Evolution of the Saxophone

[badger2]

Two copies of the "Christchurch" APOE3 mutation in this recently reported Columbian case supports an isoelectric hypothesis. APOE3 differs from APOE2 by a single amino acid substitution of arginine for cysteine at residue 158. The "Christchurch" mutation sequence shows a valine flanked by two arginines, one of which will subsequently become a serine. From position 133 to 140, the sequence is LRVR/LASH, slash mark being at 136. Branched-chain aminos in this sequence are leucine(L) and valine (V). Intriguingly, regardless of whether it's APOE or presenilin sequences, the phantom potential of alanine-to-valine (and vice versa), remains.

 

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Outer layers of the dentate gyrus (above) and to presenilin (senescence) link to the hypothesis of Hughlings Jackson:

'Hughlings Jackson. Though a neurologist, Hughlings Jackson put forward some concepts and models which seem more relevant to mental than to neurological disorder. Yet he did not believe in 'mental' illness, and suggested that all the 'insanities', from the obsessional to the delusional states and the dementias, were simply the behavioural reflection of successive stages of the dismantling of cerebral structures -- which Jackson called 'dissolution.' He believed these various layers of the brain had been deposited by evolution, and ranged from the most primitive, stable, and organised, to the more human, disorganised, and unstable. Since the top layers were assumed to inhibit the lower ones, diseases affected the top layers and in destroying them, obliterated their function (negative symptoms), while the lower structures tried to compensate, causing positive symptoms. On the effect of age, Jackson wrote, 'we rarely, if ever, meet with a dissolution from disease which is the exact reversal of evolution. Probably healthy senescence is the dissolution most nearly the exact reversal of evolution.' The deepest form of dissolution, coma, he called 'acute temporary dementia: Let us say that the patient is, or is nearly, mentally dead.' For Jackson, dementia was the only form of insanity without positive symptoms. Jackson's treatment of dementia, like other mental disorders, was theoretical and related little to clinical practice. Though criticised by the alienists of his time, this model became influential later in French psychiatry. Julian de Ajurriaguerra combined it with Piagetian ideas of development and suggested that in dementia, there is an ordered dismantling of layers which can explain the various serial syndromes observed in Alzheimer's disease, including the stage when the subject may exhibit hallucinations and delusions.'
(Alzheimer and the Dementias, eds. Berrios GE, Freeman HL, Royal Society of Medicine Services Limited, London/New York [1991] pp. 22-3)

 

[badger2]

As we will show, this recent APOE report has broader implications.

4 Nov 2019 New York Times, Why Didn't She Get Alzheimer's?
(URL functions if typed in the spacebar)
nytimes.com/2019/11/04/health/alzheimers-treatment-genetics.html
'....The woman's APOE3 mutation is in an area of the gene that binds with a sugar-protein compound that is involved in spreading tau in Alzheimer's disease. In laboratory experiments, the researchers found that the less a variant of APOE binds to that compound, the less it is linked to Alzheimer's. With the Christchurch mutation, there was barely any binding.'

4 Nov 2019 Nature Medicine, An Alzheimer's Disease Protective APOE Mutation
nature.com/articles/s41591-019-0634-9
'....The authors note that the APOE3-R136S mutation affects a region of APOE known to play a key role in binding to lipoprotein receptors, such as the low-density lipoprotein receptor (LDLR). and to heparan sulfate proteoglycans (HSPG). Importantly, HSPGs are reported to promote neuronal uptake of extracellular tau, potentially exacerbating tau spreading and pathologies. The authors' own analysis showed that APOE3-R136S has markedly lower binding affinity for heparan than any of the three common APOE isoforms, including APOE2.'

