A unique Thy-1-negative immuno-fibroblast population emerges as a key determinant of fibrotic outcomes to biomaterials

Microporous annealed particle (MAP) hydrogels are an exciting new development in biomaterial design. They regulate innate and acquired immunity which has been linked to their ability to evade normal host-material fibrosis. Yet, resident stromal fibroblasts, not immune cells, are the arbiters of the extracellular matrix assembly that characterizes fibrosis. In other idiopathic fibrotic disorders, a fibroblast subpopulation defined by its loss of cell surface Thy-1 expression is strongly correlated with degree of fibrosis. We have previously shown that Thy-1 is a critical αvβ3 integrin regulator that enables normal fibroblast mechanosensing and here, leveraging non-fibrosing MAP gels, we demonstrate that Thy-1-/- mice mount a robust response to MAP gels that remarkably resembles a classical foreign body response. We further find that within the naive, Thy-1+ fibroblast population exists a distinct and cryptic αSMA+ Thy-1- population that emerges in response to IL-1β and TNFα. Employing single-cell RNA sequencing, we find that IL-1β/TNFα-induced Thy-1- fibroblasts actually consist of two distinct subpopulations, both of which are strongly pro-inflammatory. These findings illustrate the emergence of a unique pro-inflammatory, pro-fibrotic fibroblast subpopulation that is central to material-associated fibrosis likely through amplifying local inflammatory signaling.

Fast Barycentric-Based Evaluation Over Spectral/hp Elements

As the use of spectral/hp element methods, and high-order finite element methods in general, continues to spread, community efforts to create efficient, optimized algorithms associated with fundamental high-order operations have grown. Core tasks such as solution expansion evaluation at quadrature points, stiffness and mass matrix generation, and matrix assembly have received tremendous attention. With the expansion of the types of problems to which high-order methods are applied, and correspondingly the growth in types of numerical tasks accomplished through high-order methods, the number and types of these core operations broaden. This work focuses on solution expansion evaluation at arbitrary points within an element. This operation is core to many postprocessing applications such as evaluation of streamlines and pathlines, as well as to field projection techniques such as mortaring. We expand barycentric interpolation techniques developed on an interval to 2D (triangles and quadrilaterals) and 3D (tetrahedra, prisms, pyramids, and hexahedra) spectral/hp element methods. We provide efficient algorithms for their implementations, and demonstrate their effectiveness using the spectral/hp element library Nektar++ by running a series of baseline evaluations against the ‘standard’ Lagrangian method, where an interpolation matrix is generated and matrix-multiplication applied to evaluate a point at a given location. We present results from a rigorous series of benchmarking tests for a variety of element shapes, polynomial orders and dimensions. We show that when the point of interest is to be repeatedly evaluated, the barycentric method performs at worst $$50\%$$ 50 % slower, when compared to a cached matrix evaluation. However, when the point of interest changes repeatedly so that the interpolation matrix must be regenerated in the ‘standard’ approach, the barycentric method yields far greater performance, with a minimum speedup factor of $$7\times $$ 7 × . Furthermore, when derivatives of the solution evaluation are also required, the barycentric method in general slightly outperforms the cached interpolation matrix method across all elements and orders, with an up to $$30\%$$ 30 % speedup. Finally we investigate a real-world example of scalar transport using a non-conformal discontinuous Galerkin simulation, in which we observe around $$6\times $$ 6 × speedup in computational time for the barycentric method compared to the matrix-based approach. We also explore the complexity of both interpolation methods and show that the barycentric interpolation method requires $${\mathcal {O}}(k)$$ O ( k ) storage compared to a best case space complexity of $${\mathcal {O}}(k^2)$$ O ( k 2 ) for the Lagrangian interpolation matrix method.

