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Review| Volume 74, ISSUE 2, P136-143, August 2019
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Genetic basis of hereditary thoracic aortic aneurysms and dissections
Norifumi Takeda, MD, PhD
Norifumi Takeda
Corresponding author at: Department of Cardiovascular Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Department of Cardiovascular Medicine, The University of Tokyo Hospital, Tokyo, Japan
Issei Komuro, MD, PhD, FJCC
Issei Komuro
Open ArchivePublished:April 15, 2019DOI:https://doi.org/10.1016/j.jjcc.2019.03.014
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Syndromic hereditary aortopathies are caused by mutations in the transforming growth factor-β-related genes.
Patients with Marfan syndrome exhibiting a FBN1 truncating variant carry an increased risk of aortic events.
There is a limitation to identify the underlying causative genes of non-syndromic juvenile aortopathies.
Genetic testing for hereditary thoracic aortic aneurysms and dissections should be performed with appropriate counseling.
Recent advances in DNA sequencing technology have identified several causative genes for hereditary thoracic aortic aneurysms and dissections (TAADs), including Marfan syndrome (MFS), Loeys–Dietz syndrome, vascular Ehlers–Danlos syndrome, and familial non-syndromic TAADs. Syndromic TAADs are typically caused by pathogenic variants in the transforming growth factor-β signal and extracellular matrix-related genes (e.g. FBN1, TGFBR1, TGFBR2, SMAD3, TGFB2, and COL3A1). On the other hand, approximately 20% of the non-syndromic hereditary TAADs result from altered components of the contractile apparatus of vascular smooth muscle cells, which are encoded by ACTA2, MYH11, MYLK, and PRKG1 genes; however, the remaining 80% cannot be explained by previously reported candidate genes. Moreover, the relationship between the genotype and phenotype of TAADs has extensively been reported to investigate better methods for risk stratification and further personalized treatment strategies. With regard to MFS-causing FBN1, recent reports have shown significantly increased risk of aortic events in patients carrying a truncating variant or a variant exhibiting a haploinsufficient-type effect, typically comprising nonsense or small insertions/deletions resulting in out-of-frame effects, compared to those carrying a variant with dominant negative-type effect, typically comprising missense variants. Therefore, cardiologists are required to have sufficient knowledge regarding the genetics of hereditary TAADs for providing the best clinical management, with an appropriate genetic counseling. In the current review, we present current advances in the genetics of hereditary TAADs and discuss the benefits and limitations with respect to the use of this genetic understanding in clinical settings.
Loeys–Dietz syndrome
Fibrillin-1
Transforming growth factor-β signaling
Improved technology and decreased costs for DNA sequencing have identified the predisposition genes in hereditary thoracic aortic aneurysm and dissection (HTAAD), including those associated with Marfan syndrome (MFS), Loeys–Dietz syndrome (LDS), vascular Ehlers–Danlos syndrome (vEDS), and familial non-syndromic TAAD, and such genetic tests to guide precision medicine have been covered by health insurance in Japan since 2016. The ClinGen Aortopathy Expert Panel have classified 11 causative genes (FBN1, TGFBR1, TGFBR2, SMAD3, TGFB2, COL3A1, ACTA2, MYH11, MYLK, LOX, and PRKG1) for HTAAD as category A genes in 2018 (Table 1) [
Renard M.
Francis C.
Ghosh R.
Scott A.F.
Witmer P.D.
Ades L.C.
Clinical validity of genes for heritable thoracic aortic aneurysm and dissection.
J Am Coll Cardiol. 2018; 72: 605-615
]; this classification should trigger aortic imaging, medical therapy, and screening of family members for the variant with the goal of preventing acute aortic dissections, and thus cardiologists are required to have sufficient knowledge regarding the genetics of HTAAD for providing the best clinical management. In the current review, we present and discuss current advances in the genetics of HTAAD for its diagnosis and long-term management, with a focus on the category A genes.
Table 1Genes associated with familial thoracic aortic aneurysm
OMIM No.
Category A1 and recently identified (uncertain) genes, associated with syndromic TAAD
A1 FBN1 Marfan syndrome (MFS) 154700
A1 TGFBR1, TGFBR2, SMAD3, TGFB2 Loeys–Dietz syndrome (LDS), type 1–4 609192, 610168, 613795, 614816
Uncertain TGFB3, SMAD2 Loeys–Dietz syndrome (LDS), type 5 and 6 615582, unassigned
Uncertain BGN LDS-like and MFS-like 301870
A1 COL3A1 Ehlers–Danlos syndrome (EDS), vascular type 130050
Category A2 and recently identified (uncertain) genes, associated with non-syndromic TAAD
A2 ATCA2 Aortic aneurysm, familial thoracic 6 611788
A2 MYH11 Aortic aneurysm, familial thoracic 4 132900
A2 MYLK Aortic aneurysm, familial thoracic 7 613780
A2 PRKG1 Aortic aneurysm, familial thoracic 8 615436
A2 LOX Aortic aneurysm, familial thoracic 10 617168
Uncertain FOXE3 Aortic aneurysm, familial thoracic 11 617349
Uncertain HCN4 Sick sinus syndrome 2 163800
Uncertain MAT2A Aortic dilatation, bicuspid aortic valve Unassigned
Uncertain MFAP5 Aortic aneurysm, familial thoracic 9 616166
Category B: genes without significant risks of progression or aortic dissection
B SKI Shprintzen–Goldberg syndrome 182212
B FBN2 Congenital contractural arachnodactyly 121050
B FLNA Periventricular nodular heterotopia 300049
B ELN Cutis laxa, autosomal dominant 123700
B EFEMP2 (FBLN4) Cutis laxa, autosomal recessive, type IB 604633
B SLC2A10 Arterial tortuosity syndrome 208050
B NOTCH1 Bicuspid aortic valve with aneurysm 109730
B SMAD4 Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome 175050
Category C: low risk genes for TAAD
C COL4A5 Alport syndrome, X-linked 301050
C PKD1, PKD2 Polycystic kidney disease 1 and 2 173900, 613095
C CBS Homocystinuria 236200
Category D: some experimental data may suggest a link with TAAD, but no clinical evidence is available.
D Gene lists: ACVRL1, ADAMTS10, B3GAT3, COL1A1, COL1A2, COL4A1, COL5A1, COL5A2, COL9A1, COL9A2, COL11A1, COL18A1, EMILIN1, ENG, GATA5, GJA1, JAG1, MED12, PLOD1, PLOD3, SMAD6, UPF3B, VCAN
TAAD, thoracic aneurysm and dissection.
MFS is an autosomal dominant heritable disorder of the connective tissues with prominent involvement of skeletal, ocular, cardiovascular, and pulmonary organ systems. The estimated prevalence ranges from 1/5000 to 1/10,000, and approximately 75% cases of MFS have an affected parent and the remaining 25% of probands are sporadic [
Takeda N.
Yagi H.
Hara H.
Fujiwara T.
Fujita D.
Nawata K.
Pathophysiology and management of cardiovascular manifestations in Marfan and Loeys–Dietz syndromes.
Int Heart J. 2016; 57: 271-277
]. Recent advances in surgical therapies for TAADs have improved life expectancy from approximately 30 years to >70 years; however, the comprehensive management strategies for preventing multiple organ system disorders remain inadequate to relieve lifetime anxiety and enhance the quality of life (QOL) of patients, despite the administration of β-blockers and angiotensin II receptor blockers, such as losartan [
].
The diagnosis can be made according to the 2010 revised Ghent criteria (Table 2) [
Loeys B.L.
Dietz H.C.
Braverman A.C.
Callewaert B.L.
De Backer J.
Devereux R.B.
The revised Ghent nosology for the Marfan syndrome.
J Med Genet. 2010; 47: 476-485
], which place particular focus on the cardiovascular manifestations (aortic root aneurysm and/or dissection), ectopia lentis, and molecular genetic testing of FBN1. FBN1 spans about 230 kb of genomic DNA containing 66 exons (NM_000138.4), and >3000 different pathogenic variants have been identified and are distributed throughout the entire region of the gene [
]. In addition, we have identified 243 pathogenic and likely pathogenic variants (mutations) from 288 Japanese MFS families at our institute until February 2019. We have observed that missense mutations affecting/creating cysteine residues are the major variant type (85/243; 35.0%), followed by other missense (44/243; 18.1%), nonsense (44/243; 18.1%), in-frame and out-of-frame deletion/insertions (44/243; 18.1%), and splice (26/243; 10.7%) mutations, which is consistent with data previously reported [
Faivre L.
Collod-Beroud G.
Child A.
Binquet C.
Gautier E.
Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study.
Am J Hum Genet. 2007; 81: 454-466
Morisaki T.
Morisaki H.
Genetics of hereditary large vessel diseases.
J Hum Genet. 2016; 61: 21-26
Table 2The revised Ghent nosology for Marfan syndrome
In the absence of family history:
(1) Aortic aneurysm (Z ≥ 2) AND ectopia lentis
(2) Aortic aneurysm (Z ≥ 2) AND FBN1 mutation
(3) Aortic aneurysm (Z ≥ 2) AND systemic score (≥7 pts)
(4) Ectopia lentis AND FBN1 mutation with known aortic aneurysm
- Ectopia lentis syndrome: Ectopia lentis with or without systemic score AND with an FBN1 mutation not known with aortic aneurysm or no FBN1 mutation
- MASS: Aortic aneurysm (Z < 2) AND systemic score (5 ≥ with at least one skeletal feature) without ectopia lentis
- Mitral valve prolapse syndrome: mitral valve prolapse AND aortic aneurysm (Z < 2) AND systemic score (<5) without ectopia lentis
In the presence of family history:
(5) Ectopia lentis AND family history of MFS (as defined above)
(6) Systemic score (≥7 pts) AND family history of MFS (as defined above)
(7) Aortic aneurysm (Z ≥ 2 above 20 years old, ≥3 below 20 years) AND family history of MFS (as defined above)
Scoring of systemic features:
Maximum total: 20 points; score ≥7 indicates systemic involvement
Wrist AND thumb sign – 3 (wrist OR thumb sign – 1)
Pectus carinatum deformity – 2 (pectus excavatum or chest asymmetry – 1)
Hind foot deformity – 2 (plain pes planus – 1)
Pneumothorax – 2
Dural ectasia – 2
Protrusio acetabuli – 2
Reduced US/LS AND increased arm/height AND no severe scoliosis – 1
Scoliosis or thoracolumbar kyphosis – 1
Reduced elbow extension – 1
Facial features (3/5) – 1 (dolichocephaly, enophthalmos, down-slanting palpebral fissures, malar hypoplasia, retrognathia)
Skin striae – 1
Myopia >3 diopters – 1
Mitral valve prolapse (all types) – 1
MFS, Marfan syndrome; MASS, myopia, mitral valve prolapse, borderline (Z < 2) aortic root dilatation, striae, skeletal findings phenotype; US/LS, upper segment/lower segment ratio; and Z, Z-score.
The encoded fibrillin-1 is a major component of elastic fibers that are widely expressed in structural elements of the affected organs and tissues, and MFS is traditionally considered to result from the structural weakness of the connective tissue. However, recent reports on molecular mechanisms of MFS have indicated that fibrillin-1 interacts with latent transforming growth factor-β (TGF-β) binding protein-1 (LTBP) to regulate TGF-β activity (Fig. 1A ), and therefore defective fibrillin-1 results in the structural weakness and excessive activity of TGF-β signaling—both of which contribute to the complicated pathogenesis [
]. Fibrillin-1 contains 7 TGF-β binding protein-like (TB) domains and 47 epidermal growth factor (EGF)-like domains (Fig. 1B), which include 8 and 6 cysteine residues that are involved in 4 and 3 intramodule disulfide bond formation, respectively. Of the 47 EGF-like domains, 43 contain a consensus sequence for calcium binding (cb-EGF) that is typically present as multiple tandem repeats and play a crucial role in microfibril stability and assembly [
Fig. 1Mutations in the FBN1 gene encoding fibrillin-1 cause dysregulation of transforming growth factor (TGF)-β bioavailability. (A) (Left side) TGF-β is secreted in an inactivated latent form that requires proteolysis for activation. (Right side) Mutated fibrillin-1 in Marfan syndrome leads to failed sequestration of latent TGF-β in the extracellular matrix (ECM) and subsequent activation of TGF-β signaling cascades. (B) Domain structure of fibrillin-1.
Show full caption
LLC, large latent complexes; LAP, latency-associated peptide; LTBP, latent TGF-β binding protein; EGF, epidermal growth factor-like domains; cb-EGF, EGF-like domains with a calcium binding domain; TB, TGF-β binding protein-like domains; Hybrid, hybrid domain containing features of both TB and cb-EGF domains.
Although there are no obvious mutational hot spots and the precise molecular mechanism for how mutations affect fibrillin-1 structure and function remains largely elusive, the relationships between the location or type of FBN1 mutations and phenotypes have been extensively reported to search for better methods for risk stratification and personalized treatment strategies [