 

[badger2]

Due to circumstances, we have recently concentrated on a kidney disease known as IgA nephropathy. With the serendipitous APOE report, the heparan sulfate connection is here:

'These gradients of stimulatory and inhibitory growth factors and other secreted molecules are thought to be responsible for the maintenance of tubule architecture....A model has been proposed, which suggests each of these stages has a distinct gene network architecture of hubs and nodes that determines its susceptibility to perturbation. The switching between stages is proposed to be part a function of growth factor-heparan sulfate proteoglycan (HSPG) interactions, inducing their epithelialization....HSPGs appear to have central roles in modulating ureteric bud (UB) branching morphogenesis....Embryonic mice that are homozygous for a gene-trap mutation of the heparan sulfate 2-O-sulfotransferase gene (Hs2st) display UBs that invade the metanephric mesenchyme (MM), but fail to divide and are typically stillborn.'
(Epstein, Inborn Errors of Development, Development of the Kidney)

 

[badger2]

From the Czech Republic comes an important study from 2016 linking non-invasive diagnosis of IgA nephropathy to heparan sulfate:

Non-Invasive IgA Nephropathy Diagnosis
Toward Noninvasive Diagnosis of IgA Nephropathy: A Pilot Urinary Metabolomic and Proteomic Study. - PubMed - NCBI

Heparan sulfate can link back to Alzheimer's via a 1992 study from Japan:

Heparan Sulfate Inhibits Herpes Simplex Virus Plaque Formation
Heparan sulfate as a mediator of herpes simplex virus binding to basement membrane. - PubMed - NCBI
'....only heparan sulfate inhibited HSV plaque formation by competing for virus adsorption to HEp-2 cells....de-N-sulfation resulted in significant decrease of their inhibitory activity. These findings suggest that heparan sulfate is involved in the binding of HSV to the basement membrane and that N-sulfated glucosamine residues of heparan sulfate are essential for HSV binding.'

Next we link psychiatric co-morbidities to HSV-2 and the use of valtrex, a marvelous cutting-edge pro-drug:

HSV / Valtrex / Psychiatric Co-Morbidities (April 2019 Kentucky)
Herpes Simplex Virus Type 2 Radiculomyelitis Disguised as Conversion Disorder. - PubMed - NCBI

Pubmed shows only three entries linking Alzheimer's and valtrex. This is one of them:

Viral Hypothesis and Antiviral Treatment of Alzheimer's / Biomarker Potential (July 2018 New York)
Viral Hypothesis and Antiviral Treatment in Alzheimer's Disease. - PubMed - NCBI
'....HSV 1 & 2 can trigger amyloid aggregation....'

 

[badger2]

As a prodrug, Valtrex, (Valacyclovir, 2[(2-Amino-1,6-dihydro-6-oxo-9H-purin-9-yl) methoxyl] ethyl ester-L-valine monohydrochloride), valine is crucial to its conversion into the active aciclovir. This valine moiety links not only to the valtrex-Alzheimer's assemblage (post #165), but also to the number of valine mutations that have been mentioned in this thread (post #16, etc.), which include early onset forms of AD.

 

[badger2]

The amino acid music in this thread is based on their isoelectric points. The Hofmeister series, developed by a Czech pharmacist, is also based on isoelectric points. A Russian-Georgia Tech report below explains the Hofmeister series as it relates to prions and Alzheimer's. A real challenge for the musician would be to modulate a played amino acid sequence. For sax, for instance, this would implicate an entirely new fingering pattern every time they modulated, which is much more difficult than modulating on the piano or guitar.

Modulation of the Formation of Abeta- and Sup35NM-Based Amyloids by Complex Interplay of Specific and Nonspecific Ion Effects
Modulation of the Formation of Aβ- and Sup35NM-Based Amyloids by Complex Interplay of Specific and Nonspecific Ion Effects. - PubMed - NCBI

Important applications of this technology are also seen in this report from Rocky Mountain Labs in Montana, automatically implicating tests for humans as well as CWD in deer:

Nov 2019 Million-Fold Sensitivity / Hofmeister Ion Effects
Million-fold sensitivity enhancement in proteopathic seed amplification assays for biospecimens by Hofmeister ion comparisons. - PubMed - NCBI

 

[badger2]

It should be mentioned that honeybee venom degrades heparan sulfate, whereas the Christchurch mutation (post # 163) prevents heparin binding to APOE3. The Columbian woman had two copies of this mutation (APOE3 R136S) as well as a PSEN1 E280A mutation. According to amino acid assignments in post #2, these mutations can be set to music. Here we reproduce the natural sequences, and the music will obviously change when the mutations are inserted. The reader-composer can decide what chords may be applicable through experimentation:

PSEN1 sequence, from position 271 to 290: LVETAQERN(E)TLFPALIYSS....the mutation@ 280 changes the (E) to A.

