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| -rw-r--r-- | brain.mdwn | 6 | ||||
| -rw-r--r-- | cell_therapy.mdwn | 106 | ||||
| -rw-r--r-- | gene-editing.mdwn | 2 | ||||
| -rw-r--r-- | gene-therapy.mdwn | 2 | ||||
| -rw-r--r-- | genetic-modifications.mdwn | 8 | ||||
| -rw-r--r-- | in_vitro_fertilization.mdwn | 14 | ||||
| -rw-r--r-- | nerve_graft.mdwn | 10 | ||||
| -rw-r--r-- | neurosurgery.mdwn | 14 | ||||
| -rw-r--r-- | reservoir_computing.mdwn | 9 | ||||
| -rw-r--r-- | sleep.mdwn | 17 | ||||
| -rw-r--r-- | volitional_control.mdwn | 6 |
11 files changed, 185 insertions, 9 deletions
diff --git a/brain.mdwn b/brain.mdwn new file mode 100644 index 0000000..a757c4a --- /dev/null +++ b/brain.mdwn @@ -0,0 +1,6 @@ +[Identification and application of cell-type-specific enhancers for the macaque brain](https://www.cell.com/cell/abstract/S0092-8674(25)00742-1) + + +see also [[genetic-modifications]] and [[neurosurgery]] + + diff --git a/cell_therapy.mdwn b/cell_therapy.mdwn index 5420a5a..bde8cab 100644 --- a/cell_therapy.mdwn +++ b/cell_therapy.mdwn @@ -1,6 +1,6 @@ # Cell therapy -Cell therapy surpasses gene therapy in precision and durability of therapeutic effect because it engineers autologous (or, increasingly, allogeneic but universally edited) cells ex vivo. +Cell therapy surpasses [[gene therapy]] in precision and durability of therapeutic effect because it engineers autologous (or, increasingly, allogeneic but universally edited) cells ex vivo. Our ability to engineer large synthetic programs into cells ex vivo is vastly greater than our ability to deliver large multi-kb upgrades through in vivo gene therapy. In addition, you can get quality assurance and validation while in vitro before insertion into human. Or, alternatively, you can also test in vitro, in vivo in animals, etc. @@ -40,9 +40,10 @@ Some other things that can be done: These strategies are modular and combinations might be able to achieve layered immunity control while still permitting sustained systemic secretion of the therapeutic compound. - ## CAR T cell therapy +[In vivo CAR T cell generation to treat cancer and autoimmune disease](https://www.science.org/doi/10.1126/science.ads8473) -- a gene-delivery system to generate CAR-T cells in vivo by dosing of a CD8-targeted lipid nanoparticle carrying anti-CD19 CAR mRNA. + ## various autologous stem cell therapy methods ## xenotransplantation, transplants, implants @@ -136,3 +137,104 @@ other immune focused trogocytosis articles: * Historical review and approvals up to 2023: Mitra et al., *J Transl Med* (2023). [PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC10225594/?utm_source=chatgpt.com) * Monitoring/persistence & antigen loss tech landscape: Chen & Ma, *Am J Pathol* (2024). [ScienceDirect](https://www.sciencedirect.com/science/article/pii/S0002944024001627?utm_source=chatgpt.com) +# MHC editing strategies + +goal: better resist the host immune system, like in allogeneic cell therapies or universal donor stem cells. + +## MHC (HLA) Editing Techniques + +See [[gene editing]] for more gene editing techniques. + +[Synthetic immune checkpoint engagers protect HLA-deficient iPSCs and derivatives from innate immune cell cytotoxicity](https://www.cell.com/cell-stem-cell/fulltext/S1934-5909%2823%2900365-X) + +### Direct MHC Disruption + +Knocking out MHC class I and/or II expression in therapeutic cells reduces visibility to CD8⁺ T cells. Since MHC-I isn't essential for cell survival, many cancers naturally employ this as an immune-evasion tactic [ScienceDirect](https://www.sciencedirect.com/science/article/pii/S1525001620305530?utm_source=chatgpt.com), [Frontiers](https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.636568/full?utm_source=chatgpt.com). + +Conversely, this tactic risks triggering natural killer (NK) cells, which attack cells lacking MHC-I—termed “missing self.” + +### Stealth Transgenes + +“Stealth” transgene strategies target both MHC class I and II to evade host immune detection. Early studies show promise in engineered T cells successfully avoiding cellular immune responses [Journal of Infection and Chemotherapy](https://jitc.bmj.com/content/12/5/e008417?utm_source=chatgpt.com). + +### Viral-Strategy Mimicry + +Many viruses have evolved to inhibit MHC antigen presentation by: + +* Blocking peptide entry via TAP inhibitors +* Retaining MHC-I in the endoplasmic reticulum (ER) or Golgi apparatus +* Directing MHC for degradation via ER-associated pathways [Frontiers](https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1540159/full?utm_source=chatgpt.com). + +Therapeutic cells imght be able to mimic immune stealth we see in some viruses by co-opting these mechanisms with targeted gene edits, like by modifying antigen-processing pathways. + +--- + +## Immune-Modulating Receptor Engineering + +### Alloimmune Defense Receptor (ADR) + +In alloimmune defense receptor (ADR) strategies, therapeutic T cells are empowered to eliminate activated host T and NK cells while sparing resting immune cells. By targeting the avictation marker 4‑1BB, ADR-expressing T cells resist rejection and persist in vivo when co-expressed with CAR constructs [PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC7854790/?utm_source=chatgpt.com). + +--- + +## Stem Cells & Allogeneic Grafts: Toward Universal Donors + +[[Gene editing]] of pluripotent stem cells (iPSCs) to make "stealthy" universal donor cells for cell replacement therapies that need to avoid immune attack [Nature](https://www.nature.com/articles/d41586-024-00590-y?utm_source=chatgpt.com). Strategies include MHC knockout combined with immune shielding techniques to evade T and NK cells. + +--- + +## Epigenetic & Transcriptional Modulation + +### Reactivating MHC or Downregulating Detection Pathways* + +* Tumors often downregulate MHC via epigenetic suppression or via downregulating key transcription factors like NLRC5 [Frontiers](https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.844866/full?utm_source=chatgpt.com). +* CRISPR–dCas9 epigenetic tools can potentially be used to fine-tune gene expression, such as either dampening antigen presentation in therapeutic cells or, in broader contexts, restoring it during immunotherapy [ScienceDirect](https://www.sciencedirect.com/science/article/pii/S2329050121000759?utm_source=chatgpt.com). + +--- + +## Emerging strategies for immmune system evasion + +* **Partial MHC Retention + Non-classical HLA**: Completely removing classical MHC risks NK detection. A nuanced approach might knock down classical MHC while expressing non-classical or inhibitory HLA molecules to suppress NK activity, akin to tumor evasion tactics [Wikipedia](https://en.wikipedia.org/wiki/Immunoediting?utm_source=chatgpt.com). +* **NK Checkpoint Modulation**: Therapeutic cells might express ligands that bind NK inhibitory receptors (like HLA-E to interact with KIRs), or modulate KIR pathways to escape NK-mediated killing [Nature](https://www.nature.com/articles/s41392-025-02280-1?utm_source=chatgpt.com). +* **Local Immune Suppression**: Engineering cells to secrete immunosuppressive cytokines (e.g., TGF-β) selectively could locally dampen the host immune response while minimizing systemic impact. +* **Mapping Virus-Derived Peptides**: Incorporating viral peptide sequences that interfere with MHC pathways—as viruses do—for controlled immune evasion, though highly speculative and risky. +* **Combining ADR and MHC Editing**: Pairing MHC disruption with ADR-type systems might create "immune-evasive but immune-persistent" cells that both hide and defend. + +--- + +## Summary table + +| Strategy | Description | Pros | Cons / Risks | +| ---------------------------------------- | ---------------------------------------------------------- | --------------------------- | ---------------------------------------- | +| **MHC (HLA) knockout** | Remove MHC-I/II to evade T-cell detection | Strong stealth | NK-mediated rejection | +| **Stealth transgenes** | Modulate both MHC classes | Broader evasion | Complex engineering | +| **Viral mimicry (TAP, retention, etc.)