MCell4 with BioNetGen: A Monte Carlo simulator of rule-based reaction-diffusion systems with Python interface.

Biochemical signaling pathways in living cells are often highly organized into spatially segregated volumes, membranes, scaffolds, subcellular compartments, and organelles comprising small numbers of interacting molecules. At this level of granularity stochastic behavior dominates, well-mixed continuum approximations based on concentrations break down and a particle-based approach is more accurate and more efficient. We describe and validate a new version of the open-source MCell simulation program (MCell4), which supports generalized 3D Monte Carlo modeling of diffusion and chemical reaction of discrete molecules and macromolecular complexes in solution, on surfaces representing membranes, and combinations thereof. The main improvements in MCell4 compared to the previous versions, MCell3 and MCell3-R, include a Python interface and native BioNetGen reaction language (BNGL) support. MCell4's Python interface opens up completely new possibilities for interfacing with external simulators to allow creation of sophisticated event-driven multiscale/multiphysics simulations. The native BNGL support, implemented through a new open-source library libBNG (also introduced in this paper), provides the capability to run a given BNGL model spatially resolved in MCell4 and, with appropriate simplifying assumptions, also in the BioNetGen simulation environment, greatly accelerating and simplifying model validation and comparison.

Multi-omic comparison of Alzheimer's variants in human ESC-derived microglia reveals convergence at APOE.

Variations in many genes linked to sporadic Alzheimer's disease (AD) show abundant expression in microglia, but relationships among these genes remain largely elusive. Here, we establish isogenic human ESC-derived microglia-like cell lines (hMGLs) harboring AD variants in CD33, INPP5D, SORL1, and TREM2 loci and curate a comprehensive atlas comprising ATAC-seq, ChIP-seq, RNA-seq, and proteomics datasets. AD-like expression signatures are observed in AD mutant SORL1 and TREM2 hMGLs, while integrative multi-omic analysis of combined epigenetic and expression datasets indicates up-regulation of APOE as a convergent pathogenic node. We also observe cross-regulatory relationships between SORL1 and TREM2, in which SORL1R744X hMGLs induce TREM2 expression to enhance APOE expression. AD-associated SORL1 and TREM2 mutations also impaired hMGL Aß uptake in an APOE-dependent manner in vitro and attenuated Aß uptake/clearance in mouse AD brain xenotransplants. Using this modeling and analysis platform for human microglia, we provide new insight into epistatic interactions in AD genes and demonstrate convergence of microglial AD genes at the APOE locus.

Role of Rab GTPases in Alzheimer's Disease.

Alzheimer's disease (AD) comprises two major pathological hallmarks: extraneuronal deposition of ß-amyloid (Aß) peptides ("senile plaques") and intraneuronal aggregation of the microtubule-associated protein tau ("neurofibrillary tangles"). Aß is derived from sequential cleavage of the ß-amyloid precursor protein by ß- and γ-secretases, while aggregated tau is hyperphosphorylated in AD. Mounting evidence suggests that dysregulated trafficking of these AD-related proteins contributes to AD pathogenesis. Rab proteins are small GTPases that function as master regulators of vesicular transport and membrane trafficking. Multiple Rab GTPases have been implicated in AD-related protein trafficking, and their expression has been observed to be altered in postmortem AD brain. Here we review current implicated roles of Rab GTPase dysregulation in AD pathogenesis. Further elucidation of the pathophysiological role of Rab GTPases will likely reveal novel targets for AD therapeutics.

Antenatal sexually transmitted infection screening in private and indigent clinics in a community hospital system.

OBJECTIVE: To determine whether clinics that serve indigent patients demonstrate equal compliance with sexually transmitted infection testing guidelines when compared with private clinics. STUDY DESIGN: One hundred eighty-three women were divided into cohorts based on whether they received prenatal care at a private or indigent clinic. Timing of required antenatal sexually transmitted infection screening was collected for 8 tests and compliance scores were calculated. Primary outcome was average compliance score compared between clinic types. Secondary outcomes included disease-specific compliance and percent of perfect compliance at different office types. RESULTS: Compliance was found to be different between clinic types (P = .023). Indigent clinics had the same median with slightly higher inner-quartile range than private clinics (7 [7-8], 7 [7-7]). Indigent clinics had higher mean compliance scores (7.1 vs 6.9) and a greater percentage of patients demonstrating perfect compliance (42% vs 14%, P < .001). CONCLUSION: Clinics serving indigent patient populations had a higher compliance with required testing compared to private clinics. HIV testing in the third trimester remains the greatest need for improvement for all practice types.