microRNAs in the Lymphatic Endothelium : Master Regulators of Lineage Plasticity and Inflammation

microRNAs (miRNAs) are highly conserved, small non-coding RNAs that regulate gene expression at the posttranscriptional level. They have crucial roles in organismal development, homeostasis, and cellular responses to pathological stress. The lymphatic system is a large vascular network that actively regulates the immune response through antigen trafficking, cytokine secretion, and inducing peripheral tolerance. Here, we review the role of miRNAs in the lymphatic endothelium with a particular focus on their role in lymphatic endothelial cell (LEC) plasticity, inflammation, and regulatory function. We highlight the lineage plasticity of LECs during inflammation and the importance of understanding the regulatory role of miRNAs in these processes. We propose that targeting miRNA expression in lymphatic endothelium can be a novel strategy in treating human pathologies associated with lymphatic dysfunction

High-speed single-molecule tracking of CXCL13 in the B-Follicle

Soluble factors are an essential means of communication between cells and their environment. However, many molecules readily interact with extracellular matrix components, giving rise to multiple modes of diffusion. The molecular quantification of diffusion in situ is thus a challenging imaging frontier, requiring very high spatial and temporal resolution. Overcoming this methodological barrier is key to understanding the precise spatial patterning of the extracellular factors that regulate immune function. To address this, we have developed a high-speed light microscopy system capable of millisecond sampling in ex vivo tissue samples and sub-millisecond sampling in controlled in vitro samples to characterize molecular diffusion in a range of complex microenvironments. We demonstrate that this method outperforms competing tools for determining molecular mobility of fluorescence correlation spectroscopy (FCS) and fluorescence recovery after photobleaching (FRAP) for evaluation of diffusion. We then apply this approach to study the chemokine CXCL13, a key determinant of lymphoid tissue architecture, and B-cell mediated immunity. Super-resolution single-molecule tracking of fluorescently labeled CCL19 and CXCL13 in collagen matrix was used to assess the heterogeneity of chemokine mobility behaviors, with results indicating an immobile fraction and a mobile fraction for both molecules, with distinct diffusion rates of 8.4 ± 0.2 µm2s-1 and 6.2 ± 0.3 µm2s-1 respectively. To better understand mobility behaviors in situ we analyzed CXCL13-AF647 diffusion in murine lymph node tissue sections and observed both an immobile fraction and a mobile fraction with a diffusion coefficient of 6.6 ± 0.4 µm2s 1, suggesting that mobility within the follicle is also multimodal. In quantitatively studying mobility behaviors at the molecular level, we have obtained an increased understanding of CXCL13 bioavailability within the follicle. Our high-speed single-molecule tracking approach affords a novel perspective from which to understand the mobility of soluble factors relevant to the immune system

Trematode infections in cattle in Arumeru District, Tanzania are associated with irrigation

Background The relationship between the environment and infection of cattle with trematodes was studied at Arumeru District, Arusha Region, northern Tanzania. Randomly selected villages were grouped into three cattle management strata, (i) zero-grazing (ZZ) (ii) communal grazing without irrigation (ZC) and (iii) communal grazing with irrigation (ZCI). Methods Faecal samples were collected from 241 cattle, and processed using the Flukefinder® method. Snail intermediate hosts were collected with a snail scoop from the water bodies in the study villages and identified morphologically. Results The overall prevalence of F. gigantica, paramphistomes and S. bovis were 33%, 37% and 2% respectively. Prevalence for F. gigantica, paramphistomes, and S. bovis for each stratum were, zero-grazing (ZZ) (29.7%, 36.0% and 0%), communal grazing without irrigation (ZC) (6.3%, 15.0% and 3.8%) and communal grazing with irrigation (ZCI) (57.7%, 56.7% and 1.0%) respectively. The differences between strata were significant for F. gigantica (p < 0.001) and paramphistomes (p < 0.05) but not for S. bovis. Irrigation could account for the high prevalence of F. gigantica and paramphistomes in the ZCI stratum as compared to the ZZ and ZC strata. The higher prevalences of F. gigantica and paramphistomes in the ZZ stratum compared with the ZC stratum were unexpected and attributed to the practice of farmers in some ZZ stratum villages buying fodder for their cattle obtained from pastures in ZCI villages. Conclusion Trematode infections in cattle are prevalent in Arumeru District. Fasciola gigantica and paramphistomes are associated with grazing in areas with irrigation of crops. Zero-grazing of cattle does not necessarily prevent the risk of infection

MicroRNA-155 induction via TNF-α and IFN-γ suppresses expression of programmed death ligand-1 (PD-L1) in human primary cells

Programmed death ligand-1 (PD-L1) is a critical regulator of T cell function contributing to peripheral immune tolerance. Although it has been shown that posttranscriptional regulatory mechanisms control PD-L1 expression in cancer, it remains unknown whether such regulatory loops operate also in non-transformed cells. Here we studied PD-L1 expression in human dermal lymphatic endothelial cells (HDLECs), which play key roles in immunity and cancer. Treatment of HDLECs with the pro-inflammatory cytokines IFN-γ and TNF-α synergistically upregulated PDL1 expression. IFN-γ and TNF-α also affected expression of several microRNAs (miRNAs) that have the potential to suppress PD-L1 expression. The most highly upregulated miRNA following IFN-γ and TNF-α treatment in HDLECs was miR- 155, which has a central role in the immune system and cancer. Induction of miR-155 was driven by TNF-α, the effect of which was significantly enhanced by IFN-γ. The PD-L1 3'- UTR contains two functional miR-155 binding sites. Endogenous miR-155 controlled the kinetics and maximal levels of PD-L1 induction upon IFN-γ and TNF-α treatment. We obtained similar findings in dermal fibroblasts, demonstrating that the IFN-γ/TNF-α/miR-155/PD-L1 pathway is not restricted to HDLECs. These results reveal miR- 155 as a critical component of an inflammationinduced regulatory loop controlling PD-L1 expression in primary cells

Inducible ablation of CD11c+ cells to determine their role in skin wound repair

Wound healing in healthy skin requires a complex interplay between immune and non‐immune cells. In addition to their roles in infection control and cell debridement, leukocytes secrete factors to orchestrate the timing of the repair process via cross‐talk with epithelia. This critical role in wound timing is vital as failure to induce wound closure leads to debilitating chronic wounds susceptible to further infection and patient sepsis

On the inadequacy of N-point correlation functions to describe nonlinear cosmological fields: explicit examples and connection to simulations

Motivated by recent results on lognormal statistics showing that the moment hierarchy of a lognormal variable completely fails at capturing its information content in the large variance regime, we discuss in this work the inadequacy of the hierarchy of correlation functions to describe a correlated lognormal field, which provides a roughly accurate description of the non-linear cosmological matter density field. We present families of fields having the same hierarchy of correlation functions than the lognormal field at all orders. This explicitly demonstrates the little studied though known fact that the correlation function hierarchy never provides a complete description of a lognormal field, and that it fails to capture information in the non-linear regime, where other simple observables are left totally unconstrained. We discuss why perturbative, Edgeworth-like approaches to statistics in the non-linear regime, common in cosmology, can never reproduce or predict that effect, and why it is however generic for tailed fields, hinting at a breakdown of the perturbation theory based on the field fluctuations. We make a rough but successful quantitative connection to N-body simulations results, that showed that the spectrum of the log-density field carries more information than the spectrum of the field entering the non-linear regime.Comment: 10 pages, 3 figures, matches version accepted for publication by ApJ. Some editing in the conclusion and minor changes w.r.t. v

Rejuvenating Power Spectra II: the Gaussianized galaxy density field

We find that, even in the presence of discreteness noise, a Gaussianizing transform (producing a more-Gaussian one-point distribution) reduces nonlinearities in the power spectra of cosmological matter and galaxy density fields, in many cases drastically. Although Gaussianization does increase the effective shot noise, it also increases the power spectrum's fidelity to the linear power spectrum on scales where the shot noise is negligible. Gaussianizing also increases the Fisher information in the power spectrum in all cases and resolutions, although the gains are smaller in redshift space than in real space. We also find that the gain in cumulative Fisher information from Gaussianizing peaks at a particular grid resolution that depends on the sampling level.Comment: Slight changes to match version accepted to ApJ. 7 pages, 8 figure

Quantifying distortions of the Lagrangian dark-matter mesh in cosmology

We examine the Lagrangian divergence of the displacement field, arguably a more natural object than the density in a Lagrangian description of cosmological large-scale structure. This quantity, which we denote \psi, quantifies the stretching and distortion of the initially homogeneous lattice of dark-matter particles in the universe. \psi\ encodes similar information as the density, but the correspondence has subtleties. It corresponds better to the log-density A than the overdensity \delta. A Gaussian distribution in \psi\ produces a distribution in A with slight skewness; in \delta, we find that in many cases the skewness is further increased by 3. A local spherical-collapse-based (SC) fit found by Bernardeau gives a formula for \psi's particle-by-particle behavior that works quite well, better than applying Lagrangian perturbation theory (LPT) at first or second (2LPT) order. In 2LPT, there is a roughly parabolic relation between initial and final \psi\ that can give overdensities in deep voids, so low-redshift, high-resolution 2LPT realizations should be used with caution. The SC fit excels at predicting \psi\ until streams cross; then, for particles forming haloes, \psi\ plummets as in a waterfall to -3. This gives a new method for producing N-particle realizations. Compared to LPT realizations, such SC realizations give reduced stream-crossing, and better visual and 1-point-PDF correspondence to the results of full gravity. LPT, on the other hand, predicts large-scale flows and the large-scale power-spectrum amplitude better, unless an empirical correction is added to the SC formula.Comment: Changes in presentation to match MNRAS-accepted version, 14 pages, 15 figure

A galaxy-halo model of large-scale structure

We present a new, galaxy-halo model of large-scale structure, in which the galaxies entering a given sample are the fundamental objects. Haloes attach to galaxies, in contrast to the standard halo model, in which galaxies attach to haloes. The galaxy-halo model pertains mainly to the relationships between the power spectra of galaxies and mass, and their cross-power spectrum. With surprisingly little input, an intuition-aiding approximation to the galaxy-matter cross-correlation coefficient R(k) emerges, in terms of the halo mass dispersion. This approximation seems valid to mildly non-linear scales (k < ~3 h/Mpc), allowing measurement of the bias and the matter power spectrum from measurements of the galaxy and galaxy-matter power spectra (or correlation functions). This is especially relevant given the recent advances in precision in measurements of the galaxy-matter correlation function from weak gravitational lensing. The galaxy-halo model also addresses the issue of interpreting the galaxy-matter correlation function as an average halo density profile, and provides a simple description of galaxy bias as a function of scale.Comment: 13 pages, 9 figures, submitted to MNRAS. Minor changes, suggested by refere