Vertices of Self-Similar Tiles

The set Vn of n-vertices of a tile T in \Rd is the common intersection of T with at least n of its neighbors in a tiling determined by T. Motivated by the recent interest in the topological structure as well as the associated canonical number systems of self-similar tiles, we study the structure of Vn for general and strictly self-similar tiles. We show that if T is a general self-similar tile in \R2 whose interior consists of finitely many components, then any tile in any self-similar tiling generated by T has a finite number of vertices. This work is also motivated by the efforts to understand the structure of the well-known L\\u27evy dragon. In the case T is a strictly self-similar tile or multitile in \Rd, we describe a method to compute the Hausdorff and box dimensions of Vn. By applying this method, we obtain the dimensions of the set of n-vertices of the L\\u27evy dragon for all n≥1

Wen-Luo-Tong Decoction Attenuates Paclitaxel-Induced Peripheral Neuropathy by Regulating Linoleic Acid and Glycerophospholipid Metabolism Pathways

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious dose-limiting toxicity of many anti-neoplastic agents, especially paclitaxel, and oxaliplatin. Up to 62% of patients receiving paclitaxel regimens turn out to develop CIPN. Unfortunately, there are so few agents proved effective for prevention or management of CIPN. The reason for the current situation is that the mechanisms of CIPN are still not explicit. Traditional Chinese Medicine (TCM) has unique advantages for dealing with complex diseases. Wen-Luo-Tong (WLT) is a TCM ointment for topical application. It has been applied for prevention and management of CIPN clinically for more than 10 years. Previous animal experiments and clinical studies had manifested the availability of WLT. However, due to the unclear mechanisms of WLT, further transformation has been restricted. To investigate the therapeutic mechanisms of WLT, a metabolomic method on the basis of UPLC- MS was developed in this study. Multivariate analysis techniques, such as principal component analysis (PCA) and partial least squares discriminate analysis (PLS-DA), were applied to observe the disturbance in the metabolic state of the paclitaxel-induced peripheral neuropathy (PIPN) rat model, as well as the recovering tendency of WLT treatment. A total of 19 significant variations associated with PIPN were identified as biomarkers. Results of pathway analysis indicated that the metabolic disturbance of pathways of linoleic acid (LA) metabolism and glycerophospholipid metabolism. WLT attenuated mechanical allodynia and rebalanced the metabolic disturbances of PIPN by primarily regulating LA and glycerophospholipid metabolism pathway. Further molecular docking analysis showed some ingredients of WLT, such as hydroxysafflor yellow A (HSYA), icariin, epimedin B and 4-dihydroxybenzoic acid (DHBA), had high affinity to plenty of proteins within these two pathways

Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma.

Cross-talk among oncogenic signaling and metabolic pathways may create opportunities for new therapeutic strategies in cancer. Here we show that although acute inhibition of EGFR-driven glucose metabolism induces only minimal cell death, it lowers the apoptotic threshold in a subset of patient-derived glioblastoma (GBM) cells. Mechanistic studies revealed that after attenuated glucose consumption, Bcl-xL blocks cytoplasmic p53 from triggering intrinsic apoptosis. Consequently, targeting of EGFR-driven glucose metabolism in combination with pharmacological stabilization of p53 with the brain-penetrant small molecule idasanutlin resulted in synthetic lethality in orthotopic glioblastoma xenograft models. Notably, neither the degree of EGFR-signaling inhibition nor genetic analysis of EGFR was sufficient to predict sensitivity to this therapeutic combination. However, detection of rapid inhibitory effects on [18F]fluorodeoxyglucose uptake, assessed through noninvasive positron emission tomography, was an effective predictive biomarker of response in vivo. Together, these studies identify a crucial link among oncogene signaling, glucose metabolism, and cytoplasmic p53, which may potentially be exploited for combination therapy in GBM and possibly other malignancies

Efficient Utilization of Rare Variants for Detection of Disease-Related Genomic Regions

