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Hierarchical surfaces comprised of both microscale and nanoscale structures have been previously studied as a means of targeting multiple length scales to achieve superior pool boiling performance. However, preceding studies have focused almost exclusively on high surface tension working fluids while technologically important low surface tension fluids have remained largely unexplored. In this work, we utilize scalable manufacturing techniques to realize four separate surface types (planar, nanoscale-modified, microscale-modified, and hierarchical) and experimentally determine their respective pool boiling performance within the low surface tension commercial working fluid HFE-7100. A maximum heat transfer enhancement of 125 % at 38 K of superheat was observed for the best performing samples, which interestingly were nanoscale-modified and not those of the hierarchical type. Visual observations via high-speed video analysis of vapor bubble behaviour are utilized to explain the underlying multiphase physics as to why these samples performed so well and future directions for achieving surface optimization across multiple length scales. 

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson’s disease (PD). These mutations elevate the LRRK2 kinase activity, making LRRK2 kinase inhibitors an attractive therapeutic. LRRK2 kinase activity has been consistently linked to specific cell signaling pathways, mostly related to organelle trafficking and homeostasis, but its relationship to PD pathogenesis has been more difficult to define.LRRK2-PD patients consistently present with loss of dopaminergic neurons in the substantia nigra but show variable development of Lewy body or tau tangle pathology. Animal models carryingLRRK2mutations do not develop robust PD-related phenotypes spontaneously, hampering the assessment of the efficacy of LRRK2 inhibitors against disease processes. We hypothesized that mutations inLRRK2may not be directly related to a single disease pathway, but instead may elevate the susceptibility to multiple disease processes, depending on the disease trigger. To test this hypothesis, we have previously evaluated progression of α-synuclein and tau pathologies following injection of proteopathic seeds. We demonstrated that transgenic mice overexpressing mutant LRRK2 show alterations in the brain-wide progression of pathology, especially at older ages.

Here, we assess tau pathology progression in relation to long-term LRRK2 kinase inhibition. Wild-type or LRRK2^G2019Sknock-in mice were injected with tau fibrils and treated with control diet or diet containing LRRK2 kinase inhibitor MLi-2 targeting the IC50 or IC90 of LRRK2 for 3–6 months. Mice were evaluated for tau pathology by brain-wide quantitative pathology in 844 brain regions and subsequent linear diffusion modeling of progression.

Consistent with our previous work, we found systemic alterations in the progression of tau pathology in LRRK2^G2019Smice, which were most pronounced at 6 months. Importantly, LRRK2 kinase inhibition reversed these effects in LRRK2^G2019Smice, but had minimal effect in wild-type mice, suggesting that LRRK2 kinase inhibition is likely to reverse specific disease processes in G2019S mutation carriers. Additional work may be necessary to determine the potential effect in non-carriers.

This work supports a protective role of LRRK2 kinase inhibition in G2019S carriers and provides a rational workflow for systematic evaluation of brain-wide phenotypes in therapeutic development.

 

Biomolecular condensates are important structures in various cellular processes but are challenging to study using traditional experimental techniques. In silico simulations with residue-level coarse-grained models strike a balance between computational efficiency and chemical accuracy. They could offer valuable insights by connecting the emergent properties of these complex systems with molecular sequences. However, existing coarse-grained models often lack easy-to-follow tutorials and are implemented in software that is not optimal for condensate simulations. To address these issues, we introduce OpenABC, a software package that greatly simplifies the setup and execution of coarse-grained condensate simulations with multiple force fields using Python scripting. OpenABC seamlessly integrates with the OpenMM molecular dynamics engine, enabling efficient simulations with performance on a single GPU that rivals the speed achieved by hundreds of CPUs. We also provide tools that convert coarse-grained configurations to all-atom structures for atomistic simulations. We anticipate that OpenABC will significantly facilitate the adoption of in silico simulations by a broader community to investigate the structural and dynamical properties of condensates.

 

Software components such as application programming interfaces (APIs) provided by external developers are vital to online digital platforms. Although APIs generally increase the variety of products according to anecdote, the precise relationship between the categories of APIs and product variety is not yet known. We find that APIs, regarding their use frequency, are categorized into three groups. The core is a group of frequently used APIs, whereas the periphery is a group of sparsely used APIs. In a large and mature platform ecosystem, an additional group of APIs, the regular core, mainly provided by third-party developers, emerges. APIs in the regular core are the main driver of product variety. However, we also find that the strength of this effect diminishes in a newly created product category when most of the new products are built by duplicating the usage of APIs from other products. A platform owner can stimulate developers’ creativity by acting as a bridge between digital product providers and third-party developers. It can collect functional needs from third-party developers and then share them with product providers. Therefore, the latter can build APIs that developers need.

 

The arrangement of nucleosomes inside chromatin is of extensive interest. While in vitro experiments have revealed the formation of 30 nm fibers, most in vivo studies have failed to confirm their presence in cell nuclei. To reconcile the diverging experimental findings, we characterized chromatin organization using a residue-level coarse-grained model. The computed force–extension curve matches well with measurements from single-molecule experiments. Notably, we found that a dodeca-nucleosome in the two-helix zigzag conformation breaks into structures with nucleosome clutches and a mix of trimers and tetramers under tension. Such unfolded configurations can also be stabilized through trans interactions with other chromatin chains. Our study suggests that unfolding from chromatin fibers could contribute to the irregularity of in vivo chromatin configurations. We further revealed that chromatin segments with fibril or clutch structures engaged in distinct binding modes and discussed the implications of these inter-chain interactions for a potential sol–gel phase transition.