Ground State Structure in a Highly Disordered Spin Glass Model

We propose a new Ising spin glass model on $Z^d$ of Edwards-Anderson type, but with highly disordered coupling magnitudes, in which a greedy algorithm for producing ground states is exact. We find that the procedure for determining (infinite volume) ground states for this model can be related to invasion percolation with the number of ground states identified as $2^{\cal N}$, where ${\cal N} = {\cal N}(d)$ is the number of distinct global components in the ``invasion forest''. We prove that ${\cal N}(d) = \infty$ if the invasion connectivity function is square summable. We argue that the critical dimension separating ${\cal N} = 1$ and ${\cal N} = \infty$ is $d_c = 8$. When ${\cal N}(d) = \infty$, we consider free or periodic boundary conditions on cubes of side length $L$ and show that frustration leads to chaotic $L$ dependence with {\it all} pairs of ground states occuring as subsequence limits. We briefly discuss applications of our results to random walk problems on rugged landscapes.Comment: LaTex fil

Repeated exposure to transient obstructive sleep apnea-related conditions causes an atrial fibrillation substrate in a chronic rat model

Background High night-to-night variability in obstructive sleep apnea (OSA) is associated with atrial fibrillation (AF). Obstructive apneas are characterized by intermittent deoxygenation-reoxygenation and intrathoracic pressure swings during ineffective inspiration against occluded upper airways. Objective We elucidated the effect of repeated exposure to transient OSA conditions simulated by intermittent negative upper airway pressure (INAP) on the development of an AF substrate. Methods INAP (48 events/4 h; apnea-hypopnea index 12 events/h) was applied in sedated spontaneously breathing rats (2% isoflurane) to simulate mild-to-moderate OSA. Rats without INAP served as a control group (CTR). In an acute test series (ATS), rats were either killed immediately (n = 9 per group) or after 24 hours of recovery (ATS-REC: n = 5 per group). To simulate high night-to-night variability in OSA, INAP applications (n = 10; 24 events/4 h; apnea-hypopnea index 6/h) were repeated every second day for 3 weeks in a chronic test series (CTS). Results INAP increased atrial oxidative stress acutely, represented in decreases of reduced to oxidized glutathione ratio (ATS: INAP: 0.33 ± 0.05 vs CTR: 1 ± 0.26; P = .016), which was reversible after 24 hours (ATS-REC: INAP vs CTR; P = .274). Although atrial oxidative stress did not accumulate in the CTS, atrial histological analysis revealed increased cardiomyocyte diameters, reduced connexin 43 expression, and increased interstitial fibrosis formation (CTS: INAP 7.0% ± 0.5% vs CTR 5.1% ± 0.3%; P = .013), which were associated with longer inducible AF episodes (CTS: INAP: 11.65 ± 4.43 seconds vs CTR: 0.7 ± 0.33 seconds; P = .033). Conclusion Acute simulation of OSA was associated with reversible atrial oxidative stress. Cumulative exposure to these transient OSA-related conditions resulted in AF substrates and was associated with increased AF susceptibility. Mild-to-moderate OSA with high night-to-night variability may deserve intensive management to prevent atrial substrate development

Tachycardiomyopathy entails a dysfunctional pattern of interrelated mitochondrial functions

Tachycardiomyopathy is characterised by reversible left ventricular dysfunction, provoked by rapid ventricular rate. While the knowledge of mitochondria advanced in most cardiomyopathies, mitochondrial functions await elucidation in tachycardiomyopathy. Pacemakers were implanted in 61 rabbits. Tachypacing was performed with 330 bpm for 10 days (n = 11, early left ventricular dysfunction) or with up to 380 bpm over 30 days (n = 24, tachycardiomyopathy, TCM). In n = 26, pacemakers remained inactive (SHAM). Left ventricular tissue was subjected to respirometry, metabolomics and acetylomics. Results were assessed for translational relevance using a human-based model: induced pluripotent stem cell derived cardiomyocytes underwent field stimulation for 7 days (TACH–iPSC–CM). TCM animals showed systolic dysfunction compared to SHAM (fractional shortening 37.8 ± 1.0% vs. 21.9 ± 1.2%, SHAM vs. TCM, p < 0.0001). Histology revealed cardiomyocyte hypertrophy (cross-sectional area 393.2 ± 14.5 µm2 vs. 538.9 ± 23.8 µm2, p < 0.001) without fibrosis. Mitochondria were shifted to the intercalated discs and enlarged. Mitochondrial membrane potential remained stable in TCM. The metabolite profiles of ELVD and TCM were characterised by profound depletion of tricarboxylic acid cycle intermediates. Redox balance was shifted towards a more oxidised state (ratio of reduced to oxidised nicotinamide adenine dinucleotide 10.5 ± 2.1 vs. 4.0 ± 0.8, p < 0.01). The mitochondrial acetylome remained largely unchanged. Neither TCM nor TACH–iPSC–CM showed relevantly increased levels of reactive oxygen species. Oxidative phosphorylation capacity of TCM decreased modestly in skinned fibres (168.9 ± 11.2 vs. 124.6 ± 11.45 pmol·O2·s−1·mg−1 tissue, p < 0.05), but it did not in isolated mitochondria. The pattern of mitochondrial dysfunctions detected in two models of tachycardiomyopathy diverges from previously published characteristic signs of other heart failure aetiologies

