Screening for prostate cancer is frequent in high-income countries, including Switzerland. Notably due to overdiagnosis and overtreatment, various organisations have recently recommended against routine screening, potentially having an impact on incidence, mortality, and surgery rates. Our aim was therefore to examine whether secular trends in the incidence and mortality of prostate cancer, and in prostatectomy rates, have recently changed in Switzerland.

Lagunamide D, a new cytotoxic macrocyclic depsipeptide, was discovered from a collection of marine cyanobacteria from Loggerhead Key in the Dry Tortugas, Florida. An intramolecular ester exchange was observed, where the 26-membered macrocycle could contract to a 24-membered compound via acyl migration at the 1,3-diol unit, and the transformation product was named lagunamide D'. The planar structures of both compounds were elucidated using a combination of nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectroscopy (HRMS). The absolute configurations were determined on the basis of enantioselective analysis, modified Mosher's analysis, Kishi NMR database, and direct comparison with lagunamide A, a structure closely resembling lagunamide D. Lagunamides A and D displayed low-nanomolar antiproliferative activity against A549 human lung adenocarcinoma cells, while the structural transformation from the 26-membered lagunamide D macrocycle to the 24-membered ring structure for lagunamide D' led to a 9.6-fold decrease in activity. Lagunamide D also displayed potent activity in triggering apoptosis in a dose- and time-dependent manner. Further investigation on the mechanism of action of the lagunamide scaffold is needed to fully explore its therapeutic potential as an anticancer agent.

Chikungunya virus (CHIKV) is a medically important mosquito-borne virus transmitted to humans by infected Aedes (Stegomyia) species. In 2013⁻2014, Ae. aegypti transmitted CHIKV to humans in the Caribbean and in 2005⁻2006, Ae. albopictus transmitted CHIKV on La Réunion Island (Indian Ocean basin). CHIKV LR2006 OPY1 from the La Réunion epidemic was associated with a mutation (E1:A226V) in the viral E1 glycoprotein that enhanced CHIKV transmission by Ae. albopictus. CHIKV R99659 from the Caribbean outbreak did not have the E1:A226V mutation. Here, we analyzed the salivary glands and saliva of Ae. albopictus strains from New Jersey, Florida, Louisiana and La Réunion after infection with each virus to determine their transmission potential. We infected the Ae. albopictus strains with blood meals containing 3⁻7 × 10⁷ PFU/mL of each virus and analyzed the mosquitoes nine days later to maximize infection of their salivary glands. All four Ae. albopictus strains were highly susceptible to LR2006 OPY1 and R99659 viruses and their CHIKV disseminated infection rates (DIR) were statistically similar (p = 0.3916). The transmission efficiency rate (TER) was significantly lower for R99659 virus compared to LR2006 OPY1 virus in all Ae. albopictus strains and Ae. aegypti (Poza Rica) (p = 0.012) suggesting a salivary gland exit barrier to R99659 virus not seen with LR2006 OPY1 infections. If introduced, LR2006 OPY1 virus poses an increased risk of transmission by both Aedes species in the western hemisphere.

Bifurcaria bifurcata is a marine brown seaweed mainly found on the Atlantic coast. Herein, we report the antioxidant and neuroprotective activities of seven fractions (F1⁻F7) obtained by normal phase chromatography from the B. bifurcata dichloromethane extract, as well as of its two major isolated diterpenes. Total phenolic content of fractions was determined by the Folin⁻Ciocalteu method, while antioxidant activity was evaluated by the DPPH, ORAC, and FRAP assays. Neuroprotective effects were evaluated in a neurotoxic model induced by 6-hydroxydopamine (6-OHDA) in a human neuroblastoma cell line (SH-SY5Y), while the mechanisms associated to neuroprotection were investigated by the determination of mitochondrial membrane potential, H₂O₂ production, Caspase-3 activity, and by observation of DNA fragmentation. Fractions F4 and F5 exhibited the best neuroprotective and antioxidant activities, respectively. F4 fraction prevented changes in mitochondrial potential, and induced a reduction of H₂O₂ levels production and an increase in cell viability, suggesting that it may contain multi-target compounds acting on different pathways. Hence, this fraction was subjected to purification steps, affording the known diterpenes eleganolone and eleganonal. Both compounds exhibited antioxidant potential, being interesting candidates for further neuroprotective studies.

