Glucose Homeostatic Law: Insulin Clearance Predicts the Progression of Glucose Intolerance in Humans

Homeostatic control of blood glucose is regulated by a complex feedback loop between glucose and insulin, of which failure leads to diabetes mellitus. However, physiological and pathological nature of the feedback loop is not fully understood. We made a mathematical model of the feedback loop between glucose and insulin using time course of blood glucose and insulin during consecutive hyperglycemic and hyperinsulinemic-euglycemic clamps in 113 subjects with variety of glucose tolerance including normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM). We analyzed the correlation of the parameters in the model with the progression of glucose intolerance and the conserved relationship between parameters. The model parameters of insulin sensitivity and insulin secretion significantly declined from NGT to IGT, and from IGT to T2DM, respectively, consistent with previous clinical observations. Importantly, insulin clearance, an insulin degradation rate, significantly declined from NGT, IGT to T2DM along the progression of glucose intolerance in the mathematical model. Insulin clearance was positively correlated with a product of insulin sensitivity and secretion assessed by the clamp analysis or determined with the mathematical model. Insulin clearance was correlated negatively with postprandial glucose at 2h after oral glucose tolerance test. We also inferred a square-law between the rate constant of insulin clearance and a product of rate constants of insulin sensitivity and secretion in the model, which is also conserved among NGT, IGT and T2DM subjects. Insulin clearance shows a conserved relationship with the capacity of glucose disposal among the NGT, IGT and T2DM subjects. The decrease of insulin clearance predicts the progression of glucose intolerance.     

Comparison of brain–computer interface decoding algorithms in open-loop and closed-loop control

Neuroprosthetic devices such as a computer cursor can be controlled by the activity of cortical neurons when an appropriate algorithm is used to decode motor intention. Algorithms which have been proposed for this purpose range from the simple population vector algorithm (PVA) and optimal linear estimator (OLE) to various versions of Bayesian decoders. Although Bayesian decoders typically provide the most accurate off-line reconstructions, it is not known which model assumptions in these algorithms are critical for improving decoding performance. Furthermore, it is not necessarily true that improvements (or deficits) in off-line reconstruction will translate into improvements (or deficits) in on-line control, as the subject might compensate for the specifics of the decoder in use at the time. Here we show that by comparing the performance of nine decoders, assumptions about uniformly distributed preferred directions and the way the cursor trajectories are smoothed have the most impact on decoder performance in off-line reconstruction, while assumptions about tuning curve linearity and spike count variance play relatively minor roles. In on-line control, subjects compensate for directional biases caused by non-uniformly distributed preferred directions, leaving cursor smoothing differences as the largest single algorithmic difference driving decoder performance.     

Effects of Parenteral Supply of Iron on RBC Parameters,Performance, and Health in Neonatal Dairy Calves

The present study was designed to evaluate the effects of parenteral iron on red blood cell parameters, performance, and health in dairy Holstein calves. Twenty neonatal calves were equally divided at random into two groups, one of which served as controls. Care was taken to ensure homogeneity of sex, age, and general health status of the animals. The controls received a normal diet and water ad libitum, while the study animals were injected with 1 g iron as Fe-dextran 2 days after birth. A daily record was kept of the calves’ weight and growth parameters. At periods of 24–48 h after birth and at 14, 28, and 42 days of age, jugular blood was drawn from all the experimental and control animals to measure the packed cell volume, red blood count, hemoglobin, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and iron levels. At the start of the experiments, there were no significant differences between these parameters between the two study groups (p > 0.05). With time, significant differences were seen between most of the values measured (p < 0.05) except for the mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and iron level. Significant differences were seen for total weight gain and mean daily weight gain, which were higher in the iron-supplemented group (p < 0.05).     

