The quotients between the (revised) Szeged index and Wiener index of graphs

Let $Sz(G),Sz^*(G)$ and $W(G)$ be the Szeged index, revised Szeged index and Wiener index of a graph $G.$ In this paper, the graphs with the fourth, fifth, sixth and seventh largest Wiener indices among all unicyclic graphs of order $n\geqslant 10$ are characterized; as well the graphs with the first, second, third, and fourth largest Wiener indices among all bicyclic graphs are identified. Based on these results, further relation on the quotients between the (revised) Szeged index and the Wiener index are studied. Sharp lower bound on $Sz(G)/W(G)$ is determined for all connected graphs each of which contains at least one non-complete block. As well the connected graph with the second smallest value on $Sz^*(G)/W(G)$ is identified for $G$ containing at least one cycle.Comment: 25 pages, 5 figure

Role of the p53/miR-34a pathway in the response to tumor hypoxia

In colorectal cancer (CRC), hypoxia causes resistance to therapy and promotes metastasis. Mutation of the tumor suppressor TP53 provides a selective advantage to cancer cells under conditions of hypoxia, but little is known about the mediators of this effect. In this thesis I could show that the hypoxia inducible factor 1 alpha subunit (HIF1A) directly represses the MIR34A gene in TP53-defective CRC cells, whereas expression of MIR34A was induced in TP53-proficient CRC cells exposed to hypoxia. Down-regulation of MIR34A was required for hypoxia-induced epithelial to mesenchymal transition (EMT), invasion and migration, and activation of STAT3 in CRC cells. In this study the PPP1R11 (protein phosphatase 1 regulatory inhibitor subunit 11; INH3; HCGV; IPP3; HCG-V; TCTE5; TCTEX5; CFAP255), was identified and characterized as a target of MIR34A. PPP1R11 mediates phosphorylation (activation) of STAT3 by inhibiting protein phosphatase (PP1), so expression of MIR34A inhibited STAT3 activity in TP53-negative CRC cells. Ectopic expression of INH3 in CRC cells induced EMT, invasion, and migration, which all required STAT3. Increased expression of INH3 in TP53-negative CRC cells was required for hypoxia-induced EMT, invasion, migration, and chemo-resistance to 5-fluorouracil, as well as metastases of xenograft tumors to lungs of mice. Adenomas and derived tumoroids of ApcMin/+ mice with disruption miR34a, miR34b and miR34c expressed increased levels of INH3. Colorectal tumors from patients dispalyed increased levels of INH3 at areas of invasion, compared with other areas of the tumor. Increased INH3 levels associated with TP53 mutations and metastasis to liver. HIF1A represses, whereas p53 increases, expression of MIR34A in CRC cells. MIR34A reduces expression of INH3 to prevent activation of STAT3 and inhibit the EMT and metastasis. In the future strategies to target this pathway might be developed to inhibit CRC metastasis and overcome resistance to therapy associated with hypoxia.Hypoxie verursacht Therapieresistenz und fördert die Metastasierung von kolorektalen Karzinomen (KRK). Unter hypoxischen Bedingungen verleiht die Mutation des Tumorsuppressorgens TP53 den Krebszellen einen selektiven Vorteil. Die Mediatoren dieses Effektes sind jedoch weitgehend unbekannt. In der vorliegenden Arbeit konnte ich zeigen, dass unter Hypoxie der Hypoxie-induzierbare Faktor-1 (HIF1A) das MIR34A-Gen in TP53-defekten KRK-Zellen unterdrückt, während in TP53-kompetenten KRK-Zellen die Expression von MIR34A induziert wird. Die Herabregulierung von MIR34A in KRK-Zellen war für die Hypoxie-induzierte Epithelial-Mesenchymale-Transition (EMT), Invasion und Migration, sowie Aktivierung von STAT3 verantwortlich. In dieser Arbeit wurde die Protein Phosphatase 1 regulatorische Inhibitor Untereinheit 11 (PPP1R11; INH3; HCGV; IPP3; HCG-V; TCTE5; TCTEX5; CFAP255), welche einen Inhibitor der Protein Phosphatase 1 (PP1) kodiert, als eine durch MIR34A-regulierte mRNA identifiziert und charakterisiert. INH3 vermittelt die Phosphorylierung und damit Aktivierung des STAT3 Proteins durch Inhibition von PP1. Die Expression von MIR34A in TP53-negativen KRK-Zellen reduzierte daher die Aktivität von STAT3. Die ektopische Expression von INH3 in KRK-Zellen induzierte STAT3-abhängige EMT, Invasion und Migration. Die erhöhte Expression der INH3 in TP53-negativen CRC-Zellen war erforderlich für Hypoxie-induzierte EMT, Invasion, Migration und Chemo-Resistenz gegenüber 5-Fluorouracil, sowie für die Metastasierung von Xeno-transplantierten KRK-Zellen in Lungen von Mäusen. Adenome und abgeleitete Tumoroide von ApcMin/+ Mäusen mit Deletion von miR34a, miR34b und miR34c zeigten eine erhöhte INH3 Proteinexpression. Primäre KRKs von Patienten wiesen erhöhte INH3 Proteinexpression an der Invasionsfront im Vergleich zu anderen Bereichen des Tumors auf. Erhöhte INH3-Levels waren mit TP53-Mutationen und Lebermetastasen assoziiert. Insgesamt konnte gezeigt werden, dass die Expression von MIR34A in KRK-Zellen durch HIF1A inhibiert und durch p53 hingegen erhöht wird. MIR34A unterdrückt die Expression von INH3 und verhindert so die Aktivierung von STAT3 und hemmt EMT und Metastasierung. In der Zukunft könnten Strategien zur gezielten Beeinflussung dieses Signalwegs genutzt werden, um die Metastasierung von KRKs zu hemmen und die Hypoxie-induzierte Therapieresistenz beim KRK zu überwinden