A novel, cold-adapted, and acid-base stable manganese superoxide dismutase (Ps-Mn-SOD) was cloned from hadal sea cucumber Paelopatides sp. The dimeric recombinant enzyme exhibited approximately 60 kDa in molecular weight, expressed activity from 0 °C to 70 °C with an optimal temperature of 0 °C, and resisted wide pH values from 2.2⁻13.0 with optimal activity (> 70%) at pH 5.0⁻12.0. The Km and Vmax of Ps-Mn-SOD were 0.0329 ± 0.0040 mM and 9112 ± 248 U/mg, respectively. At tested conditions, Ps-Mn-SOD was relatively stable in divalent metal ion and other chemicals, such as β-mercaptoethanol, dithiothreitol, Tween 20, Triton X-100, and Chaps. Furthermore, the enzyme showed striking stability in 5 M urea or 4 M guanidine hydrochloride, resisted digestion by proteases, and tolerated a high hydrostatic pressure of 100 MPa. The resistance of Ps-Mn-SOD against low temperature, extreme acidity and alkalinity, chemicals, proteases, and high pressure make it a potential candidate in biopharmaceutical and nutraceutical fields.

The neuropsychiatric symptoms of multiple sclerosis (MS), such as anxiety and depression, can result from disease activity itself as well as psychological reaction to an unfavorable diagnosis. Accordingly, the literature reports evidence of increased anxiety-like behavior in experimental autoimmune encephalomyelitis (EAE), an accepted MS model. Due to the recently described critical role of platelets in inflammation and autoimmune disease, we examined the relationship between platelets, inflammation, and anxiety-like behavior in EAE. In the elevated plus maze, EAE-induced C57BL/6J mice showed decreased time spent in the open arms relative to vehicle-only controls, demonstrating an increase in anxiety-like behavior. This effect occurred in the presence of platelet⁻neuron association, but absence of lymphocytic infiltration, in the hippocampal parenchyma. Platelet depletion at the pre-clinical disease stage, using antibody-mediated lysis prevented the EAE-induced increase in anxiety-like behavior, while no significant difference in distance moved was recorded. Furthermore, platelet depletion was also associated with reduction of the pro-inflammatory environment to control levels in the hippocampus and prevention of EAE disease symptomology. These studies demonstrate the high efficacy of a platelet-targeting approach in preventing anxiety-like symptoms and clinical manifestations of EAE and have implications for the treatment of neuropsychiatric symptoms in MS.

Bioactive metabolites in Codonopsis pilosula are of particular interest as an immunostimulant. Methyl jasmonate (MeJA) plays an important role in the elicitation of metabolite biosynthesis. Here, we explored the response of metabolites to MeJA elicitation in C. pilosula adventitious roots and multiple shoots. The results showed that the biomass, polysaccharide, and lobetyolin content of adventitious roots exhibited the highest increases with 100 µmol·L-1 MeJA at the 16th day of subculture, whereas the atractylenolide III (a terpenoid) content increased extremely with 50 µmol·L-1 MeJA treatment at the 7th day of subculture. In addition, the biomass and lobetyolin content significantly increased at the 4th day after treatment. Similarly, the polysaccharide and lobetyolin content increased in multiple shoots. Further identification of different metabolites responding to MeJA by ¹H-NMR showed an extremely significant increase of the lobetyolinin level, which coincided with lobetyolin. Accordingly, the precursor, fatty acids, showed a highly significant decrease in their levels. Furthermore, a significant increase in β-d-fructose-butanol glycoside was detected, which was accompanied by a decrease in the sucrose level. Accordingly, the enzyme genes responsible for terpenoid and carbohydrate biosynthesis, CpUGPase, and CpPMK, were up regulated. In conclusion, MeJA promoted culture growth and accelerated bioactive metabolite accumulation by regulating the expression of the metabolite biosynthesis related genes, CpUGPase and CpPMK in C. pilosula.

