Mannose binding lectin is required for alphavirus-induced arthritis/myositis

Mosquito-borne alphaviruses such as chikungunya virus and Ross River virus (RRV) are emerging pathogens capable of causing large-scale epidemics of virus-induced arthritis and myositis. The pathology of RRV-induced disease in both humans and mice is associated with induction of the host inflammatory response within the muscle and joints, and prior studies have demonstrated that the host complement system contributes to development of disease. In this study, we have used a mouse model of RRV-induced disease to identify and characterize which complement activation pathways mediate disease progression after infection, and we have identified the mannose binding lectin (MBL) pathway, but not the classical or alternative complement activation pathways, as essential for development of RRV-induced disease. MBL deposition was enhanced in RRV infected muscle tissue from wild type mice and RRV infected MBL deficient mice exhibited reduced disease, tissue damage, and complement deposition compared to wild-type mice. In contrast, mice deficient for key components of the classical or alternative complement activation pathways still developed severe RRV-induced disease. Further characterization of MBL deficient mice demonstrated that similar to C3(-/-) mice, viral replication and inflammatory cell recruitment were equivalent to wild type animals, suggesting that RRV-mediated induction of complement dependent immune pathology is largely MBL dependent. Consistent with these findings, human patients diagnosed with RRV disease had elevated serum MBL levels compared to healthy controls, and MBL levels in the serum and synovial fluid correlated with severity of disease. These findings demonstrate a role for MBL in promoting RRV-induced disease in both mice and humans and suggest that the MBL pathway of complement activation may be an effective target for therapeutic intervention for humans suffering from RRV-induced arthritis and myositis.This work was supported by NIH/NIAMS R01 AR 047190 awarded to MTH

Satellite and ground atmospheric particulate matter detection over Tucuman city, Argentina, space-time distribution, climatic and seasonal variability

The analysis of atmospheric particles (aerosols) is of special interest due to their potential effects on human health and other applications. In this paper the climatic and seasonal effects on aerosols have been characterized in Tucumán city (26°50’ S, 65° 13’ W,450 masl),Argentina, for the 2006–2013 period. The atmospheric aerosols in Tucumán city result from both stationary and mobile sources such as: industrial activity of sugar cane and alcohol distilleries, paper industry, biomass burning (mainly sugarcane waste crop and grasslands), household waste burning and transport emissions. The peak of industrial activity is seasonal, coincident with the austral winter (July-August-September), when accumulation of particles in the lower atmosphere occurs. In this region, there are no studies like the present one that evaluate, using “in situ” equipment, the temporal variation of aerosols and its causes, by applying modern analytical techniques. A continuous volumetric and isokinetic sampler of Hirst type (Burkard), was used for atmospheric particle sampling, in weekly records between 2006 and 2013. The particle concentration (number of particles per cubic meter) showed an increasing trend in the studied period. The monthly variation of: the particle concentration; the aerosol optical thickness at a wavelength of 550 nm (AOD550) obtained from the Moderate Resolution Imaging Spectroradiometer (MODIS) sensors onboard Aqua (NASA) satellite, and the AOD from different aerosol tracers (black and organic carbon, sea salt, sulfates, dust) obtained from the Modern-Era Retrospective Analysis for Research and Applications (MERRA-2), were also analyzed. The temporal variation in particle concentration was explained mostly by wind direction, while the corresponding variation for AOD550(MODIS) was explained by temperature and seasonality (as by-product of climatic variation and anthropogenic particle emission sources). The variation in the AOD550(MERRA-2) data series were explained by temperature, humidity, precipitation, and seasonality, with less effect of wind speed and direction. Particle concentration, AOD550(MODIS), and AOD550(MERRA-2) were highly variable. The cross-correlation between AOD550(MODIS) and AOD550(MERRA-2) time series was significantly positive at lag zero. Other contribution was the determination of the space-time distribution of aerosols on a monthly basis considering AOD550 MODIS (3 km × 3 km) data. The present study suggests that these variables are affected by temperature and wind dynamics driven by seasonal and high-order autoregressive non-linear processes.Fil: García, María E.. Laboratorio de Palinología; ArgentinaFil: Della Ceca, Lara Sofia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Física de Rosario. Universidad Nacional de Rosario. Instituto de Física de Rosario; ArgentinaFil: Micheletti, Maria Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Física de Rosario. Universidad Nacional de Rosario. Instituto de Física de Rosario; ArgentinaFil: Piacentini, Ruben Dario Narciso. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Física de Rosario. Universidad Nacional de Rosario. Instituto de Física de Rosario; ArgentinaFil: Ordano, Mariano Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico - Tucumán. Unidad Ejecutora Lillo; ArgentinaFil: Reyes, Nora J. F.. Fundación Miguel Lillo; ArgentinaFil: Buedo, Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico - Tucumán. Unidad Ejecutora Lillo; ArgentinaFil: González, Juan A.. Fundación Miguel Lillo; Argentin

