A novel cost function to estimate parameters of oscillatory biochemical systems

Oscillatory pathways are among the most important classes of biochemical systems with examples ranging from circadian rhythms and cell cycle maintenance. Mathematical modeling of these highly interconnected biochemical networks is needed to meet numerous objectives such as investigating, predicting and controlling the dynamics of these systems. Identifying the kinetic rate parameters is essential for fully modeling these and other biological processes. These kinetic parameters, however, are not usually available from measurements and most of them have to be estimated by parameter fitting techniques. One of the issues with estimating kinetic parameters in oscillatory systems is the irregularities in the least square (LS) cost function surface used to estimate these parameters, which is caused by the periodicity of the measurements. These irregularities result in numerous local minima, which limit the performance of even some of the most robust global optimization algorithms. We proposed a parameter estimation framework to address these issues that integrates temporal information with periodic information embedded in the measurements used to estimate these parameters. This periodic information is used to build a proposed cost function with better surface properties leading to fewer local minima and better performance of global optimization algorithms. We verified for three oscillatory biochemical systems that our proposed cost function results in an increased ability to estimate accurate kinetic parameters as compared to the traditional LS cost function. We combine this cost function with an improved noise removal approach that leverages periodic characteristics embedded in the measurements to effectively reduce noise. The results provide strong evidence on the efficacy of this noise removal approach over the previous commonly used wavelet hard-thresholding noise removal methods. This proposed optimization framework results in more accurate kinetic parameters that will eventually lead to biochemical models that are more precise, predictable, and controllable

Functional analysis of Pro-inflammatory properties within the cerebrospinal fluid after subarachnoid hemorrhage in vivo and in vitro

<p>Abstract</p> <p>Background</p> <p>To functionally characterize pro-inflammatory and vasoconstrictive properties of cerebrospinal fluid after aneurysmal subarachnoid hemorrhage (SAH) in vivo and in vitro.</p> <p>Methods</p> <p>The cerebrospinal fluid (CSF) of 10 patients suffering from SAH was applied to the transparent skinfold chamber model in male NMRI mice which allows for in vivo analysis of the microcirculatory response to a superfusat. Microvascular diameter changes were quantified and the numbers of rolling and sticking leukocytes were documented using intravital multifluorescence imaging techniques. Furthermore, the pro-inflammatory properties of CSF were assessed in vitro using a monocyte transendothelial migration assay.</p> <p>Results</p> <p>CSF superfusion started to induce significant vasoconstriction on days 4 and 6 after SAH. In parallel, CSF superfusion induced a microvascular leukocyte recruitment, with a significant number of leukocytes rolling (day 6) and sticking (days 2-4) to the endothelium. CSF of patients presenting with cerebral edema induced breakdown of blood vessel integrity in our assay as evidenced by fluorescent marker extravasation. In accordance with leukocyte activation in vivo, significantly higher in vitro monocyte migration rates were found after SAH.</p> <p>Conclusion</p> <p>We functionally characterized inflammatory and vasoactive properties of patients' CSF after SAH in vivo and in vitro. This pro-inflammatory milieu in the subarachnoid space might play a pivotal role in the pathophysiology of early and delayed brain injury as well as vasospasm development following SAH.</p

Effect of garlic on cardiovascular disorders: a review

Garlic and its preparations have been widely recognized as agents for prevention and treatment of cardiovascular and other metabolic diseases, atherosclerosis, hyperlipidemia, thrombosis, hypertension and diabetes. Effectiveness of garlic in cardiovascular diseases was more encouraging in experimental studies, which prompted several clinical trials. Though many clinical trials showed a positive effect of garlic on almost all cardiovascular conditions mentioned above, however a number of negative studies have recently cast doubt on the efficary of garlic specially its cholesterol lowering effect of garlic. It is a great challenge for scientists all over the world to make a proper use of garlic and enjoy its maximum beneficial effect as it is the cheapest way to prevent cardiovascular disease. This review has attempted to make a bridge the gap between experimental and clinical study and to discuss the possible mechanisms of such therapeutic actions of garlic

Adapting brief CBT-I for depressed adolescents: a case illustration of the sleeping better program

Disturbed sleep is a common symptom of depression in adolescents, but this symptom is not often targeted in psychological therapies for depression. Although the causal relationship between sleep and depression is unclear, there is increasing evidence that in adults, Cognitive Behavioral Therapy for Insomnia (CBT-I) improves sleep problems and reduces symptoms of depression; however, there has been little investigation of using this approach with adolescents. This article describes the adaptation of brief CBT-I for adolescents with depression. A single case study is reported to illustrate the use of the Sleeping Better program. Adaptations for adolescents include increased emphasis on engagement of the young person and the inclusion of parents in treatment. The treatment program was acceptable to the adolescent and parent, and treatment outcome, as indicated by sleep diaries and standardized measures of depression and anxiety, was positive. Further evaluation of the Sleeping Better program is needed to establish if it is an effective low-intensity intervention for sleep problems in adolescents who have depression or anxiety

The effects of early life nutrient restriction on the cardiovascular system of the adult sheep

There is now strong epidemiological and animal research showing that undernutrition in gestation and early postnatal life is linked with a higher incidence of cardiovascular disease in adulthood. The physiological processes involved are not yet clear. The aim of this thesis was to investigate how aspects of the cardiovascular system in the adult sheep are affected by early life periods of undernutrition, and to investigate to concept that mismatches in these periods may influence these responses.Welsh Mountain ewes received 100% of global nutritional requirements at all times (C) except from minus 30 to day of conception (B), from minus 15 to 15 days after conception (A), or from day 1 of gestation to 31 days gestation (U) when they received 50% of total nutrient requirements. Offspring of groups C &amp; U were then fed ad libitum (CC &amp; UC) or at a level that reduced body weight to 85% of individual target weight from 12 to 25 weeks postnatal age (CU &amp; UU). The adult sheep cardiovascular function was studied at 2.5 years and 3.3 years.At 2.5 years the UC males showed an increased interventricular wall thickness without loss in function. These effects were not seen if early postnatal restriction was also received. In contrast, females subject in the gestational undernutrition (UC) showed a dampened heart rate response to a stressor, which was not seen when combined with a postnatal challenge (UU). Basal adrenaline was elevated in male and female singletons exposed to the postnatal challenge (CU &amp; UU). The stressor produced an enhanced adrenaline response in the females in the postnatally challenged group (CU). This effect was attenuated when combined with a gestational challenge (UU).Thus early life undernutrition alters adult cardiovascular physiology and may have consequences for cardiovascular function and disease in later life. These effects are sex-specific. The cardiovascular system is affected by the mismatch between gestation and early postnatal nutrition