Abstract
Eine durch Iod (I/III) Katalyse ermöglichte Strategie zur Konstruktion eines enantioangereicherten fluorierten Isoster der Isopropylgruppe wird beschrieben. Die in situ Generierung einer ...chiralen ArIF
2
‐Spezies ermöglicht die Difluorierung von leicht zugänglichen α‐CF
3
‐Styrolen, um ein Stereozentrum mit den Substituenten F, CH
2
F und CF
3
aufzubauen (bis zu 95 %, >20:1
vicinale:geminale
Difluorierung). Der Austausch des metabolisch labilen benzylischen Protons führt zu einem stark präorganisierten Gerüst, welches durch Röntgenstrukturanalyse nachgewiesen werden konnte (π→σ* und stereoelektronische
gauche
σ→σ* Wechselwirkungen). Um die Basis für die vorläufige Validierung der Enantioselektivität zu bilden, wurde eine Katalysatoroptimierung durchgeführt.
Proton pump inhibitors: Risks of long‐term use Eusebi, Leonardo Henry; Rabitti, Stefano; Artesiani, Maria Laura ...
Journal of gastroenterology and hepatology,
July 2017, Letnik:
32, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Proton pump inhibitors are among the most commonly prescribed classes of drugs, and their use is increasing, in particular for long‐term treatment, often being over‐prescribed and used for ...inappropriate conditions. In recent years, considerable attention has been directed towards a wide range of adverse effects, and even when a potential underlying biological mechanism is plausible, the clinical evidence of the adverse effect is often weak. Several long‐term side effects have been investigated ranging from interaction with other drugs, increased risk of infection, reduced intestinal absorption of vitamins and minerals, and more recently kidney damage and dementia. The most recent literature regarding these adverse effects and their association with long‐term proton pump inhibitor treatment is reviewed, and the mechanisms through which these possible complications might develop are discussed.
We extend recent modeling studies of proton hopping, used to describe the functioning of membrane channels and axon nerve conduction, to offer an explanation of the initiation of the nerve impulse at ...an effectorligand encounter. This encounter is proposed to create a hydronium ion in the vicinity of the effector and ligand, which leads to a continuous flow of protons, called proton hopping, through water adjacent to this encounter. This proton hopping is proposed to be the message carried from the encounter to the axon of a particular nerve system associated with that particular effectorligand system. PUBLICATION ABSTRACT
With the recent clinical implementation of real‐time MRI‐guided x‐ray beam therapy (MRXT), attention is turning to the concept of combining real‐time MRI guidance with proton beam therapy; MRI‐guided ...proton beam therapy (MRPT). MRI guidance for proton beam therapy is expected to offer a compelling improvement to the current treatment workflow which is warranted arguably more than for x‐ray beam therapy. This argument is born out of the fact that proton therapy toxicity outcomes are similar to that of the most advanced IMRT treatments, despite being a fundamentally superior particle for cancer treatment.
In this Future of Medical Physics article, we describe the various software and hardware aspects of potential MRPT systems and the corresponding treatment workflow. Significant software developments, particularly focused around adaptive MRI‐based planning will be required. The magnetic interaction between the MRI and the proton beamline components will be a key area of focus. For example, the modeling and potential redesign of a magnetically compatible gantry to allow for beam delivery from multiple angles towards a patient located within the bore of an MRI scanner. Further to this, the accuracy of pencil beam scanning and beam monitoring in the presence of an MRI fringe field will require modeling, testing, and potential further development to ensure that the highly targeted radiotherapy is maintained.
Looking forward we envisage a clear and accelerated path for hardware development, leveraging from lessons learnt from MRXT development. Within few years, simple prototype systems will likely exist, and in a decade, we could envisage coupled systems with integrated gantries. Such milestones will be key in the development of a more efficient, more accurate, and more successful form of proton beam therapy for many common cancer sites.
The unique dose deposition of proton beams generates a distinctive thermoacoustic (protoacoustic) signal, which can be used to calculate the proton range. To identify the expected protoacoustic ...amplitude, frequency, and arrival time for different proton pulse characteristics encountered at hospital-based proton sources, the protoacoustic pressure emissions generated by 150 MeV, pencil-beam proton pulses were simulated in a homogeneous water medium. Proton pulses with Gaussian widths ranging up to 200 μs were considered. The protoacoustic amplitude, frequency, and time-of-flight (TOF) range accuracy were assessed. For TOF calculations, the acoustic pulse arrival time was determined based on multiple features of the wave. Based on the simulations, Gaussian proton pulses can be categorized as Dirac-delta-function-like (FWHM < 4 μs) and longer. For the δ-function-like irradiation, the protoacoustic spectrum peaks at 44.5 kHz and the systematic error in determining the Bragg peak range is <2.6 mm. For longer proton pulses, the spectrum shifts to lower frequencies, and the range calculation systematic error increases (⩽ 23 mm for FWHM of 56 μs). By mapping the protoacoustic peak arrival time to range with simulations, the residual error can be reduced. Using a proton pulse with FWHM = 2 μs results in a maximum signal-to-noise ratio per total dose. Simulations predict that a 300 nA, 150 MeV, FWHM = 4 μs Gaussian proton pulse (8.0 × 10(6) protons, 3.1 cGy dose at the Bragg peak) will generate a 146 mPa pressure wave at 5 cm beyond the Bragg peak. There is an angle dependent systematic error in the protoacoustic TOF range calculations. Placing detectors along the proton beam axis and beyond the Bragg peak minimizes this error. For clinical proton beams, protoacoustic detectors should be sensitive to <400 kHz (for -20 dB). Hospital-based synchrocyclotrons and cyclotrons are promising sources of proton pulses for generating clinically measurable protoacoustic emissions.
