Inflammation modulates intercellular adhesion and mechanotransduction in human epidermis via ROCK2

Aberrant mechanotransduction and compromised epithelial barrier function are associated with numerous human pathologies including inflammatory skin disorders. However, the cytoskeletal mechanisms regulating inflammatory responses in the epidermis are not well understood. Here we addressed this question by inducing a psoriatic phenotype in human keratinocytes and reconstructed human epidermis using a cytokine stimulation model. We show that the inflammation upregulates the Rho-myosin II pathway and destabilizes adherens junctions (AJs) promoting YAP nuclear entry. The integrity of cell-cell adhesion but not the myosin II contractilityper seis the determinative factor for the YAP regulation in epidermal keratinocytes. The inflammation-induced disruption of AJs, increased paracellular permeability, and YAP nuclear translocation are regulated by ROCK2, independently from myosin II activation. Using a specific inhibitor KD025, we show that ROCK2 executes its effects via cytoskeletal and transcription-dependent mechanisms to shape the inflammatory response in the epidermis

Comparative effectiveness of common therapies for Wilson disease: A systematic review and meta-analysis of controlled studies

BACKGROUND & AIMS: Wilson disease (WD) is a rare disorder of copper metabolism. The objective of this systematic review is to determine the comparative effectiveness and safety of common treatments of WD. METHODS: We included WD patients of any age or stage and the study drugs D-penicillamine, zinc salts, trientine, and tetrathiomolybdate. The control could be placebo, no treatment, or any other treatment. We included prospective, retrospective, randomized, and non-randomized studies. We searched Medline and Embase via Ovid, the Cochrane Central Register of Controlled Trials, and screened reference lists of included articles. Where possible, we applied random-effects meta-analyses. RESULTS: The 23 included studies reported on 2055 patients and mostly compared D-penicillamine to no treatment, zinc, trientine, or succimer. One study compared tetrathiomolybdate and trientine. Post-decoppering maintenance therapy was addressed in one study only. Eleven of 23 studies were of low quality. When compared to no treatment, D-penicillamine was associated with a lower mortality (odds ratio 0.013; 95% CI 0.0010 to 0.17). When compared to zinc, there was no association with mortality (odds ratio 0.73; 95% CI 0.16 to 3.40) and prevention or amelioration of clinical symptoms (odds ratio 0.84; 95% CI 0.48 to 1.48). Conversely, D-penicillamine may have a greater impact on side effects and treatment discontinuations than zinc. CONCLUSIONS: There are some indications that zinc is safer than D-penicillamine therapy while being similarly effective in preventing or reducing hepatic or neurologic WD symptoms. Study quality was low warranting cautious interpretation of our findings

A LOFAR-IRAS cross-match study : the far-infrared radio correlation and the 150-MHz luminosity as a star-formation rate

13 pages, 13 figures, accepted for publication in A&A, © ESO 2019Aims. We aim to study the far-infrared radio correlation (FIRC) at 150 MHz in the local Universe (at a median redshift z~0:05) and improve the use of the rest-frame 150-MHz luminosity, L150, as a star-formation rate (SFR) tracer, which is unaffected by dust extinction. Methods. We cross-match the 60-um selected Revised IRAS Faint Source Survey Redshift (RIFSCz) catalogue and the 150-MHz selected LOFAR value-added source catalogue in the Hobby-Eberly Telescope Dark Energy Experiment (HETDEX) Spring Field. We estimate L150 for the cross-matched sources and compare it with the total infrared (IR) luminosity, LIR, and various SFR tracers. Results. We find a tight linear correlation between log L150 and log LIR for star-forming galaxies, with a slope of 1.37. The median qIR value (defined as the logarithm of the LIR to L150 ratio) and its rms scatter of our main sample are 2.14 and 0.34, respectively. We also find that log L150 correlates tightly with the logarithm of SFR derived from three different tracers, i.e., SFR_Halpha based on the Halpha line luminosity, SFR_60 based on the rest-frame 60-um luminosity and SFR_IR based on LIR, with a scatter of 0.3 dex. Our best-fit relations between L150 and these SFR tracers are, log L150 (Lsun) = 1.35(0.06) x log SFR_Halpha (Msun/yr) + 3.20(0.06), log L150 (Lsun) = 1.31(0.05) x log SFR_60 (Msun/yr) + 3.14(0.06), and log L150 (Lsun) = 1.37(0.05) x log SFR_IR (Msun/yr) + 3.09(0.05), which show excellent agreement with each other.Peer reviewedFinal Accepted Versio

