Large Deviations Analysis for Distributed Algorithms in an Ergodic Markovian Environment

We provide a large deviations analysis of deadlock phenomena occurring in distributed systems sharing common resources. In our model transition probabilities of resource allocation and deallocation are time and space dependent. The process is driven by an ergodic Markov chain and is reflected on the boundary of the d-dimensional cube. In the large resource limit, we prove Freidlin-Wentzell estimates, we study the asymptotic of the deadlock time and we show that the quasi-potential is a viscosity solution of a Hamilton-Jacobi equation with a Neumann boundary condition. We give a complete analysis of the colliding 2-stacks problem and show an example where the system has a stable attractor which is a limit cycle

Recurrence of biased quantum walks on a line

The Polya number of a classical random walk on a regular lattice is known to depend solely on the dimension of the lattice. For one and two dimensions it equals one, meaning unit probability to return to the origin. This result is extremely sensitive to the directional symmetry, any deviation from the equal probability to travel in each direction results in a change of the character of the walk from recurrent to transient. Applying our definition of the Polya number to quantum walks on a line we show that the recurrence character of quantum walks is more stable against bias. We determine the range of parameters for which biased quantum walks remain recurrent. We find that there exist genuine biased quantum walks which are recurrent.Comment: Journal reference added, minor corrections in the tex

Author Correction: The mTORC1/4E-BP1 axis represents a critical signaling node during fibrogenesis

Correction to: Nature Communications https://doi.org/10.1038/s41467-018-07858-8, published online 2 January 2019

mTORC1 amplifies the ATF4-dependent de novo serine-glycine pathway to supply glycine during TGF-β1-induced collagen biosynthesis

The differentiation of fibroblasts into a transient population of highly activated, extracellular matrix (ECM)-producing myofibroblasts at sites of tissue injury is critical for normal tissue repair. Excessive myofibroblast accumulation and persistence, often as a result of a failure to undergo apoptosis when tissue repair is complete, lead to pathological fibrosis and are also features of the stromal response in cancer. Myofibroblast differentiation is accompanied by changes in cellular metabolism, including increased glycolysis, to meet the biosynthetic demands of enhanced ECM production. Here, we showed that transforming growth factor-β1 (TGF-β1), the key pro-fibrotic cytokine implicated in multiple fibrotic conditions, increased the production of activating transcription factor 4 (ATF4), the transcriptional master regulator of amino acid metabolism, to supply glucose-derived glycine to meet the amino acid requirements associated with enhanced collagen production in response to myofibroblast differentiation. We further delineated the signaling pathways involved and showed that TGF-β1-induced ATF4 production depended on cooperation between canonical TGF-β1 signaling through Smad3 and activation of mechanistic target of rapamycin complex 1 (mTORC1) and its downstream target eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). ATF4, in turn, promoted the transcription of genes encoding enzymes of the de novo serine-glycine biosynthetic pathway and glucose transporter 1 (GLUT1). Our findings suggest that targeting the TGF-β1-mTORC1-ATF4 axis may represent a novel therapeutic strategy for interfering with myofibroblast function in fibrosis and potentially in other conditions, including cancer

Perivascular-like cells contribute to the stability of the vascular network of osteogenic tissue formed from cell sheet-based constructs

In recent years several studies have been supporting the existence of a close relationship in terms of function and progeny between Mesenchymal Stem Cells (MSCs) and Pericytes. This concept has opened new perspectives for the application of MSCs in Tissue Engineering (TE), with special interest for the pre-vascularization of cell dense constructs. In this work, cell sheet technology was used to create a scaffold-free construct composed of osteogenic, endothelial and perivascular-like (CD146+) cells for improved in vivo vessel formation, maturation and stability. The CD146 pericyte-associated phenotype was induced from human bone marrow mesenchymal stem cells (hBMSCs) by the supplementation of standard culture medium with TGF-b1. Co-cultured cell sheets were obtained by culturing perivascular-like (CD146+) cells and human umbilical vein endothelial cells (HUVECs) on an hBMSCs monolayer maintained in osteogenic medium for 7 days. The perivascular-like (CD146+) cells and the HUVECs migrated and organized over the collagen-rich osteogenic cell sheet, suggesting the existence of cross-talk involving the co-cultured cell types. Furthermore the presence of that particular ECM produced by the osteoblastic cells was shown to be the key regulator for the singular observed organization. The osteogenic and angiogenic character of the proposed constructs was assessed in vivo. Immunohistochemistry analysis of the explants revealed the integration of HUVECs with the host vasculature as well as the osteogenic potential of the created construct, by the expression of osteocalcin. Additionally, the analysis of the diameter of human CD146 positive blood vessels showed a higher mean vessel diameter for the co-cultured cell sheet condition, reinforcing the advantage of the proposed model regarding blood vessels maturation and stability and for the in vitro pre-vascularization of TE constructs.Funding provided by Fundacao para a Ciencia e a Tecnologia project Skingineering (PTDC/SAU-OSM/099422/2008). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Combining regenerative medicine strategies to provide durable reconstructive options: auricular cartilage tissue engineering

