Sarcomeres in cardiac myocytes (heart muscle cells) are mechanically coupled to focal adhesions through dorsal stress fiber-like structures. #cardiotwitter #CellBiology
1/13
A thread based on Figure 1

A mature adult cardiac myocyte is packed with sarcomeres, whose contractile forces are coupled to the extracellular environment. With sarcomeres so close to the plasma membrane, how can we study the nature of this coupling?
2/13
Short answer: find a model system where the sarcomeres are not so close to what the cardiac myocyte is attached to. Enter, iPS cell-derived cardiac myocytes. These are “immature” in culture as they resemble fetal or neonatal cardiac myocytes.
3/13
Our previous work on iPS cardiac myocytes reported that sarcomere containing myofibrils assembled on the top surface of the myocyte.
https://t.co/xIBCu3hG1W
4/13
The sarcomeres seemed to be connected to focal adhesions on the bottom of the cell by thin actin bundles that resembled the dorsal stress fibers (DSF) commonly found in non-muscle cells. This movie steps through a Z stack of a myocyte starting at the bottom of the cell.
5/13
Another way of visualizing dorsal stress fibers. This montage steps through the edge of a myocyte in the Z dimension. Arrows denote individual dorsal stress fibers.
6/13
Another way of visualizing the paths of the dorsal stress fibers is by using a color overlay.
7/13
In non-muscle cells, dorsal stress fibers can mechanically couple adhesions to the substrate to stress fibers on top of the cell.
This led us to this hypothesis: dorsal stress fibers also mechanically couple focal adhesions and sarcomeres. But how to test it? Answer- LASERS!
8/13
If the contractile forces generated by the sarcomeres are balanced by attachment to focal adhesions, then we reasoned that cutting a dorsal stress fiber would result in the sarcomeres rabidly moving (i.e., snapping) away from the adhesions.
Enter: laser ablation.
9/13
Cutting a dorsal stress fiber did make the sarcomeres it was attached to move away from the edge of the cardiac myocyte. What? Don’t you see that it moved? Maybe we should look at it in a different—animated—way.
10/13
This gif shows just before (0s) and just after (2s) the dorsal stress fiber was cut. The movement of the sarcomeres was clear but subtle, so we sought to test the mechanical connection in another way.
Enter: cutting sarcomeres to test if dorsal stress fibers move.
11/13
If the sarcomeres and dorsal stress fibers are mechanically coupled, then cutting the sarcomeres should result in the movement of the dorsal stress fibers. It did.
Blue arrowheads show the dorsal stress fibers.
12/13
So what is the implication of the mechanical coupling between sarcomeres and dorsal stress fibers?
Our interpretation from 8 additional data figures: Strong coupling facilitates the maturation of sarcomeres. Weak coupling slows maturation down.
13/13
https://t.co/cKnT7wXo0w

More from Health

Now you know I love to sh-t in Harvard. But I also like accuracy. So I decided to go look at Harvard’s catalog to see its lack of military history that this article describes (they only teach history of pets it claims) and what I found shocked me! Shocked me! A thread: 1/


First off, Harvard students literally have multiple sections of military history that they can take listed. (It appears these ones are taught at MIT, so they might have to walk down the street for these) but... 2/


Say they want to stay on campus...they can only take numerous classes on war and diplomacy...3/


They have an entire class on Yalta. That’s right. An entire class on Yalta. 4/


But wait! There is more! They can take the British Empire, The Fall of the Roman Empire for those wanting traditional topics... 5/
1/15
Why can cefepime cause neurological toxicity?

And why is renal failure the main risk factor for this complication?

The answer requires us to learn about cefepime's structure and why it unexpectedly binds to a certain CNS receptor.

#MedTwitter #Tweetorial


2/
Let's establish a few facts about cefepime:

🔺4th generation cephalosporin antibiotic
🔺Excretion = exclusively in the urine (mostly as unchanged drug)
🔺Readily crosses the blood-brain barrier (so it easily accesses the brain)

https://t.co/rjYG1BfGPR


3/
The first report of cefepime neurotoxicity was in 1999.

A patient w/ renal failure received high doses of cefepime and then developed encephalopathy, tremors, myoclonic jerks, and tonic-clonic seizures.

