Formation and mobilization of methylmercury across natural and experimental sulfur deposition gradients

We investigated the influence of sulfate (SO42-) deposition and concentrations on the net formation and solubility of methylmercury (MeHg) in peat soils. We used data from a natural sulfate deposition gradient running 300 km across southern Sweden to test the hypothesis posed by results from an experimental field study in northern Sweden: that increased loading of SO42- both increases net MeHg formation and redistributes methylmercury (MeHg) from the peat soil to its porewater. Sulfur concentrations in peat soils correlated positively with MeHg concentrations in peat porewater, along the deposition gradient similar to the response to added SO42- in the experimental field study. The combined results from the experimental field study and deposition gradient accentuate the multiple, distinct and interacting roles of SO42- deposition in the formation and redistribution of MeHg in the environment. (c) 2020 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Frk/Shb Signalling in Pancreatic Beta-cells : Roles in Islet Function, Beta-cell Development and Survival as Implicated in Mouse Knockout Models

The adaptor protein Shb and the non-receptor tyrosine kinase Frk have been implicated in intracellular signalling in insulin-producing beta cells. In this thesis, knockout mice are used to further elucidate the role of Shb and Frk for beta cell number, cytokine-induced cell death, and glucose homeostasis. In addition, the effect of Shb deficiency upon tumour growth is studied in a mouse model of endogenous tumourigenesis. Previously, overexpression of Frk has been associated with increased beta cell replication, and increased susceptibility to cytokine induced beta cell destruction. To test whether Frk has a non-redundant role in regulating beta cell mass, beta cell number in Frk-/- mice was assessed at different stages of life. The results showed that Frk is involved in regulating beta cell number during embryonal and early postnatal life, but is probably redundant in the adult. An earlier study had suggested that Shb participates in cytokine-induced beta cell death, a model of autoimmune diabetes. To test this further, Shb-/- islets were exposed to cytokines, or to an ER-stress inducing agent. Shb knockout islets exhibited decreased cell death, and this effect appeared to be independent of NO, JNK, p38 MAP kinase, FAK and c-Abl, but may involve an augmented induction of Hsp70. Furthermore, glucose homeostasis in Shb-/- mice was impaired, with elevated basal blood sugar concentration and reduced glucose-induced insulin secretion. Previously Shb deficient mice had showed an impaired ability to sustain growth of implanted tumour cells, due to reduced angiogenesis. Tumour growth and angiogenesis were here assessed in an inheritable tumour model. Shb deficient mice exhibited fewer tumours, and reduced vessel density in small tumours, indicating impaired angiogenesis. However, a few large tumours developed in Shb-/- mice, suggesting that tumours can escape the angiogenic restriction caused by the absence of Shb

The role of the Src Homology-2 domain containing protein B (SHB) in β cells

This review will describe the SH2-domain signaling protein Src Homology-2 domaincontaining protein B (SHB) and its role in various physiological processes relating inparticular to glucose homeostasis andbcell function. SHB operates downstream of severaltyrosine kinase receptors and assembles signaling complexes in response to receptoractivation by interacting with other signaling proteins via its other domains (proline-rich,phosphotyrosine-binding and tyrosine-phosphorylation sites). The subsequent responsesare context-dependent. Absence ofShbin mice has been found to exert effects onhematopoiesis, angiogenesis and glucose metabolism. Specifically, first-phase insulinsecretion in response to glucose was impaired and this effect was related to alteredcharacteristics of focal adhesion kinase activation modulating signaling through Akt, ERK,bcatenin and cAMP. It is believed that SHB plays a role in integrating adaptive responses tovarious stimuli by simultaneously modulating cellular responses in different cell-types, thusplaying a role in maintaining physiological homeostasi

Heterogeneity among RIP-Tag2 insulinomas allows vascular endothelial growth factor-A independent tumor expansion as revealed by studies in Shb mutant mice : implications for tumor angiogenesis

