julilili42/papers huggingface dataset:
Novel Calibration Method for Switched Capacitor Arrays Enables Time Measurements With Sub-Picosecond Resolution
2014-11-21

Switched capacitor arrays (SCA) ASICs are becoming more and more popular for\\nthe readout of detector signals, since the sampling frequency of typically\\nseveral gigasamples per second allows excellent pile-up rejection and time\\nmeasurements. They suffer however from the fact that their sampling bins are\\nnot equidistant in time, given by limitations of the chip process. In the past,\\nthis limited time measurements of optimal signals to standard deviations\\n({\\\\sigma}) of about 4-25 ps in accuracy for the split pulse test, depending on\\nthe specific chip. This paper introduces a novel time calibration, which\\ndetermines the true sampling speed of an SCA. Additionally, for two\\nindependently running SCA chips, the achieved time resolution improved to less\\nthan 3 ps ({\\\\sigma}) independently from the delay for the split pulse test,\\nwhen simply applying a linear interpolation. When using a more advanced\\nanalyzing technique for the split pulse test with a single SCA, this limit is\\npushed below 1 ps ({\\\\sigma}) for delays up to 8 ns. Various test measurements\\nwith different boards based on the DRS4 ASIC indicate that the new calibration\\nis stable over time but not over larger temperature variations.\\n
A Biophysical Study with Carbohydrate Derivatives Explains the Molecular Basis of Monosaccharide Selectivity of the Pseudomonas aeruginosa Lectin LecB
2014-11-21

The rise of resistances against antibiotics in bacteria is a major threat for public health and demands the development of novel antibacterial therapies. Infections with Pseudomonas aeruginosa are a severe problem for hospitalized patients and for patients suffering from cystic fibrosis. These bacteria can form biofilms and thereby increase their resistance towards antibiotics. The bacterial lectin LecB was shown to be necessary for biofilm formation and the inhibition with its carbohydrate ligands resulted in reduced amounts of biofilm. The natural ligands for LecB are glycosides of D-mannose and L-fucose, the latter displaying an unusual strong affinity. Interestingly, although mannosides are much weaker ligands for LecB, they do form an additional hydrogen bond with the protein in the crystal structure. To analyze the individual contributions of the methyl group in fucosides and the hydroxymethyl group in mannosides to the binding, we designed and synthesized derivatives of these saccharides. We report glycomimetic inhibitors that dissect the individual interactions of their saccharide precursors with LecB and give insight into the biophysics of binding by LecB. Furthermore, theoretical calculations supported by experimental thermodynamic data suggest a perturbed hydrogen bonding network for mannose derivatives as molecular basis for the selectivity of LecB for fucosides. Knowledge gained on the mode of interaction of LecB with its ligands at ambient conditions will be useful for future drug design.
Antigen-Specific Interferon-Gamma Responses and Innate Cytokine Balance in TB-IRIS
2014-11-21

TB-IRIS patients did not display excessive IFNγ responses to TB-antigens. In contrast, the reconstitution of CMV and LPS responses was delayed in the TB-IRIS group. For LPS, this was linked with a pro-inflammatory shift in the innate cytokine balance. These data are in support of a prominent role of the innate immune system in TB-IRIS.
Reply
2014-11-22

Sir: We appreciate the authors’ interest in our study.1 The question has been asked regarding whether the presented case-control study is “prospective” or “retrospective” while referring to the meanings in the context of “prospective cohort studies” and “retrospective cohort studies.” Cohort studies are longitudinal studies that involve repeated observations of the same variables over time and can be classified as prospective or retrospective based on when the disease occurred in relation to the enrollment in the study. Cross-sectional studies and case-control studies examine parameters at one specific point in time. Cross-sectional studies differ from case-control studies in that they describe a group sample exposed to a specified risk factor, whereas case-control studies typically compare individuals with a specific disease to a sample representative of the rest of the population. The purpose of the case-control study design is to look backward, from the diagnosis of the disease to putative exposure. Because a case-control study design implies that a diagnosis has been established, the term “prospective case-control study” is commonly used to refer to prospectively collected data (the title “prospective case-control study” is used for this purpose in over 230 titles in the Ovid MEDLINE database). Contrary to a retrospective case-control study based on chart analysis only, in the presented case-control study, the patients were examined in a follow-up examination, an interview, and a questionnaire summing up to 247 prospectively collected parameters. DISCLOSURE No benefits in any form were received from a commercial party related directly or indirectly to the subject of this communication. There was no direct funding of this study by any commercial source. Stéphane Stahl, M.D. Pascal J. H. Hentschel Department of Plastic, Hand, and Reconstructive Surgery Burn Center, BG-Trauma Center Tübingen, Germany Christoph Meisner, Sc.D. Institute for Clinical Epidemiology and Applied Biometry Tübingen, Germany Theodora üManoli, M.D. Hans-Eberhard Schaller, M.D., Ph.D. Department of Plastic, Hand, and Reconstructive Surgery Burn Center, BG-Trauma Center Eberhard-Karls-University Tübingen Tübingen, Germany Adelana Santos Stahl, M.D. Department for Plastic Surgery Marienhospital Stuttgart Stuttgart, Germany
Stratified medicine for the use of antidiabetic medication in treatment of type II diabetes and cancer: where do we go from here?
2014-11-24

