knockdown on recombinational repair does not lead to increased apoptosis in MSH2-deficient cells.
SENP6 knockdown induces a hyper-acute apoptotic response in MSH2-deficient human cells. (A-D) Efficient targeted knockdown of SENP6 or SENP7 in MSH2-deficient HEC59 cells. In A, B mRNA was quantified by qPCR; in C, D SENP6 protein was detected by flow cytometry (see Methods). Note specificity of SENP6 knockdown in response to siSENP6-C or siSENP6-1, but not siSENP7 (pooled siSENP7-1 and siSENP7-2) or non-targeted siNT-1. (E) SENP6 (but not SENP7) knockdown induces apoptosis in HEC59 cells (MSH2") relative to an isogenic chromosome 2 complemented population (MSH2+). Caspase 3+ cells were identified 48h after siRNA transfection (see Methods), normalized to siNT-1 in each population, and significance determined by unpaired t-test (ns, not significant; *, P <0.01). (F) PARP inhibition induces DNA DSBs (γH2AX+), and to a greater degree in MSH2 − cells. γH2AX+ cells were identified 72h after siRNA transfection/24h after PARP inhibition (20μM olaparib; see Methods) and the significance of pairwise comparisons determined by unpaired t-test: (1) P <10−4; (2) ns, not significant; (3) P <0.008; (4) P <0.002. Panels (F-H) use the same color key and siSENP6-1 for SENP6 knockdown (previous studies suggest off-target effects are unlikely ). (G) MSH2 − cells show reduced clonogenic survival (see Methods) in response to SENP6 knockdown, PARP inhibition, or their combination. Any significance of indicated pairwise combinations was determined by unpaired t-test: (1) P <0.02 (may be related to the additional copy of chromosome 2); (2) ns, not significant; (3) P <0.001; (4) P <0.01; (5) P <0.0007; (6) P <0.03; (7) P <0.01. (H) (MSH2/SENP6) deficient cells exhibit a hyper-apoptotic response to PARP inhibition. Activated caspase 3 levels 72h after siRNA transfection/24h after PARP inhibition (20μM olaparib) were quantified by flow cytometry and normalized to siNT-1 (no drug). Any significance of various pairwise combinations was determined by unpaired t-test: (1) P <10−5; (2) P <10−6 (also seen with MSH3 − ); (3) P <10−7.
Human SENP6 maintains the hypo-sumoylation of RPA70, and thus regulates homologous recombination-mediated repair during S-phase . This finding allied with our results in yeast may imply that the conserved synthetic interaction between MSH2/msh2 and SENP6/ ulp2 is due to the combined loss of MutSβ- and RPA-mediated DNA DSB repair. Consistent with this notion, the addition of Olaparib (a PARP inhibitor that induces the accumulation of ssDNA breaks that ultimately result in DSBs during replication -) rendered a significantly greater number of γH2AX+ cells in the (MSH2/SENP6) deficient population versus singly-deficient controls (Figure5F). This is accompanied by the reduced clonogenic survival of MSH2 - cells in response to SENP6 knockdown, olaparib treatment, or their combination (Figure5F). In isolation this synthetic interaction provides no direct mechanistic insight, but further analyses showed that the (MSH2/SENP6) deficient population also displayed a hyper-acute apoptotic response to olaparib (Figure5H). It appears likely that (MSH2/SENP6) deficient cells are incapable of resolving the genomic lesions induced by PARP-inhibition, with apoptosis becoming a preferred response. Olaparib is currently in phase II clinical trials for the treatment of BRCA1/2-dependent breast and ovarian cancers -. Our findings suggest that it may also enhance the efficacy of strategies that target components of DSB repair pathways in MSH2-deficient tumors.
This study describes the identification of conserved genetic interactions between the MutSβ subunits and orthologous genes encoding diverse biological functions in two evolutionarily distant yeast species. It further demonstrates that unexpected genetic relationships could be exploited to treat loss-of-function disorders. In the specific example presented, the synthetic interaction of (MSH2/SENP6) deficiency enhanced by PARP inhibitors indicates that a significant proportion of MMR-deficient cancers could be targeted via their loss of function in MutSβ-mediated recombinatorial, rather than mismatch, repair  (Figure1A). Ongoing studies have established the central role of reversible sumoylation in an efficient DNA damage response, suggesting that the SUMO pathway might contain novel druggable targets for anticancer therapeutics ,. In this work we suggest that targeting specific SUMO proteases may be highly effective in the treatment of MMR-deficient cancers. The recent development of SENP6-specific small molecule inhibitors  could prove invaluable for further experiments in this regard.
CJR is supported by ICON plc and the UCD Newman Fellowship Program. This work was supported by the NIH (ES019966, CA76329 and CA93484) and an NCI Cancer Center Support grant to Albert Einstein College of Medicine (CA013330).
ET, JAK, NJK, DP, MCK, and WE designed the experiments; ET, JAK, SS, HSK, CJR, and AR performed the research; ET, JAK, SS, CJR, MS, NJK, DP, MCK, and WE analyzed the data; ET, MCK, and WE wrote the paper. All authors read and approved the final manuscript.


At Home opening store in Dayton: What should you know?
At Home, the home decor superstore that is expanding in Dayton, just reported its most recent financial results and the chain retailer is making solid gains.
At Home Group Inc. announced its second quarter results — reporting 23 percent net sales growth and a nearly 8 percent comparable store sales increase. This is the 13th consecutive quarter of net sales growth that was more than 20 percent, and the 14th consecutive quarter of positive comparable store sales increases.
"Customers continue to respond positively to our trend-relevant assortment of home décor at a compelling value, driving growth in both new and existing stores across a wide range of geographies, price points, everyday and seasonal merchandise," said Lee Bird, chairman and chief executive officer.
At Home opened eight new stores in the second quarter and closed one, and the chain has 136 stores in 33 states. That's an increase of more than 18 percent in stores since 2016.
The Texas-based home decor retailer will open its first location in the old Kmart building off of Indian Ripple Road. Beavercreek Planning Commissions approved the plans for the retailer to renovate the space at a meeting early last month. The former Kmart building, which has stood there for more than 40 years, has been deteriorating significantly in recent years.


