Sublethal Doses of Anthrax Lethal Toxin on the Suppression of Macrophage Phagocytosis

BACKGROUND: Lethal toxin (LT), the major virulence factor produced by Bacillus anthracis, has been shown to suppress the immune system, which is beneficial to the establishment of B. anthracis infections. It has been suggested that the suppression of MEK/MAPK signaling pathways of leukocytes contributes to LT-mediated immunosuppressive effects. However, the involvement of MAPK independent pathways has not been clearly elucidated; nor has the crucial role played by LT in the early stages of infection. Determining whether LT exerts any pathological effects before being enriched to an MEK inhibitory level is an important next step in the furtherance of this field. METHODOLOGY/PRINCIPAL FINDINGS: Using a cell culture model, we determined that low doses of LT inhibited phagocytosis of macrophages, without influencing MAPK pathways. Consistent low doses of LT significantly suppressed bacterial clearance and enhanced the mortality of mice with bacteremia, without suppressing the MEK1 of splenic and peripheral blood mononuclear cells. CONCLUSION/SIGNIFICANCE: These results suggest that LT suppresses the phagocytes in a dose range lower than that required to suppress MEK1 in the early stages of infection

Cationic polyamines inhibit anthrax lethal factor protease

BACKGROUND: Anthrax is a human disease that results from infection by the bacteria, Bacillus anthracis and has recently been used as a bioterrorist agent. Historically, this disease was associated with Bacillus spore exposure from wool or animal carcasses. While current vaccine approaches (targeted against the protective antigen) are effective for prophylaxis, multiple doses must be injected. Common antibiotics that block the germination process are effective but must be administered early in the infection cycle. In addition, new therapeutics are needed to specifically target the proteolytic activity of lethal factor (LF) associated with this bacterial infection. RESULTS: Using a fluorescence-based assay to identify and characterize inhibitors of anthrax lethal factor protease activity, we identified several chemically-distinct classes of inhibitory molecules including polyamines, aminoglycosides and cationic peptides. In these studies, spermine was demonstrated for the first time to inhibit anthrax LF with a K(i )value of 0.9 ± 0.09 μM (mean ± SEM; n = 3). Additional linear polyamines were also active as LF inhibitors with lower potencies. CONCLUSION: Based upon the studies reported herein, we chose linear polyamines related to spermine as potential lead optimization candidates and additional testing in cell-based models where cell penetration could be studied. During our screening process, we reproducibly demonstrated that the potencies of certain compounds, including neomycin but not neamine or spermine, were different depending upon the presence or absence of nucleic acids. Differential sensitivity to the presence/absence of nucleic acids may be an additional point to consider when comparing various classes of active compounds for lead optimization

Multicentre observational study on multisystem inflammatory syndrome related to COVID-19 in Argentina