APOE3 sequence, from position 131 to 140: EELRV(R)LASH....the mutation @ 136 changes the (R) to S

 

[badger2]

Amino acid letters can be assigned to the keys of a musical keyboard. An initial system starts with concert B on the sax, which is located on a 61-key keyboard at the right-most black key of the second group of three black keys counting from the left of the keyboard. One can use the chart in post #2, the concert B is amino acid N on the chart (the first one below the octave key line). One can mark keys with masking tape, and the sequence goes in both directions according to isoelectric points. Once one has finished the first line of amino acid letters, a second line is placed above the first. The pattern will become obvious once the top line is finished. One places an A over the N (at the concert B) and works both ways from there, noticing that not all keys will have to be marked. Now, one can play amino acid sequences but also chords as they may seem to fit into the melody line of the amino acid sequence. This second line stays true to musical notation, allows for convenience in voicing chords, and chords can now be named in amino acids instead of musical notation.

 

[badger2]

In setting up any keyboard, there is no law that says the profane black-and-white keys must be gazed at for any length of time. In our sax-amino acid set-up, the marked keys will consist of lighted buttons, which also makes it very adaptable to low-light situations: the amino letters can easily be seen. The background can be an overlay of, say, midnight blue. Thus, there will be two rows of lighted buttons, and an overlay background of some type which eliminates the black and white keys.

The concert assignment for notes means that a concert b on the tenor sax is a b flat on the keyboard. The saxist thinks with regard to the pianist. Currently, an Air Didge is being fitted with a set of Hamzer electric piano lighted buttons. There is some reach difficulty, though overall it is somewhat similar to a soprano sax or clarinet, the buttons being arranged in a row down the length of the didge. One may wish to look where the fingers are moving, though this is not mandatory. This Air Didge can now be played simultaneously along with the Hamzer.

 

[badger2]

Besides a sax-switching harness for the didgeridoo mentioned previously, the Air Didge can be aligned parallel to a frame on which are mounted buttons (the actual membrane switches of the Hamzer. It is as if the piano keyboard (without the keys) was brought up close to the didge but not connected to it. The difference is that the buttons represent amino acid letters. They can be marked, but also can be removed when learned. The sections of the Air Didge assist in learning the positions for each musical note (each button), because the player can get a good general view of where the fingers are moving though does not have to precisely look at where the fingers are moving. Unfortunately, the Hamzer membrane-switch circuit board does not allow one to split the keyboard so as to lessen the length of reach when mounted close to the didge, or even place one half of the keyboard to be operated by the left hand and the other half, the right.

What happens if and when we can eliminate four lines of the traditional musical staff, when the names of the notes are changed to amino acid letters? 25 or so years of experience says that playing in concert pitch is worth learning. Revisiting the pathology, at saxophonepeople.com. The URL should work when typed in the spacebar:

Concert Pitch On My Tenor Sax | Saxophone People

 

[badger2]

One can apply the master chromatic sequence to fill in all of the known chords. In amino acid music (on graph paper), note that the two reference lines are the bottom ones:

Using the master sequence, F T Q Y S M W I D E C N,

arrange in columns, top line (for major chords, written from left to right): I D E C N F T Q Y S M W

below that, write S M W I D E C N F T Q Y

next, F T Q Y S M W I D E C N

below that, write c(major) C# D Eflat E F F# G Aflat A Bflat B

One now has the means to write down all the major chords. The chord is stacked and read from the root note on bottom (F[phenylalanine] = C, T [threonine] = C#, etc.), and the master sequence can be seen along every horizontal line. The reason the chord is written vertically becomes evident once one begins to read amino acid sheet music: the chord is placed directly under/over the precise point in time with the melody. One can now fill in all the blanks, like a crossword puzzle, for all major chords. Ditto for minor, diminished (dim), dim7 augmented (aug), C maj 7-5 (C major seventh flat fifth), 9ths, 11ths, 13ths, etc. Notice that we could have used other amino names, but that the word " WIDE" helps to remember when compiling the chord chart, as do other partial sequences (CNF, for example), whatever sequence one chooses to help remember the master sequence.

