Comparison of the biotypes of Yersinia enterocolitica isolated from pigs, cattle and sheep at slaughter and from humans with yersiniosis in Great Britain during 1999-2000

Aims: To investigate the relationship between livestock carriage of Yersinia enterocolitica and human disease. The biotypes/serotypes of strains recovered from the faeces of pigs, cattle and sheep at slaughter during a national survey in Great Britain in 1999-2000, were compared with those of strains isolated from human cases of yersiniosis during the same period. Methods and Results: The faecal carriage of Y. enterocolitica by cattle, sheep and pigs at slaughter was 6.3, 10.7 and 26.1%, respectively. Yersinia enterocolitica biotype (BT) 1a was the most frequently isolated biotype from livestock (58%) and was the predominant biotype (53%) isolated from human cases over the same period. The main recognized pathogenic Y. enterocolitica biotype isolated from livestock was BT3 (O:5,27) (35% of sheep, 22% of pigs and 4% of cattle) but this biotype was not detected in any of the human isolates investigated. The major pathogenic biotypes of strains isolated from humans were BT3 (O:9) (24%) and BT4 (O:3) (19%) whereas of the veterinary isolates investigated, only pigs (11%) carried BT3 (O:9) strains. Conclusions: Because of significant overlaps in phenotypes of the veterinary and human strains it is not possible to comment on the correlation between host and pathogenicity, especially of biotype 1a. Significance and Impact of the Study: The data suggest that further investigations using methods with greater discriminatory power are required. However the data also suggests that pigs may be the primary reservoir for human pathogenic Y. enterocolitica infection

Northern Hemisphere blocking simulation in current climate models: evaluating progress from the Climate Model Intercomparison Project Phase 5 to 6 and sensitivity to resolution

Global climate models (GCMs) are known to suffer from biases in the simulation of atmospheric blocking, and this study provides an assessment of how blocking is represented by the latest generation of GCMs. It is evaluated (i) how historical CMIP6 (Climate Model Intercomparison Project Phase 6) simulations perform compared to CMIP5 simulations and (ii) how horizontal model resolution affects the simulation of blocking in the CMIP6-HighResMIP (PRIMAVERA – PRocess-based climate sIMulation: AdVances in high-resolution modelling and European climate Risk Assessment) model ensemble, which is designed to address this type of question. Two blocking indices are used to evaluate the simulated mean blocking frequency and blocking persistence for the Euro-Atlantic and Pacific regions in winter and summer against the corresponding estimates from atmospheric reanalysis data. There is robust evidence that CMIP6 models simulate blocking frequency and persistence better than CMIP5 models in the Atlantic and Pacific and during winter and summer. This improvement is sizeable so that, for example, winter blocking frequency in the median CMIP5 model in a large Euro-Atlantic domain is underestimated by 33 % using the absolute geopotential height (AGP) blocking index, whereas the same number is 18 % for the median CMIP6 model. As for the sensitivity of simulated blocking to resolution, it is found that the resolution increase, from typically 100 to 20 km grid spacing, in most of the PRIMAVERA models, which are not re-tuned at the higher resolutions, benefits the mean blocking frequency in the Atlantic in winter and summer and in the Pacific in summer. Simulated blocking persistence, however, is not seen to improve with resolution. Our results are consistent with previous studies suggesting that resolution is one of a number of interacting factors necessary for an adequate simulation of blocking in GCMs. The improvements reported in this study hold promise for further reductions in blocking biases as model development continues

Does the HadGEM3-GC3.1 GCM overestimate land precipitation at high resolution? A constraint based on observed river discharge