The Shb adapter protein is a signaling intermediate that operates downstream of vascular endothelial growth factor receptor-2 (VEGFR-2) in endothelial cells. The Shb knockout mouse displays a dysfunctional microvasculature and impaired growth of subcutaneously implanted tumor cells. We decided to investigate tumor growth and angiogenesis in the absence of Shb in an inheritable tumor model, the RIP-Tag2 mouse, which produces insulinomas in a manner highly dependent on de novo angiogenesis. We observed a reduced tumor incidence and burden in both RIP-Tag2 Shb-/- and RIP-Tag2 Shb+/- mice. This correlated with a reduced microvascular density, measured as percentage of insulinoma area positive for CD31 staining, and altered vascular morphology. However, treatment with a VEGF-A blocking antibody was without effect on the Shb mutant tumor volume whereas it significantly inhibited tumor volume in the wild-type mice, suggesting that in mice with reduced Shb expression tumor angiogenesis was primarily sustained by VEGF-A independent pathway(s). This notion was further substantiated by gene expression analysis of angiogenic markers showing reduced VEGF-A expression in Shb deficient tumors. Considerable heterogeneity with respect to the gene expression profiles of other angiogenic markers and the signal-transduction characteristics was observed between different tumors, suggesting that multiple “rescue” pathways could be operating. The numbers of invasive tumors or metastases were unchanged in the Shb mutant. It is concluded that the Shb mutant background reduces tumor frequency by chronically suppressing VEGF-A dependent angiogenesis. However, VEGF-A independent angiogenesis supports a significant degree of tumor expansion in Shbdeficient mice, indicating heterogeneity in the mechanisms by which tumor expansion is promoted. Interference with Shb signaling may provide novel means for future cancer therapy

A network analysis of clinical variables in chronic pain: a study from the Swedish quality registry for pain rehabilitation (SQRP)

Background. Efforts to identify specific variables that impact most on outcomes from interdisciplinary pain rehabilitation are challenged by the complexity of chronic pain. Methods to manage this complexity are needed. The purpose of the study was to determine the network structure entailed in a set of self-reported variables, examine change, and look at potential predictors of outcome, from a network perspective. Methods. In this study we apply network analysis to a large sample of people seeking interdisciplinary pain treatment (N = 2,241). Variables analyzed include pain intensity, pain interference, extent of pain, depression, anxiety, insomnia, and psychological variables from cognitive behavioral models of chronic pain. Results. We found that Acceptance, Pain Interference, and Depression were key, “central,” variables in the pretreatment network. Interestingly, there were few changes in the overall network configuration following treatment, specifically with respect to which variables appear most central relative to each other. On the other hand, Catastrophizing, Depression, Anxiety, and Pain Interference each became less central over time. Changes in Life Control, Acceptance, and Anxiety were most strongly related to changes in the remainder of the network as a whole. Finally, no network differences were found between treatment responders and non-responders. Conclusions. This study highlights potential future targets for pain treatment. Further application of a network approach to interdisciplinary pain rehabilitation data is recommended. Going forward, it may be better to next do this in a more comprehensive theoretically guided fashion, and ideographically, to detect unique individual differences in potential treatment processes

A network analysis of chronic pain rehabilitation program registry data: Structure, change, and responder analyses

Background: Efforts to identify specific variables most related to outcomes in interdisciplinary pain rehabilitation are challenged by the complexity of chronic pain. Methods to manage this complexity are needed. In this study we apply network analysis to a large sample of people seeking interdisciplinary pain treatment. The purpose of the study was to determine the network structure entailed in the set of variables, examine change, and look at potential predictors of outcome, from a network perspective. Methods: Participants in this research (N = 2,421, age M = 43.8 years, % women = 82.2%) were all those consecutive cases providing pre- and post treatment data in the Swedish Quality Registry for Pain Rehabilitation (SQRP). Variables analyzed include pain intensity, pain interference, extent of pain, depression, anxiety, insomnia, and psychological variables from cognitive behavioral models of chronic pain. Network estimation, plotting, accuracy, and changes were call calculated in R. Results: We found Acceptance, Pain Interference, and Depression to be key, “central,” variables in the network of self-reported clinical variables. Interestingly, there were few changes in the network structure following treatment, particularly with respect to which variables appeared most central. On the other hand, Catastrophizing, Depression, Anxiety, and Pain Interference each became less central. The variables where changes were most strongly related to changes in the remainder of the network as a whole were Life Control, Acceptance, and Anxiety. Finally, no network differences were found between treatment responders and non-responders. Conclusions: Further application of a network approach to pain rehabilitation data is recommended. Future studies may improve upon the current results by selecting variables for analysis in a theoretically guided fashion and approaching the data ideographically, to detect unique individual differences in potential treatment processes

