Glucose delays age-dependent proteotoxicity

Nutrient availability influences an organism's life history with profound effects on metabolism and lifespan. The association between a healthy lifespan and metabolism is incompletely understood, but a central factor is glucose metabolism. Although glucose is an important cellular energy source, glucose restriction is associated with extended lifespan in simple animals and a reduced incidence of age-dependent pathologies in humans. We report here that glucose enrichment delays mutant polyglutamine, TDP-43, FUS, and amyloid-β toxicity in Caenorhabditis elegans models of neurodegeneration by reducing protein misfolding. Dysregulated metabolism is common to neurodegeneration and we show that glucose enrichment is broadly protective against proteotoxicity.     

Cancer-type regulation of MIG-6 expression by inhibitors of methylation and histone deacetylation

Epigenetic silencing is one of the mechanisms leading to inactivation of a tumor suppressor gene, either by DNA methylation or histone modification in a promoter regulatory region. Mitogen inducible gene 6 (MIG-6), mainly known as a negative feedback inhibitor of the epidermal growth factor receptor (EGFR) family, is a tumor suppressor gene that is associated with many human cancers. To determine if MIG-6 is inactivated by epigenetic alteration, we identified a group of human lung cancer and melanoma cell lines in which its expression is either low or undetectable and studied the effects of methylation and of histone deacetylation on its expression. The DNA methyltransferase (DNMT) inhibitor 5-aza-2'-deoxycytidine (5-aza-dC) induced MIG-6 expression in melanoma cell lines but little in lung cancer lines. By contrast, the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) induced MIG-6 expression in lung cancer lines but had little effect in melanoma lines. However, the MIG-6 promoter itself did not appear to be directly affected by either methylation or histone deacetylation, indicating an indirect regulatory mechanism. Luciferase reporter assays revealed that a short segment of exon 1 in the MIG-6 gene is responsible for TSA response in the lung cancer cells; thus, the MIG-6 gene can be epigenetically silenced through an indirect mechanism without having a physical alteration in its promoter. Furthermore, our data also suggest that MIG-6 gene expression is differentially regulated in lung cancer and melanoma.     

Autocrine activation of the MET receptor tyrosine kinase in acute myeloid leukemia

Although the treatment of acute myeloid leukemia (AML) has improved substantially in the past three decades, more than half of all patients develop disease that is refractory to intensive chemotherapy. Functional genomics approaches offer a means to discover specific molecules mediating the aberrant growth and survival of cancer cells. Thus, using a loss-of-function RNA interference genomic screen, we identified the aberrant expression of hepatocyte growth factor (HGF) as a crucial element in AML pathogenesis. We found HGF expression leading to autocrine activation of its receptor tyrosine kinase, MET, in nearly half of the AML cell lines and clinical samples we studied. Genetic depletion of HGF or MET potently inhibited the growth and survival of HGF-expressing AML cells. However, leukemic cells treated with the specific MET kinase inhibitor crizotinib developed resistance resulting from compensatory upregulation of HGF expression, leading to the restoration of MET signaling. In cases of AML where MET is coactivated with other tyrosine kinases, such as fibroblast growth factor receptor 1 (FGFR1), concomitant inhibition of FGFR1 and MET blocked this compensatory HGF upregulation, resulting in sustained logarithmic cell killing both in vitro and in xenograft models in vivo. Our results show a widespread dependence of AML cells on autocrine activation of MET, as well as the key role of compensatory upregulation of HGF expression in maintaining leukemogenic signaling by this receptor. We anticipate that these findings will lead to the design of additional strategies to block adaptive cellular responses that drive compensatory ligand expression as an essential component of the targeted inhibition of oncogenic receptors in human cancers.     

Remote monitoring and follow-up of cardiovascular implantable electronic devices in the Netherlands : An expert consensus report of the Netherlands Society of Cardiology

Remote monitoring of cardiac implanted electronic devices (CIED: pacemaker, cardiac resynchronisation therapy device and implantable cardioverter defibrillator) has been developed for technical control and follow-up using transtelephonic data transmission. In addition, automatic or patient-triggered alerts are sent to the cardiologist or allied professional who can respond if necessary with various interventions. The advantage of remote monitoring appears obvious in impending CIED failures and suspected symptoms but is less likely in routine follow-up of CIED. For this follow-up the indications, quality of care, cost-effectiveneness and patient satisfaction have to be determined before remote CIED monitoring can be applied in daily practice. Nevertheless remote CIED monitoring is expanding rapidly in the Netherlands without professional agreements about methodology, responsibilities of all the parties involved and that of the device patient, and reimbursement. The purpose of this consensus document on remote CIED monitoring and follow-up is to lay the base for a nationwide, uniform implementation in the Netherlands. This report describes the technical communication, current indications, benefits and limitations of remote CIED monitoring and follow-up, the role of the patient and device manufacturer, and costs and reimbursement. The view of cardiology experts and of other disciplines in conjunction with literature was incorporated in a preliminary series of recommendations. In addition, an overview of the questions related to remote CIED monitoring that need to be answered is given. This consensus document can be used for future guidelines for the Dutch profession.     