The architecture of Recent brachiopod shells: diversity of biocrystal and biopolymer assemblages in rhynchonellide, terebratulide, thecideide and craniide shells

Biological hard tissues are a rich source of design concepts for the generation of advanced materials. They represent the most important library of information on the evolution of life and its environmental conditions. Organisms produce soft and hard tissues in a bottom-up process, a construction principle that is intrinsic to biologically secreted materials. This process emerged early on in the geological record, with the onset of biological mineralization. The phylum Brachiopoda is a marine animal group that has an excellent and continuous fossil record from the early Cambrian to the Recent. Throughout this time interval, the Brachiopoda secreted phosphate and carbonate shells and populated many and highly diverse marine habitats. This required great flexibility in the adaptation of soft and hard tissues to the different marine environments and living conditions. This review presents, juxtaposes and discusses the main modes of mineral and biopolymer organization in Recent, carbonate shell-producing, brachiopods. We describe shell tissue characteristics for taxa of the orders Rhynchonellida, Terebratulida, Thecideida and Craniida. We highlight modes of calcite and organic matrix assembly at the macro-, micro-, and nano-scales based on results obtained by Electron Backscatter Diffraction, Atomic Force Microscopy, Field Emission Scanning Electron Microscopy and Scanning Transmission Electron Microscopy. We show variation in composite hard tissue organization for taxa with different lifestyles, visualize nanometer-scale calcite assemblies for rhynchonellide and terebratulide fibers, highlight thecideide shell microstructure, texture and chemistry characteristics, and discuss the feasibility to use thecideide shells as archives of proxies for paleoenvironment and paleoclimate reconstructions.

Coordination of fungal biofilm development by extracellular vesicle cargo

The fungal pathogen Candida albicans can form biofilms that protect it from drugs and the immune system. The biofilm cells release extracellular vesicles (EVs) that promote extracellular matrix formation and resistance to antifungal drugs. Here, we define functions for numerous EV cargo proteins in biofilm matrix assembly and drug resistance, as well as in fungal cell adhesion and dissemination. We use a machine-learning analysis of cargo proteomic data from mutants with EV production defects to identify 63 candidate gene products for which we construct mutant and complemented strains for study. Among these, 17 mutants display reduced biofilm matrix accumulation and antifungal drug resistance. An additional subset of 8 cargo mutants exhibit defects in adhesion and/or dispersion. Representative cargo proteins are shown to function as EV cargo through the ability of exogenous wild-type EVs to complement mutant phenotypic defects. Most functionally assigned cargo proteins have roles in two or more of the biofilm phases. Our results support that EVs provide community coordination throughout biofilm development in C. albicans.

Proteomics analysis identifies PEA-15 as an endosomal phosphoprotein that regulates α5β1 integrin endocytosis

Endosomal trafficking of cell surface receptors is essential to their function. Integrins are transmembrane receptors that integrate adhesion to the extracellular matrix with engagement of the cytoskeleton. Ligated integrins mediate diverse signals that regulate matrix assembly, cell survival, cell morphology, and cell motility. Endosomal trafficking of integrins modulates these signals and contributes to cell motility and is required for cancer cell invasion. The phosphoprotein PEA-15 modulates integrin activation and ERK MAP Kinase signaling. To elucidate novel PEA-15 functions we utilized an unbiased proteomics approach. We identified several binding partners for PEA-15 in the endosome including clathrin and AP-2 as well as integrin β1 and other focal adhesion complex proteins. We confirmed these interactions using proximity ligation analysis, immunofluorescence imaging, pull-down and co-immunoprecipitation. We further found that PEA-15 is enriched in endosomes and was required for efficient endosomal internalization of α5β1 integrin and cellular migration. Importantly, PEA-15 promotion of migration was dependent on PEA-15 phosphorylation at serines 104 and 116. These data support a novel endosomal role for PEA-15 in control of endosomal trafficking of integrins through an association with the β1 integrin and clathrin complexes, and thereby regulation of cell motility.

