iOPs: A New Tool for Studying Myelin Pathologies?

Generating patient-specific oligodendrocyte progenitors capable of repairing myelination defects observed in multiple neurological afflictions holds great therapeutic potential. Recently in Nature Biotechnology, Najm et al. (2013) and Yang et al. (2013) generated these progenitors by direct reprogramming, bringing us closer to their use in disease analysis and autologous transplantation strategies

Transplanted astrocytes derived from BMP- or CNTF-treated glial-restricted precursors have opposite effects on recovery and allodynia after spinal cord injury

<p>Abstract</p> <p>Background</p> <p>Two critical challenges in developing cell-transplantation therapies for injured or diseased tissues are to identify optimal cells and harmful side effects. This is of particular concern in the case of spinal cord injury, where recent studies have shown that transplanted neuroepithelial stem cells can generate pain syndromes.</p> <p>Results</p> <p>We have previously shown that astrocytes derived from glial-restricted precursor cells (GRPs) treated with bone morphogenetic protein-4 (BMP-4) can promote robust axon regeneration and functional recovery when transplanted into rat spinal cord injuries. In contrast, we now show that transplantation of GRP-derived astrocytes (GDAs) generated by exposure to the gp130 agonist ciliary neurotrophic factor (GDAs^CNTF), the other major signaling pathway involved in astrogenesis, results in failure of axon regeneration and functional recovery. Moreover, transplantation of GDA^CNTFcells promoted the onset of mechanical allodynia and thermal hyperalgesia at 2 weeks after injury, an effect that persisted through 5 weeks post-injury. Delayed onset of similar neuropathic pain was also caused by transplantation of undifferentiated GRPs. In contrast, rats transplanted with GDAs^BMP did not exhibit pain syndromes.</p> <p>Conclusion</p> <p>Our results show that not all astrocytes derived from embryonic precursors are equally beneficial for spinal cord repair and they provide the first identification of a differentiated neural cell type that can cause pain syndromes on transplantation into the damaged spinal cord, emphasizing the importance of evaluating the capacity of candidate cells to cause allodynia before initiating clinical trials. They also confirm the particular promise of GDAs treated with bone morphogenetic protein for spinal cord injury repair.</p

Improving International Climate Policy via Mutually Conditional Binding Commitments

This paper proposes enhancements to the RICE-N simulation and multi-agent reinforcement learning framework to improve the realism of international climate policy negotiations. Acknowledging the framework's value, we highlight the necessity of significant enhancements to address the diverse array of factors in modeling climate negotiations. Building upon our previous work on the "Conditional Commitments Mechanism" (CCF mechanism) we discuss ways to bridge the gap between simulation and reality. We suggest the inclusion of a recommender or planner agent to enhance coordination, address the Real2Sim gap by incorporating social factors and non-party stakeholder sub-agents, and propose enhancements to the underlying Reinforcement Learning solution algorithm. These proposed improvements aim to advance the evaluation and formulation of negotiation protocols for more effective international climate policy decision-making in Rice-N. However, further experimentation and testing are required to determine the implications and effectiveness of these suggestions.Comment: Presented at AI For Global Climate Cooperation Competition, 2023 (arXiv:cs/2307.06951

Improving International Climate Policy via Mutually Conditional Binding Commitments

The Paris Agreement, considered a significant milestone in climate negotiations, has faced challenges in effectively addressing climate change due to the unconditional nature of most Nationally Determined Contributions (NDCs). This has resulted in a prevalence of free-riding behavior among major polluters and a lack of concrete conditionality in NDCs. To address this issue, we propose the implementation of a decentralized, bottom-up approach called the Conditional Commitment Mechanism. This mechanism, inspired by the National Popular Vote Interstate Compact, offers flexibility and incentives for early adopters, aiming to formalize conditional cooperation in international climate policy. In this paper, we provide an overview of the mechanism, its performance in the AI4ClimateCooperation challenge, and discuss potential real-world implementation aspects. Prior knowledge of the climate mitigation collective action problem, basic economic principles, and game theory concepts are assumed.Comment: Presented at AI For Global Climate Cooperation Competition, 2023 (arXiv:cs/2307.06951

LIM-kinase1 Hemizygosity Implicated in Impaired Visuospatial Constructive Cognition

AbstractTo identify genes important for human cognitive development, we studied Williams syndrome (WS), a developmental disorder that includes poor visuospatial constructive cognition. Here we describe two families with a partial WS phenotype; affected members have the specific WS cognitive profile and vascular disease, but lack other WS features. Submicroscopic chromosome 7q11.23 deletions cosegregate with this phenotype in both families. DNA sequence analyses of the region affected by the smallest deletion (83.6 kb) revealed two genes, elastin (ELN ) and LIM-kinase1 (LIMK1). The latter encodes a novel protein kinase with LIM domains and is strongly expressed in the brain. Because ELN mutations cause vascular disease but not cognitive abnormalities, these data implicate LIMK1 hemizygosity in impaired visuospatial constructive cognition

The Tripotential Glial-Restricted Precursor (GRP) Cell and Glial Development in the Spinal Cord: Generation of Bipotential Oligodendrocyte-Type-2 Astrocyte Progenitor Cells and Dorsal–Ventral Differences in GRP Cell Function

