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I have far more federal court trial experience than Weissmann, lost only 2 of 65+ jury trials as a AUSA--none reversed on appeal, much less losing 9-0 in SCOTUS on an argument I championed.
Dismantling here his criticism of the SPLC indictment. First of 2 parts.
Link below.
Dismantling here his criticism of the SPLC indictment. First of 2 parts.
Link below.
Paywalled but 7 day free trials are available.
Substack allows free subscribers to read one "paid" article at no charge.
Comments and RPs greatly appreciated.
open.substack.com/pub/shipwrecke…
Substack allows free subscribers to read one "paid" article at no charge.
Comments and RPs greatly appreciated.
open.substack.com/pub/shipwrecke…
Petraeus: Iran is unquestionably much weaker militarily.
The US and Israel have badly damaged its leadership, missile and drone production, navy, air force, air defenses, security headquarters, logistics bases, and further damaged the nuclear program. 1/
The US and Israel have badly damaged its leadership, missile and drone production, navy, air force, air defenses, security headquarters, logistics bases, and further damaged the nuclear program. 1/
Petraeus: Military objectives largely have been met, but Iran could still emerge strategically stronger if Hormuz stays shut.
It cannot be acceptable for Iran to turn the strait into an “Iranian canal” and charge tolls for ships going in and out. 2/
It cannot be acceptable for Iran to turn the strait into an “Iranian canal” and charge tolls for ships going in and out. 2/
Petraeus: Reopening Hormuz is a very challenging mission.
The defender has to be perfect, while the attacker only has to succeed every few days to destroy confidence. Hit two or three ships, and owners decide they are not taking that risk. 3/
The defender has to be perfect, while the attacker only has to succeed every few days to destroy confidence. Hit two or three ships, and owners decide they are not taking that risk. 3/
The Molecular Spectrum: From Inflammation to Chronic Fatigue
🧵
A Continuum of Immune Dysregulation 🧬
Lupus (SLE), ME/CFS, PIMS, and Kawasaki are not isolated diseases but rather different outcomes of a misaligned immune response to pathogens.
🧵
A Continuum of Immune Dysregulation 🧬
Lupus (SLE), ME/CFS, PIMS, and Kawasaki are not isolated diseases but rather different outcomes of a misaligned immune response to pathogens.
The core difference lies in the molecular targets and the duration of the inflammatory fire.
Lupus vs. ME/CFS – The Chronic Front
While both share activated monocytes and inflammatory pathways (IL-1β, TNF-α), they diverge significantly:
Lupus vs. ME/CFS – The Chronic Front
While both share activated monocytes and inflammatory pathways (IL-1β, TNF-α), they diverge significantly:
Lupus: Driven by a massive Type-I Interferon (IFN-α) signature and antibodies against the nucleus (ANA), leading to direct organ damage.
ME/CFS: Characterized by mitochondrial fragmentation and metabolic failure. Instead of organ destruction,
ME/CFS: Characterized by mitochondrial fragmentation and metabolic failure. Instead of organ destruction,
Everyone's focused on Iran's crude oil export/extraction disruptions. But there is another real domestic crisis: gasoline. Pre war, Iran was burning through 126 million liters of fuel per day while producing only ~110 million liters domestically. That 15-20M liter/day gap was being covered by imports costing ~$6 billion a year.
1/6 On March 7, strikes hit oil storage depots in Tehran and Alborz Province. ~30 tanks hit in southern Tehran alone. The immediate response: per-fill limits in Tehran cut from 30 liters to 20 liters overnight. Stations reported running dry. Citizens described it as "سهمیهبندی خاموش" or "silent rationing."
1/6 On March 7, strikes hit oil storage depots in Tehran and Alborz Province. ~30 tanks hit in southern Tehran alone. The immediate response: per-fill limits in Tehran cut from 30 liters to 20 liters overnight. Stations reported running dry. Citizens described it as "سهمیهبندی خاموش" or "silent rationing."
2/6 Here's what most people missed: Iran's largest gasoline producer is Persian Gulf Star refinery in Bandar Abbas, ~40M liters/day, roughly 35% of national output. It runs on condensate from South Pars, not crude oil. When Israel struck South Pars in March, it didn't just hit gas exports. It cut the feedstock to the refinery Iran depends on most for gasoline.