Campens L.
Muino Mosquera L.
Looking for the missing links: challenges in the search for genotype-phenotype correlation in Marfan syndrome.
Circ Genomic Precis Med. 2018; 11: e002185
]. It has long been known that a higher probability of ectopia lentis is found in patients with a missense variant affecting a cysteine residue particularly in the first 16 exons, and exons 25–33 including a central stretch of cb-EGF domains are recognized as a critical region for severe form of neonatal MFS, which is characterized by severe mitral and/or tricuspid valvular insufficiency and pulmonary emphysema. In addition, recent reports have shown significantly increased risk of aortic events in patients carrying a truncating variant or a variant with a haploinsufficient (HI)-type effect, typically comprising nonsense and splice site variant, or small insertions/deletions leading to out-of-frame effects, compared to patients carrying a variant with dominant negative (DN)-type effect, typically comprising missense variants or small insertions/deletions leading to in-frame effects (Fig. 2) [
Fig. 2FBN1 genotypes and aortopathy in Marfan syndrome. Haploinsufficient-type variants, such as nonsense and out-of-frame variants that presumably cause nonsense-mediated mRNA decay, result in more severe aortic phenotypes than those with dominant negative-type variants, such as missense and in-frame variants that are expected to exert loss-of-function effects
Kanaya T.
Maemura S.
Komuro I.
TGF-beta signaling-related genes and thoracic aortic aneurysms and dissections.
Int J Mol Sci. 2018; 19 (pii:E2125)
TGF, transforming growth factor.
To elucidate the relationship between FBN1 genotype and severe aortopathy (aortic root replacement, type A dissections, and related death) in Japanese patients with MFS, we have recently evaluated 248 patients with pathogenic or likely pathogenic FBN1 variants [
Inuzuka R.
Morita H.
Impact of pathogenic FBN1 variant types on the progression of aortic disease in patients with Marfan syndrome.
]. Only FBN1 variants fulfilling the 2015 American College of Medical Genetics and Genomics-Association for Molecular Pathology criteria for pathogenicity (≥class 4) were included. Variants were simply subcategorized into 2 groups (HI and DN) according to the predicted effects on protein structure and function; however, most splice site variants were classified into DN variants in this study, because most exons in FBN1 have lengths that are multiples of 3 bp and the defective proteins presumably exert in-frame exon skipping effects. Prophylactic aortic root replacement had been recommended for those having an aortic diameter ≥45 mm at our institute.
The main results from our Japanese patients were consistent with previous data from non-Japanese patients that show HI patients had a 2.1-fold higher risk of severe aortic events compared with DN patients, and male patients had an increased risk: the median event-free survival period from birth for men and women was 31.0 and 41.0 years, respectively, in HI group and 41.0 and 55.0 years, respectively, in DN group [
]. The increased risk in men is attributed not only to the absolute threshold for aortic surgery independent of body size and the larger overall body surface area of men, but also to rapid growth in men. In addition, we newly identified an early-onset genetic subgroup within the slow-onset DN group, showing that patients with variants affecting or creating Cysteine residues and in-frame Deletion (DN-CD) variants in the central tandem cb-EGF domains (exons 26–37, c.3083–4582 and 44–50, c.5297–6163) were as deleterious as HI patients and were at a 6.3-fold higher risk than those with other types of DN variants (DN-nonCD) (Fig. 3) [
]. Because the underlying mechanisms are unknown and variability in phenotypes has been reported not only across families with the same FBN1 genotype but also within families, MFS patients should not be monitored based on genotype alone. However, we believe that our simple genetic classification would provide valuable directives and perspectives to patients and relatives with tremendous amount of anxiety during their long-term follow-up period. Further investigations are expected to reveal the relationship between FBN1 genotype and other manifestations influencing QOL, such as kyphoscoliosis and myocardial function as well as potential differences in drug response.
Fig. 3Kaplan–Meier estimates comparing the probability of the first severe aortic event between genotypes. Severe aortic event is defined as aortic root replacement, type A dissections, and related death. Cumulative aortic event-free probability of 28 dominant negative (DN)-CD Japanese patients (green), 93 haploinsufficient-type (HI) patients (red), and 127 DN-nonCD patients (blue) are shown
. DN-CDs are variants affecting or creating Cysteine residues or in-frame Deletion (DN-CD) variants in the central tandem cb-EGF domains (exons 26–37 and 44–50, shown in green line in Fig. 1B).
LDS is a recently established autosomal dominant heritable MFS-like syndrome, caused by pathogenic variants in TGF-β signal-related genes, and LDS patients were classified according to the mutated genes in the 2014 revised nosology for LDS diagnosis: TGFBR1 (LDS1), TGFBR2 (LDS2), SMAD3 (LDS3), and TGFB2 (LDS4) [
MacCarrick G.
Black 3rd, J.H.
Bowdin S.
El-Hamamsy I.
Frischmeyer-Guerrerio P.A.
Guerrerio A.L.
Loeys–Dietz syndrome: a primer for diagnosis and management.
Genet Med. 2014; 16: 576-587
]. TGFB3 (LDS5) and SMAD2 (LDS6) have been also recently reported to be causing genes for MFS-like syndromic HDAAD, but are still assigned to category "uncertain" for the clinical validity in 2018 (Table 1) [
], pending additional evidence showing the severity of associated aortic disease and risk of progression. Estimated incidence of LDS is approximately 5%–10% among patients with suspected MFS, and the frequency of mutation in the TGFBR2 seems to be more frequent (55%–60%) than other gene mutations (TGFBR1, 20%–25%; SMAD3, 5%–10%, TGFB2, 5%–10%; TGFB3, 1%–5%; and SMAD2, 1%–5%) [
Meester J.A.N.
Verstraeten A.
Schepers D.
Alaerts M.
Van Laer L.
Differences in manifestations of Marfan syndrome, Ehlers–Danlos syndrome, and Loeys–Dietz syndrome.
Ann Cardiothorac Surg. 2017; 6: 582-594
Vascular and skeletal features in LDS demonstrate overlap with those of MFS, and 20% LDS patients have systemic score of ≥7 points of the 2010 revised Ghent criteria for MFS (Table 2). However, LDS patients do not show ectopia lentis and the majority do not have prominent overgrowth of the long bones (tall height and long arms and legs), and approximately 10%–20% of patients have congenital heart defects, such as patent ductus arteriosus (PDA), atrial septal defect, bicuspid aortic valve (BAV), and ventricular septal defect (VSD) [
Jondeau G.
Ropers J.
Regalado E.
Braverman A.
Evangelista A.
Teixedo G.
International registry of patients carrying TGFBR1 or TGFBR2 mutations: results of the MAC (Montalcino Aortic Consortium).
Circ Cardiovasc Genet. 2016; 9: 548-558
]. Further characteristically, LDS patients have a triad of clinical features: hypertelorism (widely spaced eyes), cleft palate or bifid (split) uvula, and aortic/arterial tortuosity and aneurysms (Fig. 4), and other LDS-specific features can include cervical spine malformation and/or instability, translucent skin with easy bruising, and dystrophic scars. These indicate that TGF-β signaling pathways play crucial roles in the development and maintenance of various tissues, including arteries and craniofacial growth and patterning. Pathogenic variants in LDS are predicted to lead to loss of protein function; however, aortic tissues from affected patients and LDS knock-in mice showed overactivity of TGF-β signaling cascades, and the molecular mechanisms for the TGF-β paradox have been actively investigated [
Akhurst R.J.
The paradoxical TGF-beta vasculopathies.
Nat Genet. 2012; 44: 838-839
Fig. 4Loeys–Dietz syndrome. (A) Bifid (split) uvula in a patient with a TGFBR2 pathogenic variant. (B) Ascending thoracic aortic aneurysm and arterial tortuosity and aneurysms in a patient aged 4 years with a TGFBR1 pathogenic variant.
Pathogenic variants in TGFBR1 and TGFBR2 are mostly missense and detected within the serine/threonine kinase (STK)-encoding regions of the receptors. Although TGFBR2 forms heteromeric complex with TGFBR1 and cooperatively initiates signaling after binding TGF-β ligands, clinical features associated with a pathogenic variant in TGFBR1 slightly differ from that in TGFBR2 [
]; to date, patients with LDS1 and LDS2 had been recognized to rapidly develop progressive aortic/arterial aneurysms, resulting in ruptures at an early age and at smaller dimensions, and surgical repair of the aortic root has been recommended earlier than MFS, potentially at a diameter of ≥40 mm in Japan, and indeed even children <10 years of age have a higher risk for developing aortic dissections (Fig. 4B) [
Patel N.D.
Alejo D.
Crawford T.
Hibino N.
Cameron D.E.
Aortic root replacement for children with Loeys–Dietz syndrome.
Ann Thorac Surg. 2017; 103: 1513-1518
]. However, recent international registry data gathered by the Montalcino Aortic Consortium (MAC 2016) revealed that the survival of patients with a TGFBR1 or a TGFBR2 pathogenic variant is much better than initially reported [
Schwarze U.
Holm T.
Thomas G.H.
Pannu H.
Aneurysm syndromes caused by mutations in the TGF-beta receptor.
N Engl J Med. 2006; 355: 788-798
] with approximately 75% survival at 75 years of age [
]. In addition, TGFBR1 males have a greater aortic risk than females, whereas there is no similar sex effect among TGFBR2 patients, and TGFBR2 females are prone to develop type A aortic dissection at a diameter ≤45 mm. Furthermore, aortic tortuosity, hypertelorism, and translucent skin are associated with an increased aortic dissection risk, suggesting that syndromic patients with these LDS phenotypic features should be managed more aggressively than patients lacking them [
]. Valve-sparing aortic root replacement is recommended in LDS1/2 adults with dimension >40 mm in the 2014 revised nosology [
]; however, the MAC recommends prophylactic surgery when the diameter reaches 45 mm, and the threshold could be lowered toward 40 mm in TGFBR2 females with low body surface area and presenting with extra-aortic features [
]. A less aggressive surgical treatment strategy could be pursued in the absence of any familial event or rapid increase in aortic diameter, particularly in TGFBR1 females [
With respect to LDS3–6, the reported number of patients with SMAD3, TGFB2, TGFB3, or SMAD2 pathogenic variants may be inadequate to draw any conclusions on the phenotypic spectrum. In 2018, a multi-country survey on SMAD2/3 and TGFB2/3 variants summarized and compared the clinical features of LDS3–6 patients with 45 new pathogenic variants as well as 74 previously reported ones [
Tortora G.
Lindsay M.
Liang D.
A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3.
Hum Mutat. 2018; 39: 621-634
]: The aortic phenotype in LDS3 patients is similar to that of LDS1/2 patients and LDS4/5 represents mild cardiovascular features. Accordantly, the recommended threshold diameter for prophylactic surgery in LDS3 and LDS4 is 40 and 50 mm in the 2014 revised nosology, respectively [
In MAC study, there seem not to be increased risks of the occurrence of uterine rupture and pregnancy-related aortic dissections in LDS1/2 compared to MFS patients that were initially emphasized in 2006 [
], and osteoarthritis could be observed in all LDS types that was initially described in aneurysms-osteoarthritis syndrome caused by pathogenic variants in SMAD3 [
van de Laar I.M.
Oldenburg R.A.
Pals G.
Roos-Hesselink J.W.
de Graaf B.M.
Verhagen J.M.
Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis.
]. Further investigations on relationship between LDS genotype and phenotype are needed to detect high-risk subgroups warranting improved risk stratification and management.
Vascular Ehlers–Danlos syndrome
EDS is a clinically and genetically heterogeneous group of hereditary connective tissue disorders characterized by skin hyperextensibility, joint hypermobility, and tissue fragility, which is caused by pathogenic variants of genes encoding collagen or collagen-modifying enzymes [
Malfait F.
Francomano C.
Byers P.
Belmont J.
Berglund B.
Black J.
The 2017 international classification of the Ehlers–Danlos syndromes.
