Mechanistic-based Approach Research Articles

An Adverse Outcome Pathway for food nanomaterial-induced intestinal barrier disruption.

The ingestion of nanomaterials (NMs) may impair the intestinal barrier, but the underlying mechanisms remain evasive, and evidence has not been systematically gathered or produced. A mechanistic-based approach would be instrumental in assessing whether relevant NMs disrupt the intestinal barrier, thereby supporting the NM risk assessment in the food sector. In this study, we developed an adverse outcome pathway (AOP) based on biological plausibility and by leveraging information from an existing NM-relevant AOP that leads to hepatic outcomes. We then extracted the current evidence from the literature for a targeted selection of NMs with high relevance to the food sector, namely, ZnO, CuO, FeO, SiO2, and Ag NMs and nanocellulose. We propose a new AOP (AOP 530) that starts with endocytic lysosomal uptake, leading to lysosomal disruption inducing mitochondrial dysfunction. Mitochondrial impairments can lead to cell injury/death and disrupt the intestinal barrier. The evidence collected supports that these food-related NMs can be taken up by intestinal cells and indicates that intestinal barrier disruption may occur due to Ag, CuO, and SiO2 NMs, while only few studies support this outcome for FeO and ZnO. Lysosomal disruption and mitochondrial dysfunction are rarely evaluated. For nanocellulose, none of the studies report toxicity-related events. The collection of existing scientific evidence supporting our AOP linking NM uptake to intestinal barrier impairments allowed us to highlight current evidence gaps and data inconsistencies. These inconsistencies could be associated with the variety of stressors, biological systems, and key event (KE)-related assays used in different studies. This underscores the need for further harmonized methodologies and the production of mechanistic evidence for the safety regulatory assessment of NMs in the food sector.

Bridging the gap: Mechanistic-based cyclist injury risk curves using two decades of crash data

Objective Injury risk curves are vital in quantifying the relative safety consequences of real-world collisions. Previous injury risk curves for bicycle-passenger vehicle crashes have predominantly focused on frontal impacts. This creates a gap in cyclist injury risk assessment for other geometric crash configurations. The goal of this study was to create an “omnidirectional” injury risk model, informed by known injury causing mechanisms, that is applicable to most geometric configurations. Methods We used data from years 1999–2022 of the German In-Depth Accident Study (GIDAS). We describe the pattern of injuries for cyclists involved in collisions with passenger vehicles, and we developed injury risk functions at various AIS levels for these collisions. A mechanistic-based approach accounting for biomechanically-relevant variables was used to select model parameters a priori. Cyclist age (including children) and sex were regarded as relevant predictors of injury risk. Speed and impact geometry were captured through a novel predictor, Effective Collision Speed, which transforms the vehicle and cyclist speeds into a single value and incorporates frictional considerations observed during side engagements. Cyclist engagement with the vehicle was captured with a variable demonstrating the potential for a normal projection. We additionally present analyses weighted toward German nationwide data. Results We identified 6,576 cyclists involved in collisions with passenger vehicles. AIS3+ cyclist injuries occurred most often in the head, thorax, and lower extremities. Effective Collision Speed was a strong predictor of injury risk. Collisions with a potential for a normal projection were associated with increased risk, though this was only significant at the MAIS2+F severity level. Younger children had slightly higher injury risk compared to young adults, while elderly cyclists had the highest risk of AIS3+ injury. Sex was a significant predictor only for the MAIS2+F injury risk curves. Significance U.S. cyclist fatalities increased 55% from 2010 to 2021. To reduce injuries and fatalities, it is crucial to understand cyclist injury risk. This study builds on previous analyses by including children, incorporating additional mechanistic predictors, broadening the scope of included crashes, and using weighting to generalize these estimates toward national German statistics.

