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Abnormal expression of homeobox genes and transthyretin in C9ORF72 expansion carriers
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Objective: We performed a genome-wide brain expression study to reveal the underpinnings of diseases linked to a repeat expansion in chromosome 9 open reading frame 72 (C9ORF72).
Methods: The genome-wide expression profile was investigated in brain tissue obtained from C9ORF72 expansion carriers (n = 32), patients without this expansion (n = 30), and controls (n = 20). Using quantitative real-time PCR, findings were confirmed in our entire pathologic cohort of expansion carriers (n = 56) as well as nonexpansion carriers (n = 31) and controls (n = 20).
Results: Our findings were most profound in the cerebellum, where we identified 40 differentially expressed genes, when comparing expansion carriers to patients without this expansion, including 22 genes that have a homeobox (e.g., HOX genes) and/or are located within the HOX gene cluster (top hit: homeobox A5 [HOXA5]). In addition to the upregulation of multiple homeobox genes that play a vital role in neuronal development, we noticed an upregulation of transthyretin (TTR), an extracellular protein that is thought to be involved in neuroprotection. Pathway analysis aligned with these findings and revealed enrichment for gene ontology processes involved in (anatomic) development (e.g., organ morphogenesis). Additional analyses uncovered that HOXA5 and TTR levels are associated with C9ORF72 variant 2 levels as well as with intron-containing transcript levels, and thus, disease-related changes in those transcripts may have triggered the upregulation of HOXA5 and TTR.
Conclusions: In conclusion, our identification of genes involved in developmental processes and neuroprotection sheds light on potential compensatory mechanisms influencing the occurrence, presentation, and/or progression of C9ORF72-related diseases.
- amyotrophic lateral sclerosis;
- frontotemporal dementia;
- frontotemporal lobar degeneration;
- interquartile range;
- motor neuron disease
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of a disease continuum. Although ALS is the most common form of motor neuron disease (MND) and results in progressive muscle weakness, FTD is a frequent cause of dementia and is associated with changes in personality, behavior, and language. A hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) is a major genetic cause of both diseases.1,2 Emerging evidence suggests that C9ORF72-related diseases are characterized by a loss of C9ORF72 expression,1 the formation of RNA foci with flawed RNA transcripts,1 and the generation of dipeptide repeat proteins aberrantly translated from the repeat expansion,3,4 with both RNA foci and dipeptide repeat proteins potentially contributing to disease by compromising nucleocytoplasmic transport.5,–,7
In our quest to increase our understanding of C9ORF72-related diseases, we assessed the genome-wide expression profile in brain tissue obtained from the Mayo Clinic Florida Brain Bank (n = 82). Of interest, in C9ORF72 expansion carriers, we discovered an upregulation of genes involved in developmental processes and neuroprotection, particularly in the cerebellum, a region without substantial neuronal loss that demonstrates pathologic hallmarks of C9ORF72-related diseases,3,8 and in which abnormalities associate with neuropathologic and clinical phenotypes.9,10 Such findings may point toward mechanisms that could compensate for the harmful effects of C9ORF72 repeat expansions.
Participant selection.
From the Mayo Clinic Florida Brain Bank, participants were selected for our genome-wide expression study: patients with a pathologic diagnosis of frontotemporal lobar degeneration (FTLD) and/or MND who harbored C9ORF72 repeat expansions (n = 32), patients with FTLD and/or MND without repeat expansions (n = 30), and controls without neurologic diseases (n = 20, table 1). To confirm the observed upregulation of homeobox A5 (HOXA5) and transthyretin (TTR), quantitative real-time PCR was performed, when expanding investigations to our entire pathologic cohort of C9ORF72 expansion carriers for whom brain tissue was available (n = 56) as well as FTLD and/or MND patients without an expansion (n = 31) and controls without any neurologic disease (n = 20).11 In this cohort, C9ORF72 transcript levels, the length of the repeat expansion, and dipeptide repeat protein levels had already been determined.10,–,12 To examine the cerebellar TTR protein, Western blots (n = 10) and immunohistochemistry (n = 13) were performed on a representative subset of samples (table e-1 at Neurology.org/ng). Next, an immunoassay was used to evaluate TTR protein levels in the CSF, studying 2 independent clinical cohorts obtained at either the Mayo Clinic (n = 67) or the University of Miami (n = 40, table e-1).
Standard protocol approvals, registrations, and patient consents.
All participants agreed to participate in the study, and biological samples were obtained after informed consent with ethical committee approval from the respective institutions.
Methods and statistical analysis.
To examine the genome-wide expression pattern, Whole-Genome DASL HT assays (Illumina, San Diego, CA) were used, which were processed by the Mayo Clinic Core Facility. Validation was performed with quantitative real-time PCR using TaqMan gene expression assays (Life Technologies, Carlsbad, CA). Western blotting was used to evaluate cerebellar TTR protein levels, complemented with immunohistochemistry to assess the presence of potential TTR protein aggregates. Meso Scale Discovery (MSD, Rockville, MD) electrochemiluminescence detection technology was used to establish a sandwich immunoassay for TTR. Cell culture experiments were then performed in an attempt to clarify underlying mechanisms. In U251 and HepG2 cells, a loss of C9ORF72 expression was mimicked with small interfering RNAs (siRNAs, Dharmacon, Lafayette, CO), and in addition, the effect of full-length C9ORF72 and the repeat expansion itself was examined by transfecting cells with expression vectors.13 A detailed description of our methods and statistical analysis is provided in the supplemental data.
Upregulation of homeobox genes and TTR in C9ORF72 expansion carriers.
We performed a genome-wide expression study in the cerebellum and frontal cortex to identify genes involved in C9ORF72-related diseases. First, we compared patients with or without a repeat expansion in C9ORF72. Although participants included in those groups are both affected by neurodegenerative diseases, this enabled us to find C9ORF72-specific differences. Second, we compared expansion carriers with controls without neurodegenerative diseases, allowing the detection of more general differences that could, theoretically, be due to the presence of a neurodegenerative disease.
In the cerebellum, when comparing expansion carriers to patients without expansions, we detected 40 differentially expressed genes (table e-2). Generation of a heat map of those genes revealed that expansion carriers generally cluster together (figure 1). Of interest, our list of differentially expressed genes contained 22 genes that have a homeobox (e.g., HOX genes) and/or are located within the HOX gene cluster (table e-2). In addition to the upregulation of multiple homeobox genes (top hit: HOXA5) that play a vital role in neuronal development,14 we noticed a cerebellar upregulation of TTR (table e-2), an extracellular protein that is thought to be involved in neuroprotection.15,–,19 We then compared expansion carriers with controls and discovered 1,575 differentially expressed genes in the cerebellum (table e-2). Again, our heat map showed that expansion carriers tend to cluster together (figure 1). Of interest, our new list contained 37 of the 40 (93%) genes we identified previously (table e-2), including homeobox genes and TTR.
We also performed gene ontology analysis and observed an enrichment for pathways involved in the regulation of (anatomic) development, which was most profound when comparing expansion carriers with disease controls (e.g., organ morphogenesis, pattern specification process, regionalization, and skeletal system development, table e-3), but which was also seen when comparing expansion carriers with controls (table e-3).
In the frontal cortex, a comparison between patients with or without repeat expansions resulted in the detection of 3 differentially expressed genes: HOXA5, C9ORF72, and POU class 4 homeobox 2 (POU4F2; table e-2). We also compared expansion carriers with controls and revealed 679 differentially expressed genes, including C9ORF72 and TTR (table e-2). Again, enrichment was observed for pathways involved in developmental processes (table e-3).
Associations of C9ORF72 transcripts with HOXA5 and TTR transcripts in our overall cohort.
In previously published studies, we investigated the levels of known C9ORF72 transcript variants (variant 1 [NM_145005.6], variant 2 [NM_018325.4], and variant 3 [NM_001256054.2]) as well as 2 intronic regions (1 upstream of the repeat expansion [intron 1a] and 1 downstream of the repeat expansion [intron 1b]).11 In this study, we examined the same cohort to validate our findings related to HOXA5 and TTR, which demonstrated that their cerebellar levels are indeed higher in C9ORF72 expansion carriers than in (disease) controls (table 2, figure 1). In addition, in the frontal cortex, we showed that TTR levels are elevated in patients with a C9ORF72 repeat expansion as compared to controls (table 2). Of note, we also performed a sensitivity analysis to assess whether our findings could have been biased by differences in age at death. It is important that similar findings were observed when restricting our analysis to a subset of participants with a comparable age at death (not shown). In addition, given the low levels of TTR and HOXA5, especially in (disease) controls, we also validated their upregulation in a subset of participants using other techniques, including digital molecular barcoding (not shown) and previously published RNA sequencing data (figure e-1).20
The vast amount of C9ORF72 expression data available for this cohort then allowed us to determine whether the levels of C9ORF72 transcripts were associated with the levels of HOXA5 and TTR. In our overall cohort (expansion carriers, disease controls, and controls), lower cerebellar levels of C9ORF72 transcript variant 2 were associated with higher cerebellar levels of both HOXA5 (r = −0.60, p = 3.21e-09, Spearman test of correlation) and TTR (r = −0.47, p = 2.21e-06, Spearman test of correlation, table 3), which is not surprising given the fact that expansion carriers demonstrate decreased levels of C9ORF72 transcript variant 2.11 More excitingly, we noticed that higher cerebellar levels of intron-containing transcripts (both intron 1a and intron 1b) are associated with higher cerebellar levels of HOXA5 transcripts (intron 1a: r = 0.43, p = 6.47e-05, intron 1b: r = 0.36, p = 0.0008, Spearman test of correlation, table 3). In the frontal cortex, lower C9ORF72 variant 2 levels were also associated with higher TTR levels (r = −0.28, p = 0.006, Spearman test of correlation, table 3).
