The Virtual Physiological Human: Ten Years After

Biomedical research and clinical practice are struggling to cope with the growing complexity that the progress of health care involves. The most challenging diseases, those with the largest socioeconomic impact (cardiovascular conditions; musculoskeletal conditions; cancer; metabolic, immunity, and neurodegenerative conditions), are all characterized by a complex genotype–phenotype interaction and by a “systemic” nature that poses a challenge to the traditional reductionist approach. In 2005 a small group of researchers discussed how the vision of computational physiology promoted by the Physiome Project could be translated into clinical practice and formally proposed the term Virtual Physiological Human. Our knowledge about these diseases is fragmentary, as it is associated with molecular and cellular processes on the one hand and with tissue and organ phenotype changes (related to clinical symptoms of disease conditions) on the other. The problem could be solved if we could capture all these fragments of knowledge into predictive models and then compose them into hypermodels that help us tame the complexity that such systemic behavior involves. In 2005 this was simply not possible—the necessary methods and technologies were not available. Now, 10 years later, it seems the right time to reflect on the original vision, the results achieved so far, and what remains to be done

Phase diagram of bismuth in the extreme quantum limit

Elemental bismuth provides a rare opportunity to explore the fate of a three-dimensional gas of highly mobile electrons confined to their lowest Landau level. Coulomb interaction, neglected in the band picture, is expected to become significant in this extreme quantum limit with poorly understood consequences. Here, we present a study of the angular-dependent Nernst effect in bismuth, which establishes the existence of ultraquantum field scales on top of its complex single-particle spectrum. Each time a Landau level crosses the Fermi level, the Nernst response sharply peaks. All such peaks are resolved by the experiment and their complex angular-dependence is in very good agreement with the theory. Beyond the quantum limit, we resolve additional Nernst peaks signaling a cascade of additional Landau sub-levels caused by electron interaction

Holographic flows to IR Lifshitz spacetimes

Recently we studied `vanishing' horizon limits of `boosted' black D3-brane geometry \cite{hsnr}. The type IIB solutions obtained by taking these special double limits were found to describe nonrelativistic Lifshitz spacetimes at zero temperature. In the present work we study these limits for TsT black-hole solutions which include $B$-field. The new Galilean solutions describe a holographic RG flow from Schr\"odinger ($a=2$) spacetime in UV to a Lifshitz universe ($a=3$) in the IR.Comment: 10 pages; v2: A bad typo in eq.8 corrected; v3: Discussion and reference on Kaigorodov spaces included, correction in sec-3, to be published in JHE

Erik Oddvar Eriksen og John Erik Fossum (red.): Det norske paradoks. Om Norges forhold til Den europeiske union

Vid en jämförelse framstår den akademiska debatten i Norge om EU och dess demokratiska konsekvenser som mer levande och vital än den i Sverige. Visserligen kämpar även norska akademiker mot ett ointresse bland politiker, journalister och hos allmänheten, men det verkar finnas en skillnad i intresse och i möjligheterna till finansiering för forskning. Kanske är det oklarheterna kring det ââ¬Ânästan medlemskapââ¬Â som följer av EÃS-avtalet som bidrar till intresse i Norge? Möjligen är det faktum att man i Norge till skillnad från Sverige tidigt lyckades etablera ett långsiktigt och fristående samhällsvetenskapligt forskningsprogram, ARENA, som utgör den huvudsakliga skillnaden? Bägge faktorerna bidrar säkert, men det faktum att ARENA har funnits och haft god finansiering har gjort att debatten verkar ha en annan tyngd i Norge â åtminstone i meningen att det finns något fler forskare som lyfter fram och publicerar både normativa och empiriska bidrag till debatten om demokratin, nationalstaten och EU. Boken Den norske paradoks är ett sådant bidrag. Författarna väljer att lyfta fram relationen mellan EU och den norska demokratin utifrån ââ¬Âgrunnlovsideen â et konstitusjonelt styresett basert på en demokratisk grunnlovââ¬Â (sidan 11). Det är därför med förväntan som jag läser boken

Distribution of coronal and root caries experience among persons aged 60+ in South Australia

