Suchergebnisse

BACKGROUND: Recurring outbreaks of infectious diseases highlight the importance of population vaccination strategies. We aimed to assess the impact of national vaccination strategies on vaccine-preventable infectious diseases (VPDs) in Shanghai, China and to identify vulnerable groups that may benefit from future vaccination policies. METHODS: Infectious disease data from 1953 to 2018 was obtained from Xuhui District Center for Disease Control and Prevention, Shanghai China. We used joinpoint regression to show incidence, mortality and fatality trends and to determine annual percent change in incidence of 12 VPDs among three eras of national immunization strategies: (1)1953–1977, (2)1978–2007, and(3)2008–2018. FINDINGS: Incidence, mortality, and fatality from VPDs have decreased drastically over the three eras, despite the inclusion of more diseases over time. Strikingly, the overall yearly incidence of VPDs shows an increasing trend from 2000 to 2018 in Shanghai (annual percentage changes, APC:7.7, p = 0.025). In the third era (2008–2018), the three VPDs with the highest incidence were varicella (80.2 cases/100,000), hand, foot, and mouth disease (HFMD) (73.6 cases/100,000), and hepatitis (43.5 cases/100,000). A significant upward trend was also observed in hepatitis (APC:24.9, p<0.001), varicella (APC:5.9, p = 0.006), and HFMD (APC:11.8, p = 0.003) from 2008–2018. Hepatitis and tuberculosis are the only VPDs with fatality cases in this period. INTERPRETATION: Focus is needed in controlling adult hepatitis and tuberculosis, either by introducing adult booster vaccines or by research into more effective vaccines. Varicella and HFMD are on the rise, but vaccines for these are not included in national programs. Strategies funded by government agencies or encouraged by research incentives are needed for varicella and HFMD, such as two-dose and novel multi-valent vaccines, respectively. FUNDING: Chinese Ministry of Education, Shanghai Municipal Government.

AbstractPhenotypically discordant monozygotic twins offer the possibility of gene discovery through delineation of molecular abnormalities in one member of the twin pair. One proposed mechanism of discordance is postzygotically occurring genomic alterations resulting from mitotic recombination and other somatic changes. Detection of altered genomic fragments can reveal candidate gene loci that can be verified through additional analyses. We investigated this hypothesis using array comparative genomic hybridization; the 50K and 250K Affymetrix GeneChip® SNP arrays and an Illumina custom array consisting of 1,536 SNPs, to scan for genomic alterations in a sample of monozygotic twin pairs with discordant cleft lip and/or palate phenotypes. Paired analysis for deletions, amplifications and loss of heterozygosity, along with sequence verification of SNPs with discordant genotype calls did not reveal any genomic discordance between twin pairs in lymphocyte DNA samples. Our results demonstrate that postzygotic genomic alterations are not a common cause of monozygotic twin discordance for isolated cleft lip and/or palate. However, rare or balanced genomic alterations, tissue-specific events and small aberrations beyond the detection level of our experimental approach cannot be ruled out. The stability of genomes we observed in our study samples also suggests that detection of discordant events in other monozygotic twin pairs would be remarkable and of potential disease significance.

Ye Wang,1,* Qi-Wei Yang,1,2,* Qing Yang,2,* Tie Zhou,1 Min-Feng Shi,1,3 Chen-Xia Sun,4 Xiu-Xia Gao,4 Yan-Qiong Cheng,1 Xin-Gang Cui,2 Ying-Hao Sun1 1Department of Urology, Changhai Hospital, 2Department of Urology, The Third Affiliated Hospital, 3Reproductive Center, Changhai Hospital, Second Military Medical University, Shanghai, 4The Reproductive Center, Institute for Nutritional Sciences, Shanghai Institute for Biological Science, Chinese Academy of Science, Shanghai, People's Republic of China *These authors contributed equally to this work Abstract: Disordered copper metabolism plays a critical role in the development of various cancers. As a nanomedicine containing copper, cuprous oxide nanoparticles (CONPs) exert ideal antitumor pharmacological effects in vitro and in vivo. Prostate cancer is a frequently diagnosed male malignancy prone to relapse, and castration resistance is the main reason for endocrine therapy failure. However, whether CONPs have the potential to treat castration-resistant prostate cancer is still unknown. Here, using the castration-resistant PC-3 human prostate cancer cell line as a model, we report that CONPs can selectively induce apoptosis and inhibit the proliferation of cancer cells in vitro and in vivo without affecting normal prostate epithelial cells. CONPs can also attenuate the stemness of cancer cells and inhibit the Wnt signaling pathway, both of which highlight the great potential of CONPs as a new clinical castration-resistant prostate cancer therapy. Keywords: cuprous oxide nanoparticle, prostate cancer, CRPC, nanomedicine, Wnt signaling pathway

Abstract
Aggregated α-synuclein (α-syn) accumulates in the neuronal Lewy body (LB) inclusions in Parkinson's disease (PD) and LB dementia. Yet, under nonpathological conditions, monomeric α-syn is hypothesized to exist in an equilibrium between disordered cytosolic- and partially α-helical lipid-bound states: a feature presumably important in synaptic vesicle release machinery. The exact underlying role of α-syn in these processes, and the mechanisms regulating membrane-binding of α-syn remains poorly understood. Herein we demonstrate that Protein kinase R (PKR) can phosphorylate α-syn at several Ser/Thr residues located in the membrane-binding region that is essential for α-syn's vesicle-interactions. α-Syn phosphorylated by PKR or α-syn isolated from PKR overexpressing cells, exhibit decreased binding to lipid membranes. Phosphorylation of Thr64 and Thr72 appears as the major contributor to this effect, as the phosphomimetic Thr64Glu/Thr72Glu-α-syn mutant displays reduced overall attachment to brain vesicles due to a decrease in vesicle-affinity of the last two thirds of α-syn's membrane binding region. This allows enhancement of the "double-anchor" vesicle-binding mechanism that tethers two vesicles and thus promote the clustering of presynaptic vesicles in vitro. Furthermore, phosphomimetic Thr64Glu/Thr72Glu-α-syn inhibits α-syn oligomerization and completely abolishes nucleation, elongation, and seeding of α-syn fibrillation in vitro and in cells, and prevents trans-synaptic spreading of aggregated α-syn pathology in organotypic hippocampal slice cultures. Overall, our findings demonstrate that normal and abnormal functions of α-syn, like membrane-binding, synaptic vesicle clustering and aggregation can be regulated by phosphorylation, e.g., via PKR. Mechanisms that could potentially be modulated for the benefit of patients suffering from α-syn aggregate-related diseases.