Associations of C9ORF72 transcripts with HOXA5 and TTR transcripts in expansion carriers.
Because we were able to validate our findings related to HOXA5 and TTR and detect significant associations with specific C9ORF72 transcripts in our overall cohort, we then evaluated the presence of any potential associations within our cohort of C9ORF72 expansion carriers. In the cerebellum, increased levels of total C9ORF72 transcripts were associated with increased HOXA5 transcripts (r = 0.51, p = 8.86e-05, Spearman test of correlation, table 4), most prominently in patients with a pathologic diagnosis of FTLD (r = 0.65, p = 0.0009, Spearman test of correlation). Of interest, we also noticed that elevated levels of intron-containing transcripts were associated with elevated levels of HOXA5 or TTR (table 4). For HOXA5, this association (intron 1a: r = 0.60, p = 1.61e-06, intron 1b: r = 0.54, p = 2.75e-05, Spearman test of correlation, table 4) was driven by patients with a pathologic diagnosis of FTLD (intron 1a: r = 0.72, p = 0.0001, intron 1b: r = 0.59, p = 0.003, Spearman test of correlation). For TTR, however, the association (intron 1a: r = 0.40, p = 0.003, intron 1b: r = 0.43, p = 0.001, Spearman test of correlation, table 4) was most profound in patients with a pathologic diagnosis of MND (intron 1a: r = 0.83, p = 0.0002, intron 1b: r = 0.88, p = 3.78e-05, Spearman test of correlation).
Because we previously discovered associations between dipeptide repeat proteins and intron-containing transcripts,11 we subsequently evaluated potential associations with poly(GP) and poly(GA) proteins, which can form abundant inclusions in the neocortical regions, hippocampus, thalamus, and cerebellum.3,4,9,21,–,24 Although no significant associations were detected for TTR, we did observe an association for HOXA5: higher levels of dipeptide repeat proteins were associated with higher levels of HOXA5 (poly[GP]: r = 0.52, p = 0.0002, poly[GA]: r = 0.56, p = 3.89e-05, Spearman test of correlation, table 4).
In the frontal cortex, we noted a trend between C9ORF72 variant 2 and TTR (r = −0.39, p = 0.004, Spearman test of correlation), particularly in the subset of patients with a pathologic diagnosis of FTLD (r = −0.62, p = 0.002, Spearman test of correlation, table 4).
In both brain regions, we did not detect significant associations with other variables, such as expansion size (table 4), disease subgroup, sex, age at onset, age at death, or survival after onset (not shown).
Cerebellar changes in TTR transcripts are reflected by changes in protein levels.
Given the fact that TTR is an extracellular protein, we determined whether changes in RNA levels were reflected by changes in protein levels, which could indicate that TTR may serve as a biomarker for C9ORF72-related diseases. Because our findings were most profound in the cerebellum, we extracted protein from this neuroanatomic region and performed Western blots. As expected, we detected a significant increase in cerebellar TTR protein levels in patients with a repeat expansion (mean 174% ± 34%) as compared to patients without a repeat expansion (mean 100% ± 18%, p < 0.05, 2-sample t test, figure 1). We also performed immunohistochemistry to examine whether an aggregated form of the TTR protein was present in the cerebellum because TTR protein aggregates have been reported in other diseases, such as familial amyloid polyneuropathy.25 We observed diffuse cytoplasmic TTR staining in pyramidal neurons and Purkinje cells, and in the neuropil; however, no TTR deposits were detected similar to those seen in patients with TTR amyloidosis (not shown).
To further evaluate TTR as a potential biomarker, we determined its protein levels in the CSF. In our first cohort, the median TTR protein level in expansion carriers was 15.5 μg/mL (interquartile range [IQR] 13.7–17.6) and in the remaining participants 16.3 μg/mL (IQR 14.5–17.7), which was not significantly different (p = 0.29, Wilcoxon rank-sum test). Our second cohort revealed a median TTR protein level of 12.5 μg/mL in expansion carriers (IQR 11.0–12.6) and 12.3 μg/mL in other participants (IQR 11.8–14.4); again, this difference did not reach statistical significance (p = 0.58, Wilcoxon rank-sum test). Of note, similar findings were obtained when adjusting for possible confounders, when removing outliers, and when restricting our analysis to specific (sub)groups (e.g., symptomatic participants).
Loss of C9ORF72 expression increases HOXA5 and TTR transcripts.
Next, we performed cell culture experiments to determine which C9ORF72-related disease characteristics might drive the specific upregulation of HOXA5 and TTR. Of interest, we observed an increase of HOXA5 in response to a knock-down of total C9ORF72 transcripts (mean 193% ± 3%, p = 0.0002, 2-sample t test). A comparable effect was seen on TTR (mean 129% ± 6%, p = 0.01, 2-sample t test) after knocking down total C9ORF72 transcripts. Given our significant findings related to C9ORF72 transcript variant 2, we then targeted variant 2. It is important that knocking down of variant 2 was sufficient to increase HOXA5 levels (mean 274% ± 12%, p = 0.005, 2-sample t test). For TTR, targeting C9ORF72 variant 2 also affected TTR levels (mean 293% ± 37%, p = 0.03, 2-sample t test). Overexpression of full-length C9ORF72 or expression of 66 GGGGCC repeats, however, did not seem to affect HOXA5 or TTR (not shown). Consequently, it seems that a loss of C9ORF72 expression triggers an increase in HOXA5 and TTR.
We set out to increase our understanding of C9ORF72-related diseases and revealed elevated levels of multiple homeobox genes (e.g., HOXA5) and TTR. Of interest, our findings were most profound in the cerebellum, a region without substantial neuronal loss that demonstrates pathologic characteristics of diseases linked to a repeat expansion in C9ORF72.3,8 In fact, in this neuroanatomic region, associations with neuropathologic and clinical features of the disease have already been reported. It has been shown, for instance, that dipeptide repeat protein levels are lower in pathologically diagnosed patients with MND as compared to patients with FTLD,9,10 and that they are associated with the cognitive score of clinically diagnosed patients with ALS.10 Moreover, an association between dipeptide repeat proteins and intron-containing transcripts has been described in the cerebellum, indicating that transcripts containing the entire first intron may serve as templates for repeat-associated non-ATG translation.11 In addition, extensive alternative splicing and polyadenylation defects have been reported in the cerebellum of C9ORF72 expansion carriers.20 The fact that our findings were most prominent in the cerebellum emphasizes that this region may have been underappreciated and could play an important role in C9ORF72-related diseases.
The upregulation of multiple homeobox genes and TTR was further substantiated by the results of our gene ontology analysis that revealed enrichment for developmental processes. The observed enrichment for developmental processes is not surprising given the function of homeobox genes and TTR in neuronal development and neuroprotection.14,–,19 Homeobox genes, for example, are involved in neuronal specification and target connectivity; they play a key role in the identity, organization, and peripheral connectivity of motor neuron subtypes.14 TTR is important for the transportation of thyroid hormones (thyroxine [T4]) and retinol (vitamin A), and in addition, it is thought to participate in behavior, maintenance of normal cognitive processes during aging, neuropeptide processing, and nerve regeneration.26 Of interest, homeobox genes and TTR are linked. For instance, an active metabolite of vitamin A (all-trans retinoic acid) functions in maintenance of many processes (e.g., brain function) and is essential for limb and organ development through homeobox gene–mediated mechanisms.27
Although the relative differences we observed in HOXA5 and TTR are a reflection of small absolute differences, the fact that their levels are barely detectable in (disease) controls raises the possibility that their expression may have been (re)activated in the adult brain. Such a (re)activation could be specific to C9ORF72-related diseases and might be driven by certain mechanisms underlying those diseases. It is currently unknown where the elevated HOXA5 and TTR levels are coming from; a change in cell-type composition, invading progenitor cells, and cell-autonomous effects need to be taken into consideration.
One of the pathologic hallmarks of C9ORF72-related diseases is a reduction in C9ORF72 expression levels.1 Because the most prominent decrease has been reported for C9ORF72 variant 2 transcripts,11 one could speculate that levels of this transcript might be associated with levels of HOXA5 or TTR. Indeed, in our overall cohort, we demonstrated that lower levels of C9ORF72 variant 2 transcripts were associated with higher levels of HOXA5 and TTR transcripts. We also detected associations with intron-containing transcripts; in our expansion carriers, for instance, higher levels of intron-containing transcripts were associated with HOXA5 transcript levels, especially in patients with a pathologic diagnosis of FTLD. In addition, HOXA5 transcript levels were associated with dipeptide repeat proteins, which is in agreement with reports that describe associations between intron-containing transcripts and dipeptide repeat proteins.11 For TTR, we also observed a correlation with intron-containing transcripts, but this association was most profound in patients with a pathologic diagnosis of MND; no significant associations were observed with dipeptide repeat proteins. Thus, although some associations were shared between HOXA5 and TTR, others differed.
We emphasize that in our study, as in any observational study, performing association analysis between 2 variables is not intended to provide information about possible mechanisms, but rather is intended to address the initial question whether 2 variables are related in any way. It is only after this initial question is addressed that further questions, such as mechanism, become relevant. To determine what may have driven an increase in HOXA5 and TTR, we already performed cell culture experiments, demonstrating that lower levels of C9ORF72 resulted in higher levels of HOXA5 and TTR. These effects were observed when targeting either total C9ORF72 transcripts or C9ORF72 transcript variant 2; we cannot, however, exclude nonspecific effects on other transcript variants, and further studies are warranted. Additional studies could also help to learn more about mechanisms that link C9ORF72 to HOXA5 and TTR, particularly because little is known about the function, and interaction partners, of C9ORF72. Moreover, future studies could examine downstream targets and/or upstream regulators that might contribute to the observed differences.
