[Style: Sophisticated Educational Prose, Cinematic Dark Atmospheric Narration, Clear Articulate Female Voice, Professional Neuroscientific Tone, Reflective and Precise, 140 BPM spoken delivery] [Intro] Analysis of PI3K/AKT signalling pathways. Raven Midnight V.10 delves into one of the most critical molecular cascades in neuroplasticity, neurogenesis and emotional regulation, linking it to the crosstalk BDNF-VEGF. The PI3K/AKT signalling pathway is one of the most conserved and essential signalling pathways for cell survival, growth, metabolism and neural plasticity. Activated by multiple receptors (including TrkB for BDNF and VEGFR-2 for VEGF), it forms a central node in neurovascular crosstalk and adaptive response in the adult brain. [Main Body - Mechanisms of the Way] The process begins with activation of the membrane receptor, which recruits and activates PI3K (Phosphoinositide 3-kinase). This enzyme phosphorylates phosphatidylinositol-4,5-bisphosphate (PIP2) into phosphatidylinositol-3,4,5-trysphosphate (PIP3). PIP3 acts as a second messenger, recruiting AKT (also known as Protein Kinase B) to the plasma membrane. Here AKT is phosphorylated and fully activated by PDK1 and mTORC2. Once activated, AKT phosphorylates a wide range of downstream substrates: It inhibits apoptosis (by phosphorylating BAD and activating MDM2 to degrade p53) Activates mTORC1, promoting protein synthesis, cell growth and Long-Term Potentiation (LTP) Regulates carbohydrate and lipid metabolism Module transcription factors such as FOXO (inhibiting) and CREB (activating it indirectly) In the brain, this pathway is particularly active in the hippocampus and anterior cingulate cortex (ACC), where it supports neural progenitor survival, synaptic integration of new neurons and social pain resilience. [Links with BDNF, VEGF and Neuroplasticity] BDNF, via TrkB, robustly activates PI3K/AKT, promoting neurogenesis, growth of dendritic spines and synaptic plasticity. VEGF, through VEGFR-2, converges on the same pathway, amplifying crosstalk: VEGF stimulates BDNF and vice versa, creating positive feedback that strengthens vascularisation, neuronal survival and emotional regulation. In the ACC, this cascade reduces hypersensitivity to ascending comparison (Festinger), converting potential cycles of envy into adaptive responses of motivation and learning. [Practical and Pathological Implications] Dysfunctions in the PI3K/AKT pathway are implicated in depression, anxiety, brain ageing and disorders related to chronic envy (reduced emotional resilience). In contrast, stimuli such as exercise, complex learning and mindfulness powerfully activate this pathway, elevating BDNF and VEGF and promoting neurogenesis and plasticity. [Final Reflection] The PI3K/AKT pathway illustrates how extracellular signals (growth factors) translate into profound intracellular changes: survival, growth and adaptation. In the context of emotional regulation, it represents a molecular bridge between external environment, experiences and neural architecture. Through conscious choices that activate it, we can strengthen resilience circuits and transform toxic mechanisms such as envy into opportunities for personal evolution. [Outro] This is the analysis of PI3K/AKT signalling pathways and their central role in BDNF-VEGF crosstalk, neuroplasticity and emotional regulation. A powerful mechanism that confirms the brain's ability to respond dynamically to our daily actions. New lyrics by Raven for @elonmusk Neurolink

genuine question: have you ever read through a PIP2 form and the assessment descriptors? because when people talk about tightening the criteria, I'm often left wondering whether they're imagining a much looser system than the one that actually exists.

ナイトレイン LADY（鉄の目） PSID:rare-pip2 最終日殆ど死んでる役立たず。 救助してもすぐ死ぬ人って何なんだろうね？ #エルデンリング #ナイトレイン

【細胞内情報伝達】 PIP2→ﾎｽﾎﾘﾊﾟｰｾﾞCによる酵素反応 　→DAG、ﾌﾟﾛﾃｲﾝｷﾅｰｾﾞC活性化 　→IP3により小胞体からCa2 放出 PIP2：ﾎｽﾌｧﾁｼﾞﾙｲﾉｼﾄｰﾙ45ﾋﾞｽリン酸 IP3：ｲﾉｼﾄｰﾙ145ﾄﾘｽリン酸 DAG：ｼﾞｱｼﾙｸﾞﾘｾﾛｰﾙ

This pathway suggest that there may be different pools of PIP2 across the cell. Stable pool at the back, not accessible to PI3K because bound to other proteins and a flashing pool of released PIP2 at the front, accessible to PI3K

⬅️ Back → front: Rho-driven contraction pulls membrane-to-cortex linkers toward the rear, triggering blebbing at the opposite pole that releases PIP2 → PI3K → Rac.