Then there's Lavan. Iran's Lavan Island refinery, a 55,000 b/d condensate processing facility, was struck on April 7, hours after the ceasefire announcement. The National Iranian Oil Refining and Distribution Company's chief visited the island and said they could recover 70-80% of capacity in "one to two months." I don't buy it. Lavan, South Pars, Rey depot, Iran's refinery system took compounding hits, not one-off damage.
Then there's Lavan. Iran's Lavan Island refinery, a 55,000 b/d condensate processing facility, was struck on April 7, hours after the ceasefire announcement. The National Iranian Oil Refining and Distribution Company's chief visited the island and said they could recover 70-80% of capacity in "one to two months." I don't buy it. Lavan, South Pars, Rey depot, Iran's refinery system took compounding hits, not one-off damage.
3/6 Normally Iran papers over its domestic production shortfall with imports, sanctioned, shadow-fleet, intermediary-financed. But then the regime closed the Strait of Hormuz, which immediately severed Iran's own import lifeline.
Then the regime made it worse. Fujairah, the UAE's key oil hub and the port through which Iran ran much of its shadow condensate trade and refined product flows, was struck by Iranian drones in mid-March. Iran also hit the UAE Shah gas field and suspended operations at the Ruwais refinery complex. The UAE, which had served as Iran's critical intermediary hub for decades, running condensate from Iranian fields through ENOC refineries and routing fuel back, was now a war target. Iran didn't just lose the Strait. It torched the back door too.
Then the regime made it worse. Fujairah, the UAE's key oil hub and the port through which Iran ran much of its shadow condensate trade and refined product flows, was struck by Iranian drones in mid-March. Iran also hit the UAE Shah gas field and suspended operations at the Ruwais refinery complex. The UAE, which had served as Iran's critical intermediary hub for decades, running condensate from Iranian fields through ENOC refineries and routing fuel back, was now a war target. Iran didn't just lose the Strait. It torched the back door too.
The disagreement turns on what the word “racism”actually means. If it names any antipathy, contempt, or stereotype that happens to involve phenotype, then of course one can find it scattered across virtually every literate society in human history, Islamicate societies included.
But that usage drains the concept of analytical force and collapses precisely the distinction the original articulation was trying to draw.
Following Oliver Cox, racism is properly defined as a historically specific socio-attitudinal system that emerged in modern Europe alongside capitalism and nationalism,
💢 NEW: Iranian Analyst Hassan Ahmadian to Drop Site: “If There’s No Breakthrough in the Next Week, I Think Escalation Will Happen”
Hassan Ahmadian, Associate Professor of Middle East Studies at Tehran University and one of the most prominent Iranian analysts in the Arab world, spoke to Drop Site News about Iran’s strategic calculus, the state of negotiations, and what comes next.
1. On why Iran believes time is on its side:
🔸 Tehran believes it holds a three-part strategic advantage it calls “the three Ms” — munitions, markets, and the midterms.
🔸 “The Iranians are saying time is working in our favor for the three Ms: munitions, markets, and the midterms. These three Ms help Iran in its position and weaken U.S. positions. Obviously in the U.S., they want something to say, ‘We squeezed Iran and we got this.’ My perception is that the Iranians are keen to deny the United States that — they wouldn’t give what Trump wants as a victory.”
2. On what has actually changed in Iran’s position:
🔸 Despite White House claims that Iran submitted a new proposal over the weekend, Ahmadian said the shift is toward clearer conditions for resuming negotiations — not any nuclear concessions.
🔸 “There are changes, as I understand. The main change is for Iran to insist on the stop of the war regionally. That’s pivotal in Iran agreeing to discuss other issues.”
A senior official said the characterization of a new proposal was false.
3. On Trump’s narrative that Iran is in disarray:
🔸 “That’s part of the cognitive warfare on Iran. It’s targeted at the society, the elites, and the position of the Supreme Leader. It’s not news, it’s not intel that they’re talking about. It’s basically an agenda to create what they are calling division. And I think the main aim within Iran is to increase mistrust and decrease trust among elites, which I think the Iranians are now very well aware of.”
🔸 Ahmadian said Iran’s perception is that it is the U.S. leadership that is in deep disarray — as evidenced by Trump’s flip-flops, unrealized threats, and the recent chaos over which officials would travel to Islamabad.