It is important that TTR protein levels have been evaluated as a potential biomarker for ALS and FTD,28,–,33 but findings were inconsistent, which could, in part, be explained by the genetic, pathologic, and clinical heterogeneity observed in those patients. Although our results seem to indicate that cerebellar TTR protein levels are elevated in C9ORF72 expansion carriers, we could not detect significant differences in CSF TTR protein levels. The lack of a significant difference could be due to the presence of posttranslational modifications to the TTR protein that are undetectable using our immunoassay. Alternatively, it might be possible that the secretory pathway is affected, hampering the secretion of TTR into the CSF. Future experiments using mass spectrometry and immunoassays with different antibodies as well as experiments investigating the secretion of TTR (e.g., in cell culture models) should be used to test these hypotheses. In addition, future studies should examine whether TTR protein levels are associated with features of the disease (e.g., in the CSF or plasma) and whether they change over time, especially because one could postulate that a single time point in a clinical cohort may not reflect changes observed in a pathologic cohort (end-stage disease).
Thus, we discovered elevated levels of multiple homeobox genes and TTR, reported to be involved in developmental processes and neuroprotection, in brain tissue obtained from C9ORF72 expansion carriers. Our findings may point to the presence of compensatory mechanisms aiming to mitigate the progression of C9ORF72-related diseases.
NiCole A. Finch, Matthew C. Baker, Tania F. Gendron, Kevin F. Bieniek, Mariely DeJesus-Hernandez, Patricia H. Brown, Jeannie Chew, Karen R. Jansen-West, Lillian M. Daughrity, Alexandra M. Nicholson, Melissa E. Murray, and Robert Bowser: acquisition of data, analysis or interpretation of data, and revising the manuscript for content, including writing of content. Xue Wang and Yan W. Asmann: analysis or interpretation of data and drafting the manuscript for content, including writing of content. Michael G. Heckman: analysis or interpretation of data, statistical analysis, and drafting the manuscript for content, including writing of content. Joanne Wuu: contribution of vital reagents/tools/patients and revising the manuscript for content, including writing of content. Keith A. Josephs, Joseph E. Parisi, David S. Knopman, Ronald C. Petersen, Leonard Petrucelli, Bradley F. Boeve, Neill R. Graff-Radford, Dennis W. Dickson, Michael Benatar, and Kevin B. Boylan: revising the manuscript for content, including writing of content, contribution of vital reagents/tools/patients, and obtaining funding. Rosa Rademakers: study concept or design, acquisition of data, analysis or interpretation of data, drafting the manuscript for content, including writing of content, revising the manuscript for content, including writing of content, study supervision or coordination, and obtaining funding. Marka van Blitterswijk: study concept or design, acquisition of data, analysis or interpretation of data, statistical analysis, drafting the manuscript for content, including writing of content, revising the manuscript for content, study supervision or coordination, and obtaining funding.
Supported by the National Institutes of Health (R21 NS093118, R01 NS080882, R35 NS097261, R35 NS097273, P50 AG016574, P01 NS084974, and R56 NS061867) and the ALS Therapy Alliance. Dr. van Blitterswijk is a former recipient of the Milton Safenowitz Post-Doctoral Fellowship for ALS Research from the ALS Association and is currently supported by the Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Clinical Research Fellowship. CReATe (U54 NS092091) is part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR) and National Center for Advancing Translational Sciences (NCATS). CReATe is funded through collaboration between NCATS and the National Institute of Neurological Disorders and Stroke.
NiCole A. Finch and Xue Wang report no disclosures. Matthew C. Baker holds the following patents: US Patent No. 12/302,691 (Detecting and Treating Dementia [2008]) and US Patent No. 12/413,869 (Methods and Materials for Detecting and Treating Dementia [2009]). Michael G. Heckman has served on the editorial board of Parkinsonism & Related Disorders. Tania F. Gendron has received speaker honoraria from Johns Hopkins; holds a patent for Methods and materials for detecting poly(GP) proteins in tissues from C9ORF72 repeat expansion carriers; has received research support from NIH, the ALS Association, and the Muscular Dystrophy Association; and receives license fee payments for C9ORF72 repeat expansion constructs and viruses, and for antibodies against C9ORF72 dipeptide repeat proteins. Kevin F. Bieniek reports no disclosures. Joanne Wuu has received research support from the Muscular Dystrophy Association, the NIH, the Food and Drug Administration, Eli Lilly and Company, the University of Miami, Department of Neurology, the ALS Association, and the Department of Defense. Mariely DeJesus-Hernandez holds a patent on Methods to screen for the hexanucleotide repeat expansion in the C9ORF72 gene. Patricia H. Brown, Jeannie Chew, Karen R. Jansen-West, and Lillian M. Daughrity report no disclosures. Alexandra M. Nicholson has received research support from the Association for Frontotemporal Degeneration. Melissa E. Murray has served on the editorial boards of BMC Neurology and Frontiers in Neurology and has been a consultant for Avid Radiopharmaceuticals. Keith A. Josephs receives research support from the NIH, the Dana Foundation, and the Alzheimer's Association; and is an editorial board member for Acta Neuropathologica and Journal of Neuropathology & Experimental Neurology. Joseph E. Parisi has served on the Defense Health Board Health Care Delivery Subcommittee; has received publishing royalties from Oxford University Press; and has received research support from the NIH. David S. Knopman has served on the scientific advisory boards of the Bluefield Project, Lundbeck Pharmaceuticals, and DIAN study DSMB; served on a Data Safety Monitoring Board for Lundbeck Pharmaceuticals and the DIAN study; was an investigator in clinical trials sponsored by Lilly, TauRx, and Biogen Pharmaceuticals; has received travel funding/speaker honoraria from the Alzheimer Conference (Seoul, Korea) and the Behavioral Neurology Conference (Hyderabad, India); has served on the editorial board of Neurology; and has received research support from the NIH. Ronald C. Petersen has served on the scientific advisory boards of Pfizer, Janssen Alzheimer Immunotherapy, Elan Pharmaceuticals, Wyeth Pharmaceuticals, and GE Healthcare; has received publishing royalties from Oxford University Press; has been a consultant for Roche Incorporated, Merck, GeneTech, Biogen, and Eli Lilly; has received research support from the NIH; and has served on the National Advisory Council on Aging. Leonard Petrucelli has received research support from the Mayo Clinic Foundation, the NIH, the ALS Association, Lundbeck, Biogen, Robert Packard Center for ALS Research at Johns Hopkins, Target ALS, the Association for Frontotemporal Degeneration, and the Department of Defense; has received license fee payments from Lundbeck, Biogen, and Denali; has received royalty payments for the licensing of TDP-43 antibody; has served on the scientific advisory boards of SAB, Denali SAB, and Biogen; and serves on the editorial boards of the Journal of Neuroscience, Molecular Neurodegeneration, and PLoS One. Bradley F. Boeve has served as an investigator for clinical trials sponsored by GE Healthcare and FORUM Pharmaceuticals; receives royalties from the publication of a book entitled Behavioral Neurology of Dementia (Cambridge Medicine, 2009); serves on the Scientific Advisory Board of the Tau Consortium; has consulted for Isis Pharmaceuticals and Ionis Pharmaceuticals; and receives research support from the NIH, GE Healthcare, FORUM Pharmaceuticals, C2N Diagnostics, the Little Family Foundation, and the Mangurian Foundation. Neill R. Graff-Radford has served on the editorial board of Alzheimer's Research & Therapy; has received publishing royalties from UpToDate; has consulted for Cytox; and has received research support from TauRx, Lilly, Biogen, Axovant, and the NIH. Yan W. Asmann reports no disclosures relevant to this manuscript. Dennis W. Dickson has served on the editorial boards of Acta Neuropathologica, Brain, Brain Pathology, Neurobiology of Aging, Annals of Neurology, Neuropathology, International Journal of Clinical and Experimental Pathology, and American Journal of Neurodegenerative Disease; has received travel funding and speaker honoraria from Novartis; and has received research support from the NIH, the Society for PSP: Foundation for PSP/CBD and Related Disorders, and the Mangurian Foundation. Michael Benatar has served on the scientific advisory boards of Denali, Ra Pharmaceuticals, Alnylam, and Mitsubishi Tanabe; has served on the editorial board of Journal Watch Neurology; has been consultant for Congressionally Directed Medical Research Program (CDMRP) ALS Research Program Integration Panel; has received research funding from the Muscular Dystrophy Association, the ALS Association, the NIH, the Food and Drug Administration, the Department of Defense, Cytokinetics Inc., Alexion Pharmaceuticals, Kimmelman Estate, Eli Lilly and Company, Neuraltus, and the ALS Recovery Fund; and has had involvement in legal proceedings regarding Morris James LLP. Robert Bowser is a founder of Iron Horse Diagnostics, Inc. (a company focused on biomarkers related to ALS that holds patents on TTR as a biomarker for motor neuron diseases); has served on the scientific advisory boards of Denali Therapeutics and Above & Beyond, LLC; has served on the editorial boards of Scientific Reports, the International Journal of Proteomics, and the American Journal of Neurodegenerative Disease; holds patents for Biomarkers for the diagnosis and prognosis of ALS, Biomarkers to monitor drug treatment of ALS and other neuromuscular disease patients, and Biomarkers for detecting and treating joint related pain; has been a consultant for Cytonics, Inc. and Merck; has received research support from the NIH, ALS Association, and Target ALS; and holds stock/stock options for Iron Horse Diagnostics, Inc. Kevin B. Boylan receives research support from the NIH, ALS Association, Genentech, Cytokinetics Inc., the Mayo Foundation, Neuraltus Pharmaceuticals, GlaxoSmithKline, Avanir Pharmaceuticals, and Synapse Biomedical. Rosa Rademakers receives research support from the NIH, the ALS Therapy Alliance, the Consortium for Frontotemporal Degeneration Research, the Mayo Clinic Udall Center of Excellence, and the Florida State Alzheimer's Disease Research grant; received honoraria for lectures or educational activities not funded by industry; serves on the medical advisory board of the Association for Frontotemporal Degeneration and on the board of directors of the International Society for Frontotemporal Dementia; and holds patents on Methods to screen for the hexanucleotide repeat expansion in the C9ORF72 gene, and Detecting and treating dementia. Marka van Blitterswijk receives research support from the NIH; is supported by the Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Clinical Research Fellowship; and is a former recipient of the Milton Safenowitz Post-Doctoral Fellowship for ALS research from the ALS Association. Go to Neurology.org/ng for full disclosure forms.