Abstract At present, the global diabetes epidemic is affecting 347 million individuals, 90% of whom are diagnosed with type II diabetes mellitus (T2 DM ). T2 DM is commonly treated with more than one type of therapy, including oral antidiabetic drugs ( OAD s) and agents used in the treatment of diabetic complications. Several pharmacological classes of OAD s are currently available for the treatment of T2 DM , of which insulin secretagogues (i.e. sulphonylureas and meglitinides), insulin sensitizers [thiazolidinediones (TZDs)] and biguanides are the most commonly prescribed. Although many of these OAD s have been used for more than half a century in the treatment of T2 DM , the pharmacogenomic characteristics of these compounds have only recently been investigated, primarily in retrospective studies. Recent advances in pharmacogenomics have led to the identification of polymorphisms that affect the expression and function of drug‐metabolizing enzymes and drug transporters, as well as drug targets and receptors. These polymorphisms have been shown to affect the therapeutic response to and side effects associated with OAD s. The aim of this review was to provide an up‐to‐date summary of some of the pharmacogenomic data obtained from studies of T2 DM treatment, with a focus on polymorphisms in genes affecting pharmacokinetics, pharmacodynamics and treatment outcome of the most commonly prescribed OAD s. In addition, the implications of pharmacogenomics in the use of the OAD metformin in cancer will be briefly discussed. Finally, we will focus on recent advances in novel ‘omics’ technologies and discuss how these might aid in the personalized management of T2 DM .
Pathways for the cyclotetramerization of dibenz[c,e][1,2]azaborine, a BN‐phenanthryne
2014-11-24

The BN‐phenanthryne dibenz[c,e][1,2]azaborine (9) was previously inferred as a reactive intermediate in the solution phase thermolysis of 9‐azido‐9‐borafluorene by isolation of its cyclic tetramer. The mechanism of the cyclotetramerization of BN‐phenanthryne (9) is investigated using a meta‐generalized gradient approximation density functional (TPSS‐D3) in conjunction with a polarized split valence basis set and single energy points using a double‐hybrid functional (B2PYLP‐D3) with a polarized triple‐zeta basis set. The most favorable mechanism involves the dimerization of 9 to diazadiboretidine derivative 10 , followed by dimerization of 10 for which two different pathways were identified computationally. The more favorable one involves a B 4 N 4 bicyclo[4.2.0]octa‐2,4,7‐triene intermediate. An alternative mechanism, slightly higher in energy, proceeds through a B 4 N 4 cube isomer that lies in an unexpectedly deep potential energy minimum. The low barriers of dimerization of 10 make it a short lived reactive intermediate that likely is too reactive to be trapped by the still more reactive cyclic iminoborane 9. Copyright © 2014 John Wiley &amp; Sons, Ltd.
Impact induced surface heating by planetesimals on early Mars
2014-11-24

We investigate the influence of impacts of large planetesimals and small\\nplanetary embryos on the early Martian surface on the hydrodynamic escape of an\\nearly steam atmosphere that is exposed to the high soft X-ray and EUV flux of\\nthe young Sun. Impact statistics in terms of number, masses, velocities, and\\nangles of asteroid impacts onto the early Mars are determined via n-body\\nintegrations. Based on these statistics, smoothed particle hydrodynamics (SPH)\\nsimulations result in estimates of energy transfer into the planetary surface\\nmaterial and according surface heating. For the estimation of the atmospheric\\nescape rates we applied a soft X-ray and EUV absorption model and a 1-D upper\\natmosphere hydrodynamic model to a magma ocean-related catastrophically\\noutgassed steam atmosphere with surface pressure values of 52 bar H2O and 11\\nbar CO2. The estimated impact rates and energy deposition onto an early Martian\\nsurface can account for substantial heating. The energy influx and conversion\\nrate into internal energy is most likely sufficient to keep a shallow magma\\nocean liquid for an extended period of time. Higher surface temperatures keep\\nthe outgassed steam atmosphere longer in vapor form and therefore enhance its\\nescape to space within about 0.6 Myr after its formation.\\n
Relationship between N-Terminal Pro-Brain Natriuretic Peptide, Obesity and the Risk of Heart Failure in Middle-Aged German Adults
2014-11-25

