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Amyloidosis (II)

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发表于 8-26-2021 15:45:50 | 显示全部楼层 |阅读模式
(1) Julian D Gillmore & Philip N Hawkins, Pathophysiology and Treatment of Systemic Amyloidosis. Nature Review of Nephrology, 9: 574 (2013)
https://www.nature.com/articles/nrneph.2013.171
(abstract: "Amyloid is an abnormal extracellular fibrillar protein deposit in the tissues. In humans, more than 25 different proteins can adopt a fibrillar conformation in vivo that results in the pathognomonic tinctorial property of amyloid (that is, green birefringence when an affected tissue specimen is stained with Congo red dye and viewed by microscopy under cross-polarized light)" )

Note:
(a) pathognomonic (adj; Early 17th century from [Ancient] Greek pathognōmonikos skilled in diagnosis, from [noun neuter] pathos suffering + gnōmōn judge):
"(of a sign or symptom) specifically characteristic or indicative of a particular disease or condition"
https://www.lexico.com/en/definition/pathognomonic

Take notice that In English, the g in pathognomonic may (as in Lexico.com) or may not (either way in Merriam-webster.com) be pronounced, whereas the same g in gnomon is silent. Do not ask me why.
(b) tinctorial (adj; from Latin verb tingere to dye or color)
https://www.lexico.com/en/definition/tinctorial

Hence, the English noun tincture 碘酒, with the definition "a medicine made by dissolving a drug in alcohol" in Lexico.com, is also derived from tingere.
(c) "green birefringence when an affected tissue specimen is stained with Congo red dye and viewed by microscopy under cross-polarized light"
(i) First and foremost, what is birefringence?  By training, I am a biologist, not a physicist. While in the graduate school and later, I read on my own two different college physics textbooks in each period (for fun), I am not equipped to read Web pages on birefringence with even a bit of physics. What to do?  
(ii) birefringence (n; First Known Use 1879; etymology: "International Scientific Vocabulary bi-  + [adj] refringent refracting, from Latin refringent-, refringens, present participle of [verb] refringere to break up — more at REFRACT")
https://www.merriam-webster.com/dictionary/birefringence

Once you click REFRACT, you will learn that this English verb (refract) is also a descendant of the same Latin verb (refringere) via its past participle. The equivalent of present and past participles of the vern get is getting and gotten, respectively.

In a word, birefringence means two refractions.
(iii) Now view a video clip about birefringence of a crystal (as well as a gemstone) calcite.
(A) Firstly starting at 0:45 (45th second), you will see that when a calcite block is placed in front of the printed word of calcite and ROTATED (hence angles of the crystal are rendered different as th block is rotated), you may see no double vision at one point and then gradually splitted images (as the block rotates) to a maximum split and (as the block continues to rotate) the split reduces little by little until no more double vision. As the block keeps on rotting, the same cycle repeats itself.
(B) Secondly starting at 3:57, you see a polarizing filter that is being rotated in front of the block. You see the same happening again.

