text:
I remember few concrete things from the wacky Jetsons cartoon. But certain things remain sharp. They had robot football, this angered me. They also had a machine that could control dreams. You got to dream about whatever you wanted. How cool would that be?
I find the older I get the more garbage my dreams are. It's a mess of bad nonsense. I can barely remember a thing. I think a pet dinosaur stole my television. Whatever.
But Japan is there quite often in a way nowhere else is. I have no idea why. I haven't been to Japan in ten years. Money and time keep getting in my way.
I think it's because I lived there. I suppose I equally dream about places I lived growing up and just think nothing of it. Japan's different because it's the outlier.
I'm usually like scaling mountains, or somewhere near the water, and always roto-sushi. I'm always wandering around crowded streets trying to find a place to eat roto-sushi. If I was a billionaire I'd first open my own brewery. Then I'd open my own roto-sushi place so I could visit it forever.
I don't know what all this means. Don't really care. So whatever, here's a shot of Fugi in the fog I took back then. This seems dream-like. Win.


text:
In celebration of my shopping Odyssey on Saturday and Monday night, I'd like to share with you all the stores I visited in search of the perfect pair of plain, shiny, brown dress shoes (preferably a slip-on):
SATURDAY (Arizona Mills)
Famous Footwear
Kenneth Cole
Rack Room Shoes
Shoe Pavilion
Robert Wayne Footwear
I estimate on Saturday I tried on 15 pairs of shoes, finally going into any shoe store we passed just to look. Nothing. Everything was ugly, didn't fit right, didn't come in my size (I'm a perfect 11 1/2), or felt like strapping bricks to my feet.
Monday night I resolved to go out after work, with some desperation, in the hopes I could have these by the start of our conference on Wednesday. Was I being to restrictive? Too inflexible? Was I asking for too much? Did what I want even exist??
MONDAY (Biltmore Fashion Park)
Macy's–almost left with an uncomfortable pair of Steve Maddens, but pressed on
Cole Haan
Apple store (my laser printer just died and I needed to scope out prices)
While at the Apple store, I searched for the nearest DSW, which was 15 miles away…in the suburbs!
So, I drove there.
MONDAY (Chandler Fashion Center)
Spent and hour and a half trying on 13 pairs of shoes, all wrong.
Frantic, I declared a shoe crisis! I called my man in Texas and asked for suggestions. He said, "You certainly seem to know what you want," echoing the salesperson's comment to Jimmy Stewart in Vertigo. And perhaps I was that obsessed.
Beaten, desperate, uncertain, I returned to Arizona Mills.
MONDAY (Arizona Mills)
Kenneth Cole
At Sketchers, I realized what I also needed to do was replace my casual brown shoes because the soles were cracked in half. I bought those, and because they always have buy one/get one half off, I got a cute pair of sneakers as a bonus for off-setting part of the shoe crisis.
Then, on my second visit to Kenneth Cole, nearly in tears, I tried on several wrong shoes and started to leave
and there they were
just sitting there on a shelf under a sign that said "SALE"
and they were beautiful, nearly everything I'd wanted (they lace up) and when I looked, they had my EXACT SIZE.
I slipped my foot in and it was love.

subset: commoncrawl


text:
Preparing for a digital age, Logiscool at the Naples Accelerator teaches kids to code
It's 3:30 p.m. on a Wednesday, and Rillia Gurley just finished working on her reading lesson about flamingos with her daughter Portia, 5.
It's time to start her next lesson, so little Portia takes off down the hall and around the corner to her next class.
Portia, a kindergartner, is the youngest student enrolled in the first U.S. location of the international gamified coding school, Logiscool — at the Naples Accelerator, a business accelerator and co-working space.
More:Apple pushes to teach coding to students who are deaf and blind
To be fair, Portia might not necessarily be learning coding, but she's building the foundation of computer skills to get there, like some of her older peers.
"I'm happy with what I'm seeing," Rillia Gurley said. "Everything they're saying, they're doing. That's important."
Workers at the Naples Accelerator office might be surprised to know kids are getting these lessons on the second floor.
A larger class might take place in one of the conference rooms where students sit at laptops and work on their lesson for the day.
If the class is smaller, like Portia's, students might go to an office and work more closely with instructors.
Classes are offered on a semester basis and cost about $200 a month per student, although there are possibilities for scholarships and discounts available based on family circumstances, military service or financial need.
More:Why Silicon Valley is teaming up with San Quentin to train young people to code
The classes are typically offered for students between the ages of 6 and 18 and are separated into course levels depending on skill.
Peter Ocsody, head of business operations and strategy with Logiscool, said the students get some level of evaluation, although they don't get letter grades. Instructors may also recommend adjustments to which courses students are enrolled in, based on how well they're grasping the material.
"To a certain extent, it's just like a regular school. Some kids really excel," Ocsody said.
In a class including some fourth-graders, the instructor taught the students how to code a game using the proprietary coding language scoolcode. In these lessons, students learned to program a game where a cat chased a mouse in its pursuit of cheese.
The students dragged and dropped modules that dictated how the game behaved, choosing variables like whether to make the cat skinny or fat or if they wanted their mouse to be a dragon instead, and so on.
The instructors are computer science college students, although they receive training to make sure they're up to working with kids.
More:Teen wins Snapchat/Google coding contest with filter that dreams of uniting
Logiscool began in Budapest, Hungary, and now has more than 50 locations in 11 countries, and Naples, which opened in October, is the first in the U.S.
Naples has 38 students, Ocsody said, but he hopes to market the classes more aggressively to get 80-100 students for next semester, which begins in February.
Logiscool administrators also hope to expand to another permanent location in Naples, as well as opening schools in Tampa and Fort Lauderdale.
"I feel it's very important that every kid learn coding. It is an essential and a must-have skill going forward in the future," Ocsody said.
The number of jobs in the computer industry is certainly expected to grow. According to the U.S. Bureau of Labor Statistics, jobs for software developers are expected to grow by 24 percent by 2026 — much faster than average.
More:10-year-old app developer's advice to other kids: Get coding now
Bridget Guerrero, regional manager with Logiscool, said the schools help encourage creativity, in addition to coding skills.
"What we see is that when we give them the skill sets and allow them to be creative, then boom, there's just like a revolution where kids are not just able to think critically, think creatively, but let their imagination go," she said.
That's something Gurley appreciates for her daughter. Portia picked up playing "Minecraft" with her aunt after beginning at the school, Gurley said. She likes the family interaction and creativity elements.
Portia seems to like it, too. She said she likes making volcanoes, so she takes her mouse, clicks on the water and drags it up, flooding a crater jutting from the ground.
"It exploded," Portia said.
That's a creative way to make a volcano.


text:
One of the many fringe benefits of writing a book with an associated website is that I've been contacted by many old friends, colleagues and acquaintances. There was Mary McCarthy who I last spoke to at St Collette's primary school in, let me see, 1975. She's now a journalist in Spain. Then there was Stephen Davren, a chum from college days who sent me those pictures of his teddy bear enjoying my book. And now, from way across the Atlantic, up pops Colin MacPhail (pictured), former producer with BBC Radio Scotland's Tom Morton Show. He left Inverness to pursue American adventures in forestry, then gin-making and now is the owner of the Vinfabula consultancy in California and writes extremely funny and informative articles about wine under the heading Cabernet Confidential. This, for instance, is some of his advice for the would-be connoisseur:
"Rule #3 – Stop and think. One of the great blessings of wine is it causes us to pause in our busy lives and savor the moment and how lucky we are to enjoy it. Take your time. If you have a long day ahead, spit the wine out into a spit bucket. That's OK. If you have a designated driver you can forge ahead on your sampling. Taste too much and you are doing something called "drinking." That you can do at home."
That line about tasting too much reminded me of a trip I made to Washington State back before the turn of the century. This century, I mean, not the one before. Turn of the millennium really. It was one of those press junkets organised by the tourism people in Seattle and my news editor at Radio Clyde must have been in a good mood when he nominated me for the week-long jolly. As I recall, there was about eight of us on the trip. I was one of two radio reporters and the others were London-based newspaper or magazine journalists. We were ferried hundreds of miles in a luxury mini-bus and shown the delights of the Seattle grunge scene, got to do horseback riding in an upstate ranch (in a thunderstorm) and given the VIP treatment in a Washington winery. I mean, we were really welcomed as Royalty, with the management and guides addressing us collectively as Her Majesty's British Press and, initially, at least, treating us with the deference they might have shown to the Queen herself.
At this point I should admit that we sustained ourselves on these long bus trips by passing around a bottle of Jack Daniels which we washed down with more Jack Daniels, so by the time we arrived at the posh winery we were already in the party mood. Nevertheless, for the first few minutes we listened respectfully and attentively as our guide told us about the history of wine production in Washington, about soil conditions and grape varieties and then proudly poured sample after sample of their various products. There was no question of us tasting and spitting, we drank like we were on the eve of Prohibition and asked for refills. Polite murmurs of appreciation soon gave way to raucous laughter. Crystal flutes held properly by the stem, soon slipped from our fingers. The subsequent raised voices and the sound of shattering glass made me feel very much at home. Like I was back in Glasgow: The Horseshoe Bar, perhaps.
Sooner than scheduled, a Seattle P.R. representative was scooping us back on to the mini bus and we were being waved off by the open-mouthed staff. Don't ask me to tell you the name of the place. Everything after that was a blur.
I just hope the Queen never finds out about that trip.