** | Disrupt antigen presentation akin to viral proteins | Highly efficient stealth | Potential dysfunction, off target | +| **ADR (alloimmune defense receptor)** | Kill activated host T/NK cells via 4‑1BB targeting | Active defense, persistence | Target specificity, immune dysregulation | +| **iPSC “stealth” editing** | Develop universal donor cells | Wide therapeutic potential | Needs multi-path evasion strategies | +| **Epigenetic modulation (CRISPR-dCas9)** | Fine-tune MHC-related genes | Reversible, tunable | Off-target effects, stability issues | +| **NK checkpoint modulation** | Express NK inhibitory signals (e.g., HLA-E) or target KIRs | Evade NK scrutiny | Over-inhibition risks | +| **Local immunosuppression** | Local cytokine release (e.g., TGF-β) | Context-specific tolerance | Risk of local immune suppression | +| **Combined ADR + MHC editing** | Hide and defend simultaneously | Maximal persistence tactics | Highest complexity and risk | + +--- + +### MHC and HLA references + +* MHC knockout and tumor evasion: [BioMed Central](https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-023-01899-4?utm_source=chatgpt.com), [Wikipedia](https://en.wikipedia.org/wiki/Immunoediting?utm_source=chatgpt.com), [Frontiers](https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.636568/full?utm_source=chatgpt.com), [PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC7854790/?utm_source=chatgpt.com), [Wikipedia](https://en.wikipedia.org/wiki/Molecular_mimicry?utm_source=chatgpt.com), [ScienceDirect](https://www.sciencedirect.com/science/article/pii/S2329050121000759?utm_source=chatgpt.com), [Wikipedia](https://en.wikipedia.org/wiki/Cancer_immunology?utm_source=chatgpt.com) +* Stealth transgenes in T cells: [Journal of Infection and Chemotherapy](https://jitc.bmj.com/content/12/5/e008417?utm_source=chatgpt.com) +* ADR strategy for allogeneic CAR‑T: [PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC7854790/?utm_source=chatgpt.com) +* Viral immunoevasins/TAP interference: [Wikipedia](https://en.wikipedia.org/wiki/Immunoevasin?utm_source=chatgpt.com) +* Stealth stem cells/universal donors: [Nature](https://www.nature.com/articles/d41586-024-00590-y?utm_source=chatgpt.com), [PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC9643905/?utm_source=chatgpt.com) +* Epigenetic tools: [ScienceDirect](https://www.sciencedirect.com/science/article/pii/S2329050121000759?utm_source=chatgpt.com) +* NK and non-classical HLA strategy: missing ref. + +--- + +Multi-layered approach for immune evasion or resistance: + +1. **Hide** — Edit out or modify MHC molecules. +2. **Defend** — Engineer immune-targeting receptors like ADR. +3. **Suppress** — Modulate local or systemic immunity. +4. **Balance** — Evade both T cells and NK cells by blending classical and non-classical signals. +5. **Leverage Epigenetics** — Use precision control over immune-related gene expression. +6. **Combine** — Stack strategies for robust, long-lived therapeutic cells. diff --git a/gene-editing.mdwn b/gene-editing.mdwn index 824ab92..87c55e8 100644 --- a/gene-editing.mdwn +++ b/gene-editing.mdwn @@ -342,3 +342,5 @@ ligand-linked peptide inhibitor, with azobenzene, to inhibit an active domain in * [[protein engineering]] * [[genetic-modifications]] * [[gene therapy]] +* [[cell therapy]] + diff --git a/gene-therapy.mdwn b/gene-therapy.mdwn index 2ddc1da..4e1a170 100644 --- a/gene-therapy.mdwn +++ b/gene-therapy.mdwn @@ -1,5 +1,5 @@ -Here are some gene therapy delivery methods. This page deals mainly with transfection and delivery, whereas [[gene-editing]] pertains to the mechanisms