The role of T-cell protein tyrosine phosphatase in epithelial carcinogenesis

T-cell protein tyrosine phosphatase (TC-PTP, encoded by PTPN2) is a non-receptor PTP that is mostly highly expressed in hematopoietic tissues. TC-PTP modulates a variety of physiological functions including cell cycle progression, cell survival and proliferation, and hematopoiesis through tyrosine dephosphorylation of its target substrates, such as EGFR, JAK1, JAK3, STAT1, and STAT3. Studies with whole or tissue-specific loss of TC-PTP function transgenic mice have shown that TC-PTP has crucial roles in the regulation of the immune response, insulin signaling, and oncogenic signaling. More recently, generation of epidermal-specific TC-PTP-deficient mice for use in multistage skin carcinogenesis bioassays demonstrated that TC-PTP suppresses skin tumor formation by negatively regulating STAT3 and AKT signaling. Further investigation showed that TC-PTP also minimizes UVB-induced epidermal cell damage by promoting apoptosis through the negative regulation of Flk-1/JNK signaling. These findings provide major evidence for a tumor suppressive function for TC-PTP against environment-induced skin cancer. Here, we will discuss TC-PTP, its substrates, and its functions with an emphasis on its role in skin carcinogenesis

PCV2-DNA in formalin-fixed and paraffin embedded lymph nodes of wild boar (Sus scrofa ssp. scrofa): one sampling approach for two laboratory techniques

Superficial inguinal lymph nodes from 72 wild boars examined in a previous immunohistochemical (IHC) study on porcine circovirus type 2 (PCV2) were selected for a PCV2 polymerase chain reaction (PCR) analysis. Four of these lymph nodes were PCV2-IHC strongly positive with PMWS histological lesions (outcome 1), 6 weak to mild PCV2-IHC positive without PMWS histological lesions (outcome 2) and 62 PCV2-IHC negative. Considering IHC the gold standard for diagnosis, the aims of the study were to evaluate the suitability of the PCV2-DNA extraction from formalin-fixed and paraffin-embedded (FFPE) tissue and the sensitivity and specificity of PCR under two IHC interpretations criteria: (A) the sample was considered positive if the result was outcome 1; (B) the sample was considered positive if the result was outcome 1 or 2. Under (A) criteria, sensitivity and specificity of PCR were 100% and 89.7%, respectively; the Cohen's Kappa coefficient was 0.49. Under (B) criteria, sensitivity and specificity of PCR were 80.0% and 95.2%, respectively; the Cohen's Kappa coefficient was 0.72. The high Cohen's Kappa coefficient under the (B) interpretative criteria indicates good agreement between the two methods. In conclusion, 1) DNA extracted from FFPE specimens of wild boar is suitable for PCR and further represents a screening test for PCV2/PCVD (PCV2 Diseases) investigations in wild boar as well; 2) routine histological sampling can also be useful for PCV2 virological studies in wild boar

Overexpression of TC-PTP in murine epidermis attenuates skin tumor formation

T-cell protein tyrosine phosphatase (TC-PTP), encoded by Ptpn2, has been shown to function as a tumor suppressor during skin carcinogenesis. In the current study, we generated a novel epidermal-specific TC-PTP-overexpressing (K5HA.Ptpn2) mouse model to show that TC-PTP contributes to the attenuation of chemically induced skin carcinogenesis through the synergistic regulation of STAT1, STAT3, STAT5, and PI3K/AKT signaling. We found overexpression of TC-PTP increased epidermal sensitivity to DMBA-induced apoptosis and it decreased TPA-mediated hyperproliferation, coinciding with reduced epidermal thickness. Inhibition of STAT1, STAT3, STAT5, or AKT reversed the effects of TC-PTP overexpression on epidermal survival and proliferation. Mice overexpressing TC-PTP in the epidermis developed significantly reduced numbers of tumors during skin carcinogenesis and presented a prolonged latency of tumor initiation. Examination of human papillomas and squamous cell carcinomas (SCCs) revealed that TC-PTP expression was significantly reduced and TC-PTP expression was inversely correlated with the increased grade of SCCs. Our findings demonstrate that TC-PTP is a potential therapeutic target for the prevention of human skin cancer given that it is a major negative regulator of oncogenic signaling

The First Extensive Spectroscopic Study of Young Stars in the North America and Pelican Nebulae

