Atomic Dark Matter

We propose that dark matter is dominantly comprised of atomic bound states. We build a simple model and map the parameter space that results in the early universe formation of hydrogen-like dark atoms. We find that atomic dark matter has interesting implications for cosmology as well as direct detection: Protohalo formation can be suppressed below $M_{proto} \sim 10^3 - 10^6 M_{\odot}$ for weak scale dark matter due to Ion-Radiation interactions in the dark sector. Moreover, weak-scale dark atoms can accommodate hyperfine splittings of order 100 \kev, consistent with the inelastic dark matter interpretation of the DAMA data while naturally evading direct detection bounds.Comment: 17 pages, 3 figure

Skilful seasonal predictions of Summer European rainfal

This is the author accepted manuscript. The final version is available from American Geophysical Union (AGU) via the DOI in this record.Year-to-year variability in Northern European summer rainfall has profound societal and economic impacts; however current seasonal forecast systems show no significant forecast skill. Here we show skilful predictions are possible (r~0.5, p80 members) are required for skilful predictions. This work is promising for the development of European summer rainfall climate services.This work was supported by the Joint DECC/Defra Met Office Hadley Centre Climate Programme (GA01101), the EU FP7 SPECS project. We acknowledge the E-OBS dataset from the EU-FP6 project ENSEMBLES (http://ensembles-eu.metoffice.com) and the data providers in the ECA&D project (http://www.ecad.eu). We also would like to thank Gerard van der Schrier and Else Van Den Besselaar for kindly providing us the pre-release E-OBS dataset version 'v16e' and further support. Model data used to create the figures are available from the authors upon request for academic use

An intuitionistic approach to scoring DNA sequences against transcription factor binding site motifs

Background: Transcription factors (TFs) control transcription by binding to specific regions of DNA called transcription factor binding sites (TFBSs). The identification of TFBSs is a crucial problem in computational biology and includes the subtask of predicting the location of known TFBS motifs in a given DNA sequence. It has previously been shown that, when scoring matches to known TFBS motifs, interdependencies between positions within a motif should be taken into account. However, this remains a challenging task owing to the fact that sequences similar to those of known TFBSs can occur by chance with a relatively high frequency. Here we present a new method for matching sequences to TFBS motifs based on intuitionistic fuzzy sets (IFS) theory, an approach that has been shown to be particularly appropriate for tackling problems that embody a high degree of uncertainty. Results: We propose SCintuit, a new scoring method for measuring sequence-motif affinity based on IFS theory. Unlike existing methods that consider dependencies between positions, SCintuit is designed to prevent overestimation of less conserved positions of TFBSs. For a given pair of bases, SCintuit is computed not only as a function of their combined probability of occurrence, but also taking into account the individual importance of each single base at its corresponding position. We used SCintuit to identify known TFBSs in DNA sequences. Our method provides excellent results when dealing with both synthetic and real data, outperforming the sensitivity and the specificity of two existing methods in all the experiments we performed. Conclusions: The results show that SCintuit improves the prediction quality for TFs of the existing approaches without compromising sensitivity. In addition, we show how SCintuit can be successfully applied to real research problems. In this study the reliability of the IFS theory for motif discovery tasks is proven

Kinome rewiring reveals AURKA limits PI3K-pathway inhibitor efficacy in breast cancer.

Dysregulation of the PI3K-AKT-mTOR signaling network is a prominent feature of breast cancers. However, clinical responses to drugs targeting this pathway have been modest, possibly because of dynamic changes in cellular signaling that drive resistance and limit drug efficacy. Using a quantitative chemoproteomics approach, we mapped kinome dynamics in response to inhibitors of this pathway and identified signaling changes that correlate with drug sensitivity. Maintenance of AURKA after drug treatment was associated with resistance in breast cancer models. Incomplete inhibition of AURKA was a common source of therapy failure, and combinations of PI3K, AKT or mTOR inhibitors with the AURKA inhibitor MLN8237 were highly synergistic and durably suppressed mTOR signaling, resulting in apoptosis and tumor regression in vivo. This signaling map identifies survival factors whose presence limits the efficacy of targeted therapies and reveals new drug combinations that may unlock the full potential of PI3K-AKT-mTOR pathway inhibitors in breast cancer

Large volume leukapheresis for autologous peripheral blood stem cell collection in children weighting less than 25 kg

Universidade Federal de São Paulo, GRAACC, Pediat Oncol Inst, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Pathol, São Paulo, BrazilUniversidade Federal de São Paulo, GRAACC, Pediat Oncol Inst, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Pathol, São Paulo, BrazilWeb of Scienc

Kvalitativna procjena eliminacije TCP-a i TAMORF-a iz organizma štakora metodom GC-MS

