Prerupture Intracranial Aneurysm Morphology in Predicting Risk of Rupture: A Matched Case-Control Study.

Background: Maximal size and other morphological parameters of intracranial aneurysms (IAs) are used when deciding if an IA should be treated prophylactically. These parameters are derived from postrupture morphology. As time and rupture may alter the aneurysm geometry, possible morphological predictors of a rupture should be established in prerupture aneurysms.

The impact of cytokine responses in the intra- and extracellular signaling network of a traumatic injury.

Investigations of cellular responses involved in injury and repair processes have generated valuable information contributing to the advancement of wound healing and treatments. Intra- and extracellular regulators of healing mechanisms, such as cytokines, signaling proteins, and growth factors, have been described to possess significant roles in facilitating optimal recovery. This study explored a collection of 30 spatiotemporal responses comprised of cytokines (IL-1α, IL-1ß, IL-2, IL-6, TNF-α, MIP-1α), intracellular proteins (Akt, c-Jun, CREB, ERK1/2, JNK, MEK1, p38, p53, p90RSK), phosphorylated proteins (p-Akt, p-c-Jun, p-CREB, p-ERK1/2, p-GSK-3α/ß, p-HSP27, p-IκBα, p-JNK, p-MEK1, p-p38, p-p70S6K, p-p90RSK, p-STAT2, p-STAT3), and a protease (Caspase-3), measured in skeletal muscle tissue following a traumatic injury (rodent Gustilo IIIB fracture).

Interstitial solute transport in 3D reconstructed neuropil occurs by diffusion rather than bulk flow.

The brain lacks lymph vessels and must rely on other mechanisms for clearance of waste products, including amyloid [Formula: see text] that may form pathological aggregates if not effectively cleared. It has been proposed that flow of interstitial fluid through the brain's interstitial space provides a mechanism for waste clearance. Here we compute the permeability and simulate pressure-mediated bulk flow through 3D electron microscope (EM) reconstructions of interstitial space.

Inverse estimation of cardiac activation times via gradient-based optimization.

Computational modeling may provide a quantitative framework for integrating multiscale data to gain insight into mechanisms of heart disease, identify and test pharmacological and electrical therapy and interventions, and support clinical decisions. Patient-specific computational cardiac models can help guide such procedures, and cardiac inverse modeling is a promising alternative to adequately personalize these models. Indeed, full cardiac inverse modeling is currently becoming computationally feasible; however, fundamental work to assess the feasibility of emerging techniques is still needed.

Robustness of common hemodynamic indicators with respect to numerical resolution in 38 middle cerebral artery aneurysms.

Background: Using computational fluid dynamics (CFD) to compute the hemodynamics in cerebral aneurysms has received much attention in the last decade. The usability of these methods depends on the quality of the computations, highlighted in recent discussions. The purpose of this study is to investigate the convergence of common hemodynamic indicators with respect to numerical resolution.

Studying dyadic structure-function relationships: a review of current modeling approaches and new insights into Ca (mis)handling.

Excitation-contraction coupling in cardiac myocytes requires calcium influx through L-type calcium channels in the sarcolemma, which gates calcium release through sarcoplasmic reticulum ryanodine receptors in a process known as calcium-induced calcium release, producing a myoplasmic calcium transient and enabling cardiomyocyte contraction. The spatio-temporal dynamics of calcium release, buffering, and reuptake into the sarcoplasmic reticulum play a central role in excitation-contraction coupling in both normal and diseased cardiac myocytes. However, further quantitative understanding of these cells' calcium machinery and the study of mechanisms that underlie both normal cardiac function and calcium-dependent etiologies in heart disease requires accurate knowledge of cardiac ultrastructure, protein distribution and subcellular function.

Species-Dependent Mechanisms of Cardiac Arrhythmia: A Cellular Focus.

Although ventricular arrhythmia remains a leading cause of morbidity and mortality, available antiarrhythmic drugs have limited efficacy. Disappointing progress in the development of novel, clinically relevant antiarrhythmic agents may partly be attributed to discrepancies between humans and animal models used in preclinical testing. However, such differences are at present difficult to predict, requiring improved understanding of arrhythmia mechanisms across species.

A numerical investigation of intrathecal isobaric drug dispersion within the cervical subarachnoid space.

Intrathecal drug and gene vector delivery is a procedure to release a solute within the cerebrospinal fluid. This procedure is currently used in clinical practice and shows promise for treatment of several central nervous system pathologies. However, intrathecal delivery protocols and systems are not yet optimized.

