Demands for quick and accurate life cycle assessments create a need for methods to rapidly generate reliable life cycle inventories (LCI). Data mining is a suitable tool for this purpose, especially ...given the large amount of available governmental data. These data are typically applied to LCIs on a case-by-case basis. As linked open data becomes more prevalent, it may be possible to automate LCI using data mining by establishing a reproducible approach for identifying, extracting, and processing the data. This work proposes a method for standardizing and eventually automating the discovery and use of publicly available data at the United States Environmental Protection Agency for chemical-manufacturing LCI. The method is developed using a case study of acetic acid. The data quality and gap analyses for the generated inventory found that the selected data sources can provide information with equal or better reliability and representativeness on air, water, hazardous waste, on-site energy usage, and production volumes but with key data gaps including material inputs, water usage, purchased electricity, and transportation requirements. A comparison of the generated LCI with existing data revealed that the data mining inventory is in reasonable agreement with existing data and may provide a more-comprehensive inventory of air emissions and water discharges. The case study highlighted challenges for current data management practices that must be overcome to successfully automate the method using semantic technology. Benefits of the method are that the openly available data can be compiled in a standardized and transparent approach that supports potential automation with flexibility to incorporate new data sources as needed.
Dengue virus (DENV), an arbovirus, strongly activates mast cells (MCs), which are key immune cells for pathogen immune surveillance. In animal models, MCs promote clearance of local peripheral DENV ...infections but, conversely, also promote pathological vascular leakage when widely activated during systemic DENV infection. Since DENV is a human pathogen, we sought to ascertain whether a similar phenomenon could occur in humans by characterizing the products released by human MCs (huMCs) upon direct (antibody-independent) DENV exposure, using the phenotypically mature huMC line, ROSA. DENV did not productively infect huMCs but prompted huMC release of proteases and eicosanoids and induced a Th1-polarized transcriptional profile. In co-culture and trans-well systems, huMC products activated human microvascular endothelial cells, involving transcription of vasoactive mediators and increased monolayer permeability. This permeability was blocked by MC-stabilizing drugs, or limited by drugs targeting certain MC products. Thus, MC stabilizers are a viable strategy to limit MC-promoted vascular leakage during DENV infection in humans.
A significant number of tropical cyclones move into the midlatitudes and transform into extratropical cyclones. This process is generally referred to as extratropical transition (ET). During ET a ...cyclone frequently produces intense rainfall and strong winds and has increased forward motion, so that such systems pose a serious threat to land and maritime activities. Changes in the structure of a system as it evolves from a tropical to an extratropical cyclone during ET necessitate changes in forecast strategies. In this paper a brief climatology of ET is given and the challenges associated with forecasting extratropical transition are described in terms of the forecast variables (track, intensity, surface winds, precipitation) and their impacts (flooding, bush fires, ocean response). The problems associated with the numerical prediction of ET are discussed. A comprehensive review of the current understanding of the processes involved in ET is presented. Classifications of extratropical transition are described and potential vorticity thinking is presented as an aid to understanding ET. Further sections discuss the interaction between a tropical cyclone and the midlatitude environment, the role of latent heat release, convection and the underlying surface in ET, the structural changes due to frontogenesis, the mechanisms responsible for precipitation, and the energy budget during ET. Finally, a summary of the future directions for research into ET is given. PUBLICATION ABSTRACT
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The American Society for Transplantation and Cellular Therapy (ASTCT) published its first white paper on indications for autologous and allogeneic hematopoietic cell transplantation (HCT) in 2015. It ...was identified at the time that periodic updates of indications would be required to stay abreast with state of the art and emerging indications and therapy. In recent years the field has not only seen an improvement in transplantation technology, thus widening the therapeutic scope of HCT, but additionally a whole new treatment strategy using modified immune effector cells, including chimeric antigen receptor T cells and engineered T-cell receptors, has emerged. The guidelines review committee of the ASTCT deemed it optimal to update the ASTCT recommendations for indications for HCT to include new data and to incorporate indications for immune effector cell therapy (IECT) where appropriate. The guidelines committee established a multiple stakeholder task force consisting of transplant experts, payer representatives, and a patient advocate to provide guidance on indications for HCT and IECT. This article presents the updated recommendations from the ASTCT on indications for HCT and IECT. Indications for HCT/IECT were categorized as (1) Standard of care, where indication is well defined and supported by evidence; (2) Standard of care, clinical evidence available, where large clinical trials and observational studies are not available but have been shown to be effective therapy; (3) Standard of care, rare indication, for rare diseases where demonstrated effectiveness exists but large clinical trials and observational studies are not feasible; (4) Developmental, for diseases where preclinical and/or early-phase clinical studies show HCT/IECT to be a promising treatment option; and (5) Not generally recommended, where available evidence does not support the routine use of HCT/IECT. The ASTCT will continue to periodically review these guidelines and update them as new evidence becomes available.