text:
VIRTUAL REALITY MACHINE TRAINING LIMITED
Pontecraft, United Kingdom of Great Britain and Northern Ireland
Virtual Reality Machine Training was formed in 2018 by co-owners Tony Pawinski and Mark Henshaw to supply the glass bottle manufacturing industry with a unique software tool to help improve training
Basingstoke, Hampshire, United Kingdom of Great Britain and Northern Ireland
Testbourne Ltd is a professional high technology / materials company, supplying high purity materials, single crystals & wafers, evaporation sources, ceramic to metal components, thin film
Sheffield, United Kingdom of Great Britain and Northern Ireland
Pioneering new technology Our UK history begins in the late 1940s with the creation of a new glass manufacturing facility in Bilston, Staffordshire, UK. British Heat Resisting Glass was a
London, United Kingdom of Great Britain and Northern Ireland
Smart-Builder has been designing and building glass software for over 20 years with the goal of making glass software easy. Our products are created specifically for the glass industry and have been
Redhill, Surrey, United Kingdom of Great Britain and Northern Ireland
Every issue of Glass International brings you a wealth of valuable information on the hollow, container, flat, and speciality glassmaking industry. Whether it be a webinar, online story, free digital
Barnsley, United Kingdom of Great Britain and Northern Ireland
We are Pro-Sight Vision and we create bespoke vision inspection and ware handling solutions for the glass industry. Working both in the UK and overseas, we pride ourselves on high quality machines
Huddersfield, West Yorkshire, United Kingdom of Great Britain and Northern Ireland
In 2018 Pennine Industrial celebrate their 50th year in business The company was founded in 1968 by Leonard Hobbs as "Pennine Technical & Design Services Ltd" and to this day remains a family run
Halifax, United Kingdom of Great Britain and Northern Ireland
The business was established in 1800 as a partnership between the Parkinson family and the Spencer family. Caleb Spencer (1766-1847) is credited as its founder and early activities involved the two
Keighley, United Kingdom of Great Britain and Northern Ireland
Our Mission Loadhog is a multi-award winning, employee owned, UK manufacturer, dedicated to the design and manufacture, sale and pooling of Returnable Transit Packaging solutions across a diverse
Filey, United Kingdom of Great Britain and Northern Ireland
Where it all started... Hunprenco was established in 1969 by Mr Eddie Neesom, who is Chairman and Managing Director. He started a small engineering workshop in a disused stable in the North Yorkshire
Chesterfield, Derbyshire, United Kingdom of Great Britain and Northern Ireland
WELCOME TO GRAPHOIDAL Graphoidal Developments Ltd is at the forefront of designing and manufacturing the most advanced lubrication and coating technology to the glass container and tableware
Cambridge, United Kingdom of Great Britain and Northern Ireland
We are a leading developer of industrial inkjet software, drive electronics and ink / fluid delivery system components. Our customers comprise OEMs, machine builders, system integrators and printhead
West Midlands, United Kingdom of Great Britain and Northern Ireland
Based in the heartland of Britain's industrial heritage we offer engineering excellence borne from our long history of manufacturing and evolving capabilities. We are a family owned business
Hanley, Stoke-on-Trent, Staffordshire, United Kingdom of Great Britain and Northern Ireland
Solutions from the world's largest independent lubricant manufacturer FUCHS is a global Group with German roots that has developed, produced and sold lubricants and related specialties for more than
Penzance, Cornwall, United Kingdom of Great Britain and Northern Ireland
Tomorrow's Technology Today F.I.C. lead the industry in solving difficult electric melting problems for over 25 years. F.I.C. has established a worldwide reputation for design and manufacture of
Rainham, Essex, United Kingdom of Great Britain and Northern Ireland
F.H.Brundle was established in 1889 by Frederick Henry Brundle, his success was based on careful product selection, keen prices and service. He had an acute business brain and a benign
Emirates Float Glass LLC
Buxton, Derbyshire, United Kingdom of Great Britain and Northern Ireland
DSF is recognised for technical competency and the company produces a wide range of high alumina and special refractories. DSF are specialists in large and complex shapes and refractories for
Forest Row, East Sussex, United Kingdom of Great Britain and Northern Ireland

redpajama_set_name: RedPajamaCommonCrawl


What is mobile development ?
If you didn't get it yet, I'm a mobile developer. This mean that I can make Android and iOS apps. I just wanted to make it clear before start.
What is precisely mobile development?
A lot of people asked me what I do and how I do this. Everybody know that is about coding and all that stuff but… that's all? That's not.
I think that mobile development and generally mobile apps are not recognize like they should. That's normal, everybody can have a lot of apps for free. And even if for some you have to pay, it never gets up to around 10 $/€. So, for everybody an app is something easy to get and cheap. These pasts years, medias talk more and more about mobile apps, so slowly, people start to understand that it's not that free, it costs a lot, and mainly for games, it requires a lot of times and skills. As I seen around me, people think that all apps are like "Flappy bird" or "Snapchat" at the beginning. Easy to develop, you put in in the store and boom, a lot of download, with ads, a lot of money and done: You're rich. Again, it doesn't work like that.
Even for people who works on IT development, they don't really consider mobile development. How many times I heard "Mobile development? It's easy, I can do it too. If you want, in two weeks I can make an app" or something like "Mobile development is not development, it's playing, insert tech development is the real thing". To all these people, you're wrong, Sorry but not sorry. First, all techs developments are "the real thing". Second, you can't make an app in two weeks (more or less) if you don't know what you're talking about. No, you can't make a good Android app just because you know Java development. No, develop an app is not fast. If you want to make it good, it is not. Obviously, it's like everything, you can make it fast, but I can guarantee that it will not be good.
So, what is mobile development ?
It's a good question that deserve a long answer. But I will not give that long answer, I will give you quickly my point of view. I guess that if you are here, you're at the right place to learn about all of this, so I will let you time to discover this.
Mobile development is about… development. Right and…? It's also design and marketing. Like everything you will tell me. Sure. Does a Java developer have to care about the front integration? Not much. Does a Java developer have to know what is a Grid Layout? I'm not sure. Does a Java developer have to handle assets, colors, font, animations…? I'm really not sure. It was just some examples, but what I mean here is that mobile development is a whole world. Android have a world, iOS have one too (what, Windows Phone? What's this?). There are some things in common but also a lot of differences. If you want to know about one of these world, you will have to take time to discover it. And by time I don't mean few days, I talk about weeks or month. And this only to understand the mainly things to know to make A GOOD APP.
For sure, you can fast make an app (I will not talk about cross-platform tech here). But it will not being good. For the ones who have an app idea and want to make it by themselves, take time to understand this world. If you don't want, find someone who know it. But please, don't do thing without a minimum of knowledges. You can't make a good website if you don't know how internet, networks, servers etc works. It's the same for mobile development.
23 yo app entrepreneur from France. Native mobile app developer. Learner and teacher. Traveler.
Should you quit entrepreneurship ?


