Dietary divalent metal uptake and interactions in freshwater fish : implications for metal toxicity

The overall goal of the present research project was to investigate the physiology of dietary iron absorption and its interactions with the uptake and metabolism of other divalent metals, especially cadmium, in freshwater fish, using rainbow trout (Oncorhynchus mykiss) as a model species. Using intestinal sac preparations, iron absorption was found to occur along the entire intestinal tract of fish, with anterior intestine being the major site of absorption compared to either mid or posterior intestine. Ferrous iron was more bioavailable than ferric iron, and the uptake of ferrous iron was significantly reduced at alkaline pH (p < 0.05). These findings suggested that a homolog of the mammalian apical ferrous iron transporter, divalent metal transporter-1 (DMT1, a Fe2+/H+ symporter), is involved in the absorption of iron in the fish intestine. Ferric iron appeared to be absorbed through the same pathway as ferrous iron following reduction by an apical ferric reductase. Several divalent metals, both essential (nickel, copper and zinc) and non-essential (cadmium and lead), inhibited intestinal ferrous iron absorption in fish. Importantly, elevated luminal iron reciprocally reduced the accumulation of cadmium in the fish intestine, indicating the significance of the iron transport pathway in dietary cadmium absorption. Two different DMT1 isoforms, Nramp-â and -ã, were found to be expressed along the entire gastrointestinal tract of fish. My study showed that in isolated rainbow trout enterocytes, ferrous iron uptake occurred through a saturable and proton-dependent process, providing further evidence of DMT1-mediated ferrous iron transport. Both cadmium and lead inhibited ferrous iron uptake in the enterocytes in a concentration-dependent manner. Kinetic characterization revealed that the apparent affinity for ferrous iron uptake is significantly decreased (increased Km) in the presence of either cadmium or lead (p < 0.05), whereas the maximum uptake rate (Jmax) remains unchanged. These results indicated that the interaction between ferrous iron and cadmium or lead is competitive in nature, and the uptake of these metals occurs through a common transport pathway (likely DMT1). The uptake characteristics of cadmium were further examined in isolated rainbow trout enterocytes, and my findings indicated that in addition to DMT1, cadmium uptake can be mediated by zinc transport pathway (ZIP8, a Zn2+/HCO3- symporter). My study also showed that cysteine-conjugated cadmium was readily bioavailable to fish enterocytes, possibly via a cysteine-specific transport pathway. The efflux of cadmium from the enterocytes was found to occur via an ATPase-driven pathway. On the other hand, chronic exposure to dietary cadmium at an environmentally-relevant concentration significantly increased cadmium burden in target organs as well as in the whole-body of fish (p < 0.05). Exposure to dietary cadmium increased the mRNA expression level of key stress-inducible proteins such as metallothioneins (MT-A and MT-B) and heat shock proteins-70 (HSP-70a and HSP-70b). Interestingly, each MT and HSP-70 mRNA isoform responded differently in various target organs of fish following dietary cadmium exposure. Fish exposed to dietary cadmium also exhibited an increase in the hepatic transferrin mRNA level as well as the plasma transferrin protein level, indicating the role of transferrin in cadmium handling in fish. Importantly, an iron-supplemented diet reduced cadmium burden in the gut and the whole-body, and ameliorated the expression of MT and HSP-70 genes in fish. These results suggested the protective effects of elevated dietary iron against chronic dietary cadmium toxicity in fish. Overall, findings from the present research project provided novel and important physiological and molecular insights into the uptake, interactions and homeostasis of dietary divalent metals in freshwater fish. This information greatly enhances our current understanding of the toxicological implications for dietary metal exposure in metal contaminated wild fish populations, and may ultimately help the regulators to develop better strategies for ecological risk assessment of metals

Effects of Consumer Preferences on Endogenous Switching Costs

The paper provides a model that assesses the set of complementary components of varying compatibility and its effect towards consumer adoption decisions. The smartphone market is a system good which utilizes the device and a set of compatible applications (apps). The amount of switching costs may vary depending upon the consumer’s decision to switch devices or across platforms. Analyzing the Android ecosystem, the process of custom ROMs (and rooting) and the large set of games, news, etc. apps justify the existence of device-specific and platform-specific apps. The model reinforces the findings of a survey conducted by UBS suggesting the retention rate (i.e. level of switch costs) of Apple users is higher than Android users. The retention among Android devices is much lower in comparison as well. The model observes that the product fragmentation and the interdependence of apps lead to the noticeably lower retention rates across Android devices and platforms