Exploring the potential of flavonoids as efflorescing antidiabetic: An updated SAR and mechanistic based approach

Diabetes is a metabolic complication distinguished mainly by persistent hyperglycemia and is involved in the formation of reactive oxygen species, thereby causing oxidative stress, which is the major culprit for diabetic complications in different organs, including the vascular system. Controlling blood glucose is the most effective strategy for preventing diabetes and its complications. Currently, the available antidiabetic therapy is associated with several side effects, thus inexhaustible attention has been paid toward the development of natural compounds. The present review highlights the different types of flavonoids as potent antidiabetic agents along with their structure–activity relationship (SAR) studies, which will definitely aid in designing innovative molecules with improved antidiabetic efficacy. The type of substitution in the flavonoid core structure decides their bindings at different biological targets involved in diabetes development such as xanthine oxidase inhibitors, SGLT-II inhibitors, α-glucosidase inhibitors, PPAR-γ agonists, DPP-4 inhibitors, and glycogen phosphorylase inhibitors. Based on SAR investigation, a double bond between C2 and C3 positions, hydroxy substitutions at C5 and C7 positions of ring A, and substitution by the ketonic group at the C4 position were considered as lead modifications in the bioactivity of flavonoids for potent antidiabetic activity.

Bcl-2 Modulation in p53 Signaling Pathway by Flavonoids: A Potential Strategy towards the Treatment of Cancer.

Cancer is a major cause of death, affecting human life in both developed and developing countries. Numerous antitumor agents exist but their toxicity and low efficacy limits their utility. Furthermore, the complex pathophysiological mechanisms of cancer, serious side effects and poor prognosis restrict the administration of available cancer therapies. Thus, developing novel therapeutic agents are required towards a simultaneous targeting of major dysregulated signaling mediators in cancer etiology, while possessing lower side effects. In this line, the plant kingdom is introduced as a rich source of active phytochemicals. The secondary metabolites produced by plants could potentially regulate several dysregulated pathways in cancer. Among the secondary metabolites, flavonoids are hopeful phytochemicals with established biological activities and minimal side effects. Flavonoids inhibit B-cell lymphoma 2 (Bcl-2) via the p53 signaling pathway, which is a significant apoptotic target in many cancer types, hence suppressing a major dysregulated pathway in cancer. To date, there have been no studies reported which extensively highlight the role of flavonoids and especially the different classes of flavonoids in the modulation of Bcl-2 in the P53 signaling pathway. Herein, we discuss the modulation of Bcl-2 in the p53 signaling pathway by different classes of flavonoids and highlight different mechanisms through which this modulation can occur. This study will provide a rationale for the use of flavonoids against different cancers paving a new mechanistic-based approach to cancer therapy.

Model-Informed Drug Development in Pediatric Dose Selection.

Model-informed drug development (MIDD) has been a powerful and efficient tool applied widely in pediatric drug development due to its ability to integrate and leverage existing knowledge from different sources to narrow knowledge gaps. The dose selection is the most common MIDD application in regulatory submission related to pediatric drug development. This article aims to give an overview of the 3 broad categories of use of MIDD in pediatric dose selection: leveraging from adults to pediatric patients, leveraging from animals to pediatric patients, and integrating mechanism in infants and neonates. Population pharmacokinetic analyses with allometric scaling can reasonably predict the clearance in pediatric patients aged >5 years. A mechanistic-based approach, such as physiologically based pharmacokinetic accounting for ontogeny, or an allometric model with age-dependent exponent, can be applied to select the dose in pediatric patients aged ≤2 years. The exposure-response relationship from adults or from other drugs in the same class may be useful in aiding the pediatric dose selection and benefit-risk assessment. Increasing application and understanding of use of MIDD have contributed greatly to several policy developments in the pediatric field. With the increasing efforts of MIDD under the Prescription Drug User Fee Act VI, bigger impacts of MIDD approaches in pediatric dose selection can be expected. Due to the complexity of model-based analyses, early engagement between drug developers and regulatory agencies to discuss MIDD issues is highly encouraged, as it is expected to increase the efficiency and reduce the uncertainty.

A hybrid approach to complex arrhythmias.