text:
Skipper: ESPN Not Straying From Sports Brand Despite FiveThirtyEight Acquisition
Maintains that network's 'material business' will always be sports
By Tim Baysinger
Despite being the owner of political website FiveThirtyEight — which will launch its new version early next year — ESPN President John Skipper said this doesn't signal a new shift in network strategy.
"Not very much," Skipper told AllThingsD's Peter Kafka, when asked how far away from sports ESPN plans to attach itself to. "The material business of ESPN is going to be in sports."
During a discussion with FiveThirtyEight founder Nate Silver, which was moderated by Kafka, at the first day of the Paley Center's International Council Summit on Thursday, Skipper explained that buying FiveThirtyEight represented a special opportunity for ESPN.
He shared the same sentiment about the pop culture/sports site Grantland run by popular sportswriter and TV personality Bill Simmons. "If there are other unique opportunities we will look at them," he said. "But this is not a significant new [initiative]."
Skipper also explained that even though these new websites that are not entirely about sports are under the ESPN umbrella, they don't carry the ESPN brand. "Grantland is not 'ESPN Grantland;' it's Grantland. FiveThirtyEight.com is FiveThirtyEight.com."
"We have a news operation, it's called ABC News," he quipped.
ESPN and Silver are taking a longterm approach with FiveThirtyEight, noting that they won't be paying attention to how many page views a singular story may get, but rather that they are growing the brand overall.
"I don't spend a lot of time looking at statistics for individual stories," said Silver, who mentioned how websites that use SEO-generated headlines just to get clicks can "undermine" their brand. "Our metric is longterm how many consumers do we draw in."
Silver has said on multiple occasions that his new version of FiveThirtyEight will employ a similar strategy as Grantland; he explained, like the pop culture site, he wants FiveThirtyEight to be about more than just him. "Grantland has become at its best in the past year and half and or so, where it's no longer seen as just Bill Simmons' site."
Silver argued that because there are so few players in his data-driven, political journalism space means that FiveThirtyEight has more room for trial and error. "We think it's a space that's undersupplied in the market so we can probably make some mistakes."
Skipper was also asked about a variety of other topics pertaining to ESPN's overall business. A few highlights:
On ESPN's vulnerability to disruption:
"Our intention is to be both the leader and to be the most nimble, relative to innovation and adopting new technology," said Skipper. "Big companies get disrupted when they are defensive or when they are concerned with protecting what they have as opposed to building new things and doing new things."
On ESPN's thinking process when they don't buy rights to a certain sports league:
"There are lots of people who want to be in sports," he said. "We have never felt that we didn't have to prioritize the things we buy."
On cord-cutting's potential impact to ESPN's business:
"We are going to look and see where there is a significant shift," he said. "We think sports live rights are the most valuable content in media."
Fox Sports Grabs Bill Raferty From ESPN
Will call Big East basketball with Gus Johnson; keeps role with CBS sports
Sports Summit: ESPN Chief Skipper Says World Cup Will 'Dominate'
Massive 190,000-square-foot studio simply how ESPN 'rolls'
Sports Executive of the Year: Skipper Keeps ESPN Ship Steady As She Grows
New rivals crowd the sports batter's box, but leader's innovations brush them back
Skipper Named ESPN President; Bodenheimer to Exec Chairman
Disney puts in succession plan at sports network
ESPN's Rachel Nichols Joins CNN and Turner Sports
Veteran reporter will anchor weekend sports program on CNN
Nate Silver Joins ESPN
Will also contribute to ABC News, run FiveThirtyEight website a la Grantland
Survey: ESPN Most Powerful Brand in Sports
Sports Business Daily/Sports Business Journal readers also laud NBC's Michaels and Collinsworth
ESPN to Broadcast From Rio's Clube dos Marimbas During World Cup
Plans over 280 hours of original coverage across all English-language networks


I thought it would be nice to update the site a little withe the progress of the home. Yknow so when I look back I can show for a before and after and laugh at how little progress I've made.
It's the 26th of April, at least a month after purchasing the property and very little work has been started. I'm getting a little frustrated with how long the builder is taking and might very well ditch the guy.


Cottom's Wildlife Removal removes and excludes raccoons and animals from chimneys, roofs and attics for Cleveland and Akron homeowners. We set animal traps and/or use handling tools to remove raccoons, squirrels, animals, critters and birds from chimneys, attics, roofs and soffits. Our professional wildlife control experts use one-way doors to get raccoons out of attics or crawl spaces. We prevent raccoons, squirrels, birds and animals from entering chimneys by installing raccoon control screens and chimney caps, crown vent guards, roof vent guards and chimney guards, wildlife barrier kits, stainless steel wire mesh or galvanized wire mesh. We disinfect and decontaminate areas soiled by raccoons, remove animal and bird waste and feces. We repair the damage they cause to chimneys, roofs, soffits and buildings. It costs $495.00 for us to remove raccoons from a chimney and to install one chimney cap.
If you hear sounds in your chimney or on your roof at night or a noise that sounds like the scratching of raccoon claws, you may have animals or raccoons living in your smokestack, attic or roof. If you hear raccoons running on your roof, they may be living in your chimney, attic or roof. Raccoons may even start tearing up your roof to gain access to your attic. Raccoons can cause extensive roof damage. We fix roofs damaged by raccoons all the time in Cleveland and Akron. While it is not hard to scare a raccoon off your roof, they will come back. Dexterous raccoons can even climb up gutters and downspouts to get into a chimney, attic or roof. Cottom's Wildlife Removal can install exclusion devices to keep raccoons from climbing up and down gutters and downspouts.
In the spring, female raccoons frequently climb into chimneys to give birth to their young. The hollow smokey compartments in chimneys are similar to burned out hollow trees which are popular with pregnant raccoons. Sometimes raccoons will leave the chimney on their own after their babies have been born and are mature enough to climb out of the chimney, or not.
Even though the process of removing raccoons from a chimney or roof is a job for a professional animal control company, some homeowners still try to use various methods to remove raccoons from chimneys.
Please don't use smoke or fire to remove raccoons from a chimney. This may kill the adult and their raccoons pups. Having dead raccoons in your chimney is not a good situation on many levels.
Don't use raccoon eviction fluid. Some folks use raccoon eviction fluid to evict female raccoons and the raccoon babies. Raccoon eviction fluid is a natural by-product of male raccoon. Female raccoons don't like having male raccoons around her newborns. However, this product may actually draw raccoons into your chimney.
Homeowners in Cleveland and Akron should not attempt to install a chimney cap after they witness a raccoon leaving their chimney or climbing off their roof. This can trap the babies in the chimney where they will die. If raccoons are trapped in a chimney, they will try to get to safety, food and water by entering the house through the fireplace. This is not a desired outcome.
We suggest you call Cottom's Wildlife Removal at 440-236-8114 to schedule a chimney inspection and raccoon removal services.
Removal of raccoons from attics, houses, buildings, roofs, soffits, garages, businesses, barns, sheds, basements, decks and outbuildings.
The Cottom's Wildlife Removal company does not provide free raccoon or squirrel removal in Cleveland and Akron, Ohio. We do charge a fee for these services.


Washrooms and shower rooms in residential care need to be functional and meet special mobility and access needs, yet should also be attractive and homely, which is why Inscape has designed specialised products to assist with personal care routines.
Our range of residential care solutions can be adapted to protect the privacy and dignity of elderly and infirm people, and allow assistance if they need a little help. These products can also be adapted to accommodate Part M compliant furniture, sanitary-ware and fittings as a comprehensive solution to the needs of both user and carer.
This includes bespoke fitting on width and length and space-saving designs that give ample room for manoeuvre, even where space is at a premium. We also supply hygienic wall cladding, surfaces and furniture for areas that would benefit from extra defence against infection, such as kitchens, reception areas and hallways.
You can view photographs and read about residential care installations like Abbeyfield House in our case studies section.


text:
Chaleira é um utensílio culinário que, teria como sua principal função, a preparação de chá, essa função torna idealizado seu nome como "chaleira". Recipiente proprio para preparação de chás

A chaleira tradicional é um recipiente de metal com a forma de um cilindro baixo com uma tampa no topo e um bico lateral. Este utensílio foi desenhado para aquecer água para o chá colocando-se sobre uma boca de fogão.