'That character input can bypass the temporal area without a loss of understanding only confirms what we have established above in connection with "direct access," or "visual" processing of writing systems in general: that "conceptual meaning is directly connected to the visual recognition of the character and the corresponding linguistic acoustic image follows.....I have noted that characters identify morphemes, but I have not sufficiently emphasized the fact that meanings of morphemes, in Chinese or any other language, drift over time. In alphabetically written languages this drift is not a problem: users are not compelled to associate any one meaning with a given phonetic representation. Not so with Chinese characters.'
(Hannas WC, Asia's Orthographic Dilemma)

The idea here is to learn to play amino acid music without looking at sheet music or their instrument.

 

[badger2]

We will be experimenting with an amino acid sequence of the N-terminal of the tau protein, because it is the target of a new dementia vaccine. Readers can also experiment with chords along this melody line (amino acids 2-18 of tau):

A E P R G E F E V M E D H A G T Y

Because the vaccine's development includes Australian research, we will look for a didj rhythm line to complement the experimental chords and melody.

 

[badger2]

Chinese krait, Bungarus multicinctus is likely the vector of the current coronavirus epidemic. Since the venom of B. fasciatus (a phospholipase) is used against cancer, the amino acid sequence can be set to music and chords for further investigation.

Basic Phospholipase A2 from Bungarus fasciatus
(Scroll down to Sequence)
Basic phospholipase A2 BFPA precursor - Bungarus fasciatus (Banded krait)

 

[badger2]

Here is a sequence from the Wuhan 2019-nCoV spike glycoprotein, which according to post #2, can be played as music which can include added chords to accompany the melody line. This sequence compares to the reference SARS CoV sequence:

2019-nCoV

K A D E T Q A L P Q R Q K K Q Q T V T L L P A A D L D D F S K Q L Q Q S M S A D S T Q

SARS CoV

K T D E A Q P L P Q R Q K K Q P T V T L L P A A D M D D F S R Q L Q N S M S A D S T Q

 

[badger2]

Flutist A-M, welcome to the thread. There may be an invention for the flute in the works, though we will not disclose it at this time.

In the Wuhan virus sequences above, before one would learn the melody line, it can be pre-played. One method is to make it so that one can arrange the notes from the synth to coincide with the sequence, by a series of wires long enough to place the synth switches in the correct order. Our performance stick now on the bench, has this capability. Then one simply activates the melody line of the amino acid sequence by running their finger (or a wheel, etc.) along the arranged switches automatically activating the notes. For introducing the mutations, one simply takes out the amino it was mutated from and adds the correct amino. Example is an alanine (concert B, upper register) to valine (concert A flat, upper register) mutation: the alanine is removed from the series and a valine is put in its place, which will change the melody and possibly the chords the musician-composer has chosen to accompany the Wuhan virus melody, which Nature has already written.

 

[badger2]

A similar interacting amino acid sequence scenario is here:

31 Jan 2020 Science Magazine
Mining coronavirus genomes for clues to the outbreak’s origins
'....Trevor Bedford, a bioinformation specialist at University of Washington and Fred Hutchinson Cancer Research Center....the trees are interactive by dragging a computer mouse over them, it's easy to see the differences and similarities between the sequences....nexstrain.org....Ecohealth Alliance....'

Using magnets on the wired synth switches (while protecting the synthesizer circuitry from electromagnetic interference) may help to "program" any amino acid sequence quickly. As one gets familiar with the sound of sequences, it becomes easier to spot potentially interesting musical combinations in the amino acid melody.

 

[badger2]

Posts #175 & 176 link a potential coronavirus reservoir/vector, Bungarus. In the Snake Meat thread, we have already mentioned codon usage (post #413) relating to vaccine design for coronaviruses There are other sequences of Bungarus that may be interesting as we speculate on vaccine production, for ebola vaccine, no doubt the reservoir-vector is still producing the virus in Nature, which is still obviously mutating.

