Detection and identification of 700 drugs by multi-target screening with a 3200 Q TRAP LC-MS/MS system and library searching

The multi-target screening method described in this work allows the simultaneous detection and identification of 700 drugs and metabolites in biological fluids using a hybrid triple-quadrupole linear ion trap mass spectrometer in a single analytical run. After standardization of the method, the retention times of 700 compounds were determined and transitions for each compound were selected by a "scheduled" survey MRM scan, followed by an information-dependent acquisition using the sensitive enhanced product ion scan of a Q TRAP hybrid instrument. The identification of the compounds in the samples analyzed was accomplished by searching the tandem mass spectrometry (MS/MS) spectra against the library we developed, which contains electrospray ionization-MS/MS spectra of over 1,250 compounds. The multi-target screening method together with the library was included in a software program for routine screening and quantitation to achieve automated acquisition and library searching. With the help of this software application, the time for evaluation and interpretation of the results could be drastically reduced. This new multi-target screening method has been successfully applied for the analysis of postmortem and traffic offense samples as well as proficiency testing, and complements screening with immunoassays, gas chromatography-mass spectrometry, and liquid chromatography-diode-array detection. Other possible applications are analysis in clinical toxicology (for intoxication cases), in psychiatry (antidepressants and other psychoactive drugs), and in forensic toxicology (drugs and driving, workplace drug testing, oral fluid analysis, drug-facilitated sexual assault)

VNbCrMo refractory high-entropy alloy for nuclear applications

Refractory high-entropy alloys (RHEAs) with high melting points and low neutron absorption cross-section are sought for generation-IV fission and fusion reactors. A high throughput computational screening tool, Alloy Search and Predict (ASAP), was used to identify promising RHEA candidates from over 1 million four-element equimolar combinations. The selected VNbCrMo RHEA was further studied by CALPHAD to predict phase formation, which was compared to an experimentally produced ingot aged at 1200 °C. The VNbCrMo RHEA was found to constitute a majority bcc phase, with a 6% area fraction of C15-Laves formed at interdendritic regions, in contrast to the predictions of single-phase. The prediction of the yield strength by a model based upon edge dislocation mechanisms indicated 2.1 GPa at room temperature and 850 MPa at 1000 °C for the equimolar single bcc phase. The hardness of the alloy with C15-Laves was 748 HV (yield strength ∼2.4 GPa). Finally, the macroscopic neutron absorption cross-section was modelled for a wide range of energies. Displacements per atom per year and activation calculations, up to 1000 years after 2 years of continuous operation, in typical fusion and fission reactor scenarios were also performed using the inventory code FISPACT-II. This work gives new insight into the phase stability and performance of the VNbCrMo RHEA, which is compared with a similar design concept alloy, to assess the potential of novel RHEAs for use in advanced nuclear applications.Fil: Ferreirós, Pedro Antonio. Comisión Nacional de Energía Atómica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: von Tiedemann, S. O.. The University Of Birmingham (tub);Fil: Parkes, N.. The University Of Birmingham (tub);Fil: Gurah, D.. The University Of Birmingham (tub);Fil: King, D. J. M.. Imperial College London; Reino UnidoFil: Norman, P.. The University Of Birmingham (tub);Fil: Gilbert, M. R.. The University Of Birmingham (tub);Fil: Knowles, A. J.. Imperial College London; Reino Unid

Increased glucosylceramide production leads to decreased cell energy metabolism and lowered tumor marker expression in non-cancerous liver cells

Hepatocellular carcinoma (HCC) is one of the most difficult cancer types to treat. Liver cancer is often diagnosed at late stages and therapeutic treatment is frequently accompanied by development of multidrug resistance. This leads to poor outcomes for cancer patients. Understanding the fundamental molecular mechanisms leading to liver cancer development is crucial for developing new therapeutic approaches, which are more efficient in treating cancer. Mice with a liver specific UDP-glucose ceramide glucosyltransferase (UGCG) knockout (KO) show delayed diethylnitrosamine (DEN)-induced liver tumor growth. Accordingly, the rationale for our study was to determine whether UGCG overexpression is sufficient to drive cancer phenotypes in liver cells. We investigated the effect of UGCG overexpression (OE) on normal murine liver (NMuLi) cells. Increased UGCG expression results in decreased mitochondrial respiration and glycolysis, which is reversible by treatment with EtDO-P4, an UGCG inhibitor. Furthermore, tumor markers such as FGF21 and EPCAM are lowered following UGCG OE, which could be related to glucosylceramide (GlcCer) and lactosylceramide (LacCer) accumulation in glycosphingolipid-enriched microdomains (GEMs) and subsequently altered signaling protein phosphorylation. These cellular processes lead to decreased proliferation in NMuLi/UGCG OE cells. Our data show that increased UGCG expression itself does not induce pro-cancerous processes in normal liver cells, which indicates that increased GlcCer expression leads to different outcomes in different cancer types. Graphic abstract: [Figure not available: see fulltext.

