The brain's complex organization spans from molecular-level processes within neurons to large-scale networks, making it essential to understand this multiscale structure to uncover brain functions and address neurological disorders. Multiscale brain modeling has emerged as a transformative approach, integrating computational models, advanced imaging, and big data to bridge these levels of organization. This review explores the challenges and opportunities in linking microscopic phenomena to macroscopic brain functions, emphasizing the methodologies driving progress in the field. It also highlights the clinical potential of multiscale models, including their role in advancing artificial intelligence (AI) applications and improving healthcare technologies. By examining current research and proposing future directions for interdisciplinary collaboration, this work demonstrates how multiscale brain modeling can revolutionize both scientific understanding and clinical practice.

• Publication type
• Journal Article MeSH
• Review MeSH

• MeSH
• Humans MeSH
• Mammography methods   MeSH
• Breast Neoplasms diagnosis   MeSH
• Models, Statistical MeSH
• Calcium metabolism   MeSH
• Check Tag
• Humans MeSH

Acute excessive ethyl alcohol (ethanol) consumption alters cardiac electrophysiology and can evoke cardiac arrhythmias, e.g., in 'holiday heart syndrome'. Ethanol acutely modulates numerous targets in cardiomyocytes, including ion channels, Ca2+-handling proteins and gap junctions. However, the mechanisms underlying ethanol-induced arrhythmogenesis remain incompletely understood and difficult to study experimentally due to the multiple electrophysiological targets involved and their potential interactions with preexisting electrophysiological or structural substrates. Here, we employed cellular- and tissue-level in-silico analyses to characterize the acute effects of ethanol on cardiac electrophysiology and arrhythmogenesis. Acute electrophysiological effects of ethanol were incorporated into human atrial and ventricular cardiomyocyte computer models: reduced INa, ICa,L, Ito, IKr and IKur, dual effects on IK1 and IK,ACh (inhibition at low and augmentation at high concentrations), and increased INCX and SR Ca2+ leak. Multiscale simulations in the absence or presence of preexistent atrial fibrillation or heart-failure-related remodeling demonstrated that low ethanol concentrations prolonged atrial action-potential duration (APD) without effects on ventricular APD. Conversely, high ethanol concentrations abbreviated atrial APD and prolonged ventricular APD. High ethanol concentrations promoted reentry in tissue simulations, but the extent of reentry promotion was dependent on the presence of altered intercellular coupling, and the degree, type, and pattern of fibrosis. Taken together, these data provide novel mechanistic insight into the potential proarrhythmic interactions between a preexisting substrate and acute changes in cardiac electrophysiology. In particular, acute ethanol exposure has concentration-dependent electrophysiological effects that differ between atria and ventricles, and between healthy and diseased hearts. Low concentrations of ethanol can have anti-fibrillatory effects in atria, whereas high concentrations promote the inducibility and maintenance of reentrant atrial and ventricular arrhythmias, supporting a role for limiting alcohol intake as part of cardiac arrhythmia management.

• MeSH
• Action Potentials drug effects   MeSH
• Electrophysiological Phenomena drug effects   MeSH
• Ethanol adverse effects   MeSH
• Fibrosis MeSH
• Ion Channels metabolism   MeSH
• Myocytes, Cardiac drug effects   metabolism   MeSH
• Humans MeSH
• Gap Junctions drug effects   metabolism   MeSH
• Computer Simulation MeSH
• Vascular Remodeling drug effects   MeSH
• Heart drug effects   physiopathology   MeSH
• Arrhythmias, Cardiac pathology   physiopathology   MeSH
• Heart Atria drug effects   pathology   physiopathology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