Background: The impact of the pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in low- and middle-income countries remains poorly understood. Our aim was to understand the characteristics and outcomes of PIMS-TS in Argentina. Methods: This observational, prospective, and retrospective multicenter study enrolled patients younger than 18 years-old manifesting PIMS-TS, Kawasaki disease (KD) or Kawasaki shock syndrome (KSS) between March 2020 and May 2021. Patients were followed-up until hospital discharge or death (one case). The primary outcome was pediatric intensive care unit (PICU) admission. Multiple logistic regression was used to identify variables predicting PICU admission. Results: Eighty-one percent, 82%, and 14% of the 176 enrolled patients fulfilled the suspect case criteria for PIMS-TS, KD, and KSS, respectively. Temporal association with SARS-CoV-2 was confirmed in 85% of the patients and 38% were admitted to the PICU. The more common clinical manifestations were fever, abdominal pain, rash, and conjunctival injection. Lymphopenia was more common among PICU-admitted patients (87% vs. 51%, p < 0.0001), who also showed a lower platelet count and higher plasmatic levels of inflammatory and cardiac markers. Mitral valve insufficiency, left ventricular wall motion alterations, pericardial effusion, and coronary artery alterations were observed in 30%, 30%, 19.8%, and 18.6% of the patients, respectively. Days to initiation of treatment, rash, lymphopenia, and low platelet count were significant independent contributions to PICU admission. Conclusion: Rates of severe outcomes of PIMS-TS in the present study agreed with those observed in high-income countries. Together with other published studies, this work helps clinicians to better understand this novel clinical entity.Fil: Vainstein, Eduardo. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Baleani, Silvia. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Urrutia, Luis. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Affranchino, Nicolás. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Ackerman, Judith. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños Pedro Elizalde (ex Casa Cuna); ArgentinaFil: Cazalas, Mariana. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Goldsman, Alejandro. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Sardella, Angela. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Tolin, Ana Laura. Gobierno de la Provincia de Mendoza. Hospital Pediátrico Humberto Notti; ArgentinaFil: Goldaracena, Pablo. Provincia de Buenos Aires. Ministerio de Salud. Hospital de Niños "Sor María Ludovica" de La Plata; ArgentinaFil: Fabi, Mariana. Provincia de Buenos Aires. Ministerio de Salud. Hospital de Niños "Sor María Ludovica" de La Plata; ArgentinaFil: Cosentino, Mariana. Hospital Británico de Buenos Aires; ArgentinaFil: Magliola, Ricardo. Hospital Británico de Buenos Aires; ArgentinaFil: Roggiero, Gustavo. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic; ArgentinaFil: Manso, Paula. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic; ArgentinaFil: Triguy, Jésica. Gobierno de la Provincia de Mendoza. Hospital Pediátrico Humberto Notti; ArgentinaFil: Ballester, Celeste. Gobierno de la Provincia de Mendoza. Hospital Pediátrico Humberto Notti; ArgentinaFil: Cervetto, Vanesa. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños Pedro Elizalde (ex Casa Cuna); ArgentinaFil: Vaccarello, María. Sanatorio de la Trinidad; ArgentinaFil: De Carli, Domingo Norberto. Clínica del Niño de Quilmes; ArgentinaFil: De Carli, Maria Estela. Clínica del Niño de Quilmes; ArgentinaFil: Ciotti, Ana Laura. Hospital Nacional Profesor Alejandro Posadas; ArgentinaFil: Sicurello, María Irene. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Rios Leiva, Cecilia. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Villalba, Claudia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Hortas, María. Sanatorio de la Trinidad; ArgentinaFil: Peña, Sonia. Gobierno de la Provincia de Mendoza. Hospital Pediátrico Humberto Notti; ArgentinaFil: González, Gabriela. Gobierno de la Provincia de Mendoza. Hospital Pediátrico Humberto Notti; ArgentinaFil: Zold, Camila Lidia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Murer, Mario Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Grippo, M.. No especifíca;Fil: Vázquez, H.. No especifíca;Fil: Morós, C.. No especifíca;Fil: Di Santo, M.. No especifíca;Fil: Villa, A.. No especifíca;Fil: Lazota, P.. No especifíca;Fil: Foti, M.. No especifíca;Fil: Napoli, N.. No especifíca;Fil: Katsikas, M. M.. No especifíca;Fil: Tonello, L.. No especifíca;Fil: Peña, J.. No especifíca;Fil: Etcheverry, M.. No especifíca;Fil: Iglesias, D.. No especifíca;Fil: Alcalde, A. L.. No especifíca;Fil: Bruera, M.J.. No especifíca;Fil: Bruzzo, V.. No especifíca;Fil: Giordano, P.. No especifíca;Fil: Pena Acero, F.. No especifíca;Fil: Netri Pelandi, G.. No especifíca;Fil: Pastaro, D.. No especifíca;Fil: Bleiz, J.. No especifíca;Fil: Rodríguez, M. F.. No especifíca;Fil: Laghezza, L.. No especifíca;Fil: Molina, M. B.. No especifíca;Fil: Patynok, N.. No especifíca;Fil: Chatelain, M. S.. No especifíca;Fil: Aguilar, M. J.. No especifíca;Fil: Gamboa, J.. No especifíca;Fil: Cervan, M.. No especifíca;Fil: Ruggeri, A.. No especifíca;Fil: Marinelli, I.. No especifíca;Fil: Checcacci, E.. No especifíca;Fil: Meregalli, C.. No especifíca;Fil: Damksy Barbosa, J.. No especifíca;Fil: Fernie, L.. No especifíca;Fil: Fernández, M. J.. No especifíca;Fil: Saenz Tejeira, M.M.. No especifíca;Fil: Cereigido, C.. No especifíca;Fil: Nunell, A.. No especifíca;Fil: Villar, D.. No especifíca;Fil: Mansilla, A. D.. No especifíca;Fil: Darduin, M. D.. No especifíca

