Presbyterian Imitation Practices in Zachary Boyd’s Nebuchadnezzars Fierie Furnace

The university administrator, preacher and poet Zachary Boyd (1585–1653) relied heavily on epithets and similes borrowed from Josuah Sylvester's poetry when composing his scriptural versifications Zion's Flowers(c. 1640?). The composition of Boyd's adaptation of Daniel 3, Nebuchadnezzars Fierie Furnace, provides an unusually lucid example of the reading and imitation practices of a mid-seventeenth-century Scottish Presbyterian in the years preceding civil war. This article begins by re-considering a manuscript transcription of Fierie Furnace held at the British Library previously described as an anonymous playtext from the early 1610s, then establishes the nature of Boyd's reliance on Sylvester by analyzing holograph manuscripts held at Glasgow University Library, a sermon Boyd wrote on the same theme, and the copy of Sylvester's Devine Weekes, and Workes that Boyd probably used.Arts and Humanities Research Counci

Comprehensive miRNome-wide profiling in a neuronal cell model of synucleinopathy implies involvement of cell cycle genes

Growing evidence suggests that epigenetic mechanisms like microRNA-mediated transcriptional regulation contribute to the pathogenesis of parkinsonism. In order to study the influence of microRNAs (miRNAs), we analyzed the miRNome 2 days prior to major cell death in α-synuclein-overexpressing Lund human mesencephalic neurons, a well-established cell model of Parkinson\u27s disease (PD), by next-generation sequencing. The expression levels of 23 miRNAs were significantly altered in α-synuclein-overexpressing cells, 11 were down- and 12 upregulated

K-variant BCHE and pesticide exposure: Gene-environment interactions in a case-control study of Parkinson's disease in Egypt

Pesticide exposure is associated with increased risk of Parkinson's disease (PD). We investigated in Egypt whether common variants in genes involved in pesticide detoxification or transport might modify the risk of PD evoked by pesticide exposure. We recruited 416 PD patients and 445 controls. Information on environmental factors was collected by questionnaire-based structured interviews. Candidate single-nucleotide polymorphisms (SNPs) in 15 pesticide-related genes were genotyped. We analyzed the influence of environmental factors and SNPs as well as the interaction of pesticide exposure and SNPs on the risk of PD. The risk of PD was reduced by coffee consumption [OR = 0.63, 95% CI: 0.43-0.90, P = 0.013] and increased by pesticide exposure [OR = 7.09, 95% CI: 1.12-44.01, P = 0.036]. The SNP rs1126680 in the butyrylcholinesterase gene BCHE reduced the risk of PD irrespective of pesticide exposure [OR = 0.38, 95% CI: 0.20-0.70, P = 0.002]. The SNP rs1803274, defining K-variant BCHE, interacted significantly with pesticide exposure (P = 0.007) and increased the risk of PD only in pesticide-exposed individuals [OR = 2.49, 95% CI: 1.50-4.19, P = 0.0005]. The K-variant BCHE reduces serum activity of butyrylcholinesterase, a known bioscavenger for pesticides. Individuals with K-variant BCHE appear to have an increased risk for PD when exposed to pesticides

Development of a cell-free screening assay for the identification of direct PERK activators.

The activation of the unfolded protein response, particularly via the PERK pathway, has been suggested as a promising therapeutic approach in tauopathies, a group of neurodegenerative disorders characterized by the abnormal phosphorylation and aggregation of tau protein. So far, a shortage of available direct PERK activators has been limiting the progresses in this field. Our study aimed at the development of a cell-free screening assay enabling the detection of novel direct PERK activators. By applying the catalytic domain of recombinant human PERK, we initially determined ideal conditions of the kinase assay reaction, including parameters such as optimal kinase concentration, temperature, and reaction time. Instead of using PERK's natural substrate proteins, eIF2α and NRF2, we applied SMAD3 as phosphorylation-accepting protein and successfully detected cell-free PERK activation and inhibition by selected modulators (e.g., calcineurin-B, GSK2606414). The developed assay revealed to be sufficiently stable and robust to assess an activating EC50-value. Additionally, our results suggested that PERK activation may take place independent of the active site which can be blocked by a kinase inhibitor. Finally, we confirmed the applicability of the assay by measuring PERK activation by MK-28, a recently described PERK activator. Overall, our data show that a cell-free luciferase-based assay with the recombinant human PERK kinase domain and SMAD3 as substrate protein is capable of detecting PERK activation, which enables to screen large compound libraries for direct PERK activators, in a high-throughput-based approach. These activators will be useful for deepening our understanding of the PERK signaling pathway, and may also lead to the identification of new therapeutic drug candidates for neurodegenerative tauopathies

Atypical pantothenate kinase-associated neurodegeneration with variable phenotypes in an Egyptian family

