Transfer Functions for Protein Signal Transduction: Application to a Model of Striatal Neural Plasticity

We present a novel formulation for biochemical reaction networks in the context of signal transduction. The model consists of input-output transfer functions, which are derived from differential equations, using stable equilibria. We select a set of 'source' species, which receive input signals. Signals are transmitted to all other species in the system (the 'target' species) with a specific delay and transmission strength. The delay is computed as the maximal reaction time until a stable equilibrium for the target species is reached, in the context of all other reactions in the system. The transmission strength is the concentration change of the target species. The computed input-output transfer functions can be stored in a matrix, fitted with parameters, and recalled to build discrete dynamical models. By separating reaction time and concentration we can greatly simplify the model, circumventing typical problems of complex dynamical systems. The transfer function transformation can be applied to mass-action kinetic models of signal transduction. The paper shows that this approach yields significant insight, while remaining an executable dynamical model for signal transduction. In particular we can deconstruct the complex system into local transfer functions between individual species. As an example, we examine modularity and signal integration using a published model of striatal neural plasticity. The modules that emerge correspond to a known biological distinction between calcium-dependent and cAMP-dependent pathways. We also found that overall interconnectedness depends on the magnitude of input, with high connectivity at low input and less connectivity at moderate to high input. This general result, which directly follows from the properties of individual transfer functions, contradicts notions of ubiquitous complexity by showing input-dependent signal transmission inactivation.Comment: 13 pages, 5 tables, 15 figure

Susceptibility Patterns of Staphylococcus Aureus Biofilms in Diabetic Foot Infections

BACKGROUND: Foot infections are a major cause of morbidity in people with diabetes and the most common cause of diabetes-related hospitalization and lower extremity amputation. Staphylococcus aureus is by far the most frequent species isolated from these infections. In particular, methicillin-resistant S. aureus (MRSA) has emerged as a major clinical and epidemiological problem in hospitals. MRSA strains have the ability to be resistant to most β-lactam antibiotics, but also to a wide range of other antimicrobials, making infections difficult to manage and very costly to treat. To date, there are two fifth-generation cephalosporins generally efficacious against MRSA, ceftaroline and ceftobripole, sharing a similar spectrum. Biofilm formation is one of the most important virulence traits of S. aureus. Biofilm growth plays an important role during infection by providing defence against several antagonistic mechanisms. In this study, we analysed the antimicrobial susceptibility patterns of biofilm-producing S. aureus strains isolated from diabetic foot infections. The antibiotic minimum inhibitory concentration (MIC) was determined for ten antimicrobial compounds, along with the minimum biofilm inhibitory concentration (MBIC) and minimum biofilm eradication concentration (MBEC), followed by PCR identification of genetic determinants of biofilm production and antimicrobial resistance. RESULTS: Results demonstrate that very high concentrations of the most used antibiotics in treating diabetic foot infections (DFI) are required to inhibit S. aureus biofilms in vitro, which may explain why monotherapy with these agents frequently fails to eradicate biofilm infections. In fact, biofilms were resistant to antibiotics at concentrations 10-1000 times greater than the ones required to kill free-living or planktonic cells. The only antibiotics able to inhibit biofilm eradication on 50 % of isolates were ceftaroline and gentamicin. CONCLUSIONS: The results suggest that the antibiotic susceptibility patterns cannot be applied to biofilm established infections. Selection of antimicrobial therapy is a critical step in DFI and should aim at overcoming biofilm disease in order to optimize the outcomes of this complex pathology

Molecular Typing, Virulence Traits and Antimicrobial Resistance of Diabetic Foot Staphylococci

Diabetes mellitus is a major chronic disease that continues to increase significantly. One of the most important and costly complications of diabetes are foot infections that may be colonized by pathogenic and antimicrobial resistant bacteria, harboring several virulence factors, that could impair its successful treatment. Staphylococcus aureus is one of the most prevalent isolate in diabetic foot infections, together with aerobes and anaerobes

Diurnal variability of inner-shelf circulation in the lee of a cape under upwelling conditions.

