Beyond element-wise interactions: identifying complex interactions in biological processes

Background: Biological processes typically involve the interactions of a number of elements (genes, cells) acting on each others. Such processes are often modelled as networks whose nodes are the elements in question and edges pairwise relations between them (transcription, inhibition). But more often than not, elements actually work cooperatively or competitively to achieve a task. Or an element can act on the interaction between two others, as in the case of an enzyme controlling a reaction rate. We call “complex” these types of interaction and propose ways to identify them from time-series observations. Methodology: We use Granger Causality, a measure of the interaction between two signals, to characterize the influence of an enzyme on a reaction rate. We extend its traditional formulation to the case of multi-dimensional signals in order to capture group interactions, and not only element interactions. Our method is extensively tested on simulated data and applied to three biological datasets: microarray data of the Saccharomyces cerevisiae yeast, local field potential recordings of two brain areas and a metabolic reaction. Conclusions: Our results demonstrate that complex Granger causality can reveal new types of relation between signals and is particularly suited to biological data. Our approach raises some fundamental issues of the systems biology approach since finding all complex causalities (interactions) is an NP hard problem

An experimentally-achieved information-driven Brownian motor shows maximum power at the relaxation time

We present an experimental realization of an information-driven Brownian motor by periodically cooling a Brownian particle trapped in a harmonic potential connected to a single heat bath, where cooling is carried out by the information process consisting of measurement and feedback control. We show that the random motion of the particle is rectified by symmetry-broken feedback cooling where the particle is cooled only when it resides on the specific side of the potential center at the instant of measurement. Studying how the motor thermodynamics depends on cycle period tau relative to the relaxation time tau(B) of the Brownian particle, we find that the ratcheting of thermal noise produces the maximum work extraction when tau >= 5 tau(B) while the extracted power is maximum near tau= tau(B), implying the optimal operating time for the ratcheting process. In addition, we find that the average transport velocity is monotonically decreased as tau increases and present the upper bound for the velocity

A new approach to bad news effects on volatilit y: the multiple-sign-volume sensitive regime EGARCH model (MSV-EGARCH)

In this paper, using daily data for six major international stock market indexes and a modified EGARCH specification, the links between stock market returns, volatility and trading volume are investigated in a new nonlinear conditional variance framework with multiple regimes and volume eff ects. Volatility forecast comparisons, using the Harvey-Newbold test for multiple forecasts encompassing, seem to demonstrate that the MSV- EGARCH complex threshold structure is able to correctly fit GARCH- type dynamics of the series under study and dominates competing standard asymmetric models in several of the considered stock indexes.info:eu-repo/semantics/publishedVersio

Personal experience with the procurement of 132 liver allografts

A single donor surgeon's experience procuring the livers from 132 donors is described. Thirty-seven grafts (28.9%) had hepatic arterial anomalies, 19 (14.4%) of which required arterial reconstruction prior to transplantation. Of the 121 grafts evaluated for early function, 103 grafts (85.2%) functioned well, whereas 14 grafts (11.6%) functioned poorly and 4 grafts (3.3%) failed to function at all. The variables associated with less than optimal function of the graft consisted of donor age (P<0.05), duration of donor's stay in the intensive care unit (P<0.005), abnormal graft appearance (P<0.05), and such recipient problems as vascular thromboses during or immediately following transplantation (P<0.005). A new preservation fluid, University of Wisconsin solution, allowed safe and longer cold storage of the liver allograft than did Euro-Collins' solution (P<0.0001). A parameter of liver allograft viability, which is simple and predictive of allograft function prior to the actual transplant procedure, is urgently needed. © 1989 Springer-Verlag

Uncovering treatment burden as a key concept for stroke care: a systematic review of qualitative research

&lt;b&gt;Background&lt;/b&gt; Patients with chronic disease may experience complicated management plans requiring significant personal investment. This has been termed ‘treatment burden’ and has been associated with unfavourable outcomes. The aim of this systematic review is to examine the qualitative literature on treatment burden in stroke from the patient perspective.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Methods and findings&lt;/b&gt; The search strategy centred on: stroke, treatment burden, patient experience, and qualitative methods. We searched: Scopus, CINAHL, Embase, Medline, and PsycINFO. We tracked references, footnotes, and citations. Restrictions included: English language, date of publication January 2000 until February 2013. Two reviewers independently carried out the following: paper screening, data extraction, and data analysis. Data were analysed using framework synthesis, as informed by Normalization Process Theory. Sixty-nine papers were included. Treatment burden includes: (1) making sense of stroke management and planning care, (2) interacting with others, (3) enacting management strategies, and (4) reflecting on management. Health care is fragmented, with poor communication between patient and health care providers. Patients report inadequate information provision. Inpatient care is unsatisfactory, with a perceived lack of empathy from professionals and a shortage of stimulating activities on the ward. Discharge services are poorly coordinated, and accessing health and social care in the community is difficult. The study has potential limitations because it was restricted to studies published in English only and data from low-income countries were scarce.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusions&lt;/b&gt; Stroke management is extremely demanding for patients, and treatment burden is influenced by micro and macro organisation of health services. Knowledge deficits mean patients are ill equipped to organise their care and develop coping strategies, making adherence less likely. There is a need to transform the approach to care provision so that services are configured to prioritise patient needs rather than those of health care systems

Placebo Adherence and Its Association with Morbidity and Mortality in the Studies of Left Ventricular Dysfunction