The bright end of the infrared luminosity functions and the abundance of hyperluminous infrared galaxies

16 pages, 11 figures, accepted for publication in A&A as part of the LOFAR Deep Fields Paper Splash. © 2020 The European Southern Observatory (ESO)We provide the most accurate estimate yet of the bright end of the infrared (IR) luminosity functions (LFs) and the abundance of hyperluminous IR galaxies (HLIRGs) with IR luminosities > 10^13 L_solar, thanks to the combination of the high sensitivity, angular resolution, and large area of the LOFAR Deep Fields, which probes an unprecedented dynamic range of luminosity and volume. We cross-match Herschel sources and LOFAR sources in Bootes (8.63 deg^2), Lockman Hole (10.28 deg^2), and ELAIS-N1 (6.74 deg^2) with rms sensitivities of around 32, 22, and 20 mJy per beam, respectively. We divide the matched samples into unique and multiple categories. For the multiple matches, we de-blend the Herschel fluxes using the LOFAR positions and the 150-MHz flux densities as priors. We perform spectral energy distribution (SED) fitting, combined with multi-wavelength counterpart identifications and photometric redshift estimates, to derive IR luminosities. The depth of the LOFAR data allows us to identify highly complete (around 92% completeness) samples of bright Herschel sources with a simple selection based on the 250 micron flux density (45, 40, and 35 mJy in Bootes, Lockman Hole, and ELAIS-N1, respectively). Most of the bright Herschel sources fall into the unique category (i.e. a single LOFAR counterpart). For the multiple matches, there is excellent correspondence between the radio emission and the far-IR emission. We find a good agreement in the IR LFs with a previous study out to z around 6 which used de-blended Herschel data. Our sample gives the strongest and cleanest indication to date that the population of HLIRGs has surface densities of around 5 to 18 / deg^2 (with variations due to a combination of the applied flux limit and cosmic variance) and an uncertainty of a factor of 2. In comparison, the GALFORM semi-analytic model significantly under-predicts the abundance of HLIRGs.Peer reviewe

The bright end of the infrared luminosity functions and the abundance of hyperluminous infrared galaxies

© 2021 The European Southern Observatory (ESO). Article published by EDP Sciences. This is the accepted manuscript version of an article which has been published in final form at https://doi.org/10.1051/0004-6361/202038811Aims. We provide the most accurate estimate yet of the bright end of the infrared (IR) luminosity functions (LFs) and the abundance of hyperluminous IR galaxies (HLIRGs) with IR luminosities >1013L⊙, thanks to the combination of the high sensitivity, angular resolution, and large area of the LOFAR Deep Fields, which probes an unprecedented dynamic range of luminosity and volume. Methods. We cross-match Herschel sources and LOFAR sources in Boötes (8.63 deg2), Lockman Hole (10.28 deg2), and ELAIS-N1 (6.74 deg2) with rms sensitivities of ∼32, 22, and 20 μJy beam-1, respectively. We divide the matched samples into "unique"and "multiple"categories. For the multiple matches, we de-blend the Herschel fluxes using the LOFAR positions and the 150-MHz flux densities as priors. We perform spectral energy distribution fitting, combined with multi-wavelength counterpart identifications and photometric redshift estimates, to derive IR luminosities. Results. The depth of the LOFAR data allows us to identify highly complete (∼92% completeness) samples of bright Herschel sources with a simple selection based on the 250 μm flux density (45, 40, and 35 mJy in Boötes, Lockman Hole, and ELAIS-N1, respectively). Most of the bright Herschel sources fall into the unique category (i.e. a single LOFAR counterpart). For the multiple matches, there is excellent correspondence between the radio emission and the far-IR emission. We find a good agreement in the IR LFs with a previous study out to z ∼ 6 which used de-blended Herschel data. Our sample gives the strongest and cleanest indication to date that the population of HLIRGs has surface densities of ∼5 to ∼18/deg2 (with variations due to a combination of the applied flux limit and cosmic variance) and an uncertainty of a factor of 2. In comparison, the GALFORM semi-analytic model significantly under-predicts the abundance of HLIRGs.Peer reviewe

