Highlights d Chromatin serine-linked MARylation is constantly produced throughout the cell cycle d ADP-ribosylation reactions consist of distinct initiation and elongation steps d PARG and ARH3 suppression is synthetically lethal because of accumulation of PARylation d ARH3 deficiency increases PARPi resistance that can be exploited therapeutically

Background: Neonatal encephalopathy caused by hypoxia-ischemia (HI) is a major cause of childhood mortality and disability. Stem cell-based regenerative therapies seem promising to prevent long-term neurological deficits. Our previous work in neonatal HI revealed an unexpected interaction between mesenchymal stem/stromal cells (MSCs) and the brains' microenvironment leading to an altered therapeutic efficiency. MSCs are supposed to mediate most of their therapeutic effects in a paracrine mode via extracellular vesicles (EVs), which might be an alternative to cell therapy. In the present study, we investigated the impact of MSC-EVs on neonatal HI-induced brain injury.Methods: Nine-day-old C57BL/6 mice were exposed to HI through ligation of the right common carotid artery followed by 1 h hypoxia (10% oxygen). MSC-EVs were injected intraperitoneally 1, 3, and 5 days after HI. One week after HI, brain injury was evaluated by regional neuropathological scoring, atrophy measurements and immunohistochemistry to assess effects on neuronal, oligodendrocyte and vessel densities, proliferation, oligodendrocyte maturation, myelination, astro-, and microglia activation. Immunohistochemistry analyses were complemented by mRNA expression analyses for a broad set of M1/M2- and A1/A2-associated molecules and neural growth factors.Results: While total neuropathological scores and tissue atrophy were not changed, MSC-EVs significantly protected from HI-induced striatal tissue loss and decreased micro- and astroglia activation. MSC-EVs lead to a significant downregulation of the pro-inflammatory cytokine TNFa, accompanied by a significant upregulation of the M2 marker YM-1 and the anti-inflammatory cytokine TGFb. MSC-EVs significantly decreased astrocytic expression of the A1 marker C3, concomitant with an increased expression of neural growth factors (i.e., BDNF, VEGF, and EGF). These alterations were associated with an increased neuronal and vessel density, coinciding with a significant increase of proliferating cells in the neurogenic sub-ventricular zone juxtaposed to the striatum. MSC-EV-mediated neuroprotection went along with a significant improvement of oligodendrocyte maturation and myelination.Conclusion: The present study demonstrates that MSC-EVs mediate anti-inflammatory effects, promote regenerative responses and improve key developmental processes in the injured neonatal brain. The present results suggest different cellular target mechanisms of MSC-EVs, preventing secondary HI-induced brain injury. MSC-EV treatment may be a promising alternative to risk-associated cell therapies in neonatal brain injury.

The synthesis of poly(ADP-ribose) (PAR) reconfigures the local chromatin environment and recruits DNA-repair complexes to damaged chromatin. PAR degradation by poly(ADP-ribose) glycohydrolase (PARG) is essential for progression and completion of DNA repair. Here, we show that inhibition of PARG disrupts homology-directed repair (HDR) mechanisms that underpin alternative lengthening of telomeres (ALT). Proteomic analyses uncover a new role for poly(ADPribosyl)ation (PARylation) in regulating the chromatin-assembly factor HIRA in ALT cancer cells. We show that HIRA is enriched at telomeres during the G2 phase and is required for histone H3.3 deposition and telomere DNA synthesis. Depletion of HIRA elicits systemic death of ALT cancer cells that is mitigated by re-expression of ATRX, a protein that is frequently inactivated in ALT tumors. We propose that PARylation enables HIRA to fulfill its essential role in the adaptive response to ATRX deficiency that pervades ALT cancers.

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Male chickens grow faster than female chickens, which may be due to greater nutrient uptake. The transport of nutrients from the intestine to the blood is mediated by transporters located on the surface of epithelial cells lining the villi. The objective of this study was to profile the mRNA expression of an aminopeptidase and selected amino acid and monosaccharide transporters in the duodenum, jejunum, and ileum of male and female chickens at d of hatch (doh) and at d 7 and d 14 post hatch. The mRNA abundance of aminopeptidase N (APN), a peptide (PepT1), 6 amino acid transporters (ASCT1, bo,+AT, CAT1, EAAT3, LAT1, and y+LAT2), and 3 monosaccharide (GLUT2, GLUT5, and SGLT1) transporters was assayed by real-time PCR. Data were analyzed by ANOVA using JMP Pro11. The abundance of bo,+AT, EAAT3, ASCT1, y+LAT2, and GLUT2 mRNA was greater in male than female chickens (P < 0.05). There was no difference in expression between males and females for the other 5 transporters and APN. There was a sex x age interaction for bo,+AT, PepT1, SGLT1, ASCT1, and y+LAT2 mRNA, with greater mRNA abundance in males than females at doh but no difference between males and females at d 7 and d 14. A 3-way sex x age x tissue interaction was observed for GLUT2 mRNA. There was greater GLUT2 mRNA abundance for males in the duodenum and ileum at doh and in the jejunum at d 7, but no difference between males and females at d 14. Thus, there was differential expression of some nutrient transporters in male and female chicks at doh but not at later ages.

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