Structural basis for the RING catalyzed synthesis of K63 linked ubiquitin chains

This work was supported by grants from Cancer Research UK (C434/A13067), the Wellcome Trust (098391/Z/12/Z) and Biotechnology and Biological Sciences Research Council (BB/J016004/1).The RING E3 ligase catalysed formation of lysine 63 linked ubiquitin chains by the Ube2V2–Ubc13 E2 complex is required for many important biological processes. Here we report the structure of the RING domain dimer of rat RNF4 in complex with a human Ubc13~Ub conjugate and Ube2V2. The structure has captured Ube2V2 bound to the acceptor (priming) ubiquitin with Lys63 in a position that could lead to attack on the linkage between the donor (second) ubiquitin and Ubc13 that is held in the active “folded back” conformation by the RING domain of RNF4. The interfaces identified in the structure were verified by in vitro ubiquitination assays of site directed mutants. This represents the first view of the synthesis of Lys63 linked ubiquitin chains in which both substrate ubiquitin and ubiquitin-loaded E2 are juxtaposed to allow E3 ligase mediated catalysis.PostprintPeer reviewe

Controversies in the Surgical Management of Sigmoid Diverticulitis

The timing and appropriateness of surgical treatment of sigmoid diverticular disease remain a topic of controversy. We have reviewed the current literature on this topic, focusing on issues related to the indications and types of surgery. Current evidence would suggest that elective surgery for diverticulitis can be avoided in patients with uncomplicated disease, regardless of the number of recurrent episodes. Furthermore, the need for elective surgey should not be influenced by the age of the patient. Operation should be undertaken in patients with severe attacks, as determined by their clinical and radiological evaluation

Evaluating compulsory minimum volume standards in Germany: how many hospitals were compliant in 2004?

<p>Abstract</p> <p>Background</p> <p>Minimum hospital procedure volumes are discussed as an instrument for quality assurance. In 2004 Germany introduced such annual minimum volumes nationwide on five surgical procedures: kidney, liver, stem cell transplantation, complex oesophageal, and pancreatic interventions. The present investigation is the first part of a study evaluating the effects of these minimum volumes on health care provision. Research questions address how many hospitals and cases were affected by minimum volume regulations in 2004, how affected hospitals were distributed according to minimum volumes, and how many hospitals within the 16 German states complied with the standards set for 2004.</p> <p>Methods</p> <p>The evaluation is based on the mandatory hospital quality reports for 2004. In the reports, all hospitals are statutorily obliged to state the number of procedures performed for each minimum volume. The data were analyzed descriptively.</p> <p>Results</p> <p>In 2004, 485 out of 1710 German hospitals providing acute care and approximately 0.14% of all hospital cases were affected by minimum volume regulations. Liver, kidney, and stem cell transplantation affected from 23 to hospitals; complex oesophageal and pancreatic interventions affected from 297 to 455 hospitals. The inter-state comparison of the average hospital care area demonstrates large differences between city states and large area states and the eastern and western German states ranging from a minimum 51 km²up to a maximum 23.200 km², varying according to each procedure. A range of 9% – 16% of the transplantation hospitals did not comply with the standards affecting 1% – 2% of the patients whereas 29% and 18% of the hospitals treating complex oesophageal and pancreatic interventions failed the standards affecting 2% – 5% of the prevailing cases.</p> <p>Conclusion</p> <p>In 2004, the newly introduced minimum volume regulations affected only up to a quarter of German acute care hospitals and few cases. However, excluding the hospitals not meeting the minimum volume standards from providing the respective procedures deserves considering two aspects: the hospital health care provision concepts by the German states as being responsible and from a patient perspective the geographically equal access to hospital care.</p

Haemostatics in surgery and our experience in the enucleoresection of renal cell carcinoma