Proteomics-based network analysis characterizes biological processes and pathways activated by preconditioned mesenchymal stem cells in cardiac repair mechanisms.

Background: We have demonstrated that intramyocardial delivery of human mesenchymal stem cells preconditioned with a hyaluronan mixed ester of butyric and retinoic acid (MSCp) is more effective in preventing the decay of regional myocardial contractility in a swine model of myocardial infarction (MI). However, the understanding of the role of MSCp in proteomic remodeling of cardiac infarcted tissue is not complete. We therefore sought to perform a comprehensive analysis of the proteome of infarct remote (RZ) and border zone (BZ) of pigs treated with MSCp or unconditioned stem cells.

SOS1, ARHGEF1, and DOCK2 rho-GEFs Mediate JAK-Dependent LFA-1 Activation by Chemokines.

JAK-dependent activation of the rho module of integrin affinity triggering mediates chemokine-induced leukocyte adhesion. However, the signaling events linking JAKs to rho small GTPase activation by chemokines is still incompletely described. In this study, we show that son of sevenless 1 (SOS1), rho guanine nucleotide exchange factor (GEF)1 (ARHGEF1), and dedicator of cytokinesis (DOCK)2 GEFs mediate CXCL12-induced LFA-1 activation in human primary T lymphocytes.

Improved reduced-order modelling of cerebrovascular flow distribution by accounting for arterial bifurcation pressure drops.

Reduced-order modelling offers the possibility to study global flow features in cardiovascular networks. In order to validate these models, previous studies have been conducted in which they compared 3D computational fluid dynamics simulations with reduced-order simulations. Discrepancies have been reported between the two methods.

Direct numerical simulation of transitional hydrodynamics of the cerebrospinal fluid in Chiari I malformation: The role of cranio-vertebral junction.

Obstruction to the cerebrospinal fluid (CSF) outflow caused by the herniation of cerebellar tonsils as a result of Chiari malformation type I leads to altered CSF hydrodynamics. This contribution explores the minutest characteristics of the CSF hydrodynamics in cervical subarachnoid space (SAS) of a healthy subject and 2 Chiari patients by performing highly resolved direct numerical simulation. The lattice Boltzmann method is used for the simulations because of its scalability on modern supercomputers that allow us to simulate up to approximately 10 cells while resolving the Kolmogorov microscales.

Transitional hemodynamics in intracranial aneurysms - Comparative velocity investigations with high resolution lattice Boltzmann simulations, normal resolution ANSYS simulations, and MR imaging.

Purpose: Blood flow in intracranial aneurysms has, until recently, been considered to be disturbed but still laminar. Recent high resolution computational studies have demonstrated, in some situations, however, that the flow may exhibit high frequency fluctuations that resemble weakly turbulent or transitional flow. Due to numerous assumptions required for simplification in computational fluid dynamics (CFD) studies, the occurrence of these events, in vivo, remains unsettled.

MRI Phenotyping of COL9A2/Trp2 and COL9A3/Trp3 Alleles in Lumbar Disc Disease: A Case-control Study in South-Western Iranian Population Reveals a Significant Trp3-Disease Association in Males.

Study Design: A case-control study of the Trp2/3 alleles of COL9A2/3 genes and their correlation with occurrence of Lumbar disc disease (DDD) as phenotyped by magnetic resonance imaging.

Objective: To establish a better understanding of relationship between presence of said alleles and occurrence of DDD in South-Western Iranian population.

Summary Of Background Data: A number of genetic predisposing factors have been identified in elevating the risk of developing DDD.

Refractoriness in human atria: Time and voltage dependence of sodium channel availability.

Background: Refractoriness of cardiac cells limits maximum frequency of electrical activity and protects the heart from tonic contractions. Short refractory periods support major arrhythmogenic substrates and augmentation of refractoriness is therefore seen as a main mechanism of antiarrhythmic drugs. Cardiomyocyte excitability depends on availability of sodium channels, which involves both time- and voltage-dependent recovery from inactivation.

Creating, generating and comparing random network models with NetworkRandomizer.

Biological networks are becoming a fundamental tool for the investigation of high-throughput data in several fields of biology and biotechnology. With the increasing amount of information, network-based models are gaining more and more interest and new techniques are required in order to mine the information and to validate the results. To fill the validation gap we present an app, for the Cytoscape platform, which aims at creating randomised networks and randomising existing, real networks.