Opposite acute potassium and sodium shifts during transplantation of hypothermic machine perfused donor livers

Liver transplantation is frequently associated with hyperkalemia, especially after graft reperfusion. Dual hypothermic oxygenated machine perfusion (DHOPE) reduces ischemia/reperfusion injury and improves graft function, compared to conventional static cold storage (SCS). We examined the effect of DHOPE on ex situ and in vivo shifts of potassium and sodium. Potassium and sodium shifts were derived from balance measurements in a preclinical study of livers that underwent DHOPE (n = 6) or SCS alone (n = 9), followed by ex situ normothermic reperfusion. Similar measurements were performed in a clinical study of DHOPE-preserved livers (n = 10) and control livers that were transplanted after SCS only (n = 9). During DHOPE, preclinical and clinical livers released a mean of 17 +/- 2 and 34 +/- 6 mmol potassium and took up 25 +/- 9 and 24 +/- 14 mmol sodium, respectively. After subsequent normothermic reperfusion, DHOPE-preserved livers took up a mean of 19 +/- 3 mmol potassium, while controls released 8 +/- 5 mmol potassium. During liver transplantation, blood potassium levels decreased upon reperfusion of DHOPE-preserved livers while levels increased after reperfusion of SCS-preserved liver, delta potassium levels were -0.77 +/- 0.20 vs. +0.64 +/- 0.37 mmol/L, respectively (P = .002). While hyperkalemia is generally anticipated during transplantation of SCS-preserved livers, reperfusion of hypothermic machine perfused livers can lead to decreased blood potassium or even hypokalemia in the recipient

The Orbit of NGC 5907 ULX-1

© 2024. The Author(s). Published by the American Astronomical Society. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/Wereport on the orbit of the binary system powering the most extreme ultraluminous X-ray pulsar known to date: NGC5907ULX-1(hereafter ULX1). ULX1 has been the target of a substantial multi-instrument campaign, mainly in the X-ray band, but no clear counterparts are known in other bands. Although ULX1 is highly variable and pulsations can be transient (regardless of the source flux), the timing data collected so far allow us to investigate the orbit of this system. We find an orbital period P orb =+ 5.7 0.1 0.6 days and a projected semi-axis 0.8 1 A 3.1 lt s =+. The most likely ephemeris is Porb = 5.6585(6) days, A1 =3.1(4) lt-s, and the epoch of ascending nodes passage is Tasc = 57751.37(5) MJD. However, there are six similar solutions acceptable within 3σ.Wefind further indications that ULX1 is a high-mass X-ray binary. This implies that we are observing its orbit face on, with an inclination <5°.Peer reviewe

Frequent mutated B2M, EZH2, IRF8, and TNFRSF14 in primary bone diffuse large B-cell lymphoma reflect a GCB phenotype

Primary bone diffuse large B-cell lymphoma (PB-DLBCL) is a rare extranodal lymphoma subtype. This retrospective study elucidates the currently unknown genetic background of a large clinically well-annotated cohort of DLBCL with osseous localizations (O-DLBCL), including PB-DLBCL. A total of 103 patients with O-DLBCL were included and compared with 63 (extra)nodal non-osseous (NO)-DLBCLs with germinal center B-cell phenotype (NO-DLBCL-GCB). Cell-of-origin was determined by immunohistochemistry and gene-expression profiling (GEP) using (extended)-NanoString/Lymph2Cx analysis. Mutational profiles were identified with targeted next-generation deep sequencing, including 52 B-cell lymphoma-relevant genes. O-DLBCLs, including 34 PB-DLBCLs, were predominantly classified as GCB phenotype based on immunohistochemistry (74%) and NanoString analysis (88%). Unsupervised hierarchical clustering of an extended-NanoString/Lymph2Cx revealed significantly different GEP clusters for PB-DLBCL as opposed to NO-DLBCL-GCB (P < .001). Expression levels of 23 genes of 2 different targeted GEP panels indicated a centrocyte-like phenotype for PB-DLBCL, whereas NO-DLBCL-GCB exhibited a centroblast-like constitution. PB-DLBCL had significantly more frequent mutations in four GCB-associated genes (ie, B2M, EZH2, IRF8, TNFRSF14) compared with NO-DLBCL-GCB (P = .031, P = .010, P = .047, and P = .003, respectively). PB-DLBCL, with its corresponding specific mutational profile, was significantly associated with a superior survival compared with equivalent Ann Arbor limited-stage I/II NO-DLBCL-GCB (P = .016). This study is the first to show that PB-DLBCL is characterized by a GCB phenotype, with a centrocyte-like GEP pattern and a GCB-associated mutational profile (both involved in immune surveillance) and a favorable prognosis. These novel biology-associated features provide evidence that PB-DLBCL represents a distinct extranodal DLBCL entity, and its specific mutational landscape offers potential for targeted therapies (eg, EZH2 inhibitors)

