Podoplanin: Emerging Functions in Development, the Immune System, and Cancer

Podoplanin (PDPN) is a well-conserved, mucin-type transmembrane protein expressed in multiple tissues during ontogeny and in adult animals, including the brain, heart, kidney, lungs, osteoblasts, and lymphoid organs. Studies of PDPN-deficient mice have demonstrated that this molecule plays a critical role in development of the heart, lungs, and lymphatic system. PDPN is widely used as a marker for lymphatic endothelial cells and fibroblastic reticular cells of lymphoid organs and for lymphatics in the skin and tumor microenvironment. Much of the mechanistic insight into PDPN biology has been gleaned from studies of tumor cells; tumor cells often upregulate PDPN as they undergo epithelial-mesenchymal transition and this upregulation is correlated with increased motility and metastasis. The physiological role of PDPN that has been most studied is its ability to aggregate and activate CLEC-2-expressing platelets, as PDPN is the only known endogenous ligand for CLEC-2. However, more recent studies have revealed that PDPN also plays crucial roles in the biology of immune cells, including T cells and dendritic cells. This review will provide a comprehensive overview of the diverse roles of PDPN in development, immunology, and cancer

Continuum approach to wide shear zones in quasi-static granular matter

Slow and dense granular flows often exhibit narrow shear bands, making them ill-suited for a continuum description. However, smooth granular flows have been shown to occur in specific geometries such as linear shear in the absence of gravity, slow inclined plane flows and, recently, flows in split-bottom Couette geometries. The wide shear regions in these systems should be amenable to a continuum description, and the theoretical challenge lies in finding constitutive relations between the internal stresses and the flow field. We propose a set of testable constitutive assumptions, including rate-independence, and investigate the additional restrictions on the constitutive relations imposed by the flow geometries. The wide shear layers in the highly symmetric linear shear and inclined plane flows are consistent with the simple constitutive assumption that, in analogy with solid friction, the effective-friction coefficient (ratio between shear and normal stresses) is a constant. However, this standard picture of granular flows is shown to be inconsistent with flows in the less symmetric split-bottom geometry - here the effective friction coefficient must vary throughout the shear zone, or else the shear zone localizes. We suggest that a subtle dependence of the effective-friction coefficient on the orientation of the sliding layers with respect to the bulk force is crucial for the understanding of slow granular flows.Comment: 11 pages, 7 figure

Unbiased metabolomic investigation of Alzheimer's disease brain points to dysregulation of mitochondrial aspartate metabolism

Alzheimer's disease (AD) is the most common cause of adult dementia. Yet the complete set of molecular changes accompanying this inexorable, neurodegenerative disease remains elusive. Here we adopted an unbiased lipidomics and metabolomics approach to surveying frozen frontal cortex samples from clinically characterized AD patients (n = 21) and age-matched controls (n = 19), revealing marked molecular differences between them. Then, by means of metabolomic pathway analysis, we incorporated the novel molecular information into the known biochemical pathways and compared it with the results of a metabolomics meta-analysis of previously published AD research. We found six metabolic pathways of the central metabolism as well as glycerophospholipid metabolism predominantly altered in AD brains. Using targeted metabolomics approaches and MS imaging, we confirmed a marked dysregulation of mitochondrial aspartate metabolism. The altered metabolic pathways were further integrated with clinical data, showing various degrees of correlation with parameters of dementia and AD pathology. Our study highlights specific, altered biochemical pathways in the brains of individuals with AD compared with those of control subjects, emphasizing dysregulation of mitochondrial aspartate metabolism and supporting future venues of investigation

New Lipidomic Approaches in Cystic Fibrosis

Lipid analysis has been a crucial source of information in cystic fibrosis (CF). New methodologies for qualitative and quantitative lipidomics allow evaluation of a large number of samples, of special interest in patient screening for diagnostic and prognostic biological markers, as well as in cell physiology. In this chapter, two new complementary approaches are described: matrix-assisted laser desorption coupled to time of flight (MALDI-TOF-ClinProTools™) and liquid chromatography coupled to ion trap mass spectrometry (LC-MS( n )). MALDI-TOF-ClinProTools™ offers a large unbiased screening for the discovery of potential lipid alterations in diseased patients. LC-MS( n ) represents a state-of-the-art lipidomic tool for the identification and quantification of such alterations. The combination of both may open new perspectives in the quest for lipids participating in CF pathogenesis, therapy targets, and biomarkers