We present a spectroscopic survey of over 3400 potential members in the North America and Pelican Nebulae (NAP) using several low-resolution (R ≈ 1300–2000) spectrographs: Palomar/Norris, WIYN/Hydra, Keck/DEep Imaging Multi-Object Spectrograph (DEIMOS), and the Multiple Mirror Telescope (MMT)/Hectospec. We identify 580 young stars as likely members of the NAP region based on criteria involving infrared excess, Li I 6708 Å absorption, X-ray emission, parallax, and proper motions. The spectral types of individual spectra are derived by fitting them with templates that are either empirical spectra of pre-main-sequence stars or model atmospheres. The templates are artificially veiled, and a best-fit combination of spectral type and veiling parameter is derived for each star. We use the spectral types with archival photometry to derive V-band extinction and stellar luminosity. From the Hertzsprung–Russell diagram, the median age of the young stars is about 1 Myr, with a luminosity dispersion of ~0.3–0.4 dex. We investigate the photometric variability of the spectroscopic member sample using Zwicky Transient Facility data and conclude that photometric variability, while present, does not significantly contribute to the luminosity dispersion. While larger than the formal errors, the luminosity dispersion is smaller than if veiling were not taken into account in our spectral typing process. The measured ages of the stellar kinematic groups, combined with the inferred ages for embedded stellar populations revealed by Spitzer, suggest a sequential history of star formation in the NAP region

Near-Infrared Variability of Low Mass Stars in IC 1396A and Tr 37

We have monitored nearly a square degree in IC 1396A/Tr 37 over 21 epochs extending over 2014 - 2016 for sources variable in the JHK bands. In our data, 65 +\- 8 % of previously identified cluster members show variations, compared with < 0.3% of field stars. We identify 119 members of Tr 37 on the basis of variability, forming an unbiased sample down to the brown dwarf regime. The K-band luminosity function in Tr 37 is similar to that of IC 348 but shifted to somewhat brighter values, implying that the K- and M-type members of Tr 37 are younger than those in IC 348. We introduce methods to classify the causes of variability, based on behavior in the color-color and color-magnitude diagrams. Accretion hot spots cause larger variations at J than at K with substantial scatter in the diagrams; there are at least a dozen, with the most active resembling EXors. Eleven sources are probably dominated by intervention of dust clumps in their circumstellar disks with color behavior indicating the presence of grains larger than for interstellar dust, presumably due to grain growth in their disks. Thirteen sources have larger variations at K than at J or H. For 11 of them, the temperature fitted to the variable component is very close to 2000K, suggesting that the changes in output are caused by turbulence at the inner rim of the circumstellar disk exposing previously protected populations of grains.Comment: accepted by Ap

Isolating Dust and Free-Free Emission in ONC Proplyds with ALMA Band 3 Observations

The Orion Nebula Cluster (ONC) hosts protoplanetary disks experiencing external photoevaporation by the cluster's intense UV field. These ``proplyds" are comprised of a disk surrounded by an ionization front. We present ALMA Band 3 (3.1 mm) continuum observations of 12 proplyds. Thermal emission from the dust disks and free-free emission from the ionization fronts are both detected, and the high-resolution (0.057") of the observations allows us to spatially isolate these two components. The morphology is unique compared to images at shorter (sub)millimeter wavelengths, which only detect the disks, and images at longer centimeter wavelengths, which only detect the ionization fronts. The disks are small ($r_d$ = 6.4--38 au), likely due to truncation by ongoing photoevaporation. They have low spectral indices ($\alpha \lesssim 2.1$) measured between Bands 7 and 3, suggesting the dust emission is optically thick. They harbor tens of Earth masses of dust as computed from the millimeter flux using the standard method, although their true masses may be larger due to the high optical depth. We derive their photoevaporative mass-loss rates in two ways: first, by invoking ionization equilibrium, and second using the brightness of the free-free emission to compute the density of the outflow. We find decent agreement between these measurements and $\dot M$ = 0.6--18.4 $\times$ 10$^{-7}$ $M_\odot$ yr$^{-1}$. The photoevaporation timescales are generally shorter than the $\sim$1 Myr age of the ONC, underscoring the known ``proplyd lifetime problem." Disk masses that are underestimated due to being optically thick remains one explanation to ease this discrepancy.Comment: 17 pages, 12 figures, accepted for publication in Ap

Collagen Film Activation with Nanoscale IKVAV-Capped Dendrimers for Selective Neural Cell Response