We provide a high-level survey of multiscale molecular visualization techniques, with a focus on application-domain questions, challenges, and tasks. We provide a general introduction to molecular visualization basics and describe a number of domain-specific tasks that drive this work. These tasks, in turn, serve as the general structure of the following survey. First, we discuss methods that support the visual analysis of molecular dynamics simulations. We discuss, in particular, visual abstraction and temporal aggregation. In the second part, we survey multiscale approaches that support the design, analysis, and manipulation of DNA nanostructures and related concepts for abstraction, scale transition, scale-dependent modeling, and navigation of the resulting abstraction spaces. In the third part of the survey, we showcase approaches that support interactive exploration within large structural biology assemblies up to the size of bacterial cells. We describe fundamental rendering techniques as well as approaches for element instantiation, visibility management, visual guidance, camera control, and support of depth perception. We close the survey with a brief listing of important tools that implement many of the discussed approaches and a conclusion that provides some research challenges in the field.

• MeSH
• Bacteria MeSH
• DNA ultrastructure   MeSH
• Humans MeSH
• Models, Molecular MeSH
• Nanostructures * MeSH
• Proteins chemistry   MeSH
• Molecular Dynamics Simulation * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

Biological membranes are tricky to investigate. They are complex in terms of molecular composition and structure, functional over a wide range of time scales, and characterized by nonequilibrium conditions. Because of all of these features, simulations are a great technique to study biomembrane behavior. A significant part of the functional processes in biological membranes takes place at the molecular level; thus computer simulations are the method of choice to explore how their properties emerge from specific molecular features and how the interplay among the numerous molecules gives rise to function over spatial and time scales larger than the molecular ones. In this review, we focus on this broad theme. We discuss the current state-of-the-art of biomembrane simulations that, until now, have largely focused on a rather narrow picture of the complexity of the membranes. Given this, we also discuss the challenges that we should unravel in the foreseeable future. Numerous features such as the actin-cytoskeleton network, the glycocalyx network, and nonequilibrium transport under ATP-driven conditions have so far received very little attention; however, the potential of simulations to solve them would be exceptionally high. A major milestone for this research would be that one day we could say that computer simulations genuinely research biological membranes, not just lipid bilayers.

• MeSH
• Models, Biological * MeSH
• Phospholipids chemistry   metabolism   MeSH
• Carboxylic Acids chemistry   metabolism   MeSH
• Humans MeSH
• Lipidomics methods   MeSH
• Membrane Lipids chemistry   metabolism   MeSH
• Membranes chemistry   metabolism   physiology   MeSH
• Computer Simulation MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Phosphate···π, also called anion···π, contacts occur between nucleobases and anionic phosphate oxygens (OP2) in r(GNRA) and r(UNNN) U-turn motifs (N = A,G,C,U; R = A,G). These contacts were investigated using state-of-the-art quantum-chemical methods (QM) to characterize their physicochemical properties and to serve as a reference to evaluate AMBER force field (AFF) performance. We found that phosphate···π interaction energies calculated with the AFF for dimethyl phosphate···nucleobase model systems are less stabilizing in comparison with double-hybrid DFT and that minimum contact distances are larger for all nucleobases. These distance stretches are also observed in large-scale AFF vs QM/MM computations and classical molecular dynamics (MD) simulations on several r(gcGNRAgc) tetraloop hairpins when compared to experimental data extracted from X-ray/cryo-EM structures (res. ≤ 2.5 Å) using the WebFR3D bioinformatic tool. MD simulations further revealed shifted OP2/nucleobase positions. We propose that discrepancies between the QM and AFF result from a combination of missing polarization in the AFF combined with too large AFF Lennard-Jones (LJ) radii of nucleobase carbon atoms in addition to an exaggerated short-range repulsion of the r-12 LJ repulsive term. We compared these results with earlier data gathered on lone pair···π contacts in CpG Z-steps occurring in r(UNCG) tetraloops. In both instances, charge transfer calculations do not support any significant n → π* donation effects. We also investigated thiophosphate···π contacts that showed reduced stabilizing interaction energies when compared to phosphate···π contacts. Thus, we challenge suggestions that the experimentally observed enhanced thermodynamic stability of phosphorothioated r(GNRA) tetraloops can be explained by larger London dispersion.