Elevated Stearoyl-CoA Desaturase in Brains of Patients with Alzheimer's Disease

The molecular bases of Alzheimer's disease (AD) remain unclear. We used a lipidomic approach to identify lipid abnormalities in the brains of subjects with AD (N = 37) compared to age-matched controls (N = 17). The analyses revealed statistically detectable elevations in levels of non-esterified monounsaturated fatty acids (MUFAs) and mead acid (20:3n-9) in mid-frontal cortex, temporal cortex and hippocampus of AD patients. Further studies showed that brain mRNAs encoding for isoforms of the rate-limiting enzyme in MUFAs biosynthesis, stearoyl-CoA desaturase (SCD-1, SCD-5a and SCD-5b), were elevated in subjects with AD. The monounsaturated/saturated fatty acid ratio (‘desaturation index’) – displayed a strong negative correlation with measures of cognition: the Mini Mental State Examination test (r = −0.80; P = 0.0001) and the Boston Naming test (r = −0.57; P = 0.0071). Our results reveal a previously unrecognized role for the lipogenic enzyme SCD in AD

Corrosion behavior of friction stir welded lap joints of AA6061-T6 aluminum alloy

In this work, the corrosion behaviors of friction-stir lap welding of 6061-T6 Al-alloy are studied. The friction-stir lap welding was performed under different welding conditions (rotation speed and welding speed). The corrosion behavior of the parent alloy, the weld nugget zone (WNZ), and the heat affected zone (HAZ) of each welded sample working as an electrode, were investigated by the Tafel polarization test in 3.5 wt. (%) NaCl at ambient temperature. The morphology of the corroded surface of each region was analyzed by scanning electron microscopy together with energy dispersive spectroscopy (SEM-EDS). The results showed that the corrosion resistance of the parent alloy was better than the WNZ and the HAZ in both welding conditions. Localized pit dissolution and intergranular corrosion were the dominant corrosion types observed in the parent alloy, WNZ, and HAZ. The parent alloy, WNZ, and HAZ exhibited similar corrosion potentials (Ecorr) after T6 heat treatment. This treatment had a better effect on the corrosion resistance of the welded regions than the parent alloy

Adenomatous Polyposis Coli loss controls cell cycle regulators and response to paclitaxel in MDA-MB-157 metaplastic breast cancer cells

Adenomatous Polyposis Coli (APC) is lost in approximately 70% of sporadic breast cancers, with an inclination towards triple negative breast cancer (TNBC). TNBC is treated with traditional chemotherapy, such as paclitaxel (PTX); however, tumors often develop drug resistance. We previously created APC knockdown cells (APC shRNA1) using the human TNBC cells, MDA-MB-157, and showed that APC loss induces PTX resistance. To understand the mechanisms behind APC-mediated PTX response, we performed cell cycle analysis and analyzed cell cycle related proteins. Cell cycle analysis indicated increased G2/M population in both PTX-treated APC shRNA1 and parental cells, suggesting that APC expression does not alter PTX-induced G2/M arrest. We further studied the subcellular localization of the G2/M transition proteins, cyclin B1 and CDK1. The APC shRNA1 cells had increased CDK1, which was preferentially localized to the cytoplasm, and increased baseline CDK6. RNA-sequencing was performed to gain a global understanding of changes downstream of APC loss and identified a broad mis-regulation of cell cycle-related genes in APC shRNA1 cells. Our studies are the first to show an interaction between APC and taxane response in breast cancer. The implications include designing combination therapy to re-sensitize APC-mutant breast cancers to taxanes using the specific cell cycle alterations

Multiscale simulation of polymer melt viscoelasticity: Expanded-ensemble Monte Carlo coupled with atomistic nonequilibrium molecular dynamics

We present a powerful framework for computing the viscoelastic properties of polymer melts based on an efficient coupling of two different atomistic models: the first is represented by the nonequilibrium molecular dynamics method and is considered as the microscale model. The second is represented by a Monte Carlo (MC) method in an expanded statistical ensemble and is free from any long time scale constraints. Guided by recent developments in nonequilibrium thermodynamics, the expanded ensemble incorporates appropriately defined "field" variables driving the corresponding structural variables to beyond equilibrium steady states. The expanded MC is considered as the macroscale solver for the family of all viscoelastic models built on the given structural variable(s). The explicit form of the macroscopic model is not needed; only its structure in the context of the general equation for the nonequilibrium reversible irreversible coupling or generalized bracket formalisms of nonequilibrium thermodynamics is required. We illustrate the method here for the case of unentangled linear polymer melts, for which the appropriate structural variable to consider is the conformation tensor c???. The corresponding Lagrange multiplier is a tensorial field ??. We have been able to compute model-independent values of the tensor ??, which for a wide range of strain rates (covering both the linear and the nonlinear viscoelastic regimes) bring results for the overall polymer conformation from the two models (microscale and macroscale) on top of each other. In a second step, by comparing the computed values of ?? with those suggested by the macroscopic model addressed by the chosen structural variable(s), we can identify shortcomings in the building blocks of the model. How to modify the macroscopic model in order to be consistent with the results of the coupled micro-macro simulations is also discussed. From a theoretical point of view, the present multiscale modeling approach provides a solid framework for the design of improved, more accurate macroscopic models for polymer melts.open151