Despite many years of research, the different aspects of the mechanism of atrial fibrillation (AF) are still incompletely understood. And although the latest guidelines recommend catheter ablation with pulmonary vein isolation as a rhythm control strategy, long-term results in persistent and long-standing persistent AF are suboptimal. Historically, a mechanistic-based patient-tailored approach for the treatment of AF was impossible because of the lack real-time mapping techniques and advanced ablation tools. Therefore, surgeons created lesion sets based upon the anatomy of both atria and the safety of the incisions made by the knife. These complex open-heart procedures had to be performed through a sternotomy on the arrested heart and where therefore not generally adopted. The use of controlled energy sources such as cryothermy and radiofrequency where the first step to make the creation of these lesions less complex. With the development and improvement of electrophysiology techniques and catheters, this invasive and solely anatomical approach could again be partially redesigned. Now less invasive, it prepared the way for collaboration between electrophysiologists working on the endocardial side of the heart and cardiac surgeons providing epicardial access. The introduction of video-assisted technology and hybrid procedures has further increased the possibilities of new successful therapies. Now more than 40 years since the beginning of this exciting maze of AF procedures and still working towards a less aggressive and more comprehensive approach we give an overview of the history of the different minimally invasive surgical solutions and of the hybrid approach.

Grouping of endocrine disrupting chemicals for mixture risk assessment – Evidence from a rat study

Exposure to mixtures of endocrine disrupting chemicals may contribute to the rising incidence of hormone-related diseases in humans. Real-life mixtures are complex, comprised of chemicals with mixed modes of action, and essential knowledge is often lacking on how to group such chemicals into cumulative assessment groups, which is an essential prerequisite to conduct a chemical mixture risk assessment.We investigated if mixtures of chemicals with diverse endocrine modes of action can cause mixture effects on hormone sensitive endpoints in developing and adult rat offspring after perinatal exposure. Wistar rats were exposed during pregnancy and lactation simultaneously to either bisphenol A and butylparaben (Emix), diethylhexyl phthalate and procymidone (Amix), or a mixture of all four substances (Totalmix). In male offspring, the anogenital distance was significantly reduced and nipple retention increased in animals exposed to Amix and Totalmix, and the mixture effects were well approximated by the dose addition model. The combination of Amix and Emix responded with more marked changes on these and other endocrine-sensitive endpoints than each binary mixture on its own. Sperm counts were reduced by all exposures. These experimental outcomes suggest that the grouping of chemicals for mixture risk assessment should be based on common health outcomes rather than only similar modes or mechanisms of action. Mechanistic-based approaches such as the concept of Adverse Outcome Pathway (AOP) can provide important guidance if both the information on shared target tissues and the information on shared mode/mechanism of action are taken into account.

Mechanistic-Based Approach to Utilize Traffic Speed Deflectometer Measurements in Backcalculation Analysis

Backcalculation analysis of pavement layer moduli is typically conducted based on falling weight deflectometer (FWD) deflection measurements; however, the stationary nature of the FWD requires lane closure and traffic control. In recent years, traffic speed deflection devices such as the traffic speed deflectometer (TSD), which can continuously measure pavement surface deflections at traffic speed, have been introduced. In this study, a mechanistic-based approach was developed to convert TSD deflection measurements into the equivalent FWD deflections. The proposed approach uses 3D-Move software to calculate the theoretical deflection bowls corresponding to FWD and TSD loading configurations. Since 3D-Move requires the definition of the constitutive behaviors of the pavement layers, cores were extracted from 13 sections in Louisiana and were tested in the laboratory to estimate the dynamic complex modulus of asphalt concrete. The 3D-Move generated deflection bowls were validated with field TSD and FWD data with acceptable accuracy. A parametric study was then conducted using the validated 3D-Move model; the parametric study consisted of simulating pavement designs with varying thicknesses and material properties and their corresponding FWD and TSD surface deflections were calculated. The results obtained from the parametric study were then incorporated into a Windows-based software application, which uses artificial neural network as the regression algorithm to convert TSD deflections to their corresponding FWD deflections. This conversion would allow backcalculation of layer moduli using TSD-measured deflections, as equivalent FWD deflections can be used with readily available tools to backcalculate the layer moduli.

