jkochano retweeted
Now online! In vivo Gene Writing with engineered retrotransposons dlvr.it/TW30VQ
0
15
42
4,539
I agree, but Trump’s symptoms are moving quickly and will soon be visible to even the most intransigent MAGA disciple. His ending will be slow, but his downfall from power will be swift. #MAGA #trump #DementiaDon #dementia
Donald J. Trump, currently alive President of the United States of America, is now suffering a slow agonizing death preceded by the gradual dissolution of his sense of self and identity. He is living his remaining hours and days in decay untethered from his own sense of history, ery single living human being is severed like the unraveling of old, wet rope.
0
0
0
6
jkochano retweeted
Donald J. Trump, currently alive President of the United States of America, is now suffering a slow agonizing death preceded by the gradual dissolution of his sense of self and identity. He is living his remaining hours and days in decay untethered from his own sense of history, ery single living human being is severed like the unraveling of old, wet rope.
21
86
252
3,535
jkochano retweeted
"All the things my uncle invented... The RADAR. My uncle invented radar,... can you believe it?"
- An 80-year-old dementia patient who believes his uncle invented radar 😛
- An 80-year-old dementia patient who believes his uncle invented radar 😛
119
278
777
9,041
jkochano retweeted
Last night at a rally in Iowa, Donald Trump made this very bizarre face!
It looks like he was opening his mouth wide open!
It looks like he was opening his mouth wide open!
56
83
357
29,153
jkochano retweeted
Mitochondrial genome homeodynamics across scales
sciencedirect.com/science/articl…
sciencedirect.com/science/articl…
0
16
58
1,627
jkochano retweeted
@mjfree Like where was he going when he walked past his car and into an empty field. His secret service had to go get him and usher him back to the car.
0
2
7
182
jkochano retweeted
🧬🧠 Can a mitophagy activator improve brain vascular function in people with obesity—even when peripheral endothelial function remains unchanged?
A new randomized clinical trial in JAMA Network Open provides an intriguing answer.
Urolithin A (UA), a gut microbiome-derived ivate mitophagy, enhanced task-evoked cerebral hemodynamic responses in middle-aged adults with obesity—but failed to improve the trial's primary vascular endpoint.
🔬 1. Study design: Testing mitochondrial therapeutics in humans
This double-blind, placebo-controlled trial enrolled 50 adults aged 40–64 years with obesity.
• Participants: 50 (25 UA, 25 placebo)
• Mean age: 50.7 years
• Mean BMI: 38.3 kg/m²
• Women: 74%
• Intervention: Urolithin A 1,000 mg/day
• Duration: 4 weeks
The primary endpoint was brachial artery flow-mediated dilation (FMD), a measure of peripheral endothelial function.
Secondary outcomes included microvascular perfusion, cerebral hemodynamic responses, and cognitive task performance.
⚡ 2. Primary endpoint: No significant improvement
Despite excellent adherence, UA supplementation did not significantly improve brachial artery FMD.
Mean change:
Placebo: +0.3%
Urolithin A: +1.3%
Adjusted treatment effect:
β = 1.74; 95% CI −1.33 to 4.81; P = 0.33
Other peripheral vascular measurements, including reactive hyperemia and microvascular reperfusion, were also unchanged.
This is important: The study did not demonstrate improved systemic endothelial function.
🧠 3. A surprising signal in the brain
Functional near-infrared spectroscopy (fNIRS) was used to assess cortical hemodynamic responses during working-memory tasks.
Compared with placebo, UA supplementation significantly increased task-evoked responses, particularly in the left dorsolateral prefrontal cortex.
For the 2-back versus 1-back task contrast:
• Placebo: β = −1.43 ± 5.26
• Urolithin A: β = 15.53 ± 13.02
• False discovery rate-adjusted q < 0.05
This suggests that UA may influence neurovascular responses to cognitive demand.
However, increased task-evoked oxygenation does not necessarily indicate improved cerebral perfusion efficiency or neuronal function.
🧬 4. Did better brain hemodynamics translate into better cognition?
Not yet.
Neither working-memory accuracy nor reaction time improved significantly.
The investigators suggested a possible ceiling effect because many participants already performed well at baseline.
Thus, the findings support a change in cerebrovascular hemodynamic signaling—not demonstrated cognitive enhancement.
🔍 5. What about inflammation and mitochondrial biomarkers?
Circulating UA and UA-glucuronide increased substantially, confirming systemic exposure.
