Prim-pol is a recently identified DNA primase-polymerase belonging to the archaeao-eukaryotic primase (AEP) superfamily. Here, we characterize a previously unrecognized prim-pol in human cells, which we designate hPrimpol1 (human primasepolymerase 1). hPrimpol1 possesses primase and DNA polymerase activities in vitro, interacts directly with RPA1 and is recruited to sites of DNA damage and stalled replication forks in an RPA1-dependent manner. Cells depleted of hPrimpol1 display increased spontaneous DNA damage and defects in the restart of stalled replication forks. Both RPA1 binding and the primase activity of hPrimpol1 are required for its cellular function during DNA replication. Our results indicate that hPrimpol1 is a novel factor involved in the response to DNA replication stress.
Demyelinating diseases, such as multiple sclerosis, are known to result from acute or chronic injury to the myelin sheath and inadequate remyelination; however, the underlying molecular mechanisms remain unclear. Here, we performed genome occupancy analysis by chromatin immunoprecipitation sequencing in oligodendrocytes in response to lysolecithin-induced injury and found that Olig2 and its downstream target Gpr17 are critical factors in regulating oligodendrocyte survival. After injury to oligodendrocytes, Olig2 was significantly upregulated and transcriptionally targeted the Gpr17 locus. Gpr17 activation inhibited oligodendrocyte survival by reducing the intracellular cAMP level and inducing expression of the pro-apoptotic gene Xaf1. The protein kinase A signaling pathway and the transcription factor c-Fos mediated the regulatory effects of Gpr17 in oligodendrocytes. We showed that Gpr17 inhibition elevated Epac1 expression and promoted oligodendrocyte differentiation. The loss of Gpr17, either globally or specifically in oligodendrocytes, led to an earlier onset of remyelination after myelin injury in mice. Similarly, pharmacological inhibition of Gpr17 with pranlukast promoted remyelination. Our findings indicate that Gpr17, an Olig2 transcriptional target, is activated after injury to oligodendrocytes and that targeted inhibition of Gpr17 promotes oligodendrocyte remyelination.
Summary Apoptosis plays critical role in diabetic cardiomyopathy and endoplasmic reticulum stress (ERS) is one of intrinsic apoptosis pathways. For previous studies have shown that endoplasmic reticulum become swell in diabetic myocardium and ERS was involved in diabetes mellitus and heart failure, this study aimed to demonstrate whether ERS was induced in myocardium of streptozocin (STZ)-induced diabetic rats. We established type 1 diabetic rat model with STZ intraperitoneal injection, used echocardiographic evaluation, hematoxylineosin staining and the terminal deoxynucleotidyl transferase-mediated DNA nick-end labeling staining to identify the existence of diabetic cardiomyopathy and enhanced apoptosis in the diabetic heart. We performed immunohistochemistry, Western blot and real time PCR to analysis two hallmarks of ERS, glucose regulated protein78 (Grp78) and Caspase12. We found both Grp78 and Caspase12 had enhanced expression in protein and mRNA levels in diabetic myocardium than normal rat's, and Caspase12 was activated in diabetic heart. Those results suggested that ERS was induced in STZ-induced diabetic rats' myocardium, and ERS-associated apoptosis took part in the pathophysiology of diabetic cardiomyopathy.
SUMMARY
The CNS plays a pivotal role in energy homeostasis, but whether oligodendrocytes are involved has been largely unexplored. Here, we show that signaling through GPR17, a G-protein-coupled receptor predominantly expressed in the oligodendrocyte lineage, regulates food intake by modulating hypothalamic neuronal activities.
GPR17
-null mice and mice with an oligodendrocyte-specific knockout of
GPR17
have lean phenotypes on a high-fat diet, suggesting that GPR17 regulates body weight by way of oligodendrocytes. Downregulation of GPR17 results in activation of cAMP-protein kinase A (PKA) signaling in oligodendrocytes and upregulated expression of pyruvate dehydrogenase kinase 1 (PDK1), which promotes lactate production. Elevation of lactate activates AKT and STAT3 signaling in the hypothalamic neurons, leading to increased expression of
Pomc
and suppression of
Agrp
. Our findings uncover a critical role of oligodendrocytes in metabolic homeostasis, where GPR17 modulates the production of lactate, which, in turn, acts as a metabolic signal to regulate neuronal activity.
This study differentiates the risk perception and influencing factors of climate change along the dimensions of global severity and personal threat. Using the 2013 Taiwan Social Change Survey (TSGS) data (N = 2001) as a representative sample of adults from Taiwan, we investigated the influencing factors of the risk perceptions of climate change in these two dimensions (global severity and personal threat). Logistic regression models were used to examine the correlations of individual factors (gender, age, education, climate-related disaster experience and risk awareness, marital status, employment status, household income, and perceived social status) and societal factors (religion, organizational embeddedness, and political affiliations) with the above two dimensions. The results demonstrate that climate-related disaster experience has no significant impact on either the perception of global severity or the perception of personal impact. However, climate-related risk awareness (regarding typhoons, in particular) is positively associated with both dimensions of the perceived risks of climate change. With higher education, individuals are more concerned about global severity than personal threat. Regarding societal factors, the supporters of political parties have higher risk perceptions of climate change than people who have no party affiliation. Religious believers have higher risk perceptions of personal threat than non-religious people. This paper ends with a discussion about the effectiveness of efforts to enhance risk perception of climate change with regard to global severity and personal threat.
ObjectiveTo evaluate the safety and efficacy of dexmedetomidine (Dex) to prevent emergence agitation (EA) and delirium (ED) in children undergoing laparoscopic hernia repair under general anesthesia.Methods100 children (1–5 years, 10–25 kg) were randomized into four groups: controls (saline) and intravenous Dex at 0.25, 0.5, and 1.0 µg/kg (D1, D2, D3, respectively). Dex/saline infusion was started following anesthesia. EA and ED were evaluated on a 5-point scale.ResultsFor the C, D1, D2, and D3 groups, respectively, EA frequencies were 45.8%, 30.4%, 12%, 4%; ED frequencies 29.1%, 13%, 4%, 4%; CHIPPS scores 8, 6, 3, 3; sevoflurane doses from 13.2 ± 3.4 (controls) to 9.4 ± 3.5 ml (D3). Intervals until mask removal/spontaneous eye opening were significantly longer for D2 and D3 than controls. PACU stay was longer for D3.ConclusionsThere was significantly less postoperative EA and pain, with less sevoflurane required, using Dex.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.