ATP, the universal energy currency of cells, is produced by F-type ATP synthases, which are ancient, membrane-bound nanomachines. F-type ATP synthases use the energy of a transmembrane ...electrochemical gradient to generate ATP by rotary catalysis. Protons moving across the membrane drive a rotor ring composed of 8-15 c-subunits. A central stalk transmits the rotation of the c-ring to the catalytic F1 head, where a series of conformational changes results in ATP synthesis. A key unresolved question in this fundamental process is how protons pass through the membrane to drive ATP production. Mitochondrial ATP synthases form V-shaped homodimers in cristae membranes. Here we report the structure of a native and active mitochondrial ATP synthase dimer, determined by single-particle electron cryomicroscopy at 6.2 Å resolution. Our structure shows four long, horizontal membrane-intrinsic α-helices in the a-subunit, arranged in two hairpins at an angle of approximately 70° relative to the c-ring helices. It has been proposed that a strictly conserved membrane-embedded arginine in the a-subunit couples proton translocation to c-ring rotation. A fit of the conserved carboxy-terminal a-subunit sequence places the conserved arginine next to a proton-binding c-subunit glutamate. The map shows a slanting solvent-accessible channel that extends from the mitochondrial matrix to the conserved arginine. Another hydrophilic cavity on the lumenal membrane surface defines a direct route for the protons to an essential histidine-glutamate pair. Our results provide unique new insights into the structure and function of rotary ATP synthases and explain how ATP production is coupled to proton translocation.
A search for heavy neutral Higgs bosons is performed using the LHC Run 2 data, corresponding to an integrated luminosity of 139 fb−1 of proton-proton collisions at √s = 13 TeV recorded with the ...ATLAS detector. The search for heavy resonances is performed over the mass range 0.2–2.5 TeV for the τ+ τ− decay with at least one τ -lepton decaying into final states with hadrons. The data are in good agreement with the background prediction of the standard model. In the Mh125 scenario of the minimal supersymmetric standard model, values of tan β > 8 and tan β > 21 are excluded at the 95% confidence level for neutral Higgs boson masses of 1.0 and 1.5 TeV, respectively, where tan β is the ratio of the vacuum expectation values of the two Higgs doublets.
The acidity of intracellular compartments and the extracellular environment is crucial to various cellular processes, including membrane trafficking, protein degradation, bone resorption and sperm ...maturation. At the heart of regulating acidity are the vacuolar (V-)ATPases--large, multisubunit complexes that function as ATP-driven proton pumps. Their activity is controlled by regulating the assembly of the V-ATPase complex or by the dynamic regulation of V-ATPase expression on membrane surfaces. The V-ATPases have been implicated in a number of diseases and, coupled with their complex isoform composition, represent attractive and potentially highly specific drug targets.
The need for reducing the solid oxide fuel cell (SOFC) operating temperature below 600 °C is imposed by cost reduction, which is essential for widespread SOFC use, but might also disclose new ...applications. To this aim, high‐temperature proton‐conducting (HTPC) oxides have gained widespread interest as electrolyte materials alternative to oxygen‐ion conductors. This Progress Report describes recent developments in electrolyte, anode, and cathode materials for protonic SOFCs, addressing the issue of chemical stability, processability, and good power performance below 600 °C. Different fabrication methods are reported for anode‐supported SOFCs, obtained using state‐of‐the‐art, chemically stable proton‐conducting electrolyte films. Recent findings show significant improvements in the power density output of cells based on doped barium zirconate electrolytes, pointing out towards the feasibility of the next generation of protonic SOFCs, including a good potential for the development of miniaturized SOFCs as portable power supplies.
Recent developments in electrolyte, anode, and cathode materials for protonic SOFCs are here reported, addressing the issue of chemical stability, processability, and good power performance below 600 °C. Recent findings show significant improvements in the power density output of cells based on doped barium zirconate electrolytes, pointing out towards the feasibility of the next generation of protonic SOFCs.
Purpose: Currently, calculations of proton range in proton therapy patients are based on a conversion of CT Hounsfield units of patient tissues into proton relative stopping power. Uncertainties in ...this conversion necessitate larger proximal and distal planned target volume margins. Proton CT can potentially reduce these uncertainties by directly measuring proton stopping power. We aim to demonstrate proton CT imaging with complex porcine samples, to analyze in detail three‐dimensional regions of interest, and to compare proton stopping powers directly measured by proton CT to those determined from x‐ray CT scans.
Methods: We have used a prototype proton imaging system with single proton tracking to acquire proton radiography and proton CT images of a sample of porcine pectoral girdle and ribs, and a pig's head. We also acquired close in time x‐ray CT scans of the same samples and compared proton stopping power measurements from the two modalities. In the case of the pig's head, we obtained x‐ray CT scans from two different scanners and compared results from high‐dose and low‐dose settings.
Results: Comparing our reconstructed proton CT images with images derived from x‐ray CT scans, we find agreement within 1% to 2% for soft tissues and discrepancies of up to 6% for compact bone. We also observed large discrepancies, up to 40%, for cavitated regions with mixed content of air, soft tissue, and bone, such as sinus cavities or tympanic bullae.
Conclusions: Our images and findings from a clinically realistic proton CT scanner demonstrate the potential for proton CT to be used for low‐dose treatment planning with reduced margins.
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