However, circulating inflammatory and endothelial biomarkers showed no significant treatment effects.
Macrophage inflammatory protein-1α showed a nonsignificant trend toward reduction (P = 0.06).
Importantly, the investigators did not directly quantify mitophagy flux or mitochondrial function in cerebral vascular cells.
Therefore, whether the observed brain hemodynamic response was mediated by mitophagy remains unknown.
💊 6. Why might brain and peripheral vessels respond differently?
Several mechanisms warrant investigation:
Mitochondrial quality control: UA-associated mitophagy could potentially influence endothelial mitochondrial fitness.
Neurovascular coupling: Improved coordination between neuronal activity and vascular responses might alter task-evoked hemodynamics.
Neuroinflammation: Preclinical studies suggest that UA can modulate inflammatory signaling in neural and glial cells.
Tissue-specific sensitivity: Cerebral and peripheral vascular beds may differ in their responses to metabolic interventions.
These are mechanistic hypotheses, not pathways established by this trial.
🧪 7. Implications for future mitophagy-targeted therapies
A logical next-generation study would combine:
UA exposure → Mitophagy flux biomarkers → Mitochondrial functional assessment → Cerebrovascular imaging → Cognitive outcomes
Important additions include:
• Longer treatment duration (≥12 weeks)
• Larger, sex-balanced cohorts
• Baseline mitochondrial and vascular phenotyping
• More challenging cognitive tasks
• Independent confirmation using complementary neurovascular measurements
• Mechanistic studies distinguishing endothelial, neuronal, and glial effects
⚠️ 8. Important limitations
This was a small, single-center proof-of-concept trial with only four weeks of treatment.
Seven participants did not complete follow-up.
The primary endpoint was negative, and the positive cerebral hemodynamic finding was a secondary outcome.
No evidence was provided for dementia prevention, long-term cognitive benefit, or direct activation of mitophagy in human brain tissue.
💡 The broader implication
Urolithin A illustrates both the promise and challenge of translating mitochondrial therapeutics into clinical medicine.
A compound can alter a tissue-specific physiological signal without improving the primary clinical endpoint.
The next step is not to conclude that UA improves brain health, but to determine whether its cerebrovascular effects are reproducible, mechanistically linked to mitochondrial quality control, and ultimately clinically meaningful.
Mitophagy-targeted therapeutics may require tissue-specific biomarkers and functional endpoints rather than relying exclusively on systemic vascular measurements.
📄 da Costa Pinaffi-Langley AC, Gulej R, Kaposzta Z, et al.
Urolithin A and Endothelial and Cerebrovascular Function in Middle-Aged Adults With Obesity: A Randomized Clinical Trial.
JAMA Network Open. 2026;9(10).
DOI: doi.org/10.1001/jamane…
Clinical trial: NCT05921266
#UrolithinA #Mitophagy #Mitochondria #Obesity #CerebrovascularHealth #NeurovascularCoupling #BrainHealth #Geroscience #ClinicalTrials #PrecisionMedicine #HealthyAging
A new randomized clinical trial in JAMA Network Open provides an intriguing answer.
Urolithin A (UA), a gut microbiome-derived ivate mitophagy, enhanced task-evoked cerebral hemodynamic responses in middle-aged adults with obesity—but failed to improve the trial's primary vascular endpoint.
🔬 1. Study design: Testing mitochondrial therapeutics in humans
This double-blind, placebo-controlled trial enrolled 50 adults aged 40–64 years with obesity.
• Participants: 50 (25 UA, 25 placebo)
• Mean age: 50.7 years
• Mean BMI: 38.3 kg/m²
• Women: 74%
• Intervention: Urolithin A 1,000 mg/day
• Duration: 4 weeks
The primary endpoint was brachial artery flow-mediated dilation (FMD), a measure of peripheral endothelial function.
Secondary outcomes included microvascular perfusion, cerebral hemodynamic responses, and cognitive task performance.
⚡ 2. Primary endpoint: No significant improvement
Despite excellent adherence, UA supplementation did not significantly improve brachial artery FMD.
Mean change:
Placebo: +0.3%
Urolithin A: +1.3%
Adjusted treatment effect:
β = 1.74; 95% CI −1.33 to 4.81; P = 0.33
Other peripheral vascular measurements, including reactive hyperemia and microvascular reperfusion, were also unchanged.
This is important: The study did not demonstrate improved systemic endothelial function.
🧠 3. A surprising signal in the brain
Functional near-infrared spectroscopy (fNIRS) was used to assess cortical hemodynamic responses during working-memory tasks.