Computational Investigation of Cerebrospinal Fluid Dynamics in the Posterior Cranial Fossa and Cervical Subarachnoid Space in Patients with Chiari I Malformation.

Purpose: Previous computational fluid dynamics (CFD) studies have demonstrated that the Chiari malformation is associated with abnormal cerebrospinal fluid (CSF) flow in the cervical part of the subarachnoid space (SAS), but the flow in the SAS of the posterior cranial fossa has received little attention. This study extends previous modelling efforts by including the cerebellomedullary cistern, pontine cistern, and 4th ventricle in addition to the cervical subarachnoid space.

Methods: The study included one healthy control, Con1, and two patients with Chiari I malformation, P1 and P2.

Informational laws of genome structures.

In recent years, the analysis of genomes by means of strings of length k occurring in the genomes, called k-mers, has provided important insights into the basic mechanisms and design principles of genome structures. In the present study, we focus on the proper choice of the value of k for applying information theoretic concepts that express intrinsic aspects of genomes. The value k = lg2(n), where n is the genome length, is determined to be the best choice in the definition of some genomic informational indexes that are studied and computed for seventy genomes.

Computing rates of Markov models of voltage-gated ion channels by inverting partial differential equations governing the probability density functions of the conducting and non-conducting states.

Markov models are ubiquitously used to represent the function of single ion channels. However, solving the inverse problem to construct a Markov model of single channel dynamics from bilayer or patch-clamp recordings remains challenging, particularly for channels involving complex gating processes. Methods for solving the inverse problem are generally based on data from voltage clamp measurements.

Protein and Signaling Networks in Vertebrate Photoreceptor Cells.

Vertebrate photoreceptor cells are exquisite light detectors operating under very dim and bright illumination. The photoexcitation and adaptation machinery in photoreceptor cells consists of protein complexes that can form highly ordered supramolecular structures and control the homeostasis and mutual dependence of the secondary messengers cyclic guanosine monophosphate (cGMP) and Ca(2+). The visual pigment in rod photoreceptors, the G protein-coupled receptor rhodopsin is organized in tracks of dimers thereby providing a signaling platform for the dynamic scaffolding of the G protein transducin.

A guide to uncertainty quantification and sensitivity analysis for cardiovascular applications.

As we shift from population-based medicine towards a more precise patient-specific regime guided by predictions of verified and well-established cardiovascular models, an urgent question arises: how sensitive are the model predictions to errors and uncertainties in the model inputs? To make our models suitable for clinical decision-making, precise knowledge of prediction reliability is of paramount importance. Efficient and practical methods for uncertainty quantification (UQ) and sensitivity analysis (SA) are therefore essential. In this work, we explain the concepts of global UQ and global, variance-based SA along with two often-used methods that are applicable to any model without requiring model implementation changes: Monte Carlo (MC) and polynomial chaos (PC).

JAK2 tyrosine kinase mediates integrin activation induced by CXCL12 in B-cell chronic lymphocytic leukemia.

Chemokines participate to B-cell chronic lymphocytic leukemia (B-CLL) pathogenesis by promoting cell adhesion and survival in bone marrow stromal niches and mediating cell dissemination to secondary lymphoid organs. In this study we investigated the role of JAK protein tyrosine kinases (PTK) in adhesion triggering by the CXC chemokine CXCL12 in normal versus CLL B-lymphocytes. We demonstrate that CXCL12 activates JAK2 in normal as well as CLL B-lymphocytes, with kinetics consistent with rapid adhesion triggering.

Identification of Nonresponse to Treatment Using Narrative Data in an Electronic Health Record Inflammatory Bowel Disease Cohort.

Background: Electronic health records, increasingly a part of healthcare, provide a wealth of untapped narrative free text data that have the potential to accurately inform clinical outcomes.

Methods: From a validated cohort of patients with Crohn's disease or ulcerative colitis, we identified patients with ≥1 coded or narrative mention of monoclonal antibodies to tumor necrosis factor α. Chart review by ascertained true use of therapy, time of initiation, and cessation of treatment, and also clinical response stratified as nonresponse, partial, or complete response at 1 year.

Finding the shortest path with PesCa: a tool for network reconstruction.

Network analysis is of growing interest in several fields ranging from economics to biology. Several methods have been developed to investigate different properties of physical networks abstracted as graphs, including quantification of specific topological properties, contextual data enrichment, simulation of pathway dynamics and visual representation. In this context, the PesCa app for the Cytoscape network analysis environment is specifically designed to help researchers infer and manipulate networks based on the shortest path principle.