Pantothenate kinase-associated neurodegeneration (PKAN) is a rare hereditary neurodegenerative disease characterized by an accumulation of iron within the brain. In the present report, we describe a family with 4 affected siblings presenting with variable clinical manifestations, e.g., parkinsonian features, dystonia and slow disease progression over 5 years. Exome sequencing revealed a causative variant in the pantothenate kinase 2 gene (). Variant NM_024960.6:c.710C \u3e T was homozygous in all affected subjects. Our report describes the first genetically confirmed cases of PKAN in the Egyptian population. Studying genetics of neurodegenerative diseases in different ethnicities is very important for determining clinical phenotypes and understanding pathomechanisms of these diseases

Diesterified Derivatives of 5-Iodo-2′-Deoxyuridine as Cerebral Tumor Tracers

With the aim to develop beneficial tracers for cerebral tumors, we tested two novel 5-iodo-2′-deoxyuridine (IUdR) derivatives, diesterified at the deoxyribose residue. The substances were designed to enhance the uptake into brain tumor tissue and to prolong the availability in the organism. We synthesized carrier added 5-[125I]iodo-3′,5′-di-O-acetyl-2′-deoxyuridine (Ac2[125I]IUdR), 5-[125I]iodo-3′,5′-di-O-pivaloyl-2′-deoxyuridine (Piv2[125I]IUdR) and their respective precursor molecules for the first time. HPLC was used for purification and to determine the specific activities. The iodonucleoside tracer were tested for their stability against human thymidine phosphorylase. DNA integration of each tracer was determined in 2 glioma cell lines (Gl261, CRL2397) and in PC12 cells in vitro. In mice, we measured the relative biodistribution and the tracer uptake in grafted brain tumors. Ac2[125I]IUdR, Piv2[125I]IUdR and [125I]IUdR (control) were prepared with labeling yields of 31–47% and radiochemical purities of >99% (HPLC). Both diesterified iodonucleoside tracers showed a nearly 100% resistance against degradation by thymidine phosphorylase. Ac2[125I]IUdR and Piv2[125I]IUdR were specifically integrated into the DNA of all tested tumor cell lines but to a less extend than the control [125I]IUdR. In mice, 24 h after i.p. injection, brain radioactivity uptakes were in the following order Piv2[125I]IUdR>Ac2[125I]IUdR>[125I]IUdR. For Ac2[125I]IUdR we detected lower amounts of radioactivities in the thyroid and stomach, suggesting a higher stability toward deiodination. In mice bearing unilateral graft-induced brain tumors, the uptake ratios of tumor-bearing to healthy hemisphere were 51, 68 and 6 for [125I]IUdR, Ac2[125I]IUdR and Piv2[125I]IUdR, respectively. Esterifications of both deoxyribosyl hydroxyl groups of the tumor tracer IUdR lead to advantageous properties regarding uptake into brain tumor tissue and metabolic stability

Evidence for pathogenicity of variant ATM Val1729Leu in a family with ataxia telangiectasia

Ataxia telangiectasia is a rare autosomal recessive multisystem disorder caused by mutations in the gene of ATM serine/threonine kinase. It is characterized by neurodegeneration, leading to severe ataxia, immunodeficiency, increased cancer susceptibility, and telangiectasia. Here, we discovered a co-segregation of two ATM gene variants with ataxia telangiectasia in an Egyptian family. While one of these variants (NM_000051.4(ATM_i001):p.(Val128*)) has previously been reported as pathogenic, the other one (NM_000051.4(ATM_i001):p.(Val1729Leu)) is regarded as a variant of uncertain significance. Our findings in this family provide additional evidence for causality of the second variant and argue that its status should be changed to pathogenic

PERK activation mitigates tau pathology in vitro and in vivo

Abstract The RNA‐like endoplasmic reticulum kinase (PERK) is genetically associated with the tauopathy progressive supranuclear palsy (PSP). To elucidate the functional mechanisms underlying this association, we explored PERK activity in brains of PSP patients and its function in three tauopathy models (cultured human neurons overexpressing 4‐repeat wild‐type tau or treated with the environmental neurotoxin annonacin, and P301S tau transgenic mice). In vitro, treatment with a pharmacological PERK activator CCT020312 or PERK overexpression reduced tau phosphorylation, tau conformational change and 4‐repeat tau isoforms, and increased cell viability. In vivo, the PERK activator significantly improved memory and locomotor function, reduced tau pathology, and prevented dendritic spine and motoneuron loss in P301S tau mice. Importantly, the PERK substrate EIF2A, mediating some detrimental effects of PERK signaling, was downregulated in PSP brains and tauopathy models, suggesting that the alternative PERK–NRF2 pathway accounts for these beneficial effects in the context of tauopathies. In summary, PERK activation may be a novel strategy to treat PSP and eventually other tauopathies