Long Noncoding RNA Can Be a Probable Mechanism and a Novel Target for Diagnosis and Therapy in Fragile X Syndrome

Fragile X syndrome (FXS) is the most common congenital hereditary disease of low intelligence after Down syndrome. Its main pathogenic gene is fragile X mental retardation 1 (FMR1) gene associated with intellectual disability, autism, and fragile X-related primary ovarian insufficiency (FXPOI) and fragile X-associated tremor/ataxia syndrome (FXTAS). FMR1 gene transcription leads to the absence of fragile X mental retardation protein (FMRP). How to relieve or cure disorders associated with FXS has also become a clinically disturbing problem. Previous studies have recently shown that long noncoding RNAs (lncRNAs) contribute to the pathogenesis. And it has been identified that several lncRNAs including FMR4, FMR5, and FMR6 contribute to developing FXPOI/FXTAS, originating from the FMR1 gene locus. FMR4 is a product of RNA polymerase II and can regulate the expression of relevant genes during differentiation of human neural precursor cells. FMR5 is a sense-oriented transcript while FMR6 is an antisense lncRNA produced by the 3′ UTR of FMR1. FMR6 is likely to contribute to developing FXPOI, and it overlaps exons 15–17 of FMR1 as well as two microRNA binding sites. Additionally, BC1 can bind FMRP to form an inhibitory complex and lncRNA TUG1 also can control axonal development by directly interacting with FMRP through modulating SnoN–Ccd1 pathway. Therefore, these lncRNAs provide pharmaceutical targets and novel biomarkers. This review will: (1) describe the clinical manifestations and traditional pathogenesis of FXS and FXTAS/FXPOI; (2) summarize what is known about the role of lncRNAs in the pathogenesis of FXS and FXTAS/FXPOI; and (3) provide an outlook of potential effects and future directions of lncRNAs in FXS and FXTAS/FXPOI researches

MSIsensor-ct: Microsatellite instability detection using cfDNA sequencing data

MOTIVATION: Microsatellite instability (MSI) is a promising biomarker for cancer prognosis and chemosensitivity. Techniques are rapidly evolving for the detection of MSI from tumor-normal paired or tumor-only sequencing data. However, tumor tissues are often insufficient, unavailable, or otherwise difficult to procure. Increasing clinical evidence indicates the enormous potential of plasma circulating cell-free DNA (cfNDA) technology as a noninvasive MSI detection approach. RESULTS: We developed MSIsensor-ct, a bioinformatics tool based on a machine learning protocol, dedicated to detecting MSI status using cfDNA sequencing data with a potential stable MSIscore threshold of 20%. Evaluation of MSIsensor-ct on independent testing datasets with various levels of circulating tumor DNA (ctDNA) and sequencing depth showed 100% accuracy within the limit of detection (LOD) of 0.05% ctDNA content. MSIsensor-ct requires only BAM files as input, rendering it user-friendly and readily integrated into next generation sequencing (NGS) analysis pipelines. AVAILABILITY: MSIsensor-ct is freely available at https://github.com/niu-lab/MSIsensor-ct. SUPPLEMENTARY INFORMATION: Supplementary data are available at Briefings in Bioinformatics online

Decomposition and Decoupling Analysis of Carbon Emissions in Xinjiang Energy Base, China

China faces a difficult choice of maintaining socioeconomic development and carbon emissions mitigation. Analyzing the decoupling relationship between economic development and carbon emissions and its driving factors from a regional perspective is the key for the Chinese government to achieve the 2030 emission reduction target. This study adopted the logarithmic mean Divisia index (LMDI) method and Tapio index, decomposed the driving forces of the decoupling, and measured the sector’s decoupling states from carbon emissions in Xinjiang province, China. The results found that: (1) Xinjiang’s carbon emissions increased from 93.34 Mt in 2000 to 468.12 Mt in 2017. Energy-intensive industries were the key body of carbon emissions in Xinjiang. (2) The economic activity effect played the decisive factor to carbon emissions increase, which account for 93.58%, 81.51%, and 58.62% in Xinjiang during 2000–2005, 2005–2010, and 2010–2017, respectively. The energy intensity effect proved the dominant influence for carbon emissions mitigation, which accounted for −22.39% of carbon emissions increase during 2000–2010. (3) Weak decoupling (WD), expansive coupling (EC), expansive negative decoupling (END) and strong negative decoupling (SND) were identified in Xinjiang during 2001 to 2017. Gross domestic product (GDP) per capita elasticity has a major inhibitory effect on the carbon emissions decoupling. Energy intensity elasticity played a major driver to the decoupling in Xinjiang. Most industries have not reached the decoupling state in Xinjiang. Fuel processing, power generation, chemicals, non-ferrous, iron and steel industries mainly shown states of END and EC. On this basis, it is suggested that local governments should adjust the industrial structure, optimize energy consumption structure, and promote energy conservation and emission reduction to tap the potential of carbon emissions mitigation in key sectors