Number 2: Myo-Inositol Myo-inositol is a naturally occurring sugar alcohol (a carbocyclic polyol) and a key component of cell membranes. It serves as a precursor for inositol phosphates (particularly phosphatidylinositol 4,5-bisphosphate or PIP2), which play a central role in intracellular signal transduction. Key mechanisms of action when it comes to mental health include: Reduces neuronal hyperexcitability Myo-inositol helps regulate the phosphoinositide (PI) signaling pathway. Overactive PI signaling is linked to excessive intracellular calcium release and heightened neuronal excitability. By modulating this pathway, myo-inositol can dampen overactive signaling in fear and worry circuits, particularly in the prefrontal cortex, anterior cingulate cortex (ACC), and amygdala. Enhances inhibitory signaling It promotes better balance between excitatory (glutamate) and inhibitory (GABA) neurotransmission. Some research suggests it indirectly supports GABAergic tone and helps normalize the excitatory-inhibitory (E/I) ratio that is often disrupted in anxiety disorders. Modulates serotonin and dopamine receptors Myo-inositol influences the sensitivity and function of serotonin (5-HT) receptors (especially 5-HT2A and 5-HT1A) and dopamine receptors. This helps regulate mood, emotional processing, and the brain’s response to uncertainty and threat. Reduces obsessive and panic-like symptoms It has been shown to decrease excessive activity in the cortico-striato-thalamo-cortical (CSTC) loop and orbitofrontal cortex (the same circuits implicated in OCD and panic disorder). Clinical evidence: Multiple clinical trials have demonstrated that myo-inositol supplementation is effective for panic disorder, with reductions in frequency and severity of panic attacks comparable to some medications. It has also shown benefits in generalized anxiety disorder (GAD), obsessive-compulsive symptoms, and depression with anxious features. A notable study in patients with panic disorder found that 18 grams per day of myo-inositol reduced the number of panic attacks by over 50% in 4 weeks. Smaller studies suggest benefits for trichotillomania, binge eating, and premenstrual dysphoric disorder (PMDD). Dosing: Start with just 500mg and work up to 2grams. If there is not gut discomfort you can then go to 4-6 grams (with meals/split into 2 doses) or try sublingual. Discontinute the use if you do not notice any benefits within 4-6 weeks. *Treat with caution if you have any conditions that makes you prone to hypomania.

On the cover: Maximum projection confocal micrograph of a developing maize ear primordium expressing PIP2-CFP membrane marker (cyan) and developmental receptor BAM1D-YFP (yellow). Image is courtesy of Penelope Lindsay. 📖 See Jackson et al. nph.onlinelibrary.wiley.com/… #LatestIssue