Heterogeneity among RIP-Tag2 insulinomas allows vascular endothelial growth factor-A independent tumor expansion as revealed by studies in Shb mutant mice : implications for tumor angiogenesis

The Shb adapter protein is a signaling intermediate that operates downstream of vascular endothelial growth factor receptor-2 (VEGFR-2) in endothelial cells. The Shb knockout mouse displays a dysfunctional microvasculature and impaired growth of subcutaneously implanted tumor cells. We decided to investigate tumor growth and angiogenesis in the absence of Shb in an inheritable tumor model, the RIP-Tag2 mouse, which produces insulinomas in a manner highly dependent on de novo angiogenesis. We observed a reduced tumor incidence and burden in both RIP-Tag2 Shb-/- and RIP-Tag2 Shb+/- mice. This correlated with a reduced microvascular density, measured as percentage of insulinoma area positive for CD31 staining, and altered vascular morphology. However, treatment with a VEGF-A blocking antibody was without effect on the Shb mutant tumor volume whereas it significantly inhibited tumor volume in the wild-type mice, suggesting that in mice with reduced Shb expression tumor angiogenesis was primarily sustained by VEGF-A independent pathway(s). This notion was further substantiated by gene expression analysis of angiogenic markers showing reduced VEGF-A expression in Shb deficient tumors. Considerable heterogeneity with respect to the gene expression profiles of other angiogenic markers and the signal-transduction characteristics was observed between different tumors, suggesting that multiple “rescue” pathways could be operating. The numbers of invasive tumors or metastases were unchanged in the Shb mutant. It is concluded that the Shb mutant background reduces tumor frequency by chronically suppressing VEGF-A dependent angiogenesis. However, VEGF-A independent angiogenesis supports a significant degree of tumor expansion in Shbdeficient mice, indicating heterogeneity in the mechanisms by which tumor expansion is promoted. Interference with Shb signaling may provide novel means for future cancer therapy

The importance of emotional distress, cognitive behavioural factors and pain for life impact at baseline and for outcomes after rehabilitation - A SQRP study of more than 20,000 chronic pain patients

Although literature concerning chronic pain patients indicates that cognitive behavioural variables, specifically acceptance and fear of movement/(re)injury, are related to life impact, the relative roles of these factors in relation to pain characteristics (e.g. intensity and spreading) and emotional distress are unclear. Moreover, how these variables affect rehabilitation outcomes in different subgroups is insufficiently understood. This study has two aims: (1) to investigate how pain, cognitive behavioural, and emotional distress variables intercorrelate and whether these variables can regress aspects of life impact and (2) to analyse whether these variables can be used to identify clinically meaningful subgroups at baseline and which subgroups benefit most from multimodal rehabilitation programs (MMRP) immediately after and at 12-month follow-up. Pain aspects, background variables, psychological distress, cognitive behavioural variables, and two life impact variables were obtained from the Swedish Quality Registry for Pain Rehabilitation (SQRP) for chronic pain patients. These data were analysed mainly using advanced multivariate methods. The study includes 22,406 chronic pain patients. Many variables, including acceptance variables, showed important contributions to the variation in clinical presentations and in life impacts. Based on the statistically important variables considering the clinical presentation, three clusters/subgroups of patients were identified at baseline; from the worst clinical situation to the relatively good situation. These clusters showed significant differences in outcomes after participating in MMRP; the subgroup with the worst situation at baseline showed the most significant improvements. Pain intensity/severity, emotional distress, acceptance, and life impacts were important for the clinical presentation and were used to identify three clusters with marked differences at baseline (i.e. before MMRP). Life impacts showed complex relationships with acceptance, pain intensity/severity, and emotional distress. The most significant improvements after MMRP were seen in the subgroup with the lowest level of functioning before treatment, indicating that patients with complex problems should be offered MMRP. This study emphasizes the need to adopt a biopsychosocial perspective when assessing patients with chronic pain. Patients with chronic pain referred to specialist clinics are not homogenous in their clinical presentation. Instead we identified three distinct subgroups of patients. The outcomes of MMRP appears to be related to the clinical presentation. Thus, patients with the most severe clinical presentation show the most prominent improvements. However, even though this group of patients improve they still after MMRP show a complex situation and there is thus a need for optimizing the content of MMRP for these patients. The subgroup of patients with a relatively good situation with respect to pain, psychological distress, coping and life impact only showed minor improvements after MMRP. Hence, there is a need to develop other complex interventions for them