Recall that you can turn on cc (for closed caption) at the lower right corner of the video clip.
(C) Why is calcite used as a visual aide or teaching tool. That is because: "This effect [birefringence] was first described by the Danish scientist Rasmus Bartholin in 1669, who observed it in calcite, a crystal having one of the strongest birefringences. However, it was not until the 19th century that Augustin-Jean Fresnel described the phenomenon in terms of polarization." en.wikipedia.org for birefringence.
(D) John Pollard, Identifying Isotropic vs Anisotropic Gemstones. In IGI Classroom. IGI Gemblog, Feb 10, 2020
https://www.igi.org/gemblog/iden ... sotropic-gemstones/
("For heterogeneous gemstones: Light breaks down inside the gemstone and propagates with two different refractive indices (double refraction). Unless it comes from a special direction [ie, polarized light in the first place, as opposed to sunlight which is unpolarized], light becomes decomposed into two polarized beams with perpendicular vibration directions and different propagation speeds")
• Regarding "Light breaks down inside the gemstone." Another gem Web page says it more cogently. See
7.15 Double Refraction. last updated Aug 11, 2020.
https://geo.libretexts.org/Books ... A_Double_Refraction
("When a ray of light enters the gemstone, the atomic structure allows only those rays vibrating in two specific directions to continue. These two rays vibrate in planes that are mutually perpendicular and are therefore polarized. Both these rays travel at different velocities inside the gemstone and thus will refract at different angles when incident other than parallel to the normal")
• LibreTexts
https://en.wikipedia.org/wiki/LibreTexts
• polarization (waves)
https://en.wikipedia.org/wiki/Polarization_(waves)
("Light or other electromagnetic radiation from many sources, such as the sun, flames, and incandescent lamps, consists of short wave trains with an equal mixture of polarizations; this is called unpolarized light. Polarized light can be produced by passing unpolarized light through a polarizer, which allows waves of only one polarization to pass through. The most common optical materials [eg, eyeglasses] do not affect the polarization of light, however, some materials—those that exhibit birefringence, dichroism, or optical activity—affect light differently depending on its polarization. Some of these are used to make polarizing filters. Light is also partially polarized when it reflects from a surface")
• "an equal mixture of polarizations"?  See Unpolarized Light. Encyclopaedia Britannica, undated
https://www.britannica.com/science/light/Unpolarized-light
("The atoms on the surface of a heated filament, which generate light, act independently of one another. Each of their emissions can be approximately modeled as a short “wave train” lasting from about 10−9 to 10−8 second. The electromagnetic wave emanating from the filament is a superposition of these wave trains, each having its own polarization direction. The sum of the randomly oriented wave trains results in a wave whose direction of polarization changes rapidly and randomly [see illustration]. Such a wave is said to be unpolarized. All common sources of light, including the Sun, incandescent and fluorescent lights, and flames, produce unpolarized light. However, natural light is often partially polarized because of multiple scatterings and reflections")
• IGI stands for International Gemological Institute.
https://en.wikipedia.org/wiki/International_Gemological_Institute
In 2018 Fosun International Ltd acquired 80% of IGI for an undisclosed term (the founding retains 20% and management).
(d)
(i) Salt (sodium chloride) has cubic crystal
https://www.shutterstock.com/ima ... -chloride-345228074
and is isotropic.
(ii)
(A) Water and glass are amorphous (not crystallized) and hence isotropic. However, Kenneth G Libbrecht of Caltech, Feb 1, 1999 stated in a Web page: "Ice can assume a large number of different crystalline structures, more than any other known material.  At ordinary pressures the stable phase of ice is called ice I, and the various high-pressure phases of ice number up to ice XIV so far.  (Ice IX received some degree of notoriety from Kurt Vonnegut's novel Cat's Cradle.)  There are two closely related variants of ice I: hexagonal [六角形] ice Ih, which has hexagonal symmetry, and cubic ice Ic, which has a crystal structure similar to diamond.  Ice Ih is the normal form of ice; ice Ic is formed by depositing vapor at very low temperatures (below 140°K).  Amorphous ice can be made by depositing water vapor onto a substrate at still lower temperatures."
(B) ice Ih crystal:
https://condensedconcepts.blogsp ... ce-in-nutshell.html
(iii) We all know"tetrahedrical [sic; should be tetrahedral, from the noun tetrahedron 四面体] structure of diamond." See top illustration in
https://www.physics-in-a-nutshel ... 3/diamond-structure
(A) Then, how come diamond is cubic?
• Firstly, cubic crystal system
https://en.wikipedia.org/wiki/Cubic_crystal_system
(primitive cubic (such as sodium chloride); body-centered cubic (bcc); and face-centered cubic (fcc) )
• Secondly, return to
https://www.physics-in-a-nutshel ... 3/diamond-structure
to observe bottom illustration (containing four figures). You can see diamond is an fcc with four additional carbons in a cube.
• Thirdly another way to look at the diamond cube is
http://www.expertsmind.com/quest ... ture-301103694.aspx
(figure: "2 [identical] interpenetrating FCC's")
where FCC's (or FCCs) means plural of FCC.
• Marek S. Wartak and Ching-Yao Fong, Field Guide to Solid State Physics. SPIE ebook, 2019 further observed under the topic of "Diamond Structure", "Semiconductors such as diamond (C), silicon (Si), germanium ... (Ge), and grey tin (α-Sn) crystallize in this structure."