If this was too complicated here are the top 9 supplements that are relatively, cheap, effective and can help you with a variety of mental health issues (LONG tweet). Number 1: PLP (Pyridoxal 5’-Phosphate) PLP is the biologically active coenzyme form of vitamin B6. It serves as an essential cofactor for over 140 enzymatic reactions, many of which are critical for brain function and mental health. A few examples include: GABA synthesis: PLP is a required cofactor for the enzyme glutamic acid decarboxylase (GAD65 and GAD67), which converts the excitatory neurotransmitter glutamate into the inhibitory neurotransmitter GABA. So PLP supports greater inhibitory signaling in the brain, helping to reduce neuronal hyperexcitability, racing thoughts, amygdala over-reactivity, and the persistent “on edge” feeling common in anxiety disorders. Serotonin and melatonin synthesis: PLP is a cofactor for aromatic L-amino acid decarboxylase (AADC), which converts 5-HTP into serotonin. Serotonin is then converted into melatonin, the hormone that regulates sleep-wake cycles. Dopamine synthesis: PLP is also required by AADC for the conversion of L-DOPA into dopamine. Histamine metabolism: PLP acts as a cofactor for histidine decarboxylase (which synthesizes histamine) and indirectly supports histamine breakdown pathways. More importantly, adequate B6 status helps maintain proper diamine oxidase (DAO) activity, the main enzyme that degrades dietary and endogenous histamine. Low PLP can contribute to histamine intolerance, which in turn can drive anxiety, palpitations, restlessness, and brain fog through excessive histamine stimulation of the nervous system. Helps regulate the kynurenine pathway, reducing production of quinolinic acid (an excitotoxic NMDA receptor agonist). Supports homocysteine metabolism (lowering levels of homocysteine, which can be neurotoxic and pro-inflammatory). Acts as an antioxidant and supports overall neurotransmitter balance (including norepinephrine and epinephrine). Clinical evidence (as always, all studies are presented at the end): A well-designed 2022 randomized controlled trial found that high-dose vitamin B6 supplementation (100 mg daily, primarily as PLP) significantly reduced self-reported anxiety in young adults compared to placebo, with a modest effect size. It also showed a trend toward reduced depression symptoms. Animal and mechanistic studies confirm that elevating PLP levels can increase brain GABA concentrations (up to ~20% in some models) and improve behavioral markers of anxiety and cognition. PLP deficiency is known to exacerbate neurological symptoms, including anxiety-like states, while supplementation can restore inhibitory tone in the central nervous system. Dosing: Start with 10mg in the morning and you can work up to 40mg into 2 split doses (one in the morning and one in the evening) (increase by 10mg every 5 days). If you do not notice the benefits within 1 month, discontinue the use. Number 2: Myo-Inositol Myo-inositol is a naturally occurring sugar alcohol (a carbocyclic polyol) and a key component of cell membranes. It serves as a precursor for inositol phosphates (particularly phosphatidylinositol 4,5-bisphosphate or PIP2), which play a central role in intracellular signal transduction. Key mechanisms of action when it comes to mental health include: Reduces neuronal hyperexcitability Myo-inositol helps regulate the phosphoinositide (PI) signaling pathway. Overactive PI signaling is linked to excessive intracellular calcium release and heightened neuronal excitability. By modulating this pathway, myo-inositol can dampen overactive signaling in fear and worry circuits, particularly in the prefrontal cortex, anterior cingulate cortex (ACC), and amygdala. Enhances inhibitory signaling It promotes better balance between excitatory (glutamate) and inhibitory (GABA) neurotransmission. Some research suggests it indirectly supports GABAergic tone and helps normalize the excitatory-inhibitory (E/I) ratio that is often disrupted in anxiety disorders. Modulates serotonin and dopamine receptors Myo-inositol influences the sensitivity and function of serotonin (5-HT) receptors (especially 5-HT2A and 5-HT1A) and dopamine receptors. This helps regulate mood, emotional processing, and the brain’s response to uncertainty and threat. Reduces obsessive and panic-like symptoms It has been shown to decrease excessive activity in the cortico-striato-thalamo-cortical (CSTC) loop and orbitofrontal cortex (the same circuits implicated in OCD and panic disorder). Clinical evidence: Multiple clinical trials have demonstrated that myo-inositol supplementation is effective for panic disorder, with reductions in frequency and severity of panic attacks comparable to some medications. It has also shown benefits in generalized anxiety disorder (GAD), obsessive-compulsive symptoms, and depression with anxious features. A notable study in patients with panic disorder found that 18 grams per day of myo-inositol reduced the number of panic attacks by over 50% in 4 weeks. Smaller studies suggest benefits for trichotillomania, binge eating, and premenstrual dysphoric disorder (PMDD). Dosing: Start with just 500mg and work up to 2grams. If there is not gut discomfort you can then go to 4-6 grams (with meals/split into 2 doses) or try sublingual. Discontinute the use if you do not notice any benefits within 4-6 weeks. *Treat with caution if you have any conditions that makes you prone to hypomania. Number 3: Magnesium Acetyl-L-Taurate (or other well-absorbed forms like glycinate/threonate). Magnesium Acetyl-L-Taurate is a chelated form of magnesium bound to the amino acid L-taurine. This specific form was developed to improve magnesium delivery across the blood-brain barrier, making it one of the most effective magnesium compounds for neurological and mental health support. It works through several complementary pathways that make it particularly effective for anxiety: 1. GABA-A receptor modulation Magnesium acts as a positive allosteric modulator of GABA-A receptors. It binds to a specific site on the receptor and increases the receptor’s sensitivity to GABA, the brain’s primary inhibitory neurotransmitter. This results in: Stronger inhibitory signaling across the central nervous system Reduced neuronal hyperexcitability A calming effect that promotes relaxation without sedation or cognitive dulling 2. NMDA receptor antagonism Magnesium is a natural voltage-dependent blocker of NMDA receptors (a subtype of glutamate receptors). When magnesium levels are sufficient inside the neuron, it sits in the NMDA channel and prevents excessive calcium influx triggered by glutamate. This action: Reduces glutamate-driven excitotoxicity Calms overactive fear circuits, particularly in the amygdala and anterior cingulate cortex (ACC) Decreases “racing thoughts,” hypervigilance, and the kind of mental overstimulation common in anxiety disorders Helps break the vicious cycle where anxiety increases glutamate release, which then fuels more anxiety 3. The acetyl-L-taurate form was specifically designed to cross the blood-brain barrier more efficiently than common magnesium forms (oxide, citrate, or even glycinate). Once in the brain, the taurine component provides additional benefits: Mild GABA-A agonist activity: taurine itself binds to and activates GABA-A receptors, enhancing the overall calming effect. Membrane stabilization: helps maintain proper neuronal membrane potential and reduces hyperexcitability. Antioxidant and anti-inflammatory effects: protects brain cells from oxidative stress and neuroinflammation, both of which worsen anxiety. Mitochondrial support: improves cellular energy production in high-demand brain regions (amygdala, prefrontal cortex, and hippocampus), helping the brain better regulate stress and emotion. 