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DNA methylation patterns are largely established in-utero and might mediate the impacts of in-utero conditions on later health outcomes. Associations between perinatal DNA methylation marks and pregnancy-related variables, such as maternal age and gestational weight gain, have been earlier studied with methylation microarrays, which typically cover less than 2% of human CpG sites. To detect such associations outside these regions, we chose the bisulphite sequencing approach. We collected and curated clinical data on 200 newborn infants; whose umbilical cord blood samples were analysed with the reduced representation bisulphite sequencing (RRBS) method. A generalized linear mixed-effects model was fit for each high coverage CpG site, followed by spatial and multiple testing adjustment of P values to identify differentially methylated cytosines (DMCs) and regions (DMRs) associated with clinical variables, such as maternal age, mode of delivery, and birth weight. Type 1 error rate was then evaluated with a permutation analysis. We discovered a strong inflation of spatially adjusted P values through the permutation analysis, which we then applied for empirical type 1 error control. The inflation of P values was caused by a common method for spatial adjustment and DMR detection, implemented in tools comb-p and RADMeth. Based on empirically estimated significance thresholds, very little differential methylation was associated with any of the studied clinical variables, other than sex. With this analysis workflow, the sex-associated differentially methylated regions were highly reproducible across studies, technologies, and statistical models.

Abstract Renal cell carcinoma (RCC) accounts for 90% of all renal cancers and is considered highly immunogenic. Although many studies have reported the circulating peripheral cytokine profiles, the signatures between the tumor tissue and matching healthy adjacent renal tissue counterparts have not been explored. We aimed to comprehensively investigate the cytokine landscape of RCC tumors and its correlation between the amount and phenotype of the tumor infiltrating lymphocytes (TILs). We analyzed the secretion of 42 cytokines from the tumor (n = 46), adjacent healthy kidney tissues (n = 23) and matching plasma samples (n = 33) with a Luminex-based assay. We further explored the differences between the tissue types, as well as correlated the findings with clinical data and detailed immunophenotyping of the TILs. Using an unsupervised clustering approach, we observed distinct differences in the cytokine profiles between the tumor and adjacent renal tissue samples. The tumor samples clustered into three distinct profiles based on the cytokine expressions: high (52.2% of the tumors), intermediate (26.1%), and low (21.7%). Most of the tumor cytokines positively correlated with each other, except for IL-8 that showed no correlation with any of the measured cytokine expressions. Furthermore, the quantity of lymphocytes in the tumor samples analyzed with flow cytometry positively correlated with the chemokine-family of cytokines, CXCL10 (IP-10) and CXCL9 (MIG). No significant correlations were found between the tumor and matching plasma cytokines, suggesting that circulating cytokines poorly mirror the tumor cytokine environment. Our study highlights distinct cytokine profiles in the RCC tumor microenvironment and provides insights to potential biomarkers for the treatment of RCC.

Mobile applications have thoroughly pervaded the lives of today's children, who live and learn through and with them. However, limited research has been conducted on children designing such apps and not only using those designed by adults. Inviting children to design such apps is the focus of our study. Moreover, in contemporary society, it is emphasized that children should be empowered to take civic action and engage in making the world a better place. In the literature, however, less emphasis has been placed on how children can be invited to do so through the means of digital technology, particularly mobile application design. In this study, 13–15-year-old children are invited to take civic action to address the serious societal problem of bullying through the design of mobile apps. We discussed the design process and analyzed the applications the children designed from the viewpoint of how they aim to tackle bullying. We examined how their app designs aim at empowering other children in the context of bullying, and thus considered what kinds of opportunities emerge for children to learn skills related to the prevention or management of bullying in the apps they have designed. We showed that the children's app designs informed us of the seriousness of bullying in children's lives and that they advocate for the empowerment of other children in different ways. Hence, we have increased our understanding of how smart, interactive technologies designed by children address the learning and empowerment of other children, i.e., application users. We also studied the children's learning from both their and their teachers' perspectives. This study showcases an alternative way educators can integrate digital technologies and apps in school settings to educate children on important societal matters and digital technology.

