92 research outputs found

    Protestantism, colonization and the New England Company in Restoration politics

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    Established in 1662, the New England Company introduced the first crown-sponsored initiative for propagating the gospel among the native populations bordering English America. Under the leadership of Robert Boyle, its work influenced royal policy, but awakened contention over the practice of Atlantic colonization and, simultaneously, the making of the Restoration Church. This article examines the reception of the Company in England, showing how its architects sought to link the plantation process to the advancement of a global Protestant mission. The ambition drew Company leaders into debates over the reshaping of church institutions on both sides of the Atlantic. In England, the mission became a vehicle for the promotion of Protestant β€˜comprehension’, as a bid to unite the different streams of the reformed religion, and widen the fold of the established church. However, the Company was frustrated by the confessional antagonisms that entered into domestic politics. Divisions between congregations thwarted missionary collaboration, and stirred doubts in England and America over the relationship between colonization and the β€˜Protestant interest’. The article will identify the conflicts within the Restoration Church as a formative factor behind competing ideas of overseas expansion, and a substantial obstacle to the emergence of the Protestant mission as part of the colonizing strategies of the English Crown

    Proteasome Activator Enhances Survival of Huntington's Disease Neuronal Model Cells

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    In patients with Huntington's disease (HD), the proteolytic activity of the ubiquitin proteasome system (UPS) is reduced in the brain and other tissues. The pathological hallmark of HD is the intraneuronal nuclear protein aggregates of mutant huntingtin. We determined how to enhance UPS function and influence catalytic protein degradation and cell survival in HD. Proteasome activators involved in either the ubiquitinated or the non-ubiquitinated proteolysis were overexpressed in HD patients' skin fibroblasts or mutant huntingtin-expressing striatal neurons. Following compromise of the UPS, overexpression of the proteasome activator subunit PA28Ξ³, but not subunit S5a, recovered proteasome function in the HD cells. PA28Ξ³ also improved cell viability in mutant huntingtin-expressing striatal neurons exposed to pathological stressors, such as the excitotoxin quinolinic acid and the reversible proteasome inhibitor MG132. These results demonstrate the specific functional enhancements of the UPS that can provide neuroprotection in HD cells

    The DNA mismatch repair gene hMSH2 is a potent coactivator of oestrogen receptor Ξ±

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    The DNA mismatch repair gene is a key regulator in the elimination of base–base mismatches and insertion/deletion loops (IDLs). Human MutS homologue 2 (hMSH2), originally identified as a human homologue of the bacterial MutS, is a tumour suppressor gene frequently mutated in hereditary nonpolyposis colorectal cancer. Hereditary nonpolyposis colorectal cancer is characterised by the early onset of colorectal cancer and the development of extracolonic cancers such as endometrial, ovarian, and urological cancers. Oestrogen receptor (ER) Ξ± and Ξ² are members of a nuclear receptor (NR) superfamily. Ligand-dependent transcription of ER is regulated by the p160 steroid receptor coactivator family, the thyroid hormone receptor-associated proteins/the vitamin D receptor-interacting proteins (TRAP/DRIP) mediator complex, and the TATA box-binding protein (TBP)-free TBP associated factor complex (TFTC) type histone acetyltransferase complex. Here, we report the interaction between ER Ξ±/Ξ² and hMSH2. Immunoprecipitation and glutathione-S-transferase pulldown assay revealed that ER Ξ± and hMSH2 interacted in a ligand-dependent manner, whereas ER Ξ² and hMSH2 interacted in a ligand-independent manner. Oestrogen receptor Ξ±/Ξ² bound to hMSH2 through the hMSH3/hMSH6 interaction domain of hMSH2. In a transient expression assay, hMSH2 potentiated the transactivation function of liganded ER Ξ±, but not that of ER Ξ². These results suggest that hMSH2 may play an important role as a putative coactivator in ER Ξ± dependent gene expression

    Tyrosine Nitration of PA700 Links Proteasome Activation to Endothelial Dysfunction in Mouse Models with Cardiovascular Risk Factors

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    Oxidative stress is believed to cause endothelial dysfunction, an early event and a hallmark in cardiovascular diseases (CVD) including hypertension, diabetes, and dyslipidemia. However, the targets for oxidative stress-mediated endothelial dysfunction in CVD have not been completely elucidated. Here we report that 26S proteasome activation by peroxynitrite (ONOOβˆ’) is a common pathway for endothelial dysfunction in mouse models of diabetes, hypertension, and dyslipidemia. Endothelial function, assayed by acetylcholine-induced vasorelaxation, was impaired in parallel with significantly increased 26S proteasome activity in aortic homogenates from streptozotocin (STZ)-induced type I diabetic mice, angiotensin-infused hypertensive mice, and high fat-diets -fed LDL receptor knockout (LDLrβˆ’/βˆ’) mice. The elevated 26S proteasome activities were accompanied by ONOOβˆ’-mediated PA700/S10B nitration and increased 26S proteasome assembly and caused accelerated degradation of molecules (such as GTPCH I and thioredoxin) essential to endothelial homeostasis. Pharmacological (administration of MG132) or genetic inhibition (siRNA knockdown of PA700/S10B) of the 26S proteasome blocked the degradation of the vascular protective molecules and ablated endothelial dysfunction induced by diabetes, hypertension, and western diet feeding. Taken together, these results suggest that 26S proteasome activation by ONOOβˆ’-induced PA700/S10B tyrosine nitration is a common route for endothelial dysfunction seen in mouse models of hypertension, diabetes, and dyslipidemia
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