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Plasma cell-free DNA (cfDNA) is a noninvasive biomarker for cell death of all organs. Deciphering the tissue origin of cfDNA can reveal abnormal cell death because of dis- eases, which has great clinical potential in disease detection and monitoring. Despite the great promise, the sensitive and accurate quantification of tissue-derived cfDNA remains challenging to existing methods due to the limited characterization of tissue methylation and the reliance on unsupervised methods. To fully exploit the clinical potential of tissue-derived cfDNA, here we present one of the largest comprehensive and high- resolution methylation atlas based on 521 noncancer tissue samples spanning 29 major types of human tissues. We systematically identified fragment-level tissue-specific methylation patterns and extensively validated them in orthogonal datasets. Based on the rich tissue methylation atlas, we develop the first supervised tissue deconvolution approach, a deep-learning-powered model, cfSort, for sensitive and accurate tissue decon- volution in cfDNA. On the benchmarking data, cfSort showed superior sensitivity and accuracy compared to the existing methods. We further demonstrated the clinical util- ities of cfSort with two potential applications: aiding disease diagnosis and monitoring treatment side effects. The tissue-derived cfDNA fraction estimated from cfSort reflected the clinical outcomes of the patients. In summary, the tissue methylation atlas and cfSort enhanced the performance of tissue deconvolution in cfDNA, thus facilitating cfDNA-based disease detection and longitudinal treatment monitoring. [ABSTRACT FROM AUTHOR]

Objective: The standard treatment for stage II--III gastroesophageal junction adenocarcinoma (GEJA) remains controversial, and the role of radiotherapy (RT) in stage II-III GEJA is unclear. Herein, we aimed to evaluate the prognosis of different RT sequences and identify potential candidates to undergo neoadjuvant RT (NART) or adjuvant RT (ART). Materials and methods: In total, we enrolled 3,492 patients with resectable stage II--III GEJA from the Surveillance, Epidemiology, and End Results (SEER) database, subsequently assigned to three categories: T1-2N+, T3-4N-, and T3-4N+. Survival curves were evaluated using the Kaplan--Meier method along with the log-rank test. We compared survival curves for NART, ART, and non-RT in the three categories. To further determine histological types impacting RT-associated survival, we proposed new categories by combining the tumor, node, and metastasis (TNM) stage with Lauren's classification. Results: ART afforded a significant survival benefit in patients with T1-2N+ and T3-4N+ tumors. In addition, NART conferred a survival advantage in patients with T3- 4N+ and T3-4 exhibiting the intestinal type. Notably, ART and NART were both valuable in patients with T3-4N+, although no significant differences between treatment regimens were noted. Conclusions: Both NART and ART can prolong the survival of patients with stage II-III GEJA.Nevertheless, the selection of NART or ART requires a concrete analysis based on the patient's condition. [ABSTRACT FROM AUTHOR]

Background: Increasing reports have confirmed that microRNAs play an important role in breast cancer progression, particularly in triple-negative breast cancer (TNBC). The aim of our study was to investigate the role of miR-33a in TNBC progression. Methods: PCR assays were performed to detect miR-33a and EZH2 expression in TNBC tissues, adjacent nontumor tissues and cell lines. Western blot, CCK8, Transwell, cell colony formation and EdU cell proliferation, cell cycle analysis and luciferase reporter assays were used to determine the regulation of miR-33a/EZH2 in TNBC progression. Results: MiR-33a was significantly downregulated in TNBC tissues and cell lines. MiR-33a overexpression in TNBC cells significantly inhibited cell growth and mobility and induced G1 cell cycle arrest. The luciferase reporter assay revealed that EZH2 is a direct target of miR-33a and that it was upregulated in TNBC tissues and cell lines. There was a negative correlation between miR-33a and EZH2 expression in TNBC tissues. EZH2 knockdown exerted similar inhibitory effects, while ectopic expression of EZH2 showed suppressive effects on malignant behaviors induced by miR-33a overexpression in TNBC cells. Conclusions: These findings revealed that miR-33a is a tumor-suppressive miRNA in TNBC and can inhibit proliferation and mobility and induce G1 cell cycle arrest by directly targeting EZH2. [ABSTRACT FROM AUTHOR]