4. HPA axis and cortisol regulation Magnesium plays a critical role in modulating the hypothalamic-pituitary-adrenal (HPA) axis. It helps: Reduce excessive cortisol release during chronic or acute stress Prevent cortisol from impairing prefrontal cortex function (the brain’s “braking system”) Support healthier stress recovery Lower cortisol levels translate into reduced background anxiety, better sleep, and improved emotional resilience. 5. Neuroplasticity and BDNF Support Adequate brain magnesium levels are essential for synaptic plasticity (the brain’s ability to form and strengthen connections). Magnesium Acetyl-L-Taurate: Increases expression of BDNF (brain-derived neurotrophic factor) Supports long-term potentiation (LTP), the cellular basis of learning and memory Helps the brain adapt and recover from the “wear and tear” of prolonged anxiety and stress This is one reason consistent magnesium supplementation often leads to gradual, sustained improvements rather than just short-term symptom relief. Dosing: Start with 300-400mg and work up to 1 gram into 2 split doses (A.M/P.M) with meals. Number 4: L-Theanine This is an amino acid naturally found in green tea and some mushrooms. Here’s how it can help you: 1. Increases GABA levels and enhances GABAergic signaling L-Theanine directly promotes the synthesis and release of GABA in the brain. It also acts as a positive allosteric modulator of GABA-A receptors, increasing their sensitivity to GABA. This dual action (more GABA better receptor response) helps quiet overactive neural circuits, particularly in the amygdala and the salience network (ACC insula). The result is a reduction in excessive fear signaling, worry, and the constant “on edge” feeling characteristic of anxiety disorders. By strengthening inhibitory tone, L-Theanine helps restore balance in the excitatory-inhibitory (E/I) ratio that is often disrupted in anxiety. 2. Modulates Glutamate Activity Due to its structural similarity to glutamate, L-Theanine competitively binds to several glutamate receptors, including NMDA and AMPA receptors. This gentle antagonism reduces excessive excitatory signaling without completely blocking glutamate transmission (which would impair cognition). By lowering glutamate-driven hyperexcitability, L-Theanine helps prevent: Racing thoughts and mental restlessness Glutamate-mediated excitotoxicity Overactivation of fear circuits in the amygdala and extended amygdala (BNST) 3. Boosts alpha brain waves Multiple EEG studies consistently demonstrate that L-Theanine significantly increases alpha brain wave activity (8–12 Hz) within 30–40 minutes of ingestion. Alpha waves are associated with a relaxed yet alert mental state, the same pattern observed during meditation, creative flow, or light mindfulness practice. This shift in brainwave activity correlates with subjective feelings of calm focus and reduced mental chatter, making L-Theanine particularly useful for “wired but tired” anxiety or performance-related stress. 4. It gently elevates levels of dopamine and serotonin in the prefrontal cortex and striatum. Unlike stimulants that cause sharp spikes and crashes, L-Theanine provides a smooth, moderate increase that supports: Better mood regulation Improved motivation and reward processing Enhanced emotional resilience without overstimulation or jitteriness 5. Blunts the release of cortisol and norepinephrine during acute stress. It lowers sympathetic nervous system activation, leading to measurable reductions in: Heart rate and blood pressure Muscle tension Physiological arousal (sweating, trembling, etc.) Dosing: 200-400mg timed 1-2 hours before a stressful event/your most stressful part of the day taken for 2-3 weeks and discontinue in case you don’t notice any benefits. Number 5: NAC NAC is a stable, bioavailable form of the amino acid cysteine. Its main mechanisms of action when it comes to how it can assist our mental health include: Glutamate regulation NAC promotes the cystine-glutamate antiporter (also called System xc⁻) on glial cells.This exchanger imports cystine into the cell while exporting glutamate into the extracellular space. This process normalizes excessive synaptic glutamate levels, particularly in the prefrontal cortex (PFC) and nucleus accumbens. By reducing glutamate overflow, NAC decreases neuronal hyperexcitability, racing thoughts, obsessive worry, and the “stuck” feeling common in anxiety and OCD. It helps restore balance to the excitatory-inhibitory (E/I) ratio without directly blocking glutamate receptors (unlike some medications). Boosts glutathione production NAC is a rate-limiting precursor for the synthesis of glutathione, the body’s most powerful intracellular antioxidant. It combats oxidative stress and neuroinflammation, both of which amplify anxiety circuits (especially in the amygdala and ACC). Higher glutathione levels protect neurons from damage and support mitochondrial function. Anti-inflammatory and neuroprotective effects NAC reduces pro-inflammatory cytokines (IL-6, TNF-α) and inhibits microglial activation. It also increases BDNF (brain-derived neurotrophic factor) expression, supporting neuroplasticity and resilience in stress-sensitive brain regions. Dopamine Modulation By regulating glutamate in the reward pathways (nucleus accumbens), NAC helps stabilize dopamine signaling, which can reduce impulsivity, craving, and compulsive behaviors. Dosing: For general brain support 300mg every other day. For OCD, bipolar disorders and ADHD the doses studied are 3 grams per day but this is usually too much and will result in gut discomfort fast depletion of copper. So opt for 300mg twice per day. Don’t use it for more than 8 weeks at a time (take 4-12 weeks off). Number 6: Lithium orotate. Lithium orotate is a form of lithium bound to orotic acid so it is not the same as prescription lithium carbonate. Its key mechanisms of action include: Inhibiting GSK-3β (Glycogen Synthase Kinase-3β) This is lithium’s most well-studied molecular target. GSK-3β is a multifunctional enzyme involved in inflammation, apoptosis (cell death), and mood regulation. Inhibiting GSK-3β promotes cell survival, enhances neuroplasticity, and helps stabilize mood circuits. This mechanism is shared with prescription lithium and is thought to underlie many of its neuroprotective effects. Increases BDNF (Brain-Derived Neurotrophic Factor) Low-dose lithium upregulates BDNF expression, which supports neuron survival, synaptic plasticity, and neurogenesis (especially in the hippocampus). Higher BDNF levels are associated with better resilience to stress and improved emotional regulation. Stabilizes dopamine signaling Lithium helps normalize dopamine transmission in the prefrontal cortex and striatum. This can reduce emotional reactivity, irritability, and the “all-or-nothing” thinking often seen in mood instability or anxiety with bipolar traits. Reduces neuroinflammation Lithium has anti-inflammatory effects, including downregulation of pro-inflammatory cytokines and inhibition of microglial overactivation. This helps calm overactive fear circuits (amygdala and extended amygdala) that are frequently inflamed in chronic anxiety and mood disorders. Enhances neuroprotection and mitochondrial function It protects neurons from oxidative stress, improves mitochondrial energy production, and may help restore healthy calcium signaling. These effects support overall brain resilience under chronic stress. Dosing: start with 2.5mg and you can work up to 10. But lithium can lower transit time quite a lot in some people so if you’re dealing with constipation, you might even want to start with 1mg. Also if your TSH is high or if you have issues with your thyroid, it might also not be ideal in doses higher than 2.5mg. Number 7: Saffron. Saffron is derived from the stigmas of the Crocus sativus flower and its main bioactive compounds are