BC HEALTH
Saved by @jay_millerjay

Epigenomic biomarkers are becoming more established for #LiquidBiopsy and #CancerScreening, and we have seen the big players positioning themselves in this #epigenomics race recently.

 @sbarnettARK Catching signs of #cancer early is crucially important to the disease management and survival rates, so the question is: how can we find out if there is something wrong going on early enough?
@sbarnettARK The first generation of high-throughput technologies was predicated on finding mutated (tumor) DNA in the individual's body (somatic), different from their (normal) DNA. Tumor/Normal (T/N) comparisons of the individual's samples, biopsies or ctDNA will indicate if there
@sbarnettARK are signs of cancer already underway. So why do we need #epigenomic profiling if we can do all this with the detection of mutations? Well, the argument is that if you can see sufficient mutated copies of DNA, cancer may already have progressed beyond the initial stages.
@sbarnettARK Then people asked the question: is there an earlier mark that we can detect for earlier stages of cancer before the Tumor/Normal mutations signal amps up? Here is where #epigenomics profiling took hold.
@sbarnettARK Out of the big players, $GH Guardant Health was one of the early adopters of #epigenomic profiling for early cancer detection. The slide decks of their R&D projects mentioned #methylation (5mC) as a way of catching cancer earlier than with mutation profiling.
@sbarnettARK Later on, $GH brought in #fragmentomics via a combination of their own developments and acquisitions. The fragmentomics profiling of ctDNA is complementary to #methylation marks and adds up to better AUCs.
@sbarnettARK While $GH was working on this, @GrailBio came to the fore with a big couple of funding rounds, the backing of @illumina, and a very clear mission statement to go after cancer screening (I don't think it has changed since then).
@sbarnettARK @GrailBio @illumina At @GrailBio, they looked at different options, and again #methylation profiling became the tip of the arrow. I haven't followed the IP stemming from their internal work, but in slide decks and bits of PR, there is the constant mention of their bisulfite-free method to assay 5mC.
@sbarnettARK @GrailBio @illumina That's an important consideration for #LiquidBiopsy as there isn't *that* much DNA present in a 10ml draw of blood -- the size of a lipstick. There could be 500-1000 copies of the genome, most in fragments of around 150-160bp. So old school methods like bisulfite assays simply
@sbarnettARK @GrailBio @illumina destroy most of the fragments composing these 1000 copies in a #LiquidBiopsy sample, so you end up with not enough left to have a good signal-to-noise ratio. The final profile is ideally something like this screenshot:
@sbarnettARK @GrailBio @illumina where the peaks show places of presence of 5mC: the highest the peak, the higher the fraction of all copies is methylated. The places without peaks are almost always unmethylated (5C). This binary 5mC vs 5C switch for each CpG in the genome is the basis of the biomarker.
@sbarnettARK @GrailBio @illumina So what's the ideal? A method that takes the smallest amount of blood, takes into account the largest amount of genome copies (coverage) without destroying them during the assaying, and also ideally, that can find haplotypic information: long stretches of the genome where
@sbarnettARK @GrailBio @illumina the signal is "linked" (in linkage) for several of these CpGs. In terms of coverage, the more you sequence the higher depth that will be assayed, and the bigger the panel of loci, the higher the throughput needed to cover it more deeply. This has a cost consideration, as the more
@sbarnettARK @GrailBio @illumina you sequence, the more you have to pay either @illumina or @MGI_BGI or other short-read technology for a given profile. Long reads are of no benefit "per see" in #LiquidBiopsy #cfDNA, as the fragments are short in the bloodstream. If your method destroys part of the DNA while
@sbarnettARK @GrailBio @illumina @MGI_BGI assaying it, then you'll end up with a less diverse pool to start with, and more of your NGS throughput will be wasted in duplicate reads (reading the same sample fragment more than once).
@sbarnettARK @GrailBio @illumina @MGI_BGI So what's out there that's better than bisulfite 5mC? Both $GH and @GrailBio claim to have their own method. Then $EXAS acquired for a stonking $515M a company, #BaseGenomics that has a method to do this, both for 5mC or 5hmC (a related but different epigenetic mark to 5mC).
@sbarnettARK @GrailBio @illumina @MGI_BGI Then there is the De Carvalho lab who does this differently: if you need to have this signal of 5mC peaks, and most of them are going to be consistently the same for about 50-60% of the genome, why not instead of sequencing 100% of the genome, do an enrichment method that
@sbarnettARK @GrailBio @illumina @MGI_BGI gives you as many reads as the height of the peaks when they are methylated? This way, in the binary 1/0 signal, for 5mC/5C, you only spend your throughput sequencing the 1s, and don't spend it with the 0s. Then you extrapolate the 0s with the difference of the peak heights.