Although high circulating concentrations of NT-proBNP were positively associated with incident heart failure in the entire sample, the association differed according to obesity status. In obese, an increased risk of heart failure was also observed in those with low NT-proBNP concentrations. If confirmed, this observation warrants further investigation to understand underlying pathophysiological mechanisms.
Why not Commercial Assistance for Suicide? On the Question of Argumentative Coherence of Endorsing Assisted Suicide
2014-11-25

Abstract Most people who endorse physician‐assisted suicide are against commercially assisted suicide – a suicide assisted by professional non‐medical providers against payment. The article questions if this position – endorsement of physician‐assisted suicide on the one hand and rejection of commercially assisted suicide on the other hand – is a coherent ethical position. To this end the article first discusses some obvious advantages of commercially assisted suicide and then scrutinizes six types of argument about whether they can justify the rejection of commercially assisted suicide while simultaneously endorsing physician‐assisted suicide. The conclusion is that they cannot provide this justification and that the mentioned position is not coherent. People who endorse physician‐assisted suicide have to endorse commercially assisted suicide as well, or they have to revise their endorsement of physician‐assisted suicide.
Abstract 19827: Vascular Risk Levels Affect the Predictive Value of Platelet Reactivity for the Occurrence of Major Adverse Cardiovascular Events in Patients on Clopidogrel: Systematic Review and Collaborative Meta-analysis of Individual Patient Data
2014-11-25

Introduction: Prior studies have shown an association between high on-clopidogrel platelet reactivity (PR) and the risk of major adverse cardiovascular events (MACE). However, large intervention trials on PR-tailored treatments have been neutral. Hypothesis: The clinical relevance of PR in predicting MACE varies according to patients’ cardiovascular risk levels. Methods: We undertook a systematic review and meta-analysis of individual patient data on MACE outcomes (acute coronary syndromes (ACS), ischemic strokes, and vascular deaths) in relation to PR and its interaction with cardiovascular risk levels. PR was determined using ADP-induced light transmission aggregometry with a primary concentration of 20μM ADP. Results: Thirteen prospective cohort studies totalled 6,478 clopidogrel-treated patients who experienced 421 MACE (6.5%) during a median follow-up of 12 months. The risk of MACE associated with PR increased differentially according to the number of risk factors present (age&gt;75 years, ACS at inclusion, diabetes, and hypertension; interaction p=0.04): no association to PR in low-risk patients (no risk factor) (p=0.48); 3.2 times greater risk of MACE in high PR (&gt; 60%) intermediate-risk patients (one risk factor) (p=0.001); 2.9 and 3.7 times greater risk of MACE in medium PR (41%-60%) and high PR (&gt;60%) high-risk patients (≥2 risk factors) (p=0.0004 and 0.0003, respectively). These interactions followed the same trends in studies using 5μM ADP. Conclusions: The magnitude of the association between PR and MACE risk is strongly dependant on the level of cardiovascular risk faced by patients on clopidogrel suggesting that PR-tailored strategies may be most effective in higher-risk patients.
Abstract 11535: A Triple-Targeting Strategy for Characterization of Plaque Inflammation in Mice and Humans Using Molecular Imaging
2014-11-25

