Active Rho is localized to podosomes induced by oncogenic Src and is required for their assembly and function

Transformation of fibroblasts by oncogenic Src causes disruption of actin stress fibers and formation of invasive adhesions called podosomes. Because the small GTPase Rho stimulates stress fiber formation, Rho inactivation by Src has been thought to be necessary for stress fiber disruption. However, we show here that Rho[GTP] levels do not decrease after transformation by activated Src. Inactivation of Rho in Src-transformed fibroblasts by dominant negative RhoA or the Rho-specific inhibitor C3 exoenzyme disrupted podosome structure as judged by localization of podosome components F-actin, cortactin, and Fish. Inhibition of Rho strongly inhibited Src-induced proteolytic degradation of the extracellular matrix. Furthermore, development of an in situ Rho[GTP] affinity assay allowed us to detect endogenous Rho[GTP] at podosomes, where it colocalized with F-actin, cortactin, and Fish. Therefore, Rho is not globally inactivated in Src-transformed fibroblasts, but is necessary for the assembly and function of structures implicated in tumor cell invasion

Utilization of a multimodal preoperative pain regimen prior to gynecologic oncology exploratory laparotomies

Objective: The aim of this study was to evaluate the use of a combination of non-opioid preoperative pain medications including Tylenol, Lyrica, and Celecoxib (TLC) in patients undergoing gynecologic oncologic exploratory laparotomies. We evaluated postoperative narcotic use in morphine equvalents (ME) as well as pain scores, anti-emetic use, and length of stay.https://jdc.jefferson.edu/patientsafetyposters/1055/thumbnail.jp

Efficacy of Phosphatidylinositol-3 Kinase Inhibitors in a Primary Mouse Model of Undifferentiated Pleomorphic Sarcoma

Recent advances in sarcoma genomics have identified novel mutations in the PI3K pathway in human sarcomas. Here, we use a mouse model of primary soft-tissue sarcoma for preclinical testing of doxorubicin and inhibitors of the PI3K pathway: BKM120 (PI3K inhibitor) and BEZ235 (a dual PI3K/mTOR inhibitor). Doxorubicin-treated tumors (n = 15) showed a partial response rate of 6.6%, just as the majority of human sarcomas do not respond to doxorubicin. Treatment with BKM120 elicited a partial response in 50% of tumors (n = 10), which was also seen in combination with doxorubicin (n = 10). Additionally, BKM120 treatment produced a robust delay in tumor growth kinetics. BEZ235-treated tumors (n = 9) showed a complete response rate of 11.1%. Combining BEZ235 with doxorubicin (n = 10) increased the complete response rate to 50% (P = 0.035). These studies demonstrate that PI3K pathway inhibition is a viable and attractive target for soft-tissue sarcomas

ZFIRE: A KECK/MOSFIRE Spectroscopic Survey of Galaxies in Rich Environments at z~2

We present an overview and the first data release of ZFIRE, a spectroscopic redshift survey of star-forming galaxies that utilizes the MOSFIRE instrument on Keck-I to study galaxy properties in rich environments at $1.5<z<2.5$. ZFIRE measures accurate spectroscopic redshifts and basic galaxy properties derived from multiple emission lines. The galaxies are selected from a stellar mass limited sample based on deep near infra-red imaging ($\mathrm{K_{AB}<25}$) and precise photometric redshifts from the ZFOURGE and UKIDSS surveys as well as grism redshifts from 3DHST. Between 2013--2015 ZFIRE has observed the COSMOS and UDS legacy fields over 13 nights and has obtained 211 galaxy redshifts over $1.57<z<2.66$ from a combination of nebular emission lines (such as \Halpha, \NII, \Hbeta, \OII, \OIII, \SII) observed at 1--2\micron. Based on our medium-band NIR photometry, we are able to spectrophotometrically flux calibrate our spectra to \around10\% accuracy. ZFIRE reaches $5\sigma$ emission line flux limits of \around$\mathrm{3\times10^{-18}~erg/s/cm^2}$ with a resolving power of $R=3500$ and reaches masses down to \around10$^{9}$\msol. We confirm that the primary input survey, ZFOURGE, has produced photometric redshifts for star-forming galaxies (including highly attenuated ones) accurate to $\Delta z/(1+z\mathrm{_{spec})}=0.015$ with $0.7\%$ outliers. We measure a slight redshift bias of $<0.001$, and we note that the redshift bias tends to be larger at higher masses. We also examine the role of redshift on the derivation of rest-frame colours and stellar population parameters from SED fitting techniques. The ZFIRE survey extends spectroscopically-confirmed $z\sim 2$ samples across a richer range of environments, here we make available the first public release of the data for use by the community.\footnote{\url{http://zfire.swinburne.edu.au}}Comment: Published in ApJ. Data available at http://zfire.swinburne.edu.au, Code for figures at https://github.com/themiyan/zfire_survey, 31 pages, 24 figure