Terrestrial discharges mediate trophic shifts and enhance methylmercury accumulation in estuarine biota

The input of mercury (Hg) to ecosystems is estimated to have increased two- to fivefold during the industrial era, and Hg accumulates in aquatic biota as neurotoxic methylmercury (MeHg). Escalating anthropogenic land use and climate change are expected to alter the input rates of terrestrial natural organic matter (NOM) and nutrients to aquatic ecosystems. For example, climate change has been projected to induce 10 to 50% runoff increases for large coastal regions globally. A major knowledge gap is the potential effects on MeHg exposure to biota following these ecosystem changes. We monitored the fate of five enriched Hg isotope tracers added to mesocosm scale estuarine model ecosystems subjected to varying loading rates of nutrients and terrestrial NOM. We demonstrate that increased terrestrial NOM input to the pelagic zone can enhance the MeHg bioaccumulation factor in zooplankton by a factor of 2 to 7 by inducing a shift in the pelagic food web from autotrophic to heterotrophic. The terrestrial NOM input also enhanced the retention of MeHg in the water column by up to a factor of 2, resulting in further increased MeHg exposure to pelagic biota. Using mercury mass balance calculations, we predict that MeHg concentration in zooplankton can increase by a factor of 3 to 6 in coastal areas following scenarios with 15 to 30% increased terrestrial runoff. The results demonstrate the importance of incorporating the impact of climate-induced changes in food web structure on MeHg bioaccumulation in future biogeochemical cycling models and risk assessments of Hg

Opposing spatial trends in methylmercury and total mercury along a peatland chronosequence trophic gradient

9 pages, 5 figures, 2 tables, supplementary material https://doi.org/10.1016/j.scitotenv.2020.137306Peatlands are abundant elements of boreal landscapes where inorganic mercury (IHg) can be transformed into bioaccumulating and highly toxic methylmercury (MeHg). We studied fifteen peatlands divided into three age classes (young, intermediate and old) along a geographically constrained chronosequence to determine the role of biogeochemical factors and nutrient availability in controlling the formation of MeHg. In the 10 cm soil layer just below the average annual growing season water table, concentrations of MeHg and %MeHg (of total Hg) were higher in younger, more mesotrophic peatlands than in older, more oligotrophic peatlands. In contrast, total mercury (THg) concentrations were higher in the older peatlands. Partial least squares (PLS) analysis indicates that the net MeHg production was positively correlated to trophic demands of vegetation and an increased availability of potential electron acceptors and donors for Hg methylating microorganisms. An important question for further studies will be to elucidate why there is less THg in the younger peatlands compared to the older peatlands, even though the age of the superficial peat itself is similar for all sites. We hypothesize that ecosystem features which enhance microbial processes involved in Hg methylation also promote Hg reduction that makes previously deposited Hg more available for evasion back to the atmosphereThis work was supported by the China Scholarship Council (CSC, 2015–2018), the Sino-Swedish Mercury Management Research Framework (SMaReF: VR2013-6978), the National Natural Science Foundation of China (No. 41573078 and 41303098) and the Swedish Research Council Formas (2106-00896)With the funding support of the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000928-S), of the Spanish Research Agency (AEI