Event generation with SHERPA 1.1

In this paper the current release of the Monte Carlo event generator Sherpa, version 1.1, is presented. Sherpa is a general-purpose tool for the simulation of particle collisions at high-energy colliders. It contains a very flexible tree-level matrix-element generator for the calculation of hard scattering processes within the Standard Model and various new physics models. The emission of additional QCD partons off the initial and final states is described through a parton-shower model. To consistently combine multi-parton matrix elements with the QCD parton cascades the approach of Catani, Krauss, Kuhn and Webber is employed. A simple model of multiple interactions is used to account for underlying events in hadron--hadron collisions. The fragmentation of partons into primary hadrons is described using a phenomenological cluster-hadronisation model. A comprehensive library for simulating tau-lepton and hadron decays is provided. Where available form-factor models and matrix elements are used, allowing for the inclusion of spin correlations; effects of virtual and real QED corrections are included using the approach of Yennie, Frautschi and Suura.Comment: 47 pages, 21 figure

Oct4/Sox2 binding sites contribute to maintaining hypomethylation of the maternal Igf2/H19 imprinting control region

A central question in genomic imprinting is how parental-specific DNA methylation of imprinting control regions (ICR) is established during gametogenesis and maintained after fertilization. At the imprinted Igf2/H19 locus, CTCF binding maintains the unmethylated state of the maternal ICR after the blastocyst stage. In addition, evidence from Beckwith-Wiedemann patients and cultured mouse cells suggests that two Sox-Oct binding motifs within the Igf2/H19 ICR also participate in maintaining hypomethylation of the maternal allele. We found that the Sox and octamer elements from both Sox-Oct motifs were required to drive hypomethylation of integrated transgenes in mouse embryonic carcinoma cells. Oct4 and Sox2 showed cooperative binding to the Sox-Oct motifs, and both were present at the endogenous ICR. Using a mouse with mutations in the Oct4 binding sites, we found that maternally transmitted mutant ICRs acquired partial methylation in somatic tissues, but there was little effect on imprinted expression of H19 and Igf2. A subset of mature oocytes also showed partial methylation of the mutant ICR, which suggested that the Sox-Oct motifs provide some protection from methylation during oogenesis. The Sox-Oct motifs, however, were not required for erasure of paternal methylation in primordial germ cells, which indicated that the oocyte methylation was acquired post-natally. Maternally inherited mutant ICRs were unmethylated in blastocysts, which suggested that at least a portion of the methylation in somatic tissues occurred after implantation. These findings provide evidence that Sox-Oct motifs contribute to ICR hypomethylation in post-implantation embryos and maturing oocytes and link imprinted DNA methylation with key stem cell/germline transcription factors

A 0535+26 in the August/September 2005 outburst observed by RXTE and INTEGRAL

In this Letter we present results from INTEGRAL and RXTE observations of the spectral and timing behavior of the High Mass X-ray Binary A 0535+26 during its August/September 2005 normal (type I) outburst with an average flux F(5-100keV)~400mCrab. The search for cyclotron resonance scattering features (fundamental and harmonic) is one major focus of the paper. Our analysis is based on data from INTEGRAL and RXTE Target of Opportunity Observations performed during the outburst. The pulse period is determined. X-ray pulse profiles in different energy ranges are analyzed. The broad band INTEGRAL and RXTE pulse phase averaged X-ray spectra are studied. The evolution of the fundamental cyclotron line at different luminosities is analyzed. The pulse period P is measured to be 103.39315(5)s at MJD 53614.5137. Two absorption features are detected in the phase averaged spectra at E_1~45keV and E_2~100keV. These can be interpreted as the fundamental cyclotron resonance scattering feature and its first harmonic and therefore the magnetic field can be estimated to be B~4x10^12G.Comment: 4 pages, 5 figures, accepted for publication in A&A Letter

A 12-month phase 3 study of pasireotide in cushing's disease

BACKGROUND: Cushing's disease is associated with high morbidity and mortality. Pasireotide, a potential therapy, has a unique, broad somatostatin-receptor-binding profile, with high binding affinity for somatostatin-receptor subtype 5. METHODS: In this double-blind, phase 3 study, we randomly assigned 162 adults with Cushing's disease and a urinary free cortisol level of at least 1.5 times the upper limit of the normal range to receive subcutaneous pasireotide at a dose of 600 ??g (82 patients) or 900 ??g (80 patients) twice daily. Patients with urinary free cortisol not exceeding 2 times the upper limit of the normal range and not exceeding the baseline level at month 3 continued to receive their randomly assigned dose; all others received an additional 300 ??g twice daily. The primary end point was a urinary free cortisol level at or below the upper limit of the normal range at month 6 without an increased dose. Open-label treatment continued through month 12. RESULTS: Twelve of the 82 patients in the 600-??g group and 21 of the 80 patients in the 900-??g group met the primary end point. The median urinary free cortisol level decreased by approximately 50% by month 2 and remained stable in both groups. A normal urinary free cortisol level was achieved more frequently in patients with baseline levels not exceeding 5 times the upper limit of the normal range than in patients with higher baseline levels. Serum and salivary cortisol and plasma corticotropin levels decreased, and clinical signs and symptoms of Cushing's disease diminished. Pasireotide was associated with hyperglycemia-related adverse events in 118 of 162 patients; other adverse events were similar to those associated with other somatostatin analogues. Despite declines in cortisol levels, blood glucose and glycated hemoglobin levels increased soon after treatment initiation and then stabilized; treatment with a glucose-lowering medication was initiated in 74 of 162 patients. CONCLUSIONS: The significant decrease in cortisol levels in patients with Cushing's disease who received pasireotide supports its potential use as a targeted treatment for corticotropin-secreting pituitary adenomas. (Funded by Novartis Pharma; ClinicalTrials.gov number, NCT00434148.) Copyright © 2012 Massachusetts Medical Society