✅All symptoms resolved after hemodialysis.

https://t.co/u7JLVitQpp


4/
Cefepime neurotoxicity is surprisingly common, occurring in up to 15% of treated critically ill patients (w/ symptoms varying from encephalopathy to seizures).

💡The main risk factors = renal failure and lack of dose adjustment for renal function.

https://t.co/nxbnzSq8AR


5/
What about cefepime induces neurotoxicity?

One clue is that it's not the only antibiotic that causes neurotoxicity, particularly seizures.

This actually is a class effect w/ other beta-lactam antibiotics (including penicillins and carbapenems).

https://t.co/Lf4BhON9IY

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A brief analysis and comparison of the CSS for Twitter's PWA vs Twitter's legacy desktop website. The difference is dramatic and I'll touch on some reasons why.

Legacy site *downloads* ~630 KB CSS per theme and writing direction.

6,769 rules
9,252 selectors
16.7k declarations
3,370 unique declarations
44 media queries
36 unique colors
50 unique background colors
46 unique font sizes
39 unique z-indices

https://t.co/qyl4Bt1i5x


PWA *incrementally generates* ~30 KB CSS that handles all themes and writing directions.

735 rules
740 selectors
757 declarations
730 unique declarations
0 media queries
11 unique colors
32 unique background colors
15 unique font sizes
7 unique z-indices

https://t.co/w7oNG5KUkJ


The legacy site's CSS is what happens when hundreds of people directly write CSS over many years. Specificity wars, redundancy, a house of cards that can't be fixed. The result is extremely inefficient and error-prone styling that punishes users and developers.

The PWA's CSS is generated on-demand by a JS framework that manages styles and outputs "atomic CSS". The framework can enforce strict constraints and perform optimisations, which is why the CSS is so much smaller and safer. Style conflicts and unbounded CSS growth are avoided.
दधीचि ऋषि को मनाही थी कि वह अश्विनी कुमारों को किसी भी अवस्था में ब्रह्मविद्या का उपदेश नहीं दें। ये आदेश देवराज इन्द्र का था।वह नहीं चाहते थे कि उनके सिंहासन को प्रत्यक्ष या परोक्ष रुप से कोई भी खतरा हो।मगर जब अश्विनी कुमारों ने सहृदय प्रार्थना की तो महर्षि सहर्ष मान गए।


और उन्होनें ब्रह्मविद्या का ज्ञान अश्विनि कुमारों को दे दिया। गुप्तचरों के माध्यम से जब खबर इन्द्रदेव तक पहुंची तो वे क्रोध में खड़ग ले कर गए और महर्षि दधीचि का सर धड़ से अलग कर दिया।मगर अश्विनी कुमार भी कहां चुप बैठने वाले थे।उन्होने तुरंत एक अश्व का सिर महर्षि के धड़ पे...


...प्रत्यारोपित कर उन्हें जीवित रख लिया।उस दिन के पश्चात महर्षि दधीचि अश्वशिरा भी कहलाए जाने लगे।अब आगे सुनिये की किस प्रकार महर्षि दधीचि का सर काटने वाले इन्द्र कैसे अपनी रक्षा हेतु उनके आगे गिड़गिड़ाए ।

एक बार देवराज इन्द्र अपनी सभा में बैठे थे, तो उन्हे खुद पर अभिमान हो आया।


वे सोचने लगे कि हम तीनों लोकों के स्वामी हैं। ब्राह्मण हमें यज्ञ में आहुति देते हैं और हमारी उपासना करते हैं। फिर हम सामान्य ब्राह्मण बृहस्पति से क्यों डरते हैं ?उनके आने पर क्यों खड़े हो जाते हैं?वे तो हमारी जीविका से पलते हैं। देवर्षि बृहस्पति देवताओं के गुरु थे।

अभिमान के कारण ऋषि बृहस्पति के पधारने पर न तो इन्द्र ही खड़े हुए और न ही अन्य देवों को खड़े होने दिया।देवगुरु बृहस्पति इन्द्र का ये कठोर दुर्व्यवहार देख कर चुप चाप वहां से लौट गए।कुछ देर पश्चात जब देवराज का मद उतरा तो उन्हे अपनी गलती का एहसास हुआ।