Effect of additives and aging on moisture-induced damage potential of asphalt mixes using surface free energy and laboratory-based performance tests

ABSTRACT Lack of mechanistic foundation and poor correlations with field performance of conventional laboratory-based tests has accelerated the search for a mechanistic-based approach for screening of asphalt mixes for moisture-induced damages. According to recent studies, surface free energy (SFE) method can be used to mechanistically quantify bond strength and debonding of binder-aggregate system in presence of water. This study was undertaken to evaluate the effects of different additives, namely warm mix asphalt (WMA) additive (amine-derived), amine-based anti-stripping agent (ASA), polyphosphoric acid (PPA) and reclaimed asphalt pavement (RAP) on the moisture-induced damage performance of asphalt mixes through the use of laboratory-based performance tests and SFE method. For this purpose, different energy parameters were determined from SFE components of binder blends and aggregate. Asphalt mixes with different additives were produced to evaluate moisture-induced damage using indirect tensile strength (ITS) and Illinois semi-circular bend (IL-SCB) tests. A new parameter, known as fracture energy ratio (Gf ratio) obtained from IL-SCB test, was used to correlate fracture energy with moisture-induced damage potential of mixes. Also, the effect of short-term and long-term aging on the moisture-induced performance of asphalt mixes were evaluated. Furthermore, correlations between moisture-induced damage parameters from laboratory-based performance tests and SFE method were investigated.

In vitro and bioinformatics mechanistic-based approach for cadmium carcinogenicity understanding

Cadmium is a toxic metal able to enter the cells through channels and transport pathways dedicated to essential ions, leading, among others, to the dysregulation of divalent ions homeostasis. Despite its recognized human carcinogenicity, the mechanisms are still under investigation. A powerful tool for mechanistic studies of carcinogenesis is the Cell Transformation Assay (CTA). We have isolated and characterized by whole genome microarray and bioinformatics analysis of differentially expressed genes (DEGs) cadmium-transformed cells from different foci (F1, F2, and F3) at the end of CTA (6 weeks). The systematic analysis of up- and down-regulated transcripts and the comparison of DEGs in transformed cells evidence different functional targets and the complex picture of cadmium-induced transformation. Only 34 in common DEGs are found in cells from all foci, and among these, only 4 genes are jointly up-regulated (Ccl2, Ccl5, IL6 and Spp1), all responsible for cytokines/chemokines coding. Most in common DEGs are down-regulated, suggesting that the switching-off of specific functions plays a major role in this process. In addition, the comparison of dysregulated pathways immediately after cadmium treatment with those in transformed cells provides a valuable means to the comprehension of the overall process.

MRGPRX2 activation as a rapid, high-throughput mechanistic-based approach for detecting peptide-mediated human mast cell degranulation liabilities

Mast cells play key roles in allergy, anaphylaxis/anaphylactoid reactions, and defense against pathogens/toxins. These cells contain cytoplasmic granules with a wide spectrum of pleotropic mediators that are released upon activation. While mast cell degranulation (MCD) occurs upon clustering of the IgE receptor bound to IgE and antigen, MCD is also triggered through non-IgE-mediated mechanisms, one of which is via Mas-related G protein-coupled receptor X2 (MRGPRX2). MRGPRX2 can be activated by many basic biogenic amines and peptides. Consequently, MRGPRX2-mediated MCD is an important potential safety liability for peptide therapeutics. To facilitate peptide screening for this liability in early preclinical drug development, a rapid, high-throughput engineered CHO-K1 cell-based MRGPRX2 activation assay was evaluated and compared to histamine release in CD34+ stem cell-derived mature human mast cells as a reference assay, using 30 positive control and 29 negative control peptides for MCD. Both G protein-dependent (Ca2+ endpoint) and -independent (β-arrestin endpoint) pathways were assessed in the MRGPRX2 activation assay. The MRGPRX2 activation assay had a sensitivity of 100% for both Ca2+ and β-arrestin endpoints and a specificity of 93% (β-arrestin endpoint) and 83% (Ca2+ endpoint) compared to histamine release in CD34+ stem cell-derived mature human mast cells. These findings suggest that assessing MRGPRX2 activation in an engineered cell model can provide value as a rapid, high-throughput, economical mechanism-based screening tool for early MCD hazard identification during preclinical safety evaluation of peptide-based therapeutics.