Oscillation and convergence behaviors exhibited in an ‘unstable’ second-order digital filter with saturation-type nonlinearity

This letter explains the oscillatory behaviors exhibited in a second-order digital filter with saturation-type nonlinearity via the Hopf bifurcation theorem. It is shown that depending on the bifurcation parameter, the state variables may converge to zero even when the eigenvalues of the system matrix are outside the unit circle

Improvement of myocardial perfusion reserve detected by cardiovascular magnetic resonance after direct endomyocardial implantation of autologous bone marrow cells in patients with severe coronary artery disease

<p>Abstract</p> <p>Background</p> <p>Recent studies suggested that bone marrow (BM) cell implantation in patients with severe chronic coronary artery disease (CAD) resulted in modest improvement in symptoms and cardiac function. This study sought to investigate the functional changes that occur within the chronic human ischaemic myocardium after direct endomyocardial BM cells implantation by cardiovascular magnetic resonance (CMR).</p> <p>Methods and Results</p> <p>We compared the interval changes of left ventricular ejection fraction (LVEF), myocardial perfusion reserve and the extent of myocardial scar by using late gadolinium enhancement CMR in 12 patients with severe CAD. CMR was performed at baseline and at 6 months after catheter-based direct endomyocardial autologous BM cell (n = 12) injection to viable ischaemic myocardium as guided by electromechanical mapping. In patients randomized to receive BM cell injection, there was significant decrease in percentage area of peri-infarct regions (-23.6%, <it>P </it>= <it>0.04</it>) and increase in global LVEF (+9.0%, <it>P </it>= <it>0.02</it>), the percentage of regional wall thickening (+13.1%, <it>P= 0.04</it>) and MPR (+0.25%, <it>P </it>= <it>0.03</it>) over the target area at 6-months compared with baseline.</p> <p>Conclusions</p> <p>Direct endomyocardial implantation of autologous BM cells significantly improved global LVEF, regional wall thickening and myocardial perfusion reserve, and reduced percentage area of peri-infarct regions in patients with severe CAD.</p

The role of Clostridium perfringens in intestinal diseases

Clostridium perfringens, a spore-forming bacterium that produces >20 toxins, is known to cause both human and animal intestinal diseases including; foodborne diarrhoea, preterm necrotising enterocolitis (NEC) and necrotic enteritis (NE) in chickens. Currently, there is very limited information on genomic virulence determinants, and the phylogenic and epidemiology landscape of this enteric pathogen, thus in this thesis I sought to comprehensively explore intestinal-associated C. perfringens strains using both genomic and phenotypic methodologies. Whole Genome Sequencing (WGS) and bioinformatic approaches was used to examine a novel collection of C. perfringens isolates and publically available genomes (n=552, including 109 public genomes) from a diverse range of hosts and disease states including; NEC-associated preterm infants, foodborne diarrhoea patients, NEassociated broilers, and healthy humans and animals. These genomes were analysed in combination or as discreet disease subsets to determine infection-linked virulence features, genomic epidemiology and hyper-virulent genotypes, and indicated a highly diverse pangenome (7.4% core genome), toxin-specific and novel virulence factors, widespread distribution of conjugative plasmids, long-term persistence, and interregional transmission events during disease outbreaks. This work represents the largest WGS-based phylogenetic and comparative genomics on C. perfringens to date. Furthermore, a sub-set of C. perfringens isolates were characterised phenotypically using microbiological assays to determine hyper-virulent phenotypes, which linked to genomic analysis. These hyper-virulent strains were then used to establish a novel C. perfringens oral-challenge mouse model. This enteric infection model will allow further mechanistic work in understanding the role of C. perfringens in relevant intestinal diseases and may be used to facilitate therapy or vaccine development. Overall, this multidisciplinary work provides important novel insights into the intestinal pathogen C. perfringens at both a genomic and phenotypic level and provides a platform for subsequent translational studies into efforts to reduce C. perfringens-associated disease burden in both humans and animals

Structural properties and estimation of delay systems.

Thesis. 1975. Ph.D.--Massachusetts Institute of Technology. Dept. of Electrical Engineering and Computer Science.Vita.Includes bibliographical references.Ph.D