Computational Modeling Studies Research Articles

Are brain displacements and pressures within the parenchyma induced by surface pressure differences? A computational modelling study.

The intracranial pressure is implicated in many homeostatic processes in the brain and is a fundamental parameter in several diseases such as e.g. idiopathic normal pressure hydrocephalus. The presence of a small but persistent pulsatile intracranial pulsatile transmantle pressure gradient (on the order of a few mmHg/m at peak) has recently been demonstrated in hydrocephalus subjects. A key question is whether pulsatile intracranial pressure and displacements can be induced by a small pressure gradient originating from the brain surface alone. In this study, we model the brain parenchyma as either a linearly elastic or a poroelastic medium, and impose a pulsatile pressure gradient acting between the ventricular and the pial surfaces but no additional external forces. Using this high-resolution physics-based model, we use in vivo pulsatile pressure gradients from subjects with idiopathic normal pressure hydrocephalus to compute parenchyma displacement, volume change, fluid pressure, and fluid flux. The resulting displacement field is pulsatile and in qualitatively and quantitatively good agreement with the literature, both with elastic and poroelastic models. However, the pulsatile forces on the boundaries are not sufficient for pressure pulse propagation through the brain parenchyma. Our results suggest that pressure differences at the brain surface, originating e.g. from pulsating arteries surrounding the brain, are not alone sufficient to drive interstitial fluid flow within the brain parenchyma and that potential pressure gradients found within the parenchyma rather arise from a large portion of the blood vessel network, including smaller blood vessels within the brain parenchyma itself.

Humeral head size predicts baseplate lateralization in reverse shoulder arthroplasty: a comparative computer model study

BackgroundIn reverse shoulder arthroplasty (RSA), the ideal combination of baseplate lateralization (BL), glenosphere size (GS) and overhang (GOH) with a commonly used 145° neck shaft angle (NSA) is unclear. This is the first study evaluating correlations of body height (BH), humeral head size (HS), glenoid height (GH) and association of gender with best glenoid configurations for range of motion (ROM) maintaining anatomic lateralization (aLAT) for optimized muscle length in 145° and less distalized 135° RSA. MethodsIn this computer model study, 22 CTs without joint narrowing were analyzed (11 male/female). A standardized semi-inlay 145° platform stem was combined with 20 glenoid configurations (baseplate (B) 25, 25+3/+6 lateralized (l), 29, 29+3/6l combined with glenosphere36, 36+2eccentric (e), 36+3l, 39, 39+3e, 39+3l , 42, 42+4e). Abduction-adduction, flexion-extension, external rotation-internal rotation, total ROM (TROM) and total notching relevant (TNR) ROM were computed, best TROM models respecting aLAT (-1mm to +1mm) and HS/GH recorded. Secondly, the 145° models (Ascend Flex stem; Stryker, Kalamazoo, MI, USA) were converted and compared to a 135° inlay RSA (New Perform stem; Stryker, Kalamazoo, MI, USA) maintaining GOH (6.5-7mm) and aLAT. ResultsBest 145° models had eccentric glenospheres (mean BL: 3.5mm, GOH 8.8mm, GS 38.1mm, distalization (DIS) 23mm). The 135° models had concentric glenospheres, mean BL 3.8mm, GOH 6.9mm, GS 39.7mm, DIS 14.1mm. Head size showed the strongest positive correlation with BL in 145° and 135° models (0.65/0.79). Despite reduced GOH in smaller females with a 135° NSA, adduction, external rotation, extension, TNR ROM and TROM were significantly increased (p=0.02, p=0.005, p=0.005, p=0.004, p=0.003), abduction however reduced (p=0.02). The same trends were seen for males. ConclusionsHead size is a practical measure in surgery or preoperatively, and the strong positive correlation with BL is a useful planning aid. Despite reduction of GOH, conversion to a less distalized 135° NSA is powerful to maintain and even significantly increase all components of TNR ROM (extension/external rotation/adduction) in small females with the drawback of reduced abduction which may however be compensated by scapula motion. Lateralization with a less distalized 135° RSA optimizes muscle length, may facilitate subscapularis repair and maintains highest rigid body motion.

