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Introduction: Air pollution from diesel combustion is linked in part to the generation of diesel exhaust particles (DEP). DEP exposure induces various processes, including inflammation and oxidative stress, which ultimately contribute to a decline in lung function. Cyclic AMP (cAMP) signaling is critical for lung homeostasis. The impact of DEP on cAMP signaling is largely unknown.Methods: We exposed human bronchial epithelial (BEAS-2B) cells to DEP for 24–72 h and evaluated mitochondrial bioenergetics, markers of oxidative stress and inflammation and the components of cAMP signaling. Mitochondrial bioenergetics was measured at 72 h to capture the potential and accumulative effects of prolonged DEP exposure on mitochondrial function.Results: DEP profoundly altered mitochondrial morphology and network integrity, reduced both basal and ATP-linked respiration as well as the glycolytic capacity of mitochondria. DEP exposure increased gene expression of oxidative stress and inflammation markers such as interleukin-8 and interleukin-6. DEP significantly affected mRNA levels of exchange protein directly activated by cAMP-1 and -2 (Epac1, Epac2), appeared to increase Epac1 protein, but left phospho-PKA levels unhanged. DEP exposure increased A-kinase anchoring protein 1, β2‐adrenoceptor and prostanoid E receptor subtype 4 mRNA levels. Interestingly, DEP decreased mRNA levels of adenylyl cyclase 9 and reduced cAMP levels stimulated by forskolin (AC activator), fenoterol (β2-AR agonist) or PGE2 (EPR agonist).Discussion: Our findings suggest that DEP induces mitochondrial dysfunction, a process accompanied by oxidative stress and inflammation, and broadly dampens cAMP signaling. These epithelial responses may contribute to lung dysfunction induced by air pollution exposure.

We report a 7-year-old boy born with epidermal nevi (EN) arranged according to Blaschko’s lines involving the face and head, right upper limb, chest, and left lower limb, who developed a left paratesticular embryonal rhabdomyosarcoma at 18 months of age. Parallel sequencing identified a gain-of-function variant (c.37G>C, p.Gly13Arg) of HRAS in both epidermal nevus and tumor but not in leukocytes or buccal mucosal epithelial cells, indicating its postzygotic origin. The variant accounted for 33% and 92% of the total reads in the nevus and tumor DNA specimens, respectively, supporting additional somatic hits in the latter. DNA methylation (DNAm) profiling of the tumor documented a signature consistent with embryonal rhabdomyosarcoma and CNV array analysis inferred from the DNAm arrays and subsequent MLPA analysis demonstrated copy number gains of the entire paternal chromosome 11 carrying the mutated HRAS allele, likely as the result of paternal unidisomy followed by subsequent gain(s) of the paternal chromosome in the tumor. Other structural rearrangements were observed in the tumours, while no additional pathogenic variants affecting genes with role in the RAS-MAPK and PI3K-AKT-MTOR pathways were identified. Our findings provide further evidence of the contribution of “gene dosage” to the multistep process driving cell transformation associated with hyperactive HRAS function.

Human airway smooth muscle (HASM) is the primary target of ßAR agonists used to control airway hypercontractility in asthma and chronic obstructive pulmonary disease (COPD). ßAR agonists induce the production of cAMP by adenylyl cyclases (ACs), activate PKA and cause bronchodilation. Several other G-protein coupled receptors (GPCR) expressed in human airway smooth muscle cells transduce extracellular signals through cAMP but these receptors elicit different cellular responses. Some G-protein coupled receptors couple to distinct adenylyl cyclases isoforms with different localization, partly explaining this compartmentation, but little is known about the downstream networks that result. We used quantitative phosphoproteomics to define the downstream signaling networks emanating from cAMP produced by two adenylyl cyclases isoforms with contrasting localization in uman airway smooth muscle. After a short stimulus of adenylyl cyclases activity using forskolin, phosphopeptides were analyzed by LC-MS/MS and differences between cells overexpressing AC2 (localized in non-raft membranes) or AC6 (localized in lipid raft membranes) were compared to control human airway smooth muscle. The degree of AC2 and AC6 overexpression was titrated to generate roughly equal forskolin-stimulated cAMP production. 14 Differentially phosphorylated proteins (DPPs) resulted from AC2 activity and 34 differentially phosphorylated proteins resulted from AC6 activity. Analysis of these hits with the STRING protein interaction tool showed that AC2 signaling is more associated with modifications in RNA/DNA binding proteins and microtubule/spindle body proteins while AC6 signaling is associated with proteins regulating autophagy, calcium-calmodulin (Ca2+/CaM) signaling, Rho GTPases and cytoskeletal regulation. One protein, OFD1, was regulated in opposite directions, with serine 899 phosphorylation increased in the AC6 condition 1.5-fold but decreased to 0.46-fold by AC2. In conclusion, quantitative phosphoproteomics is a powerful tool for deciphering the complex signaling networks resulting from discreet signaling events that occur in cAMP compartments. Our data show key differences in the cAMP pools generated from AC2 and AC6 activity and imply that distinct cellular responses are regulated by these two compartments.