Ebola Vaccine Codon Usage
An Evolutionary Insight into Emerging Ebolavirus Strains Isolated in Africa. - PubMed - NCBI
'....according to their geographical location....with distinct codon and amino acid usage.'

 

[badger2]

Another challenge apart from amino acid music is to use the numbers denoting the frequencies of notes. A testing format can be adapted to reading problems:

'Specialized Pathways for Reading Words and Reading Numbers: Why? Why does our cognitive system allocate two separate processing pathways to words and numbers, two cultural inventions that are very recent in evolutionary terms? Dehaene and Amedi considered this question with respect to the mechanisms of visual analysis of words and numbers which, as they showed, are implemented in different brain ares -- the so-called visual word form area (VWFA) and visual number form area (VNFA). They pointed out that the reason for this neural separation is unlikely because to be the visual properties of letters versus digits, because letters and digits are visually quite similar....They proposed that the reason for the neural separation between the VWFA and VNFA is the connectivity patterns of these brain areas with the rest of the brain, in particular the regions that make use of the parsed visual information.
....
The architecture we proposed here, where reading is dominated by structural processing, offers a complementary explanation for the separation of words and numbers. Although the visual properties of letters and digits are quite similar to each other, the structural properties of letter strings and digit strings are very different from each other: the decimal structure of digits is completely different from the morphological structure of words....When a processing stage is structure-insensitive, it may be shared for words and numbers, as seems to be the case for early processes that precede the numeric/orthographic visual analyzers (McCloskey and Schubert, 2014, Shared Versus Separate Processes for Letter and Digit Identification, Cognitive Neuropsychology 31:437-60) and for post-phonological-retrieval processes (Shalev, et al 2014, Dissociation Processes Between Numbers and Words, First Conference on Cognition Research, Akko, Israel).
....
One thing is quite clear: the specialization of different cognitive processes to words and numbers is quite rigid. The growing number of word-number dissociations demonstrates that at least in some cases, a well-functioning processing of words cannot overtake an impaired processing of numbers, and vice versa, even when the impairment is developmental and presumably existed from birth. This rigidity of word-number separation accords with the rigidity we observe within each of these domains: an intact process is sometimes unable to compensate for an impaired process, even when two processes encode information that appears to be redundant (Dotan and Friedmann, 2018, A Cognitive Model for Multidigit Number Reading: Inferences from Individuals with Selective Impairments, Cortex) *
https://doi-org/10/1016/j.cortex.2017.10.025

*
This research was supported by a grant from the Bettencourt-Schueller Foundation, by the Israel Science Foundation, by the Human Frontiers Science Program, and by the Australian Research Council Centre of Excellence for Cognition and Its Disorders
ARC Centre of Excellence in Cognition and its Disorders
(Dotan D, Friedmann N, Separate Mechanisms for Number Reading and Word Reading: Evidence from Selective Impairments, Cortex [2018] 30:1-17)

 

[badger2]

If one were designing a vaccine for the COVID-19 vector-reservoir, they would already be in trouble because there is no information on the genome of Bunagarus multicinctus wanghaotingi subspecies. Partial sequences of a lectin from the venom tissue of B. multicinctus is compared with that of B. fasciatus and these with pangolin hepatitis A virus receptor:

Bungarus multicinctus C-Type Lectin-Like Protein 2, GenBank AF354272.1
(Source tissue: venom gland)

M G H F T F T G L C L L A M F L S L R G A E C Y T C P I D W L P K N G L C Y K V F S N P

B. fasciatus C-Type Lectin-Like Protein 2, GenBank AF 354271.1
(source tissue: venom gland)
M G H F T F I G L C L L A M F L S L S G A E C Y T C P I D W L P K N G L C Y K V F S K H

(threonine, isoleucine and serine differences can be seen)

Manis javanica Hepatitis A Virus Cellular Receptor 2
(source tissue: liver, female)

M F S H S P F D C V L L L L V P L T R S L E G V Y I V E V G Q N A D LO P C S C S P A A P