Reading the unique DNA methylation landscape of the brain: Non-CpG methylation,hydroxymethylation, and MeCP2

DNA methylation at CpG dinucleotides is an important epigenetic regulator common to virtually all mammalian cell types, but recent evidence indicates that during early postnatal development neuronal genomes also accumulate uniquely high levels of two alternative forms of methylation, non-CpG methylation and hydroxymethylation. Here we discuss the distinct landscape of DNA methylation in neurons, how it is established, and how it might affect the binding and function of protein readers of DNA methylation. We review studies of one critical reader of DNA methylation in the brain, the Rett syndrome protein methyl CpG-binding protein 2 (MeCP2), and discuss how differential binding affinity of MeCP2 for non-CpG and hydroxymethylation may affect the function of this methyl-binding protein in the nervous system.     

Genetic analysis of the yeast NUD1 endo-exonuclease: a role in the repair of DNA double-strand breaks

The deoxyribonucleases (DNases) have been shown genetically to be important in the vital processes of DNA repair and recombination. The NUD1 gene, which codes for an endo-exonuclease of Saccharomyces cerevisiae, was analyzed for its role in the DNA double-strand break (DSB) repair processes. While the nud1 strain is only slightly sensitive to ionizing radiation, expression of the HO-endonuclease to introduce a DSB at the MAT locus in that strain results in cell death. Cell survival is inversely proportional to the duration of HO-endonuclease expression. Analysis of the surviving colonies from the nud1 strain indicated that many of the survivors are sterile and that the proportion of these sterile survivors increases with the time of HO-endonuclease expression. On the other hand, the surviving colonies from the isogenic NUD1 strain are mating-proficient. Interestingly, double mutants of nud1 rad52 are more resistant to ionizing irradiation than the rad52 strain and have a cell-survival fraction of 32% for rad52-1 nud1 and 9% for rad52::URA3 nud1 following prolonged HO-endonuclease expression, indicating that nud1 has a suppressor effect on the DSB-induced lethality in rad52. Polymerase chain reaction analysis showed that many of the nud1 survivors contained small alterations within the MAT locus, suggesting that the survivors arose through the process of non-homologous end-joining. These results suggest that the endo-exonuclease acts at a DSB to promote DNA repair via the homologous recombination pathway. Received: 20 July / 20 September 1998     

BALAD and BALAD-2 predict survival of hepatocellular carcinoma patients: a North American cohort study

BackgroundThe BALAD score and BALAD-2 class derived from bilirubin, albumin, AFP, AFP-L3, and des-gamma-carboxyprothrombin (DCP) are effective in predicting mortality in HCC, but have not been validated in North America.Methods148 HCC patients from 2000 to 2015 who had all five biomarkers tested at diagnosis were included. Hazard ratios (HR) were calculated.Results75 patients died during a median follow-up of 21.9 months. 1-and 3-year survival rates were 70.8% and 47.6%. 114 (77%) had cirrhosis. The HR (95%CI) for death were 1.24 (0.42–3.67), 1.79 (0.61–5.26), 2.83 (0.95–8.38), and 7.19 (2.26–22.91) for BALAD scores 1, 2, 3, and 4 vs. BALAD 0. The HR (95%CI) for death were 1.25 (0.65–2.40), 1.75 (0.94–3.23), and 6.20 (3.29–11.68) for BALAD-2 classes 2, 3, and 4 vs. BALAD-2 class 1. A multivariate model incorporating maximal tumor diameter, tumor number, neutrophil-lymphocyte ratio, and BALAD had HR of 1.43 (1.14–1.81) per increase of 1 BALAD score. A similar model with BALAD-2 had HR of 1.50 (1.18–1.90) per increase of 1 BALAD-2 class.ConclusionBALAD models at diagnosis can predict the survival of HCC patients in North America. AFP, AFP-L3, and DCP reflect tumor progression and metastasis of HCC and distinguish the BALAD model from other predictive models.     

Sphingomyelinase and ceramide analogs induce vasoconstriction and leukocyte-endothelial interactions in cerebral venules in the intact rat brain: Insight into mechanisms and possible relation to brain injury and stroke

This study was designed to test the hypothesis that the sphingomyelin-ceramide signaling pathway may be important in proinflammatory-like responses in the intact brain. Effects of neutral sphingomyelinase (N-SMase), ceramide analogs, phosphorylcholine and ceramide metabolites were studied on rat brain cerebral (cortical) venule lumen sizes, leukocyte rolling, velocity and endothelial cell wall adhesion, microvessel permeability, microvessel rupture and focal hemorrhages using in vivo high resolution TV microscopy. Perivascular and close intra-arterial administration of N-SMase, C(2)-, C(8)-, and C(16)-ceramide, but not either phosphorylcholine, C(6)-ceramide, nervonic (C(24):1) ceramide, lignoceric (C(24):0) ceramide, C(8)-ceramide-1-phosphate, glucosylceramide or 1-0-acylceramide, resulted in potent, concentration-dependent constriction (and spasm) of cortical venules, followed by increased leukocyte rolling, decreased leukocyte velocities, increased leukocyte-endothelial wall adhesion, increased venular wall permeability, postcapillary venule rupture and, often, micro-hemorrhaging at high concentrations; angiotensin II, serotonin and PGF(2alpha) didn't demonstrate these characteristics. Pretreatment with either one of three different antioxidants, including inhibitors of NF-kappaB activation, or two different Ca(2+) channel blockers either prevented or attenuated the adverse venular effects of N-SMase and the ceramides. Likewise, pretreatment with either a PKCalpha-beta antagonist or a MAP kinase antagonist also attenuated the adverse venular effects. These results suggest that N-SMase and several ceramides can result in potent venular cerebrovasospasm, leukocyte-endothelial chemoattraction, and microvessel wall permeability changes in the intact rat brain. These proinflammatory-like actions suggest that N-SMase and ceramides could produce brain-vascular damage by reperfusion injury triggering lipid peroxidation, release of reactive oxygen species and activation of diverse signaling pathways: PKCalpha-beta isozymes, MAP kinase and NF-kappaB.     

