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The assimilation of clear-sky radiance in the European Centre for Medium-Range Weather Forecasts (ECMWF) atmospheric analysis relies on the clear-sky radiances observation operator. Some of these radiances have frequencies that make them sensitive to both the surface and atmosphere. Because the atmospheric and surface analyses are currently not strongly coupled, a specific treatment of the surface is required. The observation operator specifically expects a skin temperature value at the observation location and time as well as the profiles of the atmospheric variables along the viewing path. This skin temperature is added to the control variable and optimised simultaneously with all of the atmospheric variables to produce optimal simulated radiances. We present two approaches to add the skin temperature to the control variable. In the current TOVS Control Variable (TOVSCV) approach, a series of skin temperature values per observation location is added to the control variable. Effectively, in the optimisation process, the skin temperature acts as a sink variable in observation space and is uncoupled from the skin temperature at other locations. In the novel SKin Temperature in the Extended Control Vector (SKTECV) approach, two-dimensional skin temperature fields are added to the control variable. All clear-sky radiances then participate in the optimisation of these two-dimensional fields, and the analysis produces temporally and spatially consistent skin temperature fields. We compare the two approaches over two seasons of 3 months each. Overall, there is a neutral impact of the new approach on the analysis and forecast. Moreover, there is some evidence that the contribution of the subsurface layers should be represented in the new approach for the skin temperature associated with the microwave instruments.

The aim of this study is to determine whether there is a benefit of using stereotactic radiosurgery (SRS) versus surgery or conventional external beam radiotherapy (cEBRT) for spinal oligometastatic disease in terms of tumor control, pain control, toxicity and morbidity. This systematic review was conducted by searching electronic databases such as Pubmed, Medline (Ovid) and Oxford Academic using an adapted version of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) checklist. Retrospective and prospective studies were identified and investigated for methods of treatment such as SRS, surgery and radiotherapy of spinal oligometastatic disease. Local Control rates, Overall Survival (OS) rates, Pain Response (PR) and toxicities were extracted to be investigated and compared. A study eligibility criterion was made to ensure that results were valid, statistically significant and relevant to the investigation. One hundred and five articles were relevant to oligometastatic disease with the mention of spinal metastases however 89 of these articles were excluded based on irrelevance to investigation, title, abstract and duplication. Sixteen full text articles were thoroughly screened including 9 of them in the review. For 601 patients the average one year local control rate was 89%, average one year overall survival rate was 88%, evidence of pain relief was present, and some patients suffered low grade toxicities. In conclusion, stereotactic radiosurgery is an excellent modality of treatment of spinal oligometastatic disease as local control rates, overall survival rates, pain response and toxicities indicate improved outcomes in comparison to studies that investigated the same factors with the treatment of surgery or cEBRT. However, there is a lack of data here to make statistically valid claims and require more studies & data to be analyzed and compared.

The beneficial effects of human milk suppressing the development of intestinal pathologies such as necrotizing enterocolitis in preterm infants are widely known. Human milk (HM) is rich in a multitude of bioactive factors that play major roles in promoting postnatal maturation, differentiation, and the development of the microbiome. Previous studies showed that HM is rich in hyaluronan (HA) especially in colostrum and early milk. This study aims to determine the role of HA 35 KDa, a HM HA mimic, on intestinal proliferation, differentiation, and the development of the intestinal microbiome. We show that oral HA 35 KDa supplementation for 7 days in mouse pups leads to increased villus length and crypt depth, and increased goblet and Paneth cells, compared to controls. We also show that HA 35 KDa leads to an increased predominance of Clostridiales Ruminococcaceae, Lactobacillales Lactobacillaceae, and Clostridiales Lachnospiraceae. In seeking the mechanisms involved in the changes, bulk RNA seq was performed on samples from the terminal ileum and identified upregulation in several genes essential for cellular growth, proliferation, and survival. Taken together, this study shows that HA 35 KDa supplemented to mouse pups promotes intestinal epithelial cell proliferation, as well as the development of Paneth cells and goblet cell subsets. HA 35 KDa also impacted the intestinal microbiota, the implications of these responses need to be determined.