Although the safety performance of the Australian commercial fishing industry has been the subject of multiple investigations, it has ultimately remained undefined. While most Australian industries notify industry regulators of significant workplace incidents and injuries in their operations, the majority of persons in the commercial fishing industry are contractors who are paid piecework and in some jurisdictions specifically excluded from the worker compensation legislation, meaning that most occupational injuries, including fatalities, are not captured in the centralized worker compensation data sets. This study presents the analysis of a systematic review of industry databases, published academic, and, Australian coroners reports to assist improve the definition of the nation's commercial fishing industry safety performance. The analysis shows occupational fatality rates are significantly higher than currently reported, and recurring factors contributing to deaths at sea remain unaddressed. The study is significant as it demonstrates how workplace injuries and deaths can be hidden within data sets applying broad industry classification and provides a foundation for future research in Australian fishing and other industries.

Engineering applications of the fractional Weibull distribution (fWd) are quite limited because a corresponding stochastic process is not yet constituted and completely analyzed of fundamental properties. In order to fill this gap, the fractional Weibull process (fWp) is defined in this paper with the realization algorithm. The self-similarity property as well as long range dependence (LRD) are proven for the future research. The simulation is conducted by the actual data. The fWd is utilized to fit the actual probability distribution and the corresponding process is generated to reflect the stochasticity of the data. The random walk based on the fWp expands the simulation to the planar space.

AimThe purpose of this study is to collect available evidence on the feasibility and efficacy of stereotactic arrhythmia radio ablation (STAR), including both photon radiotherapy (XRT) and particle beam therapy (PBT), in the treatment of atrial fibrillation (AF), and to provide cardiologists and radiation oncologists with a practical overview on this topic.MethodsThree hundred and thirty-five articles were identified up to November 2021 according to preferred reporting items for systematic reviews and meta-analyses criteria; preclinical and clinical studies were included without data restrictions or language limitations. Selected works were analyzed for comparing target selection, treatment plan details, and the accelerator employed, addressing workup modalities, acute and long-term side-effects, and efficacy, defined either by the presence of scar or by the absence of AF recurrence.ResultsTwenty-one works published between 2010 and 2021 were included. Seventeen studies concerned XRT, three PBT, and one involved both. Nine studies (1 in silico and 8 in vivo; doses ranging from 15 to 40 Gy) comprised a total of 59 animals, 12 (8 in silico, 4 in vivo; doses ranging from 16 to 50 Gy) focused on humans, with 9 patients undergoing STAR: average follow-up duration was 5 and 6 months, respectively. Data analysis supported efficacy of the treatment in the preclinical setting, whereas in the context of clinical studies the main favorable finding consisted in the detection of electrical scar in 4/4 patients undergoing specific evaluation; the minimum dose for efficacy was 25 Gy in both humans and animals. No acute complication was recorded; severe side-effects related to the long-term were observed only for very high STAR doses in 2 animals. Significant variability was evidenced among studies in the definition of target volume and doses, and in the management of respiratory and cardiac target motion.ConclusionSTAR is an innovative non-invasive procedure already applied for experimental treatment of ventricular arrhythmias. Particular attention must be paid to safety, rather than efficacy of STAR, given the benign nature of AF. Uncertainties persist, mainly regarding the definition of the treatment plan and the role of the target motion. In this setting, more information about the toxicity profile of this new approach is compulsory before applying STAR to AF in clinical practice.

PurposeThis study represents a descriptive analysis of preliminary results of a Phase II trial on a novel mixed beam radiotherapy (RT) approach, consisting of carbon ions RT (CIRT) followed by intensity-modulated photon RT, in combination with hormonal therapy, for high-risk prostate cancer (HR PCa) with a special focus on acute toxicity.MethodsPrimary endpoint was the evaluation of safety in terms of acute toxicity. Secondary endpoints were early and long-term tolerability of treatment, quality of life (QoL), and efficacy. Data on acute and late toxicities were collected according to RTOG/EORTC. QoL of enrolled patients was assessed by IPSS, EORTC QLQ-C30, EORTC QLQ-PR25, and sexual activity by IIEF-5.ResultsTwenty-six patients were enrolled in the study, but only 15 completed so far the RT course and were included. Immediately after CIRT, no patients experienced GI/GU toxicity. At 1 and 3 months from the whole course RT completion, no GI/GU toxicities greater than grade 2 were observed. QoL scores were overall satisfactory.ConclusionsThe feasibility of the proposed mixed treatment schedule was assessed, and an excellent acute toxicity profile was recorded. Such findings instil confidence in the continuation of this mixed approach, with evaluation of long-term tolerability and efficacy.