Kirjoituksessa tarkastellaan sitä, minkälaisia haasteita arkkitehtuurihistorian tutkimus niin kutsutuissa kehitysmaissa nostaa esiin ja minkälaisia valmiuksia ne taidehistorian tutkijalta edellyttävät. Keskeisimpänä tarkastelun kohteena on taidehistorian tieteenalan suhde kehitysmaatutkimukseen. Artikkeli perustuu kirjoittajan poikkitieteellisen, suomalaisten arkkitehtien liikkuvuutta Saharan eteläpuolisessa Afrikassa kehitysyhteistyön vaikutuspiirissä 1960–1980-luvuilla tarkastelevan väitöskirjahankkeen aikana muodostuneisiin tutkimustuloksiin ja havaintoihin. Kehitysyhteistyöhankkeisiin osallistuminen edellytti arkkitehdeilta uutta ammatillista aluevaltausta alakohtaisine tiedollisine ja kyvyllisine vaatimuksineen. Samalla tavalla alan tutkimus edellyttää tutkijalta muidenkin tieteenalojen kuin taidehistorian hallintaa. Se, miten tieteenalarajat ja niiden olemus mielletään, vaikuttaa oleellisesti siihen, miten luontevana tai epäluontevana taidehistorian ja kehitysmaatutkimuksen välinen suhde näyttäytyy.

Early childhood infections have been implicated in the development of immune-mediated diseases, such as allergies, asthma, and type 1 diabetes. We set out to investigate the immunomodulatory effects of early viral infections experienced before the age of one year on the peripheral regulatory T cell population (Treg) and circulating cytokines in a birth-cohort study of Estonian and Finnish infants. We show here a temporal association of virus infection with the expression of FOXP3 in regulatory T cells. Infants with rhinovirus infection during the preceding 30 days had a higher FOXP3 expression in Treg cells and decreased levels of several cytokines related to Th1 and Th2 responses in comparison to the children without infections. In contrast, FOXP3 expression was significantly decreased in highly activated (CD4+CD127−/loCD25+FOXP3high) regulatory T cells (TregFOXP3high) in the infants who had enterovirus infection during the preceding 30 or 60 days. After enterovirus infections, the cytokine profile showed an upregulation of Th1- and Th17-related cytokines and a decreased activation of CCL22, which is a chemokine derived from dendritic cells and associated with Th2 deviation. Our results reveal that immunoregulatory mechanisms are up-regulated after rhinovirus infections, while enterovirus infections are associated with activation of proinflammatory pathways and decreased immune regulation.

Purpose: To study the association of parents’ reports about their children’s near work and outdoor habits with myopia in their children. Methods: Data from a questionnaire study conducted in 1983 among Finnish schoolchildren were reanalyzed. Vision screening had been performed for all the schoolchildren (n = 4961) in the 1st, 5th, and 8th grades (7-, 11-, and 15-year-olds) in an area of Central Finland. The questionnaire, including information about myopia, was returned by 4305 (86.7%) participants. Items concerned parents’ estimates of their child’s habitual reading distance, time spent indoors as compared with age peers, daily near work, outdoors time, and parents’ myopia. The associations of myopia with these factors were studied. Results: Myopia prevalence in those with a habitual close reading distance vs. others was 14.3% vs. 2.1%, 28.7% vs. 13.1% and 45.8% vs. 24.7% for the 7-, 11- and 15-year-olds (p < 0.001 in all age-groups). Myopia prevalence in children reported by their parents as spending more time indoors than age peers was 10.9% vs. 2.8% (p < 0.001), 25.0% vs. 14.7% (p = 0.004) and 41.9% vs. 25.7% (p < 0.001) in the three age groups. Myopia prevalence among those reported as spending both more time indoors and reading at a close distance vs. others was 44.2% vs. 11.9% (Fisher’s exact t-test, p < 0.001). In the multiple logistic regression models, parental myopia almost doubled the risk of myopia in the 11- and 15-year-olds. ORs (95% CI) for myopia adjusted for parental myopia and sex were for close reading distance 7.381 (4.054–13.440), 2.382 (1.666–3.406), 2.237 (1.498–3.057), (p < 0.001), and for more time spent indoors, 3.692 (1.714–7.954), p = 0.001, 1.861 (1.157–2.992), p = 0.010), 1.700 (1.105–2.615), p = 0.016, in the three age groups. Conclusion: Children, especially 7-year-olds, reported by their parents as having a close reading distance and spending a lot of time indoors were associated with a higher risk for myopia.

The Common Fisheries Policy of the European Union was reformed in 2013 with the aim of improving the sustainability of the fishing sector. The Landing Obligation, a cornerstone of this reform, requires fishers to land their unwanted catch instead of discarding it at sea. Existing literature pays little attention to what becomes of this unwanted catch once it is landed. To further the discourse on the sustainable valorisation of unwanted catch, this study explores whether unwanted catch that is safe for human consumption could be used for improving food security. The paper focuses on Dutch food banks, which deliver critical food aid to over 160,000 individuals yearly but struggle to provide all dependant recipients with nutritionally balanced food parcels. The research question is addressed in two ways. The food bank recipients’ willingness to consume UWC is evaluated quantitatively through a survey. Next to this, data from interviews with relevant stakeholders are analysed qualitatively. Results indicate that the Food Bank Foundation and its recipients are willing to receive this fish if it is safe to consume and accessible. However, various factors such as existing infrastructure, lack of economic incentive to donate, competition from non-food and black markets, and the fishing industry’s conflict with the landing obligation might pose barriers to this kind of valorisation. The dissonance between fisheries, food, and sustainability policies is discussed and identified as a key limiting factor. To bridge the differences between these policy areas, we propose public-private partnerships and voluntary agreements among involved stakeholders.