The document attached has been archived with permission from the Australian Dental Association. An external link to the publisher’s copy is included.This report provides epidemiological data describing caries experience among the population of non-institutionalized older adults in Adelaide and Mt Gambier. Subjects were selected in a stratified random sample of persons aged 60+ who were listed on the South Australian Electoral Database. Oral examinations were conducted by four calibrated dentists among 853 dentate persons aged 60 years and over. There was an average of 14.7 missing teeth, 8.3 filled teeth and 0.3 decayed teeth, and a further 0.2 teeth were present as retained roots. The mean number of missing teeth was higher (p < 0.05) in older compared with younger age groups, and in Mt Gambier compared with Adelaide. The mean DFS of 22.1 was significantly higher (p < 0.05) among younger persons, females and in Adelaide. Root surface caries affected an average of 3.1 surfaces, and was greater (p < 0.05) among persons aged 70-79 years, males and Adelaide residents. However, when root caries was expressed as an attack rate per 100 exposed surfaces, differences were statistically significant only among age groups. Analysis of specific teeth revealed that no more than 40 per cent of molars were retained, and between 30 and 58 per cent of retained molars had coronal fillings.Gary D. Slade, A. John Spence

Dimensional analysis of MINMOD leads to definition of the disposition index of glucose regulation and improved simulation algorithm

BACKGROUND: Frequently Sampled Intravenous Glucose Tolerance Test (FSIVGTT) together with its mathematical model, the minimal model (MINMOD), have become important clinical tools to evaluate the metabolic control of glucose in humans. Dimensional analysis of the model is up to now not available. METHODS: A formal dimensional analysis of MINMOD was carried out and the degree of freedom of MINMOD was examined. Through re-expressing all state variable and parameters in terms of their reference scales, MINMOD was transformed into a dimensionless format. Previously defined physiological indices including insulin sensitivity, glucose effectiveness, and first and second phase insulin responses were re-examined in this new formulation. Further, the parameter estimation from FSIVGTT was implemented using both the dimensional and the dimensionless formulations of MINMOD, and the performances were compared utilizing Monte Carlo simulation as well as real human FSIVGTT data. RESULTS: The degree of freedom (DOF) of MINMOD was found to be 7. The model was maximally simplified in the dimensionless formulation that normalizes the variation in glucose and insulin during FSIVGTT. In the new formulation, the disposition index (Dl), a composite parameter known to be important in diabetes pathology, was naturally defined as one of the dimensionless parameters in the system. The numerical simulation using the dimensionless formulation led to a 1.5–5 fold gain in speed, and significantly improved accuracy and robustness in parameter estimation compared to the dimensional implementation. CONCLUSION: Dimensional analysis of MINMOD led to simplification of the model, direct identification of the important composite factors in the dynamics of glucose metabolic control, and better simulations algorithms

FindFoci: a focus detection algorithm with automated parameter training that closely matches human assignments, reduces human inconsistencies and increases speed of analysis

Accurate and reproducible quantification of the accumulation of proteins into foci in cells is essential for data interpretation and for biological inferences. To improve reproducibility, much emphasis has been placed on the preparation of samples, but less attention has been given to reporting and standardizing the quantification of foci. The current standard to quantitate foci in open-source software is to manually determine a range of parameters based on the outcome of one or a few representative images and then apply the parameter combination to the analysis of a larger dataset. Here, we demonstrate the power and utility of using machine learning to train a new algorithm (FindFoci) to determine optimal parameters. FindFoci closely matches human assignments and allows rapid automated exploration of parameter space. Thus, individuals can train the algorithm to mirror their own assignments and then automate focus counting using the same parameters across a large number of images. Using the training algorithm to match human assignments of foci, we demonstrate that applying an optimal parameter combination from a single image is not broadly applicable to analysis of other images scored by the same experimenter or by other experimenters. Our analysis thus reveals wide variation in human assignment of foci and their quantification. To overcome this, we developed training on multiple images, which reduces the inconsistency of using a single or a few images to set parameters for focus detection. FindFoci is provided as an open-source plugin for ImageJ

Exogenous Glucose Administration Impairs Glucose Tolerance and Pancreatic Insulin Secretion during Acute Sepsis in Non-Diabetic Mice

Objectives:The development of hyperglycemia and the use of early parenteral feeding are associated with poor outcomes in critically ill patients. We therefore examined the impact of exogenous glucose administration on the integrated metabolic function of endotoxemic mice using our recently developed frequently sampled intravenous glucose tolerance test (FSIVGTT). We next extended our findings using a cecal ligation and puncture (CLP) sepsis model administered early parenteral glucose support.Methods:Male C57BL/6J mice, 8-12 weeks, were instrumented with chronic indwelling arterial and venous catheters. Endotoxemia was initiated with intra-arterial lipopolysaccharide (LPS; 1 mg/kg) in the presence of saline or glucose infusion (100 μL/hr), and an FSIVGTT was performed after five hours. In a second experiment, catheterized mice underwent CLP and the impact of early parenteral glucose administration on glucose homeostasis and mortality was assessed over 24 hrs.Measurements:And MAIN RESULTS: Administration of LPS alone did not impair metabolic function, whereas glucose administration alone induced an insulin sensitive state. In contrast, LPS and glucose combined caused marked glucose intolerance and insulin resistance and significantly impaired pancreatic insulin secretion. Similarly, CLP mice receiving parenteral glucose developed fulminant hyperglycemia within 18 hrs (all > 600 mg/dl) associated with increased systemic cytokine release and 40% mortality, whereas CLP alone (85 ± 2 mg/dL) or sham mice receiving parenteral glucose (113 ± 3 mg/dL) all survived and were not hyperglycemic. Despite profound hyperglycemia, plasma insulin in the CLP glucose-infused mice (3.7 ± 1.2 ng/ml) was not higher than sham glucose infused mice (2.1 ± 0.3 ng/ml).Conclusions:The combination of parenteral glucose support and the systemic inflammatory response in the acute phase of sepsis induces profound insulin resistance and impairs compensatory pancreatic insulin secretion, leading to the development of fulminant hyperglycemia. © 2013 Watanabe et al

Observer-Based State Feedback for Enhanced Insulin Control of Type ‘I’ Diabetic Patients

During the past few decades, biomedical modeling techniques have been applied to improve performance of a wide variety of medical systems that require monitoring and control. Diabetes is one of the most important medical problems. This paper focuses on designing a state feedback controller with observer to improve the performance of the insulin control for type ‘I’ diabetic patients. The dynamic model of glucose levels in diabetic patients is a nonlinear model. The system is a typical fourth-order single-input-single-output state space model. Using a linear time invariant controller based on an operating condition is a common method to simplify control design. On the other hand, adaptive control can potentially improve system performance. But it increases control complexity and may create further stability issues. This paper investigates patient models and presents a simplified control scheme using observer-based feedback controllers. By comparing different control schemes, it shows that a properly designed state feedback controller with observer can eliminate the adaptation strategy that the Proportional-Integral-Derivative (PID) controllers need to improve the control performance. Control strategies are simulated and their performance is evaluated in MATLAB and Simulink

Validation of N-myristoyltransferase as an antimalarial drug target using an integrated chemical biology approach

Malaria is an infectious disease caused by parasites of the genus Plasmodium, which leads to approximately one million deaths per annum worldwide. Chemical validation of new antimalarial targets is urgently required in view of rising resistance to current drugs. One such putative target is the enzyme N-myristoyltransferase, which catalyses the attachment of the fatty acid myristate to protein substrates (N-myristoylation). Here, we report an integrated chemical biology approach to explore protein myristoylation in the major human parasite P. falciparum, combining chemical proteomic tools for identification of the myristoylated and glycosylphosphatidylinositol-anchored proteome with selective small-molecule N-myristoyltransferase inhibitors. We demonstrate that N-myristoyltransferase is an essential and chemically tractable target in malaria parasites both in vitro and in vivo, and show that selective inhibition of N-myristoylation leads to catastrophic and irreversible failure to assemble the inner membrane complex, a critical subcellular organelle in the parasite life cycle. Our studies provide the basis for the development of new antimalarials targeting N-myristoyltransferase