Mutations in leucine-rich repeat kinase 2 (LRRK2) are commonly implicated in the pathogenesis of both familial and sporadic Parkinson's disease (PD). LRRK2 regulates critical cellular processes at membranous organelles and forms microtubule-based pathogenic filaments, yet the molecular basis underlying these biological roles of LRRK2 remains largely enigmatic. Here, we determined high-resolution structures of full-length human LRRK2, revealing its architecture and key interdomain scaffolding elements for rationalizing disease-causing mutations. The kinase domain of LRRK2 is captured in an inactive state, a conformation also adopted by the most common PD-associated mutation, LRRK2G2019S. This conformation serves as a framework for structure-guided design of conformational specific inhibitors. We further determined the structure of COR-mediated LRRK2 dimers and found that single-point mutations at the dimer interface abolished pathogenic filamentation in cells. Overall, our study provides mechanistic insights into physiological and pathological roles of LRRK2 and establishes a structural template for future therapeutic intervention in PD.Diphenylamine NSAIDs are highly prescribed therapeutics for chronic pain despite causing symptomatic hepatotoxicity through mitochondrial damage in five percent of patients taking them. Differences in toxicity are attributed to structural modifications to the diphenylamine scaffold rather than its inherent toxicity. We hypothesize that marketed diphenylamine NSAID substituents affect preference and efficiency of bioactivation pathways and clearance. We parsed the FDA DILIrank hepatotoxicity database and modeled marketed drug bioactivation into quinone-species metabolites to identify a family of seven clinically relevant diphenylamine NSAIDs. These drugs fell into two subgroups, i.e., acetic acid and propionic acid diphenylamines, varying in hepatotoxicity risks and modeled bioactivation propensities. We carried out steady-state kinetic studies to assess bioactivation pathways by trapping quinone-species metabolites with dansyl glutathione. Analysis of the glutathione adducts by mass spectrometry characterizedpatotoxicity for all drugs prevents further correlative analyses. These findings provide critical insights on the impact of diphenylamine bioactivation as a precursor to hepatotoxicity and thus, provide a foundation for better risk assessment in drug discovery and development.Atrazine is a toxic herbicide whose alarming rate of contamination in the drinking water and wastewater poses a severe threat to the environment and human health. Here in this study, the graphene oxide (GO) nanosheets were prepared using Hummers' method with minor modification and studied as a potential adsorbent for atrazine removal from simulated wastewater. The spectroscopy and microscopic analysis confirmed the successful formation of GO with a multilayer structure resembling the crumpled sheets with random stacking. The Response Surface Methodology (RSM) employing Box Behnken design (BBD) was successfully developed to predict the optimal conditions for maximal atrazine removal as adsorbent dosage 121.45 mg/L; initial feed concentration 27.03 mg/L; temperature 27.69 °C, pH 5.37, and time 180 min. The atrazine adsorption onto GO was found to be higher in acidic pH and lower temperature. Density functional theory (DFT) calculation of adsorbent-adsorbate complex in the implicit solvent medium suggests adsorption affinity energy of -24.4 kcal/mol for atrazine. A careful observation of the molecules configuration and binding energy showed that the π-π interactions and hydrogen bonds played a significant role in the adsorption phenomena. Langmuir isotherm suited well to the adsorption process with a maximum adsorption capacity of 138.19 mg/g, at 318 K. The fitness of kinetic models for atrazine adsorption onto GO nanosheets were in following order Ho less then Sobkowsk-Czerwi less then Avrami model based on their correlation coefficient (R2) values. Reusability analysis showed that GO nanosheets could be effectively recycled using 0.01 N NaOH up to six cycles of atrazine removal. Thus, this study provided a theoretical and experimental basis for the potential application of GO nanosheets as a novel adsorbent for the removal of hazardous atrazine.Adeno-associated virus (AAV) vectors for gene therapy have potential to provide a durable treatment response for a number of diseases with unmet need. DNA is released from AAV capsids at high temperatures. Less is known about DNA release that may occur under conditions relevant to clinical and commercial manufacturing, storage, and distribution. In this work we developed and applied a sensitive fluorescent dye-based method to quantitate trace levels of DNA released from AAV capsids. The method was used to characterize the impact of manufacturing process steps on the increase (up to 1.5%) and removal (down to 0.2%) of free DNA. Free DNA increased by 0.3% per day at 37 °C and by 0.4% per freeze/thaw cycle in a phosphate-buffered saline formulation. When stored for 2 years at different temperatures, free DNA remained low ( less then 0.6%) at both ≤ -60 °C and at 2-8 °C but was higher (2.6%) when the same sample was stored at -20 °C. The dye-based method may be used to further characterize release of free DNA for different processes, formulations, and stress conditions. Overall, release of free DNA was a relatively minor degradation pathway under the conditions studied in this work.Growing evidence supports that chronic or latent infection of the central nervous system might be implicated in Alzheimer's disease (AD). Among them, Herpes simplex virus type 1 (HSV-1) has emerged as a major factor in the etiology of the disease. Our group is devoted to the study of the relationship among HSV-1, oxidative stress (OS) and neurodegeneration. We have found that HSV-1 induces the main neuropathological hallmarks of AD, including the accumulation of intracellular amyloid beta (Aβ), hyperphosphorylated tau protein and autophagic vesicles, that OS exacerbates these effects, and that matrix metalloproteinase 14 (MMP-14) participates in the alterations induced by OS. Elenbecestat clinical trial In this work, we focused on the role of MMP-14 in the degenerative markers raised by HSV-1 infection. Interestingly, we found that MMP-14 blockage is a potent inhibitor of HSV-1 infection efficiency, that also reduces the degeneration markers, accumulation of Aβ and hyperphosphorylated tau, induced by the virus. Our results point to MMP-14 as a potent antiviral target to control HSV-1 infection and its associated neurodegenerative effects.