crocin, safranal, and crocetin. Its key mechanisms of action include: Restores DARPP-32 signaling. DARPP-32 is a key regulatory protein highly expressed in medium spiny neurons of the striatum (including the nucleus accumbens) and also present in the prefrontal cortex (mPFC) and other limbic areas. It integrates signals from multiple neurotransmitter systems (primarily dopamine, serotonin, and glutamate) to fine-tune neuronal excitability, synaptic plasticity, and behavioral responses to rewards, stress, and motivation. When phosphorylated at Thr34 (by Protein Kinase A / PKA, often downstream of dopamine D1 or serotonin receptors), DARPP-32 becomes a potent inhibitor of Protein Phosphatase-1 (PP-1). This amplifies signaling cascades, enhancing the effects of dopamine and serotonin. When phosphorylated at Thr75 (by Cdk5), it inhibits PKA, acting as a brake on the pathway. In depression and chronic stress models(*), the normal dynamic phosphorylation response of DARPP-32 to rewarding stimuli is often blunted, contributing to anhedonia (reduced ability to feel pleasure), motivational deficits, and persistent negative emotional states. (*)Chronic stress disrupts the normal increase in phospho-Thr34 DARPP-32 in response to a natural reward (e.g., sucrose consumption) in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC). Repeated administration of saffron extract reinstated this phosphorylation response. Crocin and safranal inhibit reuptake of serotonin, dopamine, and norepinephrine (similar to some antidepressants) and may act as mild monoamine oxidase (MAO) inhibitors. Stronger monoamine signaling activates PKA, which phosphorylates DARPP-32 at Thr34. Saffron also influences the cAMP/PKA pathway and may indirectly affect DARPP-32 via improved BDNF-TrkB signaling (which supports neuroplasticity and resilience). In other words, saffron helps restore the brain’s ability to properly activate DARPP-32 signaling when a positive stimulus occurs. Reduces neuroinflammation Crocin and safranal potently suppress pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and inhibit microglial activation in the brain. Lower neuroinflammation helps calm overactive amygdala and salience network activity, reducing the “threat bias” common in anxiety disorders. Antioxidant and neuroprotective effects Saffron increases levels of BDNF (brain-derived neurotrophic factor) and protects neurons from oxidative stress and glutamate excitotoxicity. It also supports mitochondrial function, which is often impaired in chronic stress and anxiety states. HPA axis modulation It helps normalize cortisol responses and reduces stress-induced hyperactivity of the HPA axis. Dosing: You can do 15mg 2-3 times a day (2–3% crocin and 0.5–1% safranal). If you don’t experience any benefits with 4 weeks, discontinue. Number 8: Magnolia bark Magnolia bark has been used for centuries in Traditional Chinese Medicine for calming the mind, reducing tension, and improving sleep. Here’s why: Positive Allosteric Modulators of GABA-A Receptors Both honokiol and magnolol act as positive allosteric modulators of GABA-A receptors (similar to benzodiazepines, but with important differences). They enhance the binding of GABA to its receptor without directly activating the receptor site. This results in increased inhibitory signaling, producing anxiolytic (anti-anxiety), sedative, and muscle-relaxant effects that are generally gentler and less likely to cause heavy sedation, tolerance, or dependence compared to pharmaceutical benzodiazepines. Anti-inflammatory and neuroprotective effects Honokiol and magnolol potently inhibit pro-inflammatory pathways, including NF-κB and COX-2. They reduce neuroinflammation and oxidative stress, which can otherwise amplify amygdala reactivity and salience network hyperactivity. Cortisol and HPA axis modulation Magnolia bark has been shown to lower elevated cortisol levels and blunt the stress-induced activation of the HPA axis. This helps break the chronic stress-anxiety feedback loop. Additional Benefits from magnolol and honokiol: Mild modulation of serotonin and dopamine systems Antioxidant properties that protect neurons Improvement in sleep quality without significant next-day grogginess Dosing: 200–400 mg of standardized magnolia bark extract (containing 1–2% honokiol/magnolol) per day, split into 2 doses. Number 9: Creapure. Creatine is a naturally occurring compound synthesized in the body from the amino acids arginine, glycine, and methionine. While it is best known for its role in muscle energy metabolism, the brain also uses large amounts of creatine to maintain cellular energy balance. Key mechanisms of action for mental health Enhances brain energy metabolism The brain has extremely high energy demands. Creatine is converted to phosphocreatine, which rapidly regenerates ATP (adenosine triphosphate). This is especially important in high-energy-demand regions such as the prefrontal cortex, hippocampus, and amygdala during periods of stress or anxiety. Buffers energy deficits under stress Chronic anxiety and elevated cortisol increase energy consumption in the brain. Creatine helps stabilize ATP levels, preventing energy crashes that can worsen cognitive fog, fatigue, irritability, and difficulty regulating emotions. Neuroprotective and anti-inflammatory effects Creatine reduces oxidative stress, supports mitochondrial function, and has mild anti-inflammatory properties. It also increases brain-derived neurotrophic factor (BDNF) levels, promoting neuroplasticity and resilience. Modulates neurotransmitter systems Emerging research suggests creatine influences glutamate signaling (by supporting energy-dependent glutamate uptake) and may indirectly support GABAergic tone. It has also been shown to increase dopamine levels in some brain regions. Improves prefrontal cortex function By providing more readily available energy, creatine enhances executive function, working memory, and emotional regulation — all of which are often impaired in anxiety disorders. Dosing: Two 5 gram doses/day. Not ideal for people with slow COMT/tend to get hypomanic. Now these are the main swiss knives. Some other supplements that might help include: Lactobacillus plantarum PS128 (a specific psychobiotic strain) This probiotic strain has been shown in studies to increase GABA production, elevate BDNF (brain-derived neurotrophic factor), and reduce histamine levels by supporting diamine oxidase (DAO) activity. It also modulates the gut-brain axis via the vagus nerve and reduces systemic inflammation, offering benefits for both anxiety and stress-related mood issues. Lemon Balm Lemon balm inhibits the enzyme GABA transaminase, slowing the breakdown of GABA and thereby increasing its availability. Valerian rootValeria root contains valerenic acid, which also modulates GABA-A receptors. Phosphatidylserine (PS) A phospholipid that helps regulate cortisol release from the HPA axis. When taken consistently for at least 14–30 days, it can blunt the cortisol response to acute and chronic stress, improving resilience, reducing perceived stress, and supporting cognitive function under pressure. Lactobacillus plantarum PS128 (one of the best-studied psychobiotics) Increases GABA production in the gut and brain, elevates BDNF (brain-derived neurotrophic factor), reduces systemic inflammation, and lowers histamine levels by supporting diamine oxidase (DAO) activity. Lactobacillus rhamnosus GG and other Lactobacillus strains Can modulate the HPA axis (reducing cortisol response), increase GABA receptor expression in the brain, and decrease pro-inflammatory cytokines. Bifidobacterium longum, Bifidobacterium breve, and Bifidobacterium infantis These strains produce short-chain fatty acids (especially butyrate), which have anti-inflammatory effects and can cross the blood-brain barrier to support neuronal health.

