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CADASIL: A Disease

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发表于 5-13-2019 16:27:53 | 显示全部楼层 |阅读模式
Lisa Sanders, A Husband's Confusion. Many of the symptoms pointed to multiple sclerosis. But it became clear that there might be another problem entirely. New York Times Magazine, May 5, 2019.
https://www.nytimes.com/2019/05/ ... osis-diagnosis.html

Note:
(a) "Kaiser Permanente medical center in Los Angeles * * * Dr Brandon Beaber, a fellow in a branch [no name for it, which is merely a subspecialty] of neurology specializing in diseases like MS [multiple sclerosis], was assigned to the patient. * * * The patient was a teenager when his father died, his wife explained when her husband seemed unable to answer. He [father] had severe dementia and died of what was thought at the time to be arteriosclerosis. His mother died of breast cancer within a year. He had two brothers who both died in their 40s. * * * 'I don’t think you have MS,' the doctor said slowly. His symptoms, his MRI and his family history suggested that he had a rare and newly described inherited disease called Cadasil. * * * The gene behind the disease was identified in 1993 — just a few years before this patient got his diagnosis of MS. The genetic error affects the muscles in the small vessels in the brain, causing them to thicken, cutting blood flow to the segments of the brain they supply. In short, those who have Cadasil have thousands of tiny strokes that kill off the brain bit by bit. There are no treatments for the cognitive effects and no known cure for the disease. * * * Worse still, if he had it, then his children had a 50-50 chance of having inherited the same bad link. Testing showed he had Cadasil."
(i) Kaiser Permanente
https://en.wikipedia.org/wiki/Kaiser_Permanente
(based in Oakland, California; founded in 1945 by industrialist Henry J Kaiser and physician Sidney Garfield [residency at Los Angeles County-USC Medical Center; MD University of Iowa 1928]; "As of 2017, Kaiser Permanente operates in eight states (Hawaii, Washington, Oregon, California, Colorado, Maryland, Virginia, Georgia) and the District of Columbia, and is the largest managed care organization in the United States. * * * The name Permanente came from Permanente Creek, which flowed past Henry Kaiser's Kaiser Permanente Cement Plant on Black Mountain in Cupertino, California. Kaiser's first wife, Bess Fosburgh, liked the name")
(ii) Brandon Emet Beaber, MD. Kaiser Permanente, undated
https://healthy.kaiserpermanente ... ndon-beaber-1424469
("My undergraduate education was at the University of California at Berkeley, where I earned a bachelor's degree in molecular and cellular biology with an emphasis in genetics and development. I attended medical school in Philadelphia at Drexel University College of Medicine. My internal medicine internship and neurology residency training were at Kaiser Permanente's Los Angeles Medical Center (LAMC), and I completed a fellowship in multiple sclerosis and neuroimmunology at USC (as well at LAMC)")

His bio is unremarkable.
(A) Drexel University
https://en.wikipedia.org/wiki/Drexel_University
(private; was founded in 1891 by Anthony J Drexel, a noted financier and philanthropist)
(B) "Drexel Burnham Lambert was an American investment bank that was forced into bankruptcy in February 1990 due to its involvement in illegal activities in the junk bond market, driven by Drexel employee Michael Milken [firm's junk bond head]. At its height, it was a Bulge Bracket bank, as the fifth-largest investment bank in the United States."  en.wikipedia.org for Drexel Burnham Lambert.
(C) The current world's top 10 investment banks based on revenue are: (1) JP Morgan Chase, (2) Goldman Sachs, (3)Investment bank ranking, (4) Investment bank ranking, (5) Citigrou, *6) Barclays Capital (an investment division of Barclays plc, (7) Investment bank ranking, (8) Investment bank ranking, (9) Investment bank ranking, (10) UBS.