The authors thank Dr. J. Jiang, Dr. C. Lagier-Tourenne, Dr. D. Edbauer, and Dr. D.W. Cleveland for providing antibodies used to measure dipeptide repeat proteins. In addition, they thank Dr. M. Prudencio and Dr. V.V. Belzil for sharing RNA sequencing results.
↵* These authors contributed equally to this work as co–last authors.
Funding information and disclosures are provided at the end of the article. Go to Neurology.org/ng for full disclosure forms. The Article Processing Charge was funded by the NIH.
Supplemental data at Neurology.org/ng
- Received December 28, 2016.
- Accepted in final form April 18, 2017.
- Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
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Letters: Rapid online correspondence
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The most common mistake parents make is when buying shoes for their children is thinking that once they get their children's feet measured, that size automatically translates into their correct shoe size. The size that your children measure in the foot measuring scale is only a starting point when trying to find their correct shoe size.
I have noticed how most parents only care about how much growing room there is in the front of the shoes, but the length of the foot is not the only thing you need to consider when measuring your kids' feet. Many additional considerations must be noted in order to guarantee the feel, fit, wear, and comfort of the shoe. For instance, did you know that the instep of your child's feet plays a key role in how the shoes feel?
Do you know what the instep of the foot is? The instep is the top part of the foot, and when it's high, it makes it more challenging to find shoes that fit. Take a look at the image below to identify where the instep of the foot is located:
If your child happens to have a high instep, you will need to find deeper and wider shoes.
It seems like this generation of parents doesn't put the same emphasis on the importance of well fitted shoes as the former ones. Why is it so important to get the right shoe size for your child? Because the shoes that you choose for your child can and will affect their overall foot, leg, and back health.
I have been working for a specialized children's shoe store for over 10 years now, and I know everything that relates to children's shoes and the way they fit. This is a specialized shoe store that focuses on children with foot and leg problems, but we provide regular shoe fittings as well. We carry some of the most supportive children's shoes and orthotics, and I am familiar with which shoe brands and which shoe styles are better than others.
Please avoid taking your child to be fitted for shoes at places such as Nordstrom, Stride Rite (most sorts have closed down), or Payless. I have helped parents that come with their children from these stores, and they always come wearing the wrong shoe size. I explain in more detail why you must avoid buying your kids' shoes from these stores in another article I wrote. Go to the link below:
The Best Place To Buy Kids Shoes – Avoid Stride Rite, Nordstrom, Payless…
Providing your children with the correct shoe size is extremely important if you want to keep their feet and legs healthy. The wrong shoe size will lead to all sort of foot issues such as blisters, calluses, and corns, as well as foot and leg pain.
Shoes cannot be too short, too long, too narrow, or too wide, they must fit just right.
I will show you the most effective way on how to buy shoes for kids if you don't have a local children's shoe store in your area.
Getting The Correct Shoe Size For Your Child in 5 Simple Steps ❤
If you don't have a children's shoe store in your area, there is a set of guidelines that you can follow to make sure you provide your child the correct shoe size:
1- Make sure you have a proper device at home to measure your kids' feet. In this post I describe the best foot measurement devices for kids:
Shoe Size Measuring Device – Stop Buying The Wrong Shoe Size
2- Always make sure that you measure your kids' feet when they are fully standing. On weight-bearing, the foot stretches in both length and width, so this is the only way to get the exact foot size.
3- Always make sure to measure both feet (most of us have a half a size difference between our feet). The longer of the two feet is the correct length to be fitted.
4- Measure to the longest toe, which is not always the "big" toe, but could be the second, or even the third toe.
5- Measure the wider foot.
Did you know that the volume of the foot also plays an important role when finding the correct type of shoes? The volume is the total amount of foot that is to fit inside the shoe. For example, some kids' feet are thin and bony, while others are stocky and muscular. All these different type of feet might measure the same length and width, but will fit and feel different in the same shoe because of the difference in volume they put inside the shoe.
Sounds complicated, doesn't it? Don't worry! I will show you a selection of the best fitting shoes for children, which will be supportive, lightweight, flexible, provide extra depth to fit the volume of your child's foot, and they will be available in different widths such as medium, wide, and extra wide.
How to Get the Correct Shoe Size for Your Child? – Get It Right!
You might think I am exaggerating, but there are 5 steps you must follow in order to make sure your child's gets the correct shoe size:
1- Length Fit: Allow approximately 3/8 of an inch of space from the end of the longest toe. There is a trick you can use to check this. Remove the original soles of the shoes and have your child stand up on them to be able to visualize this better.
2- Tip of the Little Toe: Make sure the little toe is not pressed inward, as this causes corns or blisters.
3- Ball or Width Fit: This can be snug, but should NEVER be tight. A tight fit can cause several foot issues, such as blisters, corns, and calluses, among others. In addition, the foot NORMALLY swells about 5% over a day's wear, so "expansion allowance" must be considered.
4- Instep Fit: Always check for any tight fit around this area. This can happen specially with fat/fleshy or stocky/muscular feet. It can exert pressure on the instep and affect circulation. Most parents don't even know what the instep of the foot is. I have created a post where I explain this in more detail:
The Best Shoes For High Instep – Stop Getting The Wrong Shoe Size For Your Child!
5- Heel Fit: Make sure the heel of the foot fits snugly without any heel slip. This allows the child to walk and run comfortably with every step he or she takes.
If these 5 points check-out properly, your child will have a good fit. I assure you that this is really hard to do, that is why it is important for you to take your child to your local kids' shoe store to have their feet properly measured.
IMPORTANT UPDATE: I recently created an article along with a video that explains how to make sure your kids' shoes are fitting correctly:
How To Tell If The Shoe Fits – The Most Effective Way To Check If Your Kid's Shoes Are The Correct Size!
Now that you know how to figure out your child's foot size from home, you are ready to take a selection of the best fitting children's shoes.
Remember when I said that figuring out your child's foot size was the first step in what final shoe size your child will get?
Please note that if your child measures a foot size 10 and that particular shoe style that you are trying on fits "short", then you will need to choose the shoe size 11 in order to allow enough wiggle room (a whole size longer instead of a half a size longer). On the other hand, if the sandals fit "long" then you will need to pick the same shoe size instead of going a half a size longer (since the shoes already fit long).
Makes sense?
I will let you know exactly how each shoe style I recommend fits so you can adjust the size that you get for your cild accordingly.
The Best Kids' Shoes ⭐⭐⭐⭐⭐
Keep in mind that I only review shoe styles that I have fitted before, since that is the only way for me to tell how well-made the shoes, the amount of support that they provide, and how they fit.
I have fitted thousands of children shoes, and I know which shoe styles fit and hold up better than others from having tested the shoes myself. If you don't have a local shoe store in your area, below you can find a selection of the best shoes for kids.
The shoes I describe below are supportive, lightweight, flexible, breathable, and durable. Most importantly, they are deep and available in different widths such as medium, wide, and extra wide widths.
The shoes below will fit a child that has narrow, medium, or wide feet (choose the width accordingly). Please refresh your browser if you can't see the recommendations.
Disclosure: Keep in mind that we may receive commissions when you click our links and make purchases.
This first selection of shoes fit "short", which means that you need to go a whole size longer of the size that your child measures in the shoe measuring scale in order to allow for growing room.
The shoes below will fit a child with medium, wide, or extra wide feet:
ToddlersToddlersLittle KidsLittle KidsBig KidsBig Kids
This selection of shoes fit "true to size", which means that you need to go a half a size longer of the size that your child measures in the shoe measuring scale in order to allow for growing room.
Shoe shopping for your child can be a very frustrating experience depending on where you take your child to get fitted for shoes. If the person helping you doesn't know what he is doing, your child might end up wearing the wrong pair of shoes.
Never assume that the shoe fits if your child doesn't complain about the shoes. Most children will not speak up even when the shoes feel too tight or too big. It is your responsibility as a parent to make sure your child is wearing the correct shoe size.
Children feet change with age, so always keep a close eye to your kids' feet. Don't assume that just because your children have been always wearing a wider shoe their feet will always stay wide.Some children's feet tend to narrow down as they grow, while others will stay wide.
Please take care of your kids' feet by providing them with the correct shoe size! Allow them to play and run comfortably in their shoes!
Are children's shoes more important than they are for adults? Yes, I believe they are! Children are still growing, developing, and working on their coordination. The right type of shoes will protect their feet, legs, and back by minimizing the impact caused by repeated running, jumping, and skidding.
Do you have a local children's shoe store in your area? Where do you purchase your kids' shoes? Have you ever purchased your kids' shoes online before? Please share your thoughts and experiences below so other parents can benefit from them.

