Non-canonical Hedgehog signaling mediates profibrotic hematopoiesis-stroma crosstalk in myeloproliferative neoplasms

The role of hematopoietic Hedgehog signaling in myeloproliferative neoplasms (MPNs) remains incompletely understood despite data suggesting that Hedgehog (Hh) pathway inhibitors have therapeutic activity in patients. We aim to systematically interrogate the role of canonical vs. non-canonical Hh signaling in MPNs. We show that Gli1 protein levels in patient peripheral blood mononuclear cells (PBMCs) mark fibrotic progression and that, in murine MPN models, absence of hematopoietic Gli1, but not Gli2 or Smo, significantly reduces MPN phenotype and fibrosis, indicating that GLI1 in the MPN clone can be activated in a non-canonical fashion. Additionally, we establish that hematopoietic Gli1 has a significant effect on stromal cells, mediated through a druggable MIF-CD74 axis. These data highlight the complex interplay between alterations in the MPN clone and activation of stromal cells and indicate that Gli1 represents a promising therapeutic target in MPNs, particularly that Hh signaling is dispensable for normal hematopoiesis.</p

Measurement of the cosmic ray spectrum above 4×10184{\times}10^{18} eV using inclined events detected with the Pierre Auger Observatory

A measurement of the cosmic-ray spectrum for energies exceeding $4{\times}10^{18}$ eV is presented, which is based on the analysis of showers with zenith angles greater than $60^{\circ}$ detected with the Pierre Auger Observatory between 1 January 2004 and 31 December 2013. The measured spectrum confirms a flux suppression at the highest energies. Above $5.3{\times}10^{18}$ eV, the "ankle", the flux can be described by a power law $E^{-\gamma}$ with index $\gamma=2.70 \pm 0.02 \,\text{(stat)} \pm 0.1\,\text{(sys)}$ followed by a smooth suppression region. For the energy ($E_\text{s}$) at which the spectral flux has fallen to one-half of its extrapolated value in the absence of suppression, we find $E_\text{s}=(5.12\pm0.25\,\text{(stat)}^{+1.0}_{-1.2}\,\text{(sys)}){\times}10^{19}$ eV.Comment: Replaced with published version. Added journal reference and DO

The consolidated European synthesis of CO2 emissions and removals for the European Union and United Kingdom:1990-2020

Quantification of land surface-atmosphere fluxes of carbon dioxide (CO2) and their trends and uncertainties is essential for monitoring progress of the EU27+UK bloc as it strives to meet ambitious targets determined by both international agreements and internal regulation. This study provides a consolidated synthesis of fossil sources (CO2 fossil) and natural (including formally managed ecosystems) sources and sinks over land (CO2 land) using bottom-up (BU) and top-down (TD) approaches for the European Union and United Kingdom (EU27+UK), updating earlier syntheses (Petrescu et al., 2020, 2021). Given the wide scope of the work and the variety of approaches involved, this study aims to answer essential questions identified in the previous syntheses and understand the differences between datasets, particularly for poorly characterized fluxes from managed and unmanaged ecosystems. The work integrates updated emission inventory data, process-based model results, data-driven categorical model results, and inverse modeling estimates, extending the previous period 1990-2018 to the year 2020 to the extent possible. BU and TD products are compared with the European national greenhouse gas inventory (NGHGI) reported by parties including the year 2019 under the United Nations Framework Convention on Climate Change (UNFCCC). The uncertainties of the EU27+UK NGHGI were evaluated using the standard deviation reported by the EU member states following the guidelines of the Intergovernmental Panel on Climate Change (IPCC) and harmonized by gap-filling procedures. Variation in estimates produced with other methods, such as atmospheric inversion models (TD) or spatially disaggregated inventory datasets (BU), originate from within-model uncertainty related to parameterization as well as structural differences between models. By comparing the NGHGI with other approaches, key sources of differences between estimates arise primarily in activities. System boundaries and emission categories create differences in CO2 fossil datasets, while different land use definitions for reporting emissions from land use, land use change, and forestry (LULUCF) activities result in differences for CO2 land. The latter has important consequences for atmospheric inversions, leading to inversions reporting stronger sinks in vegetation and soils than are reported by the NGHGI. For CO2 fossil emissions, after harmonizing estimates based on common activities and selecting the most recent year available for all datasets, the UNFCCC NGHGI for the EU27+UK accounts for 926g±g13gTggCgyr-1, while eight other BU sources report a mean value of 948 [937,961]gTggCgyr-1 (25th, 75th percentiles). The sole top-down inversion of fossil emissions currently available accounts for 875gTggC in this same year, a value outside the uncertainty of both the NGHGI and bottom-up ensemble estimates and for which uncertainty estimates are not currently available. For the net CO2 land fluxes, during the most recent 5-year period including the NGHGI estimates, the NGHGI accounted for -91g±g32gTggCgyr-1, while six other BU approaches reported a mean sink of -62 [-117,-49]gTggCgyr-1, and a 15-member ensemble of dynamic global vegetation models (DGVMs) reported -69 [-152,-5]gTggCgyr-1. The 5-year mean of three TD regional ensembles combined with one non-ensemble inversion of -73gTggCgyr-1 has a slightly smaller spread (0th-100th percentiles of [-135,+45]gTggCgyr-1), and it was calculated after removing net land-atmosphere CO2 fluxes caused by lateral transport of carbon (crop trade, wood trade, river transport, and net uptake from inland water bodies), resulting in increased agreement with the NGHGI and bottom-up approaches. Results at the category level (Forest Land, Cropland, Grassland) generally show good agreement between the NGHGI and category-specific models, but results for DGVMs are mixed. Overall, for both CO2 fossil and net CO2 land fluxes, we find that current independent approaches are consistent with the NGHGI at the scale of the EU27+UK. We conclude that CO2 emissions from fossil sources have decreased over the past 30 years in the EU27+UK, while land fluxes are relatively stable: positive or negative trends larger (smaller) than 0.07 (-0.61)gTggCgyr-2 can be ruled out for the NGHGI. In addition, a gap on the order of 1000gTggCgyr-1 between CO2 fossil emissions and net CO2 uptake by the land exists regardless of the type of approach (NGHGI, TD, BU), falling well outside all available estimates of uncertainties. However, uncertainties in top-down approaches to estimate CO2 fossil emissions remain uncharacterized and are likely substantial, in addition to known uncertainties in top-down estimates of the land fluxes. The data used to plot the figures are available at 10.5281/zenodo.8148461 (McGrath et al., 2023).</p