Mannose Binding Lectin Is Required for Alphavirus-Induced Arthritis/Myositis

Mosquito-borne alphaviruses such as chikungunya virus and Ross River virus (RRV) are emerging pathogens capable of causing large-scale epidemics of virus-induced arthritis and myositis. The pathology of RRV-induced disease in both humans and mice is associated with induction of the host inflammatory response within the muscle and joints, and prior studies have demonstrated that the host complement system contributes to development of disease. In this study, we have used a mouse model of RRV-induced disease to identify and characterize which complement activation pathways mediate disease progression after infection, and we have identified the mannose binding lectin (MBL) pathway, but not the classical or alternative complement activation pathways, as essential for development of RRV-induced disease. MBL deposition was enhanced in RRV infected muscle tissue from wild type mice and RRV infected MBL deficient mice exhibited reduced disease, tissue damage, and complement deposition compared to wild-type mice. In contrast, mice deficient for key components of the classical or alternative complement activation pathways still developed severe RRV-induced disease. Further characterization of MBL deficient mice demonstrated that similar to C3−/− mice, viral replication and inflammatory cell recruitment were equivalent to wild type animals, suggesting that RRV-mediated induction of complement dependent immune pathology is largely MBL dependent. Consistent with these findings, human patients diagnosed with RRV disease had elevated serum MBL levels compared to healthy controls, and MBL levels in the serum and synovial fluid correlated with severity of disease. These findings demonstrate a role for MBL in promoting RRV-induced disease in both mice and humans and suggest that the MBL pathway of complement activation may be an effective target for therapeutic intervention for humans suffering from RRV-induced arthritis and myositis

Whole body vibration improves cognition in healthy young adults

This study investigated the acute effects of passive whole body vibration (WBV) on executive functions in healthy young adults. Participants (112 females, 21 males; age: 20.5 +/- 2.2 years) underwent six passive WBV sessions (frequency 30 Hz, amplitude approximately 0.5 mm) and six non-vibration control sessions of two minutes each while sitting on a chair mounted on a vibrating platform. A passive WBV session was alternated with a control session. Directly after each session, performance on the Stroop Color-Block Test (CBT), Stroop Color-Word Interference Test (CWIT), Stroop Difference Score (SDS) and Digit Span Backward task (DSBT) was measured. In half of the passive WBV and control sessions the test order was CBT-CWIT-DSBT, and DSBT-CBT-CWIT in the other half. Passive WBV improved CWIT (p = 0.009; effect size r = 0.20) and SDS (p = 0.034; r = 0.16) performance, but only when the CBT and CWIT preceded the DSBT. CBT and DSBT performance did not change. This study shows that two minutes passive WBV has positive acute effects on attention and inhibition in young adults, notwithstanding their high cognitive functioning which could have hampered improvement. This finding indicates the potential of passive WBV as a cognition-enhancing therapy worth further evaluation, especially in persons unable to perform active forms of exercise

Inferring structural variant cancer cell fraction

Abstract: We present SVclone, a computational method for inferring the cancer cell fraction of structural variant (SV) breakpoints from whole-genome sequencing data. SVclone accurately determines the variant allele frequencies of both SV breakends, then simultaneously estimates the cancer cell fraction and SV copy number. We assess performance using in silico mixtures of real samples, at known proportions, created from two clonal metastases from the same patient. We find that SVclone’s performance is comparable to single-nucleotide variant-based methods, despite having an order of magnitude fewer data points. As part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) consortium, which aggregated whole-genome sequencing data from 2658 cancers across 38 tumour types, we use SVclone to reveal a subset of liver, ovarian and pancreatic cancers with subclonally enriched copy-number neutral rearrangements that show decreased overall survival. SVclone enables improved characterisation of SV intra-tumour heterogeneity

A global experiment on motivating social distancing during the COVID-19 pandemic

Finding communication strategies that effectively motivate social distancing continues to be a global public health priority during the COVID-19 pandemic. This cross-country, preregistered experiment (n = 25,718 from 89 countries) tested hypotheses concerning generalizable positive and negative outcomes of social distancing messages that promoted personal agency and reflective choices (i.e., an autonomy-supportive message) or were restrictive and shaming (i.e., a controlling message) compared with no message at all. Results partially supported experimental hypotheses in that the controlling message increased controlled motivation (a poorly internalized form of motivation relying on shame, guilt, and fear of social consequences) relative to no message. On the other hand, the autonomy-supportive message lowered feelings of defiance compared with the controlling message, but the controlling message did not differ from receiving no message at all. Unexpectedly, messages did not influence autonomous motivation (a highly internalized form of motivation relying on one’s core values) or behavioral intentions. Results supported hypothesized associations between people’s existing autonomous and controlled motivations and self-reported behavioral intentions to engage in social distancing. Controlled motivation was associated with more defiance and less long-term behavioral intention to engage in social distancing, whereas autonomous motivation was associated with less defiance and more short- and long-term intentions to social distance. Overall, this work highlights the potential harm of using shaming and pressuring language in public health communication, with implications for the current and future global health challenges