Compared with placebo, UA supplementation significantly increased task-evoked responses, particularly in the left dorsolateral prefrontal cortex.
For the 2-back versus 1-back task contrast:
• Placebo: β = −1.43 ± 5.26
• Urolithin A: β = 15.53 ± 13.02
• False discovery rate-adjusted q < 0.05
This suggests that UA may influence neurovascular responses to cognitive demand.
However, increased task-evoked oxygenation does not necessarily indicate improved cerebral perfusion efficiency or neuronal function.
🧬 4. Did better brain hemodynamics translate into better cognition?
Not yet.
Neither working-memory accuracy nor reaction time improved significantly.
The investigators suggested a possible ceiling effect because many participants already performed well at baseline.
Thus, the findings support a change in cerebrovascular hemodynamic signaling—not demonstrated cognitive enhancement.
🔍 5. What about inflammation and mitochondrial biomarkers?
Circulating UA and UA-glucuronide increased substantially, confirming systemic exposure.
However, circulating inflammatory and endothelial biomarkers showed no significant treatment effects.
Macrophage inflammatory protein-1α showed a nonsignificant trend toward reduction (P = 0.06).
Importantly, the investigators did not directly quantify mitophagy flux or mitochondrial function in cerebral vascular cells.
Therefore, whether the observed brain hemodynamic response was mediated by mitophagy remains unknown.
💊 6. Why might brain and peripheral vessels respond differently?
Several mechanisms warrant investigation:
Mitochondrial quality control: UA-associated mitophagy could potentially influence endothelial mitochondrial fitness.
Neurovascular coupling: Improved coordination between neuronal activity and vascular responses might alter task-evoked hemodynamics.
Neuroinflammation: Preclinical studies suggest that UA can modulate inflammatory signaling in neural and glial cells.
Tissue-specific sensitivity: Cerebral and peripheral vascular beds may differ in their responses to metabolic interventions.
These are mechanistic hypotheses, not pathways established by this trial.
🧪 7. Implications for future mitophagy-targeted therapies
A logical next-generation study would combine:
UA exposure → Mitophagy flux biomarkers → Mitochondrial functional assessment → Cerebrovascular imaging → Cognitive outcomes
Important additions include:
• Longer treatment duration (≥12 weeks)
• Larger, sex-balanced cohorts
• Baseline mitochondrial and vascular phenotyping
• More challenging cognitive tasks
• Independent confirmation using complementary neurovascular measurements
• Mechanistic studies distinguishing endothelial, neuronal, and glial effects
⚠️ 8. Important limitations
This was a small, single-center proof-of-concept trial with only four weeks of treatment.
Seven participants did not complete follow-up.
The primary endpoint was negative, and the positive cerebral hemodynamic finding was a secondary outcome.
No evidence was provided for dementia prevention, long-term cognitive benefit, or direct activation of mitophagy in human brain tissue.
💡 The broader implication
Urolithin A illustrates both the promise and challenge of translating mitochondrial therapeutics into clinical medicine.
A compound can alter a tissue-specific physiological signal without improving the primary clinical endpoint.
The next step is not to conclude that UA improves brain health, but to determine whether its cerebrovascular effects are reproducible, mechanistically linked to mitochondrial quality control, and ultimately clinically meaningful.
Mitophagy-targeted therapeutics may require tissue-specific biomarkers and functional endpoints rather than relying exclusively on systemic vascular measurements.
📄 da Costa Pinaffi-Langley AC, Gulej R, Kaposzta Z, et al.
Urolithin A and Endothelial and Cerebrovascular Function in Middle-Aged Adults With Obesity: A Randomized Clinical Trial.
JAMA Network Open. 2026;9(10).
DOI: doi.org/10.1001/jamane…
Clinical trial: NCT05921266
#UrolithinA #Mitophagy #Mitochondria #Obesity #CerebrovascularHealth #NeurovascularCoupling #BrainHealth #Geroscience #ClinicalTrials #PrecisionMedicine #HealthyAging
0
6
16
400
jkochano retweeted
It took 10 long years for conservative America to figure out that Trump is working with Putin to destroy the U.S., but they finally are.
Better late than later..
The National Review has turned on Putin's puppet:
"Republicans and Democrats, together, should regard this week’s t straw."
Better late than later..
The National Review has turned on Putin's puppet:
"Republicans and Democrats, together, should regard this week’s t straw."
104
995
2,600
26,982