text:
Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS1, PS3, PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Pick's disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73640371 A>C
dbSNP ID: rs63750306
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ATG to CTG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5
Research Models: 14
This pathogenic mutation has been detected in at least 15 families worldwide. In 2010, haplotype analysis revealed that these kindreds were in fact one extended kindred. A common founder effect was determined to account for the presence of this mutation in more than 148 affected individuals dispersed over several centuries and multiple continents. The origin of the mutation was traced to a single family originating from Southern Italy before the 17th century (Bruni et al., 2010; Borrello et al., 2016).
The M146L mutation was first reported in two families in conjunction with the cloning of the PSEN1 gene in 1995 (Sherrington et al., 1995). The families, known as FAD4 and Tor1.1, had roots in southern Italy and were later shown to share a common ancestor (Bruni, 1998). Age of onset in both families was approximately 43 years old.
The FAD4 pedigree, also known as the N family, was described prior to the identification of the mutation (Foncin et al., 1985). The family was reported to consist of 43 patients with Alzheimer's disease. Thirteen were known by history, 21 by medical record, and nine by clinical examination. Five were confirmed histopathologically to have AD. The clinical picture was fairly uniform: The first symptom was memory loss, beginning around age 40. Psychotic-like symptoms often followed, then profound dementia, and death around age 50. Akinesia was a prominent late feature, often with myoclonus. Grand mal seizures sometimes occurred. A branch of this family, Okla1(FAD4), with three affected individuals over two generations, closely matched what was reported for the family at large, with onset at about 43 years (Clark et al., 2005). An additional individual related to this family (p.49) with onset of dementia at 37 years has been reported elsewhere (Finckh et al., 2005).
The Tor1.1 family, from Torino Italy, had a history of early onset AD. When it was first reported in 1991, the pedigree comprised 1,500 members over eight generations. Twenty-two patients with AD were identified, one with a confirmed AD diagnosis by autopsy. The pattern of inheritance was consistent with autosomal-dominant transmission. The clinical course in this family was noted to be fairly uniform, with a high incidence of myoclonic jerks and epileptic seizures. Psychiatric symptoms such as hallucinations and delusions were frequent later symptoms (Bergamini et al., 1991; Rainero et al., 1994).
Three additional Italian families were reported (Sorbi et al., 1995) and later linked to the Italian kindreds FAD4 and Tor1.1 (Bruni et al., 2010). Two of the families had classical clinical and neuropathological AD, with mean age of onset of 45 ± 3 and 36 ± 3. Death in both families typically followed four to five years after onset. The third family had early onset age (35 ± 2 years) but a relatively slow clinical course of disease, starting with selective memory impairment for two to three years. One member of this family died 18 years after onset. Postmortem examination confirmed the diagnosis of AD.
A French family carrying this mutation was described and segregation demonstrated. As reported, the family, ALZ 204, had six affected individuals over three generations. Onset ranged from 38 to 47 years (Campion et al., 1999). This family was later determined to be a branch of the Tor1.1 family (Bruni et al., 1998).
Two patients carrying the mutation were reported (Rogaeva et al., 2001). Clinical details, demographic information, and family history were not included in the publication.
A family with three affected individuals over three generations was described. This family was of Italian and Greek heritage. Two of the affected members were examined neuropathologically following their deaths at ages at 46 and 48. Disease duration was seven and eight years, with onset at age 39 and 40. Mixed neuropathology was found at autopsy with frequent plaques and tangles (Braak and Braak score of 6) and numerous Pick bodies (Halliday et al., 2005).
The mutation is absent from the gnomAD variant database (gnomAD v.2.1.1, May 2021).
Neuropathology consistent with a diagnosis of AD was observed in multiple affected mutation carriers. Moreover, Pick bodies have been noted in some cases (Halliday et al., 2005). Also, one carrier of the M146L mutation (nucleotide change unspecified) was reported to have Lewy body pathology, as assessed by α-synuclein staining, in the amygdala, cingulate gyrus, and substantia nigra (Leverenz et al., 2020).
Biological Effect
The summary below focuses on the M146L substitution, regardless of its underlying nucleotide change which, in some cases, is not reported.
In vitro, this mutation has been found to increase Aβ42 and Aβ40 levels, as well as the Aβ42/Aβ40 and Aβ42/Aβ total ratios (Page et al., 2008; Sato et al., 2003; Shioi et al., 2007; Sun et al., 2017). Consistent with these findings, Aβ42 levels and the Aβ42/Aβ40 ratio were found increased in conditioned media from M146L mutant fibroblasts and iPSC-derived neurons (Liu et a., 2014; Schrank et al., 2020; Kakuda et al., 2021). Although one study found no significant changes in Aβ38 and Aβ40 levels (Liu et al., 2014), another reported decreases in both, as well as in Aβ43 levels (Kakuda et al., 2021). Of note, an analysis of several familial AD mutations revealed a correlation between higher Aβ40/Aβ43 ratios in cells and older onsets of disease in carriers; however, M146L was an outlier, with a high Aβ40/Aβ43 ratio and a relatively early onset of disease. Analyses of the short peptides produced during APP processing provided further insights into this and other alterations.
A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that, in wild-type PSEN1, M146 closely contacts the APP transmembrane helix, with its side-chain reaching towards the interior of the substrate-binding pore (Zhou et al., 2019; Jan 2019 news).
The M146L mutation also cleaves the calcium sensor STIM1 more efficiently than wild-type PSEN1 in vitro. This appears to impair calcium influx via STIM1 degradation and reduces spine density in cultured cells (Sep 2016 news; Tong et al., 2016). The mutation has also been reported to enhance gating of the IP3 receptor channel and increase the open probability of the mitochondrial permeability transition pore (Toglia and Ullah, 2016). Additionally, iPSC-derived neurons were found to release elevated levels of calcium from the endoplasmic reticulum in response to ryanodine receptor stimulation, a response that was normalized by incubation with dantrolene, a negative allosteric modulator (Schrank et al., 2020).
Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021).
The M146L (A>T) mutation, resulting in the same codon change, has also been found in AD patients. Of note, experiments describing the biological effects of M146L do not always specify which nucleotide change was tested.
Alzheimer's Disease : Pathogenic
This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. M146L (A>C): Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion. M146L (A>C): At least one family with >=3 affected carriers and >=1 unaffected noncarriers.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant's PHRED-scaled CADD score is greater than or equal to 20.
|Pathogenic (PS, PM, PP)
|Benign (BA, BS, BP)
|Criteria Weighting
|Strong (-S)
|Moderate (-M)
|Supporting (-P)
|Supporting (-P)
|Strong (-S)
|Strongest (BA)
Research Models
This mutation has been introduced into several mouse models of disease, including the single-transgenic PS1(M146L), the double-transgenic PS/APP, and the widely used 5xFAD, which also carries three APP mutations and the PSEN1 mutation L286V.
Last Updated: 15 Aug 2022
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Research Models Citations
News Citations
- CryoEM γ-Secretase Structures Nail APP, Notch Binding
