Uncovering allosteric pathways in caspase-1 with Markov transient analysis and multiscale community detection

Allosteric regulation at distant sites is central to many cellular processes. In particular, allosteric sites in proteins are a major target to increase the range and selectivity of new drugs, and there is a need for methods capable of identifying intra-molecular signalling pathways leading to allosteric effects. Here, we use an atomistic graph-theoretical approach that exploits Markov transients to extract such pathways and exemplify our results in an important allosteric protein, caspase-1. Firstly, we use Markov Stability community detection to perform a multiscale analysis of the structure of caspase-1 which reveals that the active conformation has a weaker, less compartmentalised large-scale structure as compared to the inactive conformation, resulting in greater intra-protein coherence and signal propagation. We also carry out a full computational point mutagenesis and identify that only a few residues are critical to such structural coherence. Secondly, we characterise explicitly the transients of random walks originating at the active site and predict the location of a known allosteric site in this protein quantifying the contribution of individual bonds to the communication pathway between the active and allosteric sites. Several of the bonds we find have been shown experimentally to be functionally critical, but we also predict a number of as yet unidentified bonds which may contribute to the pathway. Our approach offers a computationally inexpensive method for the identification of allosteric sites and communication pathways in proteins using a fully atomistic description.Comment: 14 pages, 8 figure

On the Simulations of Evolution-Communication P Systems with Energy without Antiport Rules for GPUs

In this report, we present our initial proposal on simulating computations on a restricted variant of Evolution-Communication P system with energy (ECPe system) which will then be implemented in Graphics Processing Units (GPUs). This ECPe sys- tems variant prohibits the use of antiport rules for communication. Several possible levels of parallelizations for simulating ECPe systems computations on GPUs are emphasized. Our work is based on a localized matrix representation for the mentioned variant given in a previous literature. Our proposal employs a methodology for forward computing also discussed in the said literature.Junta de Andalucía P08-TIC04200Ministerio de Ciencia e Innovación TIN2009–1319

OBSTETRIC AND PERINATAL OUTCOMES IN PREGNANCY WITH DIFFERENT SEVERITY AND TIME OF THE MANIFESTATION OF PREECLAMPSIA

The aim of the study – to conduct a retrospective analysis of the course of pregnancy and delivery to determine the nature of obstetric and perinatal complications in preeclampsia. Materials and Methods. The analysis was based on the results of the evaluation of the medical documentation (individual medical records of the pregnant woman, birth histories, developmental histories of the newborn) in 224 pregnant women with preeclampsia and 80 pregnant women without preeclampsia. In addition to the results of the clinical and laboratory examination, the analysis included the severity of preeclampsia and the time of clinical manifestations. The results of the study were statistically processed by methods of mathematical analysis with the determination of the mean values ​​(M ± m), Student's t-test and significance factor (р˂0.050 difference was statistically significant. Results and Discussion. According to the results of the analysis, mild preeclampsia was found in 32.6 % of cases, modera­te PE – in 37.5 %, severe PE – in 29.9 % of cases. The early onset of PE (up to 34 weeks) was observed in 35.7 % of pregnant women, and later onset (after 34 weeks) in 64.7 %. The analysis of the incidence of early and late PE cases at various severity levels showed that, in the case of early PE, severe disease was 2.9 times more frequent, and the moderate disease was 2.7 times more frequent than the mild disease. In the late PE, the mild PE was 1.9 times more frequent than the severe PE and 1.2 times more frequent than the moderate PE. In addition to PE, 31.7 % of women had other complications of pregnancy. The most common complications include asymptomatic bacteriuria (16.9 %), abnormal placental location (14.1 %), placental dysfunction (32.4 %), and fetal growth retardation (21.1 %). Term delivery occurred in 81.6 % of cases, premature births were in 18.3 %. Complications include premature rupture of membranes, anomalies of labor, premature detachment of the normally located placenta, postpartum hemorrhage. Among perinatal complications, fetal growth retardation, hemodynamic disorders, fetal distress, newborn asphyxia have been observed. The adverse outcome for a child in severe PE was 3 times higher than for mild PE. Conclusion. The analysis showed that obstetric and perinatal outcomes in preeclampsia are associated with the time of this pregnancy complication and its severity

Improving Simulations of Spiking Neural P Systems in NVIDIA CUDA GPUs: CuSNP

Spiking neural P systems (in short, SN P systems) are parallel models of computations inspired by the spiking ( ring) of biological neurons. In SN P systems, neurons function as spike processors and are placed on nodes of a directed graph. Synapses, the connections between neurons, are represented by arcs or directed endges in the graph. Not only do SN P systems have parallel semantics (i.e. neurons operate in parallel), but their structure as directed graphs allow them to be represented as vectors or matrices. Such representations allow the use of linear algebra operations for simulating the evolution of the system con gurations, i.e. computations. In this work, we continue the implementations of SN P systems with delays, i.e. a delay is associated with the sending of a spike from a neuron to its neighbouring neurons. Our implementation is based on a modi ed representation of SN P systems as vectors and matrices for SN P systems without delays. We us massively parallel processors known as graphics processing units (in short, GPUs) from NVIDIA. For experimental validation, we use SN P systems implementing generalized sorting networks. We report a speedup, i.e. the ratio between the running time of the sequential over the parallel simulator, of up to approximately 51 times for a 512-size input to the sorting network

