Tumor-Associated Regulatory T Cell Expression of LAIR2 Is Prognostic in Lung Adenocarcinoma

Cancer development requires a permissive microenvironment that is shaped by interactions between tumor cells, stroma, and the surrounding matrix. As collagen receptors, the leukocyte-associated immunoglobulin-like receptor (LAIR) family allows the immune system to interact with the extracellular matrix. However, little is known about their role in regulating tumor immunity and cancer progression. Methods: Genetic analysis of resected human lung adenocarcinoma was correlated to clinical-pathological characteristics, gene ontologies, and single cell RNA sequencing (scRNASeq). LAIR2 production was determined in subsets of immune cells isolated from blood leukocytes and lung adenocarcinoma tumor. Functional assays were used to determine the role of LAIR2 in tumorigenesis. Results: LAIR2 expression was adversely prognostic in lung adenocarcinoma. LAIR2 was preferentially produced by activated CD4+ T cells and enhanced in vitro tumor invasion into collagen. scRNASeq analysis of tumor infiltrating T cells revealed that LAIR2 expression co-localized with FOXP3 expressing cells and shared a transcriptional signature with tumor-associated regulatory T (Treg) cells. A CD4+LAIR2+ Treg gene signature was prognostically significant in the TCGA dataset (n = 439; hazard ratio (HR) = 1.37; 95% confidence interval (CI), 1.05–1.77, p = 0.018) and validated in NCI Director’s Challenge lung adenocarcinoma dataset (n = 488; HR = 1.54; 95% CI, 1.14–2.09, p = 0.0045). Conclusions: Our data support a role for LAIR2 in lung adenocarcinoma tumorigenesis and identify a CD4+ LAIR2+ Treg gene signature in lung adenocarcinoma prognosis. LAIR2 provides a novel target for development of immunotherapies.

Coupling BEM and VEM for the Analysis of Composite Materials with Damage

Numerical tools which are able to predict and explain the initiation and propagation of damage at the microscopic level in heterogeneous materials are of high interest for the analysis and design of modern materials. In this contribution, we report the application of a recently developed numerical scheme based on the coupling between the Virtual Element Method (VEM) and the Boundary Element Method (BEM) within the framework of continuum damage mechanics (CDM) to analyze the progressive loss of material integrity in heterogeneous materials with complex microstructures. VEM is a novel numerical technique that, allowing the use of general polygonal mesh elements, assures conspicuous simplification in the data preparation stage of the analysis, notably for computational micro-mechanics problems, whose analysis domain often features elaborate geometries. BEM is a widely adopted and efficient numerical technique that, due to its underlying formulation, allows reducing the problem dimensionality, resulting in substantial simplification of the pre-processing stage and in the decrease of the computational effort without affecting the solution accuracy. The implemented technique has been applied to an artificial microstructure, consisting of the transverse section of a circular shaped stiff inclusion embedded in a softer matrix. BEM is used to model the inclusion that is supposed to behave within the linear elastic range, while VEM is used to model the surrounding matrix material, developing more complex nonlinear behaviors. Numerical results are reported and discussed to validate the proposed method.

Development of Electrochemical Surface Treatment to Visualize Critical Corrosion-Inducing Inclusions of Zr in Chloride Environments

An electrochemical surface treatment was developed to visualize the corrosion-inducing inclusions of Zr in chloride environments. Pure Zr and Zr alloy (Zr-0.5O-0.5C) were evaluated in this study. The electrochemical surface treatment consisted of repeated galvanostatic anodic polarization and potentiostatic cathodic polarization. After the electrochemical surface treatment, only one brittle and non-conductive shell of Zr oxide was observed at the corrosion initiation site on the tested surface. The corrosion-inducing inclusions were found inside the corrosion pit under the optimum polarization conditions. At the corrosion initiation site on pure Zr, the area inside the corrosion pit contained larger amounts of O, C, and Si than the surrounding matrix. In the case of the Zr-0.5O-0.5C alloy, relatively larger inclusions were observed after the treatment. Extremely large amounts of Si, together with O and C, were present in the inclusions. The inclusions that induced localized corrosion on the pure Zr and Zr-0.5O-0.5C specimens were found to be precipitated, involving the specific aggregation of Si. The surface treatment developed in this study is expected to be utilized as a powerful tool to elucidate the localized corrosion mechanism of Zr in chloride environments.

Systems for intricate patterning of the vertebrate anatomy

Periodic patterns form intricate arrays in the vertebrate anatomy, notably the hair and feather follicles of the skin, but also internally the villi of the gut and the many branches of the lung, kidney, mammary and salivary glands. These tissues are composite structures, being composed of adjoined epithelium and mesenchyme, and the patterns that arise within them require interaction between these two tissue layers. In embryonic development, cells change both their distribution and state in a periodic manner, defining the size and relative positions of these specialized structures. Their placement is determined by simple spacing mechanisms, with substantial evidence pointing to a variety of local enhancement/lateral inhibition systems underlying the breaking of symmetry. The nature of the cellular processes involved, however, has been less clear. While much attention has focused on intercellular soluble signals, such as protein growth factors, experimental evidence has grown for contributions of cell movement or mechanical forces to symmetry breaking. In the mesenchyme, unlike the epithelium, cells may move freely and can self-organize into aggregates by chemotaxis, or through generation and response to mechanical strain on their surrounding matrix. Different modes of self-organization may coexist, either coordinated into a single system or with hierarchical relationships. Consideration of a broad range of distinct biological processes is required to advance understanding of biological pattern formation. This article is part of the theme issue 'Recent progress and open frontiers in Turing's theory of morphogenesis'.