An optimizing start-up strategy for a bio-methanator

This paper presents an optimizing start-up strategy for a bio-methanator. The goal of the control strategy is to maximize the outflow rate of methane in anaerobic digestion processes, which can be described by a two-population model. The methodology relies on a thorough analysis of the system dynamics and involves the solution of two optimization problems: steady-state optimization for determining the optimal operating point and transient optimization. The latter is a classical optimal control problem, which can be solved using the maximum principle of Pontryagin. The proposed control law is of the bang–bang type. The process is driven from an initial state to a small neighborhood of the optimal steady state by switching the manipulated variable (dilution rate) from the minimum to the maximum value at a certain time instant. Then the dilution rate is set to the optimal value and the system settles down in the optimal steady state. This control law ensures the convergence of the system to the optimal steady state and substantially increases its stability region. The region of attraction of the steady state corresponding to maximum production of methane is considerably enlarged. In some cases, which are related to the possibility of selecting the minimum dilution rate below a certain level, the stability region of the optimal steady state equals the interior of the state space. Aside its efficiency, which is evaluated not only in terms of biogas production but also from the perspective of treatment of the organic load, the strategy is also characterized by simplicity, being thus appropriate for implementation in real-life systems. Another important advantage is its generality: this technique may be applied to any anaerobic digestion process, for which the acidogenesis and methanogenesis are, respectively, characterized by Monod and Haldane kinetics.     

Transformation by bovine papillomavirus type 1 E6 requires paxillin

Papillomavirus E6 proteins are adapters that change the function of cellular regulatory proteins. The bovine papillomavirus type 1 E6 (BE6) binds to LXXLL peptide sequences termed LD motifs (consensus sequence LDXLLXXL) on the cellular protein paxillin that is a substrate of Src and focal adhesion kinases. Anchorage-independent transformation induced by BE6 required both paxillin and BE6-binding LD motifs on paxillin but was independent of the major tyrosine phosphorylation sites of paxillin. The essential role of paxillin in transformation by BE6 highlights the role of paxillin in the transduction of cellular signals that result in anchorage-independent cell proliferation.     

Mps1 phosphorylates Borealin to control Aurora B activity and chromosome alignment

Maintenance of chromosomal stability relies on coordination between various processes that are critical for proper chromosome segregation in mitosis. Here we show that monopolar spindle 1 (Mps1) kinase, which is essential for the mitotic checkpoint, also controls correction of improper chromosome attachments. We report that Borealin/DasraB, a member of the complex that regulates the Aurora B kinase, is directly phosphorylated by Mps1 on residues that are crucial for Aurora B activity and chromosome alignment. As a result, cells lacking Mps1 kinase activity fail to efficiently align chromosomes due to impaired Aurora B function at centromeres, leaving improper attachments uncorrected. Strikingly, Borealin/DasraB bearing phosphomimetic mutations restores Aurora B activity and alignment in Mps1-depleted cells. Mps1 thus coordinates attachment error correction and checkpoint signaling, two crucial responses to unproductive chromosome attachments.     

Aflatoxin genes and the aflatoxigenic potential of Koji moulds

Sixty-four Aspergillus isolates, 54 of which originated from food fermentations, and 18 Aspergillus reference strains were identified and screened for the presence of aflatoxin genes aflR and omt-1. Among the Koji moulds, not only A. oryzae but also A. flavus strains were found. Furthermore, 27% of A. oryzae and 93% of A. flavus strains lacked either aflR or both aflR- and omt-1. A selection of 29 strains was also checked for the presence of pksA and nor-1. This revealed large deletions in the aflatoxin gene cluster of some strains. The hybridisation patterns also suggested a polarity in the deletion events, originating in the vicinity of pksA and extending towards omt-1. Other strains exhibited BamHI restriction fragment length polymorphisms (RFLPs) for either aflR or for aflR and omt-1. All aflR and/or omt-1 deletion strains turned out to be unable to produce aflatoxin. The RFLP-carrying strains either produced only traces of aflatoxin or none at all. In 73% of the A. oryzae strains, no apparent deletions were detected with the aflR and omt-1 probes. Nevertheless, after incubation in aflatoxin-inducing media, no aflatoxin B1 production could be detected in those A. oryzae strains.