4. On how Iran views the U.S. negotiating team:
🔸 During the first round of direct talks in Islamabad on April 11, Iran arrived with a unified team representing all branches of the system. The American side, by contrast, appeared divided.
🔸 “The Iranians see Witkoff and Kushner as representatives of the Israeli interests, not those of the United States, as opposed to Mr. Vance, who is representing the U.S. interests in those talks. They were divided in their way of approaching the Iranians.”
5. On Araghchi’s tour and what it signals:
🔸 Araghchi’s visits to Pakistan, Oman, and Russia serve a dual purpose — laying out Tehran’s position to mediators while also preparing for the possibility that war resumes or drags into a prolonged unresolved state.
🔸 “Araghchi is Iran’s top diplomat. So even if there’s a 1% chance for a breakthrough, he would embark on it.”
🔸 Oman, which has decades of experience mediating between the U.S. and Iran, was blindsided by the February 28 attack — a day after its foreign minister visited Washington and was led to believe an agreement was within reach. Iran is eager to see Muscat reenter the diplomatic process.
6. On Russia and China’s potential role:
🔸 “Russia, and to my understanding, China, are the main parties that the Iranians might think of. A partner that is trusted more than the United States that can play a mediating role and then can be the destination if there is an agreement for the highly enriched uranium.”
🔸 Russia also played a key role in the 2015 nuclear deal. Following that agreement, Iran shipped more than 25,000 pounds — roughly 98 percent of its enriched uranium — to Moscow. Whether Russia could play a similar role now remains an open question.
[CONTINUES BELOW]
Hassan Ahmadian, Associate Professor of Middle East Studies at Tehran University and one of the most prominent Iranian analysts in the Arab world, spoke to Drop Site News about Iran’s strategic calculus, the state of negotiations, and what comes next.
1. On why Iran believes time is on its side:
🔸 Tehran believes it holds a three-part strategic advantage it calls “the three Ms” — munitions, markets, and the midterms.
🔸 “The Iranians are saying time is working in our favor for the three Ms: munitions, markets, and the midterms. These three Ms help Iran in its position and weaken U.S. positions. Obviously in the U.S., they want something to say, ‘We squeezed Iran and we got this.’ My perception is that the Iranians are keen to deny the United States that — they wouldn’t give what Trump wants as a victory.”
2. On what has actually changed in Iran’s position:
🔸 Despite White House claims that Iran submitted a new proposal over the weekend, Ahmadian said the shift is toward clearer conditions for resuming negotiations — not any nuclear concessions.
🔸 “There are changes, as I understand. The main change is for Iran to insist on the stop of the war regionally. That’s pivotal in Iran agreeing to discuss other issues.”
A senior official said the characterization of a new proposal was false.
3. On Trump’s narrative that Iran is in disarray:
🔸 “That’s part of the cognitive warfare on Iran. It’s targeted at the society, the elites, and the position of the Supreme Leader. It’s not news, it’s not intel that they’re talking about. It’s basically an agenda to create what they are calling division. And I think the main aim within Iran is to increase mistrust and decrease trust among elites, which I think the Iranians are now very well aware of.”
🔸 Ahmadian said Iran’s perception is that it is the U.S. leadership that is in deep disarray — as evidenced by Trump’s flip-flops, unrealized threats, and the recent chaos over which officials would travel to Islamabad.
4. On how Iran views the U.S. negotiating team:
🔸 During the first round of direct talks in Islamabad on April 11, Iran arrived with a unified team representing all branches of the system. The American side, by contrast, appeared divided.
🔸 “The Iranians see Witkoff and Kushner as representatives of the Israeli interests, not those of the United States, as opposed to Mr. Vance, who is representing the U.S. interests in those talks. They were divided in their way of approaching the Iranians.”
5. On Araghchi’s tour and what it signals:
🔸 Araghchi’s visits to Pakistan, Oman, and Russia serve a dual purpose — laying out Tehran’s position to mediators while also preparing for the possibility that war resumes or drags into a prolonged unresolved state.
🔸 “Araghchi is Iran’s top diplomat. So even if there’s a 1% chance for a breakthrough, he would embark on it.”
🔸 Oman, which has decades of experience mediating between the U.S. and Iran, was blindsided by the February 28 attack — a day after its foreign minister visited Washington and was led to believe an agreement was within reach. Iran is eager to see Muscat reenter the diplomatic process.
