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Surface, aircraft, and satellite measurements indicate pervasive early cold season (Augut–September) CO2 emissions across Arctic regions, consistent with increased ecosystem metabolism in plants and soils. A key remaining question is whether cold season sources will become large enough to permanently shift the Arctic into a net carbon source. Polar orbiting GHG satellites provide robust estimation of regional carbon budgets but lack sufficient spatial coverage and repeat frequency to track sink‐to‐source transitions in the early cold season. Mission concepts such as the Arctic Observing Mission (AOM) advocate for flying imaging spectrometers in highly elliptical orbits (HEO) over the Arctic to address sampling limitations. We perform retrieval and flux inversion simulation experiments using the AURORA mission concept, leveraging a Panchromatic imaging Fourier Transform Spectrometer (PanFTS) in HEO. Our simulations demonstrate the potential benefits of increased CO2 sampling for detecting emissions during the early cold season. Plain Language Summary: The Arctic is warming rapidly, leading to an acceleration of carbon exchange across tundra and boreal ecosystems. These changing flows of carbon can be difficult to detect using traditional observing systems. We propose that measurement systems which observe Arctic ecosystems continuously from a quasi‐GEO orbit can more accurately detect these important changes, such that unexpected and dangerous feedbacks to climate warming can be monitored and accounted for. Key Points: The Arctic Fourier Transform Spectrometer Investigation (AURORA) mission concept addresses GHG sampling limitations in the ArcticAURORA uses a highly elliptical orbit (HEO) to increase repeat frequency, and a panchromatic iFTS for SWIR O2 and CO2 bands (0.7–2.5 μm)Simulation experiments show potential benefits of increased sampling frequency for grid scale detection of early cold season CO2 emissions [ABSTRACT FROM AUTHOR]

Protein–protein interactions (PPIs) offer great opportunities to expand the druggable proteome and therapeutically tackle various diseases, but remain challenging targets for drug discovery. Here, we provide a comprehensive pipeline that combines experimental and computational tools to identify and validate PPI targets and perform early-stage drug discovery. We have developed a machine learning approach that prioritizes interactions by analyzing quantitative data from binary PPI assays or AlphaFold-Multimer predictions. Using the quantitative assay LuTHy together with our machine learning algorithm, we identified high-confidence interactions among SARS-CoV-2 proteins for which we predicted three-dimensional structures using AlphaFold-Multimer. We employed VirtualFlow to target the contact interface of the NSP10-NSP16 SARS-CoV-2 methyltransferase complex by ultra-large virtual drug screening. Thereby, we identified a compound that binds to NSP10 and inhibits its interaction with NSP16, while also disrupting the methyltransferase activity of the complex, and SARS-CoV-2 replication. Overall, this pipeline will help to prioritize PPI targets to accelerate the discovery of early-stage drug candidates targeting protein complexes and pathways. Synopsis: A new pipeline for prioritizing protein-protein interactions (PPIs) for drug discovery, combines machine learning-based scoring of quantitative PPI data, protein complex structure prediction and virtual drug screening. A multi-adaptive support vector machine (maSVM) classifier is used for scoring PPIs from quantitative interaction and structure prediction data. The machine learning-based classifier is applicable to PPI datasets from various assays and AlphaFold-Multimer predictions improving comparability between different methods. Interaction mapping with LuTHy and maSVM-based scoring identified high-confidence SARS-CoV-2 PPIs. Subsequent AlphaFold-Multimer predictions revealed key interaction residues within the NSP10-NSP16 methyltransferase complex. Targeting the complex with virtual compound screening identified an early-stage small molecule inhibitor that disrupts the NSP10-NSP16 interaction and SARS-CoV-2 replication. A new pipeline for prioritizing protein-protein interactions (PPIs) for drug discovery, combines machine learning-based scoring of quantitative PPI data, protein complex structure prediction and virtual drug screening. [ABSTRACT FROM AUTHOR]