Nerve agents are highly toxic organophosphorus (OP) compounds. They inhibit acetylcholinesterase (AChE), an enzyme that hydrolyses acetycholine (ACh) in the nervous system. Pathophysiological changes caused by OP poisonings are primarily the consequence of surplus ACh on cholinergic receptors and in the central nervous system. Standard treatment of OP poisoning includes combined administration of carbamates, atropine, oximes and anticonvulsants. In order to improve therapy, new compounds have been synthesised and tested. Tenocyclidine (TCP) and its adamantane derivative 1-[2-(2-thienyl)-2-adamantyl] morpholine (TAMORF) have shown interesting properties against soman poisoning. In this study, we developed a qualitative GC-MS method to measure elimination of TCP and TAMORF through rat urine in order to learn more about the mechanisms through which TCP protects an organism from OP poisoning and to determine the duration of this protective effect. GC-MS showed that six hours after treatment with TCP, rat urine contained only its metabolite 1-thienylcyclohexene, while urine of rats treated with TAMORF contained both TAMORF and its metabolites.Živčani bojni otrovi po strukturi su organofosforni (OP) spojevi, čija je zajednička značajka ireverzibilna inhibicija acetilkolinesteraze (AChE), enzima koji hidrolizira acetilkolin (ACh) u živčanom sustavu. Patofi ziološka zbivanja koja nastaju pri otrovanju OP-spojevima primarno su posljedica akumuliranog ACh na kolinergičkim receptorima i u središnjem živčanom sustavu. Još uvijek nesavršen, standardni tretman liječenja otrovanja OP-spojevima uključuje kombiniranu primjenu estera karbamata, atropina, oksima i antikonvulziva. Kako bi se unaprijedila uobičajena terapija, osobito kod otrovanja somanom, ispituju se antidotski učinci mnogih spojeva. Tenociklidin (TCP) i njegov adamantanski derivat TAMORF pokazali su zanimljiva svojstva pomoćne terapije pri otrovanju somanom. Kako bi se proširile dosadašnje spoznaje o načinu na koji tenociklidini štite organizam od trovanja OP-spojevima te također o trajanju njihova antidotskog učinka, u ovom radu razvijena je GC-MS-metoda za praćenje eliminacije TCP-a i TAMORF-a iz organizma. Rezultati GC-MS-analize pokazali su da šest sati nakon tretiranja štakora TCP-om mokraće sadržavaju metabolit TCP-a 1-tienilcikloheksen, dok šest sati nakon tretiranja štakora TAMORF-om mokraće sadržavaju i TAMORF i njegove metabolite. Drugim riječima, šest sati nakon tretmana TCP se potpuno metabolizira, dok se TAMORF metabolizira djelomično, a djelomično ostaje nepromijenjen

The association between subclass-specific IgG Fc N-glycosylation profiles and hypertension in the Uygur, Kazak, Kirgiz, and Tajik populations

Hypertension results from the interaction of genetic and acquired factors. IgG occurs in the form of different subclasses, of which the effector functions show significant variation. The detailed differences between the glycosylation profiles of the individual IgG subclasses may be lost in a profiling method for total IgG N-glycosylation. In this study, subclass-specific IgG Fc glycosylation profile was investigated in the four northwestern Chinese minority populations, namely, Uygur (UIG), Kazak (KZK), Kirgiz (KGZ), and Tajik (TJK), composed of 274 hypertensive patients and 356 healthy controls. The results showed that ten directly measured IgG N-glycan traits (i.e., IgG1G0F, IgG2G0F, IgG2G1FN, IgG2G1FS, IgG2G2S, IgG4G0F, IgG4G1FS, IgG4G1S, IgG4G2FS, and IgG4G2N) representing galactosylation and sialylation are significantly associated with hypertension, with IgG4 consistently showing weaker associations of its sialylation, across the four ethnic groups. We observed a modest improvement on the AUC of ROC curve when the IgG Fc N-glycan traits are added into the glycan-based model (difference between AUCs, 0.044, 95% CI: 0.016-0.072, P = 0.002). The AUC of the diagnostic model indicated that the subclass-specific IgG Fc N-glycan profiles provide more information reinforcing current models utilizing age, gender, BMI, and ethnicity, and demonstrate the potential of subclass-specific IgG Fc N-glycosylation profiles to serve as a biomarker for hypertension. Further research is however required to determine the additive value of subclass-specific IgG Fc N-glycosylation on top of biomarkers, which are currently used

The glutathione redox system is essential to prevent ferroptosis caused by impaired lipid metabolism in clear cell renal cell carcinoma

The publisher's final edited version of this article is available at Oncogene. 2018 Oct;37(40):5435-5450. doi: 10.1038/s41388-018-0315-z. Epub 2018 Jun 5. Non-commercial use onlyThis study was funded by Cancer Research UK, the German Research Foundation (FOR2314) and the German Cancer Aid (111917)

The ternary invariant differential operators acting on the spaces of weighted densities

Over n-dimensional manifolds, I classify ternary differential operators acting on the spaces of weighted densities and invariant with respect to the Lie algebra of vector fields. For n=1, some of these operators can be expressed in terms of the de Rham exterior differential, the Poisson bracket, the Grozman operator and the Feigin-Fuchs anti-symmetric operators; four of the operators are new, up to dualizations and permutations. For n>1, I list multidimensional conformal tranvectors, i.e.,operators acting on the spaces of weighted densities and invariant with respect to o(p+1,q+1), where p+q=n. Except for the scalar operator, these conformally invariant operators are not invariant with respect to the whole Lie algebra of vector fields.Comment: 13 pages, no figures, to appear in Theor. Math. Phy