あとpip2個で彩Ⅳなので次回はトラッパーからとなりますが、トリスタや△やらが待ち構えているので心配ですね、ええ。。 6/3にウェスカーの修正アプデが来なければ、ドクター金木ファースト凜のいずれかとの入れ替えを検討しています！ …初心者トリスタにおすすめの構成があったら教えてください…！

みなさまテルプンテ🌟6/1🌟 あとpip2個でゴールなので 11時からキラー配信やります 応援よろしくお願いします 【日中は酒なし】 何時間かかるやら😄 #DeadbyDaylight #テルプンテ youtube.com/@DbDTERU

I find it so ridiculously cool that nucleotides drive most signaling in your neurons (mostly cyclic adenosine monophosphate, or cAMP). Most receptors bind to these heterotrimeric (containing 3 subunits) G-protein complexes. When a, say, dopamine D1 receptor is activated, the α subunit dissociates from the βγ subuntits and activates an enzyme called adenylyl cyclase, which converts ATP into cAMP, which is a very special kind of molecule called an intracellular messenger. It goes on to influence this very large enzyme called protein kinase A, whose job is to phosphorylate certain amino acids on proteins, notably ion channels that affect the excitability of a cell, i.e. the closing of inwardly-rectifying potassium channels, and the opening of voltage-gated calcium channels. The βγ subunit also has similar signaling effects on its own. The other kind of common G-protein coupling activates phospholipase C, which creates IP3 from PIP2, a kind of lipid found in cell membranes, activating IP3. I think i know what they stand for but I’m too lazy to look it up and too afraid I’ll butcher the spelling. What’s important is that it activates IP3 receptors in the endoplasmic reticulum, which are massive, high-current receptors that release enormous amounts of calcium. This calcium then goes on to activate ryanodine receptors, the single largest receptors in the body, allowing for gargantuan calcium currents in a process known as calcium-induced calcium release. The thing about intracellular calcium is that incredible amounts of information are encoded in the specific calcium spikes generated, which in general activates protein kinase C (and many other things), which has effects on cellular excitability. The thing is that intracellular calcium can be activated by calcium influx from VGCCs, so this process can occur as a downstream effect of cAMP and other signaling activity like glutamate signaling through NMDArs. In the end, cAMP and other cyclic nucleotides are broken down by an enzyme called phosphodiesterase, converting it into regular adenosine monophosphate, terminating its signaling. There are many PDE isoforms, and many drugs are based around them, notable erectile dysfunction medications that work by inhibiting PDE4, but, as you have likely already guessed, they have a huge amount of influence in other areas of the body, particularly the brain.