6. On Russia and China’s potential role:
🔸 “Russia, and to my understanding, China, are the main parties that the Iranians might think of. A partner that is trusted more than the United States that can play a mediating role and then can be the destination if there is an agreement for the highly enriched uranium.”
🔸 Russia also played a key role in the 2015 nuclear deal. Following that agreement, Iran shipped more than 25,000 pounds — roughly 98 percent of its enriched uranium — to Moscow. Whether Russia could play a similar role now remains an open question.
[CONTINUES BELOW]
7. On the risk of escalation:
🔸 “I think the Iranians will not sit on their hands watching the United States harass and seize their ships. They would rather go for a war. If there’s no breakthrough in the next week, I think escalation will happen. I expect the United States to increase the pressure on Iran militarily. But the Iranians will go heavier this time.”
🔸 “Iran is saying that if its infrastructure is targeted, we will target four times what’s hitting Iran. I don’t take that as a bluff. I think they will do that because the more the pain on the other side, the less likelihood of it continuing the targeting of Iran’s infrastructure.”
— End —
🔸 “I think the Iranians will not sit on their hands watching the United States harass and seize their ships. They would rather go for a war. If there’s no breakthrough in the next week, I think escalation will happen. I expect the United States to increase the pressure on Iran militarily. But the Iranians will go heavier this time.”
🔸 “Iran is saying that if its infrastructure is targeted, we will target four times what’s hitting Iran. I don’t take that as a bluff. I think they will do that because the more the pain on the other side, the less likelihood of it continuing the targeting of Iran’s infrastructure.”
— End —
⚡️ Read @JeremyScahill’s new report for Drop Site featuring remarks from Dr. @hasanahmadian as well as a senior Iranian official at the link below:
dropsitenews.com/p/iran-war-tru…
dropsitenews.com/p/iran-war-tru…
BREAKING: AI can now build financial models like Goldman Sachs analysts (for free).
Here are 12 Claude prompts that replace $150K/year investment banking work (Save for later)
Here are 12 Claude prompts that replace $150K/year investment banking work (Save for later)
1/ DCF Valuation Model
You are a Senior Analyst at Goldman Sachs. I need a complete DCF (Discounted Cash Flow) valuation model for [COMPANY NAME].
Please provide:
- Free cash flow projections: Next 5 years with growth assumptions
- WACC calculation: Cost of equity + cost of debt breakdown
- Terminal value: Both perpetuity growth and exit multiple methods
- Sensitivity analysis: How value changes with different assumptions
- Discount rate justification: Why we chose this WACC
- Key drivers: What makes cash flow go up or down
- Comparable companies: How our assumptions compare to peers
- Valuation range: Bull case, base case, bear case scenarios
Format as investment banking pitch book valuation page with clear formulas.
Company: [DESCRIBE COMPANY, INDUSTRY, FINANCIALS]
You are a Senior Analyst at Goldman Sachs. I need a complete DCF (Discounted Cash Flow) valuation model for [COMPANY NAME].
Please provide:
- Free cash flow projections: Next 5 years with growth assumptions
- WACC calculation: Cost of equity + cost of debt breakdown
- Terminal value: Both perpetuity growth and exit multiple methods
- Sensitivity analysis: How value changes with different assumptions
- Discount rate justification: Why we chose this WACC
- Key drivers: What makes cash flow go up or down
- Comparable companies: How our assumptions compare to peers
- Valuation range: Bull case, base case, bear case scenarios
Format as investment banking pitch book valuation page with clear formulas.
Company: [DESCRIBE COMPANY, INDUSTRY, FINANCIALS]
2/ Three-Statement Financial Model
You are a VP at Morgan Stanley. I need a complete three-statement model for [COMPANY NAME].
Please provide:
- Income statement: Revenue, costs, EBITDA, net income (5 years)
- Balance sheet: Assets, liabilities, equity (5 years)
- Cash flow statement: Operating, investing, financing activities (5 years)
- Link formulas: How statements connect (net income → cash flow → balance sheet)
- Working capital: How AR, inventory, and AP change
- Debt schedule: Principal payments and interest expense
- Key assumptions: Revenue growth, margins, capex as % of sales
- Error checks: Balance sheet balancing and circular references
Format as Excel-style model with formulas explained in plain English.