Am J Med Genet C: Semin Med Genet. 2017; 175: 8-26
]. The different EDS types had been classified into 6 main subtypes according to the Villefranche nosology since 1997 [
Beighton P.
De Paepe A.
Steinmann B.
Tsipouras P.
Wenstrup R.J.
Ehlers–Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers-Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK).
Am J Med Genet. 1998; 77: 31-37
], and have been recently re-classified in a system of 13 subtypes based on clinical findings, inheritance pattern and molecular defects, by the International EDS Consortium in 2017.
Hemorrhagic manifestations, such as gum bleeding, menometrorrhagia, postnatal or peri-operative hemorrhage, are observed in varying EDS subtypes [
Vascular aspects of the Ehlers–Danlos syndromes.
Matrix Biol. 2018; 71–72: 380-395
], but vEDS (previously known as EDS type IV) is considered the most serious form of EDS owing to the possibility of arterial dissection and rupture, intestinal perforation, or uterine rupture (Table 3). Pepin et al. reviewed clinical records in 1231 individuals with vEDS (630 index cases and 601 relatives), the median survival is 46 ± 1.8 years for males and 54 ± 2.5 years for females, with an increased number of deaths in young males [
Pepin M.G.
Rice K.M.
Liu M.
Leistritz D.
Byers P.H.
Survival is affected by mutation type and molecular mechanism in vascular Ehlers–Danlos syndrome (EDS type IV).
]. vEDS patients often present with easy bruising, characteristic facial appearance, and thin skin with increased venous visibility; however, it is often difficult to make a diagnosis until serious complications occur.
Table 3Diagnostic criteria for vascular Ehlers–Danlos syndrome
Major criteria:
(1) Family history of vEDS with documented causative variant in COL3A1
(2) Arterial rupture at a young age
(3) Spontaneous sigmoid colon perforation in the absence of known diverticular disease or other bowel pathology
(4) Uterine rupture during the third trimester in the absence of previous C-section and/or severe peripartum perineum tears
(5) Carotid-cavernous sinus fistula formation in the absence of trauma
Minor criteria:
(1) Bruising unrelated to identified trauma and/or in unusual sites such as cheeks and back
(2) Thin, translucent skin with increased venous visibility
(3) Characteristic facial appearance
(4) Spontaneous pneumothorax
(5) Acrogeria
(6) Talipes equinovarus
(7) Congenital hip dislocation
(8) Hypermobility of small joints
(9) Tendon and muscle rupture
(10) Keratoconus
(11) Gingival recession and gingival fragility
(12) Early-onset varicose veins (under age 30 and nulliparous if female)
Minimal criteria suggestive for vEDS:
- A family history of the disorder, arterial rupture, or dissection in individuals <40 years of age, unexplained sigmoid colon rupture, or spontaneous pneumothorax in the presence of other features consistent with vEDS should all lead to diagnostic studies to determine if the individual has vEDS.
- Heterozygous mutation in the COL3A1 gene
- Three heterozygous COL1A1 mutations leading to a arginine-to-cysteine substitution: c.934C>T, p.Arg312Cys; c.1720C>T, p.Arg574Cys and c.3277C>T, p.Arg1093Cys
vEDS, vascular Ehlers–Danlos syndrome.
The estimated prevalence of vEDS ranges from 1/50,000 to 1/200,000 and >95% of patients carry a heterozygous mutation in the COL3A1 gene, encoding pro-alpha1 chain of type III collagen [
Schievink W.I.
Petty E.
Jaff M.R.
Babovic-Vuksanovic D.
Cherry K.J.
Haploinsufficiency for one COL3A1 allele of type III procollagen results in a phenotype similar to the vascular form of Ehlers–Danlos syndrome, Ehlers–Danlos syndrome type IV.
Am J Hum Genet. 2001; 69: 989-1001
]. Three identical pro-alpha1(III) chains, consisting of a central collagenous domain characterized by the repeated amino acid motif [Glycine (Gly)-Xaa-Yaa]343, where Xaa and Yaa can be any amino acid, and two flanking N- and C-terminal noncollagenous domains, are assembled into type III pro-collagen homotrimers (Fig. 5). Noncollagenous domains are proteolytically removed and triple helices formed associate laterally to form collagen fibrils with a characteristic banded pattern.
Fig. 5Signaling pathways and factors causing hereditary thoracic aneurysm and dissection (HTAAD).
More than 700 unique COL3A1 pathogenic variants have been identified and approximately 50% of cases are sporadic. The relationship of COL3A1 genotype to vascular phenotype has been also analyzed [
Murray M.L.
Vascular Ehlers–Danlos syndrome.
in: Adam M.P. Ardinger H.H. Pagon R.A. Wallace S.E. Bean L.J.H. Stephens K. GeneReviews((R)). University of Washington, Seattle, WA1993
Albuisson J.
Ranque B.
Golmard L.
Mazzella J.M.
Bal-Theoleyre L.
The type of variants at the COL3A1 gene associates with the phenotype and severity of vascular Ehlers–Danlos syndrome.
Eur J Hum Genet. 2015; 23: 1657-1664
]: The majority (∼2/3) are missense mutations affecting the glycine residue of Gly-Xaa-Yaa triplets. The mutated residues were mostly either valine (Val), glutamate (Glu), or aspartate (Asp), and this selection bias is positively correlated to the triple helix destabilizing effects [
Beck K.
Chan V.C.
Shenoy N.
Kirkpatrick A.
Ramshaw J.A.
Brodsky B.
Destabilization of osteogenesis imperfecta collagen-like model peptides correlates with the identity of the residue replacing glycine.
Proc Natl Acad Sci U S A. 2000; 97: 4273-4278
]. Most of the remaining pathogenic variants are located within potential splice-sites leading to an in-frame exon skipping and generation of a shorted translated product. These 2 genotypes are at high risks for arterial complications and survival. In contrast, patients with nonsense and small insertion/deletion variants leading to HI-type effects, and non-glycine sequence and N- and C-terminal missense variants, are reported to have milder clinical features and/or present at older age. These might indicate that DN-type variants profoundly disrupting and/or destabilizing the collagen triple helical structure are associated with a more severe phenotype, and it is also important to suspect that non-syndromic-appearing patients with milder arterial features may have the milder types of COL3A1 variants, even though some variants will require biochemical studies to reveal their causal role on type III collagen alteration of assembly and/or production [
The 2017 revised EDS criteria [
] classified some arginine-to-cysteine substitution variants in COL1A1 (p.Arg312Cys, p.Arg574Cys, and p.Arg1093Cys) [
Symoens S.
Hermanns-Le T.
Sakalihasan N.
Lapiere C.M.
Three arginine to cysteine substitutions in the pro-alpha (I)-collagen chain cause Ehlers–Danlos syndrome with a propensity to arterial rupture in early adulthood.
] as causal for vEDS that are associated with rupture of medium-sized arteries in adult age as well as classic EDS presentation.
Familial non-syndromic thoracic aortic aneurysm and dissection
Familial non-syndromic TAADs could be caused by pathogenic variants in genes coding proteins with functionality specific to the aorta, and the defects cause only TAADs with few outward physical manifestations; surgical repair is typically recommended when the ascending aortic size is 4.5–5.0 cm. The ClinGen Aortopathy Expert Panel classified 5 causative genes for HTAAD as category A2 genes primarily causing isolated TAAD [
]: ACTA2, MYH11, MYLK, and PRKG1 encode components of the contractile apparatus of the vascular smooth muscle cells (SMC), and LOX encodes an extracellular copper enzyme that catalyzes the cross-linking of collagens and elastin. However, the genetic etiology is substantially heterogeneous and approximately 80% of all cases of familial non-syndromic TAADs cannot be explained by pathogenic variants in any of these genes [
Luyckx I.
Loeys B.
Aetiology and management of hereditary aortopathy.
Nat Rev Cardiol. 2017; 14: 197-208
]. The natural history and clinical events of non-syndromic TAADs has not been well established; therefore, the diagnosis of familial non-syndromic TAADs is difficult. The management of family members should be carefully and appropriately performed in compliance with ethical guidelines for genetic testing.
ACTA2 is the major responsible gene for familial non-syndromic TAADs (14%–21%) and encodes aortic α-smooth muscle actin protein [
Guo D.C.
Tran-Fadulu V.
Papke C.L.
Yu R.K.
Avidan N.
Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections.
Nat Genet. 2007; 39: 1488-1493
], a transcriptional target of the TGF-β signaling. All mutations identified to date are either missense or in-frame insertion-deletion (indel) mutations with DN-type effect, and currently, there is no evidence to support that the HI variants predispose to TAADs [
Milewicz D.M.
Trybus K.M.
Sweeney H.L.
Kamm K.
Altered smooth muscle cell force generation as a driver of thoracic aortic aneurysms and dissections.
Arterioscler Thromb Vasc Biol. 2017; 37: 26-34
]. Although the penetrance is approximately 50%, patients frequently develop other vascular features and/or functional disorders of SMCs, such as cerebral aneurysm, neurovascular malformation resembling moyamoya disease, coronary artery disease, PDA, livedo reticularis, and iris floccule [
Other causative genes contribute remarkably less to the genetic etiology of non-syndromic TAADs (≤1%). MYH11 encodes SM myosin heavy chain (Myosin 11), and a considerable number of genetic variants of unknown significance (UVS) are found throughout the gene; however, most pathogenic variants responsible for TAADs are either missense or in-frame indel mutations within the coiled-coil domain and interfere with protein interactions [
Zhu L.
Vranckx R.
Khau Van Kien P.
Lalande A.
Boisset N.
Mathieu F.
Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus.
]. One missense variant (p.Arg712Gln) is located in the actin-binding and ATP-binding head region [
]. Although the penetrance is incomplete, most pathogenic variants in MYH11 have been found in patients with TAAD exhibiting PDA.
SMC contractile forces are generated by cyclic interactions between SM myosin heads and the actin filaments and regulated by the reversible phosphorylation of myosin light chain (MLC); Ca2+/calmodulin (CaM)-dependent MLC kinase (MYLK) phosphorylates MLC and increases myosin ATPase activity, creating actin–myosin cross-bridges for contraction, whereas MLC phosphatase (MLCP) dephosphorylates MLC to inhibit the cross-bridge formation resulting in the SMC relaxation, and the activity is increased by cGMP-dependent protein kinase-1 (PKG-1) (encoded by PRKG1). Consequently, mutations in MYLK and PRKG1 have been reported to cause TAADs [
Wang L.
Cao J.
Gong L.
Kamm K.E.
Mutations in myosin light chain kinase cause familial aortic dissections.
Casteel D.E.
Santos-Cortez R.L.
Kim J.J.
Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections.
], by rendering the aorta less competent to withstand biomechanical forces from pulsatile blood flow.
MYLK produces 3 isoforms and the only 130-kDa short form (amino acids 923–1914) is expressed in human aorta, which contains the catalytic and CaM domain required for activation and kinase activity, and heterozygous MYLK mutations cause either haploinsufficiency or destroy the CaM binding domain [
]. Importantly, in the majority of patients, little or even no aortic dilatation occurred before dissection [
], and thus the management of their relatives should be particularly careful. In the PRKG1 gene, a recurrent gain-of-function mutation (c.530G>A; p.Arg177Gln) causes TAADs with complete penetrance. The p.Arg177Gln mutation disrupts binding to the high-affinity cGMP binding site; however, the altered PKG-1 is constitutively active even in the absence of cGMP and hypertension is present in several patients [
LOX encodes lysyl oxidase (LOX), also known as protein-lysine 6-oxidase, plays a critical role in extracellular matrix maturation by cross-linking collagen and elastin. The heterozygous loss-of-function mutation, particularly variants that disrupt the catalytic activity or lead to haploinsufficiency, predisposes to TAADs involving both aortic root and ascending aorta [
Regalado E.S.
Duan X.
Arnaud P.
LOX mutations predispose to thoracic aortic aneurysms and dissections.
Circ Res. 2016; 118: 928-934
]. Patients exhibit some overlapping syndromic features, such as pectus deformities and striae, but do not fulfill the diagnostic criteria for MFS, and mutation carriers frequently present with BAV (∼15%) [
We reviewed here the genetic basis of HTAADs particularly caused by mutations in category A genes defined by the ClinGen Aortopathy Expert Panel [