CuSNP: Spiking Neural P Systems Simulators in CUDA

Spiking neural P systems (in short, SN P systems) are models of computation inspired by biological neurons. CuSNP is a project involving sequential (CPU) and parallel (GPU) simulators for SN P systems. In this work, we report the following results: a P-Lingua le parser is included, for ease of use when performing simulations; extension of the matrix representation of SN P systems to include delay; comparison and analysis of our simulators by simulating two types (bitonic and generalized) of parallel sorting networks; extension of supported types of regular expressions in SN P systems. Our GPU simulator is better suited for generalized sorting as compared to bitonic sorting networks, and the GPU simulators run up to 50 faster than our CPU simulator. Finally, we discuss our experiments and provide directions for further work

A GPU Simulation for Evolution-Communication P Systems with Energy Having no Antiport Rules

Evolution-Communication P system with energy (ECPe systems) is a cell- like variant P system which establishes a dependence between evolution and communi- cation through special objects, called `energy,' produced during evolution and utilized during communication. This paper presents our initial progress and e orts on the im- plementation and simulation of ECPe systems using Graphics Processing Units (GPUs). Our implementation uses matrix representation and operations presented in a previous work. Speci cally, an implementation of computations on ECPe systems without antiport rules is discussed.Junta de Andalucía P08-TIC-04200Ministerio de Ciencia e Innovación TIN2012-3743

Composition and Anticoagulant Potential of Chondroitin Sulfate and Dermatan Sulfate from Inedible Parts of Garfish (Belone belone)

Glycosaminoglycans (GAGs) play a crucial role due to their significant biomedical functions. Chondroitin sulfate (CS) and dermatan sulfate (DS), the main representative family of GAGs, were extracted and purified from garfish (Belone belone) by-products, i.e., skin (GSB), bones (GCB), and heads (GHB), and their composition and anticoagulant activity were investigated. CS/DS were purified by ion-exchange chromatography with yields of 8.1% for heads, 3.7% for skin, and 1.4% for bones. Cellulose acetate electrophoresis was also explored for analyzing the extracted CS/DS. Interestingly, GHB, GSB, and GCB possessed sulfate contents of 21 ± 2%, 20 ± 1%, and 20 ± 1.5%, respectively. Physico-chemical analysis showed that there were no significant differences (p > 0.05) between the variances for sulfate, uronic acid, and total sugars in the GAGs extracted from the different parts of fish. Disaccharide analysis by SAX-HPLC showed that the GSB and GCB were predominately composed of ΔDi-4S [ΔUA-GalNAc 6S] (74.78% and 69.22%, respectively) and ΔDi-2,4S [ΔUA2S-GalNAc 4S] (10.92% and 6.55%, respectively). However, the GHB consisted of 25.55% ΔDi-6S [ΔUA-GalNAc 6S] and 6.28% ΔDi-2,6S [ΔUA2S-GalNAc 4S]. Moreover, classical anticoagulation tests were also used to measure their anticoagulant properties in vitro, which included the activated partial thromboplastin time, prothrombin time, and thrombin time. The CS/DS isolated from garfish by-products exhibited potent anticoagulant effects. The purified CS/DS showed exceptional anticoagulant properties according to this research and can be considered as a new agent with anticoagulant properties

Small heat shock proteins are induced during multiple sclerosis lesion development in white but not grey matter

INTRODUCTION: The important protective role of small heat-shock proteins (HSPs) in regulating cellular survival and migration, counteracting protein aggregation, preventing apoptosis, and regulating inflammation in the central nervous system is now well-recognized. Yet, their role in the neuroinflammatory disorder multiple sclerosis (MS) is largely undocumented. With the exception of alpha B-crystallin (HSPB5), little is known about the roles of small HSPs in disease. RESULTS: Here, we examined the expression of four small HSPs during lesion development in MS, focussing on their cellular distribution, and regional differences between white matter (WM) and grey matter (GM). It is well known that MS lesions in these areas differ markedly in their pathology, with substantially more intense blood-brain barrier damage, leukocyte infiltration and microglial activation typifying WM but not GM lesions. We analysed transcript levels and protein distribution profiles for HSPB1, HSPB6, HSPB8 and HSPB11 in MS lesions at different stages, comparing them with normal-appearing brain tissue from MS patients and non-neurological controls. During active stages of demyelination in WM, and especially the centre of chronic active MS lesions, we found significantly increased expression of HSPB1, HSPB6 and HSPB8, but not HSPB11. When induced, small HSPs were exclusively found in astrocytes but not in oligodendrocytes, microglia or neurons. Surprisingly, while the numbers of astrocytes displaying high expression of small HSPs were markedly increased in actively demyelinating lesions in WM, no such induction was observed in GM lesions. This difference was particularly obvious in leukocortical lesions covering both WM and GM areas. CONCLUSIONS: Since induction of small HSPs in astrocytes is apparently a secondary response to damage, their differential expression between WM and GM likely reflects differences in mediators that accompany demyelination in either WM or GM during MS. Our findings also suggest that during MS, cortical structures fail to benefit from the protective actions of small HSPs. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40478-015-0267-2) contains supplementary material, which is available to authorized users