- Mutant Presenilin Skews Calcium Homeostasis by Chomping on ER Sensor
Mutations Citations
Paper Citations
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- Borrello L, Cupidi C, Laganà V, Anfossi M, Conidi ME, Smirne N, Taverniti M, Guarasci R, Bruni AC. Angela R.: a familial Alzheimer's disease case in the days of Auguste D. J Neurol. 2016 Dec;263(12):2494-2498. Epub 2016 Oct 11 PubMed.
- Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin JF, Bruni AC, Montesi MP, Sorbi S, Rainero I, Pinessi L, Nee L, Chumakov I, Pollen D, Brookes A, Sanseau P, Polinsky RJ, Wasco W, Da Silva HA, Haines JL, Perkicak-Vance MA, Tanzi RE, Roses AD, Fraser PE, Rommens JM, St George-Hyslop PH. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995 Jun 29;375(6534):754-60. PubMed.
- Bruni AC. Cloning of a gene bearing missense mutations in early onset familial Alzheimer's disease: a Calabrian study. Funct Neurol. 1998 Jul-Sep;13(3):257-61. PubMed.
- Foncin JF, Salmon D, Supino-Viterbo V, Feldman RG, Macchi G, Mariotti P, Scoppetta C, Caruso G, Bruni AC. [Alzheimer's presenile dementia transmitted in an extended kindred]. Rev Neurol (Paris). 1985;141(3):194-202. PubMed.
- Alzheimer's Disease Collaborative Group. The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Nat Genet. 1995 Oct;11(2):219-22. PubMed.
- Finckh U, Kuschel C, Anagnostouli M, Patsouris E, Pantes GV, Gatzonis S, Kapaki E, Davaki P, Lamszus K, Stavrou D, Gal A. Novel mutations and repeated findings of mutations in familial Alzheimer disease. Neurogenetics. 2005 May;6(2):85-9. Epub 2005 Mar 18 PubMed.
- Bergamini L, Pinessi L, Rainero I, Brunetti E, Cerrato P, Cosentino L, Vaula G, Bruni AC, Ermio C, Gei G. Familial Alzheimer's disease. Evidences for clinical and genetic heterogeneity. Acta Neurol (Napoli). 1991 Dec;13(6):534-8. PubMed.
- Rainero I, Bergamini L, Bruni AC, Ferini-Strambi L, Foncin JF, Gei G, Macciardi F, Montesi MP, Pinessi L, Vaula G. A new Italian pedigree with early-onset Alzheimer's disease. J Geriatr Psychiatry Neurol. 1994 Jan-Mar;7(1):28-32. PubMed.
- Sorbi S, Nacmias B, Forleo P, Piacentini S, Sherrington R, Rogaev E, St George Hyslop P, Amaducci L. Missense mutation of S182 gene in Italian families with early-onset Alzheimer's disease. Lancet. 1995 Aug 12;346(8972):439-40. PubMed.
- Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, Thomas-Anterion C, Michon A, Martin C, Charbonnier F, Raux G, Camuzat A, Penet C, Mesnage V, Martinez M, Clerget-Darpoux F, Brice A, Frebourg T. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999 Sep;65(3):664-70. PubMed.
- Rogaeva EA, Fafel KC, Song YQ, Medeiros H, Sato C, Liang Y, Richard E, Rogaev EI, Frommelt P, Sadovnick AD, Meschino W, Rockwood K, Boss MA, Mayeux R, St George-Hyslop P. Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
- Halliday GM, Song YJ, Lepar G, Brooks WS, Kwok JB, Kersaitis C, Gregory G, Shepherd CE, Rahimi F, Schofield PR, Kril JJ. Pick bodies in a family with presenilin-1 Alzheimer's disease. Ann Neurol. 2005 Jan;57(1):139-43. PubMed.
- Leverenz JB, Fishel MA, Peskind ER, Montine TJ, Nochlin D, Steinbart E, Raskind MA, Schellenberg GD, Bird TD, Tsuang D. Lewy body pathology in familial Alzheimer disease: evidence for disease- and mutation-specific pathologic phenotype. Arch Neurol. 2006 Mar;63(3):370-6. PubMed.
- Page RM, Baumann K, Tomioka M, Pérez-Revuelta BI, Fukumori A, Jacobsen H, Flohr A, Luebbers T, Ozmen L, Steiner H, Haass C. Generation of Abeta38 and Abeta42 is independently and differentially affected by familial Alzheimer disease-associated presenilin mutations and gamma-secretase modulation. J Biol Chem. 2008 Jan 11;283(2):677-83. PubMed.
- Sato T, Dohmae N, Qi Y, Kakuda N, Misonou H, Mitsumori R, Maruyama H, Koo EH, Haass C, Takio K, Morishima-Kawashima M, Ishiura S, Ihara Y. Potential link between amyloid beta-protein 42 and C-terminal fragment gamma 49-99 of beta-amyloid precursor protein. J Biol Chem. 2003 Jul 4;278(27):24294-301. PubMed.
- Shioi J, Georgakopoulos A, Mehta P, Kouchi Z, Litterst CM, Baki L, Robakis NK. FAD mutants unable to increase neurotoxic Abeta 42 suggest that mutation effects on neurodegeneration may be independent of effects on Abeta. J Neurochem. 2007 May;101(3):674-81. Epub 2007 Jan 24 PubMed.
- Sun L, Zhou R, Yang G, Shi Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.
- Liu Q, Waltz S, Woodruff G, Ouyang J, Israel MA, Herrera C, Sarsoza F, Tanzi RE, Koo EH, Ringman JM, Goldstein LS, Wagner SL, Yuan SH. Effect of potent γ-secretase modulator in human neurons derived from multiple presenilin 1-induced pluripotent stem cell mutant carriers. JAMA Neurol. 2014 Dec;71(12):1481-9. PubMed.
- Schrank S, McDaid J, Briggs CA, Mustaly-Kalimi S, Brinks D, Houcek A, Singer O, Bottero V, Marr RA, Stutzmann GE. Human-Induced Neurons from Presenilin 1 Mutant Patients Model Aspects of Alzheimer's Disease Pathology. Int J Mol Sci. 2020 Feb 4;21(3) PubMed.
- Kakuda N, Takami M, Okochi M, Kasuga K, Ihara Y, Ikeuchi T. Switched Aβ43 generation in familial Alzheimer's disease with presenilin 1 mutation. Transl Psychiatry. 2021 Nov 3;11(1):558. PubMed.
- Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
- Tong BC, Lee CS, Cheng WH, Lai KO, Foskett JK, Cheung KH. Familial Alzheimer's disease-associated presenilin 1 mutants promote γ-secretase cleavage of STIM1 to impair store-operated Ca2+ entry. Sci Signal. 2016 Sep 6;9(444):ra89. PubMed.
- Toglia P, Ullah G. The gain-of-function enhancement of IP3-receptor channel gating by familial Alzheimer's disease-linked presenilin mutants increases the open probability of mitochondrial permeability transition pore. Cell Calcium. 2016 Jul;60(1):13-24. Epub 2016 May 7 PubMed.
- Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.
Other Citations
External Citations
Further Reading
- Bernardi L, Gallo M, Anfossi M, Conidi ME, Colao R, Puccio G, Curcio SA, Frangipane F, Clodomiro A, Mirabelli M, Vasso F, Smirne N, Di Lorenzo R, Maletta R, Bruni AC. Role of TOMM40 rs10524523 Polymorphism in Onset of Alzheimer's Disease Caused by the PSEN1 M146L Mutation. J Alzheimers Dis. 2013 Jan 1;37(2):285-9. PubMed.
- Swerdlow RH. An Alzheimer disease presenilin mutation, syndrome diversity, and a shrinking world. Neurology. 2010 Mar 9;74(10):790-1. PubMed.
- Zarea A, Charbonnier C, Rovelet-Lecrux A, Nicolas G, Rousseau S, Borden A, Pariente J, Le Ber I, Pasquier F, Formaglio M, Martinaud O, Rollin-Sillaire A, Sarazin M, Croisile B, Boutoleau-Bretonnière C, Ceccaldi M, Gabelle A, Chamard L, Blanc F, Sellal F, Paquet C, Campion D, Hannequin D, Wallon D, PHRC GMAJ Collaborators. Seizures in dominantly inherited Alzheimer disease. Neurology. 2016 Aug 30;87(9):912-9. Epub 2016 Jul 27 PubMed.
- Elsworthy RJ, Crowe JA, King MC, Dunleavy C, Fisher E, Ludlam A, Parri HR, Hill EJ, Aldred S. The effect of citalopram treatment on amyloid-β precursor protein processing and oxidative stress in human hNSC-derived neurons. Transl Psychiatry. 2022 Jul 18;12(1):285. PubMed.
Protein Diagram
Primary Papers
- Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin JF, Bruni AC, Montesi MP, Sorbi S, Rainero I, Pinessi L, Nee L, Chumakov I, Pollen D, Brookes A, Sanseau P, Polinsky RJ, Wasco W, Da Silva HA, Haines JL, Perkicak-Vance MA, Tanzi RE, Roses AD, Fraser PE, Rommens JM, St George-Hyslop PH. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995 Jun 29;375(6534):754-60. PubMed.
- Sorbi S, Nacmias B, Forleo P, Piacentini S, Sherrington R, Rogaev E, St George Hyslop P, Amaducci L. Missense mutation of S182 gene in Italian families with early-onset Alzheimer's disease. Lancet. 1995 Aug 12;346(8972):439-40. PubMed.
- Alzheimer's Disease Collaborative Group. The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Nat Genet. 1995 Oct;11(2):219-22. PubMed.
Other mutations at this position
Disclaimer: Alzforum does not provide medical advice. The Content is for informational, educational, research and reference purposes only and is not intended to substitute for professional medical advice, diagnosis or treatment. Always seek advice from a qualified physician or health care professional about any medical concern, and do not disregard professional medical advice because of anything you may read on Alzforum.