Finite element modeling of fracture compression by compression plates.

Dynamic compression plating is a common type of fracture fixation used to compress between bone fragments. The quality of compression across the fracture is important for postoperative stability and primary bone healing. Compression quality may be affected by surgical variations in plate prebend, screw location, screw torque, fracture gap, and implant material. Computational modeling provides a tool for systematically examining these factors, and for visualizing the mechanisms involved. The purpose of this study was to develop a finite element model of dynamic compression plating that includes screw insertion under torque control, establish model credibility through sensitivity analyses and experimental validation, and use the model to examine the effects of surgical variables on fracture compression and postoperative stability. Model-predicted compressive pressures had good agreement with corresponding synthetic bones experiments under a variety of conditions. Models demonstrated that introducing a 1.5or 3 mm plate prebend (using a 4.5 mm narrow LCP plate) eliminated gapping at the far cortex, which is consistent with clinical recommendations. However, models also revealed that plate prebend led to sharp decreases in fracture compressive force, exceeding 80% in some cases. A 1.5 mm plate prebend resulted in the most uniform pressures across the fracture. Testing of a simplified model form used in previous computational modeling studies showed large inaccuracies for constructs with plate prebend. This study provides the first experimentally validated computational models of dynamic compression plate fracture fixation, and reveals important effects of plate prebend and fracture gap on fracture compression quality.

Clinical effectiveness of reduction and fusion versus in situ fusion in the management of degenerative lumbar spondylolisthesis: a systematic review and meta-analysis.

To compare the clinical effectiveness of reduction and fusion with in situ fusion in the management of patients with degenerative lumbar spondylolisthesis (DLS). The systematic review was conducted following the PRISMA guidelines. Relevant studies were identified from PubMed, Embase, Scopus, Cochrane Library, ClinicalTrials.gov, and Google Scholar. The inclusion criteria were: (1) comparative studies of reduction and fusion versus in situ fusion for DLS patients, (2) outcomes reported as VAS/NRS, ODI, JOA score, operating time, blood loss, complication rate, fusion rate, or reoperation rate, (3) randomized controlled trials and observational studies published in English from the inception of the databases to January 2023. The exclusion criteria included: (1) reviews, case series, case reports, letters, and conference reports, (2) in vitro biomechanical studies and computational modeling studies, (3) no report on study outcomes. The risk of bias 2 (RoB2) tool and the Newcastle-Ottawa scale was conducted to assess the risk of bias of RCTs and observational studies, respectively. Five studies with a total of 704 patients were included (375 reduction and fusion, 329 in situ fusion). Operating time was significantly longer in the reduction and fusion group compared to in situ fusion group (weighted mean difference 7.20; 95% confidence interval 0.19, 14.21; P = 0.04). No additional significant intergroup differences were noted in terms of other outcomes analyzed. While the reduction and fusion group demonstrated a statistically longer operating time compared to the in situ fusion group, the clinical significance of this difference was minimal. The findings suggest no substantial superiority of lumbar fusion with reduction over without reduction for the management of DLS.

In silico induction of missense mutation in NNRTI protein: computational modelling and stability study of modelled proteins

In silico induction of missense mutation in NNRTI protein: computational modelling and stability study of modelled proteins

Computational Modeling Study of the Binding of Aging and Non-Aging Inhibitors with Neuropathy Target Esterase

Computational Modeling Study of the Binding of Aging and Non-Aging Inhibitors with Neuropathy Target Esterase

Optimizing electrode placement for transcranial direct current stimulation in nonsuperficial cortical regions: a computational modeling study.

The online version contains supplementary material available at 10.1007/s13534-023-00335-2.