A provocative finding from several double-blind clinical trials has been the association between greater adherence to placebo study medication and better health outcomes. We used data from the Studies of Left Ventricular Dysfunction (SOLVD) Treatment Trial (SOLVD-TT) and the SOLVD Prevention Trial (SOLVD-PT) to examine whether such associations could be validated and to examine several sources of bias and potential confounding. Survival analytic methods were used to estimate the association between placebo adherence and several health outcomes, employing a number of modeling techniques to test for the existence of alternative explanations for the association. Higher adherence was defined as having taken ≥75% of prescribed study medication. Higher placebo adherence was associated with improved overall survival in both SOLVD-TT and SOLVD-PT [hazard ratio (HR) = 0.52, 95% confidence interval (CI): 0.35 to 0.79 and HR = 0.52, 95%CI: 0.38 to 0.71, respectively]. Associations were similar for fatal or non-fatal cardiovascular or coronary heart disease events. Adjustment for both modifiable and non-modifiable cardiac risk factors (including age, gender, diabetes, blood pressure, smoking, weight, alcohol use, and levels of education) had minimal effect on the strength of the association. Little evidence of bias was found as an explanation for this relationship. In these two trials, better adherence to placebo was associated with markedly superior health outcomes, including total in-study mortality and incident cardiovascular events. No important confounders were identified. These data suggest there may exist strong but unrecognized determinants of health outcomes for which placebo adherence is a marker

Inhibition of S6K1 accounts partially for the anti-inflammatory effects of the arginase inhibitor L-norvaline

<p>Abstract</p> <p>Background</p> <p>Pharmacological inhibition of endothelial arginase-II has been shown to improve endothelial nitric oxide synthase (eNOS) function and reduce atherogenesis in animal models. We investigated whether the endothelial arginase II is involved in inflammatory responses in endothelial cells.</p> <p>Methods</p> <p>Human endothelial cells were isolated from umbilical veins and stimulated with TNFα (10 ng/ml) for 4 hours. Endothelial expression of the inflammatory molecules i.e. vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin were assessed by immunoblotting.</p> <p>Results</p> <p>The induction of the expression of endothelial VCAM-1, ICAM-1 and E-selectin by TNFα was concentration-dependently reduced by incubation of the endothelial cells with the arginase inhibitor L-norvaline. However, inhibition of arginase by another arginase inhibitor S-(2-boronoethyl)-L-cysteine (BEC) had no effects. To confirm the role of arginase-II (the prominent isoform expressed in HUVECs) in the inflammatory responses, adenoviral mediated siRNA silencing of arginase-II knocked down the arginase II protein level, but did not inhibit the up-regulation of the adhesion molecules. Moreover, the inhibitory effect of L-norvaline was not reversed by the NOS inhibitor L-NAME and L-norvaline did not interfere with TNFα-induced activation of NF-κB, JNK, p38mapk, while it inhibited p70s6k (S6K1) activity. Silencing S6K1 prevented up-regulation of E-selectin, but not that of VCAM-1 or ICAM-1 induced by TNFα.</p> <p>Conclusion</p> <p>The arginase inhibitor L-norvaline exhibits anti-inflammatory effects independently of inhibition of arginase in human endothelial cells. The anti-inflammatory properties of L-norvaline are partially attributable to its ability to inhibit S6K1.</p

Cancer survivors’ experiences of a community-based cancer-specific exercise programme: results of an exploratory survey

Purpose Exercise levels often decline following cancer diagnosis despite growing evidence of its benefits. Treatment side-effects, older age, lack of confidence and opportunity to exercise with others in similar circumstances influence this. Our study explored the experiences of people attending a cancer-specific community-based exercise programme (CU Fitter™). Methods A survey distributed to those attending the programme gathered demographic/clinical information, self-reported exercise levels, information provision and barriers to/benefits of exercise. Results Sixty surveys were evaluable from 65/100 returned (62% female, 68% >60yrs, 66% breast/prostate cancer). Most (68%) were receiving treatment. 68% attended classes once or twice weekly. 55% received exercise advice after diagnosis, usually from their hospital doctor/nurse. More (73%) had read about exercising, but less used the internet to source information (32%). Self-reported exercise levels were higher currently than before diagnosis (p=0.05). 48% said their primary barrier to exercising was the physical impact of cancer/treatment. Improving fitness/health (40%) and social support (16%) were the most important gains from the programme. Many (67%) had made other lifestyle changes and intented to keep (50%), or increase (30%) exercising. Conclusions This community-based cancer-specific exercise approach engaged people with cancer and showed physical, psychological, and social benefits. Implications for cancer survivors Community grown exercise initiatives bring cancer survivors together creating their own supportive environment. Combining this with instructors familiar with the population and providing an open-ended service may prove particularly motivating and beneficial. Further work is required to provide evidence for this

Atrial fibrillation and heart failure: Factors influencing the choice of oral anticoagulant.

Atrial fibrillation (AF) and heart failure (HF) frequently coexist. AF is identified in approximately one third of patients with HF and is linked to increased morbidity and mortality than from either condition alone. AF is relatively more common in HF with preserved ejection fraction (HFpEF) than with reduced ejection fraction (HFrEF). Nevertheless, the risk of stroke and systemic embolism (SSE) is significantly increased with both HF types and the absolute risk is heavily influenced by the presence and severity of associated additional stroke risk factors. The European Society of Cardiology has very recently introduced a third HF subtype entitled HF with mid-range ejection fraction (HFmrEF). At present oral anticoagulation is recommended for all patients with AF and HF, independent of HF type. In addition to warfarin there are currently four non-vitamin K oral anticoagulants (NOACs, previously called novel oral anticoagulants) that have been approved for the prevention of SSE. They consist of one direct thrombin inhibitor, dabigatran and three factor Xa inhibitors: rivaroxaban, apixaban and, most recently, edoxaban. In this review article we present an overview of the evidence to support the use of NOACs for the prevention of SSE in patients with AF and HF and review the influence of HF subtype and co-morbidities on the potential choice of oral anticoagulant