]. Recent progress in sequencing technology would facilitate further discovery of new causative genes, and targeted multi-gene panel testing for HTAADs makes it possible to screen multiple candidate genes simultaneously in a clinical setting, including category non-A genes, such as SKI for Shprintzen–Goldberg syndrome (SGS) and FBN2 for congenital contractural arachnodactyly (also known as Beals syndrome). These can facilitate an easier and more efficient diagnosis; however, doctors and/or genetic counselors must remember to explain the benefits, risks, and limitations in detail before testing. Genetic testing can reveal information about family members, which can still result in genetic discrimination in employment or insurance. In addition, the negative test result of the proband for some known TAADs-causing genes does not suggest that family members do not have an increased risk of developing TAADs in the future. Furthermore, at the present, genetic testing does not provide adequate information on how the disorder will progress over time. Further genetic investigations are required to put precision medicine into practice, with the appropriate genetic counseling.
This work was supported by a Grant-in-Aid for Research on Rare and Intractable Diseases from the Japan Agency for Medical Research and Development.
The authors declare that there is no conflict of interest.
We are grateful to the members of Marfan Clinic at the University of Tokyo Hospital for valuable discussion and contributions.
Published online: April 15, 2019
Accepted: March 12, 2019
Received: March 12, 2019
DOI: https://doi.org/10.1016/j.jjcc.2019.03.014
© 2019 Japanese College of Cardiology. Published by Elsevier Ltd.
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text:
Pius Giraldus
Gerald J. Russello, 1971-2021
By Scott D. Moringiello
Gerald J. Russello (Screenshot from Youtube.com)
"Gerald Russello."
"Hi, Jerry, it's Scott."
"Scott! Great to hear from you. How is everything?"
That's how most of our phone conversations began. I was one of the people in Jerry Russello's life who knew him as Jerry, the guy from Regis High School in Manhattan—not Gerald, the well-respected securities lawyer, the editor of the University Bookman, the writer whose prose graced many and various publications.
I must have been fifteen when I met Jerry. Along with some Regis classmates, I had started a Catholic reading group under the tutelage of the great John L. Connelly, a legendary teacher who formed the lives of countless Regians, from Fr. Robert Imbelli (his classmate there) to novelist Phil Klay. With the kind of braggadocio not uncommon among Regis students, we fancied ourselves Catholic intellectuals, and asked Mr. Connelly if there were any heirs today to the authors we were reading. Who was engaged in writing about and therefore preserving a compelling vision of the Catholic intellectual tradition and Catholic culture? Mr. Connelly told us that we'd get to meet such a person the following week at our regular meeting time—8:00 am on Wednesdays, an hour before classes began—when we gathered to discuss Evelyn Waugh and Etienne Gilson and John Paul II and all the rest.
Twenty-seven years later I still have a vivid memory of Jerry walking through Mr. Connelly's classroom door in his suit, holding his briefcase, thanking Mr. Connelly for inviting him, and assuring him that he was in no rush—the judge he was clerking for knew he'd be coming in closer to 9:30 than 9:00. (With all he did, was Jerry ever in a rush? Did he ever not have time for you?) I confess that I don't remember much more about that day, but I know that we asked Jerry how he got started as a writer. His advice was simple: writing and exploring ideas should be exciting. Send something to a magazine and see what happens. You'll probably get rejected, but you'll also probably learn something. Do this again and again, reading as much as you can along the way, until you get published.
That first encounter with Jerry made a lasting impression on me. We all need role models, and that day I found one of mine. But if Jerry had just been someone who dispensed good advice, I don't think there would have been such an outpouring of grief and so many beautiful tributes after his death. Jerry's life was much more attractive than that.
On the façade of Regis High School there is an inscription that reads Deo et Patriae Pietas Christiana Erexit: Christian piety built this for God and country. During both of our times at Regis, Jerry and I heard a great deal about our charge to become "men for others," a goal that Fr. Pedro Arrupe, SJ, the former Superior General of the Society of Jesus, set out for all graduates of Jesuit schools. Jerry took those words to heart. He truly lived a life of service to others, in service to God and to his country.
Jerry's greatest gift to me, though, was the way he embodied pietas Christiana—Christian piety. "Piety," unfortunately, often calls to mind images of "simple" believers or uncritical religious naiveté. But piety is really an approach to life, a virtue that practices being grateful. It reminds us that we ought to be thankful to God for our country, for our family, for our friends—even for our high school. That gratitude, in turn, shapes our encounters with those around us. True piety doesn't have time for grudges; instead, like the agape for which it is most grateful, true piety "bears all things, believes all things, hopes all things, endures all things" (1 Cor. 13:7). True piety never draws attention to itself, and Jerry certainly never drew attention to himself. Those who knew where to look, however, could see the piety with which he approached education, ideas, family, and God.
Jerry would be quick to tell you that piety was a Roman virtue as much as a Christian one. He learned about piety from the Aeneid and from the Bible. And he was always learning. A few years ago, six or so of us got together for dinner with Mr. Connelly, as we did about once a year. One friend had just completed a doctorate on Spinoza, another had completed a residency in psychiatry, a third was working in consulting. As we went around the table updating each other about our lives, Jerry, typically, asked the most questions. He had a knack for being genuinely curious and genuinely affirming. He was proud of all of us, in the way an older brother looks with pride on his younger brothers' accomplishments.
He understood that, while laws could help bring order to people's lives, the goal of life wasn't order. The goal of life was love.
Jerry supported Regis and other educational endeavors because he believed they were places where students could ask enduring questions and cultivate abiding friendships. This is also what he saw in the Russell Kirk Center, the Intercollegiate Studies Institute, and the Lumen Christi Institute. His education—after Regis, he received a degree in Classics from Georgetown and graduated from NYU's law school—taught him what was worth studying, and his piety reminded him he didn't have all the answers. Jerry deeply believed that ancient Greek and Latin texts could help us encounter the permanent things, but he didn't love them just because they stood as a bulwark against the latest educational fad; he loved them because of the joy he found in getting together with friends—as we did—to read them.
Most people knew Jerry through his careers as an attorney and as the editor of the University Bookman. I can't speak to the intricacies of his work as a lawyer (I'm blissfully ignorant of securities law), but I can attest to the way he brought his piety to legal questions. Even in the rarified world of corporate law, Jerry always had an eye on what specific laws meant to people's lives, and how the practice of law affected lawyers themselves. His legal practice was important, but it was not the most important part of his life. He understood that, while laws could help bring order to people's lives, the goal of life wasn't order. The goal of life was love.
The kinds of thinkers Jerry admired displayed the same kind of piety in their writing that he exemplified in his life. Orestes Brownson, Christopher Dawson, Russell Kirk, and Roger Scruton could all be classified as "conservative" thinkers, but Jerry wasn't interested in their labels. He saw them as writers who took serious questions seriously. They were concerned about what human beings owed each other and how history and culture shape us. Jerry edited a book of Dawson's writings (Christianity and European Culture) and wrote an excellent book on Russell Kirk (The Postmodern Imagination of Russell Kirk). In those books, Jerry showed that these two thinkers were still vital for understanding contemporary life. He also wrote introductions for reissued texts of Brownson and Dawson. All these writers remained essential because they raised the most important question: How can we be faithful? Or rather, how can we be pious? They didn't answer this or any other question for you, nor would Jerry presume to do that. But they offered models, pictures of what a life well-lived looked like.
I honestly don't know how Jerry kept up with editing the University Bookman, published by the Russell Kirk Center. Every week, a new essay would appear reviewing a book about history or politics or culture. Jerry was always actively seeking out new reviewers, and he had a special gift for nurturing young writers. He had a light touch with his editing, and he always made your work better, often in ways that you couldn't quite foresee. Most importantly, though, working with Jerry was fun. It was clear that he enjoyed editorial work, but more than that he enjoyed the friendships that came with editing the Bookman. Under the @ubookman handle on Twitter, Jerry brought these qualities with him to the usually depressing world of social media. Even there, he managed to show his bonhomie, and he never failed to see the best in others and engage in actual conversations.
Part of what drew Jerry to Russell Kirk, I'm certain, was Kirk's piety toward place. Jerry had a wonderfully expansive notion of community, and the republic of letters of which Jerry was such an active citizen knew no physical boundaries. Jerry would want to remind us, however, not to forget that we are individuals from particular families who grew up in specific places. Like Jerry, I'm an Italian-American kid from Brooklyn (although my mom's family is Irish, and we moved to Long Island when I was six). Perhaps Jerry's most important lesson to me was that our grandparents—their traditions, their love of family, and yes, their piety—possessed a wisdom that our fancy degrees and "connections" could only hope to emulate. Our educations were valuable insofar as they helped us deepen our love for where we came from and for those who raised us. Sure, Washington D.C. or Oxford or Chicago or Wall Street are great. Have you ever visited Mill Basin or Bay Ridge in Brooklyn, though? You can read about filial piety when you read about Aeneas carrying Anchises, but you can actually experience it every Sunday over dinner at your grandparents while watching the Mets. These places and these people opened up our worlds. Our task was to share what we learned. I just wish I had more time to learn from Jerry.
I especially wish I had more time to learn about parenting from Jerry. He was always interested to know about my students because he always wanted to learn what sorts of questions his own children might raise. He cared deeply about passing on the faith to them. I loved getting updates on their lives, and Jerry relished his role as a father. In my sadness hearing about his death, I was heartened to know that when he died, he was surrounded by his beloved wife, his children, and his sister.
Each morning at prayer, I recite a litany of family and friends who have died. Jerry, of course, is now part of that somber list. As I say his name, I don't worry that Jerry needs to be freed from the temporary torments of purgatory. (I'm sure Dante has already Vergiled this son of Mill Basin up that particular mountain.) Instead, in mentioning Jerry I ask God to allow me to practice the piety that Jerry lived because I want to be conformed to the Love that Jerry now encounters. Oremus pro invicem, my friend, that I may see you again.
Scott D. Moringiello is an associate professor of Catholic Studies at DePaul University.
Serious Fun
Traditionalism, American-Style
Love Means Answering the Mail
The Philosophy of Mourning
By Paul J. Griffiths
'I Believe in the Beatitudes'
By Patrick Jordan