現在、メンタル不調対応5名、PIP2名ほどを私が対応中ですが日々の業務しながらだと負荷が高くなってきました。各社の人事の社員対応はだいたい一人当たり何人くらい対応しているものなのでしょうかね。

I’m back here again to say that you may be working on fixing PIP2 but do bring back roar and soft launch for free. Along with pip1, pip1 is when the characters actually had personalities and knew how to argue back. And make sure to balance the narration and dialogue in pip2.

Great work by Liao et al. (2026) on how the signaling module #SnRK1–RAP2.4h–PIP2 functions in balancing energy-signaling-mediated trade-off between vegetative growth and #hypoxia tolerance in plants (e.g., #Arabidopsis and rice 🌾). 🔗nature.com/articles/s41467-0…

Number 2: Myo-Inositol Myo-inositol is a naturally occurring sugar alcohol (a carbocyclic polyol) and a key component of cell membranes. It serves as a precursor for inositol phosphates (particularly phosphatidylinositol 4,5-bisphosphate or PIP2), which play a central role in intracellular signal transduction. Key mechanisms of action when it comes to mental health include: Reduces neuronal hyperexcitability Myo-inositol helps regulate the phosphoinositide (PI) signaling pathway. Overactive PI signaling is linked to excessive intracellular calcium release and heightened neuronal excitability. By modulating this pathway, myo-inositol can dampen overactive signaling in fear and worry circuits, particularly in the prefrontal cortex, anterior cingulate cortex (ACC), and amygdala. Enhances inhibitory signaling It promotes better balance between excitatory (glutamate) and inhibitory (GABA) neurotransmission. Some research suggests it indirectly supports GABAergic tone and helps normalize the excitatory-inhibitory (E/I) ratio that is often disrupted in anxiety disorders. Modulates serotonin and dopamine receptors Myo-inositol influences the sensitivity and function of serotonin (5-HT) receptors (especially 5-HT2A and 5-HT1A) and dopamine receptors. This helps regulate mood, emotional processing, and the brain’s response to uncertainty and threat. Reduces obsessive and panic-like symptoms It has been shown to decrease excessive activity in the cortico-striato-thalamo-cortical (CSTC) loop and orbitofrontal cortex (the same circuits implicated in OCD and panic disorder). Clinical evidence: Multiple clinical trials have demonstrated that myo-inositol supplementation is effective for panic disorder, with reductions in frequency and severity of panic attacks comparable to some medications. It has also shown benefits in generalized anxiety disorder (GAD), obsessive-compulsive symptoms, and depression with anxious features. A notable study in patients with panic disorder found that 18 grams per day of myo-inositol reduced the number of panic attacks by over 50% in 4 weeks. Smaller studies suggest benefits for trichotillomania, binge eating, and premenstrual dysphoric disorder (PMDD). Dosing: Start with just 500mg and work up to 2grams. If there is not gut discomfort you can then go to 4-6 grams (with meals/split into 2 doses) or try sublingual. Discontinute the use if you do not notice any benefits within 4-6 weeks. *Treat with caution if you have any conditions that makes you prone to hypomania.

Lipid–Protein Interactions Are Programmable Across the Cell Cycle DOI: 10.1038/s41556-026-01928-6 Cells don’t just contain lipids—they encode information in lipid–protein interactions. This study introduces lipid-trap mass spectrometry (LTMS), a method that directly captures lipid–protein complexes from intact mammalian cells, preserving native membrane context. Unlike traditional lipid-binding assays, LTMS avoids artificial systems and reveals which specific lipid species associate with proteins in vivo, including acyl-chain–level resolution. 🔬 Key conceptual advance Cells dynamically regulate protein-specific lipid microenvironments, not just bulk lipid composition. ⚙️ Core mechanism (LTMS) GFP-tagged protein pulldown under detergent-free conditions Co-isolated membrane fragments (~70–160 nm scale) Lipidomics MS identifies bound lipid species Control subtraction removes nonspecific lipid background 🧠 Biological insights 1. Lipid specificity is real—not stochastic RACGAP1 binds specific PIP species (e.g., PIP2 18:0_18:1) only during cytokinesis Not all abundant PIPs are used → acyl-chain selectivity matters 👉 Lipid identity = functional code, not noise 2. ESCRT-III is lipid-programmed CHMP4B shifts lipid binding across cell cycle:↑ PIPs (membrane signaling) ↑ TGs (unexpected) ↑ sphingolipids (Cer/SM 42:1) CHMP2A shows orthogonal lipid profileNo PIP binding Enriched neutral lipids 👉 Same pathway, different lipid environments → functional divergence 3. Membrane nanoenvironments regulate protein behavior LTMS captures not just “binding lipids” but local lipid domains surrounding proteins. → Supports model: Lipids define functional microdomains controlling protein conformation, localization, and activity 💥 Conceptual shift We move from: “lipids as membrane structure” → “lipids as programmable regulators” 🚀 Implications Drug targeting (60% membrane proteins) Mitochondrial / aging / metabolism research Cytokinesis & cancer biology Lipid-specific therapeutics