Drosophila Activated Cdc42 Kinase Has an Anti-Apoptotic Function

Activated Cdc42 kinases (Acks) are evolutionarily conserved non-receptor tyrosine kinases. Activating somatic mutations and increased ACK1 protein levels have been found in many types of human cancers and correlate with a poor prognosis. ACK1 is activated by epidermal growth factor (EGF) receptor signaling and functions to regulate EGF receptor turnover. ACK1 has additionally been found to propagate downstream signals through the phosphorylation of cancer relevant substrates. Using Drosophila as a model organism, we have determined that Drosophila Ack possesses potent anti-apoptotic activity that is dependent on Ack kinase activity and is further activated by EGF receptor/Ras signaling. Ack anti-apoptotic signaling does not function through enhancement of EGF stimulated MAP kinase signaling, suggesting that it must function through phosphorylation of some unknown effector. We isolated several putative Drosophila Ack interacting proteins, many being orthologs of previously identified human ACK1 interacting proteins. Two of these interacting proteins, Drk and yorkie, were found to influence Ack signaling. Drk is the Drosophila homolog of GRB2, which is required to couple ACK1 binding to receptor tyrosine kinases. Drk knockdown blocks Ack survival activity, suggesting that Ack localization is important for its pro-survival activity. Yorkie is a transcriptional co-activator that is downstream of the Salvador-Hippo-Warts pathway and promotes transcription of proliferative and anti-apoptotic genes. We find that yorkie and Ack synergistically interact to produce tissue overgrowth and that yorkie loss of function interferes with Ack anti-apoptotic signaling. Our results demonstrate how increased Ack signaling could contribute to cancer when coupled to proliferative signals

Insulators and imprinting from flies to mammals

The nuclear factor CTCF has been shown to be necessary for the maintenance of genetic imprinting at the mammalian H19/Igf2 locus. MacDonald and colleagues now report in BMC Biology that the mechanisms responsible for maintaining the imprinted state in Drosophila may be evolutionarily conserved and that CTCF may also play a critical role in this process

Future business and the role of purchasing and supply management: Opportunities for ‘business-not-as-usual’ PSM research

The raison d'être for this article is simple: traditional ways of researching, theorizing, and practicing purchasing and supply management (PSM) are no longer sufficient to ‘meet the moment’. Scholars need to advance a “business-not-as-usual” footing approach to their work, if they are to make a meaningful contribution to addressing the current and future emergencies, as highlighted by recent extreme weather and the COVID-19 pandemic. Yet, what can this, or should this, mean for a field rooted in traditional business thinking? This article builds on the Journal of Purchasing and Supply Management's (JPSM) 25th Anniversary Special Issue editorial (2019); members of the JPSM's editorial team advance their unique perspectives on what “business-not-as-usual” means for PSM. Specifically, we advocate both thinking much more widely, in scope and ambition, than we currently do, and simultaneously building our ability to comprehend supply chains in a more nuanced and granular way. We explore whether the bias toward positivist work has omitted potentially interesting findings, and viewpoints. This leads to a call to re-think how we approach our work: should the key criteria always be to focus on theory development or testing? Should academics “think bigger”? Turning to specific research themes, illustrations of how our current thinking can be challenged or broadened by addressing the circular economy, and role of purchasing and innovation. Specifically, the focus on the PSM function as an intrapreneur within the larger organization, and the role of innovation and technology in PSM work. Taken together, we hope the ideas and arguments presented here will inform and inspire ambitious and novel approaches to PSM research with significant and enduring impact on the transformation of business

Resonant Spin Excitation in an Overdoped High Temperature Superconductor

An inelastic neutron scattering study of overdoped Bi_2Sr_2CaCu_2O_{8+\delta} $ (T_c = 83 K) has revealed a resonant spin excitation in the superconducting state. The mode energy is E_res=38 meV, significantly lower than in optimally doped Bi_2Sr_2CaCu_2O_{8+\delta} (T_c = 91 K, E_ res =43 meV). This observation, which indicates a constant ratio E_res /k_B T_c \sim 5.4, helps resolve a long-standing controversy about the origin of the resonant spin excitation in high-temperature superconductors.Comment: final version: PRL 86, 1610 (2001