FAN1-MLH1 interaction affects repair of DNA interstrand cross-links and slipped-CAG/CTG repeats

FAN1, a DNA structure-specific nuclease, interacts with MLH1, but the repair pathways in which this complex acts are unknown. FAN1 processes DNA interstrand crosslinks (ICLs) and FAN1 variants are modifiers of the neurodegenerative Huntington's disease (HD), presumably by regulating HD-causing CAG repeat expansions. Here, we identify specific amino acid residues in two adjacent FAN1 motifs that are critical for MLH1 binding. Disruption of the FAN1-MLH1 interaction confers cellular hypersensitivity to ICL damage and defective repair of CAG/CTG slip-outs, intermediates of repeat expansion mutations. FAN1-S126 phosphorylation, which hinders FAN1-MLH1 association, is cell cycle-regulated by cyclin-dependent kinase activity and attenuated upon ICL induction. Our data highlight the FAN1-MLH1 complex as a phosphorylation-regulated determinant of ICL response and repeat stability, opening novel paths to modify cancer and neurodegeneration

Markers of Tumor-Initiating Cells Predict Chemoresistance in Breast Cancer

PURPOSE: Evidence is lacking whether the number of breast tumor-initiating cells (BT-ICs) directly correlates with the sensitivity of breast tumors to chemotherapy. Here, we evaluated the association between proportion of BT-ICs and chemoresistance of the tumors. METHODS: Immunohistochemical staining(IHC) was used to examine the expression of aldehyde dehydrogenase 1 (ALDH1) and proliferating cell nuclear antigen, and TUNEL was used to detect the apoptosis index. The significance of various variables in patient survival was analyzed using a Cox proportional hazards model. The percentage of BT-ICs in breast cancer cell lines and primary breast tumors was determined by ALDH1 enzymatic assay, CD44(+)/CD24(-) phenotype and mammosphere formation assay. RESULTS: ALDH1 expression determined by IHC in primary breast cancers was associated with poor clinical response to neoadjuvant chemotherapy and reduced survival in breast cancer patients. Breast tumors that contained higher proportion of BT-ICs with CD44(+)/CD24(-) phenotype, ALDH1 enzymatic activity and sphere forming capacity were more resistant to neoadjuvant chemotherapy. Chemoresistant cell lines AdrR/MCF-7 and SK-3rd, had increased number of cells with sphere forming capacity, CD44(+)/CD24(-) phenotype and side-population. Regardless the proportion of T-ICs, FACS-sorted CD44(+)/CD24(-) cells that derived from primary tumors or breast cancer lines were about 10-60 fold more resistant to chemotherapy relative to the non- CD44(+)/CD24(-) cells and their parental cells. Furthermore, our data demonstrated that MDR1 (multidrug resistance 1) and ABCG2 (ATP-binding cassette sub-family G member 2) were upregulated in CD44(+)/CD24(-) cells. Treatment with lapatinib or salinomycin reduced the proportion of BT-ICs by nearly 50 fold, and thus enhanced the sensitivity of breast cancer cells to chemotherapy by around 30 fold. CONCLUSIONS: These data suggest that the proportion of BT-ICs is associated with chemotherapeutic resistance of breast cancer. It highlights the importance of targeting T-ICs, rather than eliminating the bulk of rapidly dividing and terminally differentiated cells, in novel anti-cancer strategies

Rectangular Coordination Polymer Nanoplates: Large-Scale, Rapid Synthesis and Their Application as a Fluorescent Sensing Platform for DNA Detection

In this paper, we report on the large-scale, rapid synthesis of uniform rectangular coordination polymer nanoplates (RCPNs) assembled from Cu(II) and 4,4′-bipyridine for the first time. We further demonstrate that such RCPNs can be used as a very effective fluorescent sensing platform for multiple DNA detection with a detection limit as low as 30 pM and a high selectivity down to single-base mismatch. The DNA detection is accomplished by the following two steps: (1) RCPN binds dye-labeled single-stranded DNA (ssDNA) probe, which brings dye and RCPN into close proximity, leading to fluorescence quenching; (2) Specific hybridization of the probe with its target generates a double-stranded DNA (dsDNA) which detaches from RCPN, leading to fluorescence recovery. It suggests that this sensing system can well discriminate complementary and mismatched DNA sequences. The exact mechanism of fluorescence quenching involved is elucidated experimentally and its use in a human blood serum system is also demonstrated successfully