• MeSH
• Phosphates MeSH
• RNA * chemistry   MeSH
• Molecular Dynamics Simulation * MeSH
• Thermodynamics MeSH
• Computational Biology MeSH
• Publication type
• Journal Article MeSH

Cortical bone plays a vital role in determining overall bone strength. We investigate the structural, compositional, and nanomechanical properties of cortical bone following ovariectomy (OVX) of 12-week-old Sprague Dawley rats, since this animal model is frequently employed to evaluate the performance of implantable biomaterials in compromised bone healing conditions. Morphological parameters and material properties of bone in the geometrical center of the femoral cortex were investigated four and eight weeks post-OVX and in unoperated controls (Ctrl), using X-ray micro-computed tomography, backscattered electron scanning electron microscopy, Raman spectroscopy, and nanoindentation. The OVX animals showed increase in body weight, diminished bone mineral density, increased intracortical porosity, but increased bone mass through periosteal apposition (e.g., increases in periosteal perimeter, cortical cross-sectional thickness, and cross-sectional area). However, osteocyte densities, osteocyte lacunar dimensions, and the nanomechanical behavior on the single mineralized collagen fibril level remained unaffected. Our correlative multiscale investigation provides structural, chemical, and nanomechanical evidence substantiating earlier reports suggesting that rats ovariectomized at 12 weeks undergo simultaneous bone loss and growth, resulting in the effects of OVX being less obvious. Periosteal apposition contradicts the conventional view of bone loss in osteoporosis but appears advantageous for the greater functional demand imposed on the skeleton by increased body weight and fragility induced by increased intracortical porosity. Through a variety of morphological changes, it is likely that 12-week-old rats are able to adapt to OVX-related microstructural and compositional alterations. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 997-1007, 2018.

• MeSH
• Biomechanical Phenomena MeSH
• Extracellular Matrix metabolism   MeSH
• Femur pathology   physiopathology   MeSH
• Cortical Bone diagnostic imaging   pathology   physiopathology   MeSH
• Linear Models MeSH
• Minerals metabolism   MeSH
• Nanoparticles chemistry   MeSH
• Osteocytes metabolism   MeSH
• Osteoporosis diagnostic imaging   pathology   physiopathology   MeSH
• Cell Count MeSH
• Porosity MeSH
• Rats, Sprague-Dawley MeSH
• X-Ray Microtomography MeSH
• Body Weight MeSH
• Animals MeSH
• Check Tag
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

• MeSH
• Algorithms MeSH
• Diagnostic Imaging utilization   MeSH
• Financing, Organized MeSH
• Liver anatomy & histology   physiology   pathology   MeSH
• Kidney anatomy & histology   physiology   pathology   MeSH
• Humans MeSH
• Image Processing, Computer-Assisted methods   utilization   MeSH
• Models, Theoretical MeSH
• Ultrasonography methods   MeSH
• Image Enhancement methods   MeSH
• Check Tag
• Humans MeSH