Company: [DESCRIBE BUSINESS, CURRENT FINANCIALS, GROWTH STAGE]
You are a VP at Morgan Stanley. I need a complete three-statement model for [COMPANY NAME].
Please provide:
- Income statement: Revenue, costs, EBITDA, net income (5 years)
- Balance sheet: Assets, liabilities, equity (5 years)
- Cash flow statement: Operating, investing, financing activities (5 years)
- Link formulas: How statements connect (net income → cash flow → balance sheet)
- Working capital: How AR, inventory, and AP change
- Debt schedule: Principal payments and interest expense
- Key assumptions: Revenue growth, margins, capex as % of sales
- Error checks: Balance sheet balancing and circular references
Format as Excel-style model with formulas explained in plain English.
Company: [DESCRIBE BUSINESS, CURRENT FINANCIALS, GROWTH STAGE]
MICHAEL JACKSON’S DEATH AND THE JEWS.
A THREAD 🧵
A THREAD 🧵
In 1993 he toured in Israel an was shocked about how they treated Palestinians.
He came back to the US and made a song about it.
Sony records refused to release the song.
Sony records refused to release the song.
3 years of daily Claude use taught me which prompts actually make life easier.
Here are the 18 prompts I keep coming back to:
Here are the 18 prompts I keep coming back to:
1/ Plan Your Day Like an Executive
"You are a productivity strategist. Here is what I am working with today: Goals: [list] Tasks: [list] Meetings: [list] Deadlines: [list]. Find my top 3 priorities, build a structured schedule around them, flag anything I should hand off or automate, and tell me where to put my energy for maximum output."
"You are a productivity strategist. Here is what I am working with today: Goals: [list] Tasks: [list] Meetings: [list] Deadlines: [list]. Find my top 3 priorities, build a structured schedule around them, flag anything I should hand off or automate, and tell me where to put my energy for maximum output."
2/ Research Any Topic Fast
"You are a senior research analyst. Topic: [topic]. Give me the most important things to know, where the market is heading, key statistics, the main players involved, and where the real opportunities and dangers sit."
"You are a senior research analyst. Topic: [topic]. Give me the most important things to know, where the market is heading, key statistics, the main players involved, and where the real opportunities and dangers sit."
It was the police who were responsible for a vast majority of the violence on J6.
It was the police who improperly launched dozens of “Stinger Ball Grenades” and gas munitions deep into a peaceful crowd without warning on the West Plaza between 1:07pm to 2:30pm - by their own admission “hitting innocent people” (see the next reply to this post).
It was the police who used unlawful “deadly force” dozens of times by striking people in the heads with their batons when “deadly force” was not justified (see multiple examples in the second reply to this post).
It was the police who killed Ashli Babbitt in an indefensible shooting and who likely contributed to the death of Roseanne Boyland by beating her with a stick as she was unconscious on the ground (see the third reply to this post).
Most of the “violence” from protestors was in response to the extreme police brutality being exerted on innocent, non-violent people who were just exercising their first amendment rights on the West Plaza outside the Capitol and were unaware that they had entered some virtual "restricted area" due to the fences being removed long before they arrived.
That the uni-party Congress, police, FBI, DOJ and legacy media have largely hidden this from the public is a disgrace - but that will change with time.
Begin by removing the “protective orders” imposed on all J6 defendants that prevents them from revealing their own discovery to the country.
Why is it that J6 defendants want the surveillance and body-cam videos released to the public while it is the police, Congress, FBI and DOJ who fight to keep it all concealed?
It was the police who improperly launched dozens of “Stinger Ball Grenades” and gas munitions deep into a peaceful crowd without warning on the West Plaza between 1:07pm to 2:30pm - by their own admission “hitting innocent people” (see the next reply to this post).
It was the police who used unlawful “deadly force” dozens of times by striking people in the heads with their batons when “deadly force” was not justified (see multiple examples in the second reply to this post).
It was the police who killed Ashli Babbitt in an indefensible shooting and who likely contributed to the death of Roseanne Boyland by beating her with a stick as she was unconscious on the ground (see the third reply to this post).
Most of the “violence” from protestors was in response to the extreme police brutality being exerted on innocent, non-violent people who were just exercising their first amendment rights on the West Plaza outside the Capitol and were unaware that they had entered some virtual "restricted area" due to the fences being removed long before they arrived.