Enhancing the selective electrical activation of human vagal nerve fibers: a comparative computational modeling study with validation in a rat sciatic model

Objective. Vagus nerve stimulation (VNS) is an emerging treatment option for a myriad of medical disorders, where the method of delivering electrical pulses can vary depending on the clinical indication. In this study, we investigated the relative effectiveness of electrically activating the cervical vagus nerve among three different approaches: nerve cuff electrode stimulation (NCES), transcutaneous electrical nerve stimulation (TENS), and enhanced TENS (eTENS). The objectives were to characterize factors that influenced nerve activation and to compare the nerve recruitment properties as a function of nerve fiber diameter. Methods. The Finite Element Model, based on data from the Visible Human Project, was implemented in COMSOL. The three simulation types were compared under a range of vertical and horizontal displacements relative to the location of the vagus nerve. Monopolar anodic stimulation was examined, along with latency and activation of different fiber sizes. Nerve activation was determined via the activating function and McIntyre-Richardson-Grill models, and activation thresholds were validated in an in-vivo rodent model. Results. While NCES produced the lowest activation thresholds, eTENS generally performed superior to TENS under the range of conditions and fiber diameters, producing activation thresholds up to three times lower than TENS. eTENS also preserved its enhancement when surface electrodes were displaced away from the nerve. Anodic stimulation revealed an inhibitory region that removed eTENS benefits. eTENS also outperformed TENS by up to four times when targeting smaller diameter nerve fibers, scaling similar to a cuff electrode. In latency and activation of smaller diameter nerve fibers, eTENS results resembled those of NCES more than a TENS electrode. Activation threshold ratios were consistent in in-vivo validation. Significance. Our findings expand upon previously identified mechanisms for eTENS and further demonstrate how eTENS emulates a nerve cuff electrode to achieve lower activation thresholds. This work further characterizes considerations required for VNS under the three stimulation methods.

Synergistic Nitrogen Binding Sites in a Metal‐Organic Framework for Efficient N2/O2 Separation

AbstractPorous materials with d3 electronic configuration open metal sites have been proved to be effective adsorbents for N2 capture and N2/O2 separation. However, the reported materials remain challenging to address the trade‐off between adsorption capacity and selectivity. Herein, we report a robust MOF, MIL‐102Cr, that features two binding sites, can synergistically afford strong interactions for N2 capture. The synergistic adsorption site exhibits a benchmark Qst of 45.0 kJ mol−1 for N2 among the Cr‐based MOFs, a record‐high volumetric N2 uptake (31.38 cm3 cm−3), and highest N2/O2 selectivity (13.11) at 298 K and 1.0 bar. Breakthrough experiments reveal that MIL‐102Cr can efficiently capture N2 from a 79/21 N2/O2 mixture, providing a record 99.99 % pure O2 productivity of 0.75 mmol g−1. In situ infrared spectroscopy and computational modelling studies revealed that a synergistic adsorption effect by open Cr(III) and fluorine sites was accountable for the strong interactions between the MOF and N2.

Synergistic Nitrogen Binding Sites in a Metal-Organic Framework for Efficient N2 /O2 Separation.

Porous materials with d3 electronic configuration open metal sites have been proved to be effective adsorbents for N2 capture and N2 /O2 separation. However, the reported materials remain challenging to address the trade-off between adsorption capacity and selectivity. Herein, we report a robust MOF, MIL-102Cr, that features two binding sites, can synergistically afford strong interactions for N2 capture. The synergistic adsorption site exhibits a benchmark Qst of 45.0 kJ mol-1 for N2 among the Cr-based MOFs, a record-high volumetric N2 uptake (31.38 cm3 cm-3 ), and highest N2 /O2 selectivity (13.11) at 298 K and 1.0 bar. Breakthrough experiments reveal that MIL-102Cr can efficiently capture N2 from a 79/21 N2 /O2 mixture, providing a record 99.99 % pure O2 productivity of 0.75 mmol g-1 . In situ infrared spectroscopy and computational modelling studies revealed that a synergistic adsorption effect by open Cr(III) and fluorine sites was accountable for the strong interactions between the MOF and N2 .

Small Molecules N-Phenylbenzofuran-2-carboxamide and N-Phenylbenzo[b]thiophene-2-carboxamide Promote Beta-Amyloid (Aβ42) Aggregation and Mitigate Neurotoxicity.