When testing association between rare variants and diseases, an efficient analytical approach involves considering a set of variants in a genomic region as the unit of analysis. One factor complicating this approach is that the vast majority of rare variants in practical applications are believed to represent background neutral variation. As a result, analyzing a single set with all variants may not represent a powerful approach. Here, we propose two alternative strategies. In the first, we analyze the subsets of rare variants exhaustively. In the second, we categorize variants selectively into two subsets: one in which variants are overrepresented in cases, and the other in which variants are overrepresented in controls. When the proportion of neutral variants is moderate to large we show, by simulations, that the both proposed strategies improve the statistical power over methods analyzing a single set with total variants. When applied to a real sequencing association study, the proposed methods consistently produce smaller p-values than their competitors. When applied to another real sequencing dataset to study the difference of rare allele distributions between ethnic populations, the proposed methods detect the overrepresentation of variants between the CHB (Chinese Han in Beijing) and YRI (Yoruba people of Ibadan) populations with small p-values. Additional analyses suggest that there is no difference between the CHB and CHD (Chinese Han in Denver) datasets, as expected. Finally, when applied to the CHB and JPT (Japanese people in Tokyo) populations, existing methods fail to detect any difference, while it is detected by the proposed methods in several regions

The investigation of Mitogen-Activated Protein kinase Phosphatase-1 as a potential pharmacological target in non-small cell lung carcinomas, assisted by non-invasive molecular imaging

<p>Abstract</p> <p>Background</p> <p>Invasiveness and metastasis are the most common characteristics of non small cell lung cancer (NSCLC) and causes of tumour-related morbidity and mortality. Mitogen-activated protein kinases (MAPKs) signalling pathways have been shown to play critical roles in tumorigenesis. However, the precise pathological role(s) of mitogen-activated protein kinase phosphatase-1 (MKP-1) in different cancers has been controversial such that the up-regulation of MKP-1 in different cancers does not always correlate to a better prognosis. In this study, we showed that the induction of MKP-1 lead to a significant retardation of proliferation and metastasis in NSCLC cells. We also established that rosiglitazone (a PPARγ agonist) elevated MKP-1 expression level in NSCLC cells and inhibited tumour metastasis.</p> <p/> <p>Methods</p> <p>Both wildtype and dominant negative forms of MKP-1 were constitutively expressed in NSCLC cell line H441GL. The migration and invasion abilities of these cells were examined in vitro. MKP-1 modulating agents such as rosiglitazone and triptolide were used to demonstrate MKP-1's role in tumorigenesis. Bioluminescent imaging was utilized to study tumorigenesis of MKP-1 over-expressing H441GL cells and anti-metastatic effect of rosiglitazone.</p> <p>Results</p> <p>Over-expression of MKP-1 reduced NSCLC cell proliferation rate as well as cell invasive and migratory abilities, evident by the reduced expression levels of MMP-2 and CXCR4. Mice inoculated with MKP-1 over-expressing H441 cells did not develop NSCLC while their control wildtype H441 inoculated littermates developed NSCLC and bone metastasis. Pharmacologically, rosiglitazone, a peroxisome proliferator activated receptor-γ (PPARγ) agonist appeared to induce MKP-1 expression while reduce MMP-2 and CXCR4 expression. H441GL-inoculated mice receiving daily oral rosiglitazone treatment demonstrated a significant inhibition of bone metastasis when compared to mice receiving sham treatment. We found that rosiglitazone treatment impeded the ability of cell migration and invasion <it>in vitro</it>. Cells pre-treated with triptolide (a MKP-1 inhibitor), reversed rosiglitazone-mediated cell invasion and migration.</p> <p>Conclusion</p> <p>The induction of MKP-1 could significantly suppress the proliferative and metastatic abilities of NSCLC both in vitro and in vivo. Therefore, MKP-1 could be considered as a potential therapeutic target in NSCLC therapy and PPARγ agonists could be explored for combined chemotherapy.</p

Jet energy measurement with the ATLAS detector in proton-proton collisions at root s=7 TeV

The jet energy scale and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of √s = 7TeV corresponding to an integrated luminosity of 38 pb-1. Jets are reconstructed with the anti-kt algorithm with distance parameters R=0. 4 or R=0. 6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pT≥20 GeV and pseudorapidities {pipe}η{pipe}<4. 5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2. 5 % in the central calorimeter region ({pipe}η{pipe}<0. 8) for jets with 60≤pT<800 GeV, and is maximally 14 % for pT<30 GeV in the most forward region 3. 2≤{pipe}η{pipe}<4. 5. The jet energy is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon pT, the sum of the transverse momenta of tracks associated to the jet, or a system of low-pT jets recoiling against a high-pT jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-pT jets. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined. © 2013 CERN for the benefit of the ATLAS collaboration