HE-LHC: The High-Energy Large Hadron Collider – Future Circular Collider Conceptual Design Report Volume 4

In response to the 2013 Update of the European Strategy for Particle Physics (EPPSU), the Future Circular Collider (FCC) study was launched as a world-wide international collaboration hosted by CERN. The FCC study covered an energy-frontier hadron collider (FCC-hh), a highest-luminosity high-energy lepton collider (FCC-ee), the corresponding 100 km tunnel infrastructure, as well as the physics opportunities of these two colliders, and a high-energy LHC, based on FCC-hh technology. This document constitutes the third volume of the FCC Conceptual Design Report, devoted to the hadron collider FCC-hh. It summarizes the FCC-hh physics discovery opportunities, presents the FCC-hh accelerator design, performance reach, and staged operation plan, discusses the underlying technologies, the civil engineering and technical infrastructure, and also sketches a possible implementation. Combining ingredients from the Large Hadron Collider (LHC), the high-luminosity LHC upgrade and adding novel technologies and approaches, the FCC-hh design aims at significantly extending the energy frontier to 100 TeV. Its unprecedented centre-of-mass collision energy will make the FCC-hh a unique instrument to explore physics beyond the Standard Model, offering great direct sensitivity to new physics and discoveries

Comments on: ‘Preventive Effect of Dapsone on Renal Scarring following Mannose-Sensitive Piliated Bacterial Infection’ by Mochida et al. (Chemotherapy 1998;44:36–41): Comments on: ‘Preventive Effect of Dapsone on Renal Scarring following Mannose-Sensitive Piliated Bacterial Infection’ by Mochida et al. (Chemotherapy 1998;44:36–41)

Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich

Compounds with As-S bonds: Analytical and biogeochemical reasons why these species have been elusive in biota and environment: Chapter 7.2

This chapter is focussing on the interaction of arsenic, mercury and selenium with plans. Aspects of biotransformations are discussed, before the analytical methodologies are listed and critically appraised in the second part. A holistic view is given, starting from the soil environment and continuing to the plant roots and the translocations into the upper part of the plants. Under different soil conditions, different kinds of elemental species are identified, which have an impact on how the elemental species are taken up by the plant. The uptake mechanisms of these elemental species are explained and compared before the biotransformation reactions of all elemental species in the plant root; their transport into the vacuoles and translocation to the leaves and grains are discussed. Here in particular the interaction with sulphur-rich phytochelatins is described for all three elemental species. Since the sulphur chemistry is so important for the uptake, bioaccumulation and translocation of the metals and metalloids, a subchapter about sulphur chemistry in plants has been added. All aspects of biotransformation dealt with in this chapter is finally rounded up by a thorough description of the analytical methodology given with a focus on the use of HPLC-ICPMS/ESI-MS for both quantitative and molecular analysis

Solvent transfer - efficiency of risk management measures

A series of laboratory simulations were conducted in order to determine the airborne protection that might be afforded by different combinations of workplace exposure controls typically encountered when handling volatile solvents (e.g. solvent transfer). These conditions, referred to as risk management measures (RMMs) under the Registration, Evaluation and Authorisation of Chemicals Regulation (REACH), are typically described using standard phrases in safety data sheets [and specifically those of the European Phrase Catalogue (EUPhraC)]. Ethanol was used as a model compound and its emissions were monitored continuously with a portable IR spectrometer at 3000 cm−1. Theaverage emission reduction performance of the investigated RMMs (e.g. containment, extract ventilation, drum pump) exceeded 90%. They present suitable ways to reduce airborne solvent exposure in a workplace and confirmed the initial expectations derived at by the European Solvents Industry Group (ESIG) and the European Centre For Ecotoxicology and toxicology of Chemicals (ECETOC) Targeted Risk Assessment (TRA) model

HIF1α modulates cell fate reprogramming through early glycolytic shift and upregulation of PDK1-3 and PKM2

Reprogramming somatic cells to a pluripotent state drastically reconfigures the cellular anabolic requirements, thus potentially inducing cancer-like metabolic transformation. Accordingly, we and others previously showed that somatic mitochondria and bioenergetics are extensively remodeled upon derivation of induced pluripotent stem cells (iPSCs), as the cells transit from oxidative to glycolytic metabolism. In the attempt to identify possible regulatory mechanisms underlying this metabolic restructuring, we investigated the contributing role of hypoxia-inducible factor 1 {alpha} (HIF1{alpha}), a master regulator of energy metabolism, in the induction and maintenance of pluripotency. We discovered that the ablation of HIF1{alpha} function in dermal fibroblasts dramatically hampers reprogramming efficiency, while small molecule-based activation of HIF1{alpha} significantly improves cell fate conversion. Transcriptional and bioenergetic analysis during reprogramming initiation indicated that the transduction of the four factors is sufficient to up-regulate the HIF1{alpha} target pyruvate dehydrogenase kinase (PDK) 1 and set in motion the glycolytic shift. However, additional HIF1{alpha} activation appears critical in the early up-regulation of other HIF1{alpha}-associated metabolic regulators, including PDK3 and pyruvate kinase (PK) isoform M2 (PKM2), resulting in increased glycolysis and enhanced reprogramming. Accordingly, elevated levels of PDK1, PDK3, and PKM2 and reduced PK activity could be observed in iPSCs and human embryonic stem cells (hESCs) in the undifferentiated state. Overall, the findings suggest that the early induction of HIF1{alpha} targets may be instrumental in iPSC derivation via the activation of a glycolytic program. These findings implicate the HIF1{alpha} pathway as an enabling regulator of cellular reprogramming