Rectum and bladder volumes play an important role in the dose distribution reproducibility in prostate cancer adenocarcinoma (PCa) radiotherapy, especially for particle therapy, where density variation can strongly affect the dose distribution. We investigated the reliability and reproducibility of our image-guided radiotherapy (IGRT) and treatment planning protocol for carbon ion radiotherapy (CIRT) within the phase II mixed beam study (AIRC IG 14300) for the treatment of high-risk PCa. In order to calculate the daily dose distribution, a set of synthetic computed tomography (sCT) images was generated from the cone beam computed tomography (CBCT) images acquired in each treatment session. Planning target volume (PTV) together with rectum and bladder volume variation was evaluated with sCT dose-volume histogram (DVH) metric deviations from the planning values. The correlations between the bladder and rectum volumes, and the corresponding DVH metrics, were also assessed. No significant difference in the bladder, rectum, and PTV median volumes between the planning computed tomography (pCT) and the sCT was found. In addition, no significant difference was assessed when comparing the average DVHs and median DVH metrics between pCT and sCT. Dose deviations determined by bladder and rectum filling variations demonstrated that dose distributions were reproducible in terms of both target coverage and organs at risk (OARs) sparing.

Background:Haemophilus parasuis (Hps; now Glaesserella parasuis) is an infectious agent that causes severe arthritis in swines and shares sequence similarity with residues 261–273 of collagen type 2 (Coll261−273), a possible autoantigen in rheumatoid arthritis (RA).Objectives/methods: We tested the presence of Hps sequencing 16S ribosomal RNA in crevicular fluid, synovial fluids, and tissues in patients with arthritis (RA and other peripheral arthritides) and in healthy controls. Moreover, we examined the cross-recognition of Hps by Coll261−273-specific T cells in HLA-DRB1*04pos RA patients, by T-cell receptor (TCR) beta chain spectratyping and T-cell phenotyping.Results:Hps DNA was present in 57.4% of the tooth crevicular fluids of RA patients and in 31.6% of controls. Anti-Hps IgM and IgG titers were detectable and correlated with disease duration and the age of the patients. Peripheral blood mononuclear cells (PBMCs) were stimulated with Hps virulence-associated trimeric autotransporter peptide (VtaA10755−766), homologous to human Coll261−273 or co-cultured with live Hps. In both conditions, the expanded TCR repertoire overlapped with Coll261−273 and led to the production of IL-17.Discussion: We show that the DNA of an infectious agent (Hps), not previously described as pathogen in humans, is present in most patients with RA and that an Hps peptide is able to activate T cells specific for Coll261−273, likely inducing or maintaining a molecular mimicry mechanism.Conclusion: The cross-reactivity between VtaA10755−766 of a non-human infectious agent and human Coll261−273 suggests an involvement in the pathogenesis of RA. This mechanism appears emphasized in predisposed individuals, such as patients with shared epitope.

Agriculture in the boreal and Arctic regions is perceived as marginal, low intensity and inadequate to satisfy the needs of local communities, but another perspective is that northern agriculture has untapped potential to increase the local supply of food and even contribute to the global food system. Policies across northern jurisdictions target the expansion and intensification of agriculture, contextualized for the diverse social settings and market foci in the north. However, the rapid pace of climate change means that traditional methods of adapting cropping systems and developing infrastructure and regulations for this region cannot keep up with climate change impacts. Moreover, the anticipated conversion of northern cold-climate natural lands to agriculture risks a loss of up to 76% of the carbon stored in vegetation and soils, leading to further environmental impacts. The sustainable development of northern agriculture requires local solutions supported by locally relevant policies. There is an obvious need for the rapid development of a transdisciplinary, cross-jurisdictional, long-term knowledge development, and dissemination program to best serve food needs and an agricultural economy in the boreal and Arctic regions while minimizing the risks to global climate, northern ecosystems and communities.