Territorial development and rural tourism are linked. Rural tourism involves tourists in rural areas who are attracted by the distinctive character of the landscape, recreation such as local and food resources, and the potential for spiritual, environmental, and cultural growth. The aim of the present paper is to investigate the economic, sustainable, and social role of tourism in the development of the rural area of Mărginimea Sibiului in Romania. It highlights the role of local entrepreneurs in developing new practices and sustainable approaches. Drawing on the literature review on the topic of sustainable rural tourism, this paper uses the case study as a methodological approach. We have developed consistent desk research relying on the processing of official governmental data and of national statistics, supported by analytical strategies involving induction and deduction. The main findings lead towards the conclusion that Mărginimea Sibiului has managed to gain both national and international notoriety while developing coherently, capitalizing on its natural and cultural heritage, and providing services in successful agritourist boarding houses and rural guesthouses, which have continuously developed both numerically and in terms of comfort levels. Because more than two thirds of the initially established lodgings in the early 2000s continue to function today, these facilities have proven to be sustainable and attractive businesses.

The novel protein ADTRP, identified and described by us in 2011, is androgen-inducible and regulates the expression and activity of Tissue Factor Pathway Inhibitor, the major inhibitor of the Tissue Factor-dependent pathway of coagulation on endothelial cells. Single-nucleotide polymorphisms in ADTRP associate with coronary artery disease and myocardial infarction, and deep vein thrombosis/venous thromboembolism. Some athero-protective effects of androgen could exert through up-regulation of ADTRP expression. We discovered a critical role of ADTRP in vascular development and vessel integrity and function, manifested through Wnt signaling-dependent regulation of matrix metalloproteinase-9. ADTRP also hydrolyses fatty acid esters of hydroxy-fatty acids, which have anti-diabetic and anti-inflammatory effects and can control metabolic disorders. Here we summarize and analyze the knowledge on ADTRP and try to decipher its functions in health and disease.

This paper describes a new gas optical depth parameterisation implemented in the most recent release, version 13, of the radiative transfer model RTTOV (Radiative Transfer for TOVS). RTTOV is a fast, one-dimensional radiative transfer model for simulating top-of-atmosphere visible, infrared and microwave radiances observed by downward-viewing space-borne passive sensors. A key component of the model is the fast parameterisation of absorption by the various gases in the atmosphere. The existing parameterisation in RTTOV has been extended over many years to allow for additional variable gases in RTTOV simulations and to account for solar radiation and better support geostationary sensors by extending the validity to higher zenith angles. However, there are limitations inherent in the current approach which make it difficult to develop it further, for example by adding new variable gases. We describe a new parameterisation that can be applied across the whole spectrum, allows for a wide range of zenith angles in support of solar radiation and geostationary sensors, and for which it will be easier to add new variable gases in support of user requirements. Comparisons against line-by-line radiative transfer simulations, and against observations in the ECMWF operational system yield promising results, suggesting that the new parameterisation generally compares well with the old one in terms of accuracy. Further validation is planned, including testing in operational numerical weather prediction data assimilation systems.

Background During sepsis, gram‐negative bacteria induce robust inflammation primarily via lipopolysacharride (LPS) signaling through TLR4, a process that involves the glycosylphosphatidylinositol (GPI)‐anchored receptor CD14 transferring LPS to the Toll‐like receptor 4/myeloid differentiation factor 2 (TLR4/MD‐2) complex. Sepsis also triggers the onset of disseminated intravascular coagulation and consumptive coagulopathy. Objectives We investigated the effect of CD14 blockade on sepsis‐induced coagulopathy, inflammation, organ dysfunction, and mortality. Methods We used a baboon model of lethal Escherichia (E) coli sepsis to study two experimental groups (n = 5): (a) E coli challenge; (b) E coli challenge plus anti‐CD14 (23G4) inhibitory antibody administered as an intravenous bolus 30 minutes before the E coli. Results Following anti‐CD14 treatment, two animals reached the 7‐day end‐point survivor criteria, while three animals had a significantly prolonged survival as compared to the non‐treated animals that developed multiple organ failure and died within 30 hours. Anti‐CD14 reduced the activation of coagulation through inhibition of tissue factor‐dependent pathway, especially in the survivors, and enhanced the fibrinolysis due to strong inhibition of plasminogen activator inhibitor 1. The treatment prevented the robust complement activation induced by E coli, as shown by significantly decreased C3b, C5a, and sC5b‐9. Vital signs, organ function biomarkers, bacteria clearance, and leukocyte and fibrinogen consumption were all improved at varying levels. Anti‐CD14 reduced neutrophil activation, cell death, LPS levels, and pro‐inflammatory cytokines (tumor necrosis factor, interleukin (IL)‐6, IL‐1β, IL‐8, interferon gamma, monocyte chemoattractant protein‐1), more significantly in the survivors than non‐surviving animals. Conclusions Our results highlight the crosstalk between coagulation/fibrinolysis, inflammation, and complement systems and suggest a protective role of anti‐CD14 treatment in E coli sepsis.

