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Using multi-electron–ion coincidence measurements combined with high level calculations, we show that double ionisation of SO2 at 40.81 eV can be state selective. It leads to high energy products, in good yield, via a newly identified mechanism, which is likely to apply widely to multiple ionisation by almost all impact processes.

Using time-of-flight multiple electron and ion coincidence techniques in combination with a helium gas discharge lamp and synchrotron radiation, the double ionisation spectrum of disulfur (S$$_2$$ 2 ) and the subsequent fragmentation dynamics of its dication are investigated. The S$$_2$$ 2 sample was produced by heating mercury sulfide (HgS), whose vapour at a suitably chosen temperature consists primarily of two constituents: S$$_2$$ 2 and atomic Hg. A multi-particle-coincidence technique is thus particularly useful for retrieving spectra of S$$_2$$ 2 from ionisation of the mixed vapour. The results obtained are compared with detailed calculations of the electronic structure and potential energy curves of S$$_2^{2+}$$ 2 2 + which are also presented. These computations are carried out using configuration interaction methodology. The experimental results are interpreted with and strongly supported by the computational results.

Background: The most common oxidative DNA lesion is 8-oxoguanine (8-oxoG) which is mainly recognized and excised by the glycosylase OGG1, initiating the Base Excision Repair (BER) pathway. Telomeres are particularly sensitive to oxidative stress which disrupts telomere homeostasis triggering genome instability. Methods: We used U2OS OGG1-GFP osteosarcoma cell line to study the role of OGG1 at the telomeres in response to oxidative stress. Next, we investigated the effects of inactivating pharmacologically the BER during oxidative stress (OS) conditions by using a specific small molecule inhibitor of OGG1 (TH5487) in different human cell lines. Results: We have found that during OS, TH5487 effectively blocks BER initiation at telomeres causing accumulation of oxidized bases at this region, correlating with other phenotypes such as telomere losses, micronuclei formation and mild proliferation defects. Besides, the antimetabolite Methotrexate synergizes with TH5487 through induction of intracellular ROS formation, which potentiates TH5487 mediated telomere and genome instability in different cell lines. Conclusions: Our findings demonstrate that OGG1 is required to protect telomeres from OS and present OGG1 inhibitors as a tool to induce oxidative DNA damage at telomeres, with the potential for developing new combination therapies for cancer treatment.

Analysis of the Y chromosome is the best-established way to reconstruct paternal family history in humans. Here, we applied fine-scaled Y-chromosomal haplotyping in horses with biallelic markers and demonstrate the potential of our approach to address the ancestry of sire lines. We de novo assembled a draft reference of the male-specific region of the Y chromosome from Illumina short reads and then screened 5.8 million basepairs for variants in 130 specimens from intensively selected and rural breeds and nine Przewalski's horses. Among domestic horses we confirmed the predominance of a young'crown haplogroup' in Central European and North American breeds. Within the crown, we distinguished 58 haplotypes based on 211 variants, forming three major haplogroups. In addition to two previously characterised haplogroups, one observed in Arabian/Coldblooded and the other in Turkoman/Thoroughbred horses, we uncovered a third haplogroup containing Iberian lines and a North African Barb Horse. In a genealogical showcase, we distinguished the patrilines of the three English Thoroughbred founder stallions and resolved a historic controversy over the parentage of the horse 'Galopin', born in 1872. We observed two nearly instantaneous radiations in the history of Central and Northern European Y-chromosomal lineages that both occurred after domestication 5,500 years ago. ispartof: SCIENTIFIC REPORTS vol:9 issue:1 ispartof: location:England status: published

Protein-peptide interactions play an important role in major cellular processes, and are associated with several human diseases. To understand and potentially regulate these cellular function and diseases it is important to know the molecular details of the interactions. However, because of peptide flexibility and the transient nature of protein-peptide interactions, peptides are difficult to study experimentally. Thus, computational methods for predicting structural information about protein-peptide interactions are needed. Here we present InterPep, a pipeline for predicting protein-peptide interaction sites. It is a novel pipeline that, given a protein structure and a peptide sequence, utilizes structural template matches, sequence information, random forest machine learning, and hierarchical clustering to predict what region of the protein structure the peptide is most likely to bind. When tested on its ability to predict binding sites, InterPep successfully pinpointed 255 of 502 (50.7%) binding sites in experimentally determined structures at rank 1 and 348 of 502 (69.3%) among the top five predictions using only structures with no significant sequence similarity as templates. InterPep is a powerful tool for identifying peptide-binding sites; with a precision of 80% at a recall of 20% it should be an excellent starting point for docking protocols or experiments investigating peptide interactions. The source code for InterPred is available athttp://wallnerlab.org/InterPep/