Shiftwork may adversely impact an individual’s sleep-wake patterns and result in sleep loss (

Parallels exist between the domestication of new species and the improvement of various crops through selection on traits which favor the sowing, harvest and retention of yield potential and the directed efforts to improve their agronomics, disease resistance and quality characteristics. Common selection pressures may result in the parallel selection of orthologs underlying these traits and homologies between crop species can be exploited by plant breeders to improve germplasm. Perennial grains and oilseeds are a class of proposed crops for improving the diversity and sustainability of agricultural systems. Maximilian sunflower (Helianthus maximiliani Schrad.) is a perennial crop wild relative of sunflower (Helianthus annuus L.) and a candidate perennial oilseed species. Understanding parallels between cultivated H. annuus and H. maximiliani may provide new tools for the development of Maximilian sunflower and other wild relatives of sunflower as crops to enhance functional diversity in cropping systems. F2 populations of Maximilian sunflower segregating for traits associated with the domestication ideotype of cultivated sunflower including branching architecture, capitulum morphology and flowering time were developed to investigate parallels between H. maximiliani and H. annuus. Genotype-by-sequencing (GBS) was employed to genotype novel Maximilian sunflower populations and perform quantitative-trait-loci (QTL) analysis. A total of 11 QTL in five regions were identified across 21 linkage groups using 4142 GBS derived single nucleotide polymorphism markers called using the sunflower reference genome as a guide. A major QTL on linkage group 17b, associated with aspects of floral development and apical dominance, was discovered and corresponds with a known domestication QTL hotspot in H. annuus and candidate genes were identified. This suggests the potential to exploit orthologs for neo-domestication of H. maximiliani for traits such as branching architecture, timing of anthesis, and capitulum size and morphology for the development of a perennial oilseed crop from wild relatives of cultivated sunflower.

Despite general scepticism from care professionals, social robotics research is providing evidence of successful application in education and rehabilitation in clinical psychology practice. In this article, we investigate the cultural influences of English and Italian psychology students in the perception of usefulness and intention to use a robot as an instrument for future clinical practice and, secondly, the modality of presentation of the robot by comparing oral vs. video presentation. To this end, we surveyed 158 Italian and British-English psychology students after an interactive demonstration using a humanoid robot to evaluate the social robot’s acceptance and use. The Italians were positive, while the English were negative toward the perceived usefulness and intention to use the robot in psychological practice in the near future. However, most English and Italian respondents felt they did not have the necessary abilities to make good use of the robot. We concluded that it is necessary to provide psychology students with further knowledge and practical skills regarding social robotics, which could facilitate the adoption and use of this technology in clinical settings.

Chilling requirement (CR) for bud dormancy completion determines the time of bud break in apple (Malus × domestica Borkh.). The molecular control of bud dormancy is highly heritable, suggesting a strong genetic control of the trait. An available Infinium II SNP platform for genotyping containing 8,788 single nucleotide polymorphic markers was employed, and linkage maps were constructed in a F1 cross from the low CR M13/91 and the moderate CR cv. Fred Hough. These maps were used to identify quantitative trait loci (QTL) for bud break date as a trait related to dormancy release. A major QTL for bud break was detected at the beginning of linkage group 9 (LG9). This QTL remained stable during seven seasons in two different growing sites. To increase mapping efficiency in detecting contributing genes underlying this QTL, 182 additional SNP markers located at the locus for bud break were used. Combining linkage mapping and structural characterization of the region, the high proportion of the phenotypic variance in the trait explained by the QTL is related to the coincident positioning of Arabidopsis orthologs for ICE1, FLC, and PRE1 protein-coding genes. The proximity of these genes from the most explanatory markers of this QTL for bud break suggests potential genetic additive effects, reinforcing the hypothesis of inter-dependent mechanisms controlling dormancy induction and release in apple trees.

In this paper the sinc-fractional derivative is extended to the Hilbert space based on Shannon wavelets. Some new fractional operators based on wavelets are defined. One of the main task is to investigate the localization and compression properties of wavelets when dealing with the non-integer order of a differential operator.