Proposed Diagnostic Criteria and Classification of Canine Mast Cell Neoplasms: A Consensus Proposal

Mast cell neoplasms are one of the most frequently diagnosed malignancies in dogs. The clinical picture, course, and prognosis vary substantially among patients, depending on the anatomic site, grade and stage of the disease. The most frequently involved organ is the skin, followed by hematopoietic organs (lymph nodes, spleen, liver, and bone marrow) and mucosal sites of the oral cavity and the gastrointestinal tract. In cutaneous mast cell tumors, several grading and staging systems have been introduced. However, no comprehensive classification and no widely accepted diagnostic criteria have been proposed to date. To address these open issues and points we organized a Working Conference on canine mast cell neoplasms in Vienna in 2019. The outcomes of this meeting are summarized in this article. The proposed classification includes cutaneous mast cell tumors and their sub-variants defined by grading- and staging results, mucosal mast cell tumors, extracutaneous/extramucosal mast cell tumors without skin involvement, and mast cell leukemia (MCL). For each of these entities, diagnostic criteria are proposed. Moreover, we have refined grading and staging criteria for mast cell neoplasms in dogs based on consensus discussion. The criteria and classification proposed in this article should greatly facilitate diagnostic evaluation and prognostication in dogs with mast cell neoplasms and should thereby support management of these patients in daily practice and the conduct of clinical trials

Micro-a-fluidics ELISA for rapid CD4 cell count at the point-of-care

HIV has become one of the most devastating pathogens in human history. Despite fast progress in HIV-related basic research, antiretroviral therapy (ART) remains the most effective method to save AIDS patients' lives. Unfortunately, ART cannot be universally accessed, especially in developing countries, due to the lack of effective treatment monitoring diagnostics. Here, we present an inexpensive, rapid and portable micro-a-fluidic platform, which can streamline the process of an enzyme-linked immunosorbent assay (ELISA) in a fully automated manner for CD4 cell count. The micro-a-fluidic CD4 cell count is achieved by eliminating operational fluid flow via “moving the substrate”, as opposed to “flowing liquid” in traditional ELISA or microfluidic methods. This is the first demonstration of capturing and detecting cells from unprocessed whole blood using the enzyme-linked immunosorbent assay (ELISA) in a microfluidic channel. Combined with cell phone imaging, the presented micro-a-fluidic ELISA platform holds great promise for offering rapid CD4 cell count to scale up much needed ART in resource-constrained settings. The developed system can be extended to multiple areas for ELISA-related assays.the Center for Integration of Medicine and Innovative Technology ; the U.S. Army Medical Research & Materiel Command (USAMRMC) ; the Telemedicine & Advanced Technology Research Center (TATRC).publisher versio

ASKAP commissioning observations of the GAMA 23 field

© Astronomical Society of Australia 2019. We have observed the G23 field of the Galaxy AndMass Assembly (GAMA) survey using the Australian Square Kilometre Array Pathfinder (ASKAP) in its commissioning phase to validate the performance of the telescope and to characterise the detected galaxy populations. This observation covers ∼48 deg2 with synthesised beam of 32.7 arcsec by 17.8 arcsec at 936MHz, and ∼39 deg2 with synthesised beam of 15.8 arcsec by 12.0 arcsec at 1320MHz. At both frequencies, the root-mean-square (r.m.s.) noise is ∼0.1 mJy/beam. We combine these radio observations with the GAMA galaxy data, which includes spectroscopy of galaxies that are i-band selected with a magnitude limit of 19.2. Wide-field Infrared Survey Explorer (WISE) infrared (IR) photometry is used to determine which galaxies host an active galactic nucleus (AGN). In properties including source counts, mass distributions, and IR versus radio luminosity relation, the ASKAP-detected radio sources behave as expected. Radio galaxies have higher stellar mass and luminosity in IR, optical, and UV than other galaxies. We apply optical and IR AGN diagnostics and find that they disagree for ∼30% of the galaxies in our sample. We suggest possible causes for the disagreement. Some cases can be explained by optical extinction of the AGN, but for more than half of the cases we do not find a clear explanation. Radio sources aremore likely (∼6%) to have an AGN than radio quiet galaxies (∼1%), but the majority of AGN are not detected in radio at this sensitivity

