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xposure in mid-childhood (measured in urine and blood, respectively) was related to later sleep timing in adolescence.Technology innovations create possibilities to capture exposure-related data at a great depth and breadth. Considering, though, the substantial hurdles involved in collecting individual data for whole populations, this study introduces a first approach of simulating human movement and interaction behaviour, using Agent Based Modelling (ABM). A city scale ABM was developed for urban Thessaloniki, Greece that feeds into population-based exposure assessment without imposing prior bias, basing its estimations onto emerging properties of the behaviour of the computerised autonomous decision makers (agents) that compose the city-system. Population statistics, road and buildings networks data were transformed into human, road and building agents, respectively. Survey outputs with time-use patterns were associated with human agent rules, aiming to model representative to real-world behaviours. Moreover, time-geography of exposure data, derived from a local sensors campaign, was used to inform and enhance the model. Ampacts of different public health policies prior to implementation reducing, therefore, the time and expense required to identify efficient measures.Microplastic is exposed to numerous weathering processes in the environment, which change particle properties and thus influence transport behaviors, including settling and rising velocities in aquatic environments. However, the extent to which particles in the environment differ from virgin particles in their transport behaviors has not yet been investigated. The settling and rising velocities of weathered fluvial microplastic and macroplastic particles collected from environmental samples are determined in this study and the transferability of theoretical approaches to predicting their transport behaviors is examined. The settling velocities of the environmental particles were between 0.16 and 3.52 cm/s and the rising velocities between 0.18 and 19.85 cm/s. Formulas were applied that were developed using experiments with virgin microplastic, but do not account for the effects of environmental impacts such as degradation, fragmentation and biofouling on the velocities. Accordingly, the transferability of the formulas to environmental particles must be verified. The formulas proved to be suitable for describing the settling and rising velocities of environmental microplastic particles in the shapes of pellets, fragments and foams, and were less suitable for describing the velocities of films and macroplastic particles. Further experiments will be necessary in the future to integrate effects from biofilm and particle deformation on the transport behaviors to adequately model the behavior of the highly diverse micro- and macroplastic particles in the aquatic environment.Modeling and simulations are important methods in environmental research. Currently, massive simulation resources from different domains have been developed to simulate various dynamic phenomena and processes to address different environmental problems. These heterogeneous simulation resources (e.g., models, data, and servers) can be wasted if they are not shared and reused effectively. Recently, experts may exchange resources and conduct simulations in the open web environment via these shared and distributed services. However, some challenges remain, such as the heterogeneity and reusability of simulation resources. The goal of this study was to analyze typical scenarios involved in simulation tasks and design a set of service-oriented interfaces for different simulation resources. These interfaces, including the model description interface, model encapsulation interface, server management interface and sim-task operation interface, can be used to describe, encapsulate, manage and invoke environmental simulation resources, which can further contribute to resource assembly for environmental simulation tasks. #link# This study evaluated the case of PM2.5 concentration distribution simulation by meteorological data, land cover data and a random forest model in 2014. Using the designed interface, this study conducted the simulation and explored the influence of different interpolation methods (inverse distance weighting (IDW) and kriging) for meteorological data in the random forest-based PM2.5 concentration simulation. For this case, the results show that kriging is a more suitable interpolation method than IDW for meteorological data in the simulation, and this interface design can organize simulation resources, configure tasks, and balance task loads in different servers on the open web.NHA2 is a sodium/proton exchanger associated with arterial hypertension in humans, but the role of NHA2 in kidney function and blood pressure homeostasis is currently unknown. Here we show that NHA2 localizes almost exclusively to distal convoluted tubules in the kidney. NHA2 knock-out mice displayed reduced blood pressure, normocalcemic hypocalciuria and an attenuated response to the thiazide diuretic hydrochlorothiazide. Phosphorylation of the thiazide-sensitive sodium/chloride cotransporter NCC and its upstream activating kinase Ste20/SPS1-related proline/alanine rich kinase (SPAK), as well as the abundance of with no lysine kinase 4 (WNK4), were significantly reduced in the kidneys of NHA2 knock-out mice. In vitro experiments recapitulated these findings and revealed increased WNK4 ubiquitylation and enhanced proteasomal WNK4 degradation upon loss of NHA2. The effect of NHA2 on WNK4 stability was dependent from the ubiquitylation pathway protein Kelch-like 3 (KLHL3). More specifically, loss of NHA2 selectively attenuated KLHL3 phosphorylation and blunted protein kinase A- and protein kinase C-mediated decrease of