Discrete Convex Functions on Graphs and Their Algorithmic Applications

The present article is an exposition of a theory of discrete convex functions on certain graph structures, developed by the author in recent years. This theory is a spin-off of discrete convex analysis by Murota, and is motivated by combinatorial dualities in multiflow problems and the complexity classification of facility location problems on graphs. We outline the theory and algorithmic applications in combinatorial optimization problems

Microbial community succession on developing lesions on human enamel

Dental caries is one of the most common diseases in the world. However, our understanding of how the microbial community composition changes in vivo as caries develops is lacking.An in vivo model was used in a longitudinal cohort study to investigate shifts in the microbial community composition associated with the development of enamel caries.White spot lesions were generated in vivo on human teeth predetermined to be extracted for orthodontic reasons. The bacterial microbiota on sound enamel and on developing carious lesions were identified using the Human Oral Microbe Identification Microarray (HOMIM), which permits the detection of about 300 of the approximate 600 predominant bacterial species in the oral cavity.After only seven weeks, 75% of targeted teeth developed white spot lesions (8 individuals, 16 teeth). The microbial community composition of the plaque over white spot lesions differed significantly as compared to sound enamel. Twenty-five bacterial taxa, including Streptococcus mutans, Atopobium parvulum, Dialister invisus, and species of Prevotella and Scardovia, were significantly associated with initial enamel lesions. In contrast, 14 bacterial taxa, including species of Fusobacterium, Campylobacter, Kingella, and Capnocytophaga, were significantly associated with sound enamel.The bacterial community composition associated with the progression of enamel lesions is specific and much more complex than previously believed. This investigation represents one of the first longitudinally-derived studies for caries progression and supports microbial data from previous cross-sectional studies on the development of the disease. Thus, the in vivo experiments of generating lesions on teeth destined for extraction in conjunction with HOMIM analyses represent a valid model to study succession of supragingival microbial communities associated with caries development and to study efficacy of prophylactic and restorative treatments

SirT1 modulates the estrogen–insulin-like growth factor-1 signaling for postnatal development of mammary gland in mice

INTRODUCTION: Estrogen and insulin-like growth factor-1 (IGF-1) play important roles in mammary gland development and breast cancer. SirT1 is a highly conserved protein deacetylase that can regulate the insulin/IGF-1 signaling in lower organisms, as well as a growing number of transcription factors, including NF-κB, in mammalian cells. Whether SirT1 regulates the IGF-1 signaling for mammary gland development and function, however, is not clear. In the present study, this role of SirT1 was examined by studying SirT1-deficient mice. METHODS: SirT1-deficient (SirT1(ko/ko)) mice were generated by crossing a new strain of mice harboring a conditional targeted mutation in the SirT1 gene (SirT1(co/co)) with CMV-Cre transgenic mice. Whole mount and histology analyses, immunofluorescence staining, immunohistochemistry, and western blotting were used to characterize mammary gland development in virgin and pregnant mice. The effect of exogenous estrogen was also examined by subcutaneous implantation of a slow-releasing pellet in the subscapular region. RESULTS: Both male and female SirT1(ko/ko )mice can be fertile despite the growth retardation phenotype. Virgin SirT1(ko/ko )mice displayed impeded ductal morphogenesis, whereas pregnant SirT1(ko/ko )mice manifested lactation failure due to an underdeveloped lobuloalveolar network. Estrogen implantation was sufficient to rescue ductal morphogenesis. Exogenous estrogen reversed the increased basal level of IGF-1 binding protein-1 expression in SirT1(ko/ko )mammary tissues, but not that of IκBα expression, suggesting that increased levels of estrogen enhanced the production of local IGF-1 and rescued ductal morphogenesis. Additionally, TNFα treatment enhanced the level of the newly synthesized IκBα in SirT1(ko/ko )cells. SirT1 deficiency therefore affects the cellular response to multiple extrinsic signals. CONCLUSION: SirT1 modulates the IGF-1 signaling critical for both growth regulation and mammary gland development in mice. SirT1 deficiency deregulates the expression of IGF-1 binding protein-1 and attenuates the effect of IGF-1 signals, including estrogen-stimulated local IGF-1 signaling for the onset of ductal morphogenesis. These findings suggest that the enzymatic activity of SirT1 may influence both normal growth and malignant growth of mammary epithelial cells