The capture of tumour-derived extracellular vesicles (TEVs) by cells in the tumour microenvironment (TME) contributes to metastasis and notably to the formation of the pre-metastatic niche (PMN). However, due to the challenges associated with modelling release of small EVs in vivo, the kinetics of PMN formation in response to endogenously released TEVs have not been examined. Here, we have studied the endogenous release of TEVs in mice orthotopically implanted with metastatic human melanoma (MEL) and neuroblastoma (NB) cells releasing GFP-tagged EVs (GFTEVs) and their capture by host cells to demonstrate the active contribution of TEVs to metastasis. Human GFTEVs captured by mouse macrophages in vitro resulted in transfer of GFP vesicles and the human exosomal miR-1246. Mice orthotopically implanted with MEL or NB cells showed the presence of TEVs in the blood between 5 and 28 days after implantation. Moreover, kinetic analysis of TEV capture by resident cells relative to the arrival and outgrowth of TEV-producing tumour cells in metastatic organs demonstrated that the capture of TEVs by lung and liver cells precedes the homing of metastatic tumour cells, consistent with the critical roles of TEVs in PMN formation. Importantly, TEV capture at future sites of metastasis was associated with the transfer of miR-1246 to lungmacrophages, liver macrophages, and stellate cells. This is the first demonstration that the capture of endogenously released TEVs is organotropic as demonstrated by the presence of TEV-capturing cells only in metastatic organs and their absence in non-metastatic organs. The capture of TEVs in the PMN induced dynamic changes in inflammatory gene expression which evolved to a pro-tumorigenic reaction as the niche progressed to the metastatic state. Thus, our work describes a novel approach to TEV tracking in vivo that provides additional insights into their role in the earliest stages of metastatic progression. [ABSTRACT FROM AUTHOR]

The aim of this study was to compare the psychological health of children in foster care with that of children in institutional care. Social workers were asked to assess the psychological health of the children as well as several other criteria on the basis of an analysis grid. Our sample consisted of 568 children placed in foster care and 661 children placed in institutions. Our results show that children in care who lived longer with their birth parents have a lower psychological health. Furthermore, the psychological health of children in residential care is lower than children placed in foster families. As children in institution are placed later than children in foster families, this may partially explain the lower psychological health of children in residential care. As a result, children in residential care have experienced more abuse and neglect and witnessed more domestic violence than children in foster care. In addition, children in residential care have more poor‐quality contacts with their birth parents than children in foster family. These contacts negatively influence their psychological health. Finally, the factor that most influences the psychological health of children in care is the quality of the relationship with the people who care for them on a daily basis. Again, children placed in foster families have better‐quality relationships with their foster families than children placed in institutions. [ABSTRACT FROM AUTHOR]

Alexithymia (literally, difficulty finding words for emotions) and openness to emotions (OE: referring to the cognitive representation, communication, regulation, perception of internal and external bodily sensations, and social restriction of emotions) are strongly linked to psychopathology. The absolute and relative stability hypotheses were tested in order to determine whether significant changes occurred on these constructs after therapy, a condition where changes were expected for both constructs. Negative attitudes toward treatment (NTI) and perceived social support (PSS) were expected to significantly predict alexithymia and OE. Patients (N = 179) who participated in this longitudinal study filled in the Toronto Alexithymia Scale, the Dimensions of Openness to Emotions Scale, the NTI subscale, the Multidimensional Scale of Perceived Social Support, and the Social Desirability Scale. After treatment, we observed significant decrease of all alexithymia scores and significant increases of three OE scores, that is, cognitive representation, communication, and regulation of emotions. Regression analyses revealed that gender, age, NTI, and PSS were significant predictors of alexithymia and OE. NTI strongly predicted lower OE levels and higher alexithymia levels, whereas PSS had opposite predicting effects on these constructs. In conclusion, the significant changes, and the moderate to high correlational levels observed between before and after alexithymia and OE scores, strengthen the relative stability hypothesis for both constructs. In addition, PSS represents a protective factor and NTI a vulnerability indicator for therapists. Our aim is to optimize treatment by providing therapists treating emotion difficulties a more concrete array of variables that potentially either promote or subvert recovery. [ABSTRACT FROM AUTHOR]

Objective: To investigate perceptions of early pregnancy assessment units (EPAUs) among perinatal practitioners working in Belgium, France, and Switzerland.Methods: A prospective multinational survey was conducted between September 1, 2015, and May 21, 2016. Obstetricians, gynecologists, medical doctors, radiologists, and midwives were recruited during meetings, via e-mail invitations, or through the websites of regional obstetrics and gynecology scientific societies. The survey comprised 17 questions that assessed the participants' knowledge, interest, and management of early pregnancy.Results: Of the 871 individuals invited to participate in the survey, 306 (35.1%) responded. Most of the participants were gynecologists and/or obstetricians (225 [73.5%]). A total of 258 (84.3%) participants had no or limited knowledge about EPAUs. Furthermore, 211 (69.0%) participants reported incorrect management when they visualized a gestational sac without embryo and 265 (86.6%) misinterpreted changes in serum levels of chorionic gonadotropin during early pregnancy. In all, 201 (65.7%) participants were interested in collaboration with an EPAU; however, only 125 (40.8%) had sufficient time and resources available to support a patient's psychological distress after early pregnancy loss or salpingectomy.Conclusion: Knowledge about early management of pregnancy was limited among the perinatal practitioners surveyed; however, the concept of EPAUs was welcomed by many. [ABSTRACT FROM AUTHOR]