Gaia Data Release 3 The Galaxy in your preferred colours: Synthetic photometry from Gaia low-resolution spectra

Gaia Data Release 3 provides novel flux-calibrated low-resolution spectrophotometry for '220 million sources in the wavelength range 330 nm ≤ λ ≤ 1050 nm (XP spectra). Synthetic photometry directly tied to a flux in physical units can be obtained from these spectra for any passband fully enclosed in this wavelength range. We describe how synthetic photometry can be obtained from XP spectra, illustrating the performance that can be achieved under a range of different conditions - for example passband width and wavelength range - as well as the limits and the problems affecting it. Existing top-quality photometry can be reproduced within a few per cent over a wide range of magnitudes and colour, for wide and medium bands, and with up to millimag accuracy when synthetic photometry is standardised with respect to these external sources. Some examples of potential scientific application are presented, including the detection of multiple populations in globular clusters, the estimation of metallicity extended to the very metal-poor regime, and the classification of white dwarfs. A catalogue providing standardised photometry for 2.2×108sources in several wide bands of widely used photometric systems is provided (Gaia Synthetic Photometry Catalogue; GSPC) as well as a catalogue of '105 white dwarfs with DA/non-DA classification obtained with a Random Forest algorithm (Gaia Synthetic Photometry Catalogue for White Dwarfs; GSPC-WD)

Gaia Data Release 3 Mapping the asymetric disc of the Milky Way*

Context. With the most recent Gaia data release, the number of sources with complete 6D phase space information (position and velocity) has increased to well over 33 million stars, while stellar astrophysical parameters are provided for more than 470 million sources, and more than 11 million variable stars are identified. Aims. Using the astrophysical parameters and variability classifications provided in Gaia DR3, we selected various stellar populations to explore and identify non-axisymmetric features in the disc of the Milky Way in configuration and velocity space. Methods. Using more about 580 000 sources identified as hot OB stars, together with 988 known open clusters younger than 100 Myr, we mapped the spiral structure associated with star formation 4−5 kpc from the Sun. We selected over 2800 Classical Cepheids younger than 200 Myr that show spiral features extending as far as 10 kpc from the Sun in the outer disc. We also identified more than 8.7 million sources on the red giant branch (RGB), of which 5.7 million have line-of-sight velocities. This later sample allows the velocity field of the Milky Way to be mapped as far as 8 kpc from the Sun, including the inner disc. Results. The spiral structure revealed by the young populations is consistent with recent results using Gaia EDR3 astrometry and source lists based on near-infrared photometry, showing the Local (Orion) Arm to be at least 8 kpc long, and an outer arm consistent with what is seen in HI surveys, which seems to be a continuation of the Perseus arm into the third quadrant. The subset of RGB stars with velocities clearly reveals the large-scale kinematic signature of the bar in the inner disc, as well as evidence of streaming motions in the outer disc that might be associated with spiral arms or bar resonances. A local comparison of the velocity field of the OB stars reveals similarities and differences with the RGB sample. Conclusions. This cursory study of Gaia DR3 data shows there is a rich bounty of kinematic information to be explored more deeply, which will undoubtedly lead us to a clearer understanding of the dynamical nature of the non-axisymmetric structures of the Milky Way

Increased apoptosis in circulating lymphocyte cultures of anti-RNA polymerase III positive patients with systemic sclerosis.

The sera of 39 patients (38 women and 1 man), 16 with limited and 23 with diffuse clinical form of systemic sclerosis (SSc), were tested for anti-centromere (ACA), anti-topoisomerase I (ATA) and anti-RNA polymerase III (ARA) antibodies. The presence of apoptotic cells in cultures of circulating lymphocytes was investigated using the TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling) technique. ACAs were present in 16 (41%), ATA in 15 (38%) and ARA in 8 (21%) cases. The mean frequency of apoptotic lymphocytes was statistically higher in the ARA positive patients with respect to that in the control population (P < 0.001), in ACA (P < 0.001) and in the ATA (P < 0.001) groups. Moreover, apoptosis was distributed homogenously in ACA and ATA positive subjects, but not in the ARA patients. Our results show that there is an increase in apoptosis in the lymphocytes of ARA positive SSc patients