WNK4 degradation. Phenotype analysis of NHA2/NCC double knock-out mice supported the notion that NHA2 affects blood pressure homeostasis by a kidney-specific and NCC-dependent mechanism. Thus, our data show that NHA2 as a critical component of the WNK4-NCC pathway and is a novel regulator of blood pressure homeostasis in the kidney.Dermatofibrosarcoma protuberans (DFSP) is a soft-tissue sarcoma characterized by a high risk of local infiltration. The identification of the COL1A1-PDGFB t(17;22) translocation activating the PDGF pathway led to the use of imatinib in unresectable DFSP, with a response rate of 36-80%. Pazopanib is a multitarget tyrosine kinase inhibitor approved for soft-tissue sarcomas. We conducted a phase II study of patients with unresectable DFSP to evaluate the efficacy and safety of pazopanib. Patients received 800 mg of pazopanib daily. The primary endpoint was the objective response rate defined as the reduction of the largest diameter of the tumor by ≥30% at 6 months or at surgery. A total of 23 patients, including one pretreated with imatinib, were enrolled. With a median follow-up of 6.2 months (interquartile range = 5.6-7.8 months), five patients (22%, 95% confidence interval = 7-22%) had a partial response to pazopanib. The best objective response rate was 30% (95% confidence interval = 13-53%) using Response Evaluation Criteria in Solid Tumors. One patient with metastatic DFSP previously treated with imatinib died after 2.4 months. Nine patients (39%) discontinued the treatment owing to adverse events. Pharmacodynamics analyses of tumor samples were conducted the enrichment of EGF and the EGFR-associated gene panel was associated with resistance, suggesting that EGFR-targeted therapies could be a therapeutic option to explore in DFSP. TRIAL REGISTRATION ClinicalTrials.gov identifier NCT01059656.This Perspective briefly reviews the relationship between UV-induced mutations in habitually sun-exposed human skin and subsequent development of actinic keratoses (AKs) and skin cancers. It argues that field therapy rather than AK-selective therapy is the more logical approach to cancer prevention and hypothesizes that treatment early in the process of field cancerization, even prior to the appearance of AKs, may be more effective in preventing cancer as well as more beneficial for and better tolerated by at-risk individuals. Finally, the Perspective encourages use of rapidly advancing DNA analysis techniques to quantify mutational burden in sun-damaged skin and its reduction by various therapies.Angiostrongylus cantonensis is the main causative agent of eosinophilic meningoencephalitis (EoM) in humans. Molecular diagnostic methods are essential since the identification of larvae in cerebrospinal fluid (CSF) is extremely rare. link2 To date, the detection of a 31 kDa antigen by Western blotting has been the primary immunodiagnostic method for EoM caused by A. cantonensis. However, cross-reactivity with other parasites has been observed. Therefore, we conducted a comparative analysis using sera from individuals with angiostrongyliasis. We also characterized proteins isolated from different cellular sources of A. cantonensis, Toxocara canis, Schistosoma mansoni, and Strongyloides stercoralis with mass spectrometry. A total of 115 cross-reactive proteins were identified. Three of these proteins, heat shock protein, an intermediate filament protein, and galectin 1, represent potential markers for cross-reactivity. In addition, synthetic peptides were generated from previously identified diagnostic targets and tested against sera from individuals infected with several other parasites. As a result, two other markers of cross-reactivity were identified peptide #4 derived from the 14-3-3 protein and peptide #12 derived from the Lec-5 protein. In contrast, 34 proteins were exclusively present in the Angiostrongylus extracts and represent promising diagnostic molecules for specific identification of A. cantonensis infection. In particular, cytochrome oxidase subunit I is of great interest as a possible immunodiagnostic target for angiostrongyliasis.The neuropathological hallmark of Parkinsońs disease, multiple system atrophy and dementia with Lewy bodies is the accumulation of α-synuclein. The development of an imaging biomarker for α-synuclein is an unmet need. To date, no selective α-synuclein imaging agent has been identified, though initial studies suggest that the tau tracer [11C]PBB3 displays some degree of binding to α-synuclein. In this study, a series of compounds derived from the PBB3 scaffold were examined using fluorescence imaging and tissue microarrays (TMAs) derived from brain samples with different proteinopathies. One compound, C05-01, was selected based on its higher fluorescence signal associated with Lewy body aggregates compared with other PBB3 analogues. In vitro binding assays using human brain homogenates and recombinant fibrils indicated that C05-01 had higher affinity for α-synuclein (KD/Ki 25 nM for fibrils, Ki 3.5 nM for brain homogenates) as compared with PBB3 (KD 58 nM). Luminespib clinical trial In autoradiography (ARG) studies using fresh frozen human tissue and TMAs, [3H]C05-01 displayed specific binding in cases with α-synuclein pathology. C05-01 is the first PBB3 analogue developed as a potential compound targeting α-synuclein. Despite improved affinity for α-synuclein, C05-01 showed specific binding in AD tissue with Amyloid β and tau pathology, as well as relatively high non-specific and off-target binding. Additional efforts are needed to optimize the pharmacological and physicochemical properties of this series of compounds as ligands for α-synuclein. This study also showed that the construction of TMAs from different proteinopathies provides a tool for evaluation of fluorescent or radiolabelled compounds binding to misfolded proteins.