The injection of botulinum toxin type A (BoNT/A) in the masticatory muscles, to cause its temporary paralysis, is a widely used intervention for clinical disorders such as oromandibular dystonia, sleep bruxism, and aesthetics (i.e., masseteric hypertrophy). Considering that muscle contraction is required for mechano-transduction to maintain bone homeostasis, it is relevant to address the bone adverse effects associated with muscle condition after this intervention. Our aim is to condense the current and relevant literature about mandibular bone loss in fully mature mammals after BoNT/A intervention in the masticatory muscles. Here, we compile evidence from animal models (mice, rats, and rabbits) to clinical studies, demonstrating that BoNT/A-induced masticatory muscle atrophy promotes mandibular bone loss. Mandibular bone-related adverse effects involve cellular and metabolic changes, microstructure degradation, and morphological alterations. While bone loss has been detected at the mandibular condyle or alveolar bone, cellular and molecular mechanisms involved in this process must still be elucidated. Further basic research could provide evidence for designing strategies to control the undesired effects on bone during the therapeutic use of BoNT/A. However, in the meantime, we consider it essential that patients treated with BoNT/A in the masticatory muscles be warned about a putative collateral mandibular bone damage.

To analyse the predictive ability and incremental value of left ventricular longitudinal axis strain (LAS) and late gadolinium enhancement (LGE) using standard cardiovascular magnetic resonance (CMR) imaging for the diagnosis and prognosis of severe aortic stenosis (AS) in patients with an indication for aortic valve replacement. We conducted a prospective study on 52 patients with severe AS and 52 volunteers. The evaluation protocol included standard biochemistry tests, novel biomarkers of myocardial fibrosis, 12-lead electrocardiograms and 24-hour Holter, the 6-minute walk test and extensive echocardiographic and CMR imaging studies. Outcomes were defined as the composite of major cardiovascular events (MACEs). Among AS patients, most (n = 17, 77.2%) of those who exhibited LGE at CMR imaging had MACEs during follow-up. Kaplan⁻Meier curves for event-free survival showed a significantly higher rate of MACEs in patients with LGE (p < 0.01) and decreased LAS (p < 0.001). In Cox regression analysis, only reduced LAS (hazard ratio 1.33, 95% CI (1.01 to 1.74), p < 0.01) and the presence of LGE (hazard ratio 11.3, 95% CI (1.82 to 70.0), p < 0.01) were independent predictors for MACEs. The predictive value increased if both LGE and reduced LAS were added to left ventricular ejection fraction (LVEF). None of the biomarkers of increased collagen turnover exhibited any predictive value for MACEs. LAS by CMR is an independent predictor of outcomes in patients with AS and provides incremental value beyond the assessment of LVEF and the presence of LGE.

The higher-level phylogeny of Neuroptera is explored here based on the newly determined mitochondrial genomic data, with a special focus on the interfamilial relationships of this group. Despite considerable progress in our understanding of neuropteran relationships, several mutually exclusive hypotheses have come out according to morphology-based analyses and molecular sequence data. The evaluation of these hypotheses is hampered by the limited taxonomic coverage of previous studies. In this paper, we sequenced four mitochondrial genomes to improve the taxonomic sampling for families: Myrmeleontidae, Ascalaphidae and outgroup Corydalidae. Phylogenetic analyses were run using various inference methods to (1) confirm that Coniopterygidae is sister to all other Neuroptera; (2) place Hemerobiidae as sister to Chrysopidae; (3) support the monophyly of Myrmeleontiformia and define its interfamilial relationships; and (4) recover Myrmeleontidae as paraphyletic due to the nested Ascalaphidae.