@sbarnettARK @GrailBio @illumina @MGI_BGI This idea is great in principle but has been difficult to implement for small amounts of DNA. The De Carvalho lab, and their spin-off DNAmx (https://t.co/8WOh2DV0SA) has shown progress on the original work that was done by the Reik Lab in Cambridge UK.
@sbarnettARK @GrailBio @illumina @MGI_BGI So if pulling down the 5mC fraction of a cfDNA sample is cheaper because it concentrates the throughput in the 50-60% of the genome that is consistently methylated, then what else can be done to further drive down the cost of each #epigenomic profile?
@sbarnettARK @GrailBio @illumina @MGI_BGI One way is to do this in a targetted fashion: only select loci that you think are interesting as part of the biomarker. The @GrailBio approach was to solve this the "brute force" way: spend lots of money doing it genome-wide, then distill the targetted panel from it.
@sbarnettARK @GrailBio @illumina @MGI_BGI In this way, we take out the "boring" part of a 5mC profile and only include the regions that could maximally inform a healthy vs cancer diagnosis. Another approach is to find a different epigenomic mark that has less of the "boring" part, and not have to design a panel.
@sbarnettARK @GrailBio @illumina @MGI_BGI Here is where 5hmC is now shining new light in early cancer diagnosis. The 5-hydroxymethylation marks are concentrated into 8-12% of the genome, into what people would class as functionally enriched parts of the genome, such as genes (gene bodies), promoters, proximal enhancers
@sbarnettARK @GrailBio @illumina @MGI_BGI and other functional elements of the genome. This difference between 5hmC and 5mC, one being concentrated at around 8-12% of the genome and the other at 50-60% is due to a historical event in the genome of most plants and animals: the introduction of repetitive DNA in genomes.
@sbarnettARK @GrailBio @illumina @MGI_BGI Many millions of years ago, the genomes of eukaryotes (not so much bacteria and archaea) started to accumulate repetitive DNA, in many cases of foreign origin: viruses and other vectors would infect you and in some cases, they would leave a trace of DNA inserted in your genome.
@sbarnettARK @GrailBio @illumina @MGI_BGI The solution for bacteria and archaea, which need to divide very quickly and efficiently, was to have a defense mechanism to chop off this external invasive DNA, and keep their genomes nice and compact. The CRISPR technology itself has an origin in these attempts to protect your
@sbarnettARK @GrailBio @illumina @MGI_BGI genome from viruses that insert their DNA onto your genome. But for plants and animals, the solution was to not try to get rid of this repetitive DNA, but at least keep it under control. And one way of doing that was to paint it with the methylation brush: repetitive methylated
@sbarnettARK @GrailBio @illumina @MGI_BGI DNA would then not interfere with the normal functional workings of the genome, and plants and animals thus adapted to cope with repetitive DNA in their genome. And here lies the difference between the 8-12% of the genome that may contain 5hmC and the 50-60% of the genome that
@sbarnettARK @GrailBio @illumina @MGI_BGI usually contains 5mC. This boring repetitive methylated DNA is now an issue in trying to drive down costs for assays, while at the same time, we want to assay as genome-wide as possible so that we capture all functional elements of the genome.
@sbarnettARK @GrailBio @illumina @MGI_BGI So in early cancer diagnosis, there are now companies applying the same theory of 5mC biomarkers to the 5hmC profiling. https://t.co/U63NZoYMNX
@sbarnettARK @GrailBio @illumina @MGI_BGI How about combining signals? E.g. would, in theory, a 5mC+5hmC profile have a better AUC than either in isolation? How about adding fragmentomics? How about proteomics? How about CTCs? You name it.
@sbarnettARK @GrailBio @illumina @MGI_BGI In theory, yes, the wider scope of your signal, the better the specificity and sensitivity of the diagnostics assay. In practice, also yes, but with caveats: you could make the perfect early cancer diagnosis with a combination of all current technologies and future ones, but it
@sbarnettARK @GrailBio @illumina @MGI_BGI would take such a long time to train the model on a humongous training data set that encompassed enough samples to have the breath of particular cases for the training. So cutting back on the less important signals means you can then practically have better
@sbarnettARK @GrailBio @illumina @MGI_BGI AUC than any single assay and still be able to practically train the model and then apply the classifier on the next sample that comes through the door.
So what will be the future best assay for #LiquidBiopsy #cancer #screening?
@sbarnettARK @GrailBio @illumina @MGI_BGI In my opinion, we are not too far from having a multisignal (multiomics) assay that encompasses a deep 5mC profile, in breadth and coverage), a deep genome-wide 5hmC profile, and a shallow sequencing fragmentomics profile. This will take more than 10ml of blood, but could be 20ml
@sbarnettARK @GrailBio @illumina @MGI_BGI and the technology is there for that. What else we can add to it? CTCs? Proteomics? I'll leave it to the comments for people to chip in.
@sbarnettARK @GrailBio @illumina @MGI_BGI @d2unroll unroll