RATIONALE: Cardiac ECM (extracellular matrix) comprises a dynamic molecular network providing structural support to heart tissue function. Understanding the impact of ECM remodeling on cardiac cells during heart failure (HF) is essential to prevent adverse ventricular remodeling and restore organ functionality in affected patients. OBJECTIVES: We aimed to (1) identify consistent modifications to cardiac ECM structure and mechanics that contribute to HF and (2) determine the underlying molecular mechanisms. METHODS AND RESULTS: We first performed decellularization of human and murine ECM (decellularized ECM) and then analyzed the pathological changes occurring in decellularized ECM during HF by atomic force microscopy, 2-photon microscopy, high-resolution 3-dimensional image analysis, and computational fluid dynamics simulation. We then performed molecular and functional assays in patient-derived cardiac fibroblasts based on YAP (yes-associated protein)-transcriptional enhanced associate domain (TEAD) mechanosensing activity and collagen contraction assays. The analysis of HF decellularized ECM resulting from ischemic or dilated cardiomyopathy, as well as from mouse infarcted tissue, identified a common pattern of modifications in their 3-dimensional topography. As compared with healthy heart, HF ECM exhibited aligned, flat, and compact fiber bundles, with reduced elasticity and organizational complexity. At the molecular level, RNA sequencing of HF cardiac fibroblasts highlighted the overrepresentation of dysregulated genes involved in ECM organization, or being connected to TGFβ1 (transforming growth factor β1), interleukin-1, TNF-α, and BDNF signaling pathways. Functional tests performed on HF cardiac fibroblasts pointed at mechanosensor YAP as a key player in ECM remodeling in the diseased heart via transcriptional activation of focal adhesion assembly. Finally, in vitro experiments clarified pathological cardiac ECM prevents cell homing, thus providing further hints to identify a possible window of action for cell therapy in cardiac diseases. CONCLUSIONS: Our multiparametric approach has highlighted repercussions of ECM remodeling on cell homing, cardiac fibroblast activation, and focal adhesion protein expression via hyperactivated YAP signaling during HF.

• MeSH
• Adaptor Proteins, Signal Transducing genetics   metabolism   MeSH
• Mechanotransduction, Cellular MeSH
• Cardiomyopathy, Dilated genetics   metabolism   pathology   physiopathology   MeSH
• Extracellular Matrix genetics   metabolism   ultrastructure   MeSH
• Fibroblasts metabolism   ultrastructure   MeSH
• Ventricular Function, Left * MeSH
• Myocardial Infarction genetics   metabolism   pathology   physiopathology   MeSH
• Cells, Cultured MeSH
• Humans MeSH
• Disease Models, Animal MeSH
• Myocardium metabolism   ultrastructure   MeSH
• Mice, Inbred C57BL MeSH
• Cell Movement MeSH
• Ventricular Remodeling * MeSH
• Heart Failure genetics   metabolism   pathology   physiopathology   MeSH
• Case-Control Studies MeSH
• Transcription Factors genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Video-Audio Media MeSH
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Physiologically realistic results are the aim of every blood flow simulation. This is not different in aorto-coronary bypasses where the properties of the coronary circulation may significantly affect the relevance of the performed simulations. By considering three patient-specific bypass geometries, the present article focuses on two aspects of the coronary blood flow - its phasic flow pattern and its behaviour affected by blood rheology. For the phasic flow property, a multiscale modelling approach is chosen as a means to assess the ability of five different types of coronary boundary conditions (mean arterial pressure, Windkessel model and three lumped parameter models) to attain realistic coronary haemodynamics. From the analysed variants of boundary conditions, the best option in terms of physiological characteristics and its potential for use in patient-based simulations, is utilised to account for the effect of shear-dependent viscosity on the resulting haemodynamics and wall shear stress stimulation. Aside from the Newtonian model, the blood rheology is approximated by two non-Newtonian models in order to determine whether the choice of a viscosity model is important in simulations involving coronary circulation. A comprehensive analysis of obtained results demonstrated notable superiority of all lumped parameter models, especially in comparison to the constant outlet pressure, which regardless of bypass type gave overestimated and physiologically misleading results. In terms of rheology, it was noted that blood in undamaged coronary arteries behaves as a Newtonian fluid, whereas in vessels with atypical lumen geometry, such as that of anastomosis or stenosis, its shear-thinning behaviour should not be ignored.

• MeSH
• Hemodynamics * MeSH
• Coronary Vessels * surgery   MeSH
• Coronary Circulation MeSH
• Humans MeSH
• Stress, Mechanical MeSH
• Models, Cardiovascular MeSH
• Computer Simulation MeSH
• Blood Flow Velocity MeSH
• Viscosity MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH