GATA-1 as a Regulator of Mast Cell Differentiation Revealed by the Phenotype of the GATA-1low Mouse Mutant

Here it is shown that the phenotype of adult mice lacking the first enhancer (DNA hypersensitive site I) and the distal promoter of the GATA-1 gene (neoΔHS or GATA-1low mutants) reveals defects in mast cell development. These include the presence of morphologically abnormal alcian blue+ mast cells and apoptotic metachromatic− mast cell precursors in connective tissues and peritoneal lavage and numerous (60–70% of all the progenitors) “unique” trilineage cells committed to erythroid, megakaryocytic, and mast pathways in the bone marrow and spleen. These abnormalities, which were mirrored by impaired mast differentiation in vitro, were reversed by retroviral-mediated expression of GATA-1 cDNA. These data indicate an essential role for GATA-1 in mast cell differentiation

E-cigarettes fluids trigger molecular and morphological response in oral fibroblasts

Electronic-cigarettes (e-cigarettes) have been recently advertised as a safe alternative to the traditional ones and a possible smoking cessation tool. This electronic device was designed to transform a solution of variable compounds (some of them approved as food additives), in an inhalable aerosol. However, their safety is still not fully know (Lerner et al. 2016). The cytotoxicity of the fluids on human gingival fibroblasts (HGFs) was demonstrated on a previous study by Sancilio et al. (2016) where the occurrence of oxidative stress and apoptosis was found following the exposure to nicotine containing fluids. The aim of this study was to investigate the HGF biological response to e-cigarettes liquids (with and without nicotine) and to clarify the molecular mechanisms driving the cytotoxicity exerted by fluids themselves. To this purpose, cells were treated with e-cigarette fluids containing nicotine (final concentration 1mg/mL) and the equivalent volume of a fluid without nicotine, for times up to 48 h. Lactate Dehydrogenase Assay (LDH), electronic microscopy analysis, collagen I production, flow cytometry lysosome compartment evaluation and western blotting LC3 (microtubule-associated protein 1A/1B-light chain 3) expression were performed. Fluids containing nicotine exerted cytotoxicity as demonstrated by the increased levels of LDH, in parallel to the formation of numerous vacuoles in the cytoplasm, as well as a decrease in collagen I production and an augmented LC3 II expression which characterized autophagy occurrence In conclusion E-cigarette fluids (with and without nicotine) trigger modification ultrastructure, collagen production and lysosomal compartment in HGFs, suggesting an involvement in the pathogenesis of oral diseases

TGF-beta bioavailability is increased by a new interaction between megakaryocytes and fibrocytes activated in the Gata 1 low mouse

Primary myelofibrosis is the most severe of the Philadelphia-negative myeloproliferative neoplasms and is associated with progressive TGF-β1-dependent scaring of the hematopoietic microenvironment which causes hematopoietic failure in the spleen.Nevertheless, the pathogenetic roleof TGF beta is still unclear because of the modest (2-fold) increases in its plasma levels, both in patients and in animal models. Transmission electron-microscopy (TEM) observations identified that spleen from PMF patients and Gata1low mice contained megakaryocytes with abnormally high levels of TGF-β and collagen fibres embedded in their cytoplasm. Additional immuno-TEM observations of spleen from Gata1low mice revealed the presence of numerous activated fibrocytes establishing with their protrusions a novel cellular interaction, defined as peripolesis, with megakaryocytes. These protrusions infiltrated the megakaryocyte cytoplasm releasing collagen that was eventually detected in its mature polymerized form. Megakaryocytes, engulfed with mature collagen fibres, acquired the morphology of para-apoptotic cells and, in the most advanced cases, were recognized as polylobated heterochromatic nuclei surrounded by collagen fibres strictly associated with TGF-β. These areas contained concentrations of TGF-β-gold particles ~1000-fold greater than normal and numerous myofibroblasts, an indication that TGF-β was bioactive. Loss-of-function studies indicated that peripolesis between megakaryocytes and fibrocytes required both TGF-β, possibly for inducing fibrocyte activation, and P-selectin, possibly for mediating interaction between the two cell types. Loss-of-function of TGF-β and P-selectin also prevented fibrosis. These observations identify that myelofibrosis is associated with pathological increases of TGF-β bioavailability and suggest a novel megakaryocyte-mediated mechanism that may increase TGF-β bioavailability in chronic inflammation

Structural, ultrastructural and morphometric study of the zebrafish cornea: a model for human corneal diseases?

The structural and ultrastructural organization of the ocular surface of Vertebrates is still partial and often controversial. A morphological and morphometric study of the adult zebrafish (Danio rerio) cornea was performed to provide a comprehensive description of its layers and to compare its organization to the human cornea [1,2]. The eyes of adult zebrafish were processed for light, transmission and scanning electron microscopy and a morphometric analysis was performed on several morphological parameters. The zebrafish cornea is thinner in its central part, while it is thicker in its periphery. Only four layers are present, as no Descemet membrane can be demonstrated. The epithelium is formed by 5-8 layers of polygonal cells, identified as superficial, intermediate and basal, and provided of an evident peripheral cytoskeleton. The Bowman layer is particularly thin (~ 250 nm) and is placed between the basal cells and the first stromal lamella. The stroma is formed by 26-40 lamellae of collagen fibers, among which only occasional keratocytes are present, generally in the posterior part. The endothelium is formed by a single layer of flat polygonal cells, 1-1.5 μm thick. The morphometric analysis showed mild differences between the central and the peripheral cornea; furthermore, the epithelium/stroma ratio is 0.89, while it is 0.09 in the human cornea. It can be concluded that, even if the general organization of the zebrafish cornea is similar to that of mammals, there are also several significant differences, such as the presence of a very thin Bowman layer, the reduced thickness of the stroma and the absence of the Descemet membrane. Therefore, caution is required when findings obtained from zebrafish as an experimental model are applied to normal or pathological corneas in other species, such as rodents or humans

Goodbye Hartmann trial: a prospective, international, multicenter, observational study on the current use of a surgical procedure developed a century ago

Background: Literature suggests colonic resection and primary anastomosis (RPA) instead of Hartmann's procedure (HP) for the treatment of left-sided colonic emergencies. We aim to evaluate the surgical options globally used to treat patients with acute left-sided colonic emergencies and the factors that leading to the choice of treatment, comparing HP and RPA. Methods: This is a prospective, international, multicenter, observational study registered on ClinicalTrials.gov. A total 1215 patients with left-sided colonic emergencies who required surgery were included from 204 centers during the period of March 1, 2020, to May 31, 2020. with a 1-year follow-up. Results: 564 patients (43.1%) were females. The mean age was 65.9 ± 15.6 years. HP was performed in 697 (57.3%) patients and RPA in 384 (31.6%) cases. Complicated acute diverticulitis was the most common cause of left-sided colonic emergencies (40.2%), followed by colorectal malignancy (36.6%). Severe complications (Clavien-Dindo ≥ 3b) were higher in the HP group (P < 0.001). 30-day mortality was higher in HP patients (13.7%), especially in case of bowel perforation and diffused peritonitis. 1-year follow-up showed no differences on ostomy reversal rate between HP and RPA. (P = 0.127). A backward likelihood logistic regression model showed that RPA was preferred in younger patients, having low ASA score (≤ 3), in case of large bowel obstruction, absence of colonic ischemia, longer time from admission to surgery, operating early at the day working hours, by a surgeon who performed more than 50 colorectal resections. Conclusions: After 100 years since the first Hartmann's procedure, HP remains the most common treatment for left-sided colorectal emergencies. Treatment's choice depends on patient characteristics, the time of surgery and the experience of the surgeon. RPA should be considered as the gold standard for surgery, with HP being an exception

Search for gravitational-lensing signatures in the full third observing run of the LIGO-Virgo network

Gravitational lensing by massive objects along the line of sight to the source causes distortions of gravitational wave-signals; such distortions may reveal information about fundamental physics, cosmology and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO--Virgo network. We search for repeated signals from strong lensing by 1) performing targeted searches for subthreshold signals, 2) calculating the degree of overlap amongst the intrinsic parameters and sky location of pairs of signals, 3) comparing the similarities of the spectrograms amongst pairs of signals, and 4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by 1) frequency-independent phase shifts in strongly lensed images, and 2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the non-detection of gravitational-wave lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects

Search for eccentric black hole coalescences during the third observing run of LIGO and Virgo

Despite the growing number of confident binary black hole coalescences observed through gravitational waves so far, the astrophysical origin of these binaries remains uncertain. Orbital eccentricity is one of the clearest tracers of binary formation channels. Identifying binary eccentricity, however, remains challenging due to the limited availability of gravitational waveforms that include effects of eccentricity. Here, we present observational results for a waveform-independent search sensitive to eccentric black hole coalescences, covering the third observing run (O3) of the LIGO and Virgo detectors. We identified no new high-significance candidates beyond those that were already identified with searches focusing on quasi-circular binaries. We determine the sensitivity of our search to high-mass (total mass M>70 M⊙) binaries covering eccentricities up to 0.3 at 15 Hz orbital frequency, and use this to compare model predictions to search results. Assuming all detections are indeed quasi-circular, for our fiducial population model, we place an upper limit for the merger rate density of high-mass binaries with eccentricities 0<e≤0.3 at 0.33 Gpc−3 yr−1 at 90\% confidence level

Ultralight vector dark matter search using data from the KAGRA O3GK run

Among the various candidates for dark matter (DM), ultralight vector DM can be probed by laser interferometric gravitational wave detectors through the measurement of oscillating length changes in the arm cavities. In this context, KAGRA has a unique feature due to differing compositions of its mirrors, enhancing the signal of vector DM in the length change in the auxiliary channels. Here we present the result of a search for U(1)B−L gauge boson DM using the KAGRA data from auxiliary length channels during the first joint observation run together with GEO600. By applying our search pipeline, which takes into account the stochastic nature of ultralight DM, upper bounds on the coupling strength between the U(1)B−L gauge boson and ordinary matter are obtained for a range of DM masses. While our constraints are less stringent than those derived from previous experiments, this study demonstrates the applicability of our method to the lower-mass vector DM search, which is made difficult in this measurement by the short observation time compared to the auto-correlation time scale of DM