SPIE
https://en.wikipedia.org/wiki/SPIE
(iv) spinel
https://en.wikipedia.org/wiki/Spinel  
("It has the formula MgAl2O4 in the cubic crystal system. Its name comes from the Italian word spinella, which means small spine in reference to its pointed crystals")
"spinel crystal lattice with tetrahedral and octahedral sites."
https://www.shutterstock.com/ima ... ral-sites-348379409
(v) ruby
https://en.wikipedia.org/wiki/Ruby   
(like sapphire, is "a variety of the mineral corundum (aluminium oxide [Al2O3]; section 1 Physical properties: "one percent of the aluminium ions are replaced by chromium in ruby")
(A) crystal structure
https://en.wikipedia.org/wiki/Crystal_structure  
(section 1 Unit cell: "is defined as the smallest repeating unit having the full symmetry of the crystal structure"/ section 3 Atomic coordination, section 3.1 Close packing)
Take notice that in section 3.1, the balls -- be they black or white -- are all identical (the difference is layers of balls); in aluminum oxide, the balls are (bigger) oxygen ions in hexagonal close packing (hcp).
(B) An Al2O3 unit cell can be found in
https://www.quora.com/What-perce ... -an-HCP-arrangement
, with aluminum ions filling in the space among oxygen ions.
(vi) Calcite
https://en.wikipedia.org/wiki/Calcite
(CaCo3)
is a hexagonal crystal with an additional CaCo3 in the center of a hexagonal plane; it is anisotropic.
(e) Chapter 6 Light Optics. In Joseph Smyth, Geology 3010 Mineralogy Syllabus. University of Colorado, Fall, 2017
http://ruby.colorado.edu/~smyth/G30106.html
("When a beam of light strikes a polished surface of an isotropic material with a different index of refraction, it is split into two rays, a reflected and a refracted ray. The reflected ray always has the same angle to the normal [(n) 垂直线] as the incident beam. The refracted beam does not * * * The reflected and refracted beams are partially polarized in a complimentary fashion and maximum polarization is achieved when the angles of incidence and refraction are complimentary (i.e. i + r = 90º) * * * The speed of light in a substance is an inverse function of density, as we saw when we heated up the oil. Cubic and amorphous solids have the same density in all directions, as do liquids. These substances are said to be isotropic. * * *  Most minerals are non-opaque, non-isotropic substances. Hexagonal, trigonal, tetragonal, orthorhombic, monoclinic, and triclinic minerals may have different indices of refraction in different directions. * * * The property of having different indices of refraction in different directions is called birefringence). This property is illustrated by the calcite rhomb")

Thus, non-cubic (including hexagonal) crystals are always anisotropic.
(f) Congo red
https://en.wikipedia.org/wiki/Congo_red  
(is an azo dye; section 1 History: name; section 3 Diagnostic use: "Apple-green birefringence of Congo red stained preparations under polarized light is indicative of the presence of amyloid fibrils")
(i) azo compound
https://en.wikipedia.org/wiki/Azo_compound
("The name azo comes from azote, the French name for nitrogen that is derived from the [Ancient] Greek ἀ (a-, not) + ζωή (zōē life)" )
(A) Wiktionary.com says that the Modern French noun masculine anote was coined by Antoine Lavoisier (1743-1794, who also named oxygen (1778) and hydrogen (1783) ), and that the English noun nitrogen descended from French  noun masculine (now obsolete) nitrogène coined by Jean-Antoine Chaptal (1756 – 1832).
(B) Zoe or Zoë is a female given name, where diaeresis (diacritic)
https://en.wikipedia.org/wiki/Diaeresis_(diacritic)  
indicates the e is pronounced -- same as in the e in Brontë family
https://en.wikipedia.org/wiki/Brontë_family  
(section 1 Origin of the name 1830–1852: "At some point, the father of the sisters, Patrick Brontë (born [with last name] Brunty), decided on the alternative spelling with the diaeresis over the terminal e to indicate that the name has two syllables" )
(ii) "Congo red stain applied to the tissue gives the amyloid protein a salmon-pink color [under unpolarized light of light microscopy] and placed under polarized light the amyloid proteins have an apple-green birefringence." from the Web.
(iii) Alexander J Howie, Origins of a Pervasive, Erroneous Idea: The 'Green Birefringence' of Congo Red-Stained Amyloid. International Journal oF Experimental Pathology, 100: 208 (2019).
https://onlinelibrary.wiley.com/doi/full/10.1111/iep.12330

Quote:

" 'Amyloid' [from Latin noun neuter amylum starch, from Ancient Greek noun neuter ámulon starch]had been first used by the German botanists Julius Rudolf Theodore Vogel (1812-1841) and Matthias Jakob Schleiden (1804-1881) in a paper in 1839

"Congo red absorbs blue and green wavelengths, with a peak in the blue-green, and so appears red in ordinary illumination.

"A birefringent material has two extremes of refractive index, because light travels most slowly through it in one plane, called the slow axis, with the largest refractive index, and least slowly through the plane at right angles to this, called the fast axis, with the smallest refractive index. There is a range of refractive indices between these limits.