subset: commoncrawl


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An autoimmune disease is said to be a condition where your immune system attacks the healthy cells of your body by mistake.
When this happens, your body sends you symptoms that could include rheumatoid arthritis, lupus, Hashimoto's thyroiditis, psoriasis, psoriatic arthritis, allergies, and others.
The traditional way of treating these diseases is through taking medication. However, with the emergence of new healing modalities, in this age, some people prefer the natural way of treatment through total diet and lifestyle changes.
Moreover, there is the idea introduced by Medical Medium Anthony William, a person who has helped tens of thousands of people heal from ailments that have been misdiagnosed, ineffectively treated or that doctors can't resolve.
He states that, in reality, the body cannot attack itself because it only loves the self and supports it unconditionally.
With this concept in mind, you have the power to heal yourself from autoimmune diseases or whatever kind of illnesses you're suffering from right now by totally changing your perception of your body and your health.
The healing is a process that begins with the following steps.
5 Things That You Should Be Doing To Protect Yourself From Autoimmune Diseases:
1. Change the stories you tell yourself.
It is but human nature to believe the stories of others who suffer the same physical pain as you. Pain can render you helpless.
As such, when you're in the situation, you have the tendency to tell yourself stories that only weaken you more.
These disempowering thoughts can render your body helpless to heal itself. However, you can change these stories right away.
What most people don't know is, there's a strong connection between negative self talk and health. Positive mindset can do wonders, it can significantly improve your immunity.
By thinking positive and empowering thoughts you are not just empowering yourself, but you are perceiving more options that might be helpful and healthy for you.
2. Heal inner blockages of energy.
Judging and blaming yourself for a long period of time can create a misalignment of energy and this will result in a blockage of energy flow.
Once a blockage develops, and it is not treated on time, it results in physical illnesses. By neglecting your inner struggles you are neglecting the flow of your energy.
Additionally, past traumas and guilt can be stored in the areas of the lower chakras and interfere with the reproduction and digestion functions.
What you must do is to stop blaming yourself. Face your inner trauma and start to shower yourself with unconditional love.
When you stop neglecting the inner trauma you let energy flow there and eventually heal it. This eradicates the blockage and let's your energy flow undisrupted.
3. Go back to your essence.
Going back to your essence means going beyond your mind, body, heart and spirit, and creating a connection to your soul.
This connects you to the essence that projects itself through your mind, body, heart and spirit.
When you connect to your original blueprint you restore yourself to a version of you that is meant to be harmonious.
You can feel whole again and you will see the disharmony and where it resides. By knowing what to harmonize you can know what to fix.
You can do this through meditation, nature connection, and aligning yourself with who you truly are. When you're fully aware of your being, you consciously know what you need.
4. Trust your gut and intuition about what is right for you.
You are gifted with a spiritual tool that helps you sense what's best for you, and what might be wrong. This is your intuition or gut feeling.
You might do something that everybody tells you to do, but if you sense it's wrong for you than it might be wrong for you.
We might focus on healing the body when the real issue resides in our emotional self, or mental self.
It's ok to listen to other people who know more than you, but when something feels offbeat, take a pause and think twice. Find other options, evaluate and stay open.
You know yourself best. You know your flaws, triggers and warning signs. You know what makes you feel good deep within and what is just avoidance of the real problem.
5. Take the necessary steps to maintain your health.
There's nothing wrong with asking for professional help when you feel something is wrong with your body. In fact, we advise it.
However, you should know that most medical health professionals are trained only on the biological makeup of the body.
The treatments therefore focus more on the chemical and structural aspects of it. But science has shown that it works.
Maintaining your health is not just external. There is the external part, like your food choices, the activities and the chemicals you put within you.
But there is also an internal part consisting of your thought processes, beliefs and energy flow. Both of these parts these can either strengthen or weaken you.
Chronic illnesses are mostly caused by an imbalance in a person's energetic makeup. These energy fields govern the physical, emotional, mental, and spiritual aspects of our being.
Living to the truth that you're an energetic being who is composed of mind, body, heart and spirit keeps you whole and aligned with this truth.
Unless you claim your power back, you can't heal yourself fully because what happens outside is only a manifestation of what's going on inside.
There may be limiting beliefs you need to overcome or situations, thought patterns you need to change.
Start to nourish your body physically, emotionally, mentally, and spiritually. Your body is intelligent and resilient.
Health is its natural state. Support it in healing itself by making health easy. Your being knows how to heal itself naturally.
Look at your relationships and career. Are they empowering you or sucking the life out of you?
Whatever answer you may find, make sure you do the necessary steps that will lead you to wholeness and vibrant health.


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Would you drop almost a thousand smackers on a hot trend? What if that trend was unflattering to a huge portion of the population? Ankle booties with extreme heels are showing all the signs of a fall trend on the rise. Paired with short trapeze dresses and tights, they can make an outfit look like it came straight off the runway. They can also cut a woman off right at the ankles, making her legs look short and squat. Personally, I wouldn't want to risk it. For me, a trend test-drive should be less than $100. If it works, fantastic — a great look for a relative bargain. If it flops, fine — at least I didn't blow an entire paycheck.
One of the looks below meets my trend try-out criteria, ringing in at $69. The other pair retails for $965. Think you know which pair is safer bet? Take our taste test and find out.


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Pazza Photography specializes in fashion, editorial and corporate photography.
Currently based in Cleveland, Ohio.
Pazza Photography uses both film and digital equipment for photo assignments:
– Medium format film camera Contax 645 with 80mm 2.0 Carl Zeiss lens
– Canon 5D Mark III and Canon EOS 5D digital cameras with a variety of lens (24-70mm f/2.8L, 50mm f/1.4, 70-200mm f/2.8L, 90mm f/2.8 ts-e)
Awards: 2016 PIANKO Print Excellence Award in Corporate Communications Category, 2014 PIANKO Print Excellence Award in Annual Report Category, 2013 Best Cleveland Advertising Photographer, 2013 PIANKO Print Excellence Award in Annual Report Category.
Recent Publications: TED Magazine, Journal of International Innovation, Cleveland Magazine, Automobile Magazine, Pulse Magazine, Lake Erie Living Magazine, West Shore Live Well Magazine, Circle East Live Well Magazine, North Olmsted Magazine, Lakewood Magazine, Rocky River Residence Guide, Cleveland Galleries, Think Magazine, Case Alumnus Magazine.
Clients: Crate & Barrel, University Hospitals, UH Harrington Discovery Institute, Case Western Reserve University, Brink's Inc, COSE, the Young Scientist Foundation, etc.
Talent: Wilhelmina Models, Major Model New York, Heyman Talent Artists Agency, Docherty Talent and Modeling Agency, etc.


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$ 181.91
Giddings mouthpieces uses the finest production methods. Our CNC lathes and robotic polishing ensure the highest quality mouthpieces available. Based on the Farkas Medium deep cup horn mouthpieces. Very popular for all players, with clean articulations and ease of playability throughout the range.
$ 16.54
Custom Laser Engravings 24 Characters or fewer! Please enter in notes at CheckoutView full product details
$ 33.02
Dragon's Breath Dragons Breath makes articulations a snap! and projection even easier. By heat treating the material we make each mouthpiece close to 25% harder....View full product details


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|This is a story of a young "orphaned" girl who has no one but her teddy bear "Albert" to keep her company. Written in about 2011, this is one of the many children stories and/or Novellas that I have written.
|This is a sestina poem. It was actually done as a class project in my creative writing class which I took in grade 11. I really enjoyed this style of poem, it's a really cool idea and people have done some really neat things with it!
|This was done fairly recently in 2015. It is a short story set in a mythical period about a young maid who , while cleaning a chaple for a wedding, dreams of one day meeting her own prince. The stroy ends in a terrible twist of fate.
|This was writting around the same time as "Prince". It is a different take on "Prince" set from an outside perspective. It sheds some light on the curious circumstances of "Prince".
|This is a take on the style of the Shakespearean Sonnet. I wrote this for a class assignment in 2014 and was quite happy with how it turned out.
|Script writing is something I attempted during my english major at Algoma University. Here is one of the few that I wrote in 2015 about a plane wreck that may or may not have actually occured as we follow an interesting array of seemingly mentally unstable characters stranded or perhaps imprisoned on an island.
|This is a fairly long story written throughout 2010 and 2011 about a young highschool student who is kidnapped by a strange man on her prom night. What she endures during her entrappment is seemingly unnatural to the point of supernatural.
|This is a satirical monologue which I wrote for a drama project in 2009. The idea is that there is something more to the individual giving the monologue than what is being spoken. In this case, those listening to the monologue can see that the sppeaker is clearly insane meanwhile the speaker themselves is not aware of this.
|This monologue was written for the same project in 2009 for a peer. The speaker believes him or herself to be living in shambles meanwhile the outside persprective can see that the case is quite the opposite.
|This was just a fun little poem written back in 2011.