The potential role of osteoblasts in bone and bone marrow (BM) metastases in neuroblastoma (NBL) remains unclear. In this study, we examined the effect of NBL cells on the osteoblastic differentiation of BM-derived mesenchymal stromal cells (BMMSC). We show that the presence of NBL cells enhanced the osteoblastic differentiation of BMMSC driven by bone morphogenetic protein (BMP)-4, in the absence of any effect on NBL cell proliferation. Expression profiles of BMMSC driven toward osteoblastic differentiation revealed an increase in vascular endothelial growth factor A ( Vegfa) expression in the presence of NBL cells. We demonstrated that NBL cells increased BMMSC-derived VEGFA mRNA and protein and that this was enhanced by BMP-4. However, in similar conditions, neither the addition of an mVEGFA blocking antibody nor exogenous recombinant (r) mVEGFA affected osteoblastic differentiation. In contrast, siRNA- mediated knock-down of VEGFA in BMMSC prevented osteoblastic differentiation in BMP-4-treated cocultures, an effect that was not reversed in the presence of rmVEGFA. An analysis of murine bones injected with hNBL cells revealed an increase of mVEGFA producing cells near tumor cells concomitantly with an increase in Vegfa and Runx2 mRNA. This coincided with an increase in osteoclasts, in Rankl/Opg mRNA ratio and with the formation of osteolytic lesions. Thus NBL cells promote osteoblastogenesis in the BM by increasing VEGFA expression in BMMSC. Our study provides a new insight into the role of VEGFA in NBL metastases by pointing to the role of stroma-derived intracrine VEGFA in osteoblastogenesis. [ABSTRACT FROM AUTHOR]

The setting expansion is an important property for a phosphate-bonded investment material. This research was undertaken to investigate a test that might be suitable for its measurement when used in a Standard. In the ‘Casting-Ring Test’, the investment sample is contained in a steel ring and expands to displace a precisely positioned pin. Variables with the potential to alter routine reproduction of the value were investigated. The vacuum-mixer model is a production laboratory variable that must not be ignored and for this reason, experiments were repeated using a different vacuum-mixer located at a second test site. Restraint by the rigid ring material increased expansion, while force on the pin reduced it. Expansion was specific to the lining selected. Increased environmental temperature decreased the final value. Expansion was still taking place at a time at which its value might be measured. However, when these factors are set, the reproducibility of values for setting expansion was good at both test sites (coefficient of variation 14%, at most). The results revealed that with the control that is available reliable routine measurement is possible in a Standard test. The inter-laboratory variable, vacuum-mixer model, produced significant differences and it should be the subject of further investigation. [ABSTRACT FROM AUTHOR]

The best established proteolytic event of osteoclasts is bone matrix solubilization by the cysteine proteinase cathepsin K. Here, however, we draw the attention on osteoclastic activities depending on matrix metalloproteinases (MMPs). We discuss the observations supporting that MMPs contribute significantly to bone matrix solubilization in specific areas of the skeleton and in some developmental and pathological situations. Our discussion takes into account (1) the characteristics of the bone remodeling persisting in the absence of cathepsin K, (2) the ultrastructure of the resorption zone in response to inactivation of MMPs and of cathepsin K in different bone types, (3) bone resorption levels in MMP knockout mice compared to wild-type mice, (4) the identification of MMPs in osteoclasts and surrounding cells, and (5) the effect of different bone pathologies on the serum concentrations of specific collagen fragments believed to discriminate between cathepsin K and MMP cleavage. Next, we provide evidence that MMPs are very critical for osteoclast migration, thereby controlling also the cell-matrix interactions required for cell attachment/detachment. The evidence supporting this role is based on a model of osteoclast recruitment in primitive long bones, an assay of osteoclast invasion through collagen gel, and the effect of proteinase inhibitors/knockouts in these models. Furthermore, we mention observations indicating a role of MMPs in initiation of bone resorption. Finally, we emphasize the many distinct ways MMPs may alter focally the extracellular environment thereby regulating the osteoclast behavior. Although the understanding of MMPs in osteoclast biology is rapidly expanding, it is suspected that important roles remain to be discovered. Microsc. Res. Tech. 61:504–513, 2003. © 2003 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]