Heterogeneous bone-marrow stromal progenitors drive myelofibrosis via a druggable alarmin axis

Functional contributions of individual cellular components of the bone-marrow microenvironment to myelofibrosis (MF) in patients with myeloproliferative neoplasms (MPNs) are incompletely understood. We aimed to generate a comprehensive map of the stroma in MPNs/MFs on a single-cell level in murine models and patient samples. Our analysis revealed two distinct mesenchymal stromal cell (MSC) subsets as pro-fibrotic cells. MSCs were functionally reprogrammed in a stage-dependent manner with loss of their progenitor status and initiation of differentiation in the pre-fibrotic and acquisition of a pro-fibrotic and inflammatory phenotype in the fibrotic stage. The expression of the alarmin complex S100A8/S100A9 in MSC marked disease progression toward the fibrotic phase in murine models and in patient stroma and plasma. Tasquinimod, a small-molecule inhibiting S100A8/S100A9 signaling, significantly ameliorated the MPN phenotype and fibrosis in JAK2V617F-mutated murine models, highlighting that S100A8/S100A9 is an attractive therapeutic target in MPNs.Leimkühler and colleagues demonstrate that mesenchymal stromal progenitor cells are fibro

The consolidated European synthesis of CO2 emissions and removals for the European Union and United Kingdom: 1990–2020