The nearshore circulation in the lee of a cape under upwelling conditions was studied using in-situ data from 3 consecutive summers (2006–2008). Focus was given to a period between 20 July and 04 August 2006 to study the diurnal variability of the cross-shelf circulation. This period was chosen because it had a steady upwellingfavourable wind condition modulated by a diurnal cycle much similar to sea breeze. The daily variability of the observed cross-shelf circulation consisted of three distinct periods: a morning period with a 3-layer vertical structure with onshore velocities at mid-depth, a mid-day period where the flow is reversed and has a 2-layer structure with onshore velocities at the surface and offshore flow below, and, lastly, in the evening, a 2-layer period with intensified offshore velocities at the surface and onshore flow at the bottom. The observed cross-shelf circulation showed a peculiar vertical shape and diurnal variability different from several other systems described in literature. We hypothesize that the flow reversal of the cross-shelf circulation results as a response to the rapid change of the wind magnitude and direction at mid-day with the presence of the cape north of the mooring site influencing this response. A numerical modelling experiment exclusively forced by winds simulated successfully most of the circulation at the ADCP site, especially the mid-day reversal and the evening's upwelling-type structure. This supports the hypothesis that the cross-shelf circulation at diurnal timescales is mostly wind-driven. By analysing the 3D circulation in the vicinity of Cape Sines we came to the conclusion that the diurnal variability of the wind and the flow interaction with topography are responsible for the circulation variability at the ADCP site, though only a small region in the south of the cape showed a similar diurnal variability. The fact that the wind diurnally undergoes relaxation and intensification strongly affects the circulation, promoting superficial onshore flows in the leeside of Cape Sines. Despite the small-scale nature of the observed cross-shelf circulation, onshore flows as the ones described in this study can be particularly helpful to understand the transport and settlement of larvae in this region and in other regions with similar topography and wind characteristics.We thank D. Jacinto and T. Silva for help during field work and the Port of Sines Authority (APS) for providing oceanographic and meteorological data. Financial support was provided by FCT (POCI/ MAR/57630/2004; PTDC/BIA-BEC/103734/2008 and PEst-OE/ MAR/UIO199/2011). The simulations were preformed in the computational facilities provided under FCT contract RECI/GEO-MET/0380/ 2012. Luísa Lamas was funded by the FCT under a Ph.D. grant (SFRH/ BD/69533/2010)

Phosphorus removal by a fixed-bed hybrid polymer nanocomposite biofilm reactor

Eutrophication is one of the main challenges regarding the ecological quality of surface waters, phosphorus bioavailability being its main driver. In this context, a novel hybrid polymer nanocomposite (HPN-Pr) biofilm reactor aimed at integrated chemical phosphorus adsorption and biological removal was conceived. The assays pointed to removal of 1.2 mg P/g of reactive phosphorus and 1.01 mg P/g of total phosphorus under steady-state conditions. A mathematical adsorption–biological model was applied to predict reactor performance, which indicated that biological activity has a positive effect on reactor performance, increasing the amount of reactive phosphorus removed.The authors acknowledge the Portuguese Foundation for Science and Technology for the financial support under Project SFRH/BD/39085/2007

Visual Data Mining

Occlusion is one of the major problems for interactive visual knowledge discovery and data mining in the process of finding patterns in multidimensional data.This project proposes a hybrid method that combines visual and analytical means to deal with occlusion in visual knowledge discovery called as GLC-S which uses visualization of n-D data in 2D in a set of Shifted Paired Coordinates (SPC). A set of Shifted Paired Coordinates for n-D data consists of n/2 pairs of common Cartesian coordinates that are shifted relative to each other to avoid their overlap. Each n-D point A is represented as a directed graph A* in SPC, where each node is the 2D projection of A in a respective pair of the Cartesian coordinates. The proposed GLC-S method significantly decrease cognitive load for analysis of n-D data and simplify pattern discovery in n-D data. The GLC-S method iteratively splits n-D data into non-overlapping clusters (hyper-rectangles) around local centers and visualizes only data within these clusters at each iteration. The requirements for these clusters are to contain cases of only one class and be the largest cluster with this property in SPC visualization. Such sequential splitting allows: (1) avoiding occlusion, (2) finding visually local classification patterns, rules, and (3) combine local sub-rules to a global rule that classifies all given data of two or more classes. The computational experiment with Wisconsin Breast Cancer data(9-D), User Knowledge Modeling data(6-D), and Letter Recognition data(17-D) from UCI Machine Learning Repository confirm this capability. At each iteration, these data have been split into training (70%) and validation (30%) data. It required 3 iterations in Wisconsin Breast Cancer data, 4 iterations in User Knowledge Modeling and 5 iterations in Letter Recognition data and respectively 3, 4, 5 local sub-rules that covered over 95% of all n-D data points with 100% accuracy at both training and validation experiments. After each iteration, the data that were used in this iteration are removed and remaining data are used in the next iteration. This removal process helps to decrease occlusion too. The GLC-S algorithm refuses to classify remaining cases that are not covered by these rules, i.e.,., do not belong to found hyper-rectangles. The interactive visualization process in SPC allows adjusting the sides of the hyper-rectangles to maximize the size of the hyper-rectangle without its overlap with the hyper-rectangles of the opposing classes. The GLC-S method splits data using the fixed split of n coordinates to pairs. This hybrid visual and analytical approach avoids throwing all data of several classes into a visualization plot that typically ends up in a messy highly occluded picture that hides useful patterns. This approach allows revealing these hidden patterns. The visualization process in SPC is reversible (lossless). i.e.,., all n-D information is visualized in 2D and can be restored from 2D visualization for each n-D case. This hybrid visual analytics method allowed classifying n-D data in a way that can be communicated to the user’s in the understandable and visual form