Integration of Food Animal Residue Avoidance Databank (FARAD) empirical methods for drug withdrawal interval determination with a mechanistic population-based interactive physiologically based pharmacokinetic (iPBPK) modeling platform: example for flunixin meglumine administration.

Violative chemical residues in animal-derived food products affect food safety globally and have impact on the trade of international agricultural products. The Food Animal Residue Avoidance Databank program has been developing scientific tools to provide appropriate withdrawal interval (WDI) estimations after extralabel drug use in food animals for the past three decades. One of the tools is physiologically based pharmacokinetic (PBPK) modeling, which is a mechanistic-based approach that can be used to predict tissue residues and WDIs. However, PBPK models are complicated and difficult to use by non-modelers. Therefore, a user-friendly PBPK modeling framework is needed to move this field forward. Flunixin was one of the top five violative drug residues identified in the United States from 2010 to 2016. The objective of this study was to establish a web-based user-friendly framework for the development of new PBPK models for drugs administered to food animals. Specifically, a new PBPK model for both cattle and swine after administration of flunixin meglumine was developed. Population analysis using Monte Carlo simulations was incorporated into the model to predict WDIs following extralabel administration of flunixin meglumine. The population PBPK model was converted to a web-based interactive PBPK (iPBPK) framework to facilitate its application. This iPBPK framework serves as a proof-of-concept for further improvements in the future and it can be applied to develop new models for other drugs in other food animal species, thereby facilitating the application of PBPK modeling in WDI estimation and food safety assessment.

Practical overlay design method for geogrid reinforcement of asphalt layers

Geogrid reinforcement of asphalt layers is an effective method for mitigation of reflective cracking and for the extension of fatigue life of pavement structures. This paper proposes a practical procedure to account for the geogrid effect in the overlay design of flexible pavements. While there are several existing approaches, none of them became widely recognized and validated. Proposed approach utilizes both empirical and mechanistic elements together with reliability aspects. Beside presenting all steps of the proposed approach, this paper also demonstrates the performance of the proposed approach when compared with the deflection-based overlay design procedure in Poland. Paper concludes that the proposed approach is a rational compromise between empirical methods and mechanistic-based approaches. While it is ready to use and verified, paper also presents several recommendations on further improvements in the proposed approach.

Mechanics-based algorithms to determine the current state of a bridge using quasi-static loading and strain measurement

Knowing the current state of a bridge is of interest for a variety of reasons. Some parameters that determine the current state of a bridge are the material properties and boundary conditions. Using strain measurements obtained from a slow-moving vehicle on a bridge, the boundary condition and material properties are determined through a mechanistic-based approach. Observing that the sign of the curvature would change at locations near the support when a load passes over a bridge with end rotational restraints, a methodology for determining the boundary conditions is proposed and validated. The linear elastic properties of the material that the bridge is made up of is determined from the strain measured at locations where the stress is independent of the material property. In this procedure, the structure is analyzed assuming some material properties and the stress at the measured point is determined. Then, the material parameters in the isotropic Hooke’s law are determined so that the stress estimated from the experimentally determined strains agrees with that obtained from the analysis with arbitrarily assumed material parameters. A prestressed high-performance concrete pi-shaped girder tested under a three-axle slow-moving load with strains measured at different locations is used to bring out the efficacy and appropriateness of the proposed methodologies. The mean value of Young’s modulus of the prestressed concrete bridge agrees well with the experimentally determined Young’s modulus.

Treatment of Complications from Immune Checkpoint Inhibition in Patients with Lung Cancer.

Opinion statementImmune checkpoint inhibitors have revolutionized the management of advanced NSCLC. With the intention of generating an anti-tumor immune response, ICIs can also lead to inflammatory side effects involving a wide variety of organs in the body, termed immune-related adverse events. Although no prospective clinical trial exists to guide recommendations for optimal and more specific immunosuppressive treatments rather than corticosteroids, further studies may lead to a more mechanistic-based approach towards these toxicities in the future. In relation to current practice, we recommend adherence to the recent published guidelines which emphasize the importance of early recognition and administration of temporary immunosuppressive therapy with corticosteroids in most cases, depending on the organ system involved, and the severity of toxicity. Recognition of these toxicities is increasingly important as the use of these agents expand within different indications for patients with lung cancers, and to other tumor types.