Are Smell-Based Metrics Actually Useful in Effort-Aware Structural Change-Proneness Prediction? An Empirical Study

Bad code smells (also named as code smells) are symptoms of poor design choices in implementation. Existing studies empirically confirmed that the presence of code smells increases the likelihood of subsequent changes (i.e., change-proness). However, to the best of our knowledge, no prior studies have leveraged smell-based metrics to predict particular change type (i.e., structural changes). Moreover, when evaluating the effectiveness of smell-based metrics in structural change-proneness prediction, none of existing studies take into account of the effort inspecting those change-prone source code. In this paper, we consider five smell-based metrics for effort-aware structural change-proneness prediction and compare these metrics with a baseline of well-known CK metrics in predicting particular categories of change types. Specifically, we first employ univariate logistic regression to analyze the correlation between each smellbased metric and structural change-proneness. Then, we build multivariate prediction models to examine the effectiveness of smell-based metrics in effort-aware structural change-proneness prediction when used alone and used together with the baseline metrics, respectively. Our experiments are conducted on six Java open-source projects with up to 60 versions and results indicate that: (1) all smell-based metrics are significantly related to structural change-proneness, except metric ANS in hive and SCM in camel after removing confounding effect of file size; (2) in most cases, smell-based metrics outperform the baseline metrics in predicting structural change-proneness; and (3) when used together with the baseline metrics, the smell-based metrics are more effective to predict change-prone files with being aware of inspection effort

Crosstalk between Iron Metabolism and Erythropoiesis

Iron metabolism and erythropoiesis are inextricably linked. The majority of iron extracted from circulation daily is used for hemoglobin synthesis. In the last 15 years, major advances have been made in understanding the pathways regulating iron metabolism. Hepcidin is a key regulator of iron absorption and recycling and is itself regulated by erythropoiesis. While several viable candidates have been proposed, elucidating the “erythroid regulator” of hepcidin continues to generate significant experimental activity in the field. Although the mechanism responsible for sensing iron demand for erythropoiesis is still incompletely understood, evaluating diseases in which disordered erythropoiesis and/or iron metabolism are showcased has resulted in a more robust appreciation of potential candidates coordinated erythroid iron demand with regulators of iron supply. We present data drawn from four different conditions—iron deficiency, congenital hypotransferrinemia, beta-thalassemia, and hereditary hemochromatosis—both in human and non-human models of disease, together suggesting that erythroid iron demand exerts a stronger influence on circulating iron supply than systemic iron stores. Greater understanding of the interplay between the key factors involved in the regulation of iron metabolism and erythropoiesis will help develop more effective therapies for disorders of iron overload, iron deficiency, and hemoglobin synthesis

A Humble Opinion on the Architectural Construction of University Learning Organizations

AbstractIt is an important researching task for the higher education to change the traditional and purely rationalistic management ideas in the universities, to activate and strengthen the development energy. From the angle of changing the organizational model this paper researches the basic strategy of constructing university learning organizations; in another word: The organizational structure should be networking, and be oblater, opener and lexibler; and gives the architectural model of the learning organizations in the universities