text:
Sarah Koehn introduced Phase 1: Personal Leadership, the first of three phases, and left behind a couple of points for the ambassadors to ponder. "A leader leads by example whether they intend to or not," is the first thought she left them with. Everything you do, any where you go, and everybody that you meet will be affected by you and your leadership. She also expressed there is good in the bad, and bad in the good. She related this to the image of a ying yang, a little bit of white in the black and a little bit of black in the white. To apply this concept, Sarah had the ambassadors write down their good qualities, then what bad things might come out of it, and their bad qualities, and the good things that might come out of it.
Going along with Phase 1 was our first panel covering entrepreneurship. Each phase contains a panel, and each panel consists of approximately three parties. In this case, the panel included entrepreneurs that have varying experiences with starting and running their own businesses. The panelists were Dave Dreiling with GTM Sportswear, Anne and Mike Hill with HRC Apartments and Townhomes, and Erica Short with Anecdotally Yours. The panelists introduced themselves and told a little about their company before the ambassadors were encouraged to ask them questions. The ambassadors asked interesting questions about anything from advertising through social networking, to the difficulties of starting a business, to the effects on their family lives.


text:
We found 1 episode of The Earth Station One Podcast with the tag "earth station one podcast ep 544".
The Earth Station One Podcast - The Best &#$@ I Have Ever Eaten II
October 1st, 2020 | Season 11 | 2 hrs 27 mins
angela pritchett, ashley pauls, cheryl gendron, earth station one, earth station one podcast, earth station one podcast ep 544, eso, eso network, food review, food review podcast, geek podcast, keith johnson, michael gordon, michelle bourg, mike ehmcke, mike faber, monte michael moore, podcast, the best &$#% i ever ate ii
It has been said that good food brings folks together and that certainly is the case when Mike, Mike, Cheryl Gendron, and Keith Johnson are hungry for more talk on the best places to get the best food. Plus, resistance is futile for Mike Ehmcke of the We Be Geeks collective as he is assimilated into the Geek Seat, and artist Monte Michael Moore gives an advance peak at his new sketchbook. All this, along with Angela's A Geek Girl's Take, Ashley's Box Office Buzz, Michelle's Iconic Rock Moments, and Shout Outs!
We want to hear from you! Feedback is always welcome. Please write to us at firstname.lastname@example.com and subscribe and rate the show on Apple Podcast, Stitcher Radio, Google Play, Spotify, Pandora, Amazon Music, or wherever fine podcasts are found.


text:
It's funny how easy it is to forget to mention certain sensory details, whereas others come out automatically. Most of us go for visual description as our primary focus, with auditory details as a close second, touch being prominent mostly during scenes of sex or violence, with smell barely mentioned and taste almost forgotten. Granted, it's hard to separate taste and smell, since if one is mentioned the other is generally implied.
But even within the confines of visual and auditory elements, there is, in fiction in general, a woeful disregard for the atmospherics of weather. It's so much a part of our daily setting. It can color our mood, affect our decisions for what to do with our day, change the dynamics of a conversation. It changes the feel and flavor of the air, the smells that carry or get washed away, whether we listen to birdsong or rainfall all afternoon. It can be soothing, frightening, frustrating, or blissful.
How the weather affects people can be anything from a home destroyed by a tornado or a flood to road rage from not having AC in the car, from draught affecting crops to seasonal depression. A sudden thunderstorm could interrupt a lover's spat, reuniting the couple as they run for cover together, forgetting their differences just long enough to realize the whole argument is unimportant compared to their mutual affection and respect for one another. A hot summer day can sizzle away at a frustration until it festers into murderous rage. A cool rain can bring relief and cleansing on a dusty, dry garden. A snowstorm can trap a group of travelers, blocking their progress. Torrential storms can force someone to pull off the highway, giving him time that maybe he'd rather not have to think about what he just said to his mother. A clear, starry night can make a character feel small and insignificant and lost – or like she belongs to a larger whole, freeing her from the worries of the moment.
People talk about the weather, gripe about it, relish it, go out in it, stay in because of it, take shelter from it, survive it. Writers, take note, and USE IT!


text:
The Pridon den is dark and smoky, just the way I like it. I am taken into a small room where the floor is literally filled a foot deep with pillows. I find a good spot and lie down, the moment I do wisps of smoke fall from the vents around the ceiling. As it drifts down towards me I try and find a good memory to relive but only one comes to me, I can't fight it off in time.
Anita bursts through the door, gun at the ready. She likes to do the manly things without giving me the chance to, she calls it equality of the sexes but I call it emasculating. The warehouse is dark when she and I enter, I told the O.R.B. teams to stay outside for now. She takes the lead to find a way to get to the second floor. My source said that Horace would be in the design rooms of the Landen building, getting the place ready to be torched.
"Where are we Leo?" she asks, not looking back at me.
"The spectacles say we are on the east wing and need to make it to the other side of the building for the lift. Laura said he would be up on the second floor—"
I don't get to finish when the shadow men emerge and charge us. I blast two dead in the chest and they hit the ground writhing in electric pain, they won't be getting up any time soon. Anita leaps over a conveyor belt, tackling one of the assailants. Two more jump in after her; I can hear the poor fools begging her for mercy as three try to take me at once. One gets the butt of my gun to the chin, the second takes a boot to the groin and a knee to the face, and the last one squares off waiting for a fist fight… I shoot him with a suppression dart.
Fighting your way to the main target without notice only happens in video games. As we beat and blast more shadow men the intercom clicks on and Horace's laugh pierces though the air, "Look at the little mice running around the maze. Two blind mice looking for the cheese prize, little do they know that they are about to turn the wrong corner and get zapped."
The last of the shadow men falls and we continue to make our way to the lift. Anita sticks close in case there is another ambush, every machine looks like another attacker. My spectacles strain to keep us on the right track in the low light; I hate not having been authorized the upgrade for night vision. We finally reach the west wall but there is no lift, I touch the wall and hang my head in defeat.
"Buzz! Poor little mice, you are so close to the cheese." I begin to make my way to the right when his cackle rings, "Getting warmer, much warmer. Keep sniffing me out little mice."
My hand touches glass; I've found the lift door. "Good job little mice, as a reward I'll let you up without killing you in the uppidy box."
My hands shake a bit as we go into the well-lit lift, I try to hide this from Anita. She looks at me and quickly looks away. Not looking up at her I say, "There will be fewer obstacles up here, which means less cover. When the doors open you jump left and I'll go right."
Without responding she nods and jumps left as soon as the doors open. I barely make it to cover when a bullet hits the spot on the wall where my head was. Anita wastes no time in taking out more of the shadow men. While she keeps them busy I make my way back to the eastern side of the building. From where I am I can't see the design rooms, there is a large mass with a tarp over it in the center of the room. All of the prototype tables are pushed up against the walls. I crawl towards the tarp; I can hear Anita successfully fending off the shadow men. Lifting the tarp I find the Icktar, glass bricks of purple swirls, stacked underneath.
"There he is." A pair of shadow men pounce on me, I shoot wildly at them. My darts hit them square in the face. It doesn't kill them, but I need to be more careful, which is damn near impossible with my hands shaking.
Anita finds me on the floor and helps me up; I can't help but feel a bit ashamed. Dusting myself off, she says, "I think I got all of the shadow men. Horace is all that's left, let's go."
"No, no, not this. Not this memory, please." I am back in the Pridon den, forcing myself out of the hallucination. I don't want to be here anymore, let me out. It doesn't work.
"Look at you two, you found the cheese and don't know what to do with yourselves." Horace says, holding up the Icktar detonation switch. Anita and I have our guns pointed at him but are eyeing the now uncovered explosives next to us.
Horace starts to pace, never breaking eye contact with me, his long pale and slender body moving in and out of shadow. His eyes glisten with delight as he holds the detonator caringly in his left hand, the hand of a corpse. "Oh how the Master will be proud of me. You know he has taken a liking to you Leonardo. Calls you his adversary, but says you will soon become his equal."
"Who is the Master?" I need to keep him busy enough for one of us to get a good shot.
"You will find out soon enough, oh I promise you that." He stops, half in shadow. "Sadly your little mouse friend won't have the great privilege."
He throws his head back in laughter; I take a shot in the dark and hit the detonator with a slime pellet. It sticks to the window and my heart drops, both Anita and I look at the Icktar, expecting it to detonate but it sits undisturbed. This gives Horace time to activate one of the machines nearest us, Anita ducks but I'm not fast enough. The mechanical arm slams into my head and throws me into another machine, my gun goes flying. When I finally stand I only have time to see the victorious grin on Horace's face before he fires.
Anita falls backwards to the floor. Something inside me snaps and I leap at Horace, we smash into the glass doors that lead into the design rooms. The tempered glass shatters but we don't go through, instead we fall back and he lands on top of me. I punch, kick and bite my way out from under him. My gun is gone so I grab an Icktar brick and bash the side of his head with it. Blood spews out of him and lands on my face and in my mouth, I don't relent. He doesn't fight back, he only laughs. The harder I beat the harder he laughs. That sound rings through my skull like the brick through his. Suddenly the brick in my hand brightens and heats up.
"Listen little mouse, can you hear them whisper to each other?" Horace says caressing the pile of Icktar that has also activated.
I jump off of him and run to Anita. We need to get out… but when I get to her she is lying lifeless on the floor, a pool of blood spilling out of the hole in her head. Touching her still warm skin I go cold; neither of us will leave this building alive.
As the room around me brightens and heats up, her hand shoots up at me and pulls me in, with her last breath she whispers, "Run, I love…"
Her hand falls back to the floor, I've lost her. I want to stay and find her but her words drown out Horace's laughter; they build up inside of me and give me the strength to run full force at the closest window.
Instead of falling down I am lifted up—up off the soft pillows of the den and into the arms of a much stronger man then myself. My eyes open and I find myself being carried through a drug raid by none other than Commander Romdar.


text:
Quality Health Information for
Quality Life
Good life is built on good health. Every Thursday evening The Big Carrot offers free lectures lead by nutritionists, naturopaths and other health care professionals. Curious about causes of aches and pains, cancer prevention, organics, controlling metabolism and much more? Come out learn more and make your good life better.
Where: Room 212, 348 Danforth Ave, Toronto.
When: 7 pm- 8:30 pm Thursday evenings. See The Big Carrot's calendar of events to see what is on that may interest you.
Cost: free.


text:
What: Indie Fiber Arts Marketplace and Fiber Arts Classes
Who: Everyone who loves to work with beautiful and unique yarn and fiber. There will be yarn and fiber dyers, teachers, spinners, designers, creators, and sewers – and, of course, you and your fiber loving friends!
Where: Wilkins School Community Center in Regent Square, 7604 Charleston Ave, Pittsburgh, PA 15218 **
When: Saturday November 14th, 2015, Marketplace will be open 10:00-4:00 and Classes will run 9-6
Why: Because this is the best place in Pittsburgh to score fabulous hand-made fiber arts supplies and learn new things! Come shop for your holiday knitting, gifts or… just for you!
and entry is free!
**Please note, this space is not handicapped accessible, and requires the climbing of several flights of stairs to get to the show. Despite efforts to raise the funds, the Community Center has not yet succeeded in getting enough money for an elevator.


text: Film Thalaivi is an upcoming Indian biographical film about the life of J. Jayalalithaa, politician and film actress who served six times as the Chief Minister of Tamil Nadu, with Kangana Ranaut playing the role of Jayalalithaa. Simultaneously shot in Hindi, Tamil and Telugu languages, it is directed by A. L. Vijay and produced by Vibri Media in collaboration with Karma Media And Entertainment. The film is scheduled for release on 23 April 2021 through the OTT service Netflix.


text:
I'm a student currently admitted to Integrated Ph.D. in Physical Science at the Indian Institute of Science, Banglore. More specifically, I'm in my first year (so it's equivalent to first is MS). I did my bachelor's in Science at Banaras Hindu University with Physics as a Major along with Mathematics and Statistics.
I like Physics as it's fun to imagine crazy things. Apart from physics, I like mathematics, Literature, and Philosophy. Sometimes I do sketching when in a certain mood. I also like to code physics simulations and generative art stuff. I'm on OpenProcessing, look here for my sketches.
I am too intelligent, too demanding, and too resourceful for anyone to be able to take charge of me entirely. No one knows me or loves me completely. I have only myself.
I am awfully greedy; I want everything from life. I want to be a woman and to be a man, to have many friends and to have loneliness, to work much and write good books, to travel and enjoy myself, to be selfish and to be unselfish… You see, it is difficult to get all which I want. And then when I do not succeed I get mad with anger.
Profile pic is a studio ghibli character from the movie Wishper of the heart.
Unsung HeroNov 24, 2020
FanaticJan 17, 2021
GeneralistDec 9, 2021
Strunk & WhiteNov 12, 2020
TenaciousNov 18, 2020
ProofreaderMar 8, 2021
quantum-mechanicsSep 14, 2021
ExplainerOct 31, 2020


text:
Have you ever seen the 1995 version of Sense and Sensibility starring Emma Thomson and Kate Winslet? Do you remember the song that Marianne sings in the movie (the scene where Colonel Brandon sees her for the first time)? Well, this is it! It was originally a poem supposedly written by an anonymous poet in the 1800s, although there are rumors that it was written by the English musician John Dowland in 1603 to an alternate tune. Whether either be true, it is a beautiful work of poetry and I wanted to share it.
Weep you no more, sad fountains;
What need you flow so fast?
Look how the snowy mountains
Heaven's sun doth gently waste.
But my sun's heavenly eyes
View not your weeping,
That now lie sleeping
Softly, now softly lies
Sleep is a reconciling,
A rest that peace begets.
Doth not the sun rise smiling
When fair at even he sets?
Rest you then, rest, sad eyes,
Melt not in weeping
While she lies sleeping
Softly, now softly lies
Have you ever seen the 1995 version of Sense and Sensibility?
Do you remember Marianne singing this song?
To watch a clip of this scene from Sense and Sensibility, click HERE!