Previous studies showed that high-resolution GCMs overestimate land precipitation when compared against observation-based data. Particularly, high-resolution HadGEM3-GC3.1 shows a significant precipitation increase in mountainous regions, where the scarcity of gauge stations increases the uncertainty of gridded observations and reanalyses. This work evaluates such precipitation uncertainties indirectly through the assessment of river discharge, considering that an increase of ~10% in land precipitation produces ~28% more runoff when the resolution is enhanced from 1° to 0.25°, and ~50% of the global runoff is produced in 27% of global land dominated by mountains. We diagnosed the river flow by routing the runoff generated by HadGEM3-GC3.1 low- and high-resolution simulations. The river flow is evaluated using a set of 344 monitored catchments distributed around the world. We also infer the global discharge by constraining the simulations with observations following a novel approach that implies bias correction in monitored rivers with two methods, and extension of the correction to the river mouth, and along the coast. Our global discharge estimate is 47.4 ± 1.6 × 103 km3 yr−1, which is closer to the original high-resolution estimate (50.5 × 103 km3 yr−1) than to the low-resolution (39.6 × 103 km3 yr−1). The assessment suggests that high-resolution simulations perform better in mountainous regions, either because the better-defined orography favors the placement of precipitation in the correct catchment, leading to a more accurate distribution of runoff, or the orographic precipitation increases, reducing the dry runoff bias of coarse-resolution simulations. However, high-resolution slightly increases wet biases in catchments dominated by flat terrain. The improvement of model parameterizations and tuning may reduce the remaining errors in high-resolution simulations

The use of cystatin C to inhibit epithelial–mesenchymal transition and morphological transformation stimulated by transforming growth factor-β

INTRODUCTION: Transforming growth factor-β (TGF-β) is a potent suppressor of mammary epithelial cell (MEC) proliferation and is thus an inhibitor of mammary tumor formation. Malignant MECs typically evolve resistance to TGF-β-mediated growth arrest, enhancing their proliferation, invasion, and metastasis when stimulated by TGF-β. Recent findings suggest that therapeutics designed to antagonize TGF-β signaling may alleviate breast cancer progression, thereby improving the prognosis and treatment of breast cancer patients. We identified the cysteine protease inhibitor cystatin C (CystC) as a novel TGF-β type II receptor antagonist that inhibits TGF-β binding and signaling in normal and cancer cells. We hypothesized that the oncogenic activities of TGF-β, particularly its stimulation of mammary epithelial–mesenchymal transition (EMT), can be prevented by CystC. METHOD: Retroviral infection was used to constitutively express CystC or a CystC mutant impaired in its ability to inhibit cathepsin protease activity (namely Δ14CystC) in murine NMuMG MECs and in normal rat kidney (NRK) fibroblasts. The effect of recombinant CystC administration or CystC expression on TGF-β stimulation of NMuMG cell EMT in vitro was determined with immunofluorescence to monitor rearrangements of actin cytoskeletal architecture and E-cadherin expression. Soft-agar growth assays were performed to determine the effectiveness of CystC in preventing TGF-β stimulation of morphological transformation and anchorage-independent growth in NRK fibroblasts. Matrigel invasion assays were performed to determine the ability of CystC to inhibit NMuMG and NRK motility stimulated by TGF-β. RESULTS: CystC and Δ14CystC both inhibited NMuMG cell EMT and invasion stimulated by TGF-β by preventing actin cytoskeletal rearrangements and E-cadherin downregulation. Moreover, both CystC molecules completely antagonized TGF-β-mediated morphological transformation and anchorage-independent growth of NRK cells, and inhibited their invasion through synthetic basement membranes. Both CystC and Δ14CystC also inhibited TGF-β signaling in two tumorigenic human breast cancer cell lines. CONCLUSION: Our findings show that TGF-β stimulation of initiating metastatic events, including decreased cell polarization, reduced cell–cell contact, and elevated cell invasion and migration, are prevented by CystC treatment. Our findings also suggest that the future development of CystC or its peptide mimetics hold the potential to improve the therapeutic response of human breast cancers regulated by TGF-β

Land–Atmosphere coupling sensitivity to GCMs resolution: a multimodel assessment of local and remote processes in the Sahel hot spot

