Targeting therapeutic nanoparticles to the brain poses a challenge due to the restrictive nature of the blood-brain barrier (BBB). Here we report the development of mRNA-loaded lipid nanoparticles (LNPs) functionalized with BBB-interacting small molecules, thereby enhancing brain delivery and gene expression. Screening brain-targeted mRNA-LNPs in central nervous system (CNS) in vitro models and through intravenous administration in mice demonstrated that acetylcholine-conjugated LNPs achieved superior brain tropism and gene expression, outperforming LNP modifications with nicotine, glucose, memantine, cocaine, tryptophan, and other small molecules. An artificial intelligence (AI)-based model designed to predict the BBB permeability of small-molecule ligands showed strong alignment with our experimental results, providing in vivo validation of its predictive capacity. Cell-specific biodistribution analysis in Cre-reporter Ai9 mice showed that acetylcholine-functionalized LNPs preferentially transfected neurons and astrocytes following either intravenous or intracerebral administration. Mechanistic studies suggest that acetylcholine-LNP uptake is mediated by the functional engagement of acetylcholine receptors (AchRs) followed by endocytosis, which synergistically enhances intracellular mRNA delivery. Moreover, acetylcholine-LNPs successfully crossed a human BBB-on-a-chip model, enabling transgene expression in human iPSC-derived neurons. Their effective penetration and transfection in human brain organoids further support their potential activity in human-based systems. These findings establish a predictive and modular framework for engineering CNS-targeted LNPs, advancing precision gene delivery for brain disorders.

Solving the hydrodynamical equations in urban canopies often requires substantial computational resources. This is especially the case when tackling urban wind comfort issues. In this article, a novel and efficient technique for predicting wind velocity is discussed. Reynolds-averaged Navier–Stokes (RANS) simulations of the Michaelstadt wind tunnel experiment and the Tel Aviv center are used to supervise a machine learning function. Using the machine learning function it is possible to observe wind flow patterns in the form of eddies and spirals emerging from street canyons. The flow patterns observed in urban canopies tend to be predominantly localized, as the machine learning algorithms utilized for flow prediction are based on local morphological features.

Oral drug absorption is the primary route for drug administration. However, this process hinges on multiple factors, including the drug’s physicochemical properties, formulation characteristics, and gastrointestinal physiology. Given its intricacy and the exorbitant costs associated with experimentation, the trial-and-error method proves prohibitively expensive. Theoretical models have emerged as a cost-effective alternative by assimilating data from diverse experiments and theoretical considerations. These models fall into three categories: (i) data-driven models, encompassing classical pharmacokinetics, quantitative-structure models (QSAR), and machine/deep learning; (ii) mechanism-based models, which include quasi-equilibrium, steady-state, and physiologically-based pharmacokinetics models; and (iii) first principles models, including molecular dynamics and continuum models. This review provides an overview of recent modeling endeavors across these categories while evaluating their respective advantages and limitations. Additionally, a primer on partial differential equations and their numerical solutions is included in the appendix, recognizing their utility in modeling physiological systems despite their mathematical complexity limiting widespread application in this field.

The Haifa bay area (HBA), which includes Mount Carmel and the Zevulun valley is the third largest metropolitan area in Israel. It is also a centre of heavy industry and an important transportation hub which serve as sources of local anthropogenic pollution. Such sources are associated with adverse health effects. In order to estimate the possible exposure of the inhabitants in such heterogeneous orographic area, a detailed atmospheric transport and dispersion modelling study is required, which in turn must take into account the local micrometeorology. The aim of this study is to conduct a spatio-temporal analysis of the flow field in the HBA in order to identify the common patterns of the average wind and characterize the statistical parameters of turbulence in this area, essential for detailed pollutants dispersion modelling. This study analyses data collected during four months of summer in a network of 16 weather stations which extend across Mount Carmel and the Zevulun valley. It was found that, during the evening and night time on Mount Carmel, different flow patterns may develop on each side, separated by the watershed line. When such conditions do not develop, as well as during the daytime, the wind field, both on Mount Carmel and the Zevulun valley is approximately homogenous. The analysis of the Monin–Obukhov similarity theory functions for the velocity standard deviations show a distinct difference between Mount Carmel and the Zevulun valley, as well as between strong and weak winds. This difference can be clearly seen also in the diurnal hourly distribution of atmospheric stabilities which exhibit higher proportions of unstable conditions in the Zevulun valley during day time and higher proportion of stable stratifications at the Mount Carmel during night-time.

Since its emergence, the phenomenon of SARS-CoV-2 transmission by seemingly healthy individuals has become a major challenge in the effort to achieve control of the pandemic. Identifying the modes of transmission that drive this phenomenon is a perquisite in devising effective control measures, but to date it is still under debate. To address this problem, we have formulated a detailed mathematical model of discrete human actions (such as coughs, sneezes, and touching) and the continuous decay of the virus in the environment. To take into account those discrete and continuous events we have extended the common modelling approach and employed a hybrid stochastic mathematical framework. This allowed us to calculate higher order statistics which are crucial for the reconstruction of the observed distributions. We focused on transmission within a household, the venue with the highest risk of infection and validated the model results against the observed secondary attack rate and the serial interval distribution. Detailed analysis of the model results identified the dominant driver of pre-symptomatic transmission as the contact route via hand-face transfer and showed that wearing masks and avoiding physical contact are an effective prevention strategy. These results provide a sound scientific basis to the present recommendations of the WHO and the CDC.

Levodopa is currently the standard of care treatment for Parkinson’s disease, but chronic therapy has been linked to motor complications. Designing a controlled release formulation (CRF) that maintains sustained and constant blood concentrations may reduce these complications. Still, it is challenging due to levodopa’s pharmacokinetic properties and the notion that it is absorbed only in the upper small intestine (i.e., exhibits an “absorption window”). We created and validated a physiologically based mathematical model to aid the development of such a formulation. Analysis of experimental results using the model revealed that levodopa is well absorbed throughout the entire small intestine (i.e., no “absorption window”) and that levodopa in the stomach causes fluctuations during the first 3 h after administration. Based on these insights, we developed guidelines for an improved CRF for various stages of Parkinson’s disease. Such a formulation is expected to produce steady concentrations and prolong therapeutic duration compared to a common CRF with a smaller dose per day and a lower overall dose of levodopa, thereby improving patient compliance with the dosage regime.