We have found that the tripotential glial-restricted precursor (GRP) cell of the embryonic rat spinal cord can give rise in vitro to bipotential cells that express defining characteristics of oligodendrocyte-type-2 astrocyte progenitor cells (O2A/OPCs). Generation of O2A/OPCs is regulated by environmental signals and is promoted by platelet-derived growth factor (PDGF), thyroid hormone (TH) and astrocyte-conditioned medium. In contrast to multiple observations indicating that oligodendrocyte precursor cells in the embryonic day 14 (E14) spinal cord are ventrally restricted, GRP cells are already present in both the dorsal and ventral spinal cord at E13.5. Ventral-derived GRP cells, however, were more likely to generate O2A/OPCs and/or oligodendrocytes than were their dorsal counterparts when exposed to TH, PDGF, or even bone morphogenetic protein-4. The simplest explanation of our results is that oligodendrocyte generation occurs as a result of generation of GRP cells from totipotent neuroepithelial stem cells, of O2A/OPCs from GRP cells and, finally, of oligodendrocytes from O2A/OPCs. In this respect, the responsiveness of GRP cells to modulators of this process may represent a central control point in the initiation of this critical developmental sequence. Our findings provide an integration between the earliest known glial precursors and the well-studied O2A/OPCs while opening up new questions concerning the intricate spatial and temporal regulation of precursor cell differentiation in the CNS

Expression of the Human Herpesvirus 6A Latency-Associated Transcript U94A Disrupts Human Oligodendrocyte Progenitor Migration

Progression of demyelinating diseases is caused by an imbalance of two opposing processes: persistent destruction of myelin and myelin repair by differentiating oligodendrocyte progenitor cells (OPCs). Repair that cannot keep pace with destruction results in progressive loss of myelin. Viral infections have long been suspected to be involved in these processes but their specific role remains elusive. Here we describe a novel mechanism by which HHV-6A, a member of the human herpesvirus family, may contribute to inadequate myelin repair after injury

Lysosomal Re-acidification Prevents Lysosphingolipid-Induced Lysosomal Impairment and Cellular Toxicity

<div><p>Neurodegenerative lysosomal storage disorders (LSDs) are severe and untreatable, and mechanisms underlying cellular dysfunction are poorly understood. We found that toxic lipids relevant to three different LSDs disrupt multiple lysosomal and other cellular functions. Unbiased drug discovery revealed several structurally distinct protective compounds, approved for other uses, that prevent lysosomal and cellular toxicities of these lipids. Toxic lipids and protective agents show unexpected convergence on control of lysosomal pH and re-acidification as a critical component of toxicity and protection. In <i>twitcher</i> mice (a model of Krabbe disease [KD]), a central nervous system (CNS)-penetrant protective agent rescued myelin and oligodendrocyte (OL) progenitors, improved motor behavior, and extended lifespan. Our studies reveal shared principles relevant to several LSDs, in which diverse cellular and biochemical disruptions appear to be secondary to disruption of lysosomal pH regulation by specific lipids. These studies also provide novel protective strategies that confer therapeutic benefits in a mouse model of a severe LSD.</p></div

NKH-477, a protective compound identified in vitro, protects against multiple toxicities in treated <i>twitcher</i> mice.

<p>(<b>A–C)</b> Quantification of <b>(A)</b> fluoromyelin intensity, <b>(B)</b> number of GSTpi+/Olig2+ OLs, and <b>(C)</b> the relative number of dividing Ki67+/Olig2+ O-2A/OPCs in the corpus callosa of P40 <i>twitcher</i> mice and age-matched WT littermates (<i>n</i> = 3 from different litters). <b>(D)</b> Analysis of clonal composition of P15 <i>twi</i> O-2A/OPCs and WT littermates across 5d. <b>(E)</b> Quantification of the relative number of dividing Ki67+/Olig2+ O-2A/OPCs in the corpus callosa of P15 <i>twitcher</i> mice and age-matched WT littermates (<i>n</i> = 3 from different litters). <b>(F)</b> Quantification of lysosomal pH of O-2A/OPCs acutely isolated from P17 <i>twitcher</i> and WT mice. <b>(G)</b> Overview of treatment paradigm and clinical course for <i>twitcher</i> mice. <b>(H)</b> Quantification of lysosomal pH of O-2A/OPCs isolated from P35 treated mice. <b>(I)</b> Quantification of the number of dividing callosal O-2A/OPCs in P35 treated mice. <b>(J–L)</b> Representative confocal images of fluoromyelin-stained corpus callosa of the indicated treatment groups at P40, in addition to quantification of staining intensity and the number of OLs. <b>(M)</b> Kaplan–Meyer survival curve for treated and untreated <i>twi</i> mice. Median survival of <i>twi</i> mice, with dotted lines indicating reported median survival of single-therapy treatments [<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002583#pbio.1002583.ref015" target="_blank">15</a>]. <b>(N–Q)</b> Quantification of travel speed, stance time, beam traverse time, and relative weights for P25 saline-treated WT and <i>twi</i>, as well as NKH-477–treated <i>twi</i>, mice. <b>(R)</b> Quantification of brain Psy levels at P35. Data for all graphs displayed as mean ± SEM; <i>ns</i> = not significant; *<i>p</i> < 0.05, ^†<i>p</i> < 0.001 versus WT; ^b<i>p</i> < 0.01 versus vehicle-treated <i>twi</i>. Data presented in this figure can be found in <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002583#pbio.1002583.s001" target="_blank">S1 Data</a>.</p