Evaluation of a Model for Glycemic Prediction in Critically Ill Surgical Patients

We evaluated a neural network model for prediction of glucose in critically ill trauma and post-operative cardiothoracic surgical patients. A prospective, feasibility trial evaluating a continuous glucose-monitoring device was performed. After institutional review board approval, clinical data from all consenting surgical intensive care unit patients were converted to an electronic format using novel software. This data was utilized to develop and train a neural network model for real-time prediction of serum glucose concentration implementing a prediction horizon of 75 minutes. Glycemic data from 19 patients were used to “train” the neural network model. Subsequent real-time simulated testing was performed in 5 patients to whom the neural network model was naive. Performance of the model was evaluated by calculating the mean absolute difference percent (MAD%), Clarke Error Grid Analysis, and calculation of the percent of hypoglycemic (≤70 mg/dL), normoglycemic (>70 and <150 mg/dL), and hyperglycemic (≥150 mg/dL) values accurately predicted by the model; 9,405 data points were analyzed. The models successfully predicted trends in glucose in the 5 test patients. Clark Error Grid Analysis indicated that 100.0% of predictions were clinically acceptable with 87.3% and 12.7% of predicted values falling within regions A and B of the error grid respectively. Overall model error (MAD%) was 9.0% with respect to actual continuous glucose modeling data. Our model successfully predicted 96.7% and 53.6% of the normo- and hyperglycemic values respectively. No hypoglycemic events occurred in these patients. Use of neural network models for real-time prediction of glucose in the surgical intensive care unit setting offers healthcare providers potentially useful information which could facilitate optimization of glycemic control, patient safety, and improved care. Similar models can be implemented across a wider scale of biomedical variables to offer real-time optimization, training, and adaptation that increase predictive accuracy and performance of therapies.     

Phase 1 Study of a Sulforaphane-Containing Broccoli Sprout Homogenate for Sickle Cell Disease

Sickle cell disease (SCD) is the most common inherited hemoglobinopathy worldwide. Our previous results indicate that the reduced oxidative stress capacity of sickle erythrocytes may be caused by decreased expression of NRF2 (Nuclear factor (erythroid-derived 2)-like 2), an oxidative stress regulator. We found that activation of NRF2 with sulforaphane (SFN) in erythroid progenitors significantly increased the expression of NRF2 targets HMOX1, NQO1, and HBG1 (subunit of fetal hemoglobin) in a dose-dependent manner. Therefore, we hypothesized that NRF2 activation with SFN may offer therapeutic benefits for SCD patients by restoring oxidative capacity and increasing fetal hemoglobin concentration. To test this hypothesis, we performed a Phase 1, open-label, dose-escalation study of SFN, contained in a broccoli sprout homogenate (BSH) that naturally contains SFN, in adults with SCD. The primary and secondary study endpoints were safety and physiological response to NRF2 activation, respectively. We found that BSH was well tolerated, and the few adverse events that occurred during the trial were not likely related to BSH consumption. We observed an increase in the mean relative whole blood mRNA levels for the NRF2 target HMOX1 (p = 0.02) on the last day of BSH treatment, compared to pre-treatment. We also observed a trend toward increased mean relative mRNA levels of the NRF2 target HBG1 (p = 0.10) from baseline to end of treatment, but without significant changes in HbF protein. We conclude that BSH, in the provided doses, is safe in stable SCD patients and may induce changes in gene expression levels. We therefore propose investigation of more potent NRF2 inducers, which may elicit more robust physiological changes and offer clinical benefits to SCD patients.Trial Registration: ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01715480","term_id":"NCT01715480"}}NCT01715480     

Grandparentage assignments identify unexpected adfluvial life history tactic contributing offspring to a reintroduced population

Diversity in life history tactics contributes to the persistence of a population because it helps to protect against stochastic environments by varying individuals in space and time. However, some life history tactics may not be accounted for when assessing the demographic viability of a population. One important factor in demographic viability assessments is cohort replacement rate (CRR), which is defined as the number of future adults produced by an adult. We assessed if precocial resident males (<age‐3) and adfluvial Chinook salmon (Oncorhynchus tshawytscha), adults that reside in freshwater their entire lives, contributed offspring to a reintroduced population from 2008 to 2013. We found that 9 ± 5% of offspring with an unassigned parent remained unexplained after accounting for sources of human error. Using grandparentage assignments, we identified 31 precocial resident males and 48 probable adfluvial Chinook salmon produced by anadromous mate pairs from 2007 to 2012. Previously published CRR estimates for the 2007 and 2008 reintroduced adults, based on only anadromous returning adult offspring, were 0.40 and 0.31, respectively. By incorporating adfluvial females, we found CRR estimates increased by 17% (CRR: 0.46) and 13% (CRR: 0.35) for the 2007 and 2008 cohorts, respectively.     