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88 Gabriels Gully Road, Lawrence, South Otago
Modern home, 20 acres - value here!
88 Gabriels Gully Road, Lawrence, South Otago
Modern home, 20 acres - value here!
Lifestyle property For Sale
A fabulous opportunity here to purchase a wonderful modern family home on 20 acres. Situated on the edge of the bustling rural township of Lawrence, near the entrance to Gabriels Gully, this property represents the quiet and tranquil laid-back lifestyle that we would all like to enjoy.
read more +
Three bedrooms, the master is upstairs and boasts an ensuite plus walk-in wardrobe. A family bathroom, plus, next to the house, a sleepout providing extra room for family or guests. Open plan kitchen with a spacious dining and lounge area, heated by log burner and with doors opening to outdoor space, ideal for relaxing in the sun, all in the large fully fenced section.
A stream divides the flat grass paddocks from the steeper hill land. A short drive or walk into the Lawrence township that provides all services, cafes, primary and secondary schooling, the Clutha Gold Cycle Trail and much more.
property details +
Web iD: DO9798
Approximate land area: 8.1ha
Mike Dougherty
Property Consultant


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Proto-UFOs and Alien Manifestation
Lecture by Anthony Beckett
In this lecture Anthony will look at the underlying reality behind the appearance of UFOs in our skies. He will take the audience on a journey through the scientific studies that demonstrate the physical reality of the phenomenon; suggesting that the problems of acceptance of this reality come just as much from within ufology as outside of it. What is known is so often much less than what is outside of our reach and Anthony will address how we can come to expand our knowledge about UFOs and what they really mean to humanity.
Sunday October 18th, 2015


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Boyish T-shirt
Boyish cotton jersey T-shirt with a horse print
Product details
Main material: 100% Cotton Care: dry cleaning only Fit: boyish - Slips on Colour: clay brown Item code: CHC18WJH0318126M
Cut in a boyish shape, this cotton jersey T-shirt reveals a striking horse print creating a graphic contrast. It includes the Maison's signature "O" tab and features the Chloé logo at the back.
Shipping & Returns
Return Service:
We provide free pick up for your returns: you have 15 days from delivery to follow our quick and easy return procedure.
For additional information, please consult the Return Policy.
May we help?
Call us at +44 (0)2078113950
Contact us by filling out our form


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I picked up a bushel of apples yesterday in rural Ontario and have enjoyed 5 or 6 of these delicious, juicy red guys already.
But, instead of just plowing through them all, as is, I am going to try the following recipe to use up the approximately 30 more sitting on my balcony.
Waldorf Salad Recipe
- Prep time: 10 minutes
- 1/2 cup chopped, slightly toasted walnuts
- 1/2 cup celery, thinly sliced
- 1/2 cup red seedless grapes, sliced (or a 1/4 cup of raisins)
- 1 sweet apple, cored and chopped
- 3 Tbsp mayonnaise
- 1 Tbsp fresh lemon juice
- Salt
- Pepper
- Lettuce
In a medium sized bowl, whisk together the mayonnaise (or yogurt) and the lemon juice. Add 1/2 teaspoon of salt, 1/4 teaspoon of fresh ground pepper. Mix in the apple, celery, grapes, and walnuts. Serve on a bed of fresh lettuce.
Time to get chopping!!


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After more than 170 years, A Christmas Carol still sends shivers and draws tears, says actor Rod Beattie
For Rod Beattie, the secret to the ongoing success of Charles Dickens' A Christmas Carol is simple: "He's a very good writer."
The award-winning veteran of the Stratford Festival stage renowned for his performances in the Wingfield Series of plays, will be in London Monday to read Dickens' five-stave holiday classic at Bishop Cronyn Memorial Anglican Church.
He'll be joined by four other Stratford and Shaw Festival veterans, including Thom Marriott, Brian Tree, Claire Jullien and Kyle Blair. Each will read a stave with Tree handling the emotion-packed finale.
Beattie said he's been asked to read A Christmas Carol several times over the last 20 years and it never fails to take an emotional toll.
"It gets me every time," said Beattie.
"I get shivers down my spine and goose bumps. I have to hold back the tears and it usually comes out of left field, a different place in the story — some little detail or a phrase. It's a very powerful story."
Beattie suggests Dickens' story is so timeless and so much better than most because it's written like a script for a movie, the scenes woven together with words rather than images.
"But it's also just a brilliantly conceived story, perfectly balanced and perfectly executed," said Beattie, noting it hits many emotional buttons.
The Dickens tale tells the story of the miserable and miserly Ebenezer Scrooge, whose world — ideological, ethical and emotional — is transformed after a visit by the ghost of a long-dead business partner, followed by the Ghosts of Christmas Past, Present and Christmas Yet To Come, who take Scrooge on a journey to revisit his childhood, the home of his impoverished clerk, Bob Cratchit and his seriously ill son, Tiny Tim, then to the future and what will happen if Scrooge doesn't change his ways.
The evening is presented by the London Pro Musica Choir, who will perform several Christmas songs, one featuring soprano Erin Bardua and another performed by renowned soloist Vicki St. Pierre.
Admission is by donation with proceeds going to support St. Paul's Cathedral's London Daily Bread Program.
Last year, more than $6,000 was raised.
Paul Knowles, one of the organizers of the show with his wife, Nancy, choir president, said the event "is a powerful experience."
"You can't get into the Christmas spirit and better than hearing Charles Dickens' A Christmas Carol, especially when it's done well," said Knowles.
London born and raised actor Blair, who starred at Shaw this year in Sweet Charity and The Lady from the Sea and will return next year for Alice in Wonderland and Sweeney Todd, will read the first stave.
"It's just such a beautiful story," said Blair when asked about volunteering to read.
"I have been to many readings and it's a part of my Christmas tradition."
The reading comes at a time when it can have real impact on people, said Blair.
"The world is in such turmoil, it's good to be reminded what community and connection are all about," he said. "It's a lovely sentiment."
What: Charles Dickens' A Christmas Carol, featuring stars of the Stratford and Shaw festivals, including Kyle Blair, Rod Beattie, Thom Marriott, Claire Jullien and Brian Tree, accompanied by London Pro Musica Choir and singers Erin Bardua and Vicki St. Pierre.
Where: Bishop Cronyn Memorial Church, 442 William St.
When: Monday, 7:30 p.m.
Admission: By donation in support of St. Paul's Cathedral's London Daily Bread Program.


