On the control of ecdysone biosynthesis by the central nervous system of blowfly larvae

Ecdysone was found to be the major secreted steroid of ring glands dissected from blowfly larvae and incubated in vitro. Other secretory products such as 3-dehydroecdysone and 20-deoxy-makisterone A could not be detected when the glands were labelled with tritiated cholesterol. Ecdysone synthesis and secretion were found to be tightly coupled. The highest rate of secretion was observed a few hours before pupariation. In vitro, the rate of ecdysone secretion by ring glands was affected significantly by coincubation with the central nervous system (CNS). Modulating effects from the CNS to the gland were mediated both by culture medium and by nerve connections. Distinct parts of the CNS revealed multiple and partially opposite effects on ecdysone secretion, suggesting a more complex control than had been anticipated. Multiple neural control systems appear to be involved. Moreover, the observed effects changed with development during the second half of the third instar, reflecting a significant plasticity of neural control. © 1993 Wiley-Liss, Inc.     

Quorum-sensing- and type VI secretion-mediated spatiotemporal cell death drives genetic diversity in Vibrio cholerae

1. Download : Download high-res image (186KB)
2. Download : Download full-size image

     

Slow and steady is the key to β-cell replication

The β-cells of the pancreas are responsible for insulin production and their destruction results in type I diabetes. β-cell maintenance, growth and regenerative repair is thought to occur predominately, if not exclusively, through the replication of existing β-cells, not via an adult stem cell. It was recently found that all β-cells contribute equally to islet growth and maintenance. The fact that all β-cells replicate homogeneously makes it possible to set up straightforward screens for factors that increase β-cell replication either In vitro or in vivo . It is possible that a circulating factor may be capable of increasing β-cell replication or that intrinsic cell cycle regulators may affect β-cell growth. An improved understanding of the in vivo maintenance and growth of β-cells will facilitate efforts to expand β-cells In vitro and may lead to new treatments for diabetes.     

An NK-like CAR T cell transition in CAR T cell dysfunction

1. Download : Download high-res image (148KB)
2. Download : Download full-size image

     

Resistance to the tyrosine kinase inhibitor axitinib is associated with increased glucose metabolism in pancreatic adenocarcinoma

Alterations in energy (glucose) metabolism are key events in the development and progression of cancer. In pancreatic adenocarcinoma (PDAC) cells, we investigated changes in glucose metabolism induced by resistance to the receptor tyrosine kinase inhibitor (RTKI) axitinib. Here, we show that human cell lines and mouse PDAC cell lines obtained from the spontaneous pancreatic cancer mouse model (Kras^G12DPdx1-cre) were sensitive to axitinib. The anti-proliferative effect was due to a G2/M block resulting in loss of 70–75% cell viability in the most sensitive PDAC cell line. However, a surviving sub-population showed a 2- to 3-fold increase in [C-14]deoxyglucose ([C-14]DG) uptake. This was sustained in axitinib-resistant cell lines, which were derived from parental PDAC. In addition to the axitinib-induced increase in [C-14]DG uptake, we observed a translocation of glucose transporter-1 (Glut-1) transporters from cytosolic pools to the cell surface membrane and a 2-fold increase in glycolysis rates measured by the extracellular acidification rate (ECAR). We demonstrated an axitinib-induced increase in phosphorylated Protein Kinase B (pAkt) and by blocking pAkt with a phosphatidylinositol-3 kinase (PI3K) inhibitor we reversed the Glut-1 translocation and restored sensitivity to axitinib treatment. Combination treatment with both axitinib and Akt inhibitor in parental pancreatic cell line resulted in a decrease in cell viability beyond that conferred by single therapy alone. Our study shows that PDAC resistance to axitinib results in increased glucose metabolism mediated by activated Akt. Combining axitinib and an Akt inhibitor may improve treatment in PDAC.     

The TMEM16A chloride channel as an alternative therapeutic target in cystic fibrosis

Cystic fibrosis (CF), a multiorgan genetic disease, is caused by loss of function of CFTR, a cAMP-regulated anion channel. In CF airway epithelia, defective Cl⁻ and bicarbonate secretion impairs mucociliary clearance and other innate defense mechanisms, favoring the colonization of the lungs by highly virulent bacteria. The airway epithelium expresses TMEM16A, a second type of Cl⁻ channel that is activated by cytosolic Ca²⁺. TMEM16A is particularly expressed in goblet cells. This specific localization could be important in the release and hydration of mucins. Activation of TMEM16A with pharmacological agents could circumvent the primary defect in CF. This strategy needs to be carefully designed and tested to avoid possible undesired effects due to the expression of TMEM16A in other cell types such as bronchial smooth muscle cells.This article is part of a Directed Issue entitled: Cystic Fibrosis: From o-mics to cell biology, physiology, and therapeutic advances.     

Calcium and pancreatic β-cell function 7. Evidence for cyclic AMP-induced translocation of intracellular calcium

The effect of cyclic AMP on calcium movements in the pancreatic β-cell was evaluated using an experimental approach based on in situ labelling of intracellular organelles of ob/ob-mouse islets with ⁴⁵Ca. Whereas the glucose-stimulated ⁴⁵Ca incorporation by mitochondria and secretory granules was increased under a condition known to reduce cyclic AMP (starvation), raised levels of this nucleotide (addition of 3-isobutyl-1-methylxanthine or N⁶,O^2′-dibutyryl adenosine 3′,5′-cyclic monophosphate) reduced the mitochondrial accumulation of ⁴⁵Ca. Conditions with increased cyclic AMP were associated with a stimulated efflux of ⁴⁵Ca from the secretory granules but not from the mitochondria. The microsomal fraction differed from both the mitochondrial and secretory granule fractions by accumulating more ⁴⁵Ca after the addition of 3-isobutyl-1-methylxanthine. The results suggest that cyclic AMP potentiates glucose-stimulated insulin release by increasing cytoplasmic Ca²⁺ at the expense of the calcium taken up by the organelles of the pancreatic β-cells.