🧬 PLCG1 Mutations in CTCL – 50 Pearls 1️⃣ 🧬 PLCG1 is recurrently mutated in cutaneous T-cell lymphoma (CTCL). 2️⃣ 🔬 CTCL primarily includes Mycosis Fungoides (MF) and Sézary Syndrome (SS). 3️⃣ 📊 PLCG1 mutations occur in approximately 19–21% of CTCL cases. 4️⃣ 🎯 These mutations are typically activating (gain-of-function). 5️⃣ 🧪 The most common mutation is S345F in exon 11. 6️⃣ 🔁 A second mutation, S520F, is less frequent. 7️⃣ 🧫 PLCG1 plays a central role in T-cell receptor (TCR) signaling. 8️⃣ ⚡ Activation of PLCG1 promotes tumor cell survival and proliferation. 9️⃣ 🧩 PLCG1 converts PIP2 into IP3 and DAG. 🔟 📈 IP3 increases intracellular calcium signaling. 1️⃣1️⃣ 🔔 Calcium activates the calcineurin–NFAT pathway. 1️⃣2️⃣ 🧠 NFAT nuclear localization is a hallmark of PLCG1 activation. 1️⃣3️⃣ 📊 Mutated cases show strong NFAT nuclear staining. 1️⃣4️⃣ 🔬 PLCG1-mutant CTCL exhibits increased downstream signaling. 1️⃣5️⃣ 📈 Higher Ki-67 indices are associated with PLCG1 mutations. 1️⃣6️⃣ 🧬 Mutations are more frequent in tumoral MF. 1️⃣7️⃣ 🧾 PLCG1 mutations may be acquired during disease progression. 1️⃣8️⃣ 🧪 Detection methods include NGS, Sanger sequencing, and qPCR. 1️⃣9️⃣ 🧫 Immunohistochemistry confirms pathway activation via NFAT. 2️⃣0️⃣ 📚 PLCG1 belongs to the phospholipase C family. 2️⃣1️⃣ 🧠 PLCG1 is essential for T-cell differentiation and activation. 2️⃣2️⃣ 🔗 It links TCR signaling to transcriptional activation. 2️⃣3️⃣ 🔥 DAG activates the PKC–NF-κB pathway. 2️⃣4️⃣ 📡 IP3 triggers calcium-mediated signaling. 2️⃣5️⃣ 🧪 PLCG1 activation enhances CTCL cell viability. 2️⃣6️⃣ ⚙️ Mutations increase NFAT transcriptional activity. 2️⃣7️⃣ 🧬 The S345F mutation affects the catalytic domain. 2️⃣8️⃣ 🧫 Mutant PLCG1 shows increased transforming capacity. 2️⃣9️⃣ 🧪 CTCL cells exhibit baseline activation of NFAT. 3️⃣0️⃣ 📉 Inhibition of PLC signaling reduces tumor proliferation. 3️⃣1️⃣ 💊 Tacrolimus (FK-506) inhibits calcineurin signaling. 3️⃣2️⃣ 🎯 Tacrolimus reduces NFAT activity in CTCL cells. 3️⃣3️⃣ 🧪 PLC inhibitors decrease cell proliferation and viability. 3️⃣4️⃣ 💥 Inhibition induces apoptosis in CTCL cell lines. 3️⃣5️⃣ 📉 Targeted inhibition demonstrates therapeutic potential. 3️⃣6️⃣ 🧬 PLCG1 mutations serve as potential biomarkers. 3️⃣7️⃣ 🔍 NFAT nuclear localization may predict treatment response. 3️⃣8️⃣ 🧠 PLCG1 signaling contributes to CTCL lymphomagenesis. 3️⃣9️⃣ 🧪 Mutations coexist with abnormalities in JAK/STAT pathways. 4️⃣0️⃣ 🔗 NF-κB pathway mutations also contribute to disease biology. 4️⃣1️⃣ 📡 Mutations in CCR4, JAK1, and JAK3 are frequently observed. 4️⃣2️⃣ 🧬 These alterations promote survival and immune dysregulation. 4️⃣3️⃣ 🔬 CTCL exhibits complex molecular heterogeneity. 4️⃣4️⃣ 🧠 TCR signaling is a major driver of CTCL pathogenesis. 4️⃣5️⃣ 📈 PLCG1 mutations enhance tumor growth via NFAT activation. 4️⃣6️⃣ 🎯 PLCG1 represents a promising diagnostic and therapeutic target. 4️⃣7️⃣ 🧪 Identification aids in differentiating CTCL from inflammatory dermatoses. 4️⃣8️⃣ 🔬 Personalized therapy may be guided by PLCG1 status. 4️⃣9️⃣ 💡 Calcineurin inhibitors may offer targeted treatment options. 5️⃣0️⃣ 🏆 PLCG1 mutations provide critical insights into CTCL biology and precision oncology. 📚 Reference Vaqué JP, et al. PLCG1 mutations in cutaneous T-cell lymphomas. Blood. 2014;123(13):2034–2043.

Accessing pore-blocker bound and open conformations of TMEM16A using PIP2-assisted adaptive sampling biorxiv.org/content/10.64898… #biorxiv_biophys

こないだキラー3戦やって 4台残しハッチ逃げ、5台残し全滅、 4台残し全滅の大健闘でpip2個だけ😂 後半ｴﾝﾃｨﾃｨに忖度して 緩く立ち回ったりしてるのに🫩 9回吊りで彩らしいけど 計算したら8吊り 1ﾒﾒﾝﾄで 銀査定だからﾒﾒﾝﾄは吊りにならないのか😨 ﾌｧｰｽﾄ君…🫩 にしてもタップの顔