of changing the genetic material, which is what gene therapy endeavors to deliver into cells. +Here are some gene therapy delivery methods. This page deals mainly with transfection and delivery, whereas [[gene-editing]] pertains to the mechanisms of changing the genetic material, which is what gene therapy endeavors to deliver into cells. See also [[cell therapy]]. # naked DNA diff --git a/genetic-modifications.mdwn b/genetic-modifications.mdwn index fb1d941..4fa3ae5 100644 --- a/genetic-modifications.mdwn +++ b/genetic-modifications.mdwn @@ -881,8 +881,12 @@ Abbreviations: ACE, angiotensin-converting enzyme; ACTN3, actinin binding protei # Sleep +See also [[sleep]]. + 4-5 hours of sleep/night, plus resistance to sleep deprivation -- see <http://gnusha.org/logs/2016-11-25.log> +the identified genetics of short sleep humans may not be accurate: <https://forum.effectivealtruism.org/posts/nSwaDrHunt3ohh9Et/cause-area-short-sleeper-genes?commentId=GCQf5qjG4LyEdEJov> + * hSIK3 - [A mutation in salt-induced kinase 3 (hSIK3-N783Y) is identified in a human subject exhibiting the natural short sleep duration trait.](https://www.pnas.org/doi/10.1073/pnas.2500356122) "The transcriptional repressor DEC2 regulates sleep length in mammals" <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2884988/> (hDEC2-P385R) @@ -895,7 +899,7 @@ NPSR1 - [Mutant neuropeptide S receptor reduces sleep duration with preserved me ADRB1 - [Mutation in Beta1-Adrenergic Receptor Affects Sleep/Wake Behaviors](<https://www.cell.com/neuron/pdfExtended/S0896-6273(19)30652-X>) [pop article](https://www.cnn.com/2021/06/22/health/short-sleep-gene-wellness-scn/index.html) -"Resisting sleep deprivation by breaking the link between sleep and circadian rhythms" <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4173912/> +[Resisting sleep deprivation by breaking the link between sleep and circadian rhythms](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4173912/) "TNFα G308A polymorphism is associated with resilience to sleep deprivation-induced psychomotor vigilance performance impairment in healthy young adults" <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467999/> @@ -1028,7 +1032,7 @@ What about radiation resistance? Here's a case in the literature where radiation * optional or delayed puberty (trigger puberty later or whenever the child wants- wait 5 years? 20 years?) -* fertility upregulation, such as early ovarian hypertrophy during gestation, enhanced ovarian reserves such as through <a href="https://www.nature.com/articles/ncomms2861">Foxo3 overexpression</a>; enable or upregulate post-natal oogenesis. +* fertility upregulation, such as early ovarian hypertrophy during gestation, enhanced ovarian reserves such as through <a href="https://www.nature.com/articles/ncomms2861">Foxo3 overexpression</a>; enable or upregulate post-natal oogenesis (human postnatal oogenesis is currently a scientific controversy without consensus). * blood types diff --git a/in_vitro_fertilization.mdwn b/in_vitro_fertilization.mdwn index eb268c2..4288039 100644 --- a/in_vitro_fertilization.mdwn +++ b/in_vitro_fertilization.mdwn @@ -33,6 +33,20 @@ This will be a disorganized mess for a bit. * xy/xx sperm sorting (xyinc: <a href="https://gnusha.org/logs/2023-01-21.log">logs</a>) +# random + +[Rules of motor innervation in chick embryos with supernumerary limbs](https://pubmed.ncbi.nlm.nih.gov/7298909/) (1981) + +[Vascular response to embryo implantation in anterior chamber of eye following interspecies embryo transfers between the rat, mouse, and guinea-pig](https://link.springer.com/article/10.1007/BF00239463) + + + +[Application of the quail-chick chimera system to the study of brain development and behavior](https://www.science.org/doi/10.1126/science.3413496) + +"Hatched chicks with chimeric brains containing cells from both the domestic chicken (Gallus gallus domesticus) and