The development of therapeutic strategies to combat immune-associated diseases requires the molecular mechanisms of human Th17 cell differentiation to be fully identified and understood. To investigate transcriptional control of Th17 cell differentiation, we used primary human CD4+ T cells in small interfering RNA (siRNA)-mediated gene silencing and chromatin immunoprecipitation followed by massive parallel sequencing (ChIP-seq) to identify both the early direct and indirect targets of STAT3. The integrated dataset presented in this study confirms that STAT3 is critical for transcriptional regulation of early human Th17 cell differentiation. Additionally, we found that a number of SNPs from loci associated with immune-mediated disorders were located at sites where STAT3 binds to induce Th17 cell specification. Importantly, introduction of such SNPs alters STAT3 binding in DNA affinity precipitation assays. Overall, our study provides important insights for modulating Th17-mediated pathogenic immune responses in humans.

The use of medicinal herbs has increased significantly. However, the presence of pesticide residues and mycotoxins in medicinal herbs has generated constant discussion and concern among regulatory agencies. Developing and validating an analytical method for determining pesticides and mycotoxins in medicinal plants is challenging due to the naturally occurring substances in these plants. The purpose of this work was to develop and to optimize a sensitive, accurate, precise, effective QuEChERS method for simultaneous determination of over 160 pesticide and mycotoxin residues in complex medicinal plant matrices using LC-TQ-MS/MS. A comprehensive comparison of clean-up procedures and other parameters was conducted to achieve this goal. The validation procedure was performed according to SANTE 11312/2021. More polar analytes, such as acephate, methamidophos and omethoate, presented a higher negative matrix effect in both Melissa officinalis L. and Malva sylvestris L. However, other molecules, such as spirodiclofen, showed a 24% signal enhancement in M. officinalis and a 46% signal suppression in M. sylvestris , indicating that a representative matrix-matched calibration would lead to inaccurate quantification of the analyte. Accuracy and precision were satisfactory according to SANTE 11312/2021 for 157 pesticide residues and mycotoxins in M. officinalis and for 152 molecules in M. sylvestris . LOQs at 10 µg kg -1 were achieved for 117 pesticides in M. officinalis and 99 pesticides in M. sylvestris . Among the mycotoxins, all four aflatoxins (B1, B2, G1 and G2) presented LOQs of 5 µg kg -1 , and ochratoxin A had an LOQ of 10 µg kg -1 in M. officinalis . The same LOQ values were shown for these mycotoxins in M. sylvestris , except for aflatoxin B2 and ochratoxin A, which had LOQs of 20 µg kg -1 . Moreover, in Southern Brazil, there has been no previous study on mycotoxin and pesticide contamination in medicinal herbs. Therefore, the application of this method was assessed through the analysis of forty-two real samples. Imidacloprid was found in M. officinalis , and methyl pirimiphos was found in M. sylvestris . The proposed method not only serves as a helpful tool for routine monitoring but also offers a basis for further research on risk assessment and control in food safety.

Ruellia angustiflora is a shrub popularly known as flower of fire, used in traditional medicine as a healing agent. This study aims to verify the presence of characteristics of pharmaceutical interest in extracts from the root, stem and leaves of this species. The ideal time for ultrasound-assisted extraction is 60 min with a solid-liquid ratio of 1% (w/v). The kinetics of the reaction of the extracts with DPPH is biphasic, and IC 50 values are related to the total phenolic compounds. Five phenolic compounds were identified in the extracts, where ferulic acid, rutin and quercetin showed to be the main responsible for the antiradical activity. The extracts displayed considerable photoprotective activity, mainly Ra-LE (SPF = 23). Ra-RE showed an inhibition halo similar to erythromycin against Streptococcus pyogenes . Taken together, these data reveal that Ruellia angustiflora is a source of phenolic compounds and has relevant antiradical, photoprotective and antibacterial activities.

Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural clines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale.