<p>Abstract</p> <p>Background</p> <p>30 patients, with T1 renal cell carcinomas (RCC) who underwent open enucleoresection of the tumour, were randomized to the use of a topical haemostatic agent (Floseal) or to an infrared-sapphire coagulator (ISC), to compare their efficacy in achieving haemostasis. Methods: Successful intra-operative haemostasis, intra- and post-operative bleeding, operative time, hospital discharge were evaluated.</p> <p>Results</p> <p>Statistically higher rates of successful haemostasis and shorter time-to-haemostasis (8,1 vs 12,9 min) were observed in the FloSeal group (p < 0.001 both). Patients operative time was not different between Group 1 vs 2 (58.7 ± 12 vs 62.4 ± 15; p > 0.05). The average blood loss during surgery was less (60 +/- 25.5 mL) for the FloSeal group than for the ISC group (85 +/- 40.5 mL) (p < 0.05). Postoperative blood loss was 25 +/- 5 mL and 40 +/- 45 mL for Floseal and ISC respectively, (p < 0.05). Length of the postoperative hospital discharge was 2.5 +/- 1.2 days for FloSeal group and 3.5 +/- 1.3 for the Group 2 (p < 0.05). No major immediate or delayed complications were observed in either Groups.</p> <p>Conclusions</p> <p>The use of Floseal and ISC offer a safe and efficacy haemostasis in the enucleoresection of RCC. Moreover, our results show a less intra-operative and post-operative blood loss as well as a shorter time to haemostasis of Floseal in respect to ISC.</p

Non-Standard Interactions at a Neutrino Factory: Correlations and CP violation

We explore the potential of several Neutrino Factory (NF) setups to constrain, discover and measure new physics effects due to Non-Standard Interactions (NSI) in propagation through Earth matter. We first study the impact of NSI in the measurement of $\theta_{13}$: we find that these could be large due to strong correlations of $\theta_{13}$ with NSI parameters in the golden channel, and the inclusion of a detector at the magic baseline is crucial in order to reduce them as much as possible. We present, then, the sensitivity of the considered NF setups to the NSI parameters, paying special attention to correlations arising between them and the standard oscillation parameters, when all NSI parameters are introduced at once. Off-diagonal NSI parameters could be tested down to the level of $10^{-3}$, whereas the diagonal combinations $(\epsilon_{ee} - \epsilon_{\tau\tau})$ and $(\epsilon_{\mu\mu}-\epsilon_{\tau\tau})$ can be tested down to $10^{-1}$ and $10^{-2}$, respectively. The possibilities of observing CP violation in this context are also explored, by presenting a first scan of the CP discovery potential of the NF setups to the phases $\phi_{e\mu}, \phi_{e\tau}$ and $\delta$. We study separately the case where CP violation comes only from non-standard sources, and the case where it is entangled with the standard source, $\delta$. In case $\delta$ turns out to be CP conserving, the interesting possibility of observing CP violation for reasonably small values of the NSI parameters emerges.Comment: Final note added. 38 pages, 11 figure

Scintillation light detection in the 6-m drift-length ProtoDUNE Dual Phase liquid argon TPC

DUNE is a dual-site experiment for long-baseline neutrino oscillation studies, neutrino astrophysics and nucleon decay searches. ProtoDUNE Dual Phase (DP) is a 6  ×  6  ×  6 m 3 liquid argon time-projection-chamber (LArTPC) that recorded cosmic-muon data at the CERN Neutrino Platform in 2019-2020 as a prototype of the DUNE Far Detector. Charged particles propagating through the LArTPC produce ionization and scintillation light. The scintillation light signal in these detectors can provide the trigger for non-beam events. In addition, it adds precise timing capabilities and improves the calorimetry measurements. In ProtoDUNE-DP, scintillation and electroluminescence light produced by cosmic muons in the LArTPC is collected by photomultiplier tubes placed up to 7 m away from the ionizing track. In this paper, the ProtoDUNE-DP photon detection system performance is evaluated with a particular focus on the different wavelength shifters, such as PEN and TPB, and the use of Xe-doped LAr, considering its future use in giant LArTPCs. The scintillation light production and propagation processes are analyzed and a comparison of simulation to data is performed, improving understanding of the liquid argon properties

Supernova neutrino burst detection with the Deep Underground Neutrino Experiment

The Deep Underground Neutrino Experiment (DUNE), a 40-kton underground liquid argon time projection chamber experiment, will be sensitive to the electron-neutrino flavor component of the burst of neutrinos expected from the next Galactic core-collapse supernova. Such an observation will bring unique insight into the astrophysics of core collapse as well as into the properties of neutrinos. The general capabilities of DUNE for neutrino detection in the relevant few- to few-tens-of-MeV neutrino energy range will be described. As an example, DUNE's ability to constrain the νe spectral parameters of the neutrino burst will be considered