Replenishment of microRNA-188-5p restores the synaptic and cognitive deficits in 5XFAD Mouse Model of Alzheimer’s Disease

MicroRNAs have emerged as key factors in development, neurogenesis and synaptic functions in the central nervous system. In the present study, we investigated a pathophysiological significance of microRNA-188-5p (miR-188-5p) in Alzheimer’s disease (AD). We found that oligomeric Aβ(1-42) treatment diminished miR-188-5p expression in primary hippocampal neuron cultures and that miR-188-5p rescued the Aβ(1-42)-mediated synapse elimination and synaptic dysfunctions. Moreover, the impairments in cognitive function and synaptic transmission observed in 7-month-old five familial AD (5XFAD) transgenic mice, were ameliorated via viral-mediated expression of miR-188-5p. miR-188-5p expression was down-regulated in the brain tissues from AD patients and 5XFAD mice. The addition of miR-188-5p rescued the reduction in dendritic spine density in the primary hippocampal neurons treated with oligomeric Aβ(1-42) and cultured from 5XFAD mice. The reduction in the frequency of mEPSCs was also restored by addition of miR-188-5p. The impairments in basal fEPSPs and cognition observed in 7-month-old 5XFAD mice were ameliorated via the viral-mediated expression of miR-188-5p in the hippocampus. Furthermore, we found that miR-188 expression is CREB-dependent. Taken together, our results suggest that dysregulation of miR-188-5p expression contributes to the pathogenesis of AD by inducing synaptic dysfunction and cognitive deficits associated with Aβ-mediated pathophysiology in the disease

Burden of Human papillomavirus (HPV)-related disease and potential impact of HPV vaccines in the Republic of Korea

Background: We aimed to review the burden and the potential impact of human papillomavirus (HPV) vaccines on HPV-related diseases in the Republic of Korea and to discuss cervical cancer prevention practices in this country. Methods: Cancer burden statistics were retrieved from GLOBOCAN-2018 and Statistics Korea. HPV disease burden was assessed via systematic review. Vaccine types relative contribution (RC) was estimated using data from an international project using formalin-fixed paraffin-embedded specimens. Results: Despite a downtrend in cervical cancer in recent years, Korean rates remain high. In contrast, oropharyngeal cancer incidence has gradually increased and other anogenital cancers remain rare. In Korea, HPV prevalence in general population is around 20%. In cervical cancer, RC of HPVs 16/18 (74.0%) increased to 92.0% when including HPVs 31/33/45/52/58. Limited information was available for other HPV-related cancer sites. Regarding prevention, since the inclusion of the HPV vaccine into the National Immunization Program, almost half (49%) of the target cohort in 2016 had received the first dose of vaccine. Further, percentage of women screened with pap has increased from 41.1%-2009 to 53.0%-2016. Conclusions: HPV-related disease burden in Korea is significant. Results suggest that the combination of effective and high coverage HPV vaccination and screening programmes could substantially impact on HPV-related disease in Korea

Immunogenicity and Safety of Two Different Haemophilus influenzae Type b Conjugate Vaccines in Korean Infants

The incidence of invasive diseases, including meningitis caused by Haemophilus influenzae type b (Hib) was markedly decreased after routine immunization of Hib vaccine through diverse schedules in many countries. The purpose of this study was to evaluate the immunogenicity and safety of Hib conjugate vaccines in Korean children before the implementation of a national immunization program against Hib in Korea. A multicenter controlled trial was performed on two different Hib vaccines in Korean children. A total of 319 infants were enrolled: 199 infants were immunized with the Hib polysaccharide conjugated to the tetanus toxoid (PRP-T) and 120 infants with the Hib polysaccharide conjugated to the outer-membrane protein of Neisseria meningitides (PRP-OMP). Immunogenicity was evaluated by enzyme-linked immunosorbent assay (ELISA) and serum bactericidal assay. Both vaccines showed good immunologic responses after primary immunization. After 2 doses of PRP-T or PRP-OMP, 78.9% and 91.7% of infants achieved an antibody level of ≥1.0 µg/mL, respectively. Both vaccines were safe and well-tolerated. No serious adverse events were observed. Thus, Hib conjugate vaccines appear to be safe and show good immunogenicity in Korean infants. These results will be important reference data for the implementation of Hib vaccine in the national immunization program of Korea

Wavelet-based identification of DNA focal genomic aberrations from single nucleotide polymorphism arrays