The effect of poly-β-hydroxyalkanoates degradation rate on nitrous oxide production in a denitrifying phosphorus removal system

Poly-beta-hydroxyalkanoates (PHAs) and free nitrous acid (FNA) have been revealed as significant factors causing nitrous oxide (N2O) production in denitrifying phosphorus removal systems. In this study, the effect of PHA degradation rate on N2O production was studied at low FNA levels. N2O production always maintained at approximately 40% of the amount of nitrite reduced independent of the PHA degradation rate. The electrons distributed to nitrite reduction were 1.6 times that to N2O reduction. This indicated that electron competition between these two steps was not affected by the PHA degradation rate. Continuous feed of nitrate was proposed, and demonstrated to reduce N2O accumulation by 75%. While being kept low, a possible compounding effect of a low-level FNA could not be ruled out. The sludge used likely contained both polyphosphate- and glycogen-accumulating organisms, and the results could not be simply attributed to either group of organisms. (C) 2014 Elsevier Ltd. All rights reserved

Chromatin remodeling enzyme Brg1 is required for mouse lens fiber cell terminal differentiation and its denucleation

These studies demonstrate a cell-autonomous role for Brg1 in lens fiber cell terminal differentiation and identified DNase IIβ as a potential direct target of SWI/SNF complexes. Brg1 is directly or indirectly involved in processes that degrade lens fiber cell chromatin. The presence of nuclei and other organelles generates scattered light incompatible with the optical requirements for the lens

Endocrine therapy resistant ESR1 variants revealed by genomic characterization of breast cancer derived xenografts

To characterize patient-derived xenografts (PDXs) for functional studies, we made whole-genome comparisons with originating breast cancers representative of the major intrinsic subtypes. Structural and copy number aberrations were found to be retained with high fidelity. However, at the single-nucleotide level, variable numbers of PDX-specific somatic events were documented, although they were only rarely functionally significant. Variant allele frequencies were often preserved in the PDXs, demonstrating that clonal representation can be transplantable. Estrogen-receptor-positive PDXs were associated with ESR1 ligand-binding-domain mutations, gene amplification, or an ESR1/YAP1 translocation. These events produced different endocrine-therapy-response phenotypes in human, cell line, and PDX endocrine-response studies. Hence, deeply sequenced PDX models are an important resource for the search for genome-forward treatment options and capture endocrine-drug-resistance etiologies that are not observed in standard cell lines. The originating tumor genome provides a benchmark for assessing genetic drift and clonal representation after transplantation

Endocrine-Therapy-Resistant ESR1 Variants Revealed by Genomic Characterization of Breast-Cancer-Derived Xenografts

To characterize patient-derived xenografts (PDXs) for functional studies, we made whole-genome comparisons with originating breast cancers representative of the major intrinsic subtypes. Structural and copy number aberrations were found to be retained with high fidelity. However, at the single-nucleotide level, variable numbers of PDX-specific somatic events were documented, although they were only rarely functionally significant. Variant allele frequencies were often preserved in the PDXs, demonstrating that clonal representation can be transplantable. Estrogen-receptor-positive PDXs were associated with ESR1 ligand-binding-domain mutations, gene amplification, or an ESR1/YAP1 translocation. These events produced different endocrine-therapy-response phenotypes in human, cell line, and PDX endocrine-response studies. Hence, deeply sequenced PDX models are an important resource for the search for genome-forward treatment options and capture endocrine-drug-resistance etiologies that are not observed in standard cell lines. The originating tumor genome provides a benchmark for assessing genetic drift and clonal representation after transplantation

Specific Functions of SUMO Paralogs in Cellular Stress Responses

Small ubiquitin-related modifier (SUMO) is a post-translational protein modification that has been reported to function in many cellular processes. Three functional SUMO paralogs have been identified and well characterized in mammalian cells: SUMO1, SUMO2, and SUMO3. However, the unique roles of these individual SUMO paralogs have not been well characterized. Here, we studied the paralog-specific functions of SUMO in the context of cellular stress response using SUMO1-knockout and SUMO2-knockout U2OS cells generated by CRISPR-Cas9. By studying genotoxic and proteotoxic stress responses in these knockout cell lines, we identified unique functions for SUMO1 and SUMO2 paralogs in replication stress response pathways, p53-mediated apoptosis, endoplasmic reticulum stress response and mitochondrial function. These results demonstrate that SUMO1 and SUMO2 paralogs have unique and non-redundant functions in the regulation of cellular stress response