q-Newton binomial: from Euler to Gauss

A counter-intuitive result of Gauss (formulae (1.6), (1.7) below) is made less mysterious by virtue of being generalized through the introduction of an additional parameter

Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits : A Multi-Ethnic Meta-Analysis of 45,891 Individuals

J. Kaprio, S. Ripatti ja M.-L. Lokki työryhmien jäseniä.Peer reviewe

Cost-effectiveness of colorectal cancer screening: Comparison of community-based flexible sigmoidoscopy with fecal occult blood testing and colonoscopy

Background and Aims:  To determine the cost-effectiveness of screening for colorectal cancer using flexible sigmoidoscopy once every 10 years, compared with annual and biennial rehydrated Hemoccult fecal occult blood testing and colonoscopy once every 10 years, or no screening. Methods:  A Markov model was developed in order to simulate the progression of a cohort of asymptomatic, average-risk individuals aged 55–64 years who were moving through a defined series of states towards death. The main outcome measures were: cases of colorectal cancer averted, colorectal cancer deaths averted, and cost per life-year saved. Results:  Colonoscopy averted the greatest number of cases of colorectal cancer (35%), followed by flexible sigmoidoscopy (25%), and annual (24%) and biennial (14%) fecal occult blood testing. Colonoscopy averted the greatest number of deaths from colorectal cancer (31%), followed by annual fecal occult blood testing (29%), flexible sigmoidoscopy (21%) and biennial fecal occult blood testing (19%). Flexible sigmoidoscopy was the most efficient in terms of cost per life-year saved (A$16 801), followed by colonoscopy (A$19 285), biennial (A$41 183), and annual (A$46 900) fecal occult blood testing. Conclusions:  Flexible sigmoidoscopy and colonoscopy are cost-effective strategies for reducing the disease burden of colorectal cancer

Cadmium stress dictates central carbon flux and alters membrane composition in Streptococcus pneumoniae

Metal ion homeostasis is essential for all forms of life. However, the breadth of intracellular impacts that arise upon dysregulation of metal ion homeostasis remain to be elucidated. Here, we used cadmium, a non-physiological metal ion, to investigate how the bacterial pathogen, Streptococcus pneumoniae, resists metal ion stress and dyshomeostasis. By combining transcriptomics, metabolomics and metalloproteomics, we reveal that cadmium stress dysregulates numerous essential cellular pathways including central carbon metabolism, lipid membrane biogenesis and homeostasis, and capsule production at the transcriptional and/or functional level. Despite the breadth of cellular pathways susceptible to metal intoxication, we show that S. pneumoniae is able to maintain viability by utilizing cellular pathways that are predominately metal-independent, such as the pentose phosphate pathway to maintain energy production. Collectively, this work provides insight into the cellular processes impacted by cadmium and how resistance to metal ion toxicity is achieved in S. pneumoniae.Stephanie L. Neville, Bart A. Eijkelkamp, Amber Lothian, James C. Paton, Blaine R. Roberts, Jason W. Rosch and Christopher A. McDevit

Micro-techniques for analysis of human adipose tissue fatty acid composition in dietary studies

Background and aims: Adipose tissue (AT) fatty acid (FA) composition is considered to be the gold standard long-term biomarker of dietary fatty acid intake. Typically this measurement is made directly from samples collected via large-needle-biopsy or incision. However, with growing interest in the role of AT in relation to health, ideally the fatty acid composition would be analysed along with other measurements, such as gene expression or histology, on a single AT sample. Here we assess alternative ways of obtaining AT for measuring FA composition, in some cases in conjunction with other measurements. Methods and results: The FA composition of tissue obtained via different methods was compared to that of tissue collected via large-needle or surgical biopsy. Fatty acid composition was not significantly different in AT collected by small-needle mini-biopsy (n = 10), from an RNA ‘lipid layer’ (obtained during RNA extraction, 2 sites, n = 6 for each), or from cryosectioned tissue prepared for histology (n = 10). We also assessed the usefulness of the composition of plasma NEFA as a surrogate marker of subcutaneous AT (n = 58–80). Most FAs in plasma NEFA correlated strongly with those in AT (P < 0.05). Conclusion: It is feasible to measure the FA composition of AT on very small amounts of tissue. Additionally, it is possible to measure FA composition on the lipid rich ‘by-product’ of AT samples undergoing RNA extraction for gene expression. Samples sectioned for histology are also suitable. This provides further opportunities for multidisciplinary collaborations that may lead to a better application of dietary biomarkers

Host-Mediated Copper Stress Is Not Protective against Streptococcus pneumoniae D39 Infection