Response of antioxidative enzymes and apoplastic bypass transport in Thlaspi caerulescens and Raphanus sativus to cadmium stress

A hydroponics experiment using hyperaccumulator Thlaspi caerulescens (alpine pennycress) and non-specific accumulator Raphanus sativus (common radish) was conducted to investigate the short-term effect of increasing Cd concentrations (0, 25, 50, 75, 100 microM) on metal uptake, chlorophyll content, antioxidative enzymes, and apoplastic bypass flow. As expected, T. caerulescens generally showed better resistance to metal stress, which was reflected by higher Cd accumulation within plant tissues with no signs of chlorosis, or wilt. Glutathione reductase (GR) and superoxide dismutase (SOD) activities in fresh leaves were monitored as the plant metal-detoxifying response. In general, both plant species exhibited an increase trend of GR activity before declining at 100 microM likely due to excessive levels of phytotoxic Cd. SOD activity exhibited almost a similar variation pattern to GR and decreased also at 100 microM Cd. For both plant species, fluorescent PTS uptake (8-hydroxy-1,3,6-pyrenetrisulphonic acid) increased significantly with metal level in exposure solutions indicating that Cd has a comparable effect to drought or salinity in terms of the gain of relative importance in apoplastic bypass transport under such stress conditions.     

Piwi expression in archeocytes and choanocytes in demosponges: insights into the stem cell system in demosponges

SUMMARY Little is known about the stem cells of organisms early in metazoan evolution. To characterize the stem cell system in demosponges, we identified Piwi homologs of a freshwater sponge, Ephydatia fluviatilis, as candidate stem cell (archeocyte) markers. EfPiwiA mRNA was expressed in cells with archeocyte cell morphological features. We demonstrated that these EfPiwiA‐expressing cells were indeed stem cells by showing their ability to proliferate, as indicated by BrdU‐incorporation, and to differentiate, as indicated by the coexpression of EfPiwiA with cell‐lineage‐specific genes in presumptive committed archeocytes. EfPiwiA mRNA expression was maintained in mature choanocytes forming chambers, in contrast to the transition of gene expression from EfPiwiA to cell‐lineage‐specific markers during archeocyte differentiation into other cell types. Choanocytes are food‐entrapping cells with morphological features similar to those of choanoflagellates (microvillus collar and a flagellum). Their known abilities to transform into archeocytes under specific circumstances and to give rise to gametes (mostly sperm) indicate that even when they are fully differentiated, choanocytes maintain pluripotent stem cell‐like potential. Based on the specific expression of EfPiwiA in archeocytes and choanocytes, combined with previous studies, we propose that both archeocytes and choanocytes are components of the demosponge stem cell system. We discuss the possibility that choanocytes might represent the ancestral stem cells, whereas archeocytes might represent stem cells that further evolved in ancestral multicellular organisms.     

Contrasting Effects of the Cytotoxic Anticancer Drug Gemcitabine and the EGFR Tyrosine Kinase Inhibitor Gefitinib on NK Cell-Mediated Cytotoxicity via Regulation of NKG2D Ligand in Non-Small-Cell Lung Cancer Cells

IntroductionSeveral cytotoxic anticancer drugs inhibit DNA replication and/or mitosis, while EGFR tyrosine kinase inhibitors inactivate EGFR signalling in cancer cell. Both types of anticancer drugs improve the overall survival of the patients with non-small-cell lung cancer (NSCLC), although tumors often become refractory to this treatment. Despite several mechanisms by which the tumors become resistant having been described the effect of these compounds on anti-tumor immunity remains largely unknown.MethodsThis study examines the effect of the cytotoxic drug Gemcitabine and the EGFR tyrosine kinase inhibitor Gefitinib on the expression of NK group 2 member D (NKG2D) ligands as well as the sensitivity of NSCLC cells to the NK-mediated lysis.ResultsWe demonstrate that Gemcitabine treatment leads to an enhanced expression, while Gefitinib downregulated the expression of molecules that act as key ligands for the activating receptor NKG2D and promote NK cell-mediated recognition and cytolysis. Gemcitabine activated ATM and ATM- and Rad-3-related protein kinase (ATR) pathways. The Gemcitabine-induced phosphorylation of ATM as well as the upregulation of the NKG2D ligand expression could be blocked by an ATM-ATR inhibitor. In contrast, Gefitinib attenuated NKG2D ligand expression. Silencing EGFR using siRNA or addition of the PI3K inhibitor resulted in downregulation of NKG2D ligands. The observations suggest that the EGFR/PI3K pathway also regulates the expression of NKG2D ligands. Additionally, we showed that both ATM-ATR and EGFR regulate MICA/B via miR20a.ConclusionIn keeping with the effect on NKG2D expression, Gemcitabine enhanced NK cell-mediated cytotoxicity while Gefitinib attenuated NK cell killing in NSCLC cells.     