This study reports the unusual ability of small molecules N-phenylbenzofuran-2-carboxamide (7a) and N-phenylbenzo[b]thiophene-2-carboxamide (7b) to promote and accelerate Aβ42 aggregation. In the in vitro aggregation kinetic assays, 7a was able to demonstrate rapid increases in Aβ42 fibrillogenesis ranging from 1.5- to 4.7-fold when tested at 1, 5, 10, and 25 μM compared to Aβ42-alone control. Similarly, compound 7b also exhibited 2.9- to 4.3-fold increases in Aβ42 fibrillogenesis at the concentration range tested. Electron microscopy studies at 1, 5, 10, and 25 μM also demonstrate the ability of compounds 7a and 7b to promote and accelerate Aβ42 aggregation with the formation of long, elongated fibril structures. Both 7a and 7b were not toxic to HT22 hippocampal neuronal cells and strikingly were able to prevent Aβ42-induced cytotoxicity in HT22 hippocampal neuronal cells (cell viability ∼74%) compared to the Aβ42-treated group (cell viability ∼20%). Fluorescence imaging studies using BioTracker 490 green, Hoeschst 33342, and the amyloid binding dye ProteoStat further demonstrate the ability of 7a and 7b to promote Aβ42 fibrillogenesis and prevent Aβ42-induced cytotoxicity to HT22 hippocampal neuronal cells. Computational modeling studies suggest that both 7a and 7b can interact with the Aβ42 oligomer and pentamers and have the potential to modulate the self-assembly pathways. The 8-anilino-1-naphthalenesulfonic acid (ANS) dye binding assay also demonstrates the ability of 7a and 7b to expose the hydrophobic surface of Aβ42 to the solvent surface that promotes self-assembly and rapid fibrillogenesis. These studies demonstrate the unique ability of small molecules 7a and 7b to alter the self-assembly and misfolding pathways of Aβ42 by promoting the formation of nontoxic aggregates. These findings have direct implications in the discovery and development of novel small-molecule-based chemical and pharmacological tools to study the Aβ42 aggregation mechanisms, and in the design of novel antiamyloid therapies to treat Alzheimer's disease.

Biophysical characterization, crystallization, and solution of the first crystal structure of the 28 kDa-Schistosoma bovis glutathione transferase

Glutathione S-transferase (GST) is a potential therapeutic drug target against helminthic diseases. This essential enzyme prevents oxidative stress by inhibiting the toxic build-up of xenobiotics in the worm during human host infection. Schistosoma schistosome manifests two GST isoforms, namely the 26- and 28-kDa GST, which exhibit contrasting substrate specificities within the worm. This study was designed to explore the structural and functional relationships of Schistosoma bovis 28 kDa-GST (Sb28GST) through crystallographic studies. The 1-Chloro-2,4-Dinitrobenzene-Glutathione assay revealed that the enzyme was catalytically active. The secondary structural content confirmed that Sb28GST follows a canonical GST fold, mostly alpha-helical. Extrinsic 1-anilinonaphthalene-8-sulfonic acid substitution revealed buried hydrophobic clefts within the enzyme. Sb28GST was purified by immobilised metal affinity chromatography. Crystal structures of Sb28GST were determined for the un-ligated enzyme (resolution = 2.3 Å, Rfactor = 21.68 %). The crystals belonged to the monoclinic space group P21, which accommodated two biological molecules in the asymmetric unit with the unit-cell parameters of a = 54.133, b = 77.086, c = 54.015 Å and β = 93.15° Computational modelling studies predicted the catalytic propensity of 8ALS may vary from that of 1OE8 by differences in the molecular dynamic trajectory, especially at the dimer interface of this obligate dimeric enzyme.