text:
You met me
in Prague
waltzing around
the rim of my
wine goblet,
too late to join me
for dinner and
too late for
a shared glass
of Burgundy.
You buzzed to
let me know
you were there
–Victoria Emmons, 2017, Prague
You met me
in Prague
waltzing around
the rim of my
wine goblet,
too late to join me
for dinner and
too late for
a shared glass
of Burgundy.
You buzzed to
let me know
you were there
–Victoria Emmons, 2017, Prague
The invisible line is cast across the river,
across the canyon, or the ages, obstacles
that find us as we travel dusty roads, always
searching, forever unsure. Pleasure in
windblown branches hobbled against the slant
of a craggy mountain, predicted to lose,
yet they blossom, somehow gaining strength
from light and the occasional storm.
Rain is approaching current location
and is expected within thirty minutes.
The line reaches out, centuries compelled
to forge a lineage unbroken. The invisible line.
Our heritage. We cannot see them, nor they us.
Mere black and white images painted by the
hand of a craftsman or a Brownie Instamatic.
They smile or laugh, more often
furrow brows within the frames of their lives.
History recorded in a frown, perhaps too serious
the thought of the invisible line.
Rain is falling now.
The burden remains. Casting the line is all
too frightening, creates a link in a chain that
cannot be undone. Populate. Procreate. Pass.
The cycle begs for renewal. And so we perform.
In our innocence and duty, the people perform,
create the invisible line that stretches from
one generation to another. The line sends all
our oneness to the next and the next,
on down the line.
The wind blows harder.
Never an end of the line, just a passing
of the wonderment of life, love, creation,
knowledge, laughter, responsibility, inspiration,
thoughtfulness, caring, tolerance, joy, simplicity.
Never an end. Always a new beginning.
The invisible line is not broken, merely
reflected in the crystal blue eyes of a child,
the exploration of a scientific discovery,
the digital painting of a sorrowful face.
Black clouds ahead.
Cast your line. An ocean awaits. Sandy shores
reside amongst the clouds, no matter their color
or shape. The line must be cast. Too late for
indecision. Stretch out your heart to the next
in line. Leave your trace of glory to be retold
in story after story. The blessed line.
Follow it and find the softest space in Heaven,
find those who climbed in before you.
Rain clearing by tomorrow morning.
–Victoria Emmons, May 2017
for Uncle Jim
In fifteen minutes you and I will turn thirty.
That long ago, so much time vanished.
Fifteen minutes disappearing like thirty years.
At midnight, all those years will have passed.
That day we met, we cued up for good reason.
A boat too full let us laugh together instead,
share a beer at the hotel bar,
become friends and lovers for life.
Ten minutes remain until thirty years arrive.
We can soon celebrate a milestone,
worth a bottle of your best champagne.
Bubbles make me laugh. So do you.
I hear your laughter ring in my head. Yet
how heavy it seems. I carry that laughter with me.
Its joy and its burden. A love that will not end.
A memory that will not cease to exist.
Five more minutes and our thirty-year anniversary
becomes real. Aunt Wilma said thirties were the
best years. Best for everything. Her wisdom stays
with me. But after thirty years, a void appears.
Not the same without you, my love, despite the hour.
Remember our anniversary, my calendar tells me.
It is now done. Check you off my to-do list.
I remembered. No one else did.
–Victoria Emmons, 16 May 2017
Soft whimpers break the
silence of my room,
the only sound beyond your
breathing, the rhythm of
your chest undulating like
an ocean wave.
My toes find their way
under the sheets,
rearranging blankets
and a slippery bedspread
always askew.
Aches that appear only
at night rise up as
twists and turns remind
me of my sixth decade.
You are there, as my friend
forever loyal, cluttering
my bed with your bones.
–Victoria Emmons, 2017
The hour approaches, requires decisions to be made,
choices that will change the course of time,
forever alter your world and hers.
Mine, too.
The minute hand on the clock inches forward ever so softly without
a sound, without a warning of what is to come when that hand
strikes the hour, the hour of change. The hour you change into
someone else.
At six o'clock every day, the minute hand signals your time
to become a man I do not know. Monsieur numéro deux.
Smart at first, funny and suave, le Monsieur
slides into his role with ease.
Master of your own universe, master of what flows into your life,
into your mouth and what flows out of it. Join the party.
Forget whatever must be forgotten.
Be the life you do not lead.
The clock strikes seven, sixty minutes past the bewitching hour
of thoughtful worry about what to do. You lose track of time.
No meaning, no measure. Only the taste of decision lingers
on your tongue.
Indecision, the hand strikes again, this time for naught. Cheeky.
Lose what you have gained. Want what you do not want.
Have what you do not have. Temptation speaks.
Join the party.
Love hangs in the midst of it all, holds your heart close, drowned out
by the sound of indecision. Careful, mate. The party beckons.
Open your eyes. Reveal the party lie. Face truth. Become the original you.
Do not join the party.
–Victoria Emmons, 2017
Jump, bark, challenge
My authority
As you enter my life and
Try to take over
Just a dog from the
Animal shelter
With no place to call home
Much like me
No place to call home
Drifting everywhere
No roots to plant
Or debts to repay
Only the circus
Accepts us
who are different, strange
And demand rights
Yet there you stood
Begging for adoption
When everything was against us
Twilight seemed dim
You worked out okay
Me, too, since night was day
And you wanted to rule
But you learned
So why not stay
Circus Dog
Stay until dawn and play
With the befuddled cat
I did not know you
Would appear so sweet
Cocking your head to one side
To draw me in, to love you
And that I did, so you won
The game we play
Each night as you demand
I throw your toy for a fake pursuit
–Victoria Emmons, copyright 2017
I'm on the right
You're on the left
Sometimes you drift my way
Other times I drift yours
Often we meet
In the middle
Best of all
Warm up to each other
Now your side stripped bare
Too cold to creep over there
Empty and void of feeling
Plumped-up pillows for no purpose
Evening routine remains
Regimented, predictable
Yet morning cries reality
Evidence of attempts to reconcile
Edging slightly your way
Blanket all askew
Tugged by unknown forces
Mystic, ghost-like visions
The other side of my bed
Still lies in wait
For your arrival
That never comes
–Victoria Emmons, copyright 2017
Fat, white flakes cover rooftops, fence lines
Rain upon sidewalks and parked cars
Plant themselves in mountains of cloud-like splendor
Snow painting a merry Christmas Day
Bright sky at midnight, enough reflection to guide Santa
And his reindeer to our home where children sleep
As grandmother lies eyes open and in wait
For laughter and expectation to fill the morning light
Check the empty plate for cookie crumbs
And leftover drops of milk, evidence of parental love
While children confirm today is the day, finally
Yes, dear Alex, Christmas has arrived
Presents bear his name, a word he can spell at three
His sister's name, too, three letters he reads aloud
On a tag that hangs from a golden package
Wrapped with silver twine and sparkly stars
Help Zoe open her gifts, dear boy, you know how
She yet too young to rip paper and bows
He willing and eager to obey
Tears into each gift for baby sister
Delve into the unknown, discover what resides inside a box
Find out what hides within a heart, a soul
My decision to move, leave all that is known
Leave behind a life, a friend, a sunny world
The real gift is me, dear children, nearby you now
Far from the warmth of a California coastline
To the land of slips on the ice, long winters
Snow button in my car, four-wheel drive
The day after gifts revealed, wrapping paper gone
Two feet of snow to shovel from my deck
Under a clear, pink Boxing Day sky
Measuring love in twenty-four inches
–Victoria Emmons © 2016
First placed in a dresser drawer
Migrated to a shoebox
Burgeoned to a steamer trunk
Hidden away in a space in the wall
Letters kept safe over 50 years
Uncovered in a renovation
Home owners open them one by one
The story of two lovers unfolding on paper
Over time, through wars, marriage
And children born and died, the letters
Filled with life and hidden passion
Secrets that only lovers share
Those who discover the musings
Seek to find the children, now grown,
With no inkling of correspondence
Between mother and father, letters
Revealing struggles, patience, deep love
And devotion one to the other
Email is not wrapped in purple ribbon
Nor kept in a dresser drawer, perhaps
An iCloud drawer to be savored later
Or uncovered like Ashley Madison clients,
Not quite the same as thin Air Mail paper
With the familiar red, white and blue logo


text:
"More than the sum of its parts," was a phrase that came to mind when I finished The Sweetness of Grace: stories of Christian trial and victory by Matushka Constantina Palmer. However, that phrase doesn't quite convey what I want it to. You see, it isn't the sum of the parts that makes this book what it is, because each story carries within it the whole: the grace of Orthodoxy as lived by faithful Orthodox Christians.
Mat. Constantina admits in the introduction that it is her skills as a storyteller, not her masters degree in theology, which bring these stories to life, but I must disagree slightly. Matushka is an exceptional storyteller, but she also has the intimate knowledge of the Holy Fathers and their writings which provides the lens through which the light of the stories shine. Much like my spiritual father who has a (to me) phenomenal and encyclopedic ability to pull out exactly the right anecdote from an elder's life, a quotation from a saint, verse from holy scripture, or story from the Prologue, Matushka roots every story solidly in the Church's Tradition. This in turn brings a deeper understanding of the scripture or precept.
All of this might make the book sound too exalted to read! Do not be deceived on this front; just like Matushka Constantina's first book, The Scent of Holiness, this one is extremely approachable, easy to read, and enjoyable. I read the first third in one sitting because I couldn't put it down. After all, it is a collection of stories. The Lord himself taught us in parables, or stories, as the best way to capture our attention and instruct us. There is nothing insignificant about the humble story.
I recommend this book very highly. You will likely read it as I did, in huge gulps, but then you will return again and again to savor individual stories. Both The Sweetness of Grace and The Scent of Holiness [review here] should be in every Orthodox Christian's library. Thank you, Matushka, for your labors in collecting and sharing these stories with us.
The Sweetness of Grace: stories of Christian trial and victory is available from Ancient Faith Publishing. I received a free copy in return for my unbiased review.


