Role of Hypoxic OPC in Angiogenesis

Background－Oligodendrocyte precursor cells (OPCs) regulate neuronal, glial, and vascular systems in diverse ways and display phenotypic heterogeneity beyond their established role as a reservoir for mature oligodendrocytes. However, the detailed phenotypic changes of OPCs after cerebral ischemia remain largely unknown. Here, we aimed to investigate the roles of reactive OPCs in the ischemic brain. Methods and Results－The behavior of OPCs was evaluated in a mouse model of ischemic stroke produced by transient middle cerebral artery occlusion in vivo. For in vitro experiments, the phenotypic change of OPCs after oxygen glucose derivation was examined using a primary rat OPC culture. Furthermore, the therapeutic potential of hypoxic OPCs was evaluated in a mouse model of middle cerebral artery occlusion in vivo. Perivascular OPCs in the cerebral cortex were increased alongside poststroke angiogenesis in a mouse model of middle cerebral artery occlusion. In vitro RNA‐seq analysis revealed that primary cultured OPCs increased the gene expression of numerous pro‐angiogenic factors after oxygen glucose derivation. Hypoxic OPCs secreted a greater amount of pro‐angiogenic factors, such as vascular endothelial growth factor and angiopoietin‐1, compared with normoxic OPCs. Hypoxic OPC‐derived conditioned media increased the viability and tube formation of endothelial cells. In vivo studies also demonstrated that 5 consecutive daily treatments with hypoxic OPC‐conditioned media, beginning 2 days after middle cerebral artery occlusion, facilitated poststroke angiogenesis, alleviated infarct volume, and improved functional disabilities. Conclusions－Following cerebral ischemia, the phenotype of OPCs in the cerebral cortex shifts from the parenchymal subtype to the perivascular subtype, which can promote angiogenesis. The optimal use of hypoxic OPCs secretome would provide a novel therapeutic option for stroke

FAK acts as a suppressor of RTK-MAP kinase signalling in Drosophila melanogaster epithelia and human cancer cells

Receptor Tyrosine Kinases (RTKs) and Focal Adhesion Kinase (FAK) regulate multiple signalling pathways, including mitogen-activated protein (MAP) kinase pathway. FAK interacts with several RTKs but little is known about how FAK regulates their downstream signalling. Here we investigated how FAK regulates signalling resulting from the overexpression of the RTKs RET and EGFR. FAK suppressed RTKs signalling in Drosophila melanogaster epithelia by impairing MAPK pathway. This regulation was also observed in MDA-MB-231 human breast cancer cells, suggesting it is a conserved phenomenon in humans. Mechanistically, FAK reduced receptor recycling into the plasma membrane, which resulted in lower MAPK activation. Conversely, increasing the membrane pool of the receptor increased MAPK pathway signalling. FAK is widely considered as a therapeutic target in cancer biology; however, it also has tumour suppressor properties in some contexts. Therefore, the FAK-mediated negative regulation of RTK/MAPK signalling described here may have potential implications in the designing of therapy strategies for RTK-driven tumours

The Src/c-Abl pathway is a potential therapeutic target in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS), a fatal disease causing progressive loss of motor neurons, still has no effective treatment. We developed a phenotypic screen to repurpose existing drugs using ALS motor neuron survival as readout. Motor neurons were generated from induced pluripotent stem cells (iPSCs) derived from an ALS patient with a mutation in superoxide dismutase 1 (SOD1). Results of the screen showed that more than half of the hits targeted the Src/c-Abl signaling pathway. Src/c-Abl inhibitors increased survival of ALS iPSC-derived motor neurons in vitro. Knockdown of Src or c-Abl with small interfering RNAs (siRNAs) also rescued ALS motor neuron degeneration. One of the hits, bosutinib, boosted autophagy, reduced the amount of misfolded mutant SOD1 protein, and attenuated altered expression of mitochondrial genes. Bosutinib also increased survival in vitro of ALS iPSC-derived motor neurons from patients with sporadic ALS or other forms of familial ALS caused by mutations in TAR DNA binding protein (TDP-43) or repeat expansions in C9orf72. Furthermore, bosutinib treatment modestly extended survival of a mouse model of ALS with an SOD1 mutation, suggesting that Src/c-Abl may be a potentially useful target for developing new drugs to treat ALS

Pathological Endogenous α-Synuclein Accumulation in Oligodendrocyte Precursor Cells Potentially Induces Inclusions in Multiple System Atrophy.

Glial cytoplasmic inclusions (GCIs), commonly observed as α-synuclein (α-syn)-positive aggregates within oligodendrocytes, are the pathological hallmark of multiple system atrophy. The origin of α-syn in GCIs is uncertain; there is little evidence of endogenousα-syn expression in oligodendrocyte lineage cells, oligodendrocyte precursor cells (OPCs),and mature oligodendrocytes (OLGs). Here, based on in vitro analysis using primary rat cell cultures, we elucidated that preformed fibrils (PFFs) generated from recombinant human α-syn trigger multimerization and an upsurge of endogenous α-syn in OPCs, which is attributable to insufficient autophagic proteolysis. RNA-seq analysis of OPCs revealed that α-syn PFFs interfered with the expression of proteins associated with neuromodulation and myelination. Furthermore, we detected cytoplasmic α-syn inclusions in OLGs through differentiation of OPCs pre-incubated with PFFs. Overall, our findings suggest the possibility of endogenous α-syn accumulation in OPCs that contributes to GCI formation and perturbation of neuronal/glial support in multiple system atrophy brains

Electric dipole moments and the search for new physics

Static electric dipole moments of nondegenerate systems probe mass scales for physics beyond the Standard Model well beyond those reached directly at high energy colliders. Discrimination between different physics models, however, requires complementary searches in atomic-molecular-and-optical, nuclear and particle physics. In this report, we discuss the current status and prospects in the near future for a compelling suite of such experiments, along with developments needed in the encompassing theoretical framework.Comment: Contribution to Snowmass 2021; updated with community edits and endorsement

Cloning of a marsupial DNA photolyase gene and the lack of related nucleotide sequences in placental mammals.

Photoreactivating enzyme, DNA photolyase, reduces lethal, mutagenic and carcinogenic effects of ultraviolet light (UV) by catalyzing near UV or visible light-dependent repair of cyclobutane pyrimidine dimers (CPDs) in DNA. The enzyme activity has been detected in a wide variety of organisms ranging from bacteria to nonplacental mammals. However, the evidence for photoreactivation in placental mammals, including humans, is controversial. As a first step to identify the presence and activity of the gene in mammalian species, we isolated a cDNA clone of this gene from a marsupial, the South American opossum Monodelphis domestica. Photolyase activity was expressed in Escherichia coli from the cDNA which is predicted to encode a polypeptide of 470 amino acid residues. The deduced amino acid sequence of this protein is strikingly similar to those of photolyases from two metazoans; the opossum photolyase shares 59% and 63% sequence identity with the Drosophila melanogaster and goldfish Carassius auratus enzymes, respectively. However, no closely related nucleotide sequence was detected in higher mammals and a homologous transcript was undetectable in a number of human tissues. These results strongly suggest that humans, as well as other placental mammals, lack the photolyase gene