Land–atmosphere interactions are often interpreted as local effects, whereby the soil state drives local atmospheric conditions and feedbacks originate. However, nonlocal mechanisms can significantly modulate land–atmosphere exchanges and coupling. We make use of GCMs at different resolutions (low ~1° and high ~0.25°) to separate the two contributions to coupling: better represented local processes versus the influence of improved large-scale circulation. We use a two-legged metric, complemented by a process-based assessment of four CMIP6 GCMs. Our results show that weakening, strengthening, and relocation of coupling hot spots occur at high resolution globally. The northward expansion of the Sahel hot spot, driven by nonlocal mechanisms, is the most notable change. The African easterly jet’s horizontal wind shear is enhanced in JJA due to better resolved orography at high resolution. This effect, combined with enhanced easterly moisture flux, favors the development of African easterly waves over the Sahel. More precipitation and soil moisture recharge produce strengthening of the coupling, where evapotranspiration remains controlled by soil moisture, and weakening where evapotranspiration depends on atmospheric demand. In SON, the atmospheric influence is weaker, but soil memory helps to maintain the coupling between soil moisture and evapotranspiration and the relocation of the hot spot at high resolution. The multimodel agreement provides robust evidence that atmospheric dynamics determines the onset of land–atmosphere interactions, while the soil state modulates their duration. Comparison of precipitation, soil moisture, and evapotranspiration against satellite data reveals that the enhanced moistening at high resolution significantly reduces model biases, supporting the realism of the hot-spot relocation

Impact of higher spatial atmospheric resolution on precipitation extremes over land in global climate models

Finer grids in global climate models could lead to an improvement in the simulation of precipitation extremes. We assess the influence on model performance of increasing spatial resolution by evaluating pairs of high‐ and low‐resolution forced atmospheric simulations from six global climate models (generally the latest CMIP6 version) on a common 1° × 1° grid. The differences in tuning between the lower and higher resolution versions are as limited as possible, which allows the influence of higher resolution to be assessed exclusively. We focus on the 1985–2014 climatology of annual extremes of daily precipitation over global land, and models are compared to observations from different sources (i.e., in situ‐based and satellite‐based) to enable consideration of observational uncertainty. Finally, we address regional features of model performance based on four indices characterizing different aspects of precipitation extremes. Our analysis highlights good agreement between models that precipitation extremes are more intense at higher resolution. We find that the spread among observations is substantial and can be as large as intermodel differences, which makes the quantitative evaluation of model performance difficult. However, consistently across the four precipitation extremes indices that we investigate, models often show lower skill at higher resolution compared to their corresponding lower resolution version. Our findings suggest that increasing spatial resolution alone is not sufficient to obtain a systematic improvement in the simulation of precipitation extremes, and other improvements (e.g., physics and tuning) may be required

(Re)constructing Dimensions

Compactifying a higher-dimensional theory defined in R^{1,3+n} on an n-dimensional manifold {\cal M} results in a spectrum of four-dimensional (bosonic) fields with masses m^2_i = \lambda_i, where - \lambda_i are the eigenvalues of the Laplacian on the compact manifold. The question we address in this paper is the inverse: given the masses of the Kaluza-Klein fields in four dimensions, what can we say about the size and shape (i.e. the topology and the metric) of the compact manifold? We present some examples of isospectral manifolds (i.e., different manifolds which give rise to the same Kaluza-Klein mass spectrum). Some of these examples are Ricci-flat, complex and K\"{a}hler and so they are isospectral backgrounds for string theory. Utilizing results from finite spectral geometry, we also discuss the accuracy of reconstructing the properties of the compact manifold (e.g., its dimension, volume, and curvature etc) from measuring the masses of only a finite number of Kaluza-Klein modes.Comment: 23 pages, 3 figures, 2 references adde

Euro-Atlantic weather regimes in the PRIMAVERA coupled climate simulations: impact of resolution and mean state biases on model performance