Intracellular localization of alkaline phosphatase in freshly isolated foetal rat hepatocytes

Summary The cytochemical localization of alkaline phosphatase activity in foetal rat hepatocytes was examined in relation to the pattern of cell to cell attachment during cell isolation and culture. In foetal hepatocytesin vivo, alkaline phosphatase was exclusively localized on the bile canalicular membrane. In freshly isolated foetal hepatocytes, however, the activity was present in the endoplasmic reticulum, nuclear envelope, Golgi apparatus, tubulo-vesicular organelles, and over the entire plasma membrane. In monolayer cells cultured for one or two days, the activity was localized on the reconstituted bile canalicular membrane, plasma membrane sites adjacent to neighbouring cells and on the bottom surface of the monolayer, but was detected in none of the intracellular organelles. Biochemical alkaline phosphatase activity did not change during isolation of the cells. These results suggest that, in foetal hepatocytes, loss of cell—cell contact may induce a temporal disturbance, or dedifferentiation, in their membrane system.     

Kinetics and collagenolytic role of eosinophils in chronic gastric ulcer in the rat

 An association between eosinophils and tissue damage has been observed in numerous disorders. However, few reports have addressed the role of infiltrating eosinophils in gastric ulcer healing. The aim of this study was to investigate the kinetics and role of eosinophils infiltrating experimental chronic gastric ulcers in the rat. We developed a monoclonal antibody against human matrix metalloproteinase 1 (MMP1) purified from conditioned culture medium of human skin fibroblasts. Acetic acid-induced gastric ulcers were resected from rats on days 1, 3, 5, 10, 20, 40, and 180 after the days of induction (day 0). Tissue specimens were immunostained with this antibody and examined with an electron microscope. Few eosinophils were observed in the granulation tissue until day 20. By days 40 and 180, MMP1-positive eosinophils had increased in the granulation tissue of open ulcers. Azan staining revealed dispersed collagen fibers around infiltrating eosinophils. In contrast, scars demonstrated few eosinophils in fibrous tissue on days 40 and 180. Eosinophils which express MMP1 infiltrate granulation tissue at the chronic stage of gastric ulceration. The results suggest that eosinophils may play a role in tissue remodeling and deterioration of ulceration. Accepted: 18 March 1997     

Evolution of indirect reciprocity in groups of various sizes and comparison with direct reciprocity

Recently many studies have investigated the evolution of indirect reciprocity through which cooperative action is returned by a third individual, e.g. individual A helped B and then receives help from C. Most studies on indirect reciprocity have presumed that only two individuals take part in a single interaction (group), e.g. A helps B and C helps A. In this paper, we investigate the evolution of indirect reciprocity when more than two individuals take part in a single group, and compare the result with direct reciprocity through which cooperative action is directly returned by the recipient. Our analyses show the following. In the population with discriminating cooperators and unconditional defectors, whether implementation error is included or not, (i) both strategies are evolutionarily stable and the evolution of indirect reciprocity becomes more difficult as group size increases, and (ii) the condition for the evolution of indirect reciprocity under standing reputation criterion where the third individuals distinguish between justified and unjustified defections is more relaxed than that under image scoring reputation criterion in which the third individuals do not distinguish with. Furthermore, in the population that also includes unconditional cooperators, (iii) in the presence of errors in implementation, the discriminating strategy is evolutionarily stable not only under standing but also under image scoring if group size is larger than two. Finally, (iv) in the absence of errors in implementation, the condition for the evolution of direct reciprocity is equivalent to that for the evolution of indirect reciprocity under standing, and, in the presence of errors, the condition for the evolution of direct reciprocity is very close to that for the evolution of indirect reciprocity under image scoring.