I fail to find old ranking that included Drexel. But see Mary Zey, Banking on Fraud; Drexel, junk bonds, and buyouts. Routledge, 1983, at page 150
https://books.google.com/books?i ... tment+bank+ranking+"drexel"+goldman+sachs&source=bl&ots=HGFIxTtisc&sig=ACfU3U3ReoZSDztrxqot7T_KmFweOKzTkg&hl=en&sa=X&ved=2ahUKEwj92J3ItJniAhXvQd8KHWnpCCA4HhDoATADegQIChAB#v=onepage&q=investment%20bank%20ranking%20"drexel"%20goldman%20sachs&f=false
("Eccles and Crane (1988, pp 96-97) examined the number of mergers and acquisitions performed by the nineteen leading investment bankers between 1984 and 1986. They found a total of 1,338 mergers and acquisitions with another investment banker on the other side. Drexel ranked fifth in the number of mergers and acquisitions, with 113, behind Goldman, Sachs; Stanley; First Boston; and Shearson, Lehman. Investment bankers generally chose consistently to represent either acquirers or targets, and thus planned offensive or defensive strategy. Goldman, Sachs, because it has always represented the blue-chip stock companies that were being attacked, had an announced policy of not representing acquirers in a hostile takeover. It represented the target in 66.0 percent of its M&A activities. * * * Drexel stood out for doing the largest proportion of its M&A deals for acquirers, 63.7 percent. * * * Thus Drexel was the major underwriter for raiders during the height of the 1980s mergers and acquisitions period, but not the only one")
(D) Drexel Burnham Lambert. Wall Street: Museum of American Finance (MOAF), Nov 7, 2014
https://www.moaf.org/publication ... ion/dbl_finding_aid
("was founded as a small brokerage firm, Burnham and Company, in 1935 by IW 'Tubby' Burnham. In 1973 Burnham and Company merged with Drexel Firestone [which was cofounded by AJ Drexel's father and which AJ joined at the age of 21] to form Drexel Burnham, and in 1976 it merged with the American arm of the Belgian firm George Bruxelles Lambert and was renamed Drexel Burnham Lambert [DBL]. By the mid 1980's DBL was ranked among Wall Street's top investment banks, employing over 10,000 people. Its success was fueled by its creation of a market for first-issue junk bonds, allowing low-credit companies to raise capital by issuing bonds rather than having to offer their stock. In 1986 DBL came under investigation by the US Securities and Exchange Commission involving insider trading and other illegal trading practices. Under extreme pressure from the government and a subsequent decline in DBL's business, the company filed for bankruptcy in February of 1990")

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 楼主| 发表于 5-13-2019 16:32:21 | 显示全部楼层
(b) cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Genetic Home Reference, US National Institute of Health, undated
https://ghr.nlm.nih.gov/conditio ... leukoencephalopathy
(CADASIL)

Do not forget to click "CAUSE" (in blue).
(c) Levi Gadye, The Discovery of CADASIL. BrainFacts.org, Apr 3, 2019
www.brainfacts.org/diseases-and- ... y-of-cadasil-040319
("the extended family of those first three related patients, who all lived in small villages in western France [near city of Nantes], were more than willing to participate in the study, in Paris, in the hopes of uncovering the cause of this yet-to-be-named disease. * * * In a 1991 paper, Bousser and Tournier-Lasserve argued that they had identified a novel and heritable disease on the basis of neurological symptoms and anomalies in brain MRI scans that were present in nearly half of 45 related family members. But the researchers still needed to identify the gene that was causing the condition.  Within a few years, Bousser and Tournier-Lasserve had successfully mapped the responsible gene to human chromosome 19 [through genetic linkage: recombination/ crossover, which I will discuss in a week]. Bousser coined the term CADASIL, and in 1993, they announced their landmark findings — few diseases had ever been traced as definitively to mutations in a single gene. [You may stop reading this article here.]  * * * the first and only Notch3 mouse model of CADASIL was developed by [Anne] Joutel [MD, Neurology: University Paris 7-Medical School (1996), PhD, Neuroscience: University Paris 7 (1996)], who committed herself fully to basic research in the 1990s")
(i)
(A) the 1991 paper:
Tournier-Lasserve E, Autosomal Dominant syndrome with Strokelike Episodes and Leukoencephalopathy. Stroke, 22: 1297 (1991).
https://www.ncbi.nlm.nih.gov/pub ... rnier-Lasserve+1991
(B) "coined the term CADASIL":
Tournier-Lasserve E et al, Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Maps to Chromosome 19q12. Nature Genetics, 3: 256 (1993).
https://www.ncbi.nlm.nih.gov/pubmed/8485581
(C) identification of gene:
Joutel A et al, Notch3 Mutations in CADASIL, a Hereditary Adult-Onset Condition Causing Stroke and Dementia. Nature, 383:707 (1996).
https://www.ncbi.nlm.nih.gov/pubmed/8878478

