64 research outputs found
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
Characteristics of the Friction Between Aluminium and Steel at Elevated Temperatures During Ball-on-Disc Tests
China’s community-based strategy of universal preconception care in rural areas at a population level using a novel risk classification system for stratifying couples´ preconception health status
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Experientially Grounded Learning About the Roles of Variability, Sample Size, and Difference Between Means in Statistical Reasoning
Despite its omnipresence in this information-laden
society, statistics is hard. The present study explored the
applicability of a grounded cognition approach to learning
basic statistical concepts. Participants in 2 experiments
interacted with perceptually rich computer simulations
designed to foster understanding of the relations between
fundamental statistical concepts and to promote the ability
to reason with statistics. During training, participants were
asked to estimate the probability of two samples coming
from the same population, with sample size, variability, and
difference between means independently manipulated. The
amount of learning during training was measured by the
difference between participants’ confidence judgments and
those of an Ideal Observer. The amount of transfer was
assessed by the increase in accuracy from a pretest to a
posttest. Learning and transfer were observed when tailored
guidance was given along with the perceptually salient
properties. Implications of our quantitative measures of
human sensitivity to statistical concepts were discussed
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Visual Flexibility in Arithmetic Expressions
We investigated whether, and in what, ways people use visual
structures to evaluate mathematical expressions. We also
explored the relationship between strategy use and other
common measures in mathematics education. Participants
organized long sum/products when visual structure was
available in algebraic expressions. Two experiments showed a
similar pattern: One group of participants primarily calculated
from left to right, or combined identical numbers together. A
second group calculated adjacent pairs. A third group tended
to group terms which either produced easy sums (e.g., 6+4),
or participated in a global structure. These different strategies
were associated with different levels of success on the task,
and, in Experiment 2, with differential math anxiety and
mathematical skill. Specifically, problem solvers with lower
math anxiety and higher math ability tend to group by chunks
and easy calculation. These results identify an important role
for the perception of coherent structure and pattern
identification in mathematical reasoning
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