Background: Cornelia de Lange syndrome (CdLS) is a multisystem developmental disorder frequently associated with heterozygous loss-of-function mutations of Nipped-B-like (NIPBL), the human homolog of Drosophila Nipped-B. NIPBL loads cohesin onto chromatin. Cohesin mediates sister chromatid cohesion important for mitosis but is also increasingly recognized as a regulator of gene expression. In CdLS patient cells and animal models, expression changes of multiple genes with little or no sister chromatid cohesion defect suggests that disruption of gene regulation underlies this disorder. However, the effect of NIPBL haploinsufficiency on cohesin binding and how this relates to the clinical presentation of CdLS, has not been fully investigated. Nipbl haploinsufficiency causes CdLS-like phenotype in mice. We examined genome-wide cohesin binding and its relationship to gene expression using mouse embryonic fibroblasts (MEFs) from Nipbl+/- mice that recapitulate the CdLS phenotype. Results: We found a global decrease in cohesin binding, including at CCCTC-binding factor (CTCF) binding sites and repeat regions. Cohesin-bound genes were found to be enriched for histone H3 lysine 4 trimethylation (H3K4me3) at their promoters; were disproportionately downregulated in Nipbl mutant MEFs and displayed evidence of reduced promoter-enhancer interaction. The results suggest that gene activation is the primary cohesin function sensitive to Nipbl reduction. Over 50% of significantly dysregulated transcripts in mutant MEFs come from cohesin target genes, including genes involved in adipogenesis that have been implicated in contributing to the CdLS phenotype. Conclusions: Decreased cohesin binding at the gene regions is directly linked to disease-specific expression changes. Taken together, our Nipbl haploinsufficiency model allows us to analyze the dosage effect of cohesin loading on CdLS development. [ABSTRACT FROM AUTHOR]

T-cell development from hematopoietic progenitors depends on multiple transcription factors, mobilized and modulated by intrathymic Notch signaling. Key aspects of T-cell specification network architecture have been illuminated through recent reports defining roles of transcription factors PU.1, GATA-3, and E2A, their interactions with Notch signaling, and roles of Runx1, TCF-1, and Hes1, providing bases for a comprehensively updated model of the T-cell specification gene regulatory network presented herein. However, the role of lineage commitment factor Bcl11b has been unclear. We use self-organizing maps on 63 RNA-seq datasets from normal and perturbed T-cell development to identify functional targets of Bcl11b during commitment and relate them to other regulomes. We show that both activation and repression target genes can be bound by Bcl11b in vivo, and that Bcl11b effects overlap with E2A-dependent effects. The newly clarified role of Bcl11b distinguishes discrete components of commitment, resolving how innate lymphoid, myeloid, and dendritic, and B-cell fate alternatives are excluded by different mechanisms. [ABSTRACT FROM AUTHOR]

The concept of climate carrying capacity has been proposed recently for climate risk management. Based on identification of the concept of climate carrying capacity and analysis of the relationship among its influencing factors, this study established a comprehensive assessment indicator system of climate carrying capacity from aspects of the climate situation, the level of climate usage, and the development potential of cities. Taking Shanghai City as a case study, we developed a quantitative assessment model of climate carrying capacity. The climate carrying capacity and its influencing factors were analyzed and discussed in relation to the period 2004-2013. The results were as follows. (1) Current climate natural capacity indicator showed that the climatic situation of Shanghai City was inferior to its base climatic value and it had been in a state of fluctuation. (2) The climate stress and urban coordinated development capacity indicators increased steadily, but the growth rate of the urban coordinated development indicator was less than the growth rate of urban climate stress. (3) The climate carrying capacity was far lower than the benchmark value and it had been in a state of fluctuation mainly due to the effect of current climate situation. (4) According to a principal component analysis, seven factors of urban population density, per capita GDP, energy consumption per unit GDP, total industrial output value, investment in environment protection, spending on science and technology, and green area per capita were main influential factor of climate carrying capacity. It was proved that the proposed system for assessment of climate carrying capacity of a city was feasible. It can be used to describe the spatiotemporal changes of cities, and identify problems of regional climate carrying capacity associated with their development and function. This assessment system can provide a reference for the construction of an early warning system of climate carrying capacity for cities. [ABSTRACT FROM AUTHOR]