Ligações externas

Portal da Chaleira Elétrica - informação e da história dos Chaleira Elétrica

Utensílios para o consumo de chá

redpajama_set_name: RedPajamaWikipedia


White (Lareen) - The White family acquired these lands in the Kinlough area in the early 19th century though their main estate was at Luttrellstown, county Dublin, purchased in 1800 from the Earl of Carhampton. Frank Tracy describes the White purchases in county Leitrim in the early 19th century. See also http://homepage.eircom.net/~fmasters/landlords.html#Lareen, for more information. A branch of the Massy family (Baron Massy of Duntrileague) inherited these lands from the White family. The 4th Baron Massy of Duntrileague married Luke White's daughter, Matilda, and it was through this connection that the White lands in Leitrim passed to their second son, John Thomas, who became 6th Baron Massy of Duntrileague in February 1874 on the death of his older brother, Hugh, the 5th Baron.
White (Cahiracon) - The Whites of Woodlands, county Dublin, Rathcline, county Longford, Lareen, county Leitrim, Cahircon, county Clare all descend from Luke White, a Dublin bookseller and lottery agent. In the mid 19th century his fourth son Colonel Henry White held an estate comprised of at least 24 townlands in the parishes of Abbey, Drumcreehy and Rathborney, barony of Burren, county Clare which he bought from the Duke of Buckingham circa 1848. The Whites also bought some of the Scott of Cahiracon estate and the Westropp of Attyflin estate, both in county Clare. At the time of Griffith's Valuation the Colonel held an estate in the county Limerick parishes of Rathkeale, barony of Connello Lower, Newcastle, barony of Glenquin, Cloncagh, Cloncrew, Dromcolleher and Kilmeedy, barony of Connello Upper, as well as his county Clare estates. In 1863 the Colonel was raised to the peerage as Baron Annaly of Annaly and Rathcline, county Longford. He was succeeded by his eldest son Luke as 2nd Baron in 1873. His fifth son Charles William White of Cahiracon, Killadysert and Annaly Lodge, Broadford, inherited the county Clare estates comprised of 18,226 acres plus 5,731 acres in county Tipperary. In 1878 Charles William White sold the Broadford estate, barony of Tulla Lower to John Lecky Phelps. In the 1870s Lord Annaly of Woodlands (Luttrellstown), Clonsilla, county Dublin, owned 5,428 acres in county Limerick, 12,600 acres in county Longford and 2,139 acres in county Dublin. In 1906 Baron Annaly held untenanted land in the parish of Kilcooly, barony of Slievardagh, county Tipperary.
Butler (Carrick) - In July 1677 Pierce Butler and his wife Ellice were granted 648 acres in the barony of Bunratty, county Clare and in December 1668 Pierce was granted a large estate in counties Tipperary and Kilkenny. Pierce succeeded his father as 4th Viscount Ikerrin in 1688. His grandnephew, Somerset Hamilton Butler, 8th Viscount, was created Earl of Carrick in 1748. The main seat of this family was Mount Juliet, Thomastown, county Kilkenny. In 1774 Henry Thomas, 2nd Earl, married Sarah, daughter and co heiress with her sister Lady Massy, of Edward Taylor of Ballynort, county Limerick. In the 19th century the Earl of Carrick and the Honourable Edward Taylor Massy jointly held an estate in county Limerick, in the parishes of Loghill, Nantinan, Rathronan and Robertstown, barony of Shanid and Adare and Iveruss in the barony of Kenry. Their agent was Edward Green of Greenmount, Patrickwell. By the early 1870s some of the land in the parish of Robertstown, county Limerick, was owned by Francis Octavius Montgomery. Lewis writes that the Earl of Carrick and the representatives of Lord Massy also received compensation when Askeaton was deprived of its franchise following The Union of 1800. By the 1870s the Earl of Carrick owned 1,368 acres in county Kilkenny but only 64 acres in county Limerick. His county Limerick estate of over 2,200 acres in the baronies of Shanid and Connello Lower, with some 439 acres in county Kilkenny, was advertised for sale in November 1855. The county Tipperary estate of the Earl of Carrick was in the parishes of Lismalin, barony of Slievardagh, Twomileborris, barony of Eliogarty and Killavinoge and Templetuohy, barony of Ikerrin in the mid 19th century. In July 1851 over 3,000 acres in county Tipperary and over 600 acres in county Kilkenny were advertised for sale. The Freeman's Journal reported on the outcome of this sale in February 1852. Estates in counties Kilkenny (including Mount Juliet) and Tipperary were advertised for sale in November 1855 by the trustees of the will of Somerset Richard, Earl of Carrick.
Taylor (Ballynort & Holly Park ) - An entry in ''Pue's Occurances'' 19-23 June 1739 indicates that the Taylors were resident at Ballynort, Holly Park and Woodcliff in county Limerick from at least that date. Feheney writes that the Taylors acquired their Askeaton lands through marriage with a Berkeley heiress and their Holly Park estate by purchase from Queen Anne (Chichester House Commissioners) in 1706. The Parliamentary Papers record the purchase by William Tayler of Burton, county Cork, of part of the confiscated estate of James II in the barony of Kenry, county Limerick, in 1703 for £3,059. Colonel Edward Taylor of Ballynort had two daughters, his co heiresses. Catherine married Hugh Massy, 2nd Baron Massy, in 1760 and Sarah married the Earl of Carrick. At the time of Griffith's Valuation Edward Taylor Massy and the Trustees of the Earl of Carrick jointly held an estate in the parishes of Loghill, Nantinan, Rathronan and Robertstown, barony of Shanid and Iveruss, barony of Kenry. At the same time Richard Taylor held two townlands in the parish of Kilcornan, barony of Kenry, county Limerick, amounting to over 800 acres. In 1852 he purchased the Woodcliff estate of Anselm Taylor in the Encumbered Estates Court. In the 1870s William Taylor of Holly Park, Pallaskenry owned 2,570 acres and Catherine Taylor of Holly Park, Adare, owned 669 acres in county Limerick.
Massy (Glenwilliam) - A junior branch of the Massys of Duntrileague, county Limerick, descended from the Reverend Godfrey Massy of Mount Sion, county Limerick and Vicar of Dysart and Prebendery of Limerick. In 1819 George Massy of Glenwilliam married as his second wife Eliza Odell of the Grove, county Limerick. She married secondly Daniel Power. The Glenwilliam estate and the lands of Gortroe amounting to 942 acres belonging to George Thomas De Massy, a minor, were advertised for sale in June 1851. Sales of other lands continued to be advertised in the following years, including land in the barony of Orrery and Kilmore, county Cork in November 1857. Glenwilliam was bought by Edward Atkinson some time in the 1850s. At the time of Griffith's Valuation the Massy estate in the parishes of Ballingarry and Croom was in the hands of the Court of Chancery. George Rollo Massy, a younger son of George and Eliza Massy, held land in th parish of Kilfinnane, barony of Coshlea, at the time of Griffith's Valuation and in the 1870s he owned 1,000 acres in county Limerick. His address was Usher's Quay, Dublin. In July 1866 and July 1875 lands at Ballinanima (178 acres), barony of Coshlea, the estate of George Rollo Massy were advertised for sale. A Mr. Sharp purchased some of these lands in trust in July 1866. A further sale of George Rollo Massey's property was advertised in the Land Judges' Court in November 1888.
Massy (Ballynort) - In 1760 Hugh, 2nd Baron Massy, married Catherine, daughter and co heiress with her sister Lady Carrick, of Edward Taylor of Ballynort, county Limerick. Their second son Edward succeeded to Ballynort and the Massy interest in the Taylor estate. At the time of Griffith's Valuation, Edward Taylor Massy and the Trustees of the Earl of Carrick jointly held the [former Taylor] estate in the parishes of Loghill, Nantinan, Rathronan and Robertstown, barony of Shanid and Iveruss, barony of Kenry. By the early 1870s some of this land in the parish of Robertstown was owned by Francis Octavius Montgomery. Lewis writes that the Earl of Carrick and the representatives of Lord Massy also received compensation when Askeaton was deprived of its franchise following the Union of 1800. In the 1870s Edward Taylor Massy of Haversford West, Wales, owned 4,620 acres in county Limerick.
Dawson/Massy-Dawson (Ballynacourte) - In 1666 John Dawson was granted an estate of over 2,900 acres in county Tipperary including the castle of Ballinecourte. In 1703 James Dawson of Ballynecourty, county Tipperary, purchased land in the baronies of Coonagh and Clanwilliam, county Limerick and Clanwilliam, county Tipperary, part of the confiscated estate of King James II. The 1st Baron Massy married as his first wife, Mary Dawson, daughter and heiress of James Dawson of Ballynacourty. Their second son, James (born 1736), assumed the additional surname of Dawson and his family succeeded to Ballynacourty. The estate of Reverend John Massy Dawson, grandson of James, is recorded as the immediate lessor of at least 20 townlands in the parish of Clonbeg, barony of Clanwilliam, at the time of Griffith's Valuation, though he himself died in 1850. His estate also held land in the parishes of Clonbullogue and Killardry, barony of Clanwilliam and Ballybacon, barony of Iffa and Offa West. In the 1870s his brother, George Staunton King Massy Dawson of Ballinacourty, owned 19,093 acres in county Tipperary.
Massy (Suir Castle) - Francis Hugh Massy of Suir Castle, county Tipperary, (born 1755) was the fourth son of the the 1st Baron Massy. His son, also named Francis Hugh, married Anne Bomford Molloy (c.1820s) and in the 1850s held land in the parishes of Magorban, barony of Middlethird, Killardry and Reclickmurry and Athassel, barony of Clanwilliam, county Tipperary. Lands belonging to Francis Massey of Suir Castle in the barony of Middlethird, county Tipperary and an undivided moiety of lands in the barony of Dunkellin, county Galway, were advertised for sale in May 1852. The estate of Francis Massy of Suir Castle amounted to 506 acres in the 1870s.