Quantification of land surface–atmosphere fluxes of carbon dioxide (CO2) and their trends and uncertainties is essential for monitoring progress of the EU27+UK bloc as it strives to meet ambitious targets determined by both international agreements and internal regulation. This study provides a consolidated synthesis of fossil sources (CO2 fossil) and natural (including formally managed ecosystems) sources and sinks over land (CO2 land) using bottom-up (BU) and top-down (TD) approaches for the European Union and United Kingdom (EU27+UK), updating earlier syntheses (Petrescu et al., 2020, 2021). Given the wide scope of the work and the variety of approaches involved, this study aims to answer essential questions identified in the previous syntheses and understand the differences between datasets, particularly for poorly characterized fluxes from managed and unmanaged ecosystems. The work integrates updated emission inventory data, process-based model results, data-driven categorical model results, and inverse modeling estimates, extending the previous period 1990–2018 to the year 2020 to the extent possible. BU and TD products are compared with the European national greenhouse gas inventory (NGHGI) reported by parties including the year 2019 under the United Nations Framework Convention on Climate Change (UNFCCC). The uncertainties of the EU27+UK NGHGI were evaluated using the standard deviation reported by the EU member states following the guidelines of the Intergovernmental Panel on Climate Change (IPCC) and harmonized by gap-filling procedures. Variation in estimates produced with other methods, such as atmospheric inversion models (TD) or spatially disaggregated inventory datasets (BU), originate from within-model uncertainty related to parameterization as well as structural differences between models. By comparing the NGHGI with other approaches, key sources of differences between estimates arise primarily in activities. System boundaries and emission categories create differences in CO2 fossil datasets, while different land use definitions for reporting emissions from land use, land use change, and forestry (LULUCF) activities result in differences for CO2 land. The latter has important consequences for atmospheric inversions, leading to inversions reporting stronger sinks in vegetation and soils than are reported by the NGHGI. For CO2 fossil emissions, after harmonizing estimates based on common activities and selecting the most recent year available for all datasets, the UNFCCC NGHGI for the EU27+UK accounts for 926 ± 13 Tg C yr−1, while eight other BU sources report a mean value of 948 [937,961] Tg C yr−1 (25th, 75th percentiles). The sole top-down inversion of fossil emissions currently available accounts for 875 Tg C in this same year, a value outside the uncertainty of both the NGHGI and bottom-up ensemble estimates and for which uncertainty estimates are not currently available. For the net CO2 land fluxes, during the most recent 5-year period including the NGHGI estimates, the NGHGI accounted for −91 ± 32 Tg C yr−1, while six other BU approaches reported a mean sink of −62 [] Tg C yr−1, and a 15-member ensemble of dynamic global vegetation models (DGVMs) reported −69 [] Tg C yr−1. The 5-year mean of three TD regional ensembles combined with one non-ensemble inversion of −73 Tg C yr−1 has a slightly smaller spread (0th–100th percentiles of [] Tg C yr−1), and it was calculated after removing net land–atmosphere CO2 fluxes caused by lateral transport of carbon (crop trade, wood trade, river transport, and net uptake from inland water bodies), resulting in increased agreement with the NGHGI and bottom-up approaches. Results at the category level (Forest Land, Cropland, Grassland) generally show good agreement between the NGHGI and category-specific models, but results for DGVMs are mixed. Overall, for both CO2 fossil and net CO2 land fluxes, we find that current independent approaches are consistent with the NGHGI at the scale of the EU27+UK. We conclude that CO2 emissions from fossil sources have decreased over the past 30 years in the EU27+UK, while land fluxes are relatively stable: positive or negative trends larger (smaller) than 0.07 (−0.61) Tg C yr−2 can be ruled out for the NGHGI. In addition, a gap on the order of 1000 Tg C yr−1 between CO2 fossil emissions and net CO2 uptake by the land exists regardless of the type of approach (NGHGI, TD, BU), falling well outside all available estimates of uncertainties. However, uncertainties in top-down approaches to estimate CO2 fossil emissions remain uncharacterized and are likely substantial, in addition to known uncertainties in top-down estimates of the land fluxes. The data used to plot the figures are available at https://doi.org/10.5281/zenodo.8148461 (McGrath et al., 2023)

The Handmade Effect: What&apos;s Love Got to Do with It?