redpajama_set_name: RedPajamaCommonCrawl


text:
Iris Skateboards
Iris Skateboards creates unique handmade one of a kind skateboards using recycled skateboards. We are based in San Francisco California where we skate to live and live to skate.
Every new Iris board contains the wood from over 20 old skateboards, that would normally go to the landfill. We believe that skateboards should remain above ground and under your feet!
Iris Skateboards Story
Tucked away in the western fringes of San Francisco, where the city meets the sea, you'll find the headquarters of Iris Skateboards. No sign. No phone number. No twitter handle. Just George Rocha hunched over a bandsaw in his garage, blasting garage rock, upcycling stacks of battered and forgotten skateboard decks into rideable works of art. "Sure you could hang these on your wall and be stoked," says George. "But they ride as good as they look."
He should know, he's tested his creations on the streets of his Outer Sunset neighborhood, and even in the right-handed kidney shaped concrete bowl he and a bunch of friends built in his backyard.
George had seen the work of Japanese artist and skater Haroshi—wildly detailed figurative sculptures crafted entirely from old skateboard decks. Like most skaters, George had stacks of old boards collecting dust. On a whim he glued up a stack of old tails as his first canvas and fired up just about every power tool he had: sawzall, table saw, circular saw. Finally he found his grinder worked the best for task. Before he knew it, he had a pretty decent piece—a three dimensional heart for this girlfriend. It was close to Valentine's Day. Cut the guy some slack.
Next he set out to make a fully functioning sculpture of a skateboard, made entirely of cast-off skateboard decks. He spent days working on the first truck alone. "This thing was really going to work," says George. It soon occurred to him that he would have to tackle crafting the deck. So he glued up a pile of busted boards, sliced them up, and the result was a handful of colorful, planed, raw planks. That was the birth of Iris Skateboards.
George only uses unrideable boards. "The whole point is to take something that would have gone into a landfill and make it into something functional," he says. "What better destiny for a broken skateboard than to continue being a skateboard." He broke a lot of boards figuring out how to build a structurally sound, durable deck without compromising the aesthetics that first drew him in. Borrowing some techniques from surf board building, he arrived at the prototype Iris board. In a nod to his roots, he named it the Ripride, (Rhode Island Pride).
There's a gentle nostalgia to the first generation of Iris boards and that's no accident. The spare simplicity of Iris reflects the pure affection that filled George from that first moment he jumped on a board. "Because it's still fun to just ride a board down the street," he says. "Just to cruise really fast and carve."
In 1980 a five-year-old George Rocha bombed the hill behind his grandparents' house in Pawtucket Rhode Island on a green plastic 70s-era cruiser salvaged from a yard sale. "All you could do was stand on it and go," says George. "The perfect board to learn on."
Speed. Weightlessness. Freedom. Something clicked into place. He quickly graduated to a Veriflex Chaos, and soon after a hand-me-down Schmitt Stix Ripsaw—his first pro board. He tagged along with a pack of older kids, mastering his boneless, and skating around from parking lots to schoolyards. Back then, there were only a handful of tricks.
Come junior high George plopped down his savings on a Vision Gator and then a Santa Cruz Rob Roskopp and then a SMA Natas. He remembers every board he ever rode. He loved all of them. Well, maybe not that Vision Gator. Something about that one wasn't quite right.
One day after flipping through a Thrasher magazine, George began tinkering in his driveway, trying to replicate the terrain seen in those pages. Soon he had an array of launch ramps, boxes, and quarter pipes. There wasn't many other skateboarders around, but word got out, and soon kids from the next town over came to skate the Rocha driveway.
Soon he was volunteering to help anywhere a backyard ramp, contest or skatepark was being built, and from there he built a career of nearly two decades crafting wood and concrete parks all over the country. "Too many to count," he says. Among the gifts he has offered the skating world: Thrasher's Double Rock, the annual FTC pop-up in-store competition park, and a string of concrete gems during a dozen-year run with Breaking Ground Skateparks.
George is a skater's skater. He has built his life around his passion for the sport and he knows he's fortunate to be able to fully pursue that elemental bliss he first felt as a 5 year old. "Ever since I fell in love with skateboarding, it's been on my mind," says Rocha. "It still is today. I'm still that kid."