We previously demonstrated that an aspalathin-enriched green rooibos extract (GRE) reversed palmitate-induced insulin resistance in C2C12 skeletal muscle and 3T3-L1 fat cells by modulating key effectors of insulin signalling such as phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B (PI3K/AKT) and AMP-activated protein kinase (AMPK). However, the effect of GRE on hepatic insulin resistance is unknown. The effects of GRE on lipid-induced hepatic insulin resistance using palmitate-exposed C3A liver cells and obese insulin resistant (OBIR) rats were explored. GRE attenuated the palmitate-induced impairment of glucose and lipid metabolism in treated C3A cells and improved insulin sensitivity in OBIR rats. Mechanistically, GRE treatment significantly increased PI3K/AKT and AMPK phosphorylation while concurrently enhancing glucose transporter 2 expression. These findings were further supported by marked stimulation of genes involved in glucose metabolism, such as insulin receptor (Insr) and insulin receptor substrate 1 and 2 (Irs1 and Irs2), as well as those involved in lipid metabolism, including Forkhead box protein O1 (FOXO1) and carnitine palmitoyl transferase 1 (CPT1) following GRE treatment. GRE showed a strong potential to ameliorate hepatic insulin resistance by improving insulin sensitivity through the regulation of PI3K/AKT, FOXO1 and AMPK-mediated pathways.

The fungus Fusarium verticillioides can infect maize ears, causing Fusarium ear rot (FER) and contaminating the grain with fumonisins (FUM), which are harmful to humans and animals. Breeding for resistance to FER and FUM and post-harvest sorting of grain are two strategies for reducing FUM in the food system. Kernel and cob tissues have been previously associated with differential FER and FUM. Four recombinant inbred line families from the maize nested associated mapping population were grown and inoculated with F. verticillioides across four environments, and we evaluated the kernels for external and internal infection severity as well as FUM contamination. We also employed publicly available phenotypes on innate ear morphology to explore genetic relationships between ear architecture and resistance to FER and FUM. The four families revealed wide variation in external symptomatology at the phenotypic level. Kernel bulk density under inoculation was an accurate indicator of FUM levels. Genotypes with lower kernel density-under both inoculated and uninoculated conditions-and larger cobs were more susceptible to infection and FUM contamination. Quantitative trait locus (QTL) intervals could be classified as putatively resistance-specific and putatively shared for ear and resistance traits. Both types of QTL mapped in this study had substantial overlap with previously reported loci for resistance to FER and FUM. Ear morphology may be a component of resistance to F. verticillioides infection and FUM accumulation.

Background: Lead exposure, even at low levels, is associated with adverse health effects in humans. We investigated the determinants of individual lead levels in a general population-based sample of adults from Florence, Italy. Methods: Erythrocyte lead levels were measured (using inductively coupled plasma-mass spectrometry) in 454 subjects enrolled in the Florence cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC) study in 1992⁻1998. Multiple linear regression models were used to study the association between demographics, education and working history, lifestyle, dietary habits, anthropometry, residential history, and (among women) menstrual and reproductive history and use of exogenous sex hormones, and erythrocyte lead levels. Results: Median lead levels were 86.1 μg/L (inter-quartile range 65.5⁻111.9 μg/L). Male gender, older age, cigarette smoking and number of pack-years, alcohol intake, and residing in urban areas were positively associated with higher erythrocyte lead levels, while performing professional/managerial or administrative work or being retired was inversely associated with lead levels. Among women, lead levels were higher for those already in menopause, and lower among those who ever used hormone replacement therapy. Conclusions: Avoidable risk factors contribute to the lead body burden among adults, which could therefore be lowered through targeted public health measures.

To understand the underlying mechanisms of endoplasmic reticulum (ER) stress caused by human rhinovirus (HRV) 16 and non-structural transmembrane protein 2B, the expressions of ER chaperone glucose-regulated protein 78 (GRP78) and three signal transduction pathways, including protein kinase RNA-like ER kinase (PERK), activating transcription factor 6 (ATF6) and inositol-requiring enzyme 1 (IRE1), were evaluated after HRV16 infection and 2B gene transfection. Our results showed that both HRV16 infection and 2B gene transfection increased the expression of ER chaperone GRP78, and induced phosphorylation of PERK and cleavage of ATF6 in a time-dependent manner. Our data also revealed that the HRV16 2B protein was localized to the ER membrane. However, both HRV16 infection and HRV16 2B gene transfection did not induce ER stress through the IRE1 pathway. Moreover, our results showed that apoptosis occurred in H1-HeLa cells infected with HRV16 or transfected with 2B gene accompanied with increased expression of CHOP and cleaved caspase-3. Taken together, non-structural protein 2B of HRV16 induced an ER stress response through the PERK and ATF6 pathways rather than the IRE1 pathway.