Why 'scaffolding' is the wrong metaphor : the cognitive usefulness of mathematical representations.

The metaphor of scaffolding has become current in discussions of the cognitive help we get from artefacts, environmental affordances and each other. Consideration of mathematical tools and representations indicates that in these cases at least (and plausibly for others), scaffolding is the wrong picture, because scaffolding in good order is immobile, temporary and crude. Mathematical representations can be manipulated, are not temporary structures to aid development, and are refined. Reflection on examples from elementary algebra indicates that Menary is on the right track with his ‘enculturation’ view of mathematical cognition. Moreover, these examples allow us to elaborate his remarks on the uniqueness of mathematical representations and their role in the emergence of new thoughts.Peer reviewe

From Euclidean Geometry to Knots and Nets

This document is the Accepted Manuscript of an article accepted for publication in Synthese. Under embargo until 19 September 2018. The final publication is available at Springer via https://doi.org/10.1007/s11229-017-1558-x.This paper assumes the success of arguments against the view that informal mathematical proofs secure rational conviction in virtue of their relations with corresponding formal derivations. This assumption entails a need for an alternative account of the logic of informal mathematical proofs. Following examination of case studies by Manders, De Toffoli and Giardino, Leitgeb, Feferman and others, this paper proposes a framework for analysing those informal proofs that appeal to the perception or modification of diagrams or to the inspection or imaginative manipulation of mental models of mathematical phenomena. Proofs relying on diagrams can be rigorous if (a) it is easy to draw a diagram that shares or otherwise indicates the structure of the mathematical object, (b) the information thus displayed is not metrical and (c) it is possible to put the inferences into systematic mathematical relation with other mathematical inferential practices. Proofs that appeal to mental models can be rigorous if the mental models can be externalised as diagrammatic practice that satisfies these three conditions.Peer reviewe

Grain refinement techniques in Fe78Al10V12 alloy

Las aleaciones base Fe-Al son estudiadas como alternativa al uso de aceros ferríticos en las centrales eléctricas en alta temperatura. Sus principales ventajas en comparación con éstos, radican en primer lugar en que ofrecen una menor densidad y una buena resistencia a la corrosión en alta temperatura, en combinación con alta resistencia mecánica a temperaturas intermedias. Además, cuentan con un bajo costo de materias primas, facilidad de producción de lingotes o partes de piezas mediante técnicas convencionales de colada o metalurgia de polvos y la posibilidad de tratamientos termomecánicos con parámetros normales para los aceros. Sin embargo, las aleaciones binarias Fe-Al presentan una fuerte caída de su resistencia sobre los 600 °C. Una mejora en la resistencia se obtuvo por precipitación de una segunda fase coherente con la matriz en aleaciones ternarias Fe-Al-V. Sin embargo, en estas aleaciones se registraron temperaturas de transición dúctil-frágil (BDTT) demasiado elevadas para su aplicación. Seguimos en este trabajo el concepto de Joffé, quien mostró que una reducción del tamaño de grano puede derivar bajo ciertas condiciones en una disminución de la BDTT. Ensayamos en una aleación Fe78Al10V12 dos técnicas metalúrgicas para refinar el tamaño de grano: i) agregado de refinadores durante la fundición y ii) trabajado mecánico. Para la primera técnica, se fundieron lingotes cilíndricos de 2 kg utilizando materias primas comerciales y se estudió el efecto de tres compuestos como potenciales agentes de nucleación durante la solidificación. Esta primera estrategia no mostró resultados positivos. En segundo lugar, se estudió el efecto del trabajado en caliente sobre la microestructura. Se aplicaron procesos consecutivos de forja y laminación a 1100 °C y 950 ºC, respectivamente. Se logró refinar el tamaño de grano de fundición entre 110 y 160 veces (hasta 44 y 31 µm).Fe-Al alloys have been studied as an alternative to the use of high-temperature ferritic steels at modern electric power plants. Their advantages over them lie, in first place, in their lower density and good corrosion resistance at high temperature combined with a high mechanical resistance intermediate temperatures. Further advantages are the low materials costs and the possibility of applying conventional metallurgical and thermomechanical production techniques used for steels. However, binary Fe-Al alloys present a strong loss of strength above 600 °C. It was possible to enhance their strength using ternary Fe-Al-V alloys hardened by second phase coherent precipitates, but the brittle-ductile transition temperature (BDTT) registered in these alloys is excessively high for their application. According to Joffé´s criterion, a reduction in grain size can be reflected, under certain conditions, in a reduction of the BDTT. We tested two metallurgical techniques to reduce grain size in a Fe78Al10V12 alloy: i) the incorporation of refinement agents during casting and ii) hot working. The first technique was carried out casting 2 kg cylindrical ingots from commercial materials and studying the effect of three compounds as potential nucleation agents during solidification. This first strategy did not show positive results. In the second technique, we studied the effect of hot working on the microstructure. Two successive processes of forging at 1100 ºC followed by rolling at 950 ºC were applied. We succeeded in refining the as-cast grain size from 110 to 160 times (up to 44 and 31 µm).Fil: Sterin, Uriel Alejandro. Comisión Nacional de Energía Atómica. Centro Atómico Constituyentes; Argentina. Universidad Nacional de San Martín. Instituto Sabato; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ilarri, Sergio V.. Comisión Nacional de Energía Atómica. Centro Atómico Constituyentes; Argentina. Universidad Nacional de San Martín. Instituto Sabato; ArgentinaFil: Alderete, Cristian N.. Comisión Nacional de Energía Atómica. Centro Atómico Constituyentes; Argentina. Universidad Nacional de San Martín. Instituto Sabato; ArgentinaFil: Gargano, Pablo. Comisión Nacional de Energía Atómica. Centro Atómico Constituyentes; Argentina. Universidad Nacional de San Martín. Instituto Sabato; ArgentinaFil: Rubiolo, Gerardo Hector. Comisión Nacional de Energía Atómica. Centro Atómico Constituyentes; Argentina. Universidad Nacional de San Martín. Instituto Sabato; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Alonso, Paula Regina. Comisión Nacional de Energía Atómica. Centro Atómico Constituyentes; Argentina. Universidad Nacional de San Martín. Instituto Sabato; ArgentinaFil: Ferreirós, Pedro Antonio. Comisión Nacional de Energía Atómica. Centro Atómico Constituyentes; Argentina. Universidad Nacional de San Martín. Instituto Sabato; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Tecnológica Nacional. Facultad Regional General Pacheco; Argentin