Recent advances in regenerative medicine place us in a unique position to improve the quality of engineered tissue. We use auricular cartilage as an exemplar to illustrate how the use of tissue-specific adult stem cells, assembly through additive manufacturing and improved understanding of postnatal tissue maturation will allow us to more accurately replicate native tissue anisotropy. This review highlights the limitations of autologous auricular reconstruction, including donor site morbidity, technical considerations and long-term complications. Current tissue-engineered auricular constructs implanted into immune-competent animal models have been observed to undergo inflammation, fibrosis, foreign body reaction, calcification and degradation. Combining biomimetic regenerative medicine strategies will allow us to improve tissue-engineered auricular cartilage with respect to biochemical composition and functionality, as well as microstructural organization and overall shape. Creating functional and durable tissue has the potential to shift the paradigm in reconstructive surgery by obviating the need for donor sites

Biofabrication: an overview of the approaches used for printing of living cells

The development of cell printing is vital for establishing biofabrication approaches as clinically relevant tools. Achieving this requires bio-inks which must not only be easily printable, but also allow controllable and reproducible printing of cells. This review outlines the general principles and current progress and compares the advantages and challenges for the most widely used biofabrication techniques for printing cells: extrusion, laser, microvalve, inkjet and tissue fragment printing. It is expected that significant advances in cell printing will result from synergistic combinations of these techniques and lead to optimised resolution, throughput and the overall complexity of printed constructs

The promise of mTOR as a therapeutic target pathway in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is characterised by the progressive deposition of excessive extracellular matrix proteins within the lung parenchyma and represents the most rapidly progressive and fatal of all fibrotic conditions. Current anti-fibrotic drugs approved for the treatment of IPF fail to halt disease progression and have significant side-effect profiles. Therefore, there remains a pressing need to develop novel therapeutic strategies for IPF. Mammalian target of rapamycin (mTOR) forms the catalytic subunit of two complexes, mTORC1 and mTORC2. mTORC1 acts as critical cellular sensor which integrates intracellular and extracellular signals to reciprocally regulate a variety of anabolic and catabolic processes. The emerging evidence for a critical role for mTORC1 in influencing extracellular matrix production, metabolism, autophagy and senescence in the setting of IPF highlights this axis as a novel therapeutic target with the potential to impact multiple IPF pathomechanisms

A rapid and sensitive, multiplex, whole mount RNA fluorescence in situ hybridization and immunohistochemistry protocol

Abstract Background In the past few years, there has been an explosion in single-cell transcriptomics datasets, yet in vivo confirmation of these datasets is hampered in plants due to lack of robust validation methods. Likewise, modeling of plant development is hampered by paucity of spatial gene expression data. RNA fluorescence in situ hybridization (FISH) enables investigation of gene expression in the context of tissue type. Despite development of FISH methods for plants, easy and reliable whole mount FISH protocols have not yet been reported. Results We adapt a 3-day whole mount RNA-FISH method for plant species based on a combination of prior protocols that employs hybridization chain reaction (HCR), which amplifies the probe signal in an antibody-free manner. Our whole mount HCR RNA-FISH method shows expected spatial signals with low background for gene transcripts with known spatial expression patterns in Arabidopsis inflorescences and monocot roots. It allows simultaneous detection of three transcripts in 3D. We also show that HCR RNA-FISH can be combined with endogenous fluorescent protein detection and with our improved immunohistochemistry (IHC) protocol. Conclusions The whole mount HCR RNA-FISH and IHC methods allow easy investigation of 3D spatial gene expression patterns in entire plant tissues