In that period, both Bousser and Tournier-Lasserve were with Necker-Enfants Malades Hospital.
https://en.wikipedia.org/wiki/Necker-Enfants_Malades_Hospital
(is affiliated to the University of Paris Descartes [or Paris V; the original University of Paris was divided in 1970 into University of Paris I-XIII]; section 1 History)
(ii) Brain Prize (2011- ; funded by Copenhagen-based Lundbeck Foundation, which owns 70% of stocks of Lundbeck, a pharmaceutical) announced on Mar 5, 2019 the 2019 Brain Prize to the four individuals whose photo appears at the top of BrainFacts article.
(iii) Marie-Germaine Bousser, MD, and Elisabeth Tournier-Lasserve ("obtained her MD in Paris in 1984": from the Web).

A high school student graduate with baccalaureat entera a medical school (there are 30 in France) and after six years receives a State Diploma of Doctor of Medicine (MD; French: Diplôme d'Etat de Doctorat en Medecine).  en.wikipedia.org for "medical school" (section 4.10: France_
(iv) Nantes
https://en.wikipedia.org/wiki/Nantes
(section 1 Etymology)
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 楼主| 发表于 5-13-2019 16:35:35 | 显示全部楼层
(d) basic research:
(i) "Notch signaling is evolutionarily conserved from Drosophila to human."  from the Web.
(ii) Notch proteins
https://en.wikipedia.org/wiki/Notch_proteins
(A) If you can, manage to read the entire page.
(B) The introduction early on mentions DSL family ligands." Not until section 4 Ligand interactions does the page explain "the Delta/Serrate/Lag-2 (DSL) family of proteins which is named after the three canonical Notch ligands. Delta and Serrate are found in Drosophila while Lag-2 is found in C elegans [a kind of round worm, 1 mm in length]. Human contain 3 Delta homologs, Delta-like 1, 3, and 4, as well as two Serrate homolgs, Jagged 1 and 2."

Heed section 3 Structure -- and its cartoon.

"The jagged 1 protein encoded by JAG1 is the human homolog of the Drosophila jagged protein."   :from the Web.
(iii) Salazar JL et al, Integration of Drosophila and Human Genetics to Understand Notch Signaling Related Diseases. Advances in Experimental Medicine and Biology, 1066: 141 (2018; review).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233323/

Please read paragraph 1 under section "1. Discovery and expansion of the Notch signaling pathway in Drosophila" to appreciate how genes for ligands and more are discovered in fruit fly.
(iv) How in humans, a ligand and Notch receptor interacts, as revealed through x-ray (crystallography).

Luca VC et al, Notch-Jagged Complex Structure Implicates a Catch Bond in Tuning Ligand Sensitivity. Science, 355: 1320 (2017).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5459593/
shows in right panel of Fig 1 that an EGF domain of Notch protein (pink) interacts with an EGF domain of Jag1 (green).

(The gray arcs at the top and bottom of the panel represents cell surface of two cells. EGF stands for epidermal growth factor. In that panel, not all EGF domains are shown in 3-D; many are depicted as disks, such asteh first  and last part of extracellular part of the Notch protein (pink).)
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