Expression of vesicular glutamate transporters in sensory and autonomic neurons innervating the mouse urinary bladder

Purpose: Vesicular glutamate transporters (VGLUTs), essential for loading glutamate into synaptic vesicles, are present in various neuronal systems. However, the expression of VGLUTs in neurons innervating the urinary bladder has not yet been analyzed. Here, we study the presence of VGLUTs type-1, -2 and -3 (VGLUT1, VGLUT2 and VGLUT3, respectively) in mouse urinary bladder neurons. Materials and Methods: Expression of VGLUT1, VGLUT2 and calcitonin gene-related peptide (CGRP) was analyzed by immunohistochemistry in retrogradely labeled primary afferent and autonomic neurons of BALB/C mice after injecting Fast Blue in the urinary bladder wall. To study VGLUT3, retrograde tracing of the urinary bladder was performed in transgenic mice where VGLUT3 is identified by detection of enhanced green fluorescent protein (EGFP). Results: Most urinary bladder DRG neurons expressed VGLUT2. A smaller percentage of neurons also expressed VGLUT1 or VGLUT3. Coexpression with CGRP was only observed for VGLUT2. Occasional VGLUT2-immunoreactive (IR) neurons were seen in the major pelvic ganglion (MPG). Abundant VGLUT2-IR nerves were detected in the urinary bladder dome, trigone and also the urethra; VGLUT1-IR nerves were discretely present. Conclusions: We present novel data on the expression of VGLUTs in sensory and autonomic neurons innervating the mouse urinary bladder. The frequent association of VGLUT2 and CGRP in sensory neurons suggests interactions between glutamatergic and peptidergic neurotransmissions, potentially influencing commonly perceived sensations in the urinary bladder, such as discomfort and pain.Fil: Brumovsky, Pablo Rodolfo. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Investigaciones Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. University of Pittsburgh. Department of Anesthesiology. Pittsburgh Center for Pain Research; Estados UnidosFil: Seal, Rebecca P.. University of Pittsburgh. Department of Anesthesiology. Pittsburgh Center for Pain Research; Estados UnidosFil: Lundgren, Kerstin H.. University of Cincinnati. Department of Neurology; Estados UnidosFil: Seroogy, Kim B.. University of Cincinnati. Department of Neurology; Estados UnidosFil: Watanabe, Masahiko. Hokkaido University School of Medicine. Department of Anatomy; JapónFil: Gebhart, G. F.. University of Pittsburgh. Department of Anesthesiology. Pittsburgh Center for Pain Research; Estados Unido

Enabling precision medicine in neonatology, an integrated repository for preterm birth research.

Preterm birth, or the delivery of an infant prior to 37 weeks of gestation, is a significant cause of infant morbidity and mortality. In the last decade, the advent and continued development of molecular profiling technologies has enabled researchers to generate vast amount of 'omics' data, which together with integrative computational approaches, can help refine the current knowledge about disease mechanisms, diagnostics, and therapeutics. Here we describe the March of Dimes' Database for Preterm Birth Research (http://www.immport.org/resources/mod), a unique resource that contains a variety of 'omics' datasets related to preterm birth. The database is open publicly, and as of January 2018, links 13 molecular studies with data across tens of thousands of patients from 6 measurement modalities. The data in the repository are highly diverse and include genomic, transcriptomic, immunological, and microbiome data. Relevant datasets are augmented with additional molecular characterizations of almost 25,000 biological samples from public databases. We believe our data-sharing efforts will lead to enhanced research collaborations and coordination accelerating the overall pace of discovery in preterm birth research