Understanding the effects of inhaler resistance on particle deposition behaviour – A computational modelling study

Background and objectiveUnderstanding the impact of inhaler resistance on particle transport and deposition in the human upper airway is essential for optimizing inhaler designs, thereby contributing to the enhancement of the therapeutic efficacy of inhaled drug delivery. This study demonstrates the potential effects of inhaler resistance on particle deposition characteristics in an anatomically realistic human oropharynx and the United States Pharmacopeia (USP) throat using computational fluid dynamics (CFD). MethodMagnetic resonance (MR) imaging was performed on a healthy volunteer biting on a small mockup inhaler mouthpiece. Three-dimensional geometry of the oropharynx and mouthpiece were reconstructed from the MR images. CFD simulations coupled with discrete phase modelling were conducted. Inhaled polydisperse particles under two different transient flow profiles with peak inspiratory flow rates (PIFR) of 30 L/min and 60 L/min were investigated. The effect of inhaler mouthpiece resistance was modelled as a porous medium by varying the initial resistance (Ri) and viscous resistance (Rv). Three resistance values, 0.02 kPa0.5minL−1, 0.035 kPa0.5minL−1 and 0.05 kPa0.5 minL−1, were simulated. The inhaler outlet velocity was set to be consistent across all models for both flow rate conditions to enable a meaningful comparison of models with different inhaler resistances. ResultThe results from this study demonstrate that investigating the effect of inhaler resistance by solely relying on the USP throat model may yield misleading results. For the geometrically realistic oropharyngeal model, both the pressure and kinetic energy profiles at the mid-sagittal plane of the airway change dramatically when connected to a higher-resistance inhaler. In addition, the geometrically realistic oropharyngeal model appears to have a resistance threshold. When this threshold is surpassed, significant changes in flow dynamics become evident, which is not observed in the USP throat model. Furthermore, this study also reveals that the impact of inhaler resistance in a geometrically realistic throat model extends beyond the oral cavity and affects particle deposition downstream of the oral cavity, including the oropharynx region. ConclusionResults from this study suggest that key mechanisms underpinning the working principles of inhaler resistance are intricately connected to their complex interaction with the pharynx geometry, which affects the local pressure, local variation in velocity and kinetic energy profile in the airway.

Abstract 14702: Roles of Atrial Mass Reduction and Gaps on the Anti-Atrial Fibrillatory Effects of Pulmonary Vein Isolation: A Computational Modeling Study

Background: Although pulmonary vein isolation (PVI) is the basis of atrial fibrillation (AF) catheter ablation (AFCA), the conditional changes of an anti-AF effect and the wave-dynamic mechanism are poorly understood. Therefore, we compared the effects of PVI based on the ablation circumference, width, and number or locations of gaps with or without amiodarone at the same condition in realistic computational modeling of human AF. Hypothesis: An anatomical level of PVI and characteristics of the PVI gap would affect the anti-AF effects of the AFCA. Methods: We included 50 patients (76.0% persistent AF) who underwent AFCA. Realistic AF modeling reflecting the computed tomography (CT) and the electroanatomical map was performed on each patient. We compared the AF defragmentation rate (DeFR; change to atrial tachycardia (AT) or termination), termination rate (TnR), and changes in the dominant frequency (DF) and the number of phase singularities (PSs) based on the PVI level (antral vs. ostial), PVI width (single vs. 3х width), number and location of 2-mm PVI gaps with or without amiodarone (10mM). We randomly assigned the number and location of the PVI gaps to the AF models. Results: The antral PVI had a significantly higher DeFR (p for trend <0.001) and TnR (p for trend <0.001) than the ostial PVI, PVI gaps, or baseline AF. However, there was no difference depending on PVI width. Among the PVI gaps, the DeFR (p for trend<0.001) decreased as the gap number increased. Additional amiodarone increased DeFR (p=0.003) and TnR (p=0.034) and reduced DF (p<0.001) and the number of PSs (p<0.001) with PVI-gap, especially with a single PVI-gap. Conclusions: In this realistic computational modeling study with integrated patients’ atrial anatomy and electrophysiology, the atrial mass reduction depending on the anatomical PVI level, number of PVI gaps, and additional antiarrhythmic drug significantly affected the AF maintenance mechanisms.