Biocompatible neural guidance conduits are alternatives to less abundant autologous tissue grafts for small nerve gap injuries. To address larger peripheral nerve injuries, it is necessary to design cell selective biomaterials that attract neuronal and/or glial cells to an injury site while preventing the intrusion of fibroblasts that cause inhibitory scarring. Here, we investigate a potential method for obtaining this selective cellular response by analysing the responses of rat Schwann cells and human dermal fibroblasts to isoleucine-lysine-valine-alanine-valine (IKVAV)-capped dendrimer-activated collagen films. A high quantity of nanoscale IKVAV-capped dendrimers incorporated onto pre-crosslinked collagen films promoted rat Schwann cell attachment and proliferation, and inhibited human dermal fibroblast proliferation. In addition, while pre-crosslinked dendrimer-activated films inhibited fibroblast proliferation, non-crosslinked dendrimer-activated films and films that were crosslinked after dendrimer-activation (post-crosslinked films) did not. The different cellular responses to pre-crosslinked and post-crosslinked films highlight the importance of having fully exposed, non-covalently bound biochemical motifs (pre-crosslinked films) directing certain cellular responses. These results also suggest that high concentrations of nanoscale IKVAV motifs can inhibit fibroblast attachment to biological substrates, such as collagen, which inherently attract fibroblasts. Therefore, this work points toward the potential of IKVAV-capped dendrimer-activated collagen biomaterials in limiting neuropathy caused by fibrotic scarring at peripheral nerve injury sites

The APOGEE-2 Survey of the Orion Star Forming Complex: I. Target Selection and Validation with early observations

The Orion Star Forming Complex (OSFC) is a central target for the APOGEE-2 Young Cluster Survey. Existing membership catalogs span limited portions of the OSFC, reflecting the difficulty of selecting targets homogeneously across this extended, highly structured region. We have used data from wide field photometric surveys to produce a less biased parent sample of young stellar objects (YSOs) with infrared (IR) excesses indicative of warm circumstellar material or photometric variability at optical wavelengths across the full 420 square degrees extent of the OSFC. When restricted to YSO candidates with H < 12.4, to ensure S/N ~100 for a six visit source, this uniformly selected sample includes 1307 IR excess sources selected using criteria vetted by Koenig & Liesawitz and 990 optical variables identified in the Pan-STARRS1 3$\pi$ survey: 319 sources exhibit both optical variability and evidence of circumstellar disks through IR excess. Objects from this uniformly selected sample received the highest priority for targeting, but required fewer than half of the fibers on each APOGEE-2 plate. We fill the remaining fibers with previously confirmed and new color-magnitude selected candidate OSFC members. Radial velocity measurements from APOGEE-1 and new APOGEE-2 observations taken in the survey's first year indicate that ~90% of the uniformly selected targets have radial velocities consistent with Orion membership.The APOGEE-2 Orion survey will include >1100 bona fide YSOs whose uniform selection function will provide a robust sample for comparative analyses of the stellar populations and properties across all sub-regions of Orion.Comment: Accepted for publication in ApJ

Predictive modeling of die filling of the pharmaceutical granules using the flexible neural tree

In this work, a computational intelligence (CI) technique named flexible neural tree (FNT) was developed to predict die filling performance of pharmaceutical granules and to identify significant die filling process variables. FNT resembles feedforward neural network, which creates a tree-like structure by using genetic programming. To improve accuracy, FNT parameters were optimized by using differential evolution algorithm. The performance of the FNT-based CI model was evaluated and compared with other CI techniques: multilayer perceptron, Gaussian process regression, and reduced error pruning tree. The accuracy of the CI model was evaluated experimentally using die filling as a case study. The die filling experiments were performed using a model shoe system and three different grades of microcrystalline cellulose (MCC) powders (MCC PH 101, MCC PH 102, and MCC DG). The feed powders were roll-compacted and milled into granules. The granules were then sieved into samples of various size classes. The mass of granules deposited into the die at different shoe speeds was measured. From these experiments, a dataset consisting true density, mean diameter (d50), granule size, and shoe speed as the inputs and the deposited mass as the output was generated. Cross-validation (CV) methods such as 10FCV and 5x2FCV were applied to develop and to validate the predictive models. It was found that the FNT-based CI model (for both CV methods) performed much better than other CI models. Additionally, it was observed that process variables such as the granule size and the shoe speed had a higher impact on the predictability than that of the powder property such as d50. Furthermore, validation of model prediction with experimental data showed that the die filling behavior of coarse granules could be better predicted than that of fine granules