Static Output Feedback H-infinity Control for a Fractional-Order Glucose-Insulin System

in International Journal of Control, Automation, and Systems (2015), 13(4), 798-807

This paper presents the H∞ static output feedback control of nonlinear fractional-order systems. Based on the extended bounded real lemma, the H∞ control is formulated and sufficient conditions are ... [more ▼]

This paper presents the H∞ static output feedback control of nonlinear fractional-order systems. Based on the extended bounded real lemma, the H∞ control is formulated and sufficient conditions are derived in terms of linear matrix inequalities (LMIs) formulation by using the fractional Lyapunov direct method where the fractional-order α belongs to 0 < α < 1. The control approach is finally applied to the regulation of the glucose level in diabetes type 1 treatment. Therefore, it is attempted to incorporate fractional-order into the mathematical minimal model of glucose-insulin system dynamics and it is still an interesting challenge to show, how the order of a fractional differential system affects the dynamics of the system in the presence of meal disturbance. Numerical simulations are carried out to illustrate our proposed results and show that the nonlinear fractional-order glucose-insulin systems are, at least, as stable as their integer-order counterpart in the presence of exogenous glucose infusion or meal disturbance. [less ▲]

Dynamic change of host gastrointestinal microbiome and immune status in relation to mucosal barrier effects during chemotherapy and immune ablative intervention in humans.

Poster (2015, June)

Changes in the human gastrointestinal microbiome during cancer treatments

Poster (2015, March)

Comparison of a healthy miRNome with melanoma patient miRNomes: are microRNAs suitable serum biomarkers for cancer?

in Oncotarget (2015), 6(14), 12110-27

MiRNAs are increasingly recognized as biomarkers for the diagnosis of cancers where they are profiled from tumor tissue (intracellular miRNAs) or serum/plasma samples (extracellular miRNAs). To improve ... [more ▼]

MiRNAs are increasingly recognized as biomarkers for the diagnosis of cancers where they are profiled from tumor tissue (intracellular miRNAs) or serum/plasma samples (extracellular miRNAs). To improve detection of reliable biomarkers from blood samples, we first compiled a healthy reference miRNome and established a well-controlled analysis pipeline allowing for standardized quantification of circulating miRNAs. Using whole miRNome and custom qPCR arrays, miRNA expression profiles were analyzed in 126 serum, whole blood and tissue samples of healthy volunteers and melanoma patients and in primary melanocyte and keratinocyte cell lines. We found characteristic signatures with excellent prognostic scores only in late stage but not in early stage melanoma patients. Upon comparison of melanoma tissue miRNomes with matching serum samples, several miRNAs were identified to be exclusively tissue-derived (miR-30b-5p, miR-374a-5p and others) while others had higher expression levels in serum (miR-3201 and miR-122-5p). Here we have compiled a healthy and widely applicable miRNome from serum samples and we provide strong evidence that levels of cell-free miRNAs only change significantly at later stages of melanoma progression, which has serious implications for miRNA biomarker studies in cancer. [less ▲]

Turn up the heat: circulating serotonin tunes our internal heating system.

in Cell metabolism (2015), 21(2), 156-8

Serotonin acts as neurotransmitter in the brain and as a multifaceted signaling molecule coordinating many physiological processes in the periphery. In a recent issue of Nature Medicine, Crane et al ... [more ▼]

Serotonin acts as neurotransmitter in the brain and as a multifaceted signaling molecule coordinating many physiological processes in the periphery. In a recent issue of Nature Medicine, Crane et al. (2014) find that peripheral serotonin controls thermogenesis in adipose tissue by modulating beta-adrenergic stimulation of UCP-1, thereby affecting glucose homeostasis and weight gain. [less ▲]

Platelet activation and aggregation promote lung inflammation and influenza virus pathogenesis.

in American journal of respiratory and critical care medicine (2015), 191(7), 804-19

RATIONALE: The hallmark of severe influenza virus infection is excessive inflammation of the lungs. Platelets are activated during influenza, but their role in influenza virus pathogenesis and ... [more ▼]

RATIONALE: The hallmark of severe influenza virus infection is excessive inflammation of the lungs. Platelets are activated during influenza, but their role in influenza virus pathogenesis and inflammatory responses is unknown. OBJECTIVES: To determine the role of platelets during influenza A virus infections and propose new therapeutics against influenza. METHODS: We used targeted gene deletion approaches and pharmacologic interventions to investigate the role of platelets during influenza virus infection in mice. MEASUREMENTS AND MAIN RESULTS: Lungs of infected mice were massively infiltrated by aggregates of activated platelets. Platelet activation promoted influenza A virus pathogenesis. Activating protease-activated receptor 4, a platelet receptor for thrombin that is crucial for platelet activation, exacerbated influenza-induced acute lung injury and death. In contrast, deficiency in the major platelet receptor glycoprotein IIIa protected mice from death caused by influenza viruses, and treating the mice with a specific glycoprotein IIb/IIIa antagonist, eptifibatide, had the same effect. Interestingly, mice treated with other antiplatelet compounds (antagonists of protease-activated receptor 4, MRS 2179, and clopidogrel) were also protected from severe lung injury and lethal infections induced by several influenza strains. CONCLUSIONS: The intricate relationship between hemostasis and inflammation has major consequences in influenza virus pathogenesis, and antiplatelet drugs might be explored to develop new antiinflammatory treatment against influenza virus infections. [less ▲]

Integrated Omic Analyses of the Human Gut Microbiome in a Multiplex Family Study of Type 1 Diabetes Mellitus

Poster (2014, April 30)