text:
Required Form
Duane Sorenson
Kelly Nordell
Trip Hedrick
Beyer Hall Pool
Register Online!
Cyclone Swimming Camps
Trip Hedrick, Former Iowa State Men's Swimming Coach
Former Iowa State Men's Coach, Trip Hedrick is back for his 19th year as a coach for the Cyclone Swim Camp. He has experienced success as a competitor, a high school coach, and as member of an NCAA Championship coaching staff with Texas in 1988.
In September of 1998, Hedrick was inducted into the Bemidji State Athletic Hall of Fame. While at Bemidji, he earned All-American honors nine times in three years.
In 1995 Hedrick led Cyclones to the Big 8 title and in the 1997-98 season his squad was a perfect 10-0. He earned Conference Coach-of-the-Year in 1995 and in 1998. He has coached 12 All Americans in his twelve seasons at ISU. His love for the sport goes beyond coaching, as he is still an active competitor in U.S. Master swimming. He is a 15 time national champion, holds the 50-and 100-yard butterfly records in his group, has set the world master records in the 100-meter freestyle and the100 meter butterfly races. While competing in the 1985 Masters World Championships in Tokyo, Japan, he was a member of the world record-setting 200-meter Medley Relay. In the 1994 Masters World Championships in Montreal, Quebec, Canada, he swam to four gold and two silver medals.
Iowa State University - Swimming powered by My Online Camp


text:
Tag: Homo nadeli
Homo naledi: an anti-climax
Published on May 10, 2017 by zooks7776 Comments
In September 2015 a barrage of publicity announced the remarkable unearthing of the remains of 15 diminutive hominins, dubbed Homo nadeli, from the floor sediments of an almost inaccessible South African cave, part of the equally hyped 'Cradle of Humankind' UNESCO World Heritage Site near Johannesburg. An international team of lithe women speleo-archaeologists was recruited for the excavation, for which the original discoverers were incapably burly. The remains included numerous examples of still articulated intricate bones, such as those of feet and hands, and none show signs of dismemberment by large scavengers. Indeed the discovery chamber was so far from the cave entrance that such animals probably were unaware of their presence. These features and the sheer complexity of the system strongly suggested that cadavers had been deliberately taken to the chamber; implying that the deep penetration had been accomplished using fire-brand illumination. What seized the headlines was the possibility of ritual burial, although sanitary disposal or panicked refuge from predators seem equally, if not more likely.
Lee Burger and the reconstructed skull of Homo naledi
Now yet more fossils have been reported from a separate chamber at a crawling distance about 150 m away from the original but closer to the system's main entrance (~85 m). These add at least other 3 individuals to the H. nadeli association, with sufficient similarity to indicate that all 18 belong to H. naledi. This wealth of detail enabled the team of authors (Hawks, J. and 37 others 2017. New fossil remains of Homo naledi from the Lesedi Chamber, South Africa. eLife, v. 6, online; http://dx.doi.org/10.7554/eLife.24232) to perform a detailed comparative anatomic analysis of the species. The results are a mosaic, showing some post-cranial affinities with australopithecines, H. habilis, H.floresiensis, H. erectus, Neanderthals and anatomically modern humans, and others, such as the hands and shoulders, that are not well matched with other hominins. Their crania show a similar broad spectrum of resemblances, and as regards dentition they are distinctly primitive. They are also on the small-brained side of the hominin clade. Despite the astonishing abundance of fossil material, not a single artifact was found in the cave system, despite the apparent similarity of its hands to those of ourselves and Neanderthals.
With plenty of scope for speculation, H. nadeli remains enigmatic. The big question looming over the 2015 announcement of the species was its age, the discovers suggesting about 2 Ma, and placing on the direct line of human descent. On the same day as the fossil description there appeared a multi-method dating analysis (Dirks, P.H.G.M. and 19 others 2017. eLife, v. 6, online; http://dx.doi.org/10.7554/eLife.24231.001), which showed that with little doubt that the H. nadeli association was deposited between 236 ka and 335 ka; around the time when anatomically modern humans first emerged and stone tools had undergone a >2 Ma technological evolution. To me, the only sensible conclusion at present is that H. nadeli is another addition to the 6 species living and in some cases coexisting across the late Pleistocene world, and that expansion of ideas beyond that must await DNA analysis; a definite possibility considering the age of the fossils, their seemingly good preservation in a relatively dry cave system and the new possibility of cave soils as well as bones yielding genetic materials. The leader of the research team, Lee Berger of the University of the Witwatersrand now maintains, together with four other members of the research team, that H. nadeli may be a coelacanth-like survivor of Homo's earliest diversification and that 'we cannot exclude that this lineage was responsible for the production of Acheulean or Middle Stone Age tool industries'.
Barras, C. 2017. Homo naledi is only 250,000 years old – here's why that matters. New Scientist, 6 May 2017 Issue
Sample, I. 2017. New haul of Homo naledi bones sheds surprising light on human evolution. The Guardian, 9 May 2017
The Hobbit: A Lineage More Ancient Than Once Thought?
Categories Anthropology and Geoarchaeology•Tags African hominins, Homo nadeli, Human evolution


