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Niemann-Pick type C (NP-C) disease is a neurodegenerative lysosomal storage disorder primarily caused by mutations in NPC1. However, its pathogenesis remains poorly understood. While mounting evidence has demonstrated the involvement of long noncoding RNAs (lncRNAs) in the pathogenesis of neurodegenerative disorders, the lncRNA expression profile in NP-C has not been determined. Here, we used RNA-seq analysis to determine lncRNA and mRNA expression profiles of the cerebella of NPC1−/− mice. We found that 272 lncRNAs and 856 mRNAs were significantly dysregulated in NPC1−/− mice relative to controls (≥ 2.0-fold, p < 0.05). Quantitative real-time PCR (qRT‐PCR) was utilized to validate the expression of selected lncRNAs and mRNAs. Next, a lncRNA-mRNA coexpression network was employed to examine the potential roles of the differentially expressed (DE) lncRNAs. Functional analysis revealed that mRNAs coexpressed with lncRNAs are mainly linked to immune system–related processes and neuroinflammation. Moreover, knockdown of the lncRNA H19 ameliorated changes in ROS levels and cell viability and suppressed the lipopolysaccharide (LPS)–induced inflammatory response in vitro. Our findings indicate that dysregulated lncRNA expression patterns are associated with NP-C pathogenesis and offer insight into the development of novel therapeutics based on lncRNAs. [ABSTRACT FROM AUTHOR]

Single-cell sequencing (SCS) is a fast-growing, exciting field in genomic medicine. It enables the high-resolution study of cellular heterogeneity, and reveals the molecular basis of complicated systems, which facilitates the identification of new biomarkers for diagnosis and for targeting therapies. It also directly promotes the next generation of genomic medicine because of its ultra-high resolution and sensitivity that allows for the non-invasive and early detection of abnormalities, such as aneuploidy, chromosomal translocation, and single-gene disorders. This review provides an overview of the current progress and prospects for the diagnostic applications of SCS, specifically in pre-implantation genetic diagnosis/screening, non-invasive prenatal diagnosis, and analysis of circulating tumor cells. These analyses will accelerate the early and precise control of germline- or somatic-mutation-based diseases, particularly single-gene disorders, chromosome abnormalities, and cancers. [ABSTRACT FROM AUTHOR]

Chronic irradiation of human or murine epidermis with ultraviolet B (UVB) induces clones of p53-mutant keratinocytes. Clones precede and parallel the induction of carcinomas, suggesting that they are an early stage of UVB carcinogenesis. In the absence of UVB, these clones rapidly regress. For UVB-induced murine skin tumors and papillomas, regression is known to involve antigen-specific immunity. To determine whether antigen-specific immunity influences the creation, expansion, or regression of p53-mutant clones, we studied Rag1 knockout mice deficient in the recombination activating gene 1 required for development of B, aßT, ?dT, and natural killer T cells. Since tissue homeostasis could affect proliferation or persistence of clones, we also examined the effect of Rag1 on UVB-induced hyperplasia and apoptosis. Mice were irradiated with UVB daily for 7-11 weeks to create p53-mutant clones, and then retained in the absence of UV. After UV ended, epidermal thickness decreased and p53-mutant clones observed in the epidermal sheets regressed, with no significant differences between Rag1-/- and wild type. During the initial chronic UVB irradiation, increasing irradiation time increased both the number and size of p53-mutant clones, with no significant difference between genotypes. We conclude that antigen-specific immunity is not involved in the initiation, expansion, or acute regression of p53-mutant clones.Oncogene (2003) 22, 6369-6376. doi:10.1038/sj.onc.1206657 [ABSTRACT FROM AUTHOR]

The E2f1 transcription factor, which regulates genes required for S-phase entry[SUP1-4], also induces apoptosis by transcriptional and post-translational mechanisms[SUP5-8]. As E2f1 is inducible by DNA damage[SUP9,10] we investigated its importancein vivo in ultraviolet (UV)-induced apoptosis, a protective mechanism that prevents the epidermis from accumulating UV-induced mutations[SUP11,12]. Contrary to expectation,E2f1[SUP-/-] mice demonstrated enhanced keratinocyte apoptosis after UVB exposure, whereas apoptosis was suppressed by epidermis-specific overexpression of human E2F1. Apoptosis induced by γ-radiation was also repressed by E2f1.E2f1[SUP-/-];Trp53[SUP-/-]double knockout mice exhibited the elevated UVB-induced apoptosis ofE2f1[SUP-/-] alone, rather than the profound apoptosis defect seen inTrp53[SUP-/-] mice, indicating that Trp53 (p53) lies functionally upstream of E2f1. Transfecting E2F1 intoE2f1[SUP-/-];Trp53[SUP-/-] primary fibroblasts suppressed UVB-induced apoptosis and this suppression was relieved byTrp53. The double knockout also reverted the abnormal sex ratio and early-onset tumours ofTrp53[SUP-/-] mice. These results imply that E2f1 functions as a suppressor of an apoptosis pathway that is initiated by DNA photoproducts and perhaps genetic abnormalities; p53 relieves this suppression. [ABSTRACT FROM AUTHOR]

Pheophorbide a (PPa), a decomposition product of chlorophyll a, is a photosensitizer. The photosensitization mechanisms (Type I and Type 11) of PPa in simple buffer solutions and in buffer solutions containing double-layered DPPC liposomes have been studied using techniques of ESR, spin-trapping, spin-counteraction and laser flash photolysis. The results showed that adding DPPC liposomes to the buffer solution caused an increase of efficiency of generating1O2 and PPa-by photoactivating PPa. The increase could be ascribed to the disaggregation of hydrophobic PPa caused by the addition of liposomes and the protective effect of liposomal media on the triplet state of PPa. It is concluded that the photosensitization of PPa in liposomal systems is different from that in simple aqueous solutions, and shows higher efficacy. The results will be useful to elucidating the mechanisms of photodynamic therapy of cancer. [ABSTRACT FROM AUTHOR]