Carbon footprints have been widely employed as an indicator for total carbon dioxide released by human activities. In this paper, we implemented a multi-regional input-output framework to evaluate the carbon footprints and embodied carbon flows for the eight regions of China from consumption-based perspective. It is found that the construction, electricity/stream supply, and machine manufacturing rank as the top sectors with the largest total carbon emissions. The construction sector alone accounts for 20%-50% of the national emissions. Besides the sectoral carbon footprints, regional footprints and their differences in carbon emissions were also observed. The middle region had the largest total carbon footprints, 1188 million ton, while the capital region ranked the first for its per capita carbon footprint, 7.77 ton/person. In regard to the embodied carbon flows within China, the study detected that the embodied carbon flows take up about 41% of the total carbon footprints of the nation. The northwest region and the eastern coast region are found to be the largest net embodied carbon exporter and importer, respectively. Further investigation revealed significant differences between production-based and consumption-based carbon emissions, both at sectoral and total amounts. Results of this paper can provide specific information to policies on sectoral and regional carbon emission reduction. [ABSTRACT FROM AUTHOR]

Cohesin is an essential multiprotein complex that mediates sister chromatid cohesion critical for proper segregation of chromosomes during cell division. Cohesin is also involved in DNA double-strand break (DSB) repair. In mammalian cells, cohesin is involved in both DSB repair and the damage checkpoint response, although the relationship between these two functions is unclear. Two cohesins differing by one subunit (SA1 or SA2) are present in somatic cells, but their functional specificities with regard to DNA repair remain enigmatic. We found that cohesin-SA2 is the main complex corecruited with the cohesin-loading factor NIPBL to DNA damage sites in an S/G2-phase-specific manner. Replacing the diverged C-terminal region of SA1 with the corresponding region of SA2 confers this activity on SA1. Depletion of SA2 but not SA1 decreased sister chromatid homologous recombination repair and affected repair pathway choice, indicating that DNA repair activity is specifically associated with cohesin recruited to damage sites. In contrast, both cohesin complexes function in the intra-S checkpoint, indicating that cell cycle-specific damage site accumulation is not a prerequisite for cohesin's intra-S checkpoint function. Our findings reveal the unique ways in which cohesin-SA1 and cohesin-SA2 participate in the DNA damage response, coordinately protecting genome integrity in human cells. [ABSTRACT FROM AUTHOR]

Many rapidly developing regions have begun to draw the attention of the world. Meanwhile, the energy and environmental issues associated with rapid economic growth have aroused widespread critical concern. Therefore, studying energy, economic, and environmental systems is of great importance. This study establishes a system dynamic model that covers multiple aspects of those systems, such as energy, economy, population, water pollution, air pollution, solid waste, and technology. The model designed here attempts to determine the impacts of socioeconomic development on the energy and environment of Tongzhou District in three scenarios: under current, planning, and sustainable conditions. The results reveal that energy shortages and water pollutions are very serious and are the key issues constraining future social and economic development. Solid waste emissions increase with population growth. The prediction results provide valuable insights into social advancement. [ABSTRACT FROM AUTHOR]

An inexact fuzzy multi-objective programming model (IFMOP) based on the environmental carrying capacity is provided for industrial structure optimization problems. In the IFMOP model, both fuzzy linear programming (FLP) and inexact linear programming (ILP) methods are introduced into a multi-objective programming framework. It allows uncertainties to be directly communicated into the problem solving processing, and it can effectively reflect the complexity and uncertainty of an industrial system without impractical simplification. The two objective functions utilized in the optimization study are the maximum total output value and population size, and the constraints include water environmental capacity, water resource supply, atmospheric environmental capacity and energy supply. The model is subsequently employed in a realistic case for industrial development in the Tongzhou district, Beijing, China. The results demonstrate that the model can help to analyze whether the environmental carrying capacity of Tongzhou can meet the needs of the social economic objectives in the new town plan in the two scenarios and can assist decision makers in generating stable and balanced industrial structure patterns with consideration of the resources, energy and environmental constraints to meet the maximum social economic efficiency. [ABSTRACT FROM AUTHOR]

Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant muscular dystrophy in which no mutation of pathogenic gene(s) has been identified. Instead, the disease is, in most cases, genetically linked to a contraction in the number of 3.3 kb D4Z4 repeats on chromosome 4q. How contraction of the 4qter D4Z4 repeats causes muscular dystrophy is not understood. In addition, a smaller group of FSHD cases are not associated with D4Z4 repeat contraction (termed ''phenotypic'' FSHD), and their etiology remains undefined. We carried out chromatin immunoprecipitation analysis using D4Z4-specific PCR primers to examine the D4Z4 chromatin structure in normal and patient cells as well as in small interfering RNA (siRNA)- treated cells. We found that SUV39H1-mediated H3K9 trimethylation at D4Z4 seen in normal cells is lost in FSHD. Furthermore, the loss of this histone modification occurs not only at the contracted 4q D4Z4 allele, but also at the genetically intact D4Z4 alleles on both chromosomes 4q and 10q, providing the first evidence that the genetic change (contraction) of one 4qD4Z4 allele spreads its effect to other genomic regions. Importantly, this epigenetic change was alsoobserved in the phenotypic FSHD cases with no D4Z4 contraction, but not in other types of muscular dystrophies tested. We found that HP1γ and cohesin are co-recruited to D4Z4 in an H3K9me3-dependent and cell type-specific manner, which is disrupted in FSHD. The results indicate that cohesin plays an active role in HP1 recruitment and is involved in cell type- specific D4Z4 chromatin regulation. Taken together, we identified the loss of both histone H3K9 trimethylation and HP1γ/cohesin binding at D4Z4 to be a faithful marker for the FSHD phenotype. Based on these results, we propose a new model in which the epigenetic change initiated at 4q D4Z4 spreads its effect to other genomic regions, which compromises muscle-specific gene regulation leading to FSHD pathogenesis. [ABSTRACT FROM AUTHOR]

To better characterize immunologic aberrations in aplastic anaemia (AA), we examined peripheral blood mononuclear cells (PBMC) of 67 patients with AA and other patients with various haematological diseases for the expression of heat shock protein 72 (hsp72), which is inducible in lymphocytes by various stressors including antigenic stimulation. When freshly obtained PBMC were examined using flow cytometry, the proportion of cells expressing hsp72 in cytoplasm was significantly higher in allogeneic marrow transplant recipients (22 ± 15%, mean ±standard deviation (SD)) and AA patients (17 ± 21%) than in normal individuals (6 ± 3%). When PBMC were tested after heat treatment, only the proportion of hsp72+ cells of AA patients (37 ± 30%) was significantly higher than that of the normal control (17 ± 11%). Dual fluorescence analysis of the PBMC revealed that the majority of hsp72+ cells was CD3+. For 28 untreated AA patients, the proportion of hsp72+ cells in those who later responded to cyclosporine (CyA) (62 ± 24%) was higher than that in non-responders (19 ± 13%). Immunoblotting analysis revealed predominant expression of hsp72 in T cells. These findings indicate that high inducibility of hsp72 in PBMC by heat treatment is an immunologic aberration characteristic of CyA-responsive AA and that this simple test may be useful for identifying a subset of AA patients responsive to immunosuppressive therapy. [ABSTRACT FROM AUTHOR]

The Saccharomyces cerevisiae RAD18 gene is essential for postreplication repair but is not required for homologous recombination (HR), which is the major double-strand break (DSB) repair pathway in yeast. Accordingly, yeast rad18 mutants are tolerant of camptothecin (CPT), a topoisomerase I inhibitor, which induces DSBs by blocking replication. Surprisingly, mammalian cells and chicken DT40 cells deficient in Rad18 display reduced HR-dependent repair and are hypersensitive to CPT. Deletion of nonhomologous end joining (NHEJ), a major DSB repair pathway in vertebrates, in rad18-deficient DT40 cells completely restored HR-mediated DSB repair, suggesting that vertebrate Rad18 regulates the balance between NHEJ and HR. We previously reported that loss of NHEJ normalized the CPT sensitivity of cells deficient in poly(ADP-ribose) polymerase 1 (PARP1). Concomitant deletion of Rad18 and PARP1 synergistically increased CPT sensitivity, and additional inactivation of NHEJ normalized this hypersensitivity, indicating their parallel actions. In conclusion, higher-eukaryotic cells separately employ PARP1 and Rad18 to suppress the toxic effects of NHEJ during the HR reaction at stalled replication forks. [ABSTRACT FROM AUTHOR]