At the end of a historic season in late December, reporters asked Coach Scott Meyer about next year. Can his football team repeat a perfect season?
The Sea Kings had just beaten Atherton Sacred Heart Prep, 27-15, in the CIF State Division III Bowl Game to become the first team in the state to produce a 16-0 season. Meyer, standing inside the tunnel at the StubHub Center in Carson, tried not to look ahead.
"We're not going to think about that for a little while," Meyer said back then, before going into the number of starters expected to return, 10 on defense and five on offense, and the challenging nonleague schedule next season.
Meyer lost one of those key players to one of the teams CdM will face in five months. Sophomore standout tailback Anthony Battista is transferring to Tesoro, said Meyer in a text on Friday.
When asked about his thoughts on Battista leaving CdM, Meyer did not respond via text. While he backed up star running back Cole Martin, a member of the CalHiSports.com All-State Medium Schools Third Team for juniors, Battista contributed to the Sea Kings' postseason run. Battista, in six playoff games, recorded almost half of his 1,052 yards and 10 touchdowns on the ground.
Battista, whose role was as a change-of-pace back, turned in his best performance in the CIF Southern Section Southern Division title game at Orange Coast College. He rushed 11 times for 163 yards and two touchdowns, allowing CdM to knock off Garden Grove, 42-21, and claim the section crown for an unprecedented third straight season.
For the season, Battista, a second-team All-Pacific Coast League performer, carried the ball 153 times and averaged 6.8 yards per carry. In the playoffs, he bumped up his yards-per-carry average to 7.9.
Meyer said Battista has checked out of CdM. Battista could not be reached for comment, but on his Twitter account, Battista posted goodbyes to a couple of friends at CdM. UCLA-bound senior Giovanni Gentosi, who as a center blocked for Battista last season, said Battista told him he's moving to the Rancho Santa Margarita area.
Next fall will be interesting, as Battista is set to face his former teammates when Tesoro plays host to CdM on Sept. 26. The Sea Kings will enter next season with 26 consecutive wins, the longest current winning streak in the state.
To keep the streak alive, the Sea Kings will have to do it without Battista, and hope he doesn't get in their way of another flawless season.


The Library of Congress > Chronicling America > Lewis County advocate.
245 00 $a Lewis County advocate.
260 $a Chehalis, Wash. : $b Advocate Print. Co.
362 1 $a Began in 1902.
362 0 $a -v. 45, no. 74 (July 28, 1938).
588 $a Description based on: Vol. 29, no. 31 (Mar 17, 1922).
651 0 $a Chehalis (Wash.) $v Newspapers.
752 $a United States $b Washington $c Lewis $d Chehalis.


text:
Site LOVE
Echo Battery
2nd Missile Battalion, 562nd Artillery
Updated 29 December, 2011
What is this all about?
E Battery, 2nd Battalion, 562nd Artillery was one of five Nike-Hercules missile firing batteries that were deployed to provide a defensive ring of supersonic fire around the Fairbanks/Eielson AFB complex during the height of the Cold War. This webpage is an attempt to preserve some memory of the place and time that is rapidly disappearing. If you stumbled across this webpage by means other than the link from the NIKE-HERCULES ALASKA INDEX page, you may wish to go there first for a little background information before proceeding. Please CLICK HERE to do so, then follow the link back to Site LOVE. Thank you.
In the mid 1950's, in response to a growing Soviet bomber threat, northern Alaska was programmed to receive two Nike Hercules battalions consisting of eight firing batteries. One battalion, comprised of four firing batteries, would defend Eielson Air Force base and the other, also with four firing batteries would defend Ladd Air Force base in Fairbanks. The four Eielson batteries (Sites Jig, Tare, Mike, and Peter) were constructed and subsequently activated on 16 October, 1957.
Earlier that year the batteries planned for Ladd AFB were cancelled but recognizing that the Fort Wainwright/Eielson AFB defense had been planned as an integrated defense, the decision was made to proceed with building one of the Ladd AFB batteries. Consequently, Site Love was approved and constructed, and became operational on 15 December, 1960.
Like the other Alaskan Nike sites, LOVE's radars had improved electronic countermeasure capabilities and could sort through heavy radar jamming transmitted by Soviet bombers. The missiles were housed in above ground steel reinforced concrete bunkers (magazines). The use of deadly force was authorized to protect the missiles and warheads which were guarded by military police and large guard dogs.
Site LOVE was home to more than 100 officers and enlisted personnel who served for 18 months and then rotated to another Army assignment, many to Viet Nam service. Civilian contractors lived on site and performed non-military functions, such as plumbing, communications, road and other maintenance functions.
Many Site LOVE troops will remember Barney, the civilian contractor and authentic Alaskan sourdough, who kept the roads cleared of snow and operated the heavy equipment. Barney spent many hours spinning his yarns about living and working in Alaska and his days as a gold miner in Fox.
Located roughly 10 miles northwest of Fairbanks, Alaska, Site LOVE was the northernmost of all of the Alaskan Nike Hercules missile batteries. It was the only site situated north of the Chena River and was far removed from the four batteries surrounding Eielson AFB. The site was accessed from Murphy Dome Road, the road which eventually led to the Murphy Dome NORAD Control Center and AADCP for the Fairbanks defense.
To reach the access road, one headed northeast out of Fairbanks on the Steese Highway, turned left at Fox, which was a major gold dredging area, and headed north on the Elliot Highway to Murphy Dome Road.
Charged with directing the air defense battle in northern Alaska was the NORAD Control Center and AADCP at Murphy Dome, which was located 8 miles west of Site Love and 25 miles northwest of Fairbanks. Staffed with more than 200 Air Force and Army personnel, the mission of Murphy Dome was to direct the five Nike firing batteries and Air Force fighter interceptors in the defense of the Fairbanks/Fort Wainwright/Eielson AFB complex.
A US Army lieutenant assigned to the AADCP at Murphy Dome, remembers that the Soviets frequently probed the Alaskan air defenses by flying up and down off the Alaskan coast to see what the air defense response would be. The "hot status" battery would be called up to the highest state of alert and fighter interceptors would scramble to intercept the intruders. When the Soviets would head home the fighters would return, often tracked by the hot battery in case the returning fighters (that may be low on fuel) needed rescue assistance.
Conditions at Murphy Dome were especially harsh, even for Alaska. The Murphy Dome lieutenant states:"We were totally snowed in at Murphy Dome from late November through late March. In the heart of the winter, the tunnels connecting the BOQ and other parts of Murphy Dome were coated by 3 inches of ice. We had to call in our lounge food and beverage order to Fort Wainwright, which brought it in by chopper once a month. Mail was brought in by chopper twice a week. The road to Fairbanks was closed by snow for the same period, but we survived and thrived at Murphy Dome."(officially a hardship tour, but one has to wonder).
Site LOVE and the other Fairbanks batteries participated in the "hot", "one hour"and "released for maintenance" weekly readiness status rotation in effect for the Fairbanks defense. Five batteries made this readiness rotation somewhat easier, but there were times when only one or two batteries would be available due to maintenance issues. "Hot"status required being on site 24/7 and performing hourly equipment checks, including live tracking of an incoming aircraft if one was flying. The thrice weekly Pan Am flight arriving at Fairbanks at 2 AM was a convenient live target as were the U-2 spy planes which were leaving for or returning from missions over the Soviet Union (never confirmed by the Air Force, but widely known to Site LOVE personnel).
"Hot" status also meant that an Operations Readiness Evaluation (ORE) could be conducted by headquarters with little or no notice. Site LOVE had friendly lookouts; usually civilians who lived in Fox who would warn the battery that inspectors were on the way. Upon arrival, the inspectors found the equipment primed and ready to go and the crew mysteriously close to their duty stations.
Site LOVE was especially proficient at achieving high scores on the ORE's which were a testament to the training and quality of the enlisted and officer personnel stationed there. This quality of personnel was also demonstrated at the live firings of missiles at annual service practice evaluations (SNAP) conducted at Site PETER (B battery east of Eielson Air Force base).
A Site Love Battery Control Officer remembers having the honor of firing missiles in the winter of 1967 in both surface-to-air and surface-to-surface missions at B battery SNAP. The photo of a live firing at the top of this webpage was the surface-to-air bird that found its target, landing ten feet away from the designated point 80 miles down range.
Not every minute was spent at hot status or doing the daily chores required by the US Army. The troops assigned to Site LOVE were also busy with off-site activities which included trips to Fairbanks to soak up the local culture as well as hunting, fishing and gold mining in the local area. Wildlife was plentiful, with local streams full of arctic grayling and the surrounding hills home to moose, black bears and herds of caribou.
The aforementioned Battery Control Officer (who served as the Integrated Fire Control platoon leader and Executive Officer from 1966 to 1968) tells of arriving at the battery to begin a week of activity only to find the remains of a gutted caribou on the floor of his office which had been bagged by the battery troops over the weekend.
The village of Fox, located at the intersection of the Steese and Elliot Highways, was a local gold mining area where dredges carved up acres of ground extracting gold. The dredges only retrieved the large gold nuggets, leaving gold dust and small nuggets to be retrieved by sluicing or panning. In recent years, mining claims have been placed there. An inquiry made by one of these claimants resulted in this response from one veteran of the site:
"I was at site LOVE in the 1960's. My last post before I got discharged. But while I was there I watched the mess sergeant take his pickup and 5 mess hall barrels and go down to the gold dredge at fox. At the mounds that were left behind the dredge he would fill the mess hall barrels and bring them back to behind the mess hall where he had built a sluice. Then he would put in a couple of shovels full, put the mess hall hose at the top, and turn on the water at a slow speed to flush the dirt down the sluice and go in and drink a cup of coffee. Then he'd go back out and take the gold out and repeat the process over and over. When I left the site he told me he already had about $50,000 in gold and in the 1960's that's a lot of money.
"But what I wanted to tell who ever is looking to find gold there, is that when he was done sluicing he would take the rest of the dirt (and some of it still had gold in it) and he threw it around the site because he said the sluice would never catch it all. So good luck to whoever wants to try to find gold on that rock of a hill".
In the face of budgetary constraints imposed by the protracted Vietnam war, the changing Soviet threat, and therefore changes in the defensive requirements of NORAD, units of the 2nd Missile Battallion, 562nd Artillery were being deactivated in 1970 and 1971. Site LOVE was closed in June of 1971. It is understood that the equipment, missiles and warheads were shipped to storage in the lower 48. Non-essential equipment, such as chairs, tables, desks, and other items were buried at the site in a large hole bull dozed open by Barney, the road grader operator.
The Nike sites in the Anchorage area continued operations until 1979, but since that time no Nike-Hercules missile men have walked the halls of these decaying facilites.
Site LOVE Today
In the intervening years the buildings in the launcher area and the IFC area were cleared of asbestos and other hazardous materials and bulldozed into oblivion. The area was leveled and seeded, leaving no trace of the site's ten year military history.
Although nothing physical remains of Site LOVE today, Echo Battery, along with the other batteries of the 2/562 accomplished their mission. The Soviet bomber threat was blunted and Fort Wainwright and Eielson AFB were kept safe and ready to perform their missions.
The bulk of the above article was graciously provided by Romeo Whiskey Romeo, 17 November 2011.
- Juliet Tango Sierra,
CLICK HERE to return to the NIKE ALASKA INDEX page.