A Toxicogenomic Comparison of Primary and Photochemically Altered Air Pollutant Mixtures

Background: Air pollution contributes significantly to global increases in mortality, particularly within urban environments. Limited knowledge exists on the mechanisms underlying health effects resulting from exposure to pollutant mixtures similar to those occurring in ambient air. In order to clarify the mechanisms underlying exposure effects, toxicogenomic analyses are used to evaluate genomewide transcript responses and map these responses to molecular networks

ZFOURGE: Using Composite Spectral Energy Distributions to Characterize Galaxy Populations at 1<z<4

We investigate the properties of galaxies as they shut off star formation over the 4 billion years surrounding peak cosmic star formation. To do this we categorize $\sim7000$ galaxies from $1<z<4$ into $90$ groups based on the shape of their spectral energy distributions (SEDs) and build composite SEDs with $R\sim 50$ resolution. These composite SEDs show a variety of spectral shapes and also show trends in parameters such as color, mass, star formation rate, and emission line equivalent width. Using emission line equivalent widths and strength of the 4000\AA\ break, $D(4000)$, we categorize the composite SEDs into five classes: extreme emission line, star-forming, transitioning, post-starburst, and quiescent galaxies. The transitioning population of galaxies show modest H$\alpha$ emission ($EW_{\rm REST}\sim40$\AA) compared to more typical star-forming composite SEDs at $\log_{10}(M/M_\odot)\sim10.5$ ($EW_{\rm REST}\sim80$\AA). Together with their smaller sizes (3 kpc vs. 4 kpc) and higher S\'ersic indices (2.7 vs. 1.5), this indicates that morphological changes initiate before the cessation of star formation. The transitional group shows a strong increase of over one dex in number density from $z\sim3$ to $z\sim1$, similar to the growth in the quiescent population, while post-starburst galaxies become rarer at $z\lesssim1.5$. We calculate average quenching timescales of 1.6 Gyr at $z\sim1.5$ and 0.9 Gyr at $z\sim2.5$ and conclude that a fast quenching mechanism producing post-starbursts dominated the quenching of galaxies at early times, while a slower process has become more common since $z\sim2$.Comment: Accepted for publication in The Astrophysical Journa

Mosquitoes Inoculate High Doses of West Nile Virus as They Probe and Feed on Live Hosts

West Nile virus (WNV) is transmitted to vertebrate hosts by mosquitoes as they take a blood meal. The amount of WNV inoculated by mosquitoes as they feed on a live host is not known. Previous estimates of the amount of WNV inoculated by mosquitoes (101.2–104.3 PFU) were based on in vitro assays that do not allow mosquitoes to probe or feed naturally. Here, we developed an in vivo assay to determine the amount of WNV inoculated by mosquitoes as they probe and feed on peripheral tissues of a mouse or chick. Using our assay, we recovered approximately one-third of a known amount of virus inoculated into mouse tissues. Accounting for unrecovered virus, mean and median doses of WNV inoculated by four mosquito species were 104.3 PFU and 105.0 PFU for Culex tarsalis, 105.9 PFU and 106.1 PFU for Cx. pipiens, 104.7 PFU and 104.7 PFU for Aedes japonicus, and 103.6 PFU and 103.4 PFU for Ae. triseriatus. In a direct comparison, in vivo estimates of the viral dose inoculated by Cx. tarsalis were approximately 600 times greater than estimates obtained by an in vitro capillary tube transmission assay. Virus did not disperse rapidly, as >99% of the virus was recovered from the section fed or probed upon by the mosquito. Furthermore, 76% (22/29) of mosquitoes inoculated a small amount of virus (∼102 PFU) directly into the blood while feeding. Direct introduction of virus into the blood may alter viral tropism, lead to earlier development of viremia, and cause low rates of infection in co-feeding mosquitoes. Our data demonstrate that mosquitoes inoculate high doses of WNV extravascularly and low doses intravascularly while probing and feeding on a live host. Accurate estimates of the viral dose inoculated by mosquitoes are critical in order to administer appropriate inoculation doses to animals in vaccine, host competence, and pathogenesis studies