That the uni-party Congress, police, FBI, DOJ and legacy media have largely hidden this from the public is a disgrace - but that will change with time.
Begin by removing the “protective orders” imposed on all J6 defendants that prevents them from revealing their own discovery to the country.
Why is it that J6 defendants want the surveillance and body-cam videos released to the public while it is the police, Congress, FBI and DOJ who fight to keep it all concealed?
The video in this post below is one of the most important from J6.
Police body-cam video captures officers acknowledging in real time that they are "hitting innocent people" with their use of force on the West Plaza.
Police body-cam video captures officers acknowledging in real time that they are "hitting innocent people" with their use of force on the West Plaza.
Police used unlawful "deadly force" dozens of times on J6 by hitting protestors in the heads with batons when "deadly force" was not warranted. Multiple examples can be seen in the posts below.
A baton strike to the head is considered to be the same "deadly force" as shooting someone and requires the same level of justification. Did the people in these videos being hit in the head with batons deserve to be shot?
x.com/TheWiseJared/s…
A baton strike to the head is considered to be the same "deadly force" as shooting someone and requires the same level of justification. Did the people in these videos being hit in the head with batons deserve to be shot?
x.com/TheWiseJared/s…
Mitochondrial dysfunction is merely a downstream consequence of telomeres and rDNA driving cellular senescence through the p53 pathway, rather than the root cause of aging.
During cellular senescence, the upregulation of p53 levels not only increases the expression of certain genes and decreases that of others[58], but also causes a continuous decline in the synthesis rates of total proteins and ATP[120−123]. This is because p53 binds to the promoter of the histone deacetylase gene HDAC2 to promote its transcription[124]. HDAC2 mediates histone deacetylation, which tightens the binding between histones and DNA, impairs gene transcription, and consequently reduces the synthesis rate of total proteins. Moreover, more than 80% of the proteins involved in mitochondrial ATP synthesis are encoded by nuclear genes[125]. Accordingly, p53 upregulation leads to a concurrent reduction in the synthesis rates of both total proteins and ATP. The sequential reaction process is as follows:
Telomere and/or rDNA array shortening → p53 upregulation → differential gene expression (partial gene upregulation and downregulation) and HDAC2 upregulation → decreased synthesis rates of total proteins and ATP → decline and alteration of cellular functions.
In conclusion, cellular senescence is not driven by the mutation and accumulation of mitochondrial DNA (mtDNA), and the mitochondrial dysfunction observed in senescent cells does not stem from intrinsic defects of mitochondria themselves.
Reference:
［58］ Ergen AV, Goodell MA. Mechanisms of hematopoietic stem cell aging. Exp Gerontol. 2010 Apr;45(4):286-90. doi: 10.1016/j.exger.2009.12.010.
［120］ Cook JR, Buetow DE. Decreased protein synthesis by polysomes, tRNA and aminoacyl-tRNA synthetases isolated from senescent rat liver. Mech Ageing Dev. 1981 Sep;17(1):41-52. doi: 10.1016/0047-6374(81)90127-5.
［121］ Llewellyn J, Mallikarjun V, Appleton E, et al. Loss of regulation of protein synthesis and turnover underpins an attenuated stress response in senescent human mesenchymal stem cells. Proc Natl Acad Sci U S A. 2023 Apr 4;120(14):e2210745120. doi: 10.1073/pnas.2210745120.
［122］ Short KR, Bigelow ML, Kahl J, Singh R, Coenen-Schimke J, Raghavakaimal S, Nair KS. Decline in skeletal muscle mitochondrial function with aging in humans. Proc Natl Acad Sci U S A. 2005 Apr 12;102(15):5618-23. doi: 10.1073/pnas.0501559102.
［123］ Kim JY, Atanassov I, Dethloff F, et al. Time-resolved proteomic analyses of senescence highlight metabolic rewiring of mitochondria. Life Sci Alliance. 2023 Jun 15;6(9):e202302127. doi: 10.26508/lsa.202302127.
［124］ Li XL, Zhou J, Chen ZR, et al. P53 mutations in colorectal cancer - molecular pathogenesis and pharmacological reactivation. World J Gastroenterol. 2015 Jan 7;21(1):84-93. doi: 10.3748/wjg.v21.i1.84.