Home » News » Fit-for-purpose evaluation – if I knew then what I know now!
Fit-for-purpose evaluation – if I knew then what I know now!
Since joining the team at ESS over a year ago, I have been able to reflect on my experience of self-evaluation in previous jobs and realise how much easier life would have been if I'd known then what I know now!
In a past role I helped to coordinate a children's befriending service, delivered by volunteers. I often wondered why it was so difficult to get volunteers to submit their feedback forms after each befriending outing, and why the forms I did receive never seemed to provide me with the information I was looking for. Yes, it was always nice to read that the child had enjoyed the outing, but could I really claim that their satisfaction with a trip to the zoo meant that the outcome of 'improved communication skills' had been achieved, for example? Probably not.
I realise now that the reason for not getting strong outcome evidence was twofold.
Firstly, the questions asked on the feedback form were not the right ones, because they didn't measure relevant outcome indicators (see our Support Guides on outcomes and indicators for a refresher on these important first steps in self-evaluation). In order to know if the child's communication skills had been improved, for example, it would have made more sense to look for indicators like their ability to start a conversation with their befriender, their willingness to order their own lunch in the café, the appropriateness of the questions they asked the zoo staff, and so on.
The second issue was that the method of evidence collection itself wasn't fit-for-purpose. Some volunteer befrienders said that it didn't feel right to bring out a feedback form and ask their befriendee to complete it with them at the end of an otherwise informal and relaxed outing. They were, rightfully, reluctant to spoil the rapport they'd worked hard to build up with their respective befriendees, many of whom already had several form-wielding professionals in their lives and found sanctuary in the befriending service because it allowed them some time out to simply be children in a relaxed and fun environment. Instead of a feedback form that they were expected to complete with the child at the end of the outing, something like simple observation or capturing casual moments might have been a more appropriate way to ask volunteers to collect outcome evidence (see our Support Guide on how to choose or design suitable evaluation methods here).
So, if you find yourself struggling to collect the evidence you need, it's worth asking yourself not only if you are asking the right questions but also if the methods you're using to ask them are as fit-for-purpose and easy for people to engage with as they could be.
For support with thinking about your project's outcomes, indicators and methods, sign up to our Getting Started and Make to Measure workshops here. We can also visit you at your place of work to facilitate 1:1 tailored support.


If you are looking for affordable and quality carpet cleaning services then look no further then Chem-Dry of Charleston. We don't use galleons of waters and harsh soaps and chemicals like the competitors. We use Hot Carbonation that blasts dirt from the fibers with millions of tiny bubbles where they are lifted to the surface to be swept away. Due to this innovative process your carpets will dry in just 1-2 hours instead of days. Not only does this let your get back to life quicker, but our products are green certified meaning they are non-toxic and hypoallergenic. Professional Carpet Cleaning At Is Best. Hot Carbonated Cleaning Method. We provide superior carpet and upholstery cleaning, tile and natural stone cleaning & sealing, oriental & area rug cleaning, drapery cleaning, Pet Urine removal, and Water Damage Restoration. Specializing in Residential and Commercial Properties, Condominiums, Boats and RV's.
Do you own Chem-Dry of Charleston?
Due to the unique way that the eBusinessPages Business Directory is structured a Premium + Verified Listing is the most powerful way to get more clients to contact Chem-Dry of Charleston. Not only will your listing be more noticeable and more trustworthy, it will also be displayed more prominently in our category (Carpet and Upholstery Cleaning and Parent Categories) and location (Goose Creek, SC and USA Wide) listings. Chem-Dry of Charleston will be displayed in your competitor's listings while no ads will be shown in your own listing.
Starting at $2.78 for a Premium Verified Listing, there is every reason to give Chem-Dry of Charleston the eBusinessPages Premium treatment today.