The proton-sensing GPCRs (pH-GPCRs) GPR4 (GPR19), TDAG8 (GPR65, T-cell death associated gene 8), OGR1 (GPR68, ovarian cancer GPCR1), and G2A (GPR132, G2 accumulation protein) are involved in sensing and transducing changes in extracellular pH (pHe). Extracellular acidification is a central hallmark of solid cancer. pH-GPCR function has been associated with cancer cell proliferation, adhesion, migration and metastasis, as well as with modulation of the immune system. Little is known about the expression levels and role of pH-GPCRs in skin cancer. To better understand the functions of pH-GPCRs in skin cancer in vivo, we examined the expression-profiles of GPR4, TDAG8, OGR1 and G2A in four common skin tumors, i.e. squamous cell carcinoma (SCC), malignant melanoma (MM), compound nevus cell nevi (NCN), basal cell carcinoma (BCC). We performed immunohistochemistry and immunofluorescence staining on paraffin-embedded tissue samples acquired from patients suffering from SCC, MM, NCN or BCC. We show the expression of pH-GPCRs in four common skin cancers. Different expression patterns in the investigated skin cancer types indicate that the different pH-GPCRs may have distinct functions in tumor progression and serve as novel therapeutic targets.

The Arabian horse, one of the world’s oldest breeds of any domesticated animal, is characterized by natural beauty, graceful movement, athletic endurance, and, as a result of its development in the arid Middle East, the ability to thrive in a hot, dry environment. Here we studied 378 Arabian horses from 12 countries using equine single nucleotide polymorphism (SNP) arrays and whole-genome re-sequencing to examine hypotheses about genomic diversity, population structure, and the relationship of the Arabian to other horse breeds. We identified a high degree of genetic variation and complex ancestry in Arabian horses from the Middle East region. Also, contrary to popular belief, we could detect no significant genomic contribution of the Arabian breed to the Thoroughbred racehorse, including Y chromosome ancestry. However, we found strong evidence for recent interbreeding of Thoroughbreds with Arabians used for flat-racing competitions. Genetic signatures suggestive of selective sweeps across the Arabian breed contain candidate genes for combating oxidative damage during exercise, and within the “Straight Egyptian” subgroup, for facial morphology. Overall, our data support an origin of the Arabian horse in the Middle East, no evidence for reduced global genetic diversity across the breed, and unique genetic adaptations for both physiology and conformation.

L-shell ionisation and subsequent Coulomb explosion of fully deuterated methyl iodide, CD$_3$I, irradiated with hard x-rays has been examined by a time-of-flight multi-ion coincidence technique. The core vacancies relax efficiently by Auger cascades, leading to charge states up to 16+. The dynamics of the Coulomb explosion process are investigated by calculating the ions' flight times numerically based on a geometric model of the experimental apparatus, for comparison with the experimental data. A parametric model of the explosion, previously introduced for multi-photon induced Coulomb explosion, is applied in numerical simulations, giving good agreement with the experimental results for medium charge states. Deviations for higher charges suggest the need to include nuclear motion in a putatively more complete model. Detection efficiency corrections from the simulations are used to determine the true distributions of molecular charge state produced by initial L1, L2 and L3 ionisation., Comment: 6 pages, 4 figures

Tyrosine-kinase inhibitors (TKIs) have revolutionized cancer therapy in recent years. Although more targeted than conventional chemotherapy, TKIs exhibit substantial cardiotoxicity, often manifesting as hypertension or heart failure. Here, we assessed myocyte intrinsic cardiotoxic effects of the TKI sorafenib and investigated underlying alterations of myocyte calcium homeostasis. We found that sorafenib reversibly decreased developed force in auxotonically contracting human myocardia (3 µM: −25 ± 4%, 10 µM: −29 ± 7%, 30 µM: −43 ± 12%, p