Convergence of asymptotic systems of non-autonomous neural network models with infinite distributed delays

In this paper we investigate the global convergence of solutions of non-autonomous Hopfield neural network models with discrete time-varying delays, infinite distributed delays, and possible unbounded coefficient functions. Instead of using Lyapunov functionals, we explore intrinsic features between the non-autonomous systems and their asymptotic systems to ensure the boundedness and global convergence of the solutions of the studied models. Our results are new and complement known results in the literature. The theoretical analysis is illustrated with some examples and numerical simulations.The paper was supported by the Research Centre of Mathematics of the University of Minho with the Portuguese Funds from the "Fundacao para a Ciencia e a Tecnologia", through the Project PEstOE/MAT/UI0013/2014. The author thanks the referee for valuable comments.info:eu-repo/semantics/publishedVersio

Noncompaction Cardiomyopathy. A Review of Eight Cases

A miocardiopatia não compactada isolada é uma doença geneticamente determinada cuja patogénese parece envolver uma paragem no desenvolvimento do endomiocárdio. Morfologicamente caracteriza-se pela presença de trabeculações proeminentes separadas por profundos recessos preenchidos por fluxo e como tal por Doppler a cor no estudo ecocardiográfico. No sentido de melhor caracterizar esta entidade recentemente descrita, de prognóstico pouco esclarecido, fazemos uma revisão dos casos diagnosticados no nosso hospital, descrevendo as características clínicas, electrocardiográficas e ecocardiográficas, bem como a terapêutica instituída e seguimento clínico. A propósito da revisão dos casos, é feita uma exposição e discussão da literatura mais relevante relativamente a etiopatogenia, clínica, critérios de diagnóstico, terapêutica e prognóstico

Effectiveness of offloading interventions to heal foot ulcers in persons with diabetes: a systematic review

Background Offloading interventions are commonly used in clinical practice to heal foot ulcers. The aim of this updated systematic review is to investigate the effectiveness of offloading interventions to heal diabetic foot ulcers. Methods We updated our previous systematic review search of PubMed, EMBASE, and Cochrane databases to also include original studies published between July 29, 2014 and August 13, 2018 relating to four offloading intervention categories in populations with diabetic foot ulcers: (a) offloading devices, (b) footwear, (c) other offloading techniques, and (d) surgical offloading techniques. Outcomes included ulcer healing, plantar pressure, ambulatory activity, adherence, adverse events, patient‐reported measures, and cost‐effectiveness. Included controlled studies were assessed for methodological quality and had key data extracted into evidence and risk of bias tables. Included non‐controlled studies were summarised on a narrative basis. Results We identified 41 studies from our updated search for a total of 165 included studies. Six included studies were meta‐analyses, 26 randomised controlled trials (RCTs), 13 other controlled studies, and 120 non‐controlled studies. Five meta‐analyses and 12 RCTs provided high‐quality evidence for non‐removable knee‐high offloading devices being more effective than removable offloading devices and therapeutic footwear for healing plantar forefoot and midfoot ulcers. Total contact casts (TCCs) and non‐removable knee‐high walkers were shown to be equally effective. Moderate‐quality evidence exists for removable knee‐high and ankle‐high offloading devices being equally effective in healing, but knee‐high devices have a larger effect on reducing plantar pressure and ambulatory activity. Low‐quality evidence exists for the use of felted foam and surgical offloading to promote healing of plantar forefoot and midfoot ulcers. Very limited evidence exists for the efficacy of any offloading intervention for healing plantar heel ulcers, non‐plantar ulcers, and neuropathic ulcers with infection or ischemia. Conclusion Strong evidence supports the use of non‐removable knee‐high offloading devices (either TCC or non‐removable walker) as the first‐choice offloading intervention for healing plantar neuropathic forefoot and midfoot ulcers. Removable offloading devices, either knee‐high or ankle‐high, are preferred as second choice over other offloading interventions. The evidence bases to support any other offloading intervention is still weak and more high‐quality controlled studies are needed in these areas