Combinatorial regulation of lipoprotein lipase by microRNAs during mouse adipogenesis

in RNA Biology (2014), 11(1), 76-91

MicroRNAs (miRNAs) regulate gene expression directly through base pairing to their targets or indirectly through participating in multi-scale regulatory networks. Often miRNAs take part in feed-forward ... [more ▼]

MicroRNAs (miRNAs) regulate gene expression directly through base pairing to their targets or indirectly through participating in multi-scale regulatory networks. Often miRNAs take part in feed-forward motifs where a miRNA and a transcription factor act on shared targets to achieve accurate regulation of processes such as cell differentiation. Here we show that the expression levels of miR-27a and miR-29a inversely correlate with the mRNA levels of lipoprotein lipase (Lpl), their predicted combinatorial target, and its key transcriptional regulator peroxisome proliferator activated receptor gamma (Pparg) during 3T3-L1 adipocyte differentiation. More importantly, we show that Lpl, a key lipogenic enzyme, can be negatively regulated by the two miRNA families in a combinatorial fashion on the mRNA and functional level in maturing adipocytes. This regulation is mediated through the Lpl 3′UTR as confirmed by reporter gene assays. In addition, a small mathematical model captures the dynamics of this feed-forward motif and predicts the changes in Lpl mRNA levels upon network perturbations. The obtained results might offer an explanation to the dysregulation of LPL in diabetic conditions and could be extended to quantitative modeling of regulation of other metabolic genes under similar regulatory network motifs. [less ▲]

Prevalence and determinants of osteoporosis in patients with type 1 and type 2 diabetes mellitus.

in BMC endocrine disorders (2014), 14

BACKGROUND: Increased risk of osteoporosis and its clinical significance in patients with diabetes is controversial. We analyze osteoporosis prevalence and determinants of bone mineral density (BMD) in ... [more ▼]

BACKGROUND: Increased risk of osteoporosis and its clinical significance in patients with diabetes is controversial. We analyze osteoporosis prevalence and determinants of bone mineral density (BMD) in patients with type 1 and 2 diabetes. METHODS: Three hundred and ninety-eight consecutive diabetic patients from a single outpatient clinic received a standardized questionnaire on osteoporosis risk factors, and were evaluated for diabetes-related complications, HbA1c levels, and lumbar spine (LS) and femoral neck (FN) BMD. Of these, 139 (71 men, 68 women) type 1 and 243 (115 men, 128 women) type 2 diabetes patients were included in the study. BMD (T-scores and values adjusted for age, BMI and duration of disease) was compared between patient groups and between patients with type 2 diabetes and population-based controls (255 men, 249 women). RESULTS: For both genders, adjusted BMD was not different between the type 1 and type 2 diabetes groups but was higher in the type 2 group compared with controls (p < 0.0001). Osteoporosis prevalence (BMD T-score < -2.5 SD) at FN and LS was equivalent in the type 1 and type 2 diabetes groups, but lower in type 2 patients compared with controls (FN: 13.0% vs 21.2%, LS: 6.1% vs 14.9% men; FN: 21.9% vs 32.1%, LS: 9.4% vs 26.9% women). Osteoporosis prevalence was higher at FN-BMD than at LS-BMD. BMD was positively correlated with BMI and negatively correlated with age, but not correlated with diabetes-specific parameters (therapy, HbBA1c, micro- and macrovascular complications) in all subgroups. Fragility fracture prevalence was low (5.2%) and not different between diabetes groups. Fracture patients had lower BMDs compared with those without fractures; however, BMD T-score was above -2.5 SD in most patients. CONCLUSIONS: Diabetes-specific parameters did not predict BMD. Fracture occurrence was similar in both diabetes groups and related to lower BMD, but seems unrelated to the threshold T-score, <-2.5 SD. These results suggest that osteoporosis, and related fractures, is a clinically significant and commonly underestimated problem in diabetes patients. [less ▲]

Association between a gene variant near ataxia telangiectasia mutated and coronary artery disease in men.

in Diabetes and Vascular Disease Research (2014), 11(1), 60-3

OBJECTIVE: Type 2 diabetes is accompanied by increased mortality from coronary artery disease (CAD), but the mechanisms linking these conditions remain elusive. Hence, treatment of hyperglycaemia alone is ... [more ▼]

OBJECTIVE: Type 2 diabetes is accompanied by increased mortality from coronary artery disease (CAD), but the mechanisms linking these conditions remain elusive. Hence, treatment of hyperglycaemia alone is not sufficient to avoid CAD in diabetes. Alternative views suggest that metabolic and vascular diseases share unifying cellular defects that could serve as targets for novel therapeutic strategies. Recently, a variant [single-nucleotide polymorphism (SNP); rs11212617] near the gene for ataxia telangiectasia mutated (ATM) has been associated with glycaemic response to metformin. MATERIALS AND METHODS: We determined rs11212617 in 240 male patients who underwent elective coronary angiography. RESULTS: While the variant was not associated with glucose concentrations, the A allele was significantly associated with the presence of CAD (chi-square, p = 0.003), as well as with logarithmically transformed quantitative CAD indices [severe score (SS): 0.5 (0.4-0.6) vs 0.3 (0.2-0.5); extent score (ES): 2.63 (2.4-2.9) vs 1.94 (1.4-2.4), both p < 0.05, respectively]. Multivariate analysis revealed an independent association between the A allele with ES (beta = 0.17, p < 0.01). CONCLUSION: Our data suggest that ATM-dependent signalling might play a role in the development of atherosclerotic vascular disease, but larger studies are necessary to substantiate such a hypothesis. [less ▲]