We are experts in renovation of Tax Credit, Bond and HUD properties. Our HUD 2530 Previous Participation Certification lists over 14,000 units.
We can help you get through the lender "due diligence" phase for approval. MFRG-ICON Builders stands out as a strong team member that makes your project more attractive to potential lenders.


text:
Q: Looking for e-commerce SaaS for remote add to cart and custom product option we are looking for an e-commerce SaaS that will allow for this specific functionality:

*

*It needs to allow a product to be added to cart from a remote URL

*This product will require a unique value to be attached to it each time before it is added to cart

So for instance from a remote website the user could enter their pet's name and this value would be assigned as an option value to the product.
Ideally this software would allow us to integrate with PHP, but not a deal-breaker.
I'm sure we have done something like this before with Magento but was hoping for a lighter-weight option such as shopify.

A: In the end we decided to simply use FoxyCart as that gave a lot of control over the basket.

A: Ecwid is a SaaS shopping cart, it can be embedded into the page on your site (i.e. it is not on a remote page) and embedding can be in a visual form (store or other widgets) or merely as JavaScript library, and it allows you to put products to cart with a JavaScript call on the page.

redpajama_set_name: RedPajamaStackExchange


Caterpiller Tunnels as they are often referred have been around for a few decades, finding a place in the fringes of small growers systems in varying forms of DYI or more often than not, clumsy kit forms. This earlier tangent has completely shifted to the very real need of professional micro-farmers.
More recently the groundswell in regenerative, soil focused micro-farming has led to rethinking the need for good quality, professional use Caterpiller Tunnels that are economically justifiable.
Crop rotation is of critical importance for succesfully regenerating living soil, by using a modular/standardised bed block system we can incorporate standardised season extension tunnels into the design. This allows a number of benefits to the regenerative farmer.
Timed cover of crop/bed block for effective season extension.
Timed removal of early season cover.
Inpermanence of hothouse soil use.
Span,the Caterpiller Tunnel kits from Farmers Friend span four permabeds, about 5metres.
Height, the eight metre arcs of one inch (25mm) tube steel peak at 2.3m and is semi circular in gradient.
Length between end hoops, although lengths could easily be modified Farmers Friend's Caterpiller Tunnels are either 15 metres (50 foot) or 30 metres.
End 'triangular tie off' lengths, these can be modified slightly and range from 3 to 4 metres from the last hoop to a star picket, angled backward and centred perpendicular to the end hoop.
The beds need spare area at the bed ends ranging totalling 6 to 8 metres overall, this can be dealt with by losing a bit of end bed whie still growing within the tapered area.
Side walls, typically these can be lifted and will allow good air flow across both lengthways.
Semipermanent stays, the hoops sit over rebar inserted about 400 mm into the earth. A 'Jack Jaw' star picket remover will make easy removal of these, or a refashioned diamond jack.
Centre perlin, in the basic and effectice form the perlin is a nylon strap, tied off to the star pickets at either end. Snow protection can be added by using the static tube steel perlin option.
There is a variety of Caterpillar Tunnel options available from making your own from sourced components to buying a kit.
If not set up correctly they will be problematic.
Australian sourced hothouse film is more expensive than the foreign film of the same quality in the US kits.
Although sourcing your own may save you dollars, it may take a whole lot more time and headspace away from the matter at hand, growing and selling the food.
It may be possible to hybridise the imported kit elements with the some easily sourced affordable parts such as rope, caribeners, perlin strap, 150um film, rebar, again you will need to cut a bunch to length of about 800mm.


text:
02.10-12.2012: Weekend Box Office – The $
Posted by Regor on Feb 13, 2012 in Box Office, Film
Audiences said "I Do" to Rachel McAdams and Channing Tatum in the based-on-a-true-story The Vow as they celebrated the perfect Valentine's Day movie with heartbreaking romance. The Michael Sucsy (TV's Grey Gardens) film was the #1 of four premieres, grossing $41.202 million to its $30 million production budget.
Good Ryan Reynolds versus evil Denzel Washington in director Daniel Espinosa's first US feature, #2 Safe House, also broke the $40 million mark at $40.172 million. 2008's Journey to the Center of the Earth with Brendan Fraser was surpassed by Dwayne Johnson and sort-of sequel #3 Journey 2: The Mysterious Island with $27.335 million, which also stars Josh Hutcherson returning as Sean Anderson. Last but not least of the four was Star Wars: Episode I – The Phantom Menace in 3D.
George Lucas' umpteenth (ok, eight) re-release of a Star Wars episode was a first in 3D. Episode I – The Phantom Menace, which was originally released in May 1999 and remained #1 for three consecutive weekends, grossed $22.469 million in its 3D form at 2,655 theaters. The overall current domestic gross for the first (or fourth, depending on your viewpoint) film of the franchise is $453.558 million and $513.7 million in foreign gross.
Last weekend's surprise #1, Chronicle, dropped four spots to #5. The found footage and found super powers movie grossed $12.092 million, equivalent to its budget. It was a 45% decrease. Meanwhile, Chronicle's fellow debut film of the previous weekend, The Woman in Black, grossed $10.102 million, a 51.6% decrease. The two movies each added one theater to its 2,000+ screening theaters.
Underworld: Awakening in its fourth weekend in the top ten, was edged out to #10 after spending three weeks in the top five. The $2.48 million grossing movie has earned more overseas with $71.1 million in comparison to $58.914 million domestically.


text:
Richard Armitage tangentially related
(Wolverine): Per an interview with writer Brian Percy, news that we'll hear more of Armitage in the final episode on Monday.
(Berlin Station): Viacom (parent company of Paramount, which produces the series) sued in a sexual harassment complaint against its executives.
(Ocean's 8): There is a lot of publicity this week surrounding Sandra Bullock, and I am not going to cover it all, but there were a number of pieces in InStyle and also coverage of her convicted stalker, who killed himself this week. Awkwafina is described as a breakout star due to her prticipation in this film and Crazy Rich Asians. Helena Bonham Carter has been cast as Princess Margaret in The Crown. Rihanna plans a reggae album. And so on. OK, except this. Honestly, friends don't pressure their friends to drink.
(Wolverine): The podcast, previously added to Vulture's "year's best podcasts list so far," stays on for a second month.
(Castlevania): Makes a list of best of its genre on Netflix.
Past projects:
(Romeo & Juliet): Hewson's revised novel, Juliet and Romeo, gets a blurb from one of my goto crime writing blogs, as does "the talented Richard Armitage." The item, to be released May 17, will have a foreword or afterword or something by Armitage.
(LOTR/Hobbit): When Miramax was involved, Harvey Weinstein almost fired Jackson, Walsh and Boyens from the project. Quentin Tarantino was the proposed alternative.
Collateral attractions / degrees of separation:
(Urban & the Shed Crew): Anna Friel asserts that it's more difficult for actors from the north of England to be hired.
(The Hobbit): Emotional interview with Lee Pace about his role in Angels in America.
Things we've talked about:
A funny Bagginshield spoof.
Tags: Richard Armitage, Wolverine
18 Responses to "Richard Armitage tangentially related"
Oh what a great interview with Lee Pace! (I could "cheat" on Richard with him!) I've actually never seen him in anything except the The Hobbit movies and Guardians.
SueBC said this on	May 5, 2018 at 7:53 pm | Reply
I couldn't, but I get the appeal, even if it doesn't push my buttons in particular. People are always telling to watch the one where he plays a trans soldier, and Pushing Daisies (have not seen either) but the first season of Halt & Catch Fire is definitely worth it. He's talented.
Just his personality coming through in this interview got to me. I've looked for Halt and Catch Fire, but I don't think it's anywhere I can catch it for free.
I think AMC is keeping pretty close control of it — but if you ever get a chance the first season is really good, very controlled, tight writing. I saw all of 1, 3 and 4 and I think of those 1 was the best. I've seen pieces of 2 and liked what I saw. For my tastes the show ended much more emotionally than I would have preferred.
Did they take it off Canadian Netflix?
Fatima said this on	May 5, 2018 at 11:57 pm | Reply
Oh wow… you're right! It's there! I could have sworn I searched there. But yup. All 4 seasons are there. Thanks.
SueBC said this on	May 6, 2018 at 12:21 am | Reply
Not a problem. You can also detour into Pilgrimage, freshly added. Sadly, North and South has left. 😕
Fatima said this on	May 6, 2018 at 12:34 am | Reply
Pilgrimage has made it on? Yeah I had heard N&S was going away so I did buy it. I wouldn't have discovered RA if not for N&S being on Netflix, though. Still no Brain on Fire, even though it was bought by Netflix.
That does make no sense to me.
Fatima said this on	May 6, 2018 at 5:55 pm | Reply
lee pace was in the kids movie Marmaduke
bloodangel said this on	May 5, 2018 at 9:39 pm | Reply
Never saw that one. I just realized he was in one of the Twilight movies too.
SueBC said this on	May 5, 2018 at 10:14 pm | Reply
indeed, he was, and I saw that movie, and I didn't remember him at all. So. (?).
I didn't either. A small part I think.
Good interview with Lee Pace. He struck me as a sweetheart but a bit of a "flakey" actor nonetheless. He spoke early on (a bit unprompted I thought) about a relationship where you love someone but cannot remain with them… I think he may have been referring to his split with RA….a bitter break-up?
Zigzag said this on	May 11, 2018 at 12:08 am | Reply
There's been a lot of speculation about who he was speaking of (if anyone, or people in plural). Impossible to say.
It's interesting watching him morph from his publicity for TH, to HACF, to this. In every case he's seemed a bit like the character he was playing. So I wonder if the current iteration isn't somewhat influenced by AiA.
Servetus said this on	May 11, 2018 at 12:11 am | Reply
Posters on DL have made some disparaging comments about LP's acting ability, that he is really portraying bits of himself through his roles!
I do think RA has taken on some of the characteristics of his roles: I thought he appeared more 'bolshy', a bit abrupt in interviews when he was playing alpha male John Procter.
It all leads me to wonder what lies at the core of these actors? (Possibly not a lot…..)
Zigzag said this on	May 11, 2018 at 1:17 pm | Reply
I think it's inevitable that an actor would do that, just in terms of believability. It's not possible to become an entirely different person. I don't think the correspondence is one to one, though.
I sometimes think (after years of observing Armitage's public traces) that he has an unusually flexible sense of self. Although it's becoming harder and harder to differentiate between what he really believes and what is sales, not least because he so much talks himself into roles. In any case his sense of self is more flexible than mine! Also I remember that quote from about a decade ago where he said that you give yourself to a job and then afterwards you have to figure out who you are again.