A Single-Cell Culture System for Dissecting Microenvironmental Signaling in Development and Disease of Cartilage Tissue

Cartilage tissue is comprised of extracellular matrix and chondrocytes, a cell type with very low cellular turnover in adults, providing limited capacity for regeneration. However, in development a significant number of chondrocytes actively proliferate and remodel the surrounding matrix. Uncoupling the microenvironmental influences that determine the balance between clonogenic potential and terminal differentiation of these cells is essential for the development of novel approaches for cartilage regeneration. Unfortunately, most of the existing methods are not applicable for the analysis of functional properties of chondrocytes at a single cell resolution. Here we demonstrate that a novel 3D culture method provides a long-term and permissive in vitro niche that selects for highly clonogenic, colony-forming chondrocytes which maintain cartilage-specific matrix production, thus recapitulating the in vivo niche. As a proof of concept, clonogenicity of Sox9IRES–EGFP mouse chondrocytes is almost exclusively found in the highest GFP+ fraction known to be enriched for chondrocyte progenitor cells. Although clonogenic chondrocytes are very rare in adult cartilage, we have optimized this system to support large, single cell-derived chondrogenic organoids with complex zonal architecture and robust chondrogenic phenotype from adult pig and human articular chondrocytes. Moreover, we have demonstrated that growth trajectory and matrix biosynthesis in these organoids respond to a pro-inflammatory environment. This culture method offers a robust, defined and controllable system that can be further used to interrogate the effects of various microenvironmental signals on chondrocytes, providing a high throughput platform to assess genetic and environmental factors in development and disease.

Adaptive Multi-Scale Feature Fusion based U-net for fracture segmentation in coal rock images

Accurate segmentation of fractures in coal rock CT images is important for the development of coalbed methane. However, due to the large variation of fracture scale and the similarity of gray values between weak fractures and the surrounding matrix, it remains a challenging task. And there is no published dataset of coal rock, which make the task even harder. In this paper, a novel adaptive multi-scale feature fusion method based on U-net (AMSFF-U-net) is proposed for fracture segmentation in coal rock CT images. Specifically, encoder and decoder path consist of residual blocks (ReBlock), respectively. The attention skip concatenation (ASC) module is proposed to capture more representative and distinguishing features by combining the high-level and low-level features of adjacent layers. The adaptive multi-scale feature fusion (AMSFF) module is presented to adaptively fuse different scale feature maps of encoder path; it can effectively capture rich multi-scale features. In response to the lack of coal rock fractures training data, we applied a set of comprehensive data augmentation operations to increase the diversity of training samples. These extensive experiments are conducted via seven state-of-the-art methods (i.e., FCEM, U-net, Res-Unet, Unet++, MSN-Net, WRAU-Net and ours). The experiment results demonstrate that the proposed AMSFF-U-net can achieve better segmentation performance in our works, particularly for weak fractures and tiny scale fractures.

High-resolution high-throughput thermal neutron tomographic imaging of fossiliferous cave breccias from Sumatra

We employ high-throughput thermal-neutron tomographic imaging to visualise internal diagnostic features of dense fossiliferous breccia from three Pleistocene cave localities in Sumatra, Indonesia. We demonstrate that these seemingly homogeneous breccias are an excellent source of data to aid in determining taphonomic and depositional histories of complex depositional sites such as tropical caves. X-ray Computed Tomographic (CT) imaging is gaining importance amongst palaeontologists as a non-destructive approach to studying fossil remains. Traditional methods of fossil preparation risk damage to the specimen and may destroy contextual evidence in the surrounding matrix. CT imaging can reveal the internal composition and structure of fossils contained within consolidated sediment/rock matrices prior to any destructive mechanical or chemical preparation. Neutron computed tomography (NCT) provides an alternative contrast to X-rays, and in some circumstances, is capable of discerning denser matrices impenetrable to or yielding no contrast with CT imaging. High-throughput neutron imaging reduces neutron fluence during scanning which means there is less residual neutron-induced radioactivation in geological samples; allowing for earlier subsequent analyses. However, this approach remains unutilised in palaeontology, archaeology or geological surveys. Results suggest that the primary agents in the formation of the breccias and concentration of incorporated vertebrate remains are several rapid depositional phases of water and sediment gravity flow. This study highlights the potential for future analyses of breccia deposits in palaeontological studies in caves around the world.

Optogenetic stimulation of striatal patches modifies habit formation and inhibits dopamine release

Habits are inflexible behaviors that develop after extensive repetition, and overreliance on habits is a hallmark of many pathological states. The striatum is involved in the transition from flexible to inflexible responding, and interspersed throughout the striatum are patches, or striosomes, which make up ~15% of the volume of the striatum relative to the surrounding matrix compartment. Previous studies have suggested that patches are necessary for normal habit formation, but it remains unknown exactly how patches contribute to habit formation and expression. Here, using optogenetics, we stimulated striatal patches in Sepw1-NP67 mice during variable interval training (VI60), which is used to establish habitual responding. We found that activation of patches at reward retrieval resulted in elevated responding during VI60 training by modifying the pattern of head entry and pressing. Further, this optogenetic manipulation reduced subsequent responding following reinforcer devaluation, suggesting modified habit formation. However, patch stimulation did not generally increase extinction rates during a subsequent extinction probe, but did result in a small ‘extinction burst’, further suggesting goal-directed behavior. On the other hand, this manipulation had no effect in omission trials, where mice had to withhold responses to obtain rewards. Finally, we utilized fast-scan cyclic voltammetry to investigate how patch activation modifies evoked striatal dopamine release and found that optogenetic activation of patch projections to the substantia nigra pars compacta (SNc) is sufficient to suppress dopamine release in the dorsal striatum. Overall, this work provides novel insight into the role of the patch compartment in habit formation, and provides a potential mechanism for how patches modify habitual behavior by exerting control over dopamine signaling.