Non integer harmonic number acceleration of lead ions in the CERN SPS

The project to accelerate lead ions in the CERN complex has been successfully completed and physics has begun. In the SPS, the final machine in the chain, the ions are accelerated from an energy of 5.1 GeV/nucleon to 160 GeV/nucleon using the existing 200 MHz travelling-wave cavities. The change in revolution frequency during acceleration is much larger than can be accepted by the untuned cavities when operated at constant harmonic number. A technique has been developed to overcome this limitation which takes advantage of the filling time of this type of cavity which is shorter than one turn. Fast amplitude and frequency modulation of the RF waveform allows the cavities to operate at a constant, optimum frequency during the passage of a batch of particles in the structure. This frequency is not a multiple of the revolution frequency and therefore during the gaps between batches the phase of the composite RF waveform is changed to maintain synchronism from turn to turn as the beam accelerates. The technique and hardware are described in detail together with the first operational experience

A Superconducting RF Cavity for Bunch Compression of the High Intensity SPS Proton Beam at Transfer to LHC

The bunch length of the high-intensity proton beam ejected from the CERN SPS into LHC must be reduced to fit into the 400MHz LHC buckets. This will be done using a new 400MHz superconducting RF system in the SPS. Above transition bunch compression is obtained with a cavity tuned slightly below the bunch frequency, thus giving a very high capacitive impedeance. Such a system would however be extremely critical and very unstable without strong RF feedback. To keep the required RF power at an acceptable level during the ramp, the beam, which occupies only a third of the SPS, is accelerated in a variable harmonic mode to place the beam spectrum substantially above the cavity bandwidth. On the flat top, when the beam spectrum is moved towards the cavity resonance, the phase and amplitude of the reference voltage, including its modulation at the revolution frequency are programmed to keep the required RF power to a minimum. This scheme is described in detail together with the prototype 400MHz superconducting cavity already installed in the SPS. Initial tests with beam will also be reported

Serendipitous Discovery of Light-Induced \u3cem\u3e(In Situ)\u3c/em\u3e Formation of An Azo-Bridged Dimeric Sulfonated Naphthol as a Potent PTP1B Inhibito

Background Protein tyrosine phosphatases (PTPs) like dual specificity phosphatase 5 (DUSP5) and protein tyrosine phosphatase 1B (PTP1B) are drug targets for diseases that include cancer, diabetes, and vascular disorders such as hemangiomas. The PTPs are also known to be notoriously difficult targets for designing inihibitors that become viable drug leads. Therefore, the pipeline for approved drugs in this class is minimal. Furthermore, drug screening for targets like PTPs often produce false positive and false negative results. Results Studies presented herein provide important insights into: (a) how to detect such artifacts, (b) the importance of compound re-synthesis and verification, and (c) how in situ chemical reactivity of compounds, when diagnosed and characterized, can actually lead to serendipitous discovery of valuable new lead molecules. Initial docking of compounds from the National Cancer Institute (NCI), followed by experimental testing in enzyme inhibition assays, identified an inhibitor of DUSP5. Subsequent control experiments revealed that this compound demonstrated time-dependent inhibition, and also a time-dependent change in color of the inhibitor that correlated with potency of inhibition. In addition, the compound activity varied depending on vendor source. We hypothesized, and then confirmed by synthesis of the compound, that the actual inhibitor of DUSP5 was a dimeric form of the original inhibitor compound, formed upon exposure to light and oxygen. This compound has an IC50 of 36 μM for DUSP5, and is a competitive inhibitor. Testing against PTP1B, for selectivity, demonstrated the dimeric compound was actually a more potent inhibitor of PTP1B, with an IC50 of 2.1 μM. The compound, an azo-bridged dimer of sulfonated naphthol rings, resembles previously reported PTP inhibitors, but with 18-fold selectivity for PTP1B versus DUSP5. Conclusion We report the identification of a potent PTP1B inhibitor that was initially identified in a screen for DUSP5, implying common mechanism of inhibitory action for these scaffolds

The Ethics of Physician Migration and Their Implications for the United States

Currently, the United States trains only three quarters of the physicians it requires to fill its entry-level residency positions. The other quarter of residents employed by its hospitals is composed of immigrants who have been trained in other countries. This reliance of our healthcare system on foreign physicians puts a tremendous strain on the healthcare systems of developing nations. At the same time, by replacing American medical school graduates with graduates of foreign schools, the policy prevents a significant number of Americans who desire to practice medicine from doing so. An alarming shortage of physicians by the year 2020 has been forecasted. Discussion of how this shortage will be addressed is long overdue. The options are clear: either the United States can increase its dependence on foreign medical training programs or it can expand its own. It should choose the latter

Identification of inhibitors that target dual-specificity phosphatase 5 provide new insights into the binding requirements for the two phosphate pockets