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For this project I have decided to create a fashion arts film that has a sole focus on the artist Sun Mu. As a North Korean defector, Sun Mu embraces his experiences of North Korea and his feelings towards it after having fled from there, he uses these experiences and emotions to fuel and create narrative 'Propaganda' art.
Having watched the I AM SUN MU documentary, I was able to gain an understanding of his experiences, reasons for leaving North Korea and the new obstacles he faces as a consequence of having escaped through his own words. As a trained artist within the military group in North Korea, Sun Mu applies the same style of poster and mural work produced for the army to his new works as a means of parodies to the North Korean regime. Sun mu is an artist with a hidden identity because to produce the art he does is of high risk and can be perceived as a mockery of the regime.
Defection in itself is punishable through death, and in order to protect his family that is left behind in North Korea, Sun Mu must maintain an invisible identity much like Banksy. This is something that is very frustrating for an individual that has been renowned for these amazing works he desires to reach out to people and to be able to show himself, to say I am Sun Mu. However, this cannot be done without putting himself and his family at risk of death. Having witnessed and listened to these frustrations and obstacles, I want to use the power of fashion film and communication to help and communicate his message and artworks to a nation that is so unaware of its reality.
Sun Mu's artwork is of high importance as within the regime the Kim's (leaders) are only allowed to be painted and portrayed in a certain way that is approved and within their traditional Mao outfit. However, Sun Mu creates these artworks in his own style, painting the Kim's in controversial pink and branded tracksuits. I find this to be so relevant in terms of Anarchy, in the research of this project I wanted to look at the people and individuals that are emerging themselves into political events and fighting for freedom of expression and being.
Sun Mu is a great example of an anarchist, he is an individual that is using his skills and experiences to document and educate the world outside the regime about the life that is inaccessible and unknown to us, whilst putting his and his family's life at risk to do it.
Of all the research I have done into political movements and current headlines, I have decided to focus on North Korean defector artist Sun Mu because, personally, his work speaks out the loudest through the messages he is trying to convey. A North Korean defector isn't something that is very heard of so I want to take this opportunity to explore that further. He escaped North Korea in order to leave the suppression he faced in regards to creativity, expressionism and being, however, this suppression still lingers now even having left North Korea as he is incapable of claiming his true identity and revealing himself to the world.
I want to take this opportunity to be able to help and communicate these messages to a wider audience through the use of a Fashion arts film. If you know the artist, you are willing to go and see his exhibitions in order to understand the works produced, however in the case of Sun Mu's lack of ability to publicise himself and his work, I felt that the development of a documentary film had been the most effective way to educate people on this artist and his work. Thus I have decided to use the same platform of film to recreate some of his works and experiences to be able to show it to a wider audience.
I feel that by developing this idea through the medium of fashion film, I am able to make it seem a lot more real and alive as if to say, this is happening and this is true. A platform that offers me the ability to engage with viewers through moving image and sound I feel has a lot more impact than something that is static and less engaging.
Everything within the film is of intent and in reference to previous research, experiences and art. Each planned scene recreates either a chosen piece of art that has been produced by Sun mu or an experience that he has had to experience. I want this film to visually scream 'Sun Mu' through use of strong colouring of red and pink as seen in his art works. I plan to use a pink background for the film as it will be consisting of 6 very different scenes and they all need to link together and flow as a collective, thus I have decided to use a pink background to create a common factor within each of the scenes.
In regards to the styling of each scene, I have had to consider exactly what I am trying to portray. For instance, the scene of the schoolgirl drinking Cola is a recreation of an existing artwork thus the outfit for that scene should be styled as it has been within the painting. This means that the model within this scene should be wearing clothes that represent the classic North Korean school uniform. In contrast to this, the scene with the roses in a vase will feature the model in a navy dress. In this scene I decided to go for an elegant look as if to create an important and elite look of the model in representation of the North Korean government and their navy uniforms.
This particular scene will feature shots of the model lurking around this rose installation but then goes on to destroy the flowers and drink out of the vase to show the disrespect and carelessness for the installation. This scene reflects the time when Sun Mu invested a lot of time and effort into hosting a solo exhibition in Beijing which had then been shut down within a few hours of opening by the North Korean policing that resided in Beijing. This showed utter inconsideration for the artist and his work as they tore the exhibition apart and had taken away all of the works from it.
Much like Sun Mu's work, the film is set to be vibrant and playful in regards to the visuals whilst carrying a much deeper and darker translation. This is in reflection the Philip Guston exhibition 'Laughter in the dark', it is about taking a fun outlook and approach onto something that is essentially very dark and gloom. By recreating some art works I am restricted to the visual look of the scene but by recreating his experiences I am able to have the freedom to add a visual identity and to style those scenes in my own way whilst still keeping it all within a certain colour scheme in order to make all of the scenes flow as a collective.
In consideration for the sound aspect, I have considered to feature a narrative of quotes by Sun Mu in order to convey a stronger message of the meaning behind the film. The narrative would consist of selected quotes such as this diary entry:
Today is July 1st.
Under the street lamps, the signs of restaurants are lit along the street.
The light is coming into my empty room, Where I am sitting at the window, Smoking.
Hey you, what are you thinking about? Are you missing a hometown you left behind? Or are you dreaming about the new land you will soon enter?
The cigarette is burned out, and I'm only left with ashes.
I flick my ash and stare out the window, silently.
Well, I have no-one to talk to anyway.
I have also considered the use of music as a background track, I looked into some political and expressive sounds which include, Won't get fooled again by The who, A change is gonna come by Sam Cooke and Another day in Paradise by Philip Collins. I was more drawn to the idea of A Change is Gonna come by Sam Cooke as it speaks of the idea of change and how it will come. This is in reference to the article which spoke of the high possibilities of war breaking out between US and North Korea. Looking at how Trump had made a tweet of how the North Korean regime 'won't be around much longer' had been perceived as an indirect declaration of war. This implies a change within the running of North Korea and its dictatorship. From a perspective of the lyrics, the song opening lyrics are:
I was born by the river in a little tent
Oh and just like the river I've been running ever since
It's been a long time, a long time coming
But I know a change gonna come, oh yes it will
This verse alone reflects the setting of Sun Mu. In the documentary he spoke of how he had crossed the river from North Korea over to the Chinese side when he was escaping in order to change his life. The song reflects the idea of running and moments of weakness and the moments of hope that are felt throughout this journey with an aspiration for change.
I find this song to be very relevant, although it is rather gloom in sound it has a strong meaning and a positive outlook. I plan to develop a recording of the song being sung by my friends and then to edit it in a way to link it with the film. For this I plan to use software such as Audacity, LMMS and Garage band.


text: Today, for the first time in quite a few years I actually looked at myself full bodied in the mirror. I didn't realize how hard that was until I actually forced myself to look at myself for longer then just a glance or point out something that was wrong. Just full on, loved myself and told myself that I am proud of me, for what I have done. It made me think tho, how did I expect myself to improve on what I needed to improve on if I couldn't even face myself. All these years of self doubt and self disappointment, I should have just looked myself in the mirror and told myself I love you and you are strong. It is a little sad that it took me losing weight to finally be able to look at myself in the mirror without disgust. This feels like another turning point, this feels like a step closer to true self love and acceptance. I love myself for staying true to the goals that I have set and the goals I have accomplished. If you are struggling right now, look at yourself in the mirror, look yourself in the eyes and tell yourself, I love you. And don't look away right after you say it either, say it and mean it and look at yourself and point out the good about yourself rather then the bad. You are amazing, and you may not believe this, but you are doing better then you think you are. If you are struggling right now, please reach out. I don't have all the answers but I can definitely listen.


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December 13, 2014
Why can't the $100 billion security industry stop hackers? We have witnessed data breaches affect thousands of stores of retailers like Target Home Depot, Dairy Queen, Michaels, Neiman Marcus, Kmart, Supervalu, Albertsons and many others. But it's not just retailers who are facing flak for being the victim of leakage of sensitive payment information. A recent case highlights Charge Anywhere, a provider of electronic payment gateway solutions to retailers and other merchants. The company recently reported that its system was infiltrated five years ago, affecting unencrypted payment card data.
As of now, the company has assured that the attack has been shut down and is being fully invested. Ongoing investigations have revealed that the data breach was caused by a malware that the installed anti-virus system failed to detect. The company has hired a computer security firm to upgrade its security measures and trace how the malware affected the system. The malware had actually affected the outbound network traffic and captured some segments.
The leaked data includes cardholder's name and account number as well as expiration date and verification code. Payments cards used between November 5, 2009 and September 24, 2014 have been affected. The case of Charge Anywhere shows that retailers should perform a crucial activity of researching into the security of their payment providers. Retailers ought to make it a habit to check security habits of their payment vendors, raise queries on security controls and request audit reports and proof of compliance as well.
This also illustrates the importance for payment processors to fully encrypt sensitive data flowing through their networks. In an official notice, Charge Anywhere has instructed cardholders to review their account statements for any unauthorized activity regularly. The company has also assured the merchants that the issue did not affect any system or device at merchant locations, nor did it affect the systems of any ISO, processor, or other service providers.
Charge Anywhere is also working with the credit card companies and processors to provide them with a list of merchants and the account numbers for cards used during the period at issue so that the banks that issued those cards can be alerted. If banks receive these alerts, they can conduct heightened monitoring of transactions to detect and prevent unauthorized charges.


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You shall not murder (Exodus 20:13) sounds pretty straightforward. This verse is actually just one word in the Hebrew language: ratsach. The idea is a human killing another human in an animalistic way.
Think of a predatory animal like a lion. The lion attacks as an angry response when it is provoked. There is no thought about consequences or possible alternatives, but it simply lashes out in anger. A lion will also lie in wait to ambush its prey. Humans who kill in this animalistic way are regarded in the Bible as murderers (see Exodus 21:14; Numbers 35:20-21, and Deuteronomy 19:11, 13).
The legal definition of homicide today says it is "the killing of a human being by a sane person, with intent, malice aforethought (prior intention to kill the particular victim or anyone who gets in the way) and with no legal excuse or authority."
God determines our day of conception (Psalm 139:16), the value and purpose of our life while we are alive (Ephesians 2:10), and the day of our death (Job 14:5). Taking any of these things out of God's hand, and putting them into our own hands, not only constitutes murder but dishonors God.
Some things are obviously homicide: Abortion is murder, suicide is murder, euthanasia is murder. Because these things put man in the place of God, they are unlawful.
But think of this: Slander is also murder. According to rabbinical scholars, publicly humiliating someone is murder, because it is character assassination. Jewish law also forbids the sharing of true but harmful information about someone else. Both of these things devalue a human being's God-given value and purpose. Jesus echoed these teachings in Matthew 5:21-22 and Matthew 15:19.
J.I. Packer wrote, "We all have in us capacities for fury, fear, envy, greed, conceit, callousness, and hate that, given the right provocation, could make killers out of us all. … When the fathomless wells of rage and hatred in the normal human heart are tapped, the results are fearful."
Here's a quick checklist to make sure we aren't getting close to becoming murderers:
- Do I get too angry too quickly, and stay angry too long?
- Do I harbor unforgiveness against anyone?
- Have assassinated someone's character?
- Am I "lying in wait" for anyone to catch them doing wrong?
To stay clear of these murderous ways:
- Make amends quickly—Matthew 5:23-24
- Deal with anger quickly—Ephesians 4:26-27
- Don't seek revenge—Romans 12:19
- Endeavor to live at peace with everyone—Romans 12:18


