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     

Exomic analysis of myxoid liposarcomas,synovial sarcomas,and osteosarcomas

Bone and soft tissue sarcomas are a group of histologically heterogeneous and relatively uncommon tumors. To explore their genetic origins, we sequenced the exomes of 13 osteosarcomas, eight myxoid liposarcomas (MLPS), and seven synovial sarcomas (SYN). These tumors had few genetic alterations (median of 10.8). Nevertheless, clear examples of driver gene mutations were observed, including canonical mutations in TP53, PIK3CA, SETD2, AKT1, and subclonal mutation in FBXW7. Of particular interest were mutations in H3F3A, encoding the variant histone H3.3. Mutations in this gene have only been previously observed in gliomas. Loss of heterozygosity of exomic regions was extensive in osteosarcomas but rare in SYN and MLPS. These results provide intriguing nucleotide‐level information on these relatively uncommon neoplasms and highlight pathways that help explain their pathogenesis. © 2013 Wiley Periodicals, Inc.     

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.     

Nonfatal work-related traumatic brain injury in Minnesota, 1999-2008

The Centers for Disease Control and Prevention has identified traumatic brain injury (TBI) as a public health problem in the United States; it is notable that some variables of work-related TBI are different from those of non-work-related TBI. The Minnesota Department of Health has been conducting epidemiologic surveillance of cases of hospitalized TBI since 1993. Although most of the surveillance efforts have focused on all TBIs, the department does collect data on work-related TBIs and their associated outcomes. This article summarizes trends for nonfatal, work-related TBI cases over person, place, and time in Minnesota from 1999 to 2008. The greatest proportion of cases involved persons 35 to 44 years of age, and the most common causes were falls, motor vehicle traffic crashes, and being struck by objects. Most injuries occurred in the home, a location not routinely subjected to oversight for occupational safety concerns. The work-related TBI rate has been decreasing since 2004. This article also discusses the role of the physician in identifying and treating TBI.     

Dramatic decrease in malaria transmission after large-scale indoor residual spraying with bendiocarb in Benin, an area of high resistance of Anopheles gambiae to pyrethroids

In 2008, the National Malaria Control Program in Benin implemented a vector control intervention based on indoor residual spraying (IRS). Four districts of high resistance of Anopheles gambiae to pyrethroids were sprayed with bendiocarb. More than 350,000 inhabitants have been protected. Entomologic parameters in the control area were compared with those in intervention sites. The study has shown a drastic decrease in the An. gambiae biting rate in the sprayed areas. Results of an enzyme-linked immunosorbent assay were negative for Plasmodium falciparum antigen during the entire period of the intervention. No household members received infected bites (entomologic inoculation rate = 0 during January-July). Parous rates were low in areas covered by IRS because bendiocarb is not conducive to long-term mosquito survival. Bendiocarb was found to be a good alternative insecticide for IRS in Benin, in areas where An. gambiae has developed high resistance to pyrethroids.     

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.