Introduction: Molecular imaging using inflammatory markers might offer additional information for plaque characterization. Here, we present a novel triple-target imaging strategy for the diagnosis and characterization of inflamed plaques using antibodies against vascular cell adhesion molecule 1 (VCAM1), lectin-like ox-LDL receptor (LOX1), and glycoprotein VI (GPVI). Methods: Antibodies against VCAM1, LOX1, GPVI, as well as control antibodies were conjugated to three different fluorescent dyes for imaging with the IVIS spectrum. As a model of atherosclerosis, we used ApoE-/- mice which were divided into three groups and fed 3 months of western type diet (WTD), 6 months of WTD, or 3 months of WTD with daily high-dose atorvastatin, respectively. Afterwards, their aortic arches were removed and imaged after incubation with the antibodies. To transfer our findings into a human model, we use carotid endarterectomy specimens for IVIS as well as magnetic resonance imaging (MRI). For MRI, we coupled our antibodies to microparticles of iron oxide (MPIO), a hypo intense contrast agent, and imaged the plaques using a small animal 9.4 T MRI after incubation under flow conditions. Results: The VCAM1, LOX1, and GPVI antibody constructs showed specific binding to atherosclerotic plaques in mice (p&lt;0.05 for all three; n=4-5 per group) at both time points in comparison with their controls. The additional treatment with Atorvastatin led to a reduction for the signals of all three receptors (all p&lt;0.05). After 6 in comparison to 3 month of WTD, an increase of LOX1 (p&lt;0.05), a reduction of VCAM1 (p&lt;0.05) and no significant changes of GPVI (p=0,81) were seen. Perfusion of the endarterectomy specimens with the MPIO-labeled contrast agent led to a significant signal reduction in MRI in comparison with their controls (n=8 per group; VCAM1 p=0.02; GPVI p=0.03). Our preliminary data for LOX1 show a tendency towards reduction (n=4; p=0.15) while not reaching significance yet. Conclusion: In this approach, we apply a new strategy of molecular MRI by targeting three different inflammatory markers in murine and human atherosclerosis for the noninvasive characterization of this disease, which might help to improve early detection and therapy of vulnerable atherosclerotic plaques.
Abstract 12744: Predictors of Permanent Pacemaker Implantation After Transcatheter Aortic Valve Implantation
2014-11-25

Background: High-grade conduction disturbances (CD) requiring permanent pacemaker (PPM) implantation (impl) occur in up to 34 % of patients (pts) following transcatheter aortic valve implantation (TAVI) with the Medtronic CoreValve (MCV). Aim of the Study: The aim of this study was to asses the anatomical, clinical and ECG predictors of postinterventional PPM impl in pts undergoing TAVI with the MCV . Methods: In total 198 pts with high surgical risk underwent transfemoral TAVI with the MCV system (26/29/31mm). Pts (23) with pre-existing PPM were excluded leaving 175 pts for retrospectively evaluation for predictors for PPM impl after TAVI. To evaluate procedural data, device position was measured on fluoroscopy as distance between the proximal aspect of the MCV stent frame below the native aortic annulus. Results: In our study group 48 (27.4%) pts underwent PPM-impl post TAVI. Before TAVI 19 (10.9 %) of pts showed pre-operative abnormal CD, including first degree AV block, RBBB and LBBB. Pts with PPM imp...
Abstract 12939: Platelet Activation is Less Enhanced in Edwards Sapien 3 Valve Compared to Its Precursor Model
2014-11-25

Background: Due to a different design of the Cobalt chromium alloy frame and the additional outerskirt to minimize paravalvular leakage one might imagine that the extent of platelet activation (PA) of new Edwards Sapien 3 valve (ESV3) might differ from the Edward Sapien XT valve (ESVXT). Aim of the study: The aim of our study was to compare platelet aggregation (Agg) and platelet activation (PA) of the ESV-XT with the newer ESV-3 in pts undergoing TAVI on dual antiplatelet therapy . Methods: Pts scheduled for TAVI were loaded with 600 mg Clp and 500 mg ASA the day before intervention. Platelet Agg were evaluated in all pts by the Multiplate system (Dynabyte, Munich, Germany) before (T0), directly after intervention (T1) and on T2 (day1), T3 (day2) , T4 (day3) . PA was simultaneously assessed with the use of immunologic markers of PA as CD62P and PAC-1 by flow cytometry. Results: 43 pts (age 81.3 +1.2 years ) with severe aortic stenosis and high surgical risk (log Euroscore 18.1 +1.3 %) underwent successfully TAVI with the ESV-XT and 29 pts (age 82.6 + 1.2 years, log Euroscore 21.5 +2.9 %) underwent TAVI with the ESV-3. . Platelet Agg was inhibited to the same extent in both valve types directly after TAVI under dual antiplatelet therapy [ESV-XT (T1) versus ESV-3 3 (T1) : AggADP, (AUC): 16 (11-24) versus 16 (10-20); p=0.514; AggTRAP (AUC): 61(41-81) versus 69(52-79);p=0.244; AggASPI (AUC): 13(5-19) versus 11 (5-17); p=0.436. ] There was no significant difference in platelet drop between both valve types between day 0 and day3. [ESV-XT (T0T3) versus ESV-3 (T0T3): 55.2 ± 4.2 versus 63.5± 8.1; p=0.364. ] However there was an enhanced expression of PA markers (CD62P and PAC-1) directly after implantation in pts with ESV-XT compared to pts with the ESV-3. [ESV-XT versus ESV-3 :median (25th;75th percentile) mean immunofluorescence : CD62P : 7.4 (6.8-8.6) versus 6.6 (6-7.9), p=0.014; PAC-1 : 4.2(3.6-4.7) versus 3.4 (3.2 -4.9), p=0.045.] Conclusion: Our results show that dual antiplatelet therapy inhibits platelet Agg in both valve types to the same extent. However PA is less enhanced in pts with the ESV-3, than in pts the ESV-XT directly after implantation
Abstract 18891: Prospective Evaluation of Diagnostic Performance and Safety of Implementing a Biventricular Approach for Endomyocardial Biopsy in Patients With Suspected Myocarditis
2014-11-25