Down syndrome (DS) is due to the presence of an extra full or partial chromosome 21 (Hsa21). The identification of genes contributing to DS pathogenesis could be the key to any rational therapy of the associated intellectual disability. We aim at generating quantitative transcriptome maps in DS integrating all gene expression profile datasets available for any cell type or tissue, to obtain a complete model of the transcriptome in terms of both expression values for each gene and segmental trend of gene expression along each chromosome. We used the TRAM (Transcriptome Mapper) software for this meta-analysis, comparing transcript expression levels and profiles between DS and normal brain, lymphoblastoid cell lines, blood cells, fibroblasts, thymus and induced pluripotent stem cells, respectively. TRAM combined, normalized, and integrated datasets from different sources and across diverse experimental platforms. The main output was a linear expression value that may be used as a reference for each of up to 37,181 mapped transcripts analyzed, related to both known genes and expression sequence tag (EST) clusters. An independent example in vitro validation of fibroblast transcriptome map data was performed through “Real-Time” reverse transcription polymerase chain reaction showing an excellent correlation coefficient (r = 0.93, p < 0.0001) with data obtained in silico. The availability of linear expression values for each gene allowed the testing of the gene dosage hypothesis of the expected 3:2 DS/normal ratio for Hsa21 as well as other human genes in DS, in addition to listing genes differentially expressed with statistical significance. Although a fraction of Hsa21 genes escapes dosage effects, Hsa21 genes are selectively over-expressed in DS samples compared to genes from other chromosomes, reflecting a decisive role in the pathogenesis of the syndrome. Finally, the analysis of chromosomal segments reveals a high prevalence of Hsa21 over-expressed segments over the other genomic regions, suggesting, in particular, a specific region on Hsa21 that appears to be frequently over-expressed (21q22). Our complete datasets are released as a new framework to investigate transcription in DS for individual genes as well as chromosomal segments in different cell types and tissues.

The Santa Catarina Island has a mosaic of ecosystems, with great importance for the fishes. There is the presence of estuaries, lagoons, mangroves and sandy beaches in the same island. Thus, the objectives of this study were to evaluate the spatio and temporal fish diversity patterns in estuaries, lagoons and beach systems of Santa Catarina Island, Santa Catarina, Brazil. Fish data collected between 1983 to 2011 in the baía Norte, saco dos Limões, Itacorubi and Ratones mangroves, Conceição lagoon and Índio beach was analyzed. Fish were sampled with different gear techniques. In the North Bay and saco dos Limões individuals were caught by trawl, but in the mangroves and lagoon were used gillnets, cast nets and dip nets. In the Índio beach the fishes were collected using fyke nets. For each local, species accumulation curves were plotted to compare the observed pattern with modelled data, using first order Jackknife estimator. Species richness differences among locals and seasons were tested using PERMANOVA, followed by a canonical analysis of principal coordinates (CAP). To assess the taxonomic structures at each location, the average taxonomic distinctness (AvTD) and the variation in taxonomic distinctness (VarTD) were also used. Higher average species richness was found in the saco dos Limões (mean ± SE; 59.8 ± 2.5), followed by Índio Beach (55.7 ± 2.7), Conceição lagoon (52.3 ± 6.4), North bay (45.0 ± 2.5), mangrove Itacorubi (34.5 ± 3.2) and mangrove Ratones (30.8 ± 3.8). No significate differences for the taxonomic patterns were observed between seasons. Furthermore the hereby data suggest that the fish assemblages of the inner portion of the island of Santa Catarina are mainly formed by estuarine and marine fish, but differing in species richness among locals.

Artificial reefs (ARs) has been suggested as a possible tool for reef fish restoration and biodiversity rehabilitation. In Brazil, and since 1996, ARs has been implemented in the continental shelf between latitudes of 25.6-25.8 S. Underwater visual censuses (UVC) of fishes were conducted from 2010 to 2015 at both artificial (AR) and natural rocky (NR) reefs to assess similarity at local sites. NR were natural formations with an average depth of 10 meters, and UVC were performed between 6 to 8 meters. Protected AR (PAR) were installed between the years 1996 to 2001 at depths ranging from 15 to 18 meters. It consist of a total of 1788 hollow blocks (2.4-3.6 m2) divided into eleven groups. Non protected AR (NPAR) have been implemented between the years 2010 and 2012 at depths between 9 to 12 meters. It consist of a total of 2832 rectangular hollow blocks (1.2 m2) distributed in 10 parallel groups near the coastal line. Since 2013, NR and PAR were classified as marine protected areas (MPAs). A total of 69 fish species, distributed in 38 families and 10 orders were recorded during the UVC. PERMANOVA analysis showed a decreasing similarity between the NPAR and PAR (20.3%), NR and PAR (15.9%), and NR and NPAR (10.5%). The density of fish showed a strong correlation with the ARs, probably due to a higher perimeter-to-area ratio. Species richness and Shannon diversity index were correlated with NR, such as taxonomic distinctness was correlated to NPAR. Pielou's evenness index and taxonomic diversity were negatively correlated with PAR. Five threatened species (following IUCN), Epinephelus itajara, Epinephelus marginatus, Hyporthodus niveatus, Lutjanus cyanopterus and Lutjanus analis were recorded, which were noticeably more abundant in PAR, namely the former. The hereby data suggested the importance of the implementation of artificial reefs for conservation purposes, namely within MPAs.