Inter-rater reliability of the infectious disease modeling reproducibility checklist (IDMRC) as applied to COVID-19 computational modeling research

BackgroundInfectious disease computational modeling studies have been widely published during the coronavirus disease 2019 (COVID-19) pandemic, yet they have limited reproducibility. Developed through an iterative testing process with multiple reviewers, the Infectious Disease Modeling Reproducibility Checklist (IDMRC) enumerates the minimal elements necessary to support reproducible infectious disease computational modeling publications. The primary objective of this study was to assess the reliability of the IDMRC and to identify which reproducibility elements were unreported in a sample of COVID-19 computational modeling publications.MethodsFour reviewers used the IDMRC to assess 46 preprint and peer reviewed COVID-19 modeling studies published between March 13th, 2020, and July 30th, 2020. The inter-rater reliability was evaluated by mean percent agreement and Fleiss’ kappa coefficients (κ). Papers were ranked based on the average number of reported reproducibility elements, and average proportion of papers that reported each checklist item were tabulated.ResultsQuestions related to the computational environment (mean κ = 0.90, range = 0.90–0.90), analytical software (mean κ = 0.74, range = 0.68–0.82), model description (mean κ = 0.71, range = 0.58–0.84), model implementation (mean κ = 0.68, range = 0.39–0.86), and experimental protocol (mean κ = 0.63, range = 0.58–0.69) had moderate or greater (κ > 0.41) inter-rater reliability. Questions related to data had the lowest values (mean κ = 0.37, range = 0.23–0.59). Reviewers ranked similar papers in the upper and lower quartiles based on the proportion of reproducibility elements each paper reported. While over 70% of the publications provided data used in their models, less than 30% provided the model implementation. Conclusions: The IDMRC is the first comprehensive, quality-assessed tool for guiding researchers in reporting reproducible infectious disease computational modeling studies. The inter-rater reliability assessment found that most scores were characterized by moderate or greater agreement. These results suggest that the IDMRC might be used to provide reliable assessments of the potential for reproducibility of published infectious disease modeling publications. Results of this evaluation identified opportunities for improvement to the model implementation and data questions that can further improve the reliability of the checklist.

Computational fluid dynamics modeling and mass transfer study of an in situ gas production process

AbstractThe oxidation of cyclohexanone with nitric acid in microreactors, as a representative chemical reaction with in situ gas production, was selected as the model reaction for computational fluid dynamics (CFD) modeling. The reaction kinetics was coupled with the CFD model by user‐defined functions (UDFs) to obtain the velocity field of liquid phase, the concentration field of products, and the temperature field of gas–liquid phases during the reaction process. The simulation results were then validated by the experimental data. Based on the established model, the fluid flow behavior and mass transfer characteristics during the in situ gas production process in a microreactor were further analyzed. Finally, the effects of channel diameter and bubble velocity on gas–liquid interfacial mass transfer were investigated. This work provides an effective method for studying in situ gas production processes through modeling and simulation, which is valuable in the design and optimization of tubular reactors.

Field assessment of the potential for small scale co-cultivation of seaweed and shellfish to regulate nutrients and plankton dynamics

The co-cultivation of seaweed alongside shellfish has the potential to regulate local dissolved nutrient concentrations and consequently affect plankton dynamics. Evidence for this has until now come largely from computational modelling and laboratory studies, rather than field studies. Here we report on weekly/bi-weekly profiling of inorganic nutrient concentrations (nitrate, nitrite, ammonium, phosphate, and silicate) over two years (2019–2020) at three sampling stations across a small-scale (16 ha) kelp and mussel farm in Porthallow Bay, Cornwall, UK. Nutrient concentrations were measured in conjunction with a range of related environmental variables, including water temperature, salinity, clarity, and phyto- and zoo- plankton abundance, biomass and community composition. These environmental data were also supplemented with river discharge data. Our results indicate typical seasonal variations in chemical (nutrient), physical (hydrographic), and biological (plankton) parameters across all three sampling stations and no significant reductions in inorganic nutrient concentrations in the water column downstream from the integrated kelp and shellfish farm. We conclude that the effectiveness of nutrient regulation by integrating seaweed and shellfish aquaculture will depend on local climatic and hydro-geochemical conditions (affecting background nutrient inputs), as well as the design and scale of integrated multi–trophic aquaculture (IMTA) systems.