Ruellia angustiflora (Acanthaceae) is known as flower-of-fire, and its leaves are traditionally employed to promote wound healing. This study was aimed at extracting and characterizing the chemical constituents of the extracts of R. angustiflora obtained by ultrasound-assisted and supercritical fluid extractions, and subsequently investigate their antioxidant potential and cyto-genotoxicity. The extract obtained by ultrasound (UAE-EtOH) was characterized by ultraperformance liquid chromatography-mass spectrometer (UPLC-MS), and the extract obtained via supercritical fluid (SFE-CO 2 ) by gas chromatograph-mass spectrometer (GC-MS). The antioxidant potential was verified by the antiradical activity against the 1,1-diphenyl-2-picrylhydrazyl radical (DPPH), and the cyto-genotoxicity evaluation to test cell viability and DNA damage was performed in peripheral blood mononuclear cells (PBMC) cultures. The SFE-CO 2 extract presented some fatty acids, triterpenes, tetraterpenes, tocopherols and phytosterols. The UAE-EtOH extract contained phenolic acids and flavonoids, and showed the highest antioxidant capacity. Neither extract was genotoxic or cytotoxic at the tested concentrations.

Colletia paradoxa (Spreng.) Esc. (Rhamnaceae, Colletieae) is a medicinal plant, threatened with extinction in Brazil, presenting great morphological variability. Our objective is to investigate the phytochemical components, antioxidant capacity and antimycobacterial activity of different morphotypes of C. paradoxa in different environments. For this, the crude extract of the leaves and branches of the individuals sampled was used. The elimination capacity of the free radicals was determined by the DPPH method, the antimycobacterial activity by the broth microdilution method and the phenolic content by the spectrophotometric method using the Folin-Ciocalteu reagent and by HPLC. The extracts of C. paradoxa and its morphotypes showed significant amounts of phenolic compounds, including quercetin, quercitrin and rutin, besides considerable antioxidant and antimycobacterial activity No connection was detected between the phytochemical composition and different morphotypes of C. paradoxa .

A phylogenetic analysis of the Briza Complex was carried out using three DNA regions (ITS, GBSSI and trnL-trnL-trnF, a total of 2980bp). The searches were performed by three distinct phylogenetic methods, using plastid and nuclear data in separate matrices. All methods produced similar trees per matrix. However there were conflicts when trees resulting from distinct datasets were compared. Phylogenetic relationships were found did not completely fit any circumscription previously proposed for the complex. The early divergence of the Eurasiatic species (B. media, B. maxima and B. minor), and the monophyly of the South American group (including Erianthecium, Rhombolytrum and Gymnachne) support Briza L. sensu stricto, and a single genus for the American group. Briza sensu lato is not supported in most trees, and the American genera cannot be split due to unresolved polytomies. Conflict between chloroplast and nuclear data suggests past reticulation events, although lineage sorting or ITS paralogy cannot be ruled out. Polytomies in the American group may indicate rapid species radiation.

The present work intends to clarify the phylogenetic relationships among the species of Paspalum L. belonging to the informal groups Notata/Linearia and Dilatata, and to raise some preliminary hypotheses on the phylogeny of the genus as a whole. A combined dataset including morphological and molecular characters was used to analyze 28 species of Paspalum plus some representatives of related genera of the tribe Paniceae. Analyses were performed using both parsimony and maximum likelihood. The monophyly of Paspalum is not supported nor contradicted. The circumscription of informal groups of Paspalum is discussed, as well as the cladistic treatment of allopolyploid taxa, especially those comprising the Dilatata group. The relationships of members of the Dilatata with their putative progenitors is confirmed, but the monophyly of the group as a whole is not. A close relationship between P. dilatatum Poir. and P. lividum Trin. ex Schltdl. is shown. Our analysis is consistent with the monophyly of a group comprising Notata+Linearia, with a monophyletic Notata group nested within it. The delimitation of the core Notata is proposed by including P. conduplicatum Canto-Dorow, Valls and Longhi-Wagner, P. notatum Flüggé, P. minus E. Fourn., P. pumilum Nees and P. subciliatum Chase.

The concentration and histological distribution of hyaluronan, a tumor promoting extracellular matrix polysaccharide, and the activity of hyaluronidase, a potential source of angiogenic hyaluronan oligosaccharides, were analyzed in malignant epithelial (n = 24), borderline (n = 8), benign epithelial (n = 20), functional cyst (n = 21), and normal (n = 5) tissue samples of human ovary. Hyaluronan concentration increased specifically in cancers (P = 0.001), particularly in grade 3 tumors (>49-fold) and in metastases (>89-fold). Hyaluronan staining in the tissues correlated with hyaluronan concentration (P = 0.002). Hyaluronidase activity slightly decreased from semimalignant through low grade to high grade tumors (P = 0.041). Therefore, hyaluronan accumulation, but not hyaluronidase activation, is associated with the aggressiveness of ovarian epithelial cancer.