text:
by Lucille Clifton
BOA Editions, Ltd. – 978-1-934414-12-5 / 54pps / $16.00
A Review by Cheryl A. Townsend
Winner of the National Book Award, Clifton writes the truths of social injustice…she writes to the very the depths of love .. she sings in harmony. She is. This collection begins in the voices of the subservient, downtrodden, subdued , and persecuted .. be they animals, native Americans, children .. all essentially slaves. All living their lives as intended until man comes along and decides they should be controlled.. altered/forced into service. Owned.
These lines from the poem "horse prayer"
why i pray to You
Father Of What Runs And Swims
in the name of the fenceless
field when he declares himself
does he not understand my
Also using commercialized – accepted forms of racism as examples, as in:
aunt jemima
white folks say i remind them
of home i who have been homeless
all my life except for their
kitchen cabinets
i who have made the best
of everything
pancakes batter for chicken
my life
the shelf on which i sit
between the flour and cornmeal
is thick with dreams
oh how i long for
my own syrup
rich as blood
my true nephews my nieces
my kitchen my family
my home
And again raising the controlling issue in "uncle ben" with the theft of his life by the "pale sons/of a pale moon" .. This greed is monumental. It escalates. It is insatiable. It continues still. It has always baffled me why it is believed that wants are needs, even beyond materialistic. Why the need to be in charge.. to dominate.. to feel powerful. Yet in these voices, there is not anger. There is only sadness, loss. It almost appears like pity towards the takers.. almost a "Forgive them Lord, for they know not what they do." Ghandi-esque.
Yet controlling one's present and future is still not enough. Why not change their past, too? In the poem "mataoka" ..
in the dream was our land
stolen away and our horses
and our names
Exemplified by the subtitle (actual name of Pocahontas) .. So now, not only is their life to be lived as deemed, it was, also. Does history really repeat itself? Or are we just doing a remake? Something lost in translation? Sound Biblical? Why are most historical women known more for their purported faults than their authenticated deeds? Why the refusal to accept? Why? Fear. Fear of losing that foothold in the hierarchy. That maybe there really is a better way.
From "sorrows" comes the exasperated cry "who can distinguish/one human voice" .. especially when it's from outside the clique. And that's what society, on the whole, is. There is no unity, there are only monopolies of have and have nots, of do and do fors, of being and being had. We all see this, yet mostly ignore "as scars attach and ride the skin" because it may be too disturbing to actually face. Therefore, we enable..we perpetuate..we condone via silence. Clifton does not follow suit. Lucille does not know her place….
From the section "being heard" –
this is what I know
some womens days
are spooned out
in the kitchen of their lives
Bare foot and Pregnant? Even with the abundant progressions of humanity, there still lacks humane treatment for anything not white, male and upper class, though it seems to be improving somewhat in racial disparity. (Bravo Obama!!!!)
I had read once where Clifton's great-grandmother was legally hanged, though not what for. But given the probable time, did it matter to the masses? Acceptable behavior then, acceptable behavior now. We've just shifted it a bit under another guise of justification. I also read where she claimed her tenacity was due to being "from Dahomey women" and indeed, she is a warrior, though no longer subjected to the service of anyone but herself. Her place is wherever she damned well chooses it to be.
In the poem "my grandfather's lullaby" are the lines "theys a world outside/the window/and somebody in it hates you" .. How sad. How true. From nowhere comes hatred. Somebody – Anybody. Just hate because you were taught to. No reason required, just do it. It's all the same. They're all the same. And if that same is not our same, it's open season. Fire away with derogatory epithets, slurs.
In the final section, "ten oxherding pictures", she innocently creates from titles, poems that fall deftly into their initial meaning. From Zen Buddhism, these woodcuts with poems are intended as guides into enlightenment, with the "ox" being the "true self" to be attained. The seeker must tame and master, in essence, himself. A perfect juxtaposition of wrong and right for this collection. Learning from the earlier mistakes, we need only control our own selves "not this me/not that me/now here where/no thing is defined" and just be. Yet even in this perfection, "we meet a man who wears/authority" and he tries to control them both. But Lucille is "from Dahomey women" and wisely meditates "man is not ox/i am not ox/no thing is ox/all things are ox" and departs, and arrives.
Clifton has endured loss… the death of a brother, of a child, of her husband. She has endured the sexual abuse of her father. She has felt the sting of racism and sexism. Yet here is this voice..angelic amongst demons. Yet she still sings in harmony.. we just need to learn the tune.
Reprinted with permission from WOMEN WRITERS.net
Cheryl A Townsend writes book reviews for Women Writers net, Oranges & Sardines, epitome and other publications. Her own poetry has taken a back burner…again. She is also an avid photographer & organic gardener.


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|This specialised weapon is only given to Commander Garoos most trusted aides.
Average Rating [?]
|Actual Icons
|Restocks At
|Used By
Garoo Elite Specialist Riilan
Garoo Elite Strike Commanders
|Special Categorization
|TCG RIC Prizes - This item was released as a Rare Item Code prize from the Neopets TCG.
|Named Garoo Elite Cannon while used in battle
Ratings - Garoo Elite Blaster
|Price/power (1/5): Outclassed by Ylanas Blaster, but it can sometimes be found for around the same price.
Tactical (2/5): The 5 fire icons will be hard to fully block, but it still can't beat the Scarab Ring head to head.
Bonus (0/1): Garoo's competency can be questionable at times.
Closing remarks: Get Ylanas Blaster or any of the other common 13-iconers.
Rated on August 31, 2015
|Overview: So this is one of those weapons that is sometimes worth it but usually not. It's more of a chess piece than a brute-force weapon.
The Good: The 11 icons here are a good fit for L97 battling. I'm a fan of fire icons, especially if they can bring out a shield that you know you can cut through. You can basically use this to give someone the old switcheroo.
The Bad: Let's first consider that the Blaster can be purchased for a competitive price. Assuming that, then next I'd look at it's biggest weakness, which would be the very popular L97 shield Faerie Tabard. The Tabard completely shuts down the Blaster while being able to take on some additional water and air icons. Also, Wand of Lameness is the poor L97 Battler's way to ward off the Portable Kiln, so there are two common ways that the Garoo Elite Blaster can be matched or beat. If we look at this outside of L97, it's just too expensive for what it does.
The Ugly Truth:The Garoo Elite Blaster works well in drawing out the Faerie Tabard if your timing is decent, but one wrong use and your attack is completely crippled. Outside of L97 battling, it is mostly a collector's item.
Rated on March 31, 2014


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Under Armour star athletes Bryce Harper and Cam Newton are at the center of the brand's new campaign, "It Comes From Below."
The campaign centers on the idea that footwork is a key skill in every athlete's success, and that great moments in sports start with the feet. Ahead of the 2016 MLB All-Star Game on Tuesday, Washington Nationals player Harper is featured in a film about his story titled "Numbers" and told in the words of his high school coach, Sam Thomas.
Thomas charts Harper's career through numbers, highlighting his incredible accomplishments at a young age. Even with a tough training regimen, Thomas says nothing is as important as the first step and pivot in the batter's box. The final shot in the film is Harper's foot pivoting as he hits one out of the park.
"When we took a hard look at what really sets our athletes apart, it became clear that the journey to greatness starts from below," said Adrienne Lofton, senior vice president of global brand marketing at Under Armour. "Beyond recognizing the importance of footwork, we are committed to creating the most innovative, game-changing footwear on the planet for all athletes."
Under Armour's HarperOne Unanimous baseball cleat, inspired by last year's unanimous decision to name Harper the National League MVP, is available today. The HarperOne Platinum Edition is available Tuesday. Harper was the youngest player in MLB history to unanimously win the MVP.
Under Armour will release Carolina Panthers quarterback Newton's part of the campaign in fall 2016. Watch the full film featuring Harper below.
Want More?
Under Armour's Curry Two Low Select Colorways To Be Released
Under Armour Unveils Baltimore Manufacturing And Design Center


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GameSurge Strategy Page
Special keys:
PgUp - pick up / drop
PgDn - talk
Enter - action
CTRL - run
Alt - bend down
TAB - inventory
You begin in school. Ask twins about your quest. Go out, talk to the
guy sitting in the chair. Go to the pier. On your way pick up the brush
from the alcove under the stairs. At the start of the pier pick up the
metal bar from on top of the bales. Go to the to the lighthouse.
Throw metal bar into control panel. After the light goes down, go and bend
down to hide behind the barrels near the lighthouse. When the watchman
enters the lighthouse, run back to his office. Unlock door and enter.
Switch on the light. Open the cash register and put the brush in the tray.
Turn around and take money from the safe. Exit.
Back in school. Ask twin witches about your second quest. Take bag of
marbles from the shelf at the back of the classroom. Go out. Enter the
kitchen (door to the right). Talk to boy. Exchange bag of marbles
for potion and get chicken leg. Pick up marrow bone and empty bottle
in alley way. Go to the hungry guy give him chicken leg when he
mentions that he wants food and then fill empty bottle with wine.
Go back to alley way. Give potion to the guy sitting in chair.
Turn the knob to lower the basket. Take the sausage and handle.
Go upstairs and enter the hut. Search the room and pick up the key.
Go out and down. Give marrow bone to dog and then open door next to
the kennel. Enter and walk downstairs. Talk to guard. Go right along
the waterfront. Talk to man fixing the truck. Pick up the tool when he
is looking into the engine space. Use the tool to get the bell from the
wall. Return to the guard. Use bell on guard, use bell on stairs. Go
upstairs and enter the door. Take small safe from the table and put it onto
the spare plate on the scales. Take the jewel from the safe. Go out.
You find yourself in a room. Pick up the chock of wood. Find the handles
on the wall. Pull down left one, block with wood and pull down right one.
Take the key from the shelf. Climb on the crate, look through periscope.
Open door and go outside. Take the lighter from behind the post which is
under the hut. Follow the walkway and find a place to cross the wall by
climbing crates. Take scissors from table. Take candle from the ground
next to the wall. Put the candle under the rope. Light the candle.
Go to man painting the boat and talk to him. Climb the stairs and find the
tin can on the window sill. Go back to the guy painting the boat.
Pick up brush. Take some paint with the brush. Go back up stairs and
follow walkway to the alley way and pick up the atomiser and then go and
talk to the Chinese tattooist. Go downstairs and follow the street.
Go to the next pier. Use painted brush on guard. Go to fisherman.
Talk to him, give empty can. Go to other pier and take stick. Talk to
boatman. Go to third pier and talk to Marcello. Push the killer flea circus
with the stick. Turn the handle and play music. Use spray on Marcello.
Take watch. Go to Chinese tattooist. Pull a screw on the left of his stand
Take map. Go to boatman, give a map and a watch.
What is the sausage for and what is the bottle of wine for??
(email me if you find out)
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Walling "inbox" on Facebook: The True Reasoning
Oh you little superficial stalker. Pity. Your home page refreshes and you see one of your friends has walled another, writing nothing but "inbox". In protest you let out a nasal snigger of disapproval. You grudgingly think the only reason Jack wrote "inbox" on Jill's wall was to let their notification starved audience know they … More Walling "inbox" on Facebook: The True Reasoning