This work examines the projected image of Romania as an emerging tourism destination. Computed content-analysis was applied to the photos, text and video materials promoted online in Romania&rsquo, s last international tourism campaign. The conceptual framework used corresponds to intrinsic values (play, aesthetics, ethics and spirituality), from Holbrook&rsquo, s typology of value. Being more difficult to apprehend and therefore studied less, intrinsic values allow a more sophisticated approach to value creation. The purpose here is to identify the main attributes that are promoted about Romania by destination marketing organizations. The content analysis of text (last international promotion campaign Explore the Carpathian Garden) and visual data (27 photos from the official Facebook webpage and 7 TV videos) allow to depict an experiential view of Romania&rsquo, s image: natural resources (coded as aesthetics with 29% of references), epistemic value of discovery (play 25.8%), authentic and historical traditions (ethics 25.8%) and wellness and therapeutic activities (spirituality, 19.3%). Destination marketing organizations have the potential to develop some distinctive aspects such as authenticity (as an ethical value dimension) and play (as an active, self-oriented value). Findings also highlight that a complimentary approach using textual and visual data might be a suitable option to research destination brand image.

The analyse of land-use change has a meaningful importance in scholars research. Hence, the influence of the urbanisation beneath the conditions that lead to the increase of tourism activity in urban areas it is connected with the extinction of the land-use space. Given the fact that the development of urbanisation leads to tourism development, this paper aims to shape a model of urban growth for the city of Iaşi which emphasises the spatio-temporal growth of the city with impact on tourism growth. The data used was Corine Land Cover (CLC) for 2000 and 2006 years. The type of land use, the areas and the relationship of the driving factors were identified for further analysis. The methodology included Geographic Information System (GIS) spatial analysis and statistic functions of it. In order to obtain the model of urban growth which sustains the hypothesis that the urban increase leads to tourism development, an urban growth simulation was made through Pyhton language programming by cellular automata (CA) method.

Background Sepsis triggers dysfunction of coagulation and fibrinolytic systems leading to disseminated intravascular coagulation (DIC) that contributes to organ failure and death. Fondaparinux (FPX) is a synthetic pentasaccharide that binds to antithrombin (AT) and selectively inhibits factor (F) Xa and other upstream coagulation proteases but not thrombin (T). Objectives We used a baboon model of lethal Escherichia coli sepsis to investigate the effects of FPX treatment on DIC, organ function, and outcome. Methods Two experimental groups were studied: (a) E. coli challenge (n = 4); and (b) E coli plus FPX (n = 4). Bacteremia was modeled by intravenous infusion of pathogen (1-2 × 1010 CFU/kg). Fondaparinux (0.08 mg/kg) was administered subcutaneously, 3 h prior to and 8 h after bacteria infusion. Results Bacteremia rapidly increased plasma levels of inhibitory complexes of AT with coagulation proteases. Activation markers of both intrinsic (FXIa-AT), and extrinsic (FVIIa-AT) pathways were significantly reduced in FPX-treated animals. Factor Xa-AT and TAT complexes were maximal at 4 to 8 h post challenge and reduced >50% in FPX-treated animals. Fibrinogen consumption, fibrin generation and degradation, neutrophil and complement activation, and cytokine production were strongly induced by sepsis. All parameters were significantly reduced, while platelet count was unchanged by the treatment. Fondaparinux infusion attenuated organ dysfunction, prolonged survival, and saved two of four challenged animals (log-rank Mantel-Cox test, P = .0067). Conclusion Our data indicate that FPX-mediated inhibition of coagulation prevents sepsis coagulopathy; protects against excessive complement activation, inflammation, and organ dysfunction; and provides survival benefit in E. coli sepsis.