Interaction of the Human Papillomavirus E6 Oncoprotein with Sorting Nexin 27 Modulates Endocytic Cargo Transport Pathways

A subset of high-risk Human Papillomaviruses (HPVs) are the causative agents of a large number of human cancers, of which cervical is the most common. Two viral oncoproteins, E6 and E7, contribute directly towards the development and maintenance of malignancy. A characteristic feature of the E6 oncoproteins from cancer-causing HPV types is the presence of a PDZ binding motif (PBM) at its C-terminus, which confers interaction with cellular proteins harbouring PDZ domains. Here we show that this motif allows E6 interaction with Sorting Nexin 27 (SNX27), an essential component of endosomal recycling pathways. This interaction is highly conserved across E6 proteins from multiple high-risk HPV types and is mediated by a classical PBM-PDZ interaction but unlike many E6 targets, SNX27 is not targeted for degradation by E6. Rather, in HPV-18 positive cell lines the association of SNX27 with components of the retromer complex and the endocytic transport machinery is altered in an E6 PBM-dependent manner. Analysis of a SNX27 cargo, the glucose transporter GLUT1, reveals an E6-dependent maintenance of GLUT1 expression and alteration in its association with components of the endocytic transport machinery. Furthermore, knockdown of E6 in HPV-18 positive cervical cancer cells phenocopies the loss of SNX27, both in terms of GLUT1 expression levels and its vesicular localization, with a concomitant marked reduction in glucose uptake, whilst loss of SNX27 results in slower cell proliferation in low nutrient conditions. These results demonstrate that E6 interaction with SNX27 can alter the recycling of cargo molecules, one consequence of which is modulation of nutrient availability in HPV transformed tumour cells.     

Leveraging GWAS data to identify metabolic pathways and networks involved in maize lipid biosynthesis

Maize (Zea mays mays) oil is a rich source of polyunsaturated fatty acids (FAs) and energy, making it a valuable resource for human food, animal feed, and bio‐energy. Although this trait has been studied via conventional genome‐wide association study (GWAS), the single nucleotide polymorphism (SNP)‐trait associations generated by GWAS may miss the underlying associations when traits are based on many genes, each with small effects that can be overshadowed by genetic background and environmental variation. Detecting these SNPs statistically is also limited by the levels set for false discovery rate. A complementary pathways analysis that emphasizes the cumulative aspects of SNP‐trait associations, rather than just the significance of single SNPs, was performed to understand the balance of lipid metabolism, conversion, and catabolism in this study. This pathway analysis indicated that acyl‐lipid pathways, including biosynthesis of wax esters, sphingolipids, phospholipids and flavonoids, along with FA and triacylglycerol (TAG) biosynthesis, were important for increasing oil and FA content. The allelic variation found among the genes involved in many degradation pathways, and many biosynthesis pathways leading from FAs and carbon partitioning pathways, was critical for determining final FA content, changing FA ratios and, ultimately, to final oil content. The pathways and pathway networks identified in this study, and especially the acyl‐lipid associated pathways identified beyond what had been found with GWAS alone, provide a real opportunity to precisely and efficiently manipulate high‐oil maize genetic improvement.     

A Centipede Toxin Family Defines an Ancient Class of CSαβ Defensins

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Insulin is imprinted in the placenta of the marsupial, Macropus eugenii

Therian mammals (marsupials and eutherians) rely on a placenta for embryo survival. All mammals have a yolk sac, but while both chorio-allantoic and chorio-vitelline (yolk sac) placentation can occur, most marsupials only develop a yolk sac placenta. Insulin (INS) is unusual in that it is the only gene that is imprinted exclusively in the yolk sac placenta. Marsupials, therefore, provide a unique opportunity to examine the conservation of INS imprinting in mammalian yolk sac placentation. Marsupial INS was cloned and its imprint status in the yolk sac placenta of the tammar wallaby, Macropus eugenii, examined. In two informative individuals of the eight that showed imprinting, INS was paternally expressed. INS protein was restricted to the yolk sac endoderm, while insulin receptor, IR, protein was additionally expressed in the trophoblast. INS protein increased during late gestation up to 2 days before birth, but was low the day before and on the day of birth. The conservation of imprinted expression of insulin in the yolk sac placenta of divergent mammalian species suggests that it is of critical importance in the yolk sac placenta. The restriction of imprinting to the yolk sac suggests that imprinting of INS evolved in the chorio-vitelline placenta independently of other tissues in the therian ancestor of marsupials and eutherians.     

Characterization of glycosomal RING finger proteins of trypanosomatids

The glycosomes of trypanosomatids are essential organelles that are evolutionarily related to peroxisomes of other eukaryotes. The peroxisomal RING proteins-PEX2, PEX10 and PEX12-comprise a network of integral membrane proteins that function in the matrix protein import cycle. Here, we describe PEX10 and PEX12 in Trypanosoma brucei, Leishmania major, and Trypanosoma cruzi. We expressed GFP fusions of each T. brucei coding region in procyclic form T. brucei, where they localized to glycosomes and behaved as integral membrane proteins. Despite the weak transmembrane predictions for TbPEX12, protease protection assays demonstrated that both the N and C termini are cytosolic, similar to mammalian PEX12. GFP fusions of T. cruzi PEX10 and L. major PEX12 also localized to glycosomes in T. brucei indicating that glycosomal membrane protein targeting is conserved across trypanosomatids.