Higher Rates of Hemolysis Are Not Associated with Albuminuria in Jamaicans with Sickle Cell Disease

BACKGROUND: Albuminuria is a marker of glomerular damage in Sickle Cell Disease (SCD). In this study, we sought to determine the possible predictors of albuminuria in the two more prevalent genotypes of SCD among the Jamaica Sickle Cell Cohort Study participants. METHODS: An age-matched cohort of 122 patients with HbSS or HbSC genotypes had measurements of their morning urine albumin concentration, blood pressure, body mass index, haematology and certain biochemistry parameters done. Associations of albuminuria with possible predictors including hematological parameters, reticulocyte counts, aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) levels were examined using multiple regression models. RESULTS: A total of 122 participants were recruited (mean age 28.6 years ±2.5 years; 85 HbSS, 37 HbSC). 25.9% with HbSS and 10.8% with HbSC disease had microalbuminuria (urine albumin/creatinine ratio  =  30-300 mg/g of creatinine) whereas 16.5% of HbSS and 2.7% of HbSC disease had macroalbuminuria (urine albumin/creatinine ratio>300 mg/g of creatinine). Mean arterial pressure, hemoglobin levels, serum creatinine, reticulocyte counts and white blood cell counts were statistically significant predictors of albuminuria in HbSS, whereas white blood cell counts and serum creatinine predicted albuminuria in HbSC disease. Both markers of chronic hemolysis, i.e. AST and LDH levels, showed no associations with albuminuria in either genotype. CONCLUSIONS: Renal disease, as evidenced by excretion of increased amounts of albumin in urine due to a glomerulopathy, is a common end-organ complication in SCD. It is shown to be more severe in those with HbSS disease than in HbSC disease. Rising blood pressure, lower hemoglobin levels and higher white blood cell counts are hints to the clinician of impending renal disease, whereas higher rates of hemolysis do not appear to play a role in this complication of SCD

Pyrrolidine dithiocarbamate administered during ex-vivo lung perfusion promotes rehabilitation of injured donor rat lungs obtained after prolonged warm ischemia.

Damaged lung grafts obtained after circulatory death (DCD lungs) and warm ischemia may be at high risk of reperfusion injury after transplantation. Such lungs could be pharmacologically reconditioned using ex-vivo lung perfusion (EVLP). Since acute inflammation related to the activation of nuclear factor kappaB (NF-κB) is instrumental in lung reperfusion injury, we hypothesized that DCD lungs might be treated during EVLP by pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB. Rat lungs exposed to 1h warm ischemia and 2 h cold ischemia were subjected to EVLP during 4h, in absence (CTRL group, N = 6) or in presence of PDTC (2.5g/L, PDTC group, N = 6). Static pulmonary compliance (SPC), peak airway pressure (PAWP), pulmonary vascular resistance (PVR), and oxygenation capacity were determined during EVLP. After EVLP, we measured the weight gain of the heart-lung block (edema), and the concentration of LDH (cell damage), proteins (permeability edema) and of the cytokines IL-6, TNF-α and CINC-1 in bronchoalveolar lavage (BAL), and we evaluated NF-κB activation by the degree of phosphorylation and degradation of its inhibitor IκBα in lung tissue. In CTRL, we found significant NF-κB activation, lung edema, and a massive release of LDH, proteins and cytokines. SPC significantly decreased, PAWP and PVR increased, while oxygenation tended to decrease. Treatment with PDTC during EVLP inhibited NF-κB activation, did not influence LDH release, but markedly reduced lung edema and protein concentration in BAL, suppressed TNFα and IL-6 release, and abrogated the changes in SPC, PAWP and PVR, with unchanged oxygenation. In conclusion, suppression of innate immune activation during EVLP using the NF-κB inhibitor PDTC promotes significant improvement of damaged rat DCD lungs. Future studies will determine if such rehabilitated lungs are suitable for in vivo transplantation