<p>Abstract</p> <p>Background</p> <p>Copy number aberrations (CNAs) are an important molecular signature in cancer initiation, development, and progression. However, these aberrations span a wide range of chromosomes, making it hard to distinguish cancer related genes from other genes that are not closely related to cancer but are located in broadly aberrant regions. With the current availability of high-resolution data sets such as single nucleotide polymorphism (SNP) microarrays, it has become an important issue to develop a computational method to detect driving genes related to cancer development located in the focal regions of CNAs.</p> <p>Results</p> <p>In this study, we introduce a novel method referred to as the wavelet-based identification of focal genomic aberrations (WIFA). The use of the wavelet analysis, because it is a multi-resolution approach, makes it possible to effectively identify focal genomic aberrations in broadly aberrant regions. The proposed method integrates multiple cancer samples so that it enables the detection of the consistent aberrations across multiple samples. We then apply this method to glioblastoma multiforme and lung cancer data sets from the SNP microarray platform. Through this process, we confirm the ability to detect previously known cancer related genes from both cancer types with high accuracy. Also, the application of this approach to a lung cancer data set identifies focal amplification regions that contain known oncogenes, though these regions are not reported using a recent CNAs detecting algorithm GISTIC: SMAD7 (chr18q21.1) and FGF10 (chr5p12).</p> <p>Conclusions</p> <p>Our results suggest that WIFA can be used to reveal cancer related genes in various cancer data sets.</p

The Causative Organisms of Bacterial Meningitis in Korean Children in 1996-2005

Bacterial meningitis remains a serious cause of morbidity and mortality in childhood, despite the availability of effective vaccines against Haemophilus influenzae type b (Hib) or Streptococcus pneumoniae. The purpose of this study was to analyze data on bacterial meningitis cases in Korea from 1996 through 2005. The information of all hospitalized bacteria-proven meningitis cases was obtained from 17 university hospitals nationwide. A total of 402 cases were identified. Of these, 125 (29.9%) cases were neonates. Streptococcus agalactiae was the most common bacteria responsible for 99 (24.6%) of all cases regardless of age, followed by S. pneumoniae for 91 (22.6%) and H. influenzae for 67 (16.7%) patients. The common etiology beyond the neonatal period was S. pneumoniae for 91 (33.0%) followed by H. influenzae for 63 (22.8%) patients. The overall case fatality rate was 9.4%, which was similar with that in 1986-1995. In conclusion, S. agalactiae, S. pneumoniae and H. influenzae were important etiologic agents of bacterial meningitis in children in the last 10 yrs. It is required to establish the preventive strategy of the three bacteria. The nationwide epidemiologic study should be continued to evaluate immunization strategy and efficacy

A chemical genetic approach to the study of Syk and B cell antigen receptor signaling

Syk is an essential protein tyrosine kinase in the BCR signaling pathway. To study the role of Syk in the kinetics of BCR-signaling, we adopted the strategy of engineering an analog-sensitive form of Syk that could be inhibited by an orthogonal inhibitor. We identified Met 442 as a gatekeeper residue in the ATP-binding site of Syk. However, the substitution of M442 to glycine or alanine abrogated Syk’s activity. We identified possible residues for the generation of second-site suppressor mutations to rescue the activity of Syk(M442A) from a structural comparison of Syk and Src. Two of the residues that normally interact with M442 in Syk were replaced by the corresponding residues that interact with T338 in Src. These additional two mutations restored the ability of Syk(M442A) to signal in Syk-deficient cells. The signaling induced by the analog sensitive Syk (Syk-AQL) was specifically inhibited by the treatment with PP1 derivatives. The treatment of cells expressing Syk-AQL with the inhibitor following BCR stimulation dramatically inhibited total tyrosine phosphorylation and the activation of Erk. A brief activation of Syk following BCR stimulation was sufficient to activate NF-κB, but NFAT activation required the sustained activation of Syk. Syk’s activity was required for the retention of receptor complexes on the cell surface, suggesting the importance of Syk in sustained BCR signaling. SH2 domains have important roles in mediating protein-protein interactions in signaling pathways. A phosphopeptidomimetic compound targeting the Lck SH2 domain, RH6-22, that was synthesized as a cell-permeable prodrug that becomes quickly processed within cells into its active form was characterized. RH6-22 inhibited the growth of leukemia cells without inducing any pronounced cell cycle arrest at a specific phase, but delayed cell cycle progression as a whole. Some cell lines treated with RH6-22 exhibited polyploidy and multiple nuclei. RH6-22 also affected the microtubule network. Proteins binding the activated form of RH6-22 were adsorbed to beads conjugated with the compound and investigated via mass spectrometry. Binding proteins included proteins preventing endoreduplication or regulating mitosis. RH6-22 might inhibit the growth of leukemia cells by binding to one or multiple proteins including those important in DNA replication and mitosis

Partition of unity isogeometric analysis of two dimensional elliptic singular perturbation problems

The design basis functions on the reference domain in IGA are diversified and enhanced by extra enrichment functions and various local refinements with the use of partition of unity (PU) function with flat-top. These reconditioned and modified basis functions are pushed forward to the physical domain by the original design mapping for analysis. With this method, the corresponding stiffness matrix has a small bandwidth and local refinement is simple. Moreover, we construct the PU functions in the reference domain and then move them to a physical domain through a geometric mapping to be used for the generation of global basis functions on a physical domain. Therefore, we also have several advantages in calculating stiffness matrices and load vectors. Here we apply this method to various boundary layer problems.clos