Aberrant sense of agency induced by delayed prediction signals in schizophrenia: a computational modeling study

Aberrant sense of agency (SoA, a feeling of control over one’s own actions and their subsequent events) has been considered key to understanding the pathology of schizophrenia. Behavioral studies have demonstrated that a bidirectional (i.e., excessive and diminished) SoA is observed in schizophrenia. Several neurophysiological and theoretical studies have suggested that aberrancy may be due to temporal delays (TDs) in sensory-motor prediction signals. Here, we examined this hypothesis via computational modeling using a recurrent neural network (RNN) expressing the sensory-motor prediction process. The proposed model successfully reproduced the behavioral features of SoA in healthy controls. In addition, simulation of delayed prediction signals reproduced the bidirectional schizophrenia-pattern SoA, whereas three control experiments (random noise addition, TDs in outputs, and TDs in inputs) demonstrated no schizophrenia-pattern SoA. These results support the TD hypothesis and provide a mechanistic understanding of the pathology underlying aberrant SoA in schizophrenia.

Microscopy and modelling investigations on the morphology of the biofilm exopolysaccharide produced by Burkholderia multivorans strain C1576

Bacteria form very often biofilms where they embed in a self-synthesized matrix exhibiting a gel-like appearance. Matrices offer several advantages, including defence against external threats and the easiness of intercellular communication. In infections, biofilm formation enhances bacteria resistance against antimicrobials, causing serious clinical problems for patients' treatments. Biofilm matrices are composed of proteins, extracellular DNA, and polysaccharides, the latter being the major responsible for matrix architecture. The repeating unit of the biofilm polysaccharide synthesized by Burkholderia multivorans strain C1576 contains two mannoses and two sequentially linked rhamnoses, one of them 50 % methylated on C-3. Rhamnose, a 6-deoxysugar, has lower polarity than other common monosaccharides and its methylation further reduces polarity. This suggests a possible role of this polysaccharide in the biofilm matrix; in fact, computer modelling and atomic force microscopy studies evidenced intra- and inter-molecular non-polar interactions both within polysaccharides and with aliphatic molecules. In this paper, the polysaccharide three-dimensional morphology was investigated using atomic force microscopy in both solid and solution states. Independent evidence of the polymer conformation was obtained by transmission electron microscopy which confirmed the formation of globular compact structures. Finally, data from computer dynamic simulations were used to model the three-dimensional structure.

Reduced Bone Regeneration in Rats With Type 2 Diabetes Mellitus as a Result of Impaired Stromal Cell and Osteoblast Function-A Computer Modeling Study.

Bone has the fascinating ability to self-regenerate. However, under certain conditions, such as type 2 diabetes mellitus (T2DM), this ability is impaired. T2DM is a chronic metabolic disease known by the presence of elevated blood glucose levels that is associated with reduced bone regeneration capability, high fracture risk, and eventual non-union risk after a fracture. Several mechanical and biological factors relevant to bone regeneration have been shown to be affected in a diabetic environment. However, whether impaired bone regeneration in T2DM can be explained due to mechanical or biological alterations remains unknown. To elucidate the relevance of either one, the aim of this study was to investigate the relative contribution of T2DM-related alterations on either cellular activity or mechanical stimuli driving bone regeneration. A previously validated in silico computer modeling approach that was capable of explaining bone regeneration in uneventful conditions of healing was further developed to investigate bone regeneration in T2DM. Aspects analyzed included the presence of mesenchymal stromal cells (MSCs), cellular migration, proliferation, differentiation, apoptosis, and cellular mechanosensitivity. To further verify the computer model findings against in vivo data, an experimental setup was replicated, in which regeneration was compared in healthy and diabetic after a rat femur bone osteotomy stabilized with plate fixation. We found that mechanical alterations had little effect on the reduced bone regeneration in T2DM and that alterations in MSC proliferation, MSC migration, and osteoblast differentiation had the highest effect. In silico predictions of regenerated bone in T2DM matched qualitatively and quantitatively those from ex vivo μCT at 12 weeks post-surgery when reduced cellular activities reported in previous in vitro and in vivo studies were included in the model. The presented findings here could have clinical implications in the treatment of bone fractures in patients with T2DM. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.