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Tony Breu
Tony Breu
@tony_breu
1/16
Why do B12 and folate deficiencies lead to HUGE red blood cells?

And, if the issue is DNA synthesis, why are red blood cells (which don't have DNA) the key cell line affected?

For answers, we'll have to go back a few billion years.


2/
RNA came first. Then, ~3-4 billion years ago, DNA emerged.

Among their differences:
🔹RNA contains uracil
🔹DNA contains thymine

But why does DNA contains thymine (T) instead of uracil (U)?

https://t.co/XlxT6cLLXg


3/
🔑Cytosine (C) can undergo spontaneous deamination to uracil (U).

In the RNA world, this meant that U could appear intensionally or unintentionally. This is clearly problematic. How can you repair RNA when you can't tell if something is an error?

https://t.co/bIZGviHBUc


4/
DNA's use of T instead of U means that spontaneous C → U deamination can be corrected without worry that an intentional U is being removed.

DNA requires greater stability than RNA so the transition to a thymine-based structure was beneficial.

https://t.co/bIZGviHBUc


5/
Let's return to megaloblastic anemia secondary to B12 or folate deficiency.

When either is severely deficient deoxythymidine monophosphate (dTMP*) production is hindered. With less dTMP, DNA synthesis is abnormal.

[*Note: thymine is the base in dTMP]

https://t.co/AnDUtKkbZh
HEALTH , PATHOPHYSIO
lazy perfectionist
lazy perfectionist
@kazADHD
is ADHD a mental illness ?

a thread

ADHD is a neurodevelopmental disorder - people with it are born with it and it cannot be altered because it's part of their brain structure and is seen on brain scans. ADHD is also linked to premature births and hypothyroidism during pregnancy, among other things

from the WHO website: "neurodevelopmental disorders are disabilities in the functioning of the brain that can affect behaviour, memory and/or ability to learn."

neurodevelopmental disorders are not caused by external/environmental factors. you cannot *develop* these conditions

mental illness is a general term for a health problem that significantly affects how someone feels/thinks/behaves. mental illnesses cause suffering to those who experience them, as well as often their loved ones. ADHD does not directly cause suffering.

neurodevelopmental disorders are not mental illnesses. ADHD however, does make it more likely for a person to experience mental illness. ADHD can cause dysfunction and stress, but more often than not this comes from lack of accommodation rather than the symptoms themselves.
HEALTH
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NotTheMacAnon
NotTheMacAnon
@NotTheMacAnon1
During a normal pregnancy, oxidative stress enhances antioxidant mechanisms that are capable of reacting by way of enzyme activity and non-enzyme free radical deactivators. However, pregnancy is also a state in which this adaptation and balance may be easily disrupted.

There is strong evidence that a chronicin flammatory reaction combined with the presence of a local oxidizing environment may play a vital role in the etiology and development of complications during pregnancy.

In late pregnancy, damage to DNA (especially when it is caused by oxidative stress) is associated with pre-eclampsia(PE), intrauterine growth restriction (IUGR), and the death of mothers in developing countries; it largely determines pregnancy – related susceptibility to diseases

The referential values of ROS and NOS and their minimal and safe concentrations or physiologically beneficial concentrations are yet to be determined.

The measurement of oxidative stress in vivo is perceived as controversial,

as the sen-sitivity and specificity of various oxidative stress markers is unknown.. .
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Chris Yiu
Chris Yiu
@clry2
I think that, in the face of an ongoing global health emergency and a pressing need to reopen safely, some form of health pass is a reasonable option to consider. But debate is a good thing, so here are some brief thoughts on various concerns I've heard about them... [thread]

"A health pass discriminates against people who have refused the vaccine." No. A health pass should also support proof of test result for people who haven't been vaccinated, and exemptions for people who cannot be vaccinated (get vaccinated if you can though, for heaven's sake).

"A health pass is an invasion of privacy." No. A health pass should be privacy preserving, allowing you to prove your status to third parties without giving away personal data or letting them track you without your permission.

"A health pass is unfair to people without smartphones." No. A health pass should accommodate people without a smartphone, e.g. with a printable option as a fall-back (though for most of us, carrying a digital pass on our phone will be much more convenient).

"A health pass will become obsolete as the virus mutates." No. A health pass should actually give us more insight and flexibility to adjust our response as our knowledge of the virus, and the ways we test / treat / vaccinate for it, increases.
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Chris Hopson
Chris Hopson
@ChrisCEOHopson
1/23 We haven't had a lot to celebrate during this pandemic. But achieving the milestone of offering vaccine to the over 70s, health and care workers and the most clinically vulnerable just before target date is a huge cause for celebration, given the scale of the achievement.

2/23 When Margaret Keenan got her first jab in Coventry on December 8th last year, who’d have thought that, by Valentine’s Day, we’d have vaccinated over fourteen million people across the UK in just ten short weeks? Amazing, extraordinary and truly, really, world class!

3/23 I’ve been struck by how much joy and relief has been brought to those doing the vaccinations and those receiving them. A GP told me yesterday that nothing had given him greater pleasure in his long career. And that the patient's relief was sometimes overwhelming.

4/23 It's vital to recognise the extraordinary contribution of the staff and volunteers who have made this happen. One of my close family had their jab yesterday and was in awe of the volunteer standing outside in the freezing cold for a four hour shift meeting and greeting.

5/23 What I wanted to share in this thread was the slightly untold story of some of the extraordinary challenges the NHS has had to overcome to deliver this target. Requiring superhuman effort from NHS leaders and staff, way beyond the call of duty. Five challenges set out below.
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ARRESTS and EXECUTIONS OF FAMOUS PEOPLE 2020 UPDATED
Explanation of the latest military tribunal arrests and executions of famous people in 2020.

2. The tribunals are arresting these people in plain clothes. We saw the Obama’s arrest, although we didn’t know it was an arrest at the time. The arrest was done nonchalantly so as to not get noticed by the public.
All arrests of these famous people were done this way.

3. If the person is convicted of child sex trafficking, crimes against humanity or treason, they will be executed.
If the person arrested has evidence on someone else to help their prosecution, or is willing to help Trump, & they want to cooperate, they may be allowed to do so.

4. A sentence of execution down to life in prison may be accepted if their evidence is worth anything.
When a plea deal is done, the defendant must present evidence they have to make their sentence lighter. This information is given to the prosecution, defense, and to the judge.

5. If evidence is accepted, they are presented the plea deal. They will have to make a guilty plea to the crime with a video confession & written statement. That is how all plea deals work.

All famous people arrested were either treasonous or involved in satanic worship rituals.
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Sara Benincasa
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@SaraJBenincasa
Spent a quaint half hour in a cafe listening to a guy yell at his dad after his dad said that the women Trump molested wanted it: "Dad, that's like saying the Jews who died in the Holocaust were asking for it!" ENJOY YOUR TERRIBLE FAMILIES THIS WEEK!

"Mom, has a man ever touched you without your consent?"
"Of course."
"Did you report it?"
"No."
"Dad, your WIFE has been through this!"

Dad was unmoved and told the guy to stop arguing with him.

At this point we learned the boy child has allergies.

I forgot to remark upon the presence of the very cute grandson, who was very small and gave not one shit about the yelling. I believe a sister or aunt was present and feeling very stressed. I wanted to hand her a Xanax or seven.