• There is no need to read the rest of Howie's article.
• I read a lot for the past two days but there is nothing to explain how Congo red confers birefringence to amyloids.
• a new discovery whose significance is unclear:

Rita Strack, GFP Lights up Amyloid Fibrils; Fluorescent proteins can bind amyloid fibrils formed from natural peptides and proteins. Nature Methods, 17: 959 (October 2020; under the heading: Research Highlights; locked behind pay wall)
https://www.nature.com/articles/s41592-020-00976-6
(about Xu S et al, Sequence-independent Recognition of the Amyloid Structural Motif by GFP Protein Family. Proc Natl Acad Sci 117: 22122 (Sept 8, 2020): ("Sherry Xu * * * in the laboratory of George Makhatadze at Rensselaer Polytechnic Institute in which they show that the commonly used fluorescent proteins GFP, mCherry and mEos2 can specifically label amyloid fibers in vitro and in cells without being targeted to these structures. The researchers found, to their surprise, that these fluorescent proteins bind to over fourteen amyloid fibrils, of both biological abd chemical origins, but ot to some disease-relevant amyloid fibril such as synuclein [in Parkinson's disease] and tau fibrils [in Alzheimer's disease]")


(2)
(a) Wei Q et al, Antiparallel β-Sheet Architecture in Iowa-Mutant β-Amyloid Fibrils. Proc Natl Acad Sci, 19: 4443 (2012)
https://www.pnas.org/content/109/12/4443
, whose Fig 4(c) had a schematic display of "Wild-type, full-length (40- and 42-residue) amyloid β-peptide (Aβ) fibrils" -- quoting the first clause of Abstract. Fig 4(c) shows two almost identical cartoons, for use with 3-d glasses.

Alzheimer's disease is associated with two pathological observations: "amyloid beta, accumulating extracellularly as amyloid plaques, and [hyperphosphorylated (phosphorylation means addition of PO3- -)] tau proteins, accumulating intracellularly as neurofibrillary tangles." en.wikipedia.org for "Alzheimer's disease."

It is unclear whether either or both causes the disease, but mutations in either protein set off early-onset Alzheimer's.

The takeaway is that whatever the amyloid fibrils's origin (whatever proteins the amyloid fibrils come from), in amyloidosis beta sheets are the norm. However, so far the proof of beta sheets in amyloidosis are in peptides, not large proteins like tau or transthyretin.  

(b) "TTR amyloidosis has two forms: hereditary and non-hereditary. The hereditary form is caused by a genetic mutation [actually there are quite a few mutations in the transthyretin gene that predisposes the patient for ATTR] inherited from a family member. The non-hereditary form, also called 'wild-type,' emerges from a normal transthyretin molecule that (for reasons unknown) becomes unstable and misfolds, forming amyloid.": from the Web.

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 楼主| 发表于 8-26-2021 15:46:19 | 显示全部楼层
本帖最后由 choi 于 8-30-2021 15:23 编辑

(3) Almost four decades ago, I learned of amyloidosis and was mystified by it: Why would misfolded fibrils come into and be deposited in an organ? But there was no time to contemplate.

Four decades later, not much progress has been made, except that a new perspective starts to form)


Prion
https://en.wikipedia.org/wiki/Prion
(section 1 Etymology and pronunciation; section 4 Transmissible spongiform encephalopathies
causes prion disease, study of which has generated two Nobel Prizes in medicine. The first was discovery of Kuru (disease)
https://en.wikipedia.org/wiki/Kuru_(disease)
, which was found to be transmitted when Fore people of Papua New Guinea practiced cannibalism and ate human brains. The practice was subsequently banned and Kuru vanished.

Stanley B Prusiner of Univ of California, San Francisco theorized that prion protein misfolded, made good prion to turn bad (become misfolded) upon contact and this is how the disease worsened and transmitted. He was awarded with the Nobel Prize in 1997. After that I still did not believe him, as there was no proof (in experiments) -- until mouse was created that lacked prion protein and showed imperviousness to misfolded prion.

The normal function of prion or alpha-synnuclein (whose misfolding is culprit of Parkinson's disease) is unknown. Mice without either seem normal.

I went to a lecture of Prusiner in Boston after his Nobel award but prior to 2007. He speculated (yes, speculated; without any evidence to show) that many neurological disorders such Parkinson's and Alzheimer's may be caused by mechanism similar to prion disease. Two decades later, the thinking is that amyloidosis in body outside nervous system are also caused by mechanism similar to prion disease. In other words -- or going the other direction -- prion disease is caused by mechanism similar to that of amyloidosis. See

Araki K et al, Parkinson's Disease Is a Type of Amyloidosis Featuring Accumulation of Amyloid Fibrils of α-Synuclein. Proc Natl Acad Sci, 116: 17963 (2019).
https://pubmed.ncbi.nlm.nih.gov/31427526/

Prion misfolding causes mad cow disease, whose spreading was stopped in US when animal feed )not just for cattle but for dogs and cats also, because prion is capable of crossing species barrier) containing central nervous system (brain and spinal cord) was banned.
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