The common potato, Solanum tuberosum L., is the fourth most important agricultural crop worldwide. Until recently, vegetative propagation by tubers has been the main method of potato cultivation. A shift of interest to sexual potato reproduction by true botanical seeds is due to the appearance of a new hybrid seed breeding strategy whose successful application for many crop species has been supported by male sterility. This investigation was focused on the study of differences in the metabolite profiles of anthers at the mature pollen stage from male-fertile and male-sterile genotypes of S. tuberosum. Application of gas chromatography coupled with a mass spectrometry method allowed detection of metabolic profiles for 192 compounds. Further data analysis with several libraries fully identified 75 metabolites; a similar amount was defined up to the classes. Metabolic profiles in the anthers of fertile genotypes were significantly distinguished from male-sterile ones by the accumulation of carbohydrates, while the anthers of sterile genotypes contained a higher amount of amino acids. In comparison with male-fertile plants, male-sterile genotypes had undeveloped pollen grain characters; i.e., smaller grain size, a thicker exine, "permanent tetrads" that failed to disintegrate into microspores, and the absence of pollen apertures that might be due to a disorder in the metabolism of carbohydrates and fatty acids.

Butyric acid has been shown to reduce high-fat diet-related metabolic disturbances and to improve intestinal barrier function due to its potent anti-inflammatory capacity. This study investigates whether a butyric acid ester, monobutyrin (MB) affects lipid profiles and gut barrier function in a dose-response manner in rats fed butter- or lard-based high-fat diets. Four-week-old male Wistar rats were fed butter-based diets containing 0, 0.25, 0.75 and 1.5 MB g/100 g (dry weight basis) or 0.5 glycerol g/100 g, and diets with lard (La) containing 0 and 0.5 MB g/100 g or a low-fat control diet for 3⁻4 weeks. Lipid profiles in blood and liver tissue, intestinal permeability and cecal short-chain fatty acids were examined. The results showed a dose-dependent decrease in liver total cholesterol for 1.5 MB (p < 0.05) and liver triglycerides for 0.75 MB (p < 0.05) and 1.5 MB (p = 0.08) groups compared to the high-fat control group. Furthermore, a lower excretion of mannitol in urine in the 1.5 MB group indicated improved intestinal barrier function. When MB was supplemented in the lard-based diet, serum total cholesterol levels decreased, and total amount of liver high-density lipoprotein-cholesterol increased. Thus, MB dietary supplementation can be effective in counteracting lipid metabolism disturbances and impaired gut barrier function induced by high-fat diets.

Slit2 expression is downregulated in various cancers, including lung cancer. We identified two Slit2 splicing variants at exon15-Slit2-WT and Slit2-ΔE15. In the RT-PCR analyses, the Slit2-WT isoform was predominantly expressed in all the lung cancer specimens and in their normal lung counterparts, whereas Slit2-ΔE15 was equivalently or predominantly expressed in 41% of the pneumothorax specimens. A kRasG12D transgenic mice system was used to study the effects of tumorigenesis on the expressions of the Slit2-exon15 isoforms. The results revealed that a kRasG12D-induced lung tumor increased the Slit2-WT/Slit2-ΔE15 ratio and total Slit2 expression level. However, the lung tumors generated via a tail vein injection of lung cancer cells decreased the Slit2-WT/Slit2-ΔE15 ratio and total Slit2 expression level. Interestingly, the lipopolysaccharide (LPS)-induced lung inflammation also decreased the Slit2-WT/Slit2-ΔE15 ratio. Since Slit2 functions as an anti-inflammatory factor, the expression of Slit2 increases in kRasG12D lungs, which indicates that Slit2 suppresses immunity during tumorigenesis. However, an injection of lung cancer cells via the tail vein and the LPS-induced lung inflammation both decreased the Slit2 expression. The increased Slit2 in the tumor microenvironment was mostly Slit2-WT, which lacks growth inhibitory activity. Thus, the results of our study suggested that the upregulation of Slit2-WT, but not Slit2-ΔE15, in a cancer microenvironment is an important factor in suppressing immunity while not interfering with cancer growth.