the Japanese quail (Coturnix coturnix japonica) have been produced by transplantation of various regions of the neural tube at the 8- to 15- somite stage. The positions of host and donor cells relative to graft boundaries observed throughout embryonic development and after hatching implicated both radial and tangential cell movements in brain morphogenesis. In addition, transplants containing the entire quail mesencephalon and diencephalon resulted in the transfer of certain aspects of species-typical crowing behavior." + +# more + hybrids, mosaics, chimeras and chimerism: * <https://en.wikipedia.org/wiki/Humanzee> ("humanzee, chuman, manpanzee or chumanzee") diff --git a/nerve_graft.mdwn b/nerve_graft.mdwn new file mode 100644 index 0000000..1eb4094 --- /dev/null +++ b/nerve_graft.mdwn @@ -0,0 +1,10 @@ +[Stretch growth of integrated axon tracts: Extremes and exploitations](https://pmc.ncbi.nlm.nih.gov/articles/PMC3019093/) (2011) + +[Tissue-engineered grafts exploit axon-facilitated axon regeneration and pathway protection to enable recovery after 5-cm nerve defects in pigs](https://pmc.ncbi.nlm.nih.gov/articles/PMC9635828/) (2022) + +<https://pmc.ncbi.nlm.nih.gov/articles/PMC8610031/> "have previously developed tissue engineered nerve grafts (TENGs) through the process of axon stretch growth. TENGs consist of living, centimeter-scale, aligned axon tracts that accelerate axon regeneration at rates equivalent to the gold standard autograft in small and large animal models of PNI, by providing a newfound mechanism-of-action referred to as axon-facilitated axon regeneration (AFAR). To enable clinical-grade biomanufacturing of TENGs, a suitable cell source that is hypoimmunogenic, exhibits low batch-to-batch variability, and able to tolerate axon stretch growth must be utilized. To fulfill these requirements, a genetically engineered, FDA-approved, xenogeneic cell source, GalSafe® neurons, produced by Revivicor, Inc., have been selected to advance TENG biofabrication for eventual clinical use." + + +See [[neurosurgery]], [[organoids]] + + diff --git a/neurosurgery.mdwn b/neurosurgery.mdwn new file mode 100644 index 0000000..27e1da9 --- /dev/null +++ b/neurosurgery.mdwn @@ -0,0 +1,14 @@ +[Targeted muscle reinnervation for real-time myoelectric control of multifunction artificial arms](https://pmc.ncbi.nlm.nih.gov/articles/PMC3036162/) + +[Proof of concept for multiple nerve transfers to a single target muscle](https://pmc.ncbi.nlm.nih.gov/articles/PMC8530510/) + + +they put humpty dumpty back together wrong <https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2017.00072/full> "A 15-year-old boy, with traumatic avulsio n of nerve roots C5–C7 and a non-rupture of C8–T1, was operated 3 weeks after the injury with nerve transfers: (a) terminal part of the accessory nerve to the suprascapular nerve, (b) the second and third intercostal nerves to the axillary nerve, and (c) the fourth to sixth intercostal nerves to the musculocutaneous nerve. A second operation—free contralateral gracilis muscle transfer directly innervated by the phrenic nerve—was done after 2 years due to insufficient recovery of the biceps muscle function. One year later, electromyography showed activation of the biceps muscle essentially with coughing through the intercostal nerves, and of the transferred gracilis muscle by deep breathing through the phrenic nerve." + + +Development of short [[sleep]]er phenotype after [[brain]] surgery: [Development of a short sleeper phenotype after third ventriculostomy in a patient with ependymal cysts](https://pmc.ncbi.nlm.nih.gov/articles/PMC3899325/) + +[Rules of motor innervation in chick embryos with supernumerary limbs](https://pubmed.ncbi.nlm.nih.gov/7298909/) (1981) + +see [[nerve graft]] + diff --git a/reservoir_computing.mdwn b/reservoir_computing.mdwn index 8780a60..a5f8ca9 100644 --- a/reservoir_computing.mdwn +++ b/reservoir_computing.mdwn @@ -46,8 +46,9 @@ It could be helpful to use the concepts of physical [[reservoir computing]] when ``` -from the IRC logs: +from the IRC logs: "Natural systems possess rich nonlinear dynamics that can be harnessed for unconventional computing. Here, we report the discovery that a common potato (Solanum tuberosum) can serve as an effective physical reservoir computer, leveraging its electrochemical properties for complex data processing tasks. By introducing time-varying electrical stimuli via electrodes, we exploit the potato's internal ionic interactions and heterogeneous tissue structure to perform computational tasks, including spoken digit classification and gesture recognition. Our experiments demonstrate that this biological substrate exhibits dynamic responses comparable to traditional reservoir computing systems, achieving high accuracy in these tasks. This bio-based computing approach expands the range of material substrates suitable for physical computing, leveraging the intrinsic properties of biological materials for advanced information processing." + + +See also [[organoids]] + -``` -15:59 < kanzure> "Natural systems possess rich nonlinear dynamics that can be harnessed for unconventional computing. Here, we report the discovery that a common potato (Solanum tuberosum) can serve as an effective physical reservoir computer, leveraging its electrochemical properties for complex data processing tasks. By introducing time-varying electrical stimuli via electrodes, we exploit the potato's internal ionic interactions and heterogeneous tissue structure to perform computational tasks, including spoken digit classification and gesture recognition. Our experiments demonstrate that this biological substrate exhibits dynamic responses comparable to traditional reservoir computing systems, achieving high accuracy in these tasks. This bio-based computing approach expands the range of material substrates suitable for physical computing, leveraging the intrinsic properties of biological materials for advanced information processing." -``` diff --git a/sleep.mdwn b/sleep.mdwn new file mode 100644 index 0000000..31ac11b --- /dev/null +++ b/sleep.mdwn @@ -0,0 +1,17 @@ +# Sleep + +[Optochemical control of slow-wave sleep in the nucleus accumbens of male mice by a photoactivatable allosteric modulator of adenosine A2A receptors](https://www.nature.com/articles/s41467-024-47964-4) + +[Inactivation of the DREAM complex mimics the molecular benefits of sleep](https://www.biorxiv.org/content/10.1101/2024.06.26.600859v2) + +[Resisting sleep deprivation by breaking the link between sleep and circadian rhythms](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4173912/) + +[Mitochondrial origins of the pressure to sleep](https://www.nature.com/articles/s41586-025-09261-y) (see also [[mitochondria]]) + +the identified genetics of "short sleep" humans may not be accurate: <https://forum.effectivealtruism.org/posts/nSwaDrHunt3ohh9Et/cause-area-short-sleeper-genes?commentId=GCQf5qjG4LyEdEJov> + +Development of short sleeper phenotype after brain surgery: [Development of a short sleeper phenotype after third ventriculostomy in a patient with ependymal cysts](https://pmc.ncbi.nlm.nih.gov/articles/PMC3899325/) + + +See also [[brain]], [[genetic-modifications]] for more genetic interventions for sleep or anti-sleep. + diff --git a/volitional_control.mdwn b/volitional_control.mdwn new file mode 100644 index 0000000..c6f2c10 --- /dev/null +++ b/volitional_control.mdwn @@ -0,0 +1,6 @@ + +* [The control and training of single motor units in isometric tasks are constrained by a common input signal](https://elifesciences.org/articles/72871) +* [The volitional control of individual motor units is constrained within low-dimensional neural manifolds by common inputs](https://www.jneurosci.org/content/44/34/e0702242024.abstract) + + + |