STATegra, a comprehensive multi-omics dataset of B-cell differentiation in mouse

Multi-omics approaches use a diversity of high-throughput technologies to profile the different molecular layers of living cells. Ideally, the integration of this information should result in comprehensive systems models of cellular physiology and regulation. However, most multi-omics projects still include a limited number of molecular assays and there have been very few multi-omic studies that evaluate dynamic processes such as cellular growth, development and adaptation. Hence, we lack formal analysis methods and comprehensive multi-omics datasets that can be leveraged to develop true multi-layered models for dynamic cellular systems. Here we present the STAT egra multi-omics dataset that combines measurements from up to 10 different omics technologies applied to the same biological system, namely the well-studied mouse pre-B-cell differentiation. STATegra include

SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia.

The nucleoside analog cytarabine (Ara-C) is an essential component of primary and salvage chemotherapy regimens for acute myeloid leukemia (AML). After cellular uptake, Ara-C is converted into its therapeutically active triphosphate metabolite, Ara-CTP, which exerts antileukemic effects, primarily by inhibiting DNA synthesis in proliferating cells. Currently, a substantial fraction of patients with AML fail to respond effectively to Ara-C therapy, and reliable biomarkers for predicting the therapeutic response to Ara-C are lacking. SAMHD1 is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase that cleaves physiological dNTPs into deoxyribonucleosides and inorganic triphosphate. Although it has been postulated that SAMHD1 sensitizes cancer cells to nucleoside-analog derivatives through the depletion of competing dNTPs, we show here that SAMHD1 reduces Ara-C cytotoxicity in AML cells. Mechanistically, dGTP-activated SAMHD1 hydrolyzes Ara-CTP, which results in a drastic reduction of Ara-CTP in leukemic cells. Loss of SAMHD1 activity-through genetic depletion, mutational inactivation of its triphosphohydrolase activity or proteasomal degradation using specialized, virus-like particles-potentiates the cytotoxicity of Ara-C in AML cells. In mouse models of retroviral AML transplantation, as well as in retrospective analyses of adult patients with AML, the response to Ara-C-containing therapy was inversely correlated with SAMHD1 expression. These results identify SAMHD1 as a potential biomarker for the stratification of patients with AML who might best respond to Ara-C-based therapy and as a target for treating Ara-C-refractory AML