The skin, the largest organ in humans, is exposed to major sources of outdoor air pollution, such as fine particulate matter with a diameter ≤ 2.5 µm (PM2.5). Diphlorethohydroxycarmalol (DPHC), a marine-based compound, possesses multiple activities including antioxidant effects. In the present study, we evaluated the protective effect of DPHC on PM2.5-induced skin cell damage and elucidated the underlying mechanisms in vitro and in vivo. The results showed that DPHC blocked PM2.5-induced reactive oxygen species generation in human keratinocytes. In addition, DPHC protected cells against PM2.5-induced DNA damage, endoplasmic reticulum stress, and autophagy. HR-1 hairless mice exposed to PM2.5 showed lipid peroxidation, protein carbonylation, and increased epidermal height, which were inhibited by DPHC. Moreover, PM2.5 induced apoptosis and mitogen-activated protein kinase (MAPK) protein expression; however, these changes were attenuated by DPHC 5. MAPK inhibitors were used to elucidate the molecular mechanisms underlying these actions, and the results demonstrated that MAPK signaling pathway may play a key role in PM2.5-induced skin damage.

Fast and affordable benchtop sequencers are becoming more important in improving personalized medical treatment. Still, distinguishing genetic variants between healthy and diseased individuals from sequencing errors remains a challenge. Here we present VARIFI, a pipeline for finding reliable genetic variants (single nucleotide polymorphisms (SNPs) and insertions and deletions (indels)). We optimized parameters in VARIFI by analyzing more than 170 amplicon-sequenced cancer samples produced on the Personal Genome Machine (PGM). In contrast to existing pipelines, VARIFI combines different analysis methods and, based on their concordance, assigns a confidence score to each identified variant. Furthermore, VARIFI applies variant filters for biases associated with the sequencing technologies (e.g., incorrectly identified homopolymer-associated indels with Ion Torrent). VARIFI automatically extracts variant information from publicly available databases and incorporates methods for variant effect prediction. VARIFI requires little computational experience and no in-house compute power since the analyses are conducted on our server. VARIFI is a web-based tool available at varifi.cibiv.univie.ac.at.

Repetitive DNA including tandem repeats (TRs) is a significant part of most eukaryotic genomes. TRs include rapidly evolving satellite DNA (satDNA) that can be shared by closely related species, their abundance may be associated with evolutionary divergence, and they have been widely used for chromosome karyotyping using fluorescence in situ hybridization (FISH). The recent progress in the development of whole-genome sequencing and bioinformatics tools enables rapid and cost-effective searches for TRs including satDNA that can be converted into molecular cytogenetic markers. In the case of closely related taxa, the genome sequence of one species (donor) can be used as a base for the development of chromosome markers for related species or genomes (target). Here, we present a pipeline for rapid and high-throughput screening for new satDNA TRs in whole-genome sequencing of the donor genome and the development of chromosome markers based on them that can be applied in the target genome. One of the main peculiarities of the developed pipeline is that preliminary estimation of TR abundance using qPCR and ranking found TRs according to their copy number in the target genome; it facilitates the selection of the most prospective (most abundant) TRs that can be converted into cytogenetic markers. Another feature of our pipeline is the probe preparation for FISH using PCR with primers designed on the aligned TR unit sequences and the genomic DNA of a target species as a template that enables amplification of a whole pool of monomers inherent in the chromosomes of the target species. We demonstrate the efficiency of the developed pipeline by the example of FISH probes developed for A, B, and R subgenome chromosomes of hexaploid triticale (BBAARR) based on a bioinformatics analysis of the D genome of Aegilops tauschii (DD) whole-genome sequence. Our pipeline can be used to develop chromosome markers in closely related species for comparative cytogenetics in evolutionary and breeding studies.