Context.A complex environment exists in the inner few astronomical units of planet-forming disks. High-angular-resolution observa-tions play a key role in our understanding of the disk structure and ...the dynamical processes at work.Aims.In this study we aim to characterize the mid-infrared brightness distribution of the inner disk of the young intermediate-massstar HD 163296 from early VLTI/MATISSE observations taken in theL- andN-bands. We put special emphasis on the detection ofpotential disk asymmetries.Methods.We use simple geometric models to fit the interferometric visibilities and closure phases. Our models include a smoothedring, a flat disk with an inner cavity, and a 2D Gaussian. The models can account for disk inclination and for azimuthal asymmetriesas well. We also perform numerical hydrodynamical simulations of the inner edge of the disk.Results.Our modeling reveals a significant brightness asymmetry in theL-band disk emission. The brightness maximum of the asym-metry is located at the NW part of the disk image, nearly at the position angle of the semimajor axis. The surface brightness ratio inthe azimuthal variation is3.5±0.2. Comparing our result on the location of the asymmetry with other interferometric measurements,we confirm that the morphology of ther<0.3au disk region is time-variable. We propose that this asymmetric structure, located in ornear the inner rim of the dusty disk, orbits the star. To find the physical origin of the asymmetry, we tested a hypothesis where a vortexis created by Rossby wave instability, and we find that a unique large-scale vortex may be compatible with our data. The half-lightradius of theL-band-emitting region is0.33±0.01au, the inclination is52◦+5◦−7◦, and the position angle is143◦±3◦. Our models predictthat a non-negligible fraction of theL-band disk emission originates inside the dust sublimation radius forμm-sized grains. Refractorygrains or large (&10μm-sized) grains could be the origin of this emission.N-band observations may also support a lack of smallsilicate grains in the innermost disk (r.0.6au), in agreement with our findings fromL-band data.
Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin T cell lymphoma commonly driven by NPM-ALK. AP-1 transcription factors, cJUN and JUNb, act as downstream effectors of NPM-ALK and ...transcriptionally regulate PDGFRβ. Blocking PDGFRβ kinase activity with imatinib effectively reduces tumor burden and prolongs survival, although the downstream molecular mechanisms remain elusive.
In a transgenic mouse model that mimics PDGFRβ-driven human ALCL in vivo, we identify PDGFRβ as a driver of aggressive tumor growth. Mechanistically, PDGFRβ induces the pro-survival factor Bcl-x
and the growth-enhancing cytokine IL-10 via STAT5 activation. CRISPR/Cas9 deletion of both STAT5 gene products, STAT5A and STAT5B, results in the significant impairment of cell viability compared to deletion of STAT5A, STAT5B or STAT3 alone. Moreover, combined blockade of STAT3/5 activity with a selective SH2 domain inhibitor, AC-4-130, effectively obstructs tumor development in vivo.
We therefore propose PDGFRβ as a novel biomarker and introduce PDGFRβ-STAT3/5 signaling as an important axis in aggressive ALCL. Furthermore, we suggest that inhibition of PDGFRβ or STAT3/5 improve existing therapies for both previously untreated and relapsed/refractory ALK
ALCL patients.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Tangible evidence of Earth's earliest (Hadean; >4.0 Ga) crust, and the processes and materials that contributed to its formation, exists almost entirely in a record of detrital zircon from Jack ...Hills, Western Australia, and a few other locations. Iceland, with its thick, juvenile, basaltic crust and relatively abundant silicic rocks, is considered a potential modern analog for the Hadean magmatic environment where >4 Ga zircon formed. We present the first extensive dataset for Icelandic zircon, with trace element and oxygen isotope compositions from samples that span the island's history and full range of tectonic settings. This statistically robust zircon-based comparison between Iceland and the early Earth reveals distinctions in chemistry that suggest fundamental differences in magmatic environments. Whereas the δ18O signature of Hadean zircons generally exceed that of zircons equilibrated with mantle-derived magma (85%≥5.3‰; median 6‰), almost all Icelandic zircons are characterized by a “light” oxygen signature (98%≤5.3‰; median 3‰). Deviations from “juvenile” oxygen values indicate that many Hadean zircons and almost all Icelandic zircons grew from magmas with substantial contributions from materials that had interacted with surface waters. In the Hadean case, the interaction occurred at low temperatures, while in Iceland, it was a high-temperature interaction. Icelandic and Hadean zircons are also distinct in their Ti concentrations (Icelandic median concentration 12 ppm, Hadean median 5 ppm). Titanium in zircon correlates positively with temperature of crystallization, and this difference in median Ti concentration suggests a temperature difference of at least 50 °C. Other differences in trace elements compositions are consistent with the interpretation that Icelandic and Hadean zircons grew in magmas with very different origins and histories (e.g., the heavy rare earth element Yb is almost an order of magnitude higher in Icelandic zircon). A comparison with elemental data for Phanerozoic zircon from different environments demonstrates that the Hadean population is unusually depleted in Ti, but otherwise similar to zircons from continental arc settings. Zircons from Iceland, and from modern evolving rift environments where oceanic lithosphere and upwelling asthenosphere are replacing continental lithosphere, are compositionally intermediate between mid-ocean ridge and continental arc zircon populations. The elemental distinctions are consistent with fractionation of zircon-bearing magmas under hotter and drier conditions in Icelandic, mid-ocean ridge, and evolving rift environments and cooler and wetter conditions in arc and, especially, Hadean environments.