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My Jawbone UP still hasn't arrived from amazon. I am slightly annoyed by that, but tracking says it will be here today.
Yesterday was my first day of the Isagenix cleanse. I will say that the shakes are…mediocre. They remind me of appetite suppression/fad diet shakes my mother used to make in the 80s. The difference being about 20 years of nutritional innovation. The ingredient list, while quite long, only has one scary word: isomaltooligosaccharide. IMO is a prebiotoc starch. There are worse things that could be on a "powdered drink" ingredient list. I will deal.
I had the option to choose a diary free box or the whey protein box when I ordered. While I don't do dairy on the regular (and hate milk), I know my body works well with wey protein so I went with that option. meh… it tastes very "milky" to me, which is probably why I find it to be mediocre instead of great. If you don't have an aversion to milk, you'd probably love it. I was worried yesterday about being hungry, being jittery or being miserable. I am happy to report no jitters, hungry only just before dinner (I'll call that intuitive eating 😉 ). The only miserable effect was/is my caffeine withdrawal headache, which was to be expected. Every time I do a detox, whether it's whole foods/macrobiotic based or a juice cleanse, the damn coffee headache gets me every time.
Hubby is doing his best to be supportive, which I need and appreciate. We had a nice dinner last night – grilled chicken, asparagus, portobello mushrooms, cherry tomatoes and peppers. It was totally delish. I sorry I didn't take a picture!
This morning my headache was slight and dull. Definitely not as extreme as last night. I blended my am shake with a 1/2 a banana and I found that to take away a good amount of the "milk" flavor. Technically I don't think I am supposed to, but it's not a "cleanse" day and it's only 50 calories, so THIS health coach thinks it's fine. There was a change in my weight from yesterday morning to this morning, but I am only going to count the weekly change. My weight yoyos 4-5 lbs on a daily basis on the regular, so a daily weigh in won't work for me. Energy-wise I feel good. We'll see what the rest of the week brings. I am supposed to get my period, that could lead to disaster.


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The Scoop on People Who Scoop Out Their Bagels
Behold the bagel: equal parts doughy and crisp, hearty and cheap, a vehicle for salty cured fish and sweet raspberry jelly alike. It's an ideal breakfast food, as versatile as it is delicious. But for some, it's just too much. That's right—I'm talking bagel scoopers, those outliers who request their morning treat voided of its pillowy middle. It might seem innocuous, but at the bagel shop it's as controversial a subject as they come. Ask for your oven-fresh everything bagel hollowed out, and you'll most likely receive a raised eyebrow and a grunt of disapproval, as if you'd just dumped Sweet-n-Low in your Blue Bottle pour-over.
I conducted a quick Facebook survey that showed on the customer side, bagel loyalists overwhelmingly condemn the practice of bagel scooping. My sister-in-law went as far as to call it an "abomination," proclaiming, "Eat the bagel or don't, but for the love of God, don't destroy it." But could this blasphemous act ever be considered acceptable? I turned to the true experts, the folks behind the counter, to put this morning conundrum back to bed, once and for all.
"It all depends what kind of bagel you're eating," says Dianna Daoheung, Executive Chef at NYC's ever-popular Black Seed Bagels. Daoheung's shop, which was opened by Mile End's Noah Bernamoff, specializes in Montreal-style bagels— a thinner, denser, and slightly sweeter version that she and her team deem too small for scooping. "There would be nothing left!" she exclaims, no doubt picturing her life's work rendered into limp, hollowed-out remnants.
But despite her disdain, Daoheung concedes that scooping can serve a purpose. "If it's a smaller bagel, it can greatly impact the ratio of soft to chewy and change the sweet taste of the inside, but if it's bigger, then I don't see it as the worst thing," she reasons. "For a large, puffy bagel, I think scooping can be helpful to give it a better ratio of stuffing to filling."
The more bagel bosses I consulted, the more I discovered that this issue essentially came down to one thing: toppings. The people making your breakfast want you to enjoy it, and they're not just in it for the bread. These toastmasters put effort into the whole shebang, all the schmears, eggs, cold cuts, and salads that transform a simple, pleasurable hunk of carbs into a full-blown meal. And occasionally, the laws of physics demand more space than an un-scooped bagel can provide.
"Because of the heft of our sandwiches and the amount of toppings on many of them, a scooped-out bagel means you actually get to eat everything instead of it all falling out on the first bite," explains Kate Beacom, who makes her living hawking bagels at Brooklyn's Nagle's Bagels and reports that she's asked to scoop two to three times a shift. "We have an option for it on the POS, so it's about as special as asking for your bagel extra toasted."
Beacom went on to mention that after gaining a bit of weight from all the job perks, she even started scooping out her own bagels. "It gives it more crunch and less chew, but it doesn't dampen the experience since I'm mostly focused on what's inside."
The verdict: Scoop wisely. If you're craving something a bit more streamlined, try to keep that little beauty intact. But if your bagel of choice looks like it could single-handedly feed a family of four, there's no shame in asking for a little more interior space, and that goes double if you're loading up on extras. The authorities would rather sacrifice a bit of cushioning than see a pile of bacon slide right through the wickets. And if the person taking your order gives you any smack, just roll with it—they probably just need another cup of coffee.


text:
A federal magistrate judge has ordered Apple CEO Steve Jobs to testify in an antitrust case regarding online music sales, Bloomberg reports.
The case in question stems from a consumer complaint filed back in 2005 by iTunes customer Thomas Slattery, who said that Apple's linking of the iPod to the iTunes Music Store limited buyer options illegally.
U.S. Magistrate Judge Howard R. Lloyd issued an order on Monday requiring that Jobs answer questions in the case, focused specifically on an iTunes update from October 2004 that prevented RealNetworks MP3s from working with iPods. At that time, Apple said that RealNetworks and its Harmony technology "adopted the tactics and ethics of a hacker to break into the iPod."
Jobs will face no more than two hours of questions on Apple's iTunes change.


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Folklore and Mythology
Recent Posts
Monthly Archives: October 2011
Day of the Dead: Hollywood Forever Cemetery
I spent about 18 hours at the Hollywood Forever Cemetery yesterday for their annual Dia de los Muertos festival. I created an altar with the students from my Modern Mysticism and the Afterlife class at Otis College of Art and … Continue reading
Dia de los Muertos
Food Network Appearance – Sunday October 23rd
Heather will be appearing as a judge on the Food Network Challenge – Ghost Story Cakes Sunday October 23rd at 8 PM. She is judging as a Folklore and Mythology expert. Don't miss it!


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Westfield Shopping Centre has been evacuated for the second time in three days.
There are reports of shoppers being held inside Marks and Spencer at the Stratford shopping centre, just two days after it was evacuated after a small fire caused chaos on Saturday (November 11).
It is currently not known why the shopping centre has been evacuated today (Monday, November 13).
Follow our live blog below for all the latest updates
We'll be bringing you the very latest updates, pictures and video on this breaking news story.
For the latest news and breaking news visit http://www.essexlive.news/
Get all the big headlines, pictures, analysis, opinion and video on the stories that matter to you.
Follow us on Twitter @essexlive - the official Essex Live account - real news in real time.
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The shopping centre was evacuated on Saturday
The Stratford stores were evacuated on Saturday, November 11, due to a small fire that had broken out.
Read more here.
Shoppers describe 'fear' when 'fire alarm' went off before evacuation
so my fear in london happened, the fire alarm went off in Westfield and everyone's been evacuated— Mi (@MiaSpringford) November 13, 2017
whats going on at stratford westfield? another fire? shoppers stuck inside m&s! #westfieldstratford— Thufael Islam (@co1dt) November 13, 2017