text:
Publisher Whitaker House KJV Sword Study bible is NOT a true KJV
By jdosher,
May 27, 2018 in The Bible (KJV)
Location: ukrain
5 hours ago, Ukulelemike said:
I don't understand it, because doctrinally and theologically, it is complete gibberish. It is like those who say that each day of creation is a thousand years, because in 2Peter 3:8 says that with the Lord a thousand years is as a day, and a day as a thousand years-the two have nothing to do with each other, as one is history, and the other speaks of prophecy. Though at least there, there is somewhat of a reason people mistake them, since both have to do with God and how He understands time, while yours have nothing whatsoever to do with each other.
I am just curious of where you get it, because I'd be interested to see if there is any kind of logical joining of these completely disparate things by whoever interpreted it as such.
Maybe you do not understand this, because you believe in the human sciences exegetics and hermeneutics?
Jordan Kurecki 7 posts
Konstantin 24 posts
Tyndale 8 posts
DaChaser 8 posts
No, I don't understand it because it is gibberish and makes no sense. I believe the Bible and what it says. I understand types and pictures, even allegory, but this is none of those, you have simply p
Jordan Kurecki
While there are clearly some differences that change meaning, shew and show are the same exact word, just different spellings, Shew is British spelling and show is American, also needs and needeth are
So, "he" is archaic, and a non-issue, and must be modernized in order to make the KJV readable? "Amen" is archaic, and is a non-issue, and must be modernized in order to make the KJV readable? "Twain"
10 hours ago, Konstantin said:
Hi, a King James guy. Here we are considering the prophetic meaning of verses, i.e. "a more sure word of prophecie" (2Peter 1:19), not literal ones, i.e. "not as the word of men" 1Thess. 2:13
Charles Ryrie in his Systematic Theology has an excellent section in Bibliology about Interpretation of the Bible.
Of course he mentions the different systems such as the Allegorical, Literal and Semi Allegorical. He of course advocates for the Literal Hermaneutic, he gives a few reasons:
1. The Need for Objectivity "If one does not apply normal interpretation, then objectivity is lost to the extent that he does not use it consistently. Switching the hermeneutic base from literal to allegorical or to semi allegorical… inevitably results in different, inconsistent, and often contradictory interpretations."
2. The example of the Bible. "The prophecies of the first advent of Christ were all fulfilled literally. This obvious but extremely significant fact argues for the validity and the use of literal hermeneutics in all of biblical interpretation... It is said that over 300 such prophecies concerning the first coming of Christ were literally fulfilled…"
Ryrie does go on to acknowledge that "some prophecies of the Old Testament are given a typical fulfillment in the New, and certain of those prophecies are cited by non literalists as biblical sanction for a nonliteral hermeneutic… However, of the approximately twenty four prophecies which the New Testament gives typical fulfillment, only seven are cited as examples of nonliteral hermeneutic (and of course not all agree that these seven prove this)…remember, however, that we are not just comparing seven out of a total of twenty four, but seven out of a total of hundreds, for almost all Old Testament prophecies are clearly fulfilled literally in the New Testament.."
Now, I think most relevant discussion however for us is what Ryrie says later in his section on Objections to Normal Hermeneutics:
"The most frequent objection by Evangelicals to normal interpretation points out that since the New Testament uses the Old Testament in a non literal sense we also may interpret Old Testament Prophecies (about the millennium for example) in a non literal sense. Or to put it more simply: since the New Testament spiritualizes the Old Testament, so can we… The rule is that they [New Testament Authors] interpreted the Old Testament plainly, exceptions are rare and typological"
Now, the point Ryrie makes next I think is spot on:
"The crux of the matter is this: can we as interpreters follow the example of the biblical writers in these rare exceptional uses of the Old Testament that seem to be non literal? Of course the answer is yes, if we want to. But if we do, we do so without apostolic authority, only with personal authority, and comparatively, that is not much authority. Any and all uses of the Old Testament that the New Testament writers made were made under divine inspiration and were therefore done properly and authoritatively. If we depart from the plain sense of the text we do so improperly without such authority. What the biblical writers wrote was infallible; the work of all interpreters is fallible."
12 minutes ago, Jordan Kurecki said:
Mr. Charles Ryrie draws in his conclusions according to the sciences invented by people exegetics and hermeneutics. Therefore, his conclusions cannot correspond to the word of God.
Sorry but no, He draws his conclusions from how the scriptures themselves interpret them and according to logic.
Your method of interpretation of scripture is arbitrary and you do as the Gods word says "wrest the scriptures".
The method of handling the scriptures you have have shown here in this thread is one in which you abuse the use of language and you make authoritative statements that the Bible itself does not make. You make numbers like 60 to somehow mean 66, and you substitute words and phrases at your own discretion and pleasure. In a sense you have set yourself up as the authority when God has not given you the authority to do so. You are no prophet and have NO authority to claim that when God said 60 he somehow meant 66.
It would seem that you are the one drawing in conclusions according to your own interpretation that was invented by yourself, and frankly sir you have no authority over the word of God. in fact sir, your handling of God's word is more akin to that of Satan in which he says "hath God said". You twist God's words like Satan did in the garden of Eden. God clearly told them not to eat of the tree of knowledge of good in evil, and he said so in plain language. When God said tree, he meant tree, when he said not to eat of it, he meant not to eat of it.
"Humility before the truth of Scripture, and before the authority of Christ, demands submission to logical consistency. If you abuse logic, what are you expecting your people to base their agreement on? You can't answer, "Scripture," unless you are committed to logically consistent explanations that your conclusions actually come from Scripture. Scripture will only have authority in your preaching if your appeal to Scripture can be seen to be a valid appeal. If you draw invalid inferences from Scripture, it won't matter how loud you protest your belief in biblical inerrancy; you will not be helping your people base their lives on Scripture. You will be expecting them to base their lives on your faulty inferences from Scripture. That is not humble. It is proud. And it jeopardizes the authority of Christ, who speaks through true, and valid inferences from Scripture" -Expository Exhultation John Piper
Edited June 4, 2020 by Jordan Kurecki
...You make numbers like 60 to somehow mean 66, and you substitute words and phrases at your own discretion and pleasure. In a sense you have set yourself up as the authority when God has not given you the authority to do so. You are no prophet and have NO authority to claim that when God said 60 he somehow meant 66...
You probably do not read carefully. Scripture says: the height thereof threescore cubits, and the breadth thereof threescore cubits'.
1 hour ago, Konstantin said:
The height is 60 and the width is 60.
Apparently you can neither read nor do you know numbers. Do you know how to count?
How do you get 66 from 60 and 60?
60+60=120
60+60 does not equal 66.
DaChaser
Location: Macomb
Should we not have units and measures updated to let us know what they are in today's vernacular?
16 hours ago, Jordan Kurecki said:
the height thereof threescore cubits, and the breadth thereof threescore cubits
Yes, I know how to count.
If you consider this verse "as the word of men" 1Thess. 2:13, then 60 + 60 = 120. If we consider this place as "a more sure word of prophecie" (2Peter 1:19) then 66.
4 hours ago, Konstantin said:
Proverbs 30:5-6 KJV
[5] Every word of God is pure: he is a shield unto them that put their trust in him. [6] Add thou not unto his words, lest he reprove thee, and thou be found a liar.
[2] Ye shall not add unto the word which I command you, neither shall ye diminish ought from it, that ye may keep the commandments of the Lord your God which I command you.
2 Peter 3:16 KJV
[16] As also in all his epistles, speaking in them of these things; in which are some things hard to be understood, which they that are unlearned and unstable wrest, as they do also the other scriptures, unto their own destruction.
Thanks. I have a Bible.
Well so do many other false teachers.
1 hour ago, Jordan Kurecki said:
Are you a false teacher?
On 6/3/2020 at 8:15 PM, Konstantin said:
No, I don't understand it because it is gibberish and makes no sense. I believe the Bible and what it says. I understand types and pictures, even allegory, but this is none of those, you have simply pulled together a bunch of things from scripture and wrested them into your own idea of what they mean. It is vain babblings with no profit to them, and t is time to put it to bed.
I am closing this thread, as it has become vain and worthless.
Jim_Alaska, Rebecca, Alan and 1 other