Heme catabolism exerts physiological functions that impact health through depressing inflammation. Upon reactive pathway progression, as in Gilbert’s Syndrome (GS; UGT1A1*28 polymorphism), aggravated health effects have been determined. Based on lower inflammation and improved metabolic health reported for GS, inter-group differences in heme catabolism were explored. Therefore, a case-control study including 120 fasted, healthy, age- and gender matched subjects with/without GS, was conducted. Genetic expressions of HMOX-1 and BLVRA were measured. Additionally participants were genotyped for those polymorphisms that are known (UGT1A1*28) or likely (HMOX-1 microsatellites) to impact bilirubinemia. Intracellular interleukins (IL-6, IL-1β, TNFα), circulatory C-reactive protein (CRP), serum amyloid A (SAA) and haptoglobin (Hpt) were analysed as inflammatory markers. To assess intracellular heme oxygenase 1 (HO-1) isolated PBMCs were used. In GS vs. C, inflammation markers were significantly decreased. This was supported by an altered heme catabolism, indirectly reflecting in elevated unconjugated bilirubin (UCB; main phenotypic feature of GS) and iron, decreased hemopexin (Hpx) and Hpt and in up-regulated biliverdin reductase (BLVRA) gene expressions. Moreover, HMOX (GT)n short alleles were non-significantly more prominent in female GS individuals. Herewith, we propose a concept to elucidate why GS individuals encounter lower inflammation, and are thus less prone to oxidative-stress mediated diseases.

Associations between biodiversity, human health and well-being have never been discussed with reference to agriculturally managed, species-rich mountainous meadows. We evaluated these associations between extensively managed (one mowing a year, no fertilization) and abandoned (no mowing since more than 80 years, no fertilization) semi-dry meadows located in the Austrian and Swiss Alps. We quantified the richness and abundance of plants, grasshoppers, true bugs, bumblebees, syrphids and landscape characteristics in the surroundings of the meadows. Associations between these biodiversity attributes and short-term psychological and physiological human health effects were assessed with 22 participants (10 males, 12 females; mean age 27 years). Participants´ pulse rate, systolic blood pressure (SBP) and diastolic blood pressure (DBP) were not affected during visits to managed or abandoned meadows. However, perceived health benefits (e.g., stress reduction, attention restoration) were higher during their stays in managed than in abandoned meadows. Also, the attractiveness of the surrounding landscape and the recreation suitability were rated higher when visiting managed meadows. Perceived naturalness was positively correlated with plant richness and flower cover. A positive correlation was found between SBP and forest cover, but SBP was negatively correlated with the open landscape. A negative association was found between grasshoppers and recreational and landscape perceptions. We suggest to discuss biodiversity attributes not only in connection with agricultural management but also with cultural ecosystem services and health benefits to raise more awareness for multifaceted interrelationships between ecosystems and humans.

Skeletal muscle is under inhibitory homeostatic regulation by multiple ligands of the transforming growth factor-β (TGFβ) superfamily. Follistatin is a secreted protein that promotes muscle growth and function by sequestering these ligands extracellularly. In the present study, we evaluated the potential of ACE-083 – a locally acting, follistatin-based fusion protein – as a novel therapeutic agent for focal or asymmetric myopathies. Characterization of ACE-083 in vitro revealed its high affinity for heparin and extracellular matrix while surface plasmon resonance and cell-based assays confirmed that ACE-083 binds and potently neutralizes myostatin, activin A, activin B and growth differentiation factor 11 (GDF11). Intramuscular administration of ACE-083 caused localized, dose-dependent hypertrophy of the injected muscle in wild-type mice and mouse models of Charcot-Marie-Tooth disease (CMT) and Duchenne muscular dystrophy, with no evidence of systemic muscle effects or endocrine perturbation. Importantly, ACE-083 also increased the force of isometric contraction in situ by the injected tibialis anterior muscle in wild-type mice and disease models and increased ankle dorsiflexion torque in CMT mice. Our results demonstrate the potential of ACE-083 as a therapeutic agent for patients with CMT, muscular dystrophy and other disorders with focal or asymmetric muscle atrophy or weakness.