Recently, much attention has been devoted to better understand the internal modes of variability of the climate system. This is particularly important in mid-latitude regions like the North-Atlantic, which is characterized by a large natural variability and is intrinsically difficult to predict. A suitable framework for studying the modes of variability of the atmospheric circulation is to look for recurrent patterns, commonly referred to as Weather Regimes. Each regime is characterized by a specific large-scale atmospheric circulation pattern, thus influencing regional weather and extremes over Europe. The focus of the present paper is the study of the Euro-Atlantic wintertime Weather Regimes in the climate models participating to the PRIMAVERA project. We analyse here the set of coupled historical simulations (hist-1950), which have been performed both at standard and increased resolution, following the HighresMIP protocol. The models’ performance in reproducing the observed Weather Regimes is assessed in terms of different metrics, focussing on systematic biases and on the impact of resolution. We also analyse the connection of the Weather Regimes with the Jet Stream latitude and blocking frequency over the North-Atlantic sector. We find that—for most models—the regime patterns are better represented in the higher resolution version, for all regimes but the NAO-. On the other side, no clear impact of resolution is seen on the regime frequency of occurrence and persistence. Also, for most models, the regimes tend to be more tightly clustered in the increased resolution simulations, more closely resembling the observed ones. However, the horizontal resolution is not the only factor determining the model performance, and we find some evidence that biases in the SSTs and mean geopotential field might also play a role

TAMEP are brain tumor parenchymal cells controlling neoplastic angiogenesis and progression

Aggressive brain tumors like glioblastoma depend on support by their local environment and subsets of tumor parenchymal cells may promote specific phases of disease progression. We investigated the glioblastoma microenvironment with transgenic lineage-tracing models, intravital imaging, single-cell transcriptomics, immunofluorescence analysis as well as histopathology and characterized a previously unacknowledged population of tumor-associated cells with a myeloid-like expression profile (TAMEP) that transiently appeared during glioblastoma growth. TAMEP of mice and humans were identified with specific markers. Notably, TAMEP did not derive from microglia or peripheral monocytes but were generated by a fraction of CNS-resident, SOX2-positive progenitors. Abrogation of this progenitor cell population, by conditional Sox2-knockout, drastically reduced glioblastoma vascularization and size. Hence, TAMEP emerge as a tumor parenchymal component with a strong impact on glioblastoma progression

Combined loss of the BH3-only proteins Bim and Bmf restores B-cell development and function in TACI-Ig transgenic mice.

Terminal differentiation of B cells depends on two interconnected survival pathways, elicited by the B-cell receptor (BCR) and the BAFF receptor (BAFF-R), respectively. Loss of either signaling pathway arrests B-cell development. Although BCR-dependent survival depends mainly on the activation of the v-AKT murine thymoma viral oncogene homolog 1 (AKT)/PI3-kinase network, BAFF/BAFF-R-mediated survival engages non-canonical NF-κB signaling as well as MAPK/extracellular-signal regulated kinase and AKT/PI3-kinase modules to allow proper B-cell development. Plasma cell survival, however, is independent of BAFF-R and regulated by APRIL that signals NF-κB activation via alternative receptors, that is, transmembrane activator and CAML interactor (TACI) or B-cell maturation (BCMA). All these complex signaling events are believed to secure survival by increased expression of anti-apoptotic B-cell lymphoma 2 (Bcl2) family proteins in developing and mature B cells. Curiously, how lack of BAFF- or APRIL-mediated signaling triggers B-cell apoptosis remains largely unexplored. Here, we show that two pro-apoptotic members of the 'Bcl2 homology domain 3-only' subgroup of the Bcl2 family, Bcl2 interacting mediator of cell death (Bim) and Bcl2 modifying factor (Bmf), mediate apoptosis in the context of TACI-Ig overexpression that effectively neutralizes BAFF as well as APRIL. Surprisingly, although Bcl2 overexpression triggers B-cell hyperplasia exceeding the one observed in Bim(-/-)Bmf(-/-) mice, Bcl2 transgenic B cells remain susceptible to the effects of TACI-Ig expression in vivo, leading to ameliorated pathology in Vav-Bcl2 transgenic mice. Together, our findings shed new light on the molecular machinery restricting B-cell survival during development, normal homeostasis and under pathological conditions. Our data further suggest that Bcl2 antagonists might improve the potency of BAFF/APRIL-depletion strategies in B-cell-driven pathologies