Poly(m-Phenylenediamine) Nanospheres and Nanorods: Selective Synthesis and Their Application for Multiplex Nucleic Acid Detection

In this paper, we demonstrate for the first time that poly(m-phenylenediamine) (PMPD) nanospheres and nanorods can be selectively synthesized via chemical oxidation polymerization of m-phenylenediamine (MPD) monomers using ammonium persulfate (APS) as an oxidant at room temperature. It suggests that the pH value plays a critical role in controlling the the morphology of the nanostructures and fast polymerization rate favors the anisotropic growth of PMPD under homogeneous nucleation condition. We further demonstrate that such PMPD nanostructures can be used as an effective fluorescent sensing platform for multiplex nucleic acid detection. A detection limit as low as 50 pM and a high selectivity down to single-base mismatch could be achieved. The fluorescence quenching is attributed to photoinduced electron transfer from nitrogen atom in PMPD to excited fluorophore. Most importantly, the successful use of this sensing platform in human blood serum system is also demonstrated

Tall Fescue Cultivar and Fungal Endophyte Combinations Influence Plant Growth and Root Exudate Composition

Tall fescue [Lolium arundinaceum (Schreb.)] is a cool-season perennial grass used in pastures throughout the Southeastern United States. The grass can harbor a shoot-specific fungal endophyte (Epichloë coenophiala) thought to provide the plant with enhanced resistance to biotic and abiotic stresses. Because alkaloids produced by the common variety of the endophyte cause severe animal health issues, focus has been on replacing the common-toxic strain with novel varieties that do not produce the mammal-toxic alkaloids but maintain abiotic and biotic stress tolerance benefits. Little attention has been given to the influence of the plant-fungal symbiosis on rhizosphere processes. Therefore, our objective was to study the influence of this relationship on plant biomass production and root exudate composition in tall fescue cultivars PDF and 97TF1, which were either not infected with the endophyte (E-), infected with the common toxic endophyte (CTE+) strain or with one of two novel endophytes (AR542E+, AR584E+). Plants were grown sterile for 3 weeks after which plant biomass, total organic carbon, total phenolic content and detailed chemical composition of root exudates were determined. Plant biomass production and exudate phenolic and organic carbon content were influenced by endophyte status, tall fescue cultivar, and their interaction. GC-TOF MS identified 132 compounds, including lipids, carbohydrates and carboxylic acids. Cluster analysis showed that the interaction between endophyte and cultivar resulted in unique exudate profiles. This is the first detailed study to assess how endophyte infection, notably with novel endophytes, and tall fescue cultivar interact to influence root exudate composition. Our results illustrate that tall fescue cultivar and endophyte status can influence plant growth and root exudate composition, which may help explain the observed influence of this symbiosis on rhizosphere biogeochemical processes

Forecasting China’s GDP at the pixel level using nighttime lights time series and population images

China’s rapid economic development greatly affected not only the global economy but also the entire environment of the Earth. Forecasting China’s economic growth has become a popular and essential issue but at present, such forecasts are nearly all conducted at the national scale. In this study, we use nighttime light images and the gridded Landscan population dataset to disaggregate gross domestic product (GDP) reported at the province scale on a per pixel level for 2000–2013. Using the disaggregated GDP time series data and the statistical tool of Holt–Winters smoothing, we predict changes of GDP at each 1 km × 1 km grid area from 2014 to 2020 and then aggregate the pixel-level GDP to forecast economic growth in 23 major urban agglomerations of China. We elaborate and demonstrate that lit population (brightness of nighttime lights × population) is a better indicator than brightness of nighttime lights to estimate and disaggregate GDP. We also show that our forecast GDP has high agreement with the National Bureau of Statistics of China’s demographic data and the International Monetary Fund’s predictions. Finally, we display uncertainties and analyze potential errors of this disaggregation and forecast method