Abstract: Despite the popularity and high quality of machine-made products, handmade products have not disappeared even in many product categories where machinal production is common. We present the first systematic set of studies exploring whether and how stated production mode (handmade vs. machine-made) affects product attractiveness. Four studies provide evidence for the existence of a positive handmade effect on product attractiveness. This effect is to an important extent driven by perceptions that handmade products &quot;contain love&quot;. This love account is validated controlling for alternative value drivers of handmade production (mere effort, product quality, uniqueness, authenticity, pride). The handmade effect is moderated by two factors that affect the value of love. Specifically, consumers indicate stronger purchase intentions for handmade than machine-made products when buying gifts for their loved ones, but not for more distant gift recipients and pay more for handmade gifts when they are bought to convey love than when buying the best-performing product. Keywords: Handmade, machine-made, production mode, product attractiveness, love 3 In an era of technological advancement and widespread robotization, in which machines produce very high quality products to exacting specifications, it seems ironic that we see more and more products that are promoted as &quot;handmade.&quot; In fact, we find products explicitly advertised as handmade in many categories, such as sandwiches and bread (Pret A Manger, Udi&apos;s), soaps and cosmetics (Lush), guitars (Candelas), sneakers (Vans), eyewear (Armani), knives (Cut Brooklyn), furniture and household products (Etsy), wine (Columbia Crest), or tableware (Gmundner). Some even speak of a &quot;handmade revolution&quot; (cf. the BBC television series entitled Paul Martin&apos;s Handmade Revolution). It is interesting to us that in a time when machines produce excellent products in a precise and consistent way Considering the high quality of machinal production, it is not clear a priori if and why product attractiveness is increased by marketing a product as handmade (versus machine-made or not mentioning the production mode). Of course, one might argue that a positive handmade effect has to exist given the fact that marketers frequently choose to present their products as handmade. However, in our marketplace observations, whether a product is advertised as &quot;handmade&quot; tends not to be manipulated and can be confounded with many other factors such as price points, materials used, or design elements. Thus, we feel there is a need for a controlled empirical test of the existence of an effect of presenting a product as handmade on that product&apos;s attractiveness. To our surprise, we found no such test in the literature. In this manuscript, we therefore aim to assess the effect of stated production mode on product attractiveness by manipulating whether the same product is presented to consumers as handmade (vs. machine-made). We limit this first-of-type analysis to Western consumers (by drawing on diverse European and North American consumer samples) and discuss the 4 generalizability of our theory to non-Western societies in our General Discussion section. Conditional upon the existence of a handmade effect, our second main objective is to explore one of the processes that might underlie the effect as well its boundary conditions and moderators. It is important to note that we focus on the way companies communicate the production mode (i.e., as handmade vs. machine-made) rather than the actual, physical production mode. As has been the case since the times of the ancient Assyrian loom (Barber 2013), and probably even before that, purely hand-made production is rare. Almost no production process currently involves no machines (e.g., a maker of handmade knives uses a machine to sharpen the knives). On the other hand, many &quot;machinal&quot; production processes involve some form of human contact. Thus, it is often difficult to objectively categorize a product as completely handmade or completely machine-made (Barber 2013). This provides marketing managers with considerable degrees of freedom whether to present their products as handmade (versus machine-made or not mentioning their product&apos;s production mode). Thus, rather than the precise role of machines versus hands in the actual production process, what interests us is consumers&apos; perceptions of products that are marketed as being handmade (vs. machine-made). For our research purpose, we thus define a handmade versus machine-made product as one which is presented (e.g., by the producing company) to consumers as being made by hand or a hand-process and not by a machine or a machinal process. The manuscript offers the following contributions. First and across a variety of product domains and samples from three Western societies, we find that consumers perceive handmade products to be more attractive. We define our focal dependent variable, product attractiveness, as consumers&apos; attitudinal and behavioral predisposition toward to the underlying product using both items assessing attitude towards the product and items probing the attractiveness of the product for purchase (cf. Sweldens, van Osselaer, and Janiszewski 2010). Notably, the handmade effect is 5 found to materialize against both a control group where the products were portrayed as machinemade as well as one were no information regarding the production mode was provided (Study 1). Theoretically, this newly identified handmade effect can be understood in light of positive contagion and consumer labor theory (Argo, Dahl, and Morales 2008; Our first suspicion based on informal marketplace observation as well as positive contagion and consumer labor theories that love might play a role in the handmade effect was further corroborated by an exploratory pilot study. In this open association pilot study we asked 114 participants to write down their thoughts and feelings about handmade products. Love, either in the form of the love a handmade producer puts into the production process or in the form of love imbued in the product, emerged as a frequent robust theme (e.g., &quot;Handmade products are … built with care and love&quot; [#101], &quot;I like it [handmade product] and especially the fact that it is hand made. It is made with love&quot; [#53], &quot;There is something else in that product. …it is love&quot; [#25]). Thus, results suggested that love might indeed be worth studying as a potential driver of a handmade effect on product attractiveness. 6 As with virtually every empirical phenomenon of substantial practical importance, however, the handmade effect is unlikely to be exclusively driven by a &quot;one and only&quot; process. It is important to identify these potential co-determinants so they can be controlled for in our attempt to isolate the role of love as one significant driver of the potential handmade effect. Thus, we also used the open association pilot to find other factors that might co-determine a handmade effect on product attractiveness. We found that handmade products were perceived by some respondents to require more time to produce, which might increase perceived quality, and through increased perceived quality yield higher attractiveness. Thus, handmade production might increase attractiveness through the effort heuristic In the remainder of this manuscript, we provide a more extensive discussion of theoretical background, followed by four empirical studies. In Study 1, we demonstrate the existence of th

Reducing Consumer Alienation: the Effect of Making Product Producers Personal

In the era of mass production, consumers often know nothing about the person(s) who created the products they consume. Six studies show that exposing consumers to personal information about a product&apos;s producer increases product preference. This effect is not due to increased accountability, but to a feeling of connectedness