Oligonucleotide-based pharmaceuticals: Non-clinical and clinical safety signals and non-clinical testing strategies

Antisense oligonucleotides, short interfering RNAs (siRNAs) and aptamers are oligonucleotide-based pharmaceuticals with a promising role in targeted therapies. Currently, five oligonucleotide-based pharmaceuticals have achieved marketing authorization in Europe or USA and many more are undergoing clinical testing. However, several safety concerns have been raised in non-clinical and clinical studies. Oligonucleotides share properties with both chemical and biological pharmaceuticals and therefore they pose challenges also from the regulatory point of view. We have analyzed the safety data of oligonucleotides and evaluated the applicability of current non-clinical toxicological guidelines for assessing the safety of oligonucleotide-based pharmaceuticals. Oligonucleotide-based pharmaceuticals display a similar toxicological profile, exerting adverse effects on liver and kidney, evoking hematological alterations, as well as causing immunostimulation and prolonging the coagulation time. It is possible to extrapolate some of these effects from non-clinical studies to humans. However, evaluation strategies for genotoxicity testing of “non-natural” oligonucleotides should be revised. Additionally, the selective use of surrogates and prediction of clinical endpoints for non-clinically observed immunostimulation is complicated by its multiple potential manifestations, demanding improvements in the testing strategies. Utilizing more relevant and mechanistic-based approaches and taking better account of species differences, could possibly improve the prediction of relevant immunological/proinflammatory effects in humans.

MRGPRX2 receptor activation as a rapid, high-throughput mechanistic-based approach for detecting peptide-mediated human mast cell degranulation liabilities.

Abstract Mast cells play key roles in allergy, anaphylaxis and pathogen/toxin defense. They contain cytoplasmic granules with a wide spectrum of pleotropic mediators (e.g. histamine, tryptase, serotonin) that are released upon activation. Mast cell degranulation (MCD) occurs upon clustering of the IgE receptor in presence of antigen or via non-IgE mediated mechanisms, one of which is by means of the Mas-related G protein coupled receptor (MRGPRX2). MRGPRX2 is a non-selective, low affinity binding receptor that responds to many basic biogenic amines and peptides. Consequently, MCD is an important potential safety liability for peptide therapeutics. To improve screening of peptides for this liability, we assessed a MRGPRX2-CHO cell-based receptor activation assay using positive (n=30) and negative (n=29) control peptides, which were previously characterized for MCD liability in CD34+ bone marrow-derived human mast cell cultures. MRGPRX2-CHO cells were engineered to selectively activate beta-arrestin upon receptor stimulation. In addition to beta-arrestin, Ca2+ was also measured to determine the potential of ligand bias (selective engagement of G-protein dependent or independent pathways). The MRGPRX2-CHO receptor assay had a sensitivity of 97% (false negative 3%) and specificity of 93% (false positive 7%) against the outcome in human mast cell cultures. No clear evidence of ligand bias was observed. Because MRGPRX2 is overexpressed in CHO cells, the assay may slightly over predict, and does not inform on other mechanisms of MCD not mediated by MRGPRX2. Assessing MRGPRX2 receptor activation provides a rapid, high-throughput and economical mechanism-based approach for detecting peptide-mediated human MCD liabilities.

Activation of β-Glucocerebrosidase Reduces Pathological α-Synuclein and Restores Lysosomal Function in Parkinson's Patient Midbrain Neurons.