It was really hard to not jump in and say, "Sounds like you guys are going to have a fun meal tomorrow!" so they could unite in hatred against me, the outsider, and stop squabbling. Instead I exchanged glances with a nearby fellow lady patron, who also emotionally ate a cookie.

Anyway, I want to thank the random family for yelling about rape and the Holocaust in an Israeli cafe in the US of A today because it reminded me that while this country isn't the greatest, it is inevitably my stupid favorite and I am never, ever bored.
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Hindu Media Wiki
Hindu Media Wiki
@HinduMediaWiki
Speech Delay is most common in children nowadays

In ancient times, our grandparents used to follow typical natural way of caring the needs of a child. All they used were more of natural products than chemical based for the growth of child.


One of major step followed was to feed Gurbach Jadd/ Vasa Kommu/ Acorus Calamus for initiating good speech ability in a child. This stem was needed to babies on Tuesdays and Sundays in mother's milk.

Vasa is feed to baby after the 1st bath on 12th day in week. Weekly only thrice it is fed and named as :

Budhwar - Budhi Vasa
Mangalwar - Vaak Vasa
Ravi Vaar - Aayush Vasa

This stem is burnt and rubbed against the grinding stone in mother's milk or warm water to get a paste


The procedure to make it is in the link

https://t.co/uo4sGp7mUm

It should not be given daily to the child. Other main benefits are

1. It clears the phlegm in child's throat caused due to continuous milk intake. It clears the tracts and breathing is effortless.
2. Digestion

For children who haven't got their speech and is delayed than usual should feed this vasa on these days in week atleast for 6months. Don't get carried away with this dialogue
"Some gain speech little late"
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Ottoman History Podcast
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Here is a special thread introducing our series on “The Making of the Islamic World.” It offers 10 episodes about the transformation of Islamicate societies between the 7th and 17th centuries. You can find the series page here: https://t.co/7mL9eWmMmz


This is Chris Gratien posting. I created this series during Fall 2020 for my students as asynchronous material supported by readings and discussion. This is going to be a long thread, but it will be a great shortcut for those looking to make similar use of these materials.

There are two items worth pointing out: 1. This is an overview of the political, social, and cultural history of Islamicate societies. It does not deal with the origins of Islam or many theological questions. It does discuss Islam’s spread and the transformation of Islamic law.

2. This is the first part of a two-part sequence that takes the history of the Islamic world into the present. It emphasizes developments and themes that have particular relevance for later periods.

This is really a multivocal narrative of Islamic history. We feature over 20 scholars from almost as many institutions. Many of those who worked on it, myself included, study the early modern and modern era but have teaching obligations that take us further back in history.
RELIGION
Vibhu Vashisth
Vibhu Vashisth
@VIBHU_Tweet
THE MEANING, SIGNIFICANCE AND HISTORY OF SWASTIK

The Swastik is a geometrical figure and an ancient religious icon. Swastik has been Sanatan Dharma’s symbol of auspiciousness – mangalya since time immemorial.


The name swastika comes from Sanskrit (Devanagari: स्वस्तिक, pronounced: swastik) &denotes “conducive to wellbeing or auspicious”.
The word Swastik has a definite etymological origin in Sanskrit. It is derived from the roots su – meaning “well or auspicious” & as meaning “being”.


"सु अस्ति येन तत स्वस्तिकं"
Swastik is de symbol through which everything auspicios occurs

Scholars believe word’s origin in Vedas,known as Swasti mantra;

"🕉स्वस्ति ना इन्द्रो वृधश्रवाहा
स्वस्ति ना पूषा विश्ववेदाहा
स्वस्तिनास्तरक्ष्यो अरिश्तनेमिही
स्वस्तिनो बृहस्पतिर्दधातु"


It translates to," O famed Indra, redeem us. O Pusha, the beholder of all knowledge, redeem us. Redeem us O Garudji, of limitless speed and O Bruhaspati, redeem us".

SWASTIK’s COSMIC ORIGIN

The Swastika represents the living creation in the whole Cosmos.


Hindu astronomers divide the ecliptic circle of cosmos in 27 divisions called https://t.co/sLeuV1R2eQ this manner a cross forms in 4 directions in the celestial sky. At centre of this cross is Dhruva(Polestar). In a line from Dhruva, the stars known as Saptarishi can be observed.
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