Aldehyde dehydrogenase 1a3 defines a subset of failing pancreatic β cells in diabetic mice

Insulin-producing β cells become dedifferentiated during diabetes progression. An impaired ability to select substrates for oxidative phosphorylation, or metabolic inflexibility, initiates progression from β-cell dysfunction to β-cell dedifferentiation. The identification of pathways involved in dedifferentiation may provide clues to its reversal. Here we isolate and functionally characterize failing β cells from various experimental models of diabetes and report a striking enrichment in the expression of aldehyde dehydrogenase 1 isoform A3 (ALDH+) as β cells become dedifferentiated. Flow-sorted ALDH+ islet cells demonstrate impaired glucose-induced insulin secretion, are depleted of Foxo1 and MafA, and include a Neurogenin3-positive subset. RNA sequencing analysis demonstrates that ALDH+ cells are characterized by: (i) impaired oxidative phosphorylation and mitochondrial complex I, IV and V; (ii) activated RICTOR; and (iii) progenitor cell markers. We propose that impaired mitochondrial function marks the progression from metabolic inflexibility to dedifferentiation in the natural history of β-cell failure

Major reduction of malaria morbidity with combined vitamin A and zinc supplementation in young children in Burkina Faso: a randomized double blind trial

BACKGROUND: Vitamin A and zinc are crucial for normal immune function, and may play a synergistic role for reducing the risk of infection including malaria caused by Plasmodium falciparum. METHODS: A randomized, double-blind, placebo-controlled trial of a single dose of 200 000 IU of vitamin A with daily zinc supplementation was done in children of Sourkoudougou village, Burkina Faso. Children aged from 6 to 72 months were randomized to receive a single dose of 200 000 IU of vitamin A plus 10 mg elemental zinc, six days a week (n = 74) or placebo (n = 74) for a period of six months. Cross-sectional surveys were conducted at the beginning and the end of the study, and children were evaluated daily for fever. Microscopic examination of blood smear was done in the case of fever (temperature > or =37.5 degrees C) for malaria parasite detection. RESULTS: At the end of the study we observed a significant decrease in the prevalence malaria in the supplemented group (34%) compared to the placebo group (3.5%) (p < 0.001). Malaria episodes were lower in the supplemented group (p = 0.029), with a 30.2% reduction of malaria cases (p = 0.025). Time to first malaria episode was longer in the supplemented group (p = 0.015). The supplemented group also had 22% fewer fever episodes than the placebo group (p = 0.030). CONCLUSION: These results suggest that combined vitamin A plus zinc supplementation reduces the risk of fever and clinical malaria episodes among children, and thus may play a key role in malaria control strategies for children in Africa

Toward a Unified Genetic Map of Higher Plants, Transcending the Monocot-Dicot Divergence

Closely related (confamilial) genera often retain large chromosomal tracts in which gene order is colinear, punctuated by structural mutations such as inversions and translocations 1. To explore the possibility that conservation of gene order might extrapolate to more distantly related taxa, we first estimated an average structural mutation rate. Nine pairs of taxa, for which there exist both comparative genetic maps and plausible estimates of divergence time, showed an average of0.14 (±0.06) structural mutations per chromosome per million years of divergence (Myr; Table 1). This value is offered as a first approximation, acknowledging that refined comparative data and/or divergence estimates may impel revision

A newly developed tool for intra-tracheal temperature and humidity assessment in laryngectomized individuals: the Airway Climate Explorer (ACE)

The aim of this study is to develop a postlaryngectomy airway climate explorer (ACE) for assessment of intratracheal temperature and humidity and of influence of heat and moisture exchangers (HMEs). Engineering goals were within-device condensation prevention and fast response time characteristics. The ACE consists of a small diameter, heated air-sampling catheter connected to a heated sensor house, containing a humidity sensor. Air is sucked through the catheter by a controlled-flow pump. Validation was performed in a climate chamber using a calibrated reference sensor and in a two-flow system. Additionally, the analyser was tested in vivo. Over the clinically relevant range of humidity values (5–42 mg H2O/l air) the sensor output highly correlates with the reference sensor readings (R2 > 0.99). The 1–1/e response times are all <0.5 s. A first in vivo pilot measurement was successful. The newly developed, verified, fast-responding ACE is suitable for postlaryngectomy airway climate assessment

Mathematical modelling of polyamine metabolism in bloodstream-form trypanosoma brucei: An application to drug target identification