4‐tert‐Octylphenol and p‐nonylphenol – Determination of 4‐tert‐octylphenol and p‐nonylphenol in urine by LC‐MS/MS : Biomonitoring Methods, 2019

The working group “Analyses in Biological Materials” of the Permanent Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area developed and validated the presented biomonitoring method. The analytical method described hereinafter permits the selective detection of 4‐tert‐octylphenol as well as the sum of various branched p‐nonylphenol isomers in urine. After adding the labelled internal standards (13C6‐4‐tert‐octylphenol and 13C6‐p‐nonylphenol), the samples are enzymatically hydrolysed to release the analytes from the conjugated alkylphenols. After online SPE, the analytes are separated by liquid chromatography and analysed using tandem mass spectrometry. A quantitation limit of 2 µg/L each is obtained for the analytes. Calibration standards are prepared in pooled urine and processed in the same way as the samples to be analysed

4‐tert‐Octylphenol und p‐Nonylphenol – Bestimmung von 4‐tert‐Octylphenol und p‐Nonylphenol in Urin mittels LC‐MS/MS : Biomonitoring Methods in German language, 2019

The working group „Analyses in Biological Materials“ of the Permanent Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area developed and validated the presented biomonitoring method. The analytical method described hereinafter permits the selective detection of 4‐tert‐octylphenol as well as the sum of various branched p‐nonylphenol isomers in urine. After adding the labelled internal standards (13C6‐4‐tert‐octylphenol and 13C6‐p‐nonylphenol), the samples are enzymatically hydrolysed to release the analytes from the conjugated alkylphenols. After online SPE, the analytes are separated by liquid chromatography and analysed using tandem mass spectrometry. A quantitation limit of 2 µg/L each is obtained for the analytes. Calibration standards are prepared in pooled urine and processed in the same way as the samples to be analysed

Functional Analysis of Centrosomal Kinase Substrates in Drosophila melanogaster Reveals a New Function of the Nuclear Envelope Component Otefin in Cell Cycle Progression

Phosphorylation is one of the key mechanisms that regulate centrosome biogenesis, spindle assembly, and cell cycle progression. However, little is known about centrosome-specific phosphorylation sites and their functional relevance. Here, we identified phosphoproteins of intact Drosophila melanogaster centrosomes and found previously unknown phosphorylation sites in known and unexpected centrosomal components. We functionally characterized phosphoproteins and integrated them into regulatory signaling networks with the 3 important mitotic kinases, cdc2, polo, and aur, as well as the kinase CkIIβ. Using a combinatorial RNA interference (RNAi) strategy, we demonstrated novel functions for P granule, nuclear envelope (NE), and nuclear proteins in centrosome duplication, maturation, and separation. Peptide microarrays confirmed phosphorylation of identified residues by centrosome-associated kinases. For a subset of phosphoproteins, we identified previously unknown centrosome and/or spindle localization via expression of tagged fusion proteins in Drosophila SL2 cells. Among those was otefin (Ote), an NE protein that we found to localize to centrosomes. Furthermore, we provide evidence that it is phosphorylated in vitro at threonine 63 (T63) through Aurora-A kinase. We propose that phosphorylation of this site plays a dual role in controlling mitotic exit when phosphorylated while dephosphorylation promotes G2/M transition in Drosophila SL2 cells

Rare EIF4A2 variants are associated with a neurodevelopmental disorder characterized by intellectual disability, hypotonia, and epilepsy

: Eukaryotic initiation factor-4A2 (EIF4A2) is an ATP-dependent RNA helicase and a member of the DEAD-box protein family that recognizes the 5' cap structure of mRNAs, allows mRNA to bind to the ribosome, and plays an important role in microRNA-regulated gene repression. Here, we report on 15 individuals from 14 families presenting with global developmental delay, intellectual disability, hypotonia, epilepsy, and structural brain anomalies, all of whom have extremely rare de novo mono-allelic or inherited bi-allelic variants in EIF4A2. Neurodegeneration was predominantly reported in individuals with bi-allelic variants. Molecular modeling predicts these variants would perturb structural interactions in key protein domains. To determine the pathogenicity of the EIF4A2 variants in vivo, we examined the mono-allelic variants in Drosophila melanogaster (fruit fly) and identified variant-specific behavioral and developmental defects. The fruit fly homolog of EIF4A2 is eIF4A, a negative regulator of decapentaplegic (dpp) signaling that regulates embryo patterning, eye and wing morphogenesis, and stem cell identity determination. Our loss-of-function (LOF) rescue assay demonstrated a pupal lethality phenotype induced by loss of eIF4A, which was fully rescued with human EIF4A2 wild-type (WT) cDNA expression. In comparison, the EIF4A2 variant cDNAs failed or incompletely rescued the lethality. Overall, our findings reveal that EIF4A2 variants cause a genetic neurodevelopmental syndrome with both LOF and gain of function as underlying mechanisms