Background: Previous retrospective analyses have suggested that biventricular (BV) endomyocardial biopsy (EMB) is superior to right (RV) or left ventricular (LV) EMB only in diagnosing patients with suspected myocarditis. Aim: To prospectively assess the feasibility, safety and diagnostic yield of BV EMB in consecutive patients with suspected myocarditis. Methods: Five to six EMBs were taken from the RV and LV under fluoroscopic guidance. Biopsies were analyzed in a core lab by highly experienced investigators (KK, RK) Myocarditis/myocardial in[[Unable to Display Character: &amp;#64258;]]ammation was de[[Unable to Display Character: &amp;#64257;]]ned as the detection of ≥14 infiltrating leukocytes/mm2 (CD3 T-lymphocytes and/or CD68 macrophages) in addition to enhanced HLA class II expression in professional antigen-presenting immune cells. Results: 100 consecutive patients (mean age 44 ± 15 years) with clinically suspected myocarditis were included. RV EMB was attempted in 100 patients, in 3 the procedure was abandoned due to unsatisfying positioning on the guiding catheter, in 1/97 RV EMBs were inadequate with no myocardial tissue obtained. LV EMB was attempted in 97 patients, in 3, LV EMB was not performed due to presence of LV thrombi, in 1/97 patient LV EMBs were inadequate with no myocardial tissue obtained. Major complication rate for LV EMB was 0% and for RV EMB, 1% (pericardial tamponade requiring surgical revision). Results of adequate BV EMBs were analyzed in 92 patients. On BV EMB, myocarditis was diagnosed in 61/92 patients. When considering LV EMB only, the diagnosis would have been missed in 3/61, when considering RV EMB only in 7/61 patients. Conclusion: BV EMB is feasible and safe in the majority of patients with suspected myocarditis and yields in a superior diagnostic performance as compared to a single ventricle EMBs.
Abstract 14666: Pseudoaneurysms after TAVI Using the Prostar-XL system, a Comparison Corevalve and the Edwards Sapien XT Valve
2014-11-25

Background: Transfemoral aortic valve implantation (TAVI) requires large bore catheters. Access site and vascular complications, therefore are of concern. Beside major vascular complications, post-...
Inhibition of SGK1 enhances mAR-induced apoptosis in MCF-7 breast cancer cells
2014-11-26

Functional membrane androgen receptors (mAR) have previously been described in MCF-7 breast cancer cells. Their stimulation by specific testosterone albumin conjugates (TAC) activate rapidly non-genomic FAK/PI3K/Rac1/Cdc42 signaling, trigger actin reorganization and inhibit cell motility. PI3K stimulates serum and glucocorticoid inducible kinase SGK1, which in turn regulates the function of mAR. In the present study we addressed the role of SGK1 in mAR-induced apoptosis. TAC-stimulated mAR activation elicited apoptosis of MCF-7 cells, an effect significantly potentiated by concomitant incubation of the cells with TAC and the specific SGK1 inhibitors EMD638683 and GSK650394. In line with this, TAC and EMD638683 activated caspase-3. These effects were insensitive to the classical androgen receptor (iAR) antagonist flutamide, pointing to iAR-independent, mAR-induced responses. mAR activation and SGK1 inhibition further considerably augmented the radiation-induced apoptosis of MCF-7 cells. Moreover, TAC- and EMD638683 triggered early actin polymerization in MCF-7 cells. Blocking actin restructuring with cytochalasin B abrogated the TAC- and EMD638683-induced pro-apoptotic responses. Further analysis of the molecular signaling revealed late de-phosphorylation of FAK and Akt. Our results demonstrate that mAR activation triggers pro-apoptotic responses in breast tumor cells, an effect significantly enhanced by SGK1 inhibition, involving actin reorganization and paralleled by down-regulation of FAK/Akt signaling.