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Shaykh Hassan Al=Turabi, may Allah have mercy on him, lived a life of struggle and was an embodiment of modern Muslim scholarship and leadership. Admittedly he was human and must have had his failings, but his intellectual prowess, his energy and stamina and his staying power and strategic thinking was untypical in his generation. His contribution to Muslim reawakening, his unique sense of justice that allowed him to engage a plural society, his eclectic and encyclopedic learning, his constant prodding, if sometimes provocative and controversial, not only made him stood out among modern Muslim scholars of his time but actually kept the Muslim community, not only in Sudan, but world over, constantly on its toes. His demise, well over a year ago, is therefore a great loss to the Muslim Ummah and his contributions, indelible as they will remain, must now be harnessed for posterity and the lessons in them brought to the fore, for the benefit of the ever growing and ever complex Muslim community.
Nigeria, with its overwhelming similarities with the Sudan and its long historical and inextricable links with the Sudan has benefited from Turabi's contributions and stand to benefit from the lessons of Turabi's life struggle. Muslims in Nigeria, very much like their brothers in the Sudan, have been struggling under modern western system of democracy, which has been at variance with the values of the socio-cultural environment. This has, rather predictably, created tensions and has elicited military interventions, which only added to the complications rather than the resolutions of the problems. Some of these issues, specifically, power-sharing, wealth-sharing and the place of religion and identity in a plural society, have recently featured prominently in the re-structuring debate in Nigeria. As this debate drags on, Muslims have to leverage their intellectual heritage to engage their plural societies. The life and works of Turabi is going to be of immense benefit in this respect and we need to bring it closer to the generations of Nigerians who will ultimately bear the brunt of this intellectual struggle in Nigeria.
The importance of a conference on Dr. Hassan Al-Turabiin Nigeria is not only to commemorate his life but also to bring out its lessons for our country. Holding it in Nigeria will have the added and important benefit of bringing the life of Turabi and his contributions to the younger generation many of whom may have at best heard about or read him but never met him. This link with the young is essential for sharing knowledge, learning from experiences and sustaining the essential tempo of Islamic awareness, especially its ability to embrace and accommodate a plural society for which late Hassan has distinguished himself among modern Muslim scholars.
The objectives of the conference include:
To bring together, as full a grasp as possible, the contributions of the polymath that Shaykh Hassan had been and preserve these for posterity.
To analyze Shaykh Hassan's contribution within the context of Sudanese socio-political environment and bring out the lessons for our contemporary times.
To take specific areas like the mobilization of Muslim Women and the impact this has had on Muslim societies, not only in the Sudan, but beyond.
To collate and assess the views of contemporary scholars on some of the thoughts of Shaykh Hassan to have an idea of the debate about and around his views.
To look at a post Turabi Muslim intellectual discourse and see what is there to prepare for and how?
The theme of the conference is 'Thoughts and Ideas of Shaykh Dr. Hassan al-Turabi and the Challenges of Contemporary Muslim Society.'
This is an international conference open to all, Muslims and in the spirit of Turabi, even non-Muslims. But what is at point here are those that would need to be there to make the conference complete and worthy of the efforts. For instance, his close disciples who lived and worked with him and who can speak on his personality and some aspects of his contributions, which may not have been documented.Then there are those scholars who have written about him or his works, especially those that have or could capture his vision of the Muslim world or his vision of Africa. Also those who have had other associations with him, his students, those who met him and those who may not have had a chance to meet him but who have something tangible to say about him.Also scholars who are familiar with him and for whom this conference will deepen their understanding of him and elicit interest in his contributions for further research and writing.
There is another dimension in form of an exhibition on him and his works to bring the man closer to the younger generation in particular.
Generally, participants are expected to come primarily from Sudan and Nigeria, but others from West Africa, Egypt, UK, US, Malaysia and even China, are welcome, in keeping with his global vision and perspective.


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Christmas Gifts For Homeless Children In The City
The Highland Council's Housing and Property Services' Church Street and Homeless Day Centre Offices have joined forces with Tesco's Community Champion to ensure around 50 children in Homeless Accommodation will receive a Christmas present this year.
For the most part these households are accommodated in temporary furnished accommodation located across the city, awaiting allocation of permanent social housing through The Highland Council and Partner's Common Housing Register.
The gifts are being distributed this week to ensure that the children will have a parcel to unwrap on Christmas morning.
23 Dec 2008


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It is after midnight. Waves of sleep roll in as peace descends.
A throbbing sound from the phone nearby. Another email message from the boss. An individual's peace disturbed. An all too familiar scene in working lives where even the bedroom is no longer a proper place of refuge.
Many HR consultants and management gurus, these days, express concern about the 'long hours without boundaries' culture that has infected so many workplaces, particularly those populated by younger, smartphone users who lack career security and are open to exploitation.
During the Summer of Love a half century ago, an earlier younger generation were tossing away suits and schedules.
A future of leisure and self-empowerment beckoned.
It is all worked out rather differently.
Technologies have emerged that enable greater surveillance of employees and ensure that jobs are more fast paced and by extension, more pressured.
Despite all the talk about better work-life balance, many employers pay little regard to the longer-term needs of employees, many either with young families, or keen to start one. Indeed, leader bonuses are often linked to levels of success in squeezing costs out of the business.
One result has been high levels of burnout leading to long-term certified sickness absence, often culminating in premature retirement and a permanent loss of skills.
Last week, HR managers gathered for the annual conference of the Chartered Institute of Personnel and Development (CIPD), their professional body, in Croke Park.
CIPD director Mary Connaughton spoke of concerns expressed by her members about how line managers were getting in the way of effective performance of the functions of HR executives.
She also spoke of how "weak management is contributing to poor performance and to an increase in employee turnover". But as was made clear, line managers themselves can feel poorly supported.
HR managers have often considered themselves to be the "meat in the sandwich" when it comes to relations between profit maximising top management — with the interests of the shareholders to consider — and the body of workers reporting to them in various guises.
Peter Cheese, CEO of CIPD UK, emphasised the need to "design jobs that are good for people" in an environment of rapid technological change.
As he pointed out, in many cases, the introduction of new technologies has served to reduce peoples' autonomy, in effect, de-skilling them.
Next up at #cipdconf18 @cipdireland it's @Cheese_Peter discussing professionalism in #HR 🙌 see the complete programme for today's event @CrokePark here: https://t.co/nekOWlwWgj pic.twitter.com/uBpkuU7fxr— CIPD (@CIPD) May 22, 2018
He instanced the case of people operating in large, empty logistics warehouses, perhaps 50 metres away from the nearest worker.
Survey evidence suggests that around one in five people are dissatisfied with their job. Many more are in posts where their capacities are not properly utilised.
However, Irish broadcaster turned international trainer, John Ryan, who is CEO of Healthy Place to Work, warns of the negative impact on wellbeing of today's pressured work culture.
In particular, he points to the need for autonomy or what he refers to as "self efficacy". A name that crops up frequently these days is that of the American Professor of Organisational Behaviour, Jeffrey Pfeffer.
The Stanford Business School professor recently published a best seller called Dying for a Pay Check in which he poses the question — is your workplace killing you?
Ms Pfeffer and his team have drawn together much of the research carried out into the impact of workplace-related stress to produce a series of aggregate findings.
They have concluded that work related stress and excessive working hours have contributed to an excess of 12,000 deaths per annum in the US at a cumulative annual cost of close to $200bn.
The Stanford professor cites a number of key culprits — economic insecurity, shift work, a lack of workplace health insurance (the biggest ultimate cause of mortality, in his view).
He concludes that employers ignoring their responsibilities to their workforce are passing on a big cost to the wider society and are responsible for a form of social pollution every bit as noxious as the environmental pollution that was so prevalent a generation ago in many industrial sectors.
Says Mr Pfeffer: "You don't have to do a dangerous job in a mine, or on a commercial fishing boat to endure a life-threatening or health-destroying workplace."
He cites the case of an overworked finance manager who develops a drug or alcohol addiction; the news producer who gains 60lb because they have no time in which to eat or exercise properly; or the marketing professional who ends up being prescribed anti-depressants.
The CIPD would appear to endorse much of Mr Pfeffer's critique.
Its latest membership survey focuses on the role played by line managers in organisations and the difficulties in relations between this key grade and HR managers.
Close to one half of respondents concluded that there is a lack of support for line managers coming from the top and that this in turn, is acting as a hindrance to HR as its seeks to develop people policies and practices.
Over one quarter of respondents mentioned a lack of senior manager commitment to learning and development.
According to the CIPD, the following question must be asked: Why are the business leaders not supporting line manager so as to enable them to deliver on the people management agenda in the organisation?
In its view, 'line managers' role as people managers has to be a recognised strategic part of the business?' But how can this be achieved at a time when the current trend to squeeze the numbers of line or middle managers?
There is plenty of evidence that in mature organisations you tend to get a surplus of managers engaged often in routine tasks.
However, rounds of restructuring implemented without careful thought being put into a re-imagining of roles can produce an end result of poor morale and high levels of stress.
We are currently in that sweet spot in the economic cycle where demand for people with skills is strong and when the people at the top fret about the welfare of their staff, concerned that they may lose them to another organisation with a more compelling offering.
We have been here before during the Noughties, but there are subtle differences.
Fewer organisations are in unassailable business niches. The pace of technological change means that almost everyone must now look over their shoulder so many, if not most, of the commercial insecurities of the long economic bust persist.
At the same time, younger employees — the so called 'Millennials' — are less loyal, and far more inclined towards mobility than was the case 15 or 20 years ago.
This presents a conundrum for senior management, many of whom are engaging in firefighting as traditional customer bases experience erosion.