•98% of Icelandic, but only 15% of Hadean zircon δ18O analyses are below 5.3‰ (mantle).•Ti (temp. proxy) is distinctly higher for Icelandic, compared to Hadean, zircons.•Enrichment of heavy rare earth elements distinguishes Icelandic from Hadean zircons.•Hadean zircon compositions resemble those of zircons from Phanerozoic continental arcs.•Hot-dry genesis implied for Icelandic and rift zircon, cool-wet for Hadean and arcs.
National rates of COVID-19 infection and fatality have varied dramatically since the onset of the pandemic. Understanding the conditions associated with this cross-country variation is essential to ...guiding investment in more effective preparedness and response for future pandemics.
Daily SARS-CoV-2 infections and COVID-19 deaths for 177 countries and territories and 181 subnational locations were extracted from the Institute for Health Metrics and Evaluation's modelling database. Cumulative infection rate and infection-fatality ratio (IFR) were estimated and standardised for environmental, demographic, biological, and economic factors. For infections, we included factors associated with environmental seasonality (measured as the relative risk of pneumonia), population density, gross domestic product (GDP) per capita, proportion of the population living below 100 m, and a proxy for previous exposure to other betacoronaviruses. For IFR, factors were age distribution of the population, mean body-mass index (BMI), exposure to air pollution, smoking rates, the proxy for previous exposure to other betacoronaviruses, population density, age-standardised prevalence of chronic obstructive pulmonary disease and cancer, and GDP per capita. These were standardised using indirect age standardisation and multivariate linear models. Standardised national cumulative infection rates and IFRs were tested for associations with 12 pandemic preparedness indices, seven health-care capacity indicators, and ten other demographic, social, and political conditions using linear regression. To investigate pathways by which important factors might affect infections with SARS-CoV-2, we also assessed the relationship between interpersonal and governmental trust and corruption and changes in mobility patterns and COVID-19 vaccination rates.
The factors that explained the most variation in cumulative rates of SARS-CoV-2 infection between Jan 1, 2020, and Sept 30, 2021, included the proportion of the population living below 100 m (5·4% 4·0–7·9 of variation), GDP per capita (4·2% 1·8–6·6 of variation), and the proportion of infections attributable to seasonality (2·1% 95% uncertainty interval 1·7–2·7 of variation). Most cross-country variation in cumulative infection rates could not be explained. The factors that explained the most variation in COVID-19 IFR over the same period were the age profile of the country (46·7% 18·4–67·6 of variation), GDP per capita (3·1% 0·3–8·6 of variation), and national mean BMI (1·1% 0·2–2·6 of variation). 44·4% (29·2–61·7) of cross-national variation in IFR could not be explained. Pandemic-preparedness indices, which aim to measure health security capacity, were not meaningfully associated with standardised infection rates or IFRs. Measures of trust in the government and interpersonal trust, as well as less government corruption, had larger, statistically significant associations with lower standardised infection rates. High levels of government and interpersonal trust, as well as less government corruption, were also associated with higher COVID-19 vaccine coverage among middle-income and high-income countries where vaccine availability was more widespread, and lower corruption was associated with greater reductions in mobility. If these modelled associations were to be causal, an increase in trust of governments such that all countries had societies that attained at least the amount of trust in government or interpersonal trust measured in Denmark, which is in the 75th percentile across these spectrums, might have reduced global infections by 12·9% (5·7–17·8) for government trust and 40·3% (24·3–51·4) for interpersonal trust. Similarly, if all countries had a national BMI equal to or less than that of the 25th percentile, our analysis suggests global standardised IFR would be reduced by 11·1%.
Efforts to improve pandemic preparedness and response for the next pandemic might benefit from greater investment in risk communication and community engagement strategies to boost the confidence that individuals have in public health guidance. Our results suggest that increasing health promotion for key modifiable risks is associated with a reduction of fatalities in such a scenario.
Bill & Melinda Gates Foundation, J Stanton, T Gillespie, J and E Nordstrom, and Bloomberg Philanthropies.
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