Parkinson's disease (PD) is characterized by the accumulation of α-synuclein (α-syn) within Lewy body inclusions in the nervous system. There are currently no disease-modifying therapies capable of reducing α-syn inclusions in PD. Recent data has indicated that loss-of-function mutations in the GBA1 gene that encodes lysosomal β-glucocerebrosidase (GCase) represent an important risk factor for PD, and can lead to α-syn accumulation. Here we use a small-molecule modulator of GCase to determine whether GCase activation within lysosomes can reduce α-syn levels and ameliorate downstream toxicity. Using induced pluripotent stem cell (iPSC)-derived human midbrain dopamine (DA) neurons from synucleinopathy patients with different PD-linked mutations, we find that a non-inhibitory small molecule modulator of GCase specifically enhanced activity within lysosomal compartments. This resulted in reduction of GCase substrates and clearance of pathological α-syn, regardless of the disease causing mutations. Importantly, the reduction of α-syn was sufficient to reverse downstream cellular pathologies induced by α-syn, including perturbations in hydrolase maturation and lysosomal dysfunction. These results indicate that enhancement of a single lysosomal hydrolase, GCase, can effectively reduce α-syn and provide therapeutic benefit in human midbrain neurons. This suggests that GCase activators may prove beneficial as treatments for PD and related synucleinopathies. The presence of Lewy body inclusions comprised of fibrillar α-syn within affected regions of PD brain has been firmly documented, however no treatments exist that are capable of clearing Lewy bodies. Here, we used a mechanistic-based approach to examine the effect of GCase activation on α-syn clearance in human midbrain DA models that naturally accumulate α-syn through genetic mutations. Small molecule-mediated activation of GCase was effective at reducing α-syn inclusions in neurons, as well as associated downstream toxicity, demonstrating a therapeutic effect. Our work provides an example of how human iPSC-derived midbrain models could be used for testing potential treatments for neurodegenerative disorders, and identifies GCase as a critical therapeutic convergence point for a wide range of synucleinopathies.

Mechanics based model for predicting structure-induced rolling resistance (SRR) of the tire-pavement system

The structure-induced rolling resistance of pavements, and its impact on vehicle fuel consumption, is investigated in this study. The structural response of pavement causes additional rolling resistance and fuel consumption of vehicles through deformation of pavement and various dissipation mechanisms associated with inelastic material properties and damping. Accurate and computationally efficient models are required to capture these mechanisms and obtain realistic estimates of changes in vehicle fuel consumption. Two mechanistic-based approaches are currently used to calculate vehicle fuel consumption as related to structural rolling resistance: dissipation-induced and deflection-induced methods. The deflection-induced approach is adopted in this study, and realistic representation of pavement–vehicle interactions (PVIs) is incorporated. In addition to considering viscoelastic behavior of asphalt concrete layers, the realistic representation of PVIs in this study includes non-uniform three-dimensional tire contact stresses and dynamic analysis in pavement simulations. The effects of analysis type, tire contact stresses, pavement viscoelastic properties, pavement damping coefficients, vehicle speed, and pavement temperature are then investigated.

Activation of the PI3K/Akt/mTOR and MAPK Signaling Pathways in Response to Acute Solar-Simulated Light Exposure of Human Skin.

The incidence of skin cancer is higher than all other cancers and continues to increase, with an average annual cost over $8 billion in the United States. As a result, identifying molecular pathway alterations that occur with UV exposure to strategize more effective preventive and therapeutic approaches is essential. To that end, we evaluated phosphorylation of proteins within the PI3K/Akt and MAPK pathways by immunohistochemistry in sun-protected skin after acute doses of physiologically relevant solar-simulated ultraviolet light (SSL) in 24 volunteers. Biopsies were performed at baseline, 5 minutes, 1, 5, and 24 hours after SSL irradiation. Within the PI3K/Akt pathway, we found activation of Akt (serine 473) to be significantly increased at 5 hours while mTOR (serine 2448) was strongly activated early and was sustained over 24 hours after SSL. Downstream, we observed a marked and sustained increase in phospho-S6 (serine 235/S236), whereas phospho-4E-BP1 (threonines 37/46) was increased only at 24 hours. Within the MAPK pathway, SSL-induced expression of phospho-p38 (threonine 180/tyrosine 182) peaked at 1 to 5 hours. ERK 1/2 was observed to be immediate and sustained after SSL irradiation. Phosphorylation of histone H3 (serine 10), a core structural protein of the nucleosome, peaked at 5 hours after SSL irradiation. The expression of both p53 and COX-2 was increased at 5 hours and was maximal at 24 hours after SSL irradiation. Apoptosis was significantly increased at 24 hours as expected and indicative of a sunburn-type response to SSL. Understanding the timing of key protein expression changes in response to SSL will aid in development of mechanistic-based approaches for the prevention and control of skin cancers.