A novel stochastic simulation approach enables exploration of mechanisms for regulating polarity site movement

Cells polarize their movement or growth toward external directional cues in many different contexts. For example, budding yeast cells grow toward potential mating partners in response to pheromone gradients. Directed growth is controlled by polarity factors that assemble into clusters at the cell membrane. The clusters assemble, disassemble, and move between different regions of the membrane before eventually forming a stable polarity site directed toward the pheromone source. Pathways that regulate clustering have been identified but the molecular mechanisms that regulate cluster mobility are not well understood. To gain insight into the contribution of chemical noise to cluster behavior we simulated clustering within the reaction-diffusion master equation (RDME) framework to account for molecular-level fluctuations. RDME simulations are a computationally efficient approximation, but their results can diverge from the underlying microscopic dynamics. We implemented novel concentration-dependent rate constants that improved the accuracy of RDME-based simulations of cluster behavior, allowing us to efficiently investigate how cluster dynamics might be regulated. Molecular noise was effective in relocating clusters when the clusters contained low numbers of limiting polarity factors, and when Cdc42, the central polarity regulator, exhibited short dwell times at the polarity site. Cluster stabilization occurred when abundances or binding rates were altered to either lengthen dwell times or increase the number of polarity molecules in the cluster. We validated key results using full 3D particle-based simulations. Understanding the mechanisms cells use to regulate the dynamics of polarity clusters should provide insights into how cells dynamically track external directional cues.

Evaluating the Effectiveness of Diabetes Shared Medical Appointments (SMAs) as Implemented in Five Veterans Affairs Health Systems: a Multi-site Cluster Randomized Pragmatic Trial

Objective To examine whether diabetes shared medical appointments (SMAs) implemented as part of usual clinical practice in diverse health systems are more effective than usual care in improving and sustaining A1c improvements. Research Design and Methods A multi-site cluster randomized pragmatic trial examining implementation in clinical practice of diabetes SMAs in five Veterans Affairs (VA) health systems was conducted from 2016 to 2020 among 1537 adults with type 2 diabetes and elevated A1cs. Eligible patients were randomly assigned to either: (1) invitation to participate in a series of SMAs totaling 8–9 h; or (2) continuation of usual care. Relative change in A1c (primary outcome) and in systolic blood pressure, insulin starts, statin starts, and anti-hypertensive medication classes (secondary outcomes) were measured as part of usual clinical care at baseline, at 6 months and at 12 months (~7 months after conclusion of the final SMA in four of five sites). We examined outcomes in three samples of SMA participants: all those scheduled for a SMA, those attending at least one SMA, and those attending at least half of SMAs. Results Baseline mean A1c was 9.0%. Participants scheduled for an SMA achieved A1c reductions 0.35% points greater than the control group between baseline and 6-months follow up (p = .001). Those who attended at least one SMA achieved reductions 0.42 % points greater (p < .001), and those who attended at least half of scheduled SMAs achieved reductions 0.53 % points greater (p < .001) than the control group. At 12-month follow-up, the three SMA analysis samples achieved reductions from baseline ranging from 0.16 % points (p = 0.12) to 0.29 % points (p = .06) greater than the control group. Conclusions Diabetes SMAs as implemented in real-life diverse clinical practices improve glycemic control more than usual care immediately after the SMAs, but relative gains are not maintained. Our findings suggest the need for further study of whether a longer term SMA model or other follow-up strategies would sustain relative clinical improvements associated with this intervention. Trial Registration ClinicalTrials.gov ID NCT02132676

Application of Fossil and Artefact Collection in The Human Reservation Center Sangiran of Sragen Krikilan Cluster Based on Android

Sangiran is the biggest early man site in Indonesia which has an important value such as human evolutions, culture, early fauna, and its environments. The evidence of the living past of early man sees through fossil collection, artifact, and environment. Sangiran collections save in Sangiran Early man Museum, under the management of the Preservation Center of Early Man Site Sangiran. Sangiran site is recognized as a World Cultural Heritage that has a problem in disseminating information about its important value. There are still many people who don't know about the important value of Sangiran.Related to the problem, the writer arranges an application that aims to make it easy for the community in getting information about the collection in the Preservation Center of Early Man Site Sangiran quickly, simple, and informative. This application is designed with the Unified Modeling Language (UML) method. In making this application, the writer uses software Construct 2 that is editor of game HTML5 based developed by Scirra Ltd who maximizes the editor's visual function and behavior-based logic system.The result of the research, the writer makes a mobile informative system that is "Application of the Introduction of Fossil and Artefact Collection in the Preservation Center of Early Man Sangiran Site Cluster Krikilan Based on Android". The advantage of this system is it can be an introduction media by the Preservation Center of Early Man Site Sangiran which only used with Android, meanwhile the weakness is it can only be operated on Android, not yet able to ios and desktop.

On the TRAIL of Better Therapies: Understanding TNFRSF Structure-Function

Tumor necrosis factor (TNF) superfamily ligands show diverse biological functions, such as the induction of apoptotic cell death or cell survival and proliferation, making them excellent therapeutic targets for cancer and autoimmunity. We review the latest literature on TNF receptor superfamily signaling with a focus on structure-function. Using combinatorics, we argue that receptors that cluster on the cell surface and are activated by membrane-bound ligands need to arrange in a highly ordered manner, as the probability of random ligand and receptor arrangements matching up for receptor activation is very low. A growing body of evidence indicates that antiparallel receptor dimers that sequester the ligand binding site cluster on the cell surface, forming a hexagonal lattice. Upon ligand binding, this arrangement puts the activated receptors at the right distance to accommodate the downstream signaling partners. The data also suggest that the same geometry is utilized regardless of receptor type. The unified model provides important clues about TNF receptor signaling and should aid the design of better therapies for cancer and various immune mediated diseases.