© 2013 Gu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedThis article has been made available through the Brunel Open Access Publishing Fund.We present the first computational kinetic model of polyamine metabolism in bloodstream-form Trypanosoma brucei, the causative agent of human African trypanosomiasis. We systematically extracted the polyamine pathway from the complete metabolic network while still maintaining the predictive capability of the pathway. The kinetic model is constructed on the basis of information gleaned from the experimental biology literature and defined as a set of ordinary differential equations. We applied Michaelis-Menten kinetics featuring regulatory factors to describe enzymatic activities that are well defined. Uncharacterised enzyme kinetics were approximated and justified with available physiological properties of the system. Optimisation-based dynamic simulations were performed to train the model with experimental data and inconsistent predictions prompted an iterative procedure of model refinement. Good agreement between simulation results and measured data reported in various experimental conditions shows that the model has good applicability in spite of there being gaps in the required data. With this kinetic model, the relative importance of the individual pathway enzymes was assessed. We observed that, at low-to-moderate levels of inhibition, enzymes catalysing reactions of de novo AdoMet (MAT) and ornithine production (OrnPt) have more efficient inhibitory effect on total trypanothione content in comparison to other enzymes in the pathway. In our model, prozyme and TSHSyn (the production catalyst of total trypanothione) were also found to exhibit potent control on total trypanothione content but only when they were strongly inhibited. Different chemotherapeutic strategies against T. brucei were investigated using this model and interruption of polyamine synthesis via joint inhibition of MAT or OrnPt together with other polyamine enzymes was identified as an optimal therapeutic strategy.The work was carried out under a PhD programme partly funded by Prof. Ray Welland, School of Computing Science, University of Glasgo

An integrated MR/PET system: prospective applications

Radiology is strongly depending on medical imaging technology and consequently directing technological progress. A novel technology can only be established, however, if improved diagnostic accuracy influence on therapeutic management and/or overall reduced cost can be evidenced. It has been demonstrated recently that Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET) can technologically be integrated into one single hybrid system. Some scientific arguments on the benefits are obvious, e.g., that simultaneous imaging of morphological and functional information will improve tissue characterization. However, crossfire of questions still remains: What unmet radiological needs are addressed by the novel system? What level of hardware integration is reasonable, or would software-based image co-registration be sufficient? Will MR/PET achieve higher diagnostic accuracy compared to separate imaging? What is the added value compared to other hybrid imaging modalities like PET/CT? And finally, is the system economically reasonable and has the potential to reduce overall costs for therapy planning and monitoring? This article tries to highlight some perspectives of applying an integrated MR/PET system for simultaneous morphologic and functional imaging

Altered splicing of the BIN1 muscle-specific exon in humans and dogs with highly progressive centronuclear myopathy

Amphiphysin 2, encoded by BIN1, is a key factor for membrane sensing and remodelling in different cell types. Homozygous BIN1 mutations in ubiquitously expressed exons are associated with autosomal recessive centronuclear myopathy (CNM), a mildly progressive muscle disorder typically showing abnormal nuclear centralization on biopsies. In addition, misregulation of BIN1 splicing partially accounts for the muscle defects in myotonic dystrophy (DM). However, the muscle-specific function of amphiphysin 2 and its pathogenicity in both muscle disorders are not well understood. In this study we identified and characterized the first mutation affecting the splicing of the muscle-specific BIN1 exon 11 in a consanguineous family with rapidly progressive and ultimately fatal centronuclear myopathy. In parallel, we discovered a mutation in the same BIN1 exon 11 acceptor splice site as the genetic cause of the canine Inherited Myopathy of Great Danes (IMGD). Analysis of RNA from patient muscle demonstrated complete skipping of exon 11 and BIN1 constructs without exon 11 were unable to promote membrane tubulation in differentiated myotubes. Comparative immunofluorescence and ultrastructural analyses of patient and canine biopsies revealed common structural defects, emphasizing the importance of amphiphysin 2 in membrane remodelling and maintenance of the skeletal muscle triad. Our data demonstrate that the alteration of the muscle-specific function of amphiphysin 2 is a common pathomechanism for centronuclear myopathy, myotonic dystrophy, and IMGD. The IMGD dog is the first faithful model for human BIN1-related CNM and represents a mammalian model available for preclinical trials of potential therapies

Endotracheal temperature and humidity measurements in laryngectomized patients: intra- and inter-patient variability

This study assesses intra- and inter-patient variability in endotracheal climate (temperature and humidity) and effects of heat and moister exchangers (HME) in 16 laryngectomized individuals, measured repeatedly (N = 47). Inhalation Breath Length (IBL) was 1.35 s without HME and 1.05 s with HME (P < 0.0001). With HME, end-inspiratory (minimum) humidity values increased 5.8 mg H2O/L (P < 0.0001) and minimum temperature values decreased 1.6°C (P < 0.0001). For the temperature and humidity minimums, the inter-patient variability was much smaller than the short- and long-term intra-patient variability. For exhalation breath length and full breath length, the opposite was the case. Conclusions: (1) Because inter-patient variability is smaller than intra-patient variability, investigating endotracheal climate in a limited number of laryngectomized subjects is justified, provided repeated measurements per patient are accomplished; (2) main contributor to intra-patient variability is the positioning of the catheter tip in the trachea; (3) an HME leads to a shortened IBL which enhances the HME effect