Metal ions are required by all organisms for the chemical processes that support life. However, in excess they can also exert toxicity within biological systems. During infection, bacterial pathogens such as Streptococcus pneumoniae are exposed to host-imposed metal intoxication, where the toxic properties of metals, such as copper, are exploited to aid in microbial clearance. However, previous studies investigating the antimicrobial efficacy of copper in vivo have reported variable findings. Here, we use a highly copper-sensitive strain of S. pneumoniae, lacking both copper efflux and intracellular copper buffering by glutathione, to investigate how copper stress is managed and where it is encountered during infection. We show that this strain exhibits highly dysregulated copper homeostasis, leading to the attenuation of growth and hyperaccumulation of copper in vitro. In a murine infection model, whole-tissue copper quantitation and elemental bioimaging of the murine lung revealed that infection with S. pneumoniae resulted in increased copper abundance in specific tissues, with the formation of spatially discrete copper hot spots throughout the lung. While the increased copper was able to reduce the viability of the highly copper-sensitive strain in a pneumonia model, copper levels in professional phagocytes and in a bacteremic model were insufficient to prosecute bacterial clearance. Collectively, this study reveals that host copper is redistributed to sites of infection and can impact bacterial viability in a hypersusceptible strain. However, in wildtype S. pneumoniae, the concerted actions of the copper homeostatic mechanisms are sufficient to facilitate continued viability and virulence of the pathogen. IMPORTANCE Streptococcus pneumoniae (the pneumococcus) is one of the world’s foremost bacterial pathogens. Treatment of both localized and systemic pneumococcal infection is becoming complicated by increasing rates of multidrug resistance globally. Copper is a potent antimicrobial agent used by the mammalian immune system in the defense against bacterial pathogens. However, unlike other bacterial species, this copper stress is unable to prosecute pneumococcal clearance. This study determines how the mammalian host inflicts copper stress on S. pneumoniae and the bacterial copper tolerance mechanisms that contribute to maintenance of viability and virulence in vitro and in vivo. This work has provided insight into the chemical biology of the hostpneumococcal interaction and identified a potential avenue for novel antimicrobial development.Stephanie L. Neville, Bliss A. Cunningham, Eve A. Maunders, Aimee Tan, Jacinta A. Watts, Katherine Ganio, Bart A. Eijkelkamp, Victoria G. Pederick, Raquel GonzalezdeVega, David Clases, Philip A. Doble, Christopher A. McDevit

Structural and functional properties of deep abdominal subcutaneous adipose tissue explain its association with insulin resistance and cardiovascular risk in men

OBJECTIVE Fat distribution is an important variable explaining metabolic heterogeneity of obesity. Abdominal subcutaneous adipose tissue (SAT) is divided by the Scarpa's fascia into a deep subcutaneous adipose tissue (dSAT) and a superficial subcutaneous adipose tissue (sSAT) layer. This study sought to characterize functional differences between the two SAT layers to explore their relative contribution to metabolic traits and cardiovascular risk (CVR) profile. RESEARCH DESIGN AND METHODS We recruited 371 Caucasians consecutively from a local random, populationbased screening project in Oxford and 25 Asian Indians fromthe local community. The depth of the SAT layers was determined by ultrasound (US), and adipose tissue (AT) biopsies were performed under US guidance in a subgroup of 43 Caucasians. Visceral adipose tissue (VAT) mass was quantified by dual-energy X-ray absorptiometry scan. RESULTS Male adiposity in both ethnic groups was characterized by a disproportionate expansion of dSAT, which was strongly correlated with VAT mass. dSAT depth was a strong predictor of global insulin resistance (IR; homeostatic model assessment of IR), liver-specific IR (insulin-like growth factor binding protein-1), and Framingham risk score independently of other measures of adiposity in men. Moreover, dSAT had higher expression of proinflammatory, lipogenic, and lipolytic genes and contained higher proportions of saturated fatty acids. There was increased proportion of small adipocytes in dSAT. CONCLUSIONS SAT is heterogeneous; dSAT expands disproportionally more than sSAT with increasing obesity in Caucasian males (confirmed also in Asian Indians). Its expansion is related to increased CVR independent of other adiposity measures, and it has biological properties suggestive of higher metabolic activity contributing to global IR.© 2014 by the American Diabetes Association

Dysregulation of Streptococcus pneumoniae zinc homeostasis breaks ampicillin resistance in a pneumonia infection model

Streptococcus pneumoniae is the primary cause of community-acquired bacterial pneumonia with rates of penicillin and multidrug-resistance exceeding 80% and 40%, respectively. The innate immune response generates a variety of antimicrobial agents to control infection, including zinc stress. Here, we characterize the impact of zinc intoxication on S. pneumoniae, observing disruptions in central carbon metabolism, lipid biogenesis, and peptidoglycan biosynthesis. Characterization of the pivotal peptidoglycan biosynthetic enzyme GlmU indicates a sensitivity to zinc inhibition. Disruption of the sole zinc efflux pathway, czcD, renders S. pneumoniae highly susceptible to β-lactam antibiotics. To dysregulate zinc homeostasis in the wild-type strain, we investigated the safe-for-human-use ionophore 5,7-dichloro-2-[(dimethylamino)methyl]quinolin-8-ol (PBT2). PBT2 rendered wild-type S. pneumoniae strains sensitive to a range of antibiotics. Using an invasive ampicillin-resistant strain, we demonstrate in a murine pneumonia infection model the efficacy of PBT2 + ampicillin treatment. These findings present a therapeutic modality to break antibiotic resistance in multidrug-resistant S. pneumoniae