A Scalability Study of the Ice-sheet and Sea-level System Model (ISSM, Version 4.18)

Accurately modeling the contribution of Greenland and Antarctica to sea level rise requires to solve partial differential equations at a high spatial resolution. It is important to test the scalability of existing ice sheet models in order to assess whether they are ready to take advantage of new cluster architectures. In this paper, we discuss the overall scaling of the Ice-sheet and Sea-level System Model (ISSM) applied to the Greenland ice sheet. The model setup used as benchmark problem comprises a variety of modules with different levels of complexity and computational demands. The core builds the so-called stress balance module, which uses the higher-order approximation (or Blatter-Pattyn) of the Stokes equations and a mesh of linear prismatic finite elements to compute the ice flow. We develop a detailed user-oriented, yet low-overhead performance instrumentation tailored to the requirements of earth system models and run scaling tests up to 6 144 MPI processes. The results show that the computation of the Greenland model scales overall well up to 3 072 MPI processes, but is eventually slowed down by matrix assembly, the output handling, and lower-dimensional problems that employ lower numbers of unknowns per MPI process. We also discuss improvements of the scaling and identify further improvements needed for climate research. The instrumented version of ISSM, thus, not only identifies potential performance bottlenecks that were not present at lower core counts but also provides the capability to continually monitor the performance of ISSM code basis. This is of long-term significance as the overall performance of ISSM model depends on the subtle interplay between algorithms, their implementation, underlying libraries, compilers, run-time systems and hardware characteristics, all of which are in a constant state of flux.

Mechanisms of phosphatidylserine influence on viral production: a computational model of Ebola virus matrix protein assembly

Ebola virus (EBOV) infections continue to pose a global public health threat, with high mortality rates and sporadic outbreaks in Central and Western Africa. A quantitative understanding of the key processes driving EBOV assembly and budding could provide valuable insights to inform drug development. Here we used a computational model to evaluate EBOV matrix assembly. Our model focused on the assembly kinetics of VP40, the matrix protein in EBOV, and its interaction with phosphatidylserine (PS) in the host cell membrane. Human cells transfected with VP40-expressing plasmids are capable of producing virus-like particles (VLPs) that closely resemble EBOV virions. We used data from this in vitro VP40 system to calibrate our computational model. PS levels in the host cell membrane had been shown to affect VP40 dynamics as well as VLP production through recruiting VP40 dimers to plasma membrane inner leaflet. Our computational results indicated that PS may have direct influence on VP40 filament growth and affect multiple steps in the assembly and budding of VP40 VLPs. We also proposed that the assembly of VP40 filaments may follow the nucleation-elongation theory where initialization and oligomerization of VP40 are two separate and distinct steps in the assembly process. This work illustrated how computational and experimental approaches can be combined to allow for additional analysis and hypothesis generation. Our findings advanced understanding of the molecular process of EBOV assembly and budding processes and may help the development of new EBOV treatments targeting VP40 matrix assembly.

Physcraper: a Python package for continually updated phylogenetic trees using the Open Tree of Life

Background Phylogenies are a key part of research in many areas of biology. Tools that automate some parts of the process of phylogenetic reconstruction, mainly molecular character matrix assembly, have been developed for the advantage of both specialists in the field of phylogenetics and non-specialists. However, interpretation of results, comparison with previously available phylogenetic hypotheses, and selection of one phylogeny for downstream analyses and discussion still impose difficulties to one that is not a specialist either on phylogenetic methods or on a particular group of study. Results Physcraper is a command-line Python program that automates the update of published phylogenies by adding public DNA sequences to underlying alignments of previously published phylogenies. It also provides a framework for straightforward comparison of published phylogenies with their updated versions, by leveraging upon tools from the Open Tree of Life project to link taxonomic information across databases. The program can be used by the nonspecialist, as a tool to generate phylogenetic hypotheses based on publicly available expert phylogenetic knowledge. Phylogeneticists and taxonomic group specialists will find it useful as a tool to facilitate molecular dataset gathering and comparison of alternative phylogenetic hypotheses (topologies). Conclusion The Physcraper workflow showcases the benefits of doing open science for phylogenetics, encouraging researchers to strive for better scientific sharing practices. Physcraper can be used with any OS and is released under an open-source license. Detailed instructions for installation and usage are available at https://physcraper.readthedocs.io.