Aim of the present study was to investigate the frequency and predictors of premature discontinuation or switch of ADP receptor blockers and its association with serious adverse events. For this purpose 571 consecutive ACS patients receiving ticagrelor (n = 258, 45%) or prasugrel (n = 313, 55%) undergoing PCI were enrolled in this prospective, observational, multicenter ATLANTIS-SWITCH substudy. Predictors of premature discontinuation or switch of antiplatelet therapy and their association with major adverse cardiovascular events and TIMI bleeding events were evaluated. Premature stop/switch was found in 72 (12.6%) patients: 34 (5.9%) stopped and 38 (6.7%) switched the ADP blocker. Ticagrelor treated patients were significantly more likely to stop/switch therapy as compared to prasugrel (15.9% vs. 9.2%, p = 0.016). We identified 4 independent predictors for stop/switch of ADP blocker: major surgery, need for oral anticoagulation (OAC), TIMI major bleeding and drug intolerance. TIMI major bleeding was a driver of stop/switch actions and occurred in 4.3% vs 0.2% in patients with vs without stop/switch (p = 0.001). The majority of stop/switch actions (75%) were physicians driven decisions. Importantly, stop/switch of therapy was not associated with increased risk of MACE (p = 0.936). In conclusion premature switch/stop of ADP blockers appears to be safe when mainly driven by physician’s decision and clinical indication.

Fag s 1 is a member of the Pathogen Related protein family 10 (PR-10) and can elicit cross-reaction with IgE antibodies produced against the birch pollen allergen Bet v 1. The Nuclear Magnetic Resonance (NMR) structure of Fag s 1 is presented along with its dynamic properties. It shares 66% identity with Bet v 1 and exhibits the expected three α-helices and seven β-sheets arranged as a semi-beta barrel and exposing the residues mapped as the Bet v 1 IgE epitope. The structural dynamics of Fag s 1 were monitored on the fast and intermediate timescales, using relaxation rates. The complex dynamics of Fag s 1 are closely related to the internal cavity, and they modulate IgE and ligand binding.

Early ontogenetic periods and postnatal maturation in organisms are sex-specifically sensitive to hypothalamic-pituitary-adrenal (HPA)-axis activities, related glucocorticoid secretions, and their effects on energy balance and homeostasis. Dietary polyunsaturated (PUFAs) and saturated (SFAs) fatty acids potentially play a major role in this context because PUFAs positively affect HPA-axis functions and a shift towards SFAs may impair body homeostasis. Here we show that dietary PUFAs positively affect postnatal body mass gain and diminish negative glucocorticoid-effects on structural growth rates in male guinea pigs. In contrast, SFAs increased glucocorticoid concentrations, which positively affected testes size and testosterone concentrations in males, but limited their body mass gain and first year survival rate. No distinct diet-related effects were detectable on female growth rates. These results highlight the importance of PUFAs in balancing body homeostasis during male’s juvenile development, which clearly derived from a sex-specific energetic advantage of dietary PUFA intakes compared to SFAs.

Heart Failure with preserved Ejection Fraction (HFpEF) represents a major public health problem. The causative mechanisms are multifactorial and there are no effective treatments for HFpEF, partially attributable to the lack of well-established HFpEF animal models. We established a feline HFpEF model induced by slow-progressive pressure overload. Male domestic short hair cats (n = 20), underwent either sham procedures (n = 8) or aortic constriction (n = 12) with a customized pre-shaped band. Pulmonary function, gas exchange, and invasive hemodynamics were measured at 4-months post-banding. In banded cats, echocardiography at 4-months revealed concentric left ventricular (LV) hypertrophy, left atrial (LA) enlargement and dysfunction, and LV diastolic dysfunction with preserved systolic function, which subsequently led to elevated LV end-diastolic pressures and pulmonary hypertension. Furthermore, LV diastolic dysfunction was associated with increased LV fibrosis, cardiomyocyte hypertrophy, elevated NT-proBNP plasma levels, fluid and protein loss in pulmonary interstitium, impaired lung expansion, and alveolar-capillary membrane thickening. We report for the first time in HFpEF perivascular fluid cuff formation around extra-alveolar vessels with decreased respiratory compliance. Ultimately, these cardiopulmonary abnormalities resulted in impaired oxygenation. Our findings support the idea that this model can be used for testing novel therapeutic strategies to treat the ever growing HFpEF population.

This study analyzes the relationship between salivary cortisol and testosterone levels and performance in track and field athletes. In addition, we analyzed the influence of status among athletes (measured based on previous athletic achievement) on hormone levels. Nineteen members of the Austrian track and field team (eleven males, eight females, 25.9 ± 3.9 years of age, 74.9 ± 20.1 kg, and 179.3 ± 10 cm) participated in this study. Data was collected during the European Games in Baku. Athletes delivered saliva samples at various time-points including morning samples and samples directly before and after the competition. Scoring points of the International Association of Athletics Federation were used as an individual measure of relative performance. We found that performance was negatively correlated with rise in testosterone concentrations in the last 24 h prior to the competition. A similar trend was found for cortisol levels, but only when the three least competitive athletes were removed from analysis. Pre-competition cortisol levels were significantly increased compared to measurements 24 h earlier. No effect of status on cortisol or testosterone increase in the same timeframe was found. We conclude that the tournament represented a stressor and that excessive endocrine response was associated with reduced performance.