What is my Queue and where is it?
How to add a video to my Queue?
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You can access your queue from the Tubi grid screen, or home page. The row's placement may change depending on your viewing habits, so you may need to scroll down several rows to find it. If you haven't added any videos to your queue yet this category won't appear.
All titles are sorted from most recently saved to oldest saved.
What is the official Tubi TV logo?


Graves include Herman Sampliner (1835-1899) the founder of B'nai Jeshurun Congregation and Harry Bernstein, (1856-1920) ward boss and councilman.
The headstone and pictures on page 18 are of the Sogolovitz (Sogg) family.
By 1865 there were two swing bridges across the Cuyahoga River so ferries were no longer needed. Bridge Avenue (see map below) may have led to one.


text:
American Shakespeare Center announces titles to be accepted for year 3 of the Shakespeare's New Contemporaries project
Applications will be open to companion plays of six Shakespeare titles.
STAUNTON, VA—American Shakespeare Center (ASC) today announces that it will accept companion plays to six Shakespeare titles for its third year of submissions to the Shakespeare's New Contemporaries (SNC) project. The titles are All's Well That Ends Well, Henry V, The Merchant of Venice, Much Ado about Nothing, Titus Andronicus, and Twelfth Night.
Applications will be accepted from June 3–July 15, 2019. Two selected plays will be produced in 2021.
The SNC project is an international playwriting competition designed to create a modern canon of companion pieces for each of Shakespeare's 38 plays. ASC launched the competition in 2017 to inspire playwrights to compose original works in conversation with Shakespeare's classics and in keeping with his staging conditions. Winning playwrights receive a $25,000 cash prize. The plays are produced at the Blackfriars Playhouse in repertory with their Shakespeare counterparts.
"As Shakespeare's New Contemporaries grows, we continue to learn and refine the process. One change that we are making this year is considering six Shakespeare titles, rather than four," says literary manager Anne G. Morgan. "This provides greater programmatic latitude to the ASC while giving more options to writers wanting to engage with the project. And the six Year Three titles have much to offer."
The winning plays from the competition's first year will premiere in 2019. Amy E. Witting's Anne Page Hates Fun (a companion to The Merry Wives of Windsor) begins performances February 7. Mary Elizabeth Hamilton's 16 Winters, or the Bear's Tale (a companion to The Winter's Tale) begins performances May 1.


even with the default templates not touched. The new image is uploaded correctly and showing in the admin system.
Now I have checked the page is loading the correct category and it is. Also it worked fine with the default category image that was in place on install. Obviously I removed that image and replaced it with the new one.
I have output the $mediaItems variable and it is showing an empty array so Im a bit stuck on what to do now.
Ok after a bit more playing around, I set the image to Icon and it is now showing up. Can someone explain why the cat image set to Icon is loading in the stage template, I would have thought you would have needed to set the image type to "Stage"


Kim Kardashian and Kanye West are no strangers to the luxuries of life. But their latest real estate purchase — a $20 million apartment in Miami — takes lavish living to another level.
The couple have revealed their incredible private Boeing 747 featuring a double bed and loads of snacks.
Kim Kardashian and Kanye West have quietly bought a $AUD19.8 million apartment ($US14 million) at Miami's gleaming "billionaire beach bunker," sources exclusively tell Page Six.
The four-bedroom, 5 ½-bath, 4,700-square-foot apartment with a wraparound terrace at 3325 Collins Ave. had originally been listed for $AU22 million ($US15.5 million).
In late 2017, Alex sold his other Faena House condo, unit 6A, for $AU18.5 million to an unknown buyer.
The building has all the amenities desired by the super-rich: a private gym, spa, pool, concierge and underground parking.
Citadel founder Griffin famously paid a Miami record of $AU85 million ($US60 million) for two Faena penthouse units, which boast a pool and 360-degree terraces — and then never moved in.


Distinctively redefine long-term high-impact content for market positioning mindshare. Progressively pursue interactive benefits vis-a-vis user-centric networks. Phosfluorescently facilitate tactical e-tailers vis-a-vis alternative models. Uniquely provide access to leveraged architectures without progressive products. Compellingly simplify performance based innovation after multimedia based leadership.


text:
Erie Art Museum Awarded Museums for America Grant
The Erie Art Museum is proud to announce that it has received a Museums for America grant for $91,714 from the federal Institute of Museum and Library Services, to support the Museum's popular Kids As Curators program for the next three years. In announcing the award, IMLS noted that it had received 510 applications, but was only able to award grants to 178 projects—based on a peer review process—for a total investment of $19.5 million.
The Kids as Curators program is a unique Museum collaboration with local Erie schools, ultimately resulting in an exhibit curated by, designed by, and featuring the collections of middle school students. Teachers, museum staff, and students come together to learn the fundamentals of museum exhibition while working towards a conglomerate creative vision.
"Most thirteen year-olds have a bedroom that is a stock-pile of cultural artifacts, said Director of Education and program creator, Kelly Armor. "We make a connection between kids' love of collecting and the role of the Museum to exhibit collections. Kids as Curators lets us put teachers and students in creative control and the Erie Art Museum gets a great family friendly exhibit to share with the community."
This year's participants include Corry Middle School, Robert Benjamin Wiley Charter School, and Klein Elementary School. The program will kick off with a day-long training for teachers in September.
Along with the grant, the Museum received positive feedback of its application and program. One IMLS reviewer said, "One of the reasons that I review grants for IMLS every year is to be inspired by what other museums are doing. This project inspired me. Big time." Another said, "What an exciting and engaging project. You clearly identified a need, and then went out and filled it beautifully. The links you made between the curatorial act and the middle school curriculum focusing on classification makes complete sense."
About the Erie Art Museum
The Erie Art Museum anchors downtown Erie's cultural and economic revitalization, occupying a group of restored mid-19th century commercial buildings, including an outstanding 1839 Greek Revival Bank. It maintains an ambitious program of 15 to 18 changing exhibitions annually, embracing a wide range of subjects, both historical and contemporary and including folk art, contemporary craft, multi-disciplinary installations, community-based work, as well at traditional media.
The Erie Art Museum also holds a collection of over 6,000 objects, which includes significant works in American ceramics, Tibetan painting, Indian bronzes, contemporary baskets, and a variety of other categories.
The Museum offers a wide range of education programs and artists' services including interdisciplinary and interactive school tours and a wide variety of classes for the community. Performing arts are showcased in the 24-year-old Contemporary Music Series, which represents national and international performers of serious music with an emphasis on composer/performers, and a popular annual two-day Blues & Jazz festival.
The Erie Art Museum is open Tuesday through Saturday from 11 a.m. to 5 p.m. and Sunday from 1 to 5 p.m. Admission is free for members, free on Wednesdays, $4 for adults, $3 for senior citizens and students and $2 for children under 12.
For additional information on the Erie Art Museum, visit online at http://www.erieartmuseum.org/ or call (814) 459-5477.
Art MOVES: Featuring the Erie Art Museum's Permanent Collection and the Lake Erie Ballet Company
Teacher Week at the Erie Art Museum
Erie Art Museum Announces Creative Weekly Program for 10-14 Year-Olds
« Los Angeles County Museum of Art (LACMA) Presents Catherine Opie: Figure and Landscape Exhibition
Museum of Fine Arts Boston Opens Nicholas Nixon: Family Album Exhibition »