An Ethiopian birth cohort study

Summary. A one-year birth cohort was studied in Jimma town, South West Ethiopia, in 1992-93. We report here on the design and on the methods used in the study and describe the principal health outcomes. Infants were visited bimonthly until their first birthday. Background data on the physical, cultural and economic environment of the home were collected at the first visit, and data on nursing and weaning, on traditional surgical and other practices, and on vaccination at the first visit and at each subsequent visit. Length, weight and mid upper arm circumference were measured, and details of the mother's handling of illness episodes recorded. Of 1563 children born, 86% were successfully followed to the end of their first year or to an earlier death. There were 141 deaths, indicating an infant mortality of 115/1000 (estimated probability of surviving to 1 year 0.8851, with s.e. 0.0101). The mean length and weight of the singleton infants at the end of their first year was -1.41 and - 1.52SD from the median of the NCHS/WHO reference population. Weights throughout the first year were analysed in more detail using a Reed model, fitted as a random coefficient regression model in ML3-E. There were clear differences in growth across the different ethnic groups, with the best growing group weighing on average about l kg more at the end of the first year than the groups growing least well.     

α-Tocopherol attenuates alcohol-induced cerebral vascular damage in rats: possible role of oxidants in alcohol brain pathology and stroke

Effects of chronic (14 day) pretreatment of timed-release of α-tocopherol (∼1.25–5 mg/day) on alcohol-induced venular cerebrovasospasm, microvessel rupture and micro-hemorrhaging was studied by direct, quantitative in-vivo high-resolution TV microscopy of the intact rat brain. Sham animals chronically treated with placebo exhibited concentration-dependent venular cerebrovasospasm, microvessel rupture and focal hemorrhages, irrespective of route (i.e. perivascular, systemic) of ethanol administration. α-Tocopherol pretreatment either prevented or ameliorated greatly the cerebrovasospasm and vascular damage induced by ethanol. These results suggest that alcohol-induced cerebral vascular and brain damage by reperfusion injury events triggers lipid peroxidation of vascular smooth muscle and endothelial cell membranes; these pro-oxidant events could play a crucial role in the pathogenesis of alcohol-induced cerebral ischemia and stroke.     

An HIV-based lentiviral vector as HIV vaccine candidate: Immunogenic characterization

Recently developed viral-vectored HIV vaccine candidates, despite achieving high levels transgene expression and inducing high magnitude immune responses to HIV, have faced limitations related to anti-vector immunity. In contrast, lentiviral vectors (LV) have been shown to be less sensitive to anti-vector neutralizing activity, while displaying desirable characteristics, such as transduction of non-dividing cells, including antigen-presenting cells, and long-term transgene expression.     

Growing Ignorance of COVID-19 Preventive Measures in Ethiopia: Experts' Perspective on the Need of Effective Health Communication Strategies

Despite the recent surge of COVID-19 infections in Ethiopia, we are observing a profound ignorance of preventive measures by the general public and leaders at different levels. This is presenting considerable challenges in the effort to contain and control the pandemic. We believe that the current health communication approach implemented by the health authorities and media outlets need to be redesigned to bring a sustainable COVID-19 preventive behavior. The purpose of this perspective paper, therefore, is to stimulate discussions on effective health communication strategy to help the public persistently practice COVID-19 preventive measures over the long term. We undertook a series of discussions amongst the authors in order to synthesize individual viewpoints into ‘experts'' perspective’ driven by our daily observations and our expertise in the health service research. In light of this, we suggested that an effective health communication strategy need to address context specific situations to avoid temptation to ignore the ramifications of this very serious pandemic. This strategy includes trying to make sense of daily reported COVID-19 cases, being highly selective regarding sources of information, and being sensitive and responsive to religious and cultural factors. The media, health professionals, and leaders need to teach us how to live with the pandemic informed by robust scientific sources.     

A Comparison of Clofarabine-based (GCLAC) and Cladribine-based (CLAG) Salvage Chemotherapy for Relapsed/Refractory AML

Background

Salvage regimens for patients with relapsed/refractory acute myeloid leukemia (rrAML) lack comparative data for superiority. Thus, we conducted a retrospective analysis of clofarabine-based (GCLAC; granulocyte colony-stimulating factor [filgrastim], clofarabine, high-dose cytarabine) versus cladribine-based (CLAG; cladribine, cytarabine, granulocyte colony-stimulating factor [filgrastim]) regimens in rrAML.