Metabolic diseases like diabetes mellitus cause bone healing deficiencies. We found significant impairment of bone regeneration, osteogenic differentiation and proliferation in diabetic bone. Moreover recent studies suggest a highly underestimated importance of GDF8 (Myostatin) in bone metabolism. Our goal was to analyze the role of GDF8 as a regulator of osteogenic differentiation, proliferation and bone regeneration. We used a murine tibial defect model in diabetic (Leprdb−/−) mice. Myostatin-Inhibitor Follistatin was administered in tibial bony defects of diabetic mice. By means of histology, immunohistochemistry and QRT-PC osteogenesis, differentiation and proliferation were analyzed. Application of Myostatin-inhibitor showed a significant improvement in diabetic bone regeneration compared to the control group (6.5 fold, p

Thiopurine induced toxicity is associated with defects in the thiopurine methyltransferase (TPMT) gene. TPMT is a polymorphic enzyme, with most of the single nucleotide polymorphisms (SNPs) causing an amino acid change, altering the enzymatic activity of the TPMT protein. In this study, we characterize a novel patient allele c.719A amp;gt; C, named TPMT*41, together with the more common variant *3C c.719A amp;gt; G, resulting in an amino acid shift at tyrosine 240 to serine, p.Y240S and cysteine, p.Y240C respectively. We show that the patient heterozygote for c.719A amp;gt; C has intermediate enzymatic activity in red blood cells. Furthermore, in vitro studies, using recombinant protein, show that TPMT p.Y240S is less stable than both TPMTwt and TPMT p.Y240C. The addition of SAM increases the stability and, in agreement with Isothermal Titration Calorimetry (ITC) data, higher molar excess of SAM is needed in order to stabilize TPMT p.Y240C and TPMT p.Y240S compared to TPMTwt. Molecular dynamics simulations show that the loss of interactions is most severe for Y240S, which agrees with the thermal stability of the mutations. In conclusion, our study shows that SAM increases the stability of TPMT and that changing only one amino acid can have a dramatic effect on TPMT stability and activity. Funding Agencies|LiU Cancer Network; Medical Research Council of Southeast Sweden; Lars Hiertas Memory Foundation; Samariten Foundation; Swedish Society of Medicine Linkoping; Ostgotaregionens Cancerfond; Swedish e-Science Research Center

This article exploits a method recently incorporated in the geometric morphometric toolkit that complements previous approaches to quantifying the facial features associated with specific body characteristics and trait attribution during social perception. The new method differentiates more globally encoded from more locally encoded information by a summary scaling dimension that is estimated by fitting a line to the plot of log bending energy against log variance explained, partial warp by partial warp, for some sample of varying shapes. In the present context these variances come from the regressions of shape on some exogenous cause or effect of form. We work an example involving data from male faces. Here the regression slopes are steepest, and the sums of explained variances over the uniform component, partial warp 1 and partial warp 2 are greatest, for the conventional body mass index, followed by cortisol and, lastly, perceived health. This suggests that physiological characteristics may be represented at larger scale (global patterns), whereas cues in perception are of smaller scale (local patterns). Such a polarity within psychomorphospace, the global versus the focal, now has a metric by which patterns of morphology can be modeled in both biological and psychological studies.

Low endotoxin recovery (LER) is a recently discovered phenomenon describing the inability of limulus amebocyte lysate (LAL)-based assays to detect lipopolysaccharide (LPS) because of a "masking effect" caused by chelators or detergents commonly used in buffer formulations for medical products and recombinant proteins. This study investigates the masking capacities of different buffer formulations and whether masked endotoxin is biologically active. We show that both naturally occurring endotoxin as well as control standard endotoxin can be affected by LER. Furthermore, whereas masked endotoxin cannot be detected in Factor C based assays, it is still detectable in a cell-based TLR4-NF-κB-luciferase reporter gene assay. Moreover, in primary human monocytes, masked LPS induces the expression of pro-inflammatory cytokines and surface activation markers even at very low concentrations. We therefore conclude that masked LPS is a potent trigger of immune responses, which emphasizes the potential danger of masked LPS, as it may pose a health threat in pharmaceutical products or compromise experimental results.