Multiphysics pharmacokinetic model for targeted nanoparticles.

Nanoparticles (NP) are being increasingly explored as vehicles for targeted drug delivery because they can overcome free therapeutic limitations by drug encapsulation, thereby increasing solubility and transport across cell membranes. However, a translational gap exists from animal to human studies resulting in only several NP having FDA approval. Because of this, researchers have begun to turn toward physiologically based pharmacokinetic (PBPK) models to guide in vivo NP experimentation. However, typical PBPK models use an empirically derived framework that cannot be universally applied to varying NP constructs and experimental settings. The purpose of this study was to develop a physics-based multiscale PBPK compartmental model for determining continuous NP biodistribution. We successfully developed two versions of a physics-based compartmental model, models A and B, and validated the models with experimental data. The more physiologically relevant model (model B) had an output that more closely resembled experimental data as determined by normalized root mean squared deviation (NRMSD) analysis. A branched model was developed to enable the model to account for varying NP sizes. With the help of the branched model, we were able to show that branching in vasculature causes enhanced uptake of NP in the organ tissue. The models were solved using two of the most popular computational platforms, MATLAB and Julia. Our experimentation with the two suggests the highly optimized ODE solver package DifferentialEquations.jl in Julia outperforms MATLAB when solving a stiff system of ordinary differential equations (ODEs). We experimented with solving our PBPK model with a neural network using Julia's Flux.jl package. We were able to demonstrate that a neural network can learn to solve a system of ODEs when the system can be made non-stiff via quasi-steady-state approximation (QSSA). Our model incorporates modules that account for varying NP surface chemistries, multiscale vascular hydrodynamic effects, and effects of the immune system to create a more comprehensive and modular model for predicting NP biodistribution in a variety of NP constructs.

Effects of body size and load carriage on lower-extremity biomechanical responses in healthy women.

BACKGROUND: Musculoskeletal injuries, such as stress fractures, are the single most important medical impediment to military readiness in the U.S. Army. While multiple studies have established race- and sex-based risks associated with a stress fracture, the role of certain physical characteristics, such as body size, on stress-fracture risk is less conclusive. METHODS: In this study, we investigated the effects of body size and load carriage on lower-extremity joint mechanics, tibial strain, and tibial stress-fracture risk in women. Using individualized musculoskeletal-finite-element-models of 21 women of short, medium, and tall statures (n = 7 in each group), we computed the joint mechanics and tibial strains while running on a treadmill at 3.0 m/s without and with a load of 11.3 or 22.7 kg. We also estimated the stress-fracture risk using a probabilistic model of bone damage, repair, and adaptation. RESULTS: Under all load conditions, the peak plantarflexion moment for tall women was higher than those in short women (p < 0.05). However, regardless of the load condition, we did not observe differences in the strains and the stress-fracture risk between the stature groups. When compared to the no-load condition, a 22.7-kg load increased the peak hip extension and flexion moments for all stature groups (p < 0.05). However, when compared to the no-load condition, the 22.7-kg load increased the strains and the stress-fracture risk in short and medium women (p < 0.05), but not in tall women. CONCLUSION: These results show that women of different statures adjust their gait mechanisms differently when running with external load. This study can educate the development of new strategies to help reduce the risk of musculoskeletal injuries in women while running with external load.

Expression of domain III of the envelope protein from GP-78: a Japanese encephalitis virus.

Acute encephalitis caused by the Japanese encephalitis virus (JEV) represents a growing epidemic and is a cause for concern in Southeast Asia. JEV is transmitted to humans through the bite of the Culicine mosquito species. The virus genome comprising of an RNA strand also encodes the envelope protein (E) which surrounds the virus. The E protein aids in fusion of virus with the cellular membrane of the host cell with the help of three structurally distinct domains (DI, DII, DIII) that are connected by flexible hinge regions. Of these domains, DIII (JEV-DIII) has been reported to interact with the cellular membrane, aid viral entry and viral replication. Hence JEV-DIII has the potential to be an antigen that can provide immune protection to a JEV infection. In this study, we describe the cloning and expression of DIII of GP-78, a virulent strain of JEV prevalent in India. Our data clearly shows that JEV-DIII expressed from pVAC1 in HEK293T cells is membrane targeted. To our knowledge, this is the first demonstration of a recombinant construct that may block JEV entry into the cells and/or evoke specific antibodies against JEV. Future studies will reveal if our construct will elicit significant immune responses which will alleviate or ameliorate the pro-inflammatory responses induced by JEV.

Bacillus Calmette-Guérin Confers Neuroprotection in a Murine Model of Japanese Encephalitis.

OBJECTIVE: Japanese encephalitis (JE) is a debilitating disease caused by infection with the JE virus (JEV; family: Flaviviridae), which leaves neurological sequelae in survivors but more often leads to mortality. Neurodegeneration caused by inflammation is the primary pathology behind the clinical manifestation of encephalitis caused by JEV. Bacillus Calmette-Guérin (BCG) has been used in immunoprophylaxis for tuberculosis and in the adjuvant therapy of many malignancies, and has exhibited neuroprotective activities in experimental models of Parkinson and Alzheimer disease. This study aimed at assessing the neuroprotective role of BCG in a murine model of JE. METHODS: Suckling mice were inoculated with 106 CFU of BCG and at 18 days postinoculation were challenged with 100 LD50 of JEV. PBS-inoculated mice were used as controls. Mice were sacrificed on days 2, 4, 6, and 8. Brain tissue was homogenized for RNA extraction. One-step real-time RT-PCR was performed to assess the relative gene expressions of TNF-α, IL-6, and iNOS. RESULTS: The BCG-inoculated (BCG+JEV) group exhibited a significant delay in the presentation of neuropathological symptoms, longer survival, and a downregulation in the expression of TNF-α, IL-6, and iNOS on days 2, 4, and 6 post-JEV challenge compared to the JEV group. CONCLUSION: These findings indicate that the administration of BCG offers neuroprotection in the murine model of JE. BCG should therefore be further investigated as an adjuvant in the management of JE. BCG is an accepted vaccine for tuberculosis in many countries that are endemic for JEV. This approach may have a significant impact on the public health burden in these countries.