In this paper, we review the use of satellite-based remote sensing in combination with in situ data to inform Earth surface modelling. This involves verification and optimization methods that can handle both random and systematic errors and result in effective model improvement for both surface monitoring and prediction applications. The reasons for diverse remote sensing data and products include (i) their complementary areal and temporal coverage, (ii) their diverse and covariant information content, and (iii) their ability to complement in situ observations, which are often sparse and only locally representative. To improve our understanding of the complex behavior of the Earth system at the surface and sub-surface, we need large volumes of data from high-resolution modelling and remote sensing, since the Earth surface exhibits a high degree of heterogeneity and discontinuities in space and time. The spatial and temporal variability of the biosphere, hydrosphere, cryosphere and anthroposphere calls for an increased use of Earth observation (EO) data attaining volumes previously considered prohibitive. We review data availability and discuss recent examples where satellite remote sensing is used to infer observable surface quantities directly or indirectly, with particular emphasis on key parameters necessary for weather and climate prediction. Coordinated high-resolution remote-sensing and modelling/assimilation capabilities for the Earth surface are required to support an international application-focused effort.

Background The physiological function of ADTRP (androgen‐dependent tissue factor pathway inhibitor regulating protein) is unknown. We previously identified ADTRP as coregulating with and supporting the anticoagulant activity of tissue factor pathway inhibitor in endothelial cells in vitro. Here, we studied the role of ADTRP in vivo, specifically related to vascular development, stability, and function. Methods and Results Genetic inhibition of Adtrp produced vascular malformations in the low‐pressure vasculature of zebrafish embryos and newborn mice: dilation/tortuosity, perivascular inflammation, extravascular proteolysis, increased permeability, and microhemorrhages, which produced partially penetrant lethality. Vascular leakiness correlated with decreased endothelial cell junction components VE ‐cadherin and claudin‐5. Changes in hemostasis in young adults comprised modest decrease of tissue factor pathway inhibitor antigen and activity and increased tail bleeding time and volume. Cell‐based reporter assays revealed that ADTRP negatively regulates canonical Wnt signaling, affecting membrane events downstream of low‐density lipoprotein receptor‐related protein 6 ( LRP 6) and upstream of glycogen synthase kinase 3 beta. ADTRP deficiency increased aberrant/ectopic Wnt/β‐catenin signaling in vivo in newborn mice and zebrafish embryos, and upregulated matrix metallopeptidase ( MMP )‐9 in endothelial cells and mast cells ( MCs ). Vascular lesions in newborn Adtrp −/− pups displayed accumulation of MCs , decreased extracellular matrix content, and deficient perivascular cell coverage. Wnt‐pathway inhibition reversed the increased mmp9 in zebrafish embryos, demonstrating that mmp9 expression induced by Adtrp deficiency was downstream of canonical Wnt signaling. Conclusions Our studies demonstrate that ADTRP plays a major role in vascular development and function, most likely through expression in endothelial cells and/or perivascular cells of Wnt‐regulated genes that control vascular stability and integrity.

This paper gives an update of the RTTOV (Radiative Transfer for TOVS) fast radiative transfer model, which is widely used in the satellite retrieval and data assimilation communities. RTTOV is a fast radiative transfer model for simulating top-of-atmosphere radiances from passive visible, infrared and microwave downward-viewing satellite radiometers. In addition to the forward model, it also optionally computes the tangent linear, adjoint and Jacobian matrix providing changes in radiances for profile variable perturbations assuming a linear relationship about a given atmospheric state. This makes it a useful tool for developing physical retrievals from satellite radiances, for direct radiance assimilation in NWP models, for simulating future instruments, and for training or teaching with a graphical user interface. An overview of the RTTOV model is given, highlighting the updates and increased capability of the latest versions, and it gives some examples of its current performance when compared with more accurate line-by-line radiative transfer models and a few selected observations. The improvement over the original version of the model released in 1999 is demonstrated.

Thrombosis and cardiovascular disease (CVD) represent major causes of morbidity and mortality. Low androgen correlates with higher incidence of CVD/thrombosis. Tissue Factor Pathway Inhibitor (TFPI) is the major inhibitor of tissue factor-factor VIIa (TF-FVIIa)–dependent FXa generation. Because endothelial cell (EC) dysfunction leading to vascular disease correlates with low EC-associated TFPI, we sought to identify mechanisms that regulate the natural expression of TFPI. Data mining of NCBI's GEO microarrays revealed strong coexpression between TFPI and the uncharacterized protein encoded by C6ORF105, which is predicted to be multispan, palmitoylated and androgen-responsive. We demonstrate that this protein regulates both the native and androgen-enhanced TFPI expression and activity in cultured ECs, and we named it androgen-dependent TFPI-regulating protein (ADTRP). We confirm ADTRP expression and colocalization with TFPI and caveolin-1 in ECs. ADTRP-shRNA reduces, while over-expression of ADTRP enhances, TFPI mRNA and activity and the colocalization of TF-FVIIa–FXa-TFPI with caveolin-1. Imaging and Triton X-114–extraction confirm TFPI and ADTRP association with lipid rafts/caveolae. Dihydrotestosterone up-regulates TFPI and ADTRP expression, and increases FXa inhibition by TFPI in an ADTRP- and caveolin-1-dependent manner. We conclude that the ADTRP-dependent up-regulation of TFPI expression and activity by androgen represents a novel mechanism of increasing the anticoagulant protection of the endothelium.