Pubertal high fat diet: effects on mammary cancer development

INTRODUCTION: Epidemiological studies linking dietary fat intake and obesity to breast cancer risk have produced inconsistent results. This may be due to the difficulty of dissociating fat intake from obesity, and/or the lack of defined periods of exposure in these studies. The pubertal mammary gland is highly sensitive to cancer-causing agents. We assessed how high fat diet (HFD) affects inflammation, proliferative, and developmental events in the pubertal gland, since dysregulation of these can promote mammary tumorigenesis. To test the effect of HFD initiated during puberty on tumorigenesis, we utilized BALB/c mice, for which HFD neither induces obesity nor metabolic syndrome, allowing dissociation of HFD effects from other conditions associated with HFD. METHODS: Pubertal BALB/c mice were fed a low fat diet (12% kcal fat) or a HFD (60% kcal fat), and subjected to carcinogen 7,12-dimethylbenz[a]anthracene (DMBA)-induced tumorigenesis. RESULTS: HFD elevated mammary gland expression of inflammatory and growth factor genes at 3 and 4 weeks of diet. Receptor activator of nuclear factor kappa-B ligand (RANKL), robustly induced at 4 weeks, has direct mitogenic activity in mammary epithelial cells and, as a potent inducer of NF-κB activity, may induce inflammatory genes. Three weeks of HFD induced a transient influx of eosinophils into the mammary gland, consistent with elevated inflammatory factors. At 10 weeks, prior to the appearance of palpable tumors, there were increased numbers of abnormal mammary epithelial lesions, enhanced cellular proliferation, increased growth factors, chemokines associated with immune-suppressive regulatory T cells, increased vascularization, and elevated M2 macrophages. HFD dramatically reduced tumor latency. Early developing tumors were more proliferative and were associated with increased levels of tumor-related growth factors, including increased plasma levels of HGF in tumor-bearing animals. Early HFD tumors also had increased vascularization, and more intra-tumor and stromal M2 macrophages. CONCLUSIONS: Taken together in this non-obesogenic context, HFD promotion of inflammatory processes, as well as local and systemically increased growth factor expression, are likely responsible for the enhanced tumorigenesis. It is noteworthy that although DMBA mutagenesis is virtually random in its targeting of genes in tumorigenesis, the short latency tumors arising in animals on HFD showed a unique gene expression profile, highlighting the potent overarching influence of HFD

Identifying Low pH Active and Lactate-Utilizing Taxa within Oral Microbiome Communities from Healthy Children Using Stable Isotope Probing Techniques

<div><h3>Background</h3><p>Many human microbial infectious diseases including dental caries are polymicrobial in nature. How these complex multi-species communities evolve from a healthy to a diseased state is not well understood. Although many health- or disease-associated oral bacteria have been characterized <em>in vitro</em>, their physiology within the complex oral microbiome is difficult to determine with current approaches. In addition, about half of these species remain uncultivated to date with little known besides their 16S rRNA sequence. Lacking culture-based physiological analyses, the functional roles of uncultivated species will remain enigmatic despite their apparent disease correlation. To start addressing these knowledge gaps, we applied a combination of Magnetic Resonance Spectroscopy (MRS) with RNA and DNA based Stable Isotope Probing (SIP) to oral plaque communities from healthy children for <em>in vitro</em> temporal monitoring of metabolites and identification of metabolically active and inactive bacterial species.</p> <h3>Methodology/Principal Findings</h3><p>Supragingival plaque samples from caries-free children incubated with ¹³C-substrates under imposed healthy (buffered, pH 7) and diseased states (pH 5.5 and pH 4.5) produced lactate as the dominant organic acid from glucose metabolism. Rapid lactate utilization upon glucose depletion was observed under pH 7 conditions. SIP analyses revealed a number of genera containing cultured and uncultivated taxa with metabolic capabilities at pH 5.5. The diversity of active species decreased significantly at pH 4.5 and was dominated by <em>Lactobacillus</em> and <em>Propionibacterium</em> species, both of which have been previously found within carious lesions from children.</p> <h3>Conclusions/Significance</h3><p>Our approach allowed for identification of species that metabolize carbohydrates under different pH conditions and supports the importance of Lactobacilli and Propionibacterium in the development of childhood caries. Identification of species within healthy subjects that are active at low pH can lead to a better understanding of oral caries onset and generate appropriate targets for preventative measures in the early stages.</p> </div

Claudins in lung diseases

Tight junctions are the most apically localized part of the epithelial junctional complex. They regulate the permeability and polarity of cell layers and create compartments in cell membranes. Claudins are structural molecules of tight junctions. There are 27 claudins known, and expression of different claudins is responsible for changes in the electrolyte and solute permeability in cells layers. Studies have shown that claudins and tight junctions also protect multicellular organisms from infections and that some infectious agents may use claudins as targets to invade and weaken the host's defense. In neoplastic diseases, claudin expression may be up- or downregulated. Since their expression is associated with specific tumor types or with specific locations of tumors to a certain degree, they can, in a restricted sense, also be used as tumor markers. However, the regulation of claudin expression is complex involving growth factors and integrins, protein kinases, proto-oncogens and transcription factors. In this review, the significance of claudins is discussed in lung disease and development

Webometrics benefitting from web mining? An investigation of methods and applications of two research fields

Webometrics and web mining are two fields where research is focused on quantitative analyses of the web. This literature review outlines definitions of the fields, and then focuses on their methods and applications. It also discusses the potential of closer contact and collaboration between them. A key difference between the fields is that webometrics has focused on exploratory studies, whereas web mining has been dominated by studies focusing on development of methods and algorithms. Differences in type of data can also be seen, with webometrics more focused on analyses of the structure of the web and web mining more focused on web content and usage, even though both fields have been embracing the possibilities of user generated content. It is concluded that research problems where big data is needed can benefit from collaboration between webometricians, with their tradition of exploratory studies, and web miners, with their tradition of developing methods and algorithms