The first Black Hole image of the Event Horizon Telescope (EHT) is Wrong, it is a Fraud. The image of the supermassive Black Hole that lies at the centre of the huge Messier 87 galaxy is Einstein Black Hole image, it is Einstein description of gravity!
We do not need to look for Black Holes in another galaxy.
Milky Way galaxy has a supermassive Black Hole, 4.1 million solar masses, at its center, 26000 light-years from the Solar System.
Einstein supermassive Black Hole is a Singularity!
Ferent supermassive Black Hole has very small volume!
"Einstein bent the space, Ferent unbent the space"
Einstein supermassive Black Hole image is Black!
Ferent supermassive Black Hole image is White!
"The energy of the Gravitons inside a Black Hole, is much higher than the energy of the gluons"
"Gravitational radiation is the most penetrating type of radiation"
"Newton and Einstein did not understand Gravitation, they calculated Gravitation"
Living in Romania, the most corrupt country, I understand very well the corruption in science.
Like LIGO and the discovery of Higgs boson, the 'EHT Black Hole image' is another Fraud!
The most difficult theory is Gravitation.
Copernicus against toxic scientists confirmed that the Earth revolved around in the Sun.
Ludwig Boltzmann was 'killed' by toxic scientists.
In Ferent Quantum Gravity theory axions do not exist.
Dark matter experiment finds no evidence of axions.
Scientists in peer-reviewed journals published a lot of wrong articles about axions.
5. I discovered a new Gravitation theory based on Gravitons, which breaks the wall of Planck scale; I am the first who quantized the Gravitational Field.
6. I am the first who unified Electromagnetism and Gravity with Ferent equation for the energy of a photon E = h × f + a × f.
7. I discovered Ferent equation for elementary particles; Standard model is wrong, do not explain Gravitation and heavier elementary particles have more Dark Matter.
8. I discovered a new Evolution theory based on consciousness evolution.
9. I am the first who discovered that Gravitons with highest energy are emitted by Black Holes, they change Matter in Dark Matter inside the Black Holes; this explains the lack of extraterrestrial civilizations in the center of our galaxy.
10. I am the first who calculated the mass and the energy of a Black Hole. A Black Hole attracts with greater force a planet, than the planet attracts the Black Hole.
You learned that Dark Matter is 'invisible', is 'transparent'!
In Ferent Quantum Gravity Dark Matter is not 'invisible', is not 'transparent'.
Hawking did not understand Gravitation, Black Holes, Dark Matter and God! The equation on his gravestone is wrong.
The scientists do not understand how the Sun was formed!
You learned from your professors, from your books, from the greatest scientists…that formation of the Sun was triggered by shockwaves from one or more nearby supernovae, or by waves of energy traveling through space pressed clouds of such particles closer together!
In Ferent Quantum Gravity there are 3 Universes: the Dark Matter universe, the Matter universe and the Spiritual universe.
"I discovered that: a < h < s"
Multiverse represents multiple domains in the universe with different properties.
Here multiverse means multiple universes, means multiple contiguous domains within a larger universe, each with different properties such as different values of the physical parameters and different structures.
Our universe is an island where the parameters, the space have enough complexity, to lead to a fascinating world, with forms of life.
Our universe is the Planck universe.
Ferent Quantum Gravity theory explains what happened at Ferent wall and after the expansion of the Universe attains the Ferent wall.
There are 3 walls: the Ferent wall, the Planck wall and the Spiritual wall.
Ferent Quantum Gravity is right because in our galaxy there is 5 times more Dark Matter than Matter. This means the Dark Matter universe is much bigger than the Matter universe.
The Bible says that God created the Heavens and the Earth in six days.
The Quran says that Allah created the Universe in 6 days.
I am not talking here about things you know, like we are star dust, the carbon atoms in organic molecules were produced in dying stars by fusing helium atoms, not created by God.
I am talking here about things you did not learn from your professors, from your books, from the greatest scientists, from clerics.
In Ferent Quantum Gravity (FQG) I explained that a < h.
Is what the Bible says: The Bible says that God created the heavens and the Earth in six days, Spiritual Matter was before Matter.
Heaven, Saints were first, before Dark Matter.
This means the Saints must have density as Black Holes, how I calculated and this is wrong.
This means the Saints are made of Spiritual Matter and have a density much smaller than human body.
Third choice is right, this means a < h < s and the Bible and the Quran are wrong.
That is why Ferent equation of the material and spiritual Universe is a very important equation!
Professor Brian Cox from CERN and University of Manchester said: 'CERN disproved the existence of ghosts'.
Stephen Hawking wrote: 'God does not exist'.
I explained that the equation on Stephen Hawking gravestone is wrong!
I discovered the Soul equation, the Soul is a ghost made of Spiritual matter that can not be detected at CERN.
At CERN they did not detect Dark Matter and in my view they did not discover the Higgs boson, the 'God particle' and the Nobel Prize was a Fraud; that is why now CERN is closed.
What is the Soul, made of Spiritual Matter?
It is not easy to understand both Science and Spirituality.
My Father helped me to understand Science and my Mother helped me to understand Spirituality and I read more than 200 books about Spirituality.
You learned from your professors, from your books, from the greatest scientists that Black holes are very cold. They are cold because they absorb everything including all heat.
Bigger Black holes, they absorb more stars, planets…they become colder; because your professors, the greatest scientists did not understand Gravitation, Black holes and Dark Matter.
The power of the Hawking radiation from a solar mass black hole turns out to be minuscule: 9 x 10^(-29) W.
For a black hole of one solar mass, we get an evaporation time of 2×10^67 years, much longer than the age of the Universe.
Hawking and all the scientists did not understand Gravitation and Black holes.
Dark Matter has another structure, based on Ferent length lF = 1.296 × 10^(-69) m much smaller than Planck length lP = 1.616199×10^(-35) m.
Dark Matter does not emit, reflects, absorbs light.
Hawking Radiation: black holes will generate virtual particles right at the edge of their event horizons. The most common kind of particles is photons. A pair of these virtual particles appear right at the event horizon, one half of the pair as negative energy drops into the black hole, while the other as photon is free to escape into the Universe.
String theory and Loop Quantum Gravity are wrong theories because both of them predict Hawking radiation.
All Gravitation theories based on Einstein gravitation theory are wrong, for example String theory, Loop Quantum Gravity.
You learned from your professors, from your books, from the greatest scientists…that Dark Matter is 'invisible', is 'transparent' Matter.
You learned that Dark Matter is some form of material that does not emits, reflects, absorbs light.
This means the light goes trough Dark Matter because light does not interact with Dark Matter.
The wrong picture where Matter only accounts for 4.9 percent of our universe; another 26.8 percent is constituted of Dark Matter and 68.3 percent is constituted of Dark Energy. The scientists thought because there is 5 times more Dark Matter than Matter, because they did not detect Dark Matter which does not interact with light, the scientists have come to the conclusion that Dark Matter is 'invisible', is 'transparent' Matter.
When you look at the sky and you do not see Dark Matter, this means it is 'invisible', is 'transparent'!
Here are 2 examples, Lisa Randall professor from Harvard university and Dan Bauer physicist from Fermilab, of what the professors, the scientists think about Dark Matter: they think that Dark Matter is 'invisible', is 'transparent' Matter!
Visible light is usually defined as having the wavelength around 5 × 10^(-7) m.
In Ferent Quantum Gravity, FQG, Dark Matter with this volume has a density higher than Planck density!
I consider the Dark Matter density for this volume 5.2 × 10^99 kg/m^3, much smaller than Ferent density.
This is a huge mass, because Dark Matter has another structure, based on Ferent length much smaller than Planck length.
Light will not cross Dark Matter with the volume V and the mass M.
Light will not cross Dark Matter with the volume V because the Gravitons from Dark Matter will transform light in Dark Matter.
The human body is a quantum system composed of Matter, Dark Matter and Spiritual Matter.
The aura is the energetic field that surrounds the human body as well as every organism and object in the universe.
We see paintings of Christian saints with a circle of white or yellow light around their heads, or angels with their halos; this is the way how people imagined the energetic field of the human body.
In Christianity, the apostle Paul introduced the concept of the spiritual body, (1 Corinthians 15:44), describing the resurrection body as 'spiritual'.
The aura is made up of several layers of subtle energy.
The Spiritual body is made of Spiritual Matter evolving in time.
The most general form of the time-dependent Ferent equation of the Human body.
The Spiritual body is made of Spiritual Matter, composed of S spiritual elementary particles evolving in time.
The time-dependent Ferent equation of the Human body, which gives a description of the Human body as quantum system, made of Matter, P elementary particles, Dark Matter, R elementary particles, and Spiritual Matter, S elementary particles, evolving in time.
The solution to the Ferent equations is the wave function: Ψ.
The information about the quantum system is contained in the solution to Ferent equations, the wave function Ψ.
The square of the absolute value of the wave function, | Ψ |2 is interpreted as a probability density.
Ferent equations are Deterministic, because if I know the wave function at a moment in time I can determine the wave function later in time.
The clerics are ignorant in science and the scientists are ignorant in spirituality.
Scientists from the Pontifical Academy of Sciences were not able to discover a Transdisciplinarity equation or an equation to link Matter with Spiritual Matter.
My Father helped me to understand Science and my Mother helped me to understand Spirituality.


The Merbein Branch of the Country Women's Association has begun the task of gathering information for the publication of the first history of the Merbein Branch.
Musical Society Mildura Inc.has selected the classic musical show Les Miserables as its next show to be performed mid year.
It's that time of the month again to take a drive out to Red Cliffs to visit one of the largest markets in Sunraysia.
A new independent tyre company from Broken Hill is to expand its operation by opening a centre in Mildura as from today.
For those who have been meaning to get your affairs in order but never find the time, NSW Trustee & Guardian can make it easier for locals with a Plan Ahead day to be held in Wentworth on Thursday February 22.
The owners of the Artback Café at Wentworth have decided to close the café part of the operation.
A former Wentworth girl has been awarded the South Australian Young Citizen Award by the Australia Day Council.
Mildura brewed Fossey's Gin, will celebrate their first year of operation this Friday January 19.


text:
Los Angeles Notebook
The essay, "Los Angeles Notebook", written by Joan Didion, is about the Santa Ana winds and its affects on people. She views the winds as scientific and horrific. This is noticed by the development of the paragraphs. The paragraphs go from a deep dark tone to a more reasoning, scientific tone. Paragraph 1 she introduces the Santa Ana wind and its dark qualities. Paragraph 2 shows the wind's affects on the people in the area and its horrific qualities. Lastly, paragraph three states why the wind causes the affects on the people on Santa Ana in a scientific matter. .
In the essay, the author provides great imagery for her horrific view. For example, lines 3-8 state " tonight a Santa Ana will begin to blow, a hot wind from northeast whining down through the Cajon and San Gorgonio Passes, blowing up sandstorms out along Route 66, drying the hills and nerves to the flash point. For a few days now we will see smoke back in the canyons, and hear sirens in the night." These lines use words such as blow, hot, whining, drying nerves, smoke, and sirens show the horrific qualities of the Santa Ana wind. Other imagery was used through out the essay that describe the wind. Some examples are yellow skies, leeward slope, and cold mass.
The author uses good syntax in this essay by varying her sentence lengths. Each sentence is different. Such as in line 11, she uses "The baby frets." This sentence has only three words total, a very basic sentence. Then in lines 55-58, a much longer, more sophisticated sentence appears. The sentence uses word such as discovered, precede, ratio, positive and negative ions. By varying sentence lengths and formality, the reader become more interested in the essay. Also, this sentence shows the readers her scientific view toward the Santa Ana winds. The author using great diction, the folowing words give the sense of scientific reasoning in the essay. Some other diction used was in line 20 with "ominously glossy.
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