［125］ Koopman WJ, Distelmaier F, Smeitink JA, et al. OXPHOS mutations and neurodegeneration. EMBO J. 2013 Jan 9;32(1):9-29. doi: 10.1038/emboj.2012.300.
During cellular senescence, the upregulation of p53 levels not only increases the expression of certain genes and decreases that of others[58], but also causes a continuous decline in the synthesis rates of total proteins and ATP[120−123]. This is because p53 binds to the promoter of the histone deacetylase gene HDAC2 to promote its transcription[124]. HDAC2 mediates histone deacetylation, which tightens the binding between histones and DNA, impairs gene transcription, and consequently reduces the synthesis rate of total proteins. Moreover, more than 80% of the proteins involved in mitochondrial ATP synthesis are encoded by nuclear genes[125]. Accordingly, p53 upregulation leads to a concurrent reduction in the synthesis rates of both total proteins and ATP. The sequential reaction process is as follows:
Telomere and/or rDNA array shortening → p53 upregulation → differential gene expression (partial gene upregulation and downregulation) and HDAC2 upregulation → decreased synthesis rates of total proteins and ATP → decline and alteration of cellular functions.
In conclusion, cellular senescence is not driven by the mutation and accumulation of mitochondrial DNA (mtDNA), and the mitochondrial dysfunction observed in senescent cells does not stem from intrinsic defects of mitochondria themselves.
Reference:
［58］ Ergen AV, Goodell MA. Mechanisms of hematopoietic stem cell aging. Exp Gerontol. 2010 Apr;45(4):286-90. doi: 10.1016/j.exger.2009.12.010.
［120］ Cook JR, Buetow DE. Decreased protein synthesis by polysomes, tRNA and aminoacyl-tRNA synthetases isolated from senescent rat liver. Mech Ageing Dev. 1981 Sep;17(1):41-52. doi: 10.1016/0047-6374(81)90127-5.
［121］ Llewellyn J, Mallikarjun V, Appleton E, et al. Loss of regulation of protein synthesis and turnover underpins an attenuated stress response in senescent human mesenchymal stem cells. Proc Natl Acad Sci U S A. 2023 Apr 4;120(14):e2210745120. doi: 10.1073/pnas.2210745120.
［122］ Short KR, Bigelow ML, Kahl J, Singh R, Coenen-Schimke J, Raghavakaimal S, Nair KS. Decline in skeletal muscle mitochondrial function with aging in humans. Proc Natl Acad Sci U S A. 2005 Apr 12;102(15):5618-23. doi: 10.1073/pnas.0501559102.
［123］ Kim JY, Atanassov I, Dethloff F, et al. Time-resolved proteomic analyses of senescence highlight metabolic rewiring of mitochondria. Life Sci Alliance. 2023 Jun 15;6(9):e202302127. doi: 10.26508/lsa.202302127.
［124］ Li XL, Zhou J, Chen ZR, et al. P53 mutations in colorectal cancer - molecular pathogenesis and pharmacological reactivation. World J Gastroenterol. 2015 Jan 7;21(1):84-93. doi: 10.3748/wjg.v21.i1.84.
［125］ Koopman WJ, Distelmaier F, Smeitink JA, et al. OXPHOS mutations and neurodegeneration. EMBO J. 2013 Jan 9;32(1):9-29. doi: 10.1038/emboj.2012.300.
$SE published it’s annual report for FY2025 few days ago. I read every single page (like every investor should). I decided to give few thoughts, that aren’t as widely talked, or wasn’t published before this report. Let’s go! 🎞️👇
1/
1/
1. As we can see in the picture, $SE is growing it’s revenues in Latin America (mostly Brasil) very fast, from $3.28B to $5.53B in 2025, 69% growth.
Growth is mostly due to Shopee and Monee, but let’s not forget Garena gaming, which bounced back from year earlier.
2/
Growth is mostly due to Shopee and Monee, but let’s not forget Garena gaming, which bounced back from year earlier.
2/
2. S&M is gaining leverage, even as it grew from $3.47B to $4.49B in absolute dollars, but decreases to 19.6% of revenue compared to 20.6%.
G&A decelerated further to 5.9% of revenues compared to 7.6%.
3/
$SE
G&A decelerated further to 5.9% of revenues compared to 7.6%.
3/
$SE