Background: Dual-specificity phosphatase-5 (DUSP5) plays a central role in vascular development and disease. We present a p-nitrophenol phosphate (pNPP) based enzymatic assay to screen for inhibitors of the phosphatase domain of DUSP5. Methods: pNPP is a mimic of the phosphorylated tyrosine on the ERK2 substrate (pERK2) and binds the DUSP5 phosphatase domain with a Km of 7.6 ± 0.4 mM. Docking followed by inhibitor verification using the pNPP assay identified a series of polysulfonated aromatic inhibitors that occupy the DUSP5 active site in the region that is likely occupied by the dual-phosphorylated ERK2 substrate tripeptide (pThr-Glu-pTyr). Secondary assays were performed with full length DUSP5 with ERK2 as substrate. Results: The most potent inhibitor has a naphthalene trisulfonate (NTS) core. A search for similar compounds in a drug database identified suramin, a dimerized form of NTS. While suramin appears to be a potent and competitive inhibitor (25 ± 5 μM), binding to the DUSP5 phosphatase domain more tightly than the monomeric ligands of which it is comprised, it also aggregates. Further ligand-based screening, based on a pharmacophore derived from the 7 Å separation of sulfonates on inhibitors and on sulfates present in the DUSP5 crystal structure, identified a disulfonated and phenolic naphthalene inhibitor (CSD3 _2320) with IC50 of 33 μM that is similar to NTS and does not aggregate. Conclusions: The new DUSP5 inhibitors we identify in this study typically have sulfonates 7 Å apart, likely positioning them where the two phosphates of the substrate peptide (pThr-Glu-pTyr) bind, with one inhibitor also positioning a phenolic hydroxyl where the water nucleophile may reside. Polysulfonated aromatic compounds do not commonly appear in drugs and have a tendency to aggregate. One FDA-approved polysulfonated drug, suramin, inhibits DUSP5 and also aggregates. Docking and modeling studies presented herein identify polysulfonated aromatic inhibitors that do not aggregate, and provide insights to guide future design of mimics of the dual-phosphate loops of the ERK substrates for DUSPs. Keywords: DUSP5, Phosphatase, Drug discovery, Docking, Suramin, Vascular anomalie

Training Traditional Birth Attendants on the Use of Misoprostol and a Blood Measurement Tool to Prevent Postpartum Haemorrhage: Lessons Learnt from Bangladesh

A consensus emerged in the late 1990s among leaders in global maternal health that traditional birth attendants (TBAs) should no longer be trained in delivery skills and should instead be trained as promoters of facility-based care. Many TBAs continue to be trained in places where home deliveries are the norm and the potential impacts of this training are important to understand. The primary objective of this study was to gain a more nuanced understanding of the full impact of training TBAs to use misoprostol and a blood measurement tool (mat) for the prevention of postpartum haemorrhage (PPH) at home deliveries through the perspective of those involved in the project. This qualitative study, conducted between July 2009 and July 2010 in Bangladesh, was nested within larger operations research, testing the feasibility and acceptability of scaling up community-based provision of misoprostol and a blood measurement tool for prevention of PPH. A total of 87 in-depth interviews (IDIs) were conducted with TBAs, community health workers (CHWs), managers, and government-employed family welfare visitors (FWVs) at three time points during the study. Computer-assisted thematic data analysis was conducted using ATLAS.ti (version 5.2). Four primary themes emerged during the data analysis, which all highlight changes that occurred following the training. The first theme describes the perceived direct changes linked to the two new interventions. The following three themes describe the indirect changes that interviewees perceived: strengthened linkages between TBAs and the formal healthcare system; strengthened linkages between TBAs and the communities they serve; and improved quality of services/service utilization. The data indicate that training TBAs and CHW supervisors resulted in perceived broader and more nuanced changes than simply improvements in TBAs\u2019 knowledge, attitudes, and practices. Acknowledgeing TBAs\u2019 important role in the community and in home deliveries and integrating them into the formal healthcare system has the potential to result in changes similar to those seen in this study

Управление продвижением электромобилей BYD на рынке Китая

В ВКР проводился анализ деятельности компании BYD, внутренней и внешней среды компании, комплекса маркетинга, анализ основных конкурентов компании, оценка конкурентоспособности продукции компании BYD, анализ емкости рынка электромобилей в Китае.Research presented analysis of the BYD's activities, internal and external environment of the company, marketing complex, analysis of the company's main competitors, assessment of the competitiveness of BYD’s products, analysis of the electric car market in China

Novel Approach to Difficult Spinal Reconstruction: Bilateral Simultaneous Rib and Iliac Crest Vascularized Bone Graft Spinoplastic Surgery

Pseudoarthrosis is a severe complication of spinal fusion surgery with occurrence rates as high as 35%-40%. Current options of revision surgery to correct pseudoarthrosis frequently carry high failure rates and risk of developing junctional kyphosis. Pedicled vascularized bone grafts (VBGs) are an innovative approach to boost spinal fusion rates via improving structural integrity and increasing the delivery of blood to the donor site. This versatile technique can be performed at different spinal levels without additional skin incisions and with minimal added operative time. Here we present the first bilateral rib and iliac crest VBG spinoplastic surgery performed to augment spinal fusion in a 68-year-old woman with distal junctional kyphosis and severe positive sagittal balance with low back and neck pain and significant difficulty standing upright. The patient had history of multiple spinal operations with preoperative CT imaging demonstrating loosening and pull out of L3 and fracture of L2 screws. She underwent two-stage surgical treatment involving anterior lumbar interbody fusion L3-S1 followed by removal of hardware, T4 to pelvis fusion with L2-3 prone lateral interbody fusion, and T11-S1 posterior column osteotomies. The surgery was augmented by bilateral rib and iliac crest VBGs performed by plastic surgery. At three-month follow-up the patient demonstrated functional improvement, being able to maintain upright posture and walk; was satisfied with the result of the surgery; and demonstrated no graft-related complications. In conclusion, utilization of pedicled VBGs is a novel, promising approach to augment spinal surgery in high risk patients