Tissue factor (TF) is the cellular receptor for plasma protease factor VIIa (FVIIa), and the TF-FVIIa complex initiates coagulation in both hemostasis and thrombosis. Cell surface-exposed TF is mainly cryptic and requires activation to fully exhibit the procoagulant potential. Recently, the protein disulfide isomerase (PDI) has been hypothesized to regulate TF decryption through the redox switch of an exposed disulfide in TF extracellular domain. In this study, we analyzed PDI contribution to coagulation using an in vitro endothelial cell model. In this model, extracellular PDI is detected by imaging and flow cytometry. Inhibition of cell surface PDI induces a marked increase in TF procoagulant function, whereas exogenous addition of PDI inhibits TF decryption. The coagulant effects of PDI inhibition were sensitive to annexin V treatment, suggesting exposure of phosphatidylserine (PS), which was confirmed by prothrombinase assays and direct labeling. In contrast, exogenous PDI addition enhanced PS internalization. Analysis of fluorescent PS revealed that PDI affects both the apparent flippase and floppase activities on endothelial cells. In conclusion, we identified a new mechanism for PDI contribution to coagulation on endothelial cells, namely, the regulation of PS exposure, where PDI acts as a negative regulator of coagulation.

Anti-COVID-19 hyperimmune immunoglobulin (hIG) can provide standardized and controlled antibody content. Data from controlled clinical trials using hIG for the prevention or treatment of COVID-19 outpatients have not been reported. We assessed the safety and efficacy of subcutaneous anti-COVID-19 hyperimmune immunoglobulin 20% (C19-IG20%) compared to placebo in preventing development of symptomatic COVID-19 in asymptomatic individuals with SARS-CoV-2 infection. We did a multicentre, randomized, double-blind, placebo-controlled trial, in asymptomatic unvaccinated adults (≥18 years of age) with confirmed SARS-CoV-2 infection within 5 days between April 28 and December 27, 2021. Participants were randomly assigned (1:1:1) to receive a blinded subcutaneous infusion of 10 mL with 1 g or 2 g of C19-IG20%, or an equivalent volume of saline as placebo. The primary endpoint was the proportion of participants who remained asymptomatic through day 14 after infusion. Secondary endpoints included the proportion of individuals who required oxygen supplementation, any medically attended visit, hospitalisation, or ICU, and viral load reduction and viral clearance in nasopharyngeal swabs. Safety was assessed as the proportion of patients with adverse events. The trial was terminated early due to a lack of potential benefit in the target population in a planned interim analysis conducted in December 2021. registry: . 461 individuals (mean age 39.6 years [SD 12.8]) were randomized and received the intervention within a mean of 3.1 (SD 1.27) days from a positive SARS-CoV-2 test. In the prespecified modified intention-to-treat analysis that included only participants who received a subcutaneous infusion, the primary outcome occurred in 59.9% (91/152) of participants receiving 1 g C19-IG20%, 64.7% (99/153) receiving 2 g, and 63.5% (99/156) receiving placebo (difference in proportions 1 g C19-IG20% vs. placebo, −3.6%; 95% CI -14.6% to 7.3%, p = 0.53; 2 g C19-IG20% vs placebo, 1.1%; −9.6% to 11.9%, p = 0.85). None of the secondary clinical efficacy endpoints or virological endpoints were significantly different between study groups. Adverse event rate was similar between groups, and no severe or life-threatening adverse events related to investigational product infusion were reported. Our findings suggested that administration of subcutaneous human hyperimmune immunoglobulin C19-IG20% to asymptomatic individuals with SARS-CoV-2 infection was safe but did not prevent development of symptomatic COVID-19. .