Domain Organization of Long Signal Peptides of Single-Pass Integral Membrane Proteins Reveals Multiple Functional Capacity

Targeting signals direct proteins to their extra - or intracellular destination such as the plasma membrane or cellular organelles. Here we investigated the structure and function of exceptionally long signal peptides encompassing at least 40 amino acid residues. We discovered a two-domain organization (“NtraC model”) in many long signals from vertebrate precursor proteins. Accordingly, long signal peptides may contain an N-terminal domain (N-domain) and a C-terminal domain (C-domain) with different signal or targeting capabilities, separable by a presumably turn-rich transition area (tra). Individual domain functions were probed by cellular targeting experiments with fusion proteins containing parts of the long signal peptide of human membrane protein shrew-1 and secreted alkaline phosphatase as a reporter protein. As predicted, the N-domain of the fusion protein alone was shown to act as a mitochondrial targeting signal, whereas the C-domain alone functions as an export signal. Selective disruption of the transition area in the signal peptide impairs the export efficiency of the reporter protein. Altogether, the results of cellular targeting studies provide a proof-of-principle for our NtraC model and highlight the particular functional importance of the predicted transition area, which critically affects the rate of protein export. In conclusion, the NtraC approach enables the systematic detection and prediction of cryptic targeting signals present in one coherent sequence, and provides a structurally motivated basis for decoding the functional complexity of long protein targeting signals

Circulating Endothelial Progenitor Cells in Kidney Transplant Patients

Background: Kidney transplantation (RTx) leads to amelioration of endothelial function in patients with advanced renal failure. Endothelial progenitor cells (EPCs) may play a key role in this repair process. The aim of this study was to determine the impact of RTx and immunosuppressive therapy on the number of circulating EPCs. Methods: We analyzed 52 RTx patients (58613 years; 33 males, mean 6 SD) and 16 age- and gender-matched subjects with normal kidney function (57617; 10 males). RTx patients received a calcineurin inhibitor (CNI)-based (65%) or a CNI-free therapy (35%) and steroids. EPC number was determined by double positive staining for CD133/VEGFR2 and CD34/VEGFR2 by flow cytometry. Stromal cell-derived factor 1 alpha (SDF-1) levels were assessed by ELISA. Experimentally, to dissociate the impact of RTx from the impact of immunosuppressants, we used the 5/6 nephrectomy model. The animals were treated with a CNI-based or a CNI-free therapy, and EPCs (Sca+cKit+) and CD26+ cells were determined by flow cytometry. Results: Compared to controls, circulating number of CD34+/VEGFR2+ and CD133+/VEGFR2+ EPCs increased in RTx patients. There were no correlations between EPC levels and statin, erythropoietin or use of renin angiotensin system blockers in our study. Indeed, multivariate analysis showed that SDF-1 – a cytokine responsible for EPC mobilization – is independently associated with the EPC number. 5/6 rats presented decreased EPC counts in comparison to control animals. Immunosuppressive therapy was able to restore normal EPC values in 5/6 rats. These effects on EPC number were associated with reduced number of CD26+ cells, which might be related to consequent accumulation of SDF-1. Conclusions: We conclude that kidney transplantation and its associated use of immunosuppressive drugs increases the number of circulating EPCs via the manipulation of the CD26/SDF-1 axis. Increased EPC count may be associated to endothelial repair and function in these patients.

Peer role-play and standardised patients in communication training: a comparative study on the student perspective on acceptability, realism, and perceived effect

<p>Abstract</p> <p>Background</p> <p>To assess the student perspective on acceptability, realism, and perceived effect of communication training with peer role play (RP) and standardised patients (SP).</p> <p>Methods</p> <p>69 prefinal year students from a large German medical faculty were randomly assigned to one of two groups receiving communication training with RP (N = 34) or SP (N = 35) in the course of their paediatric rotation. In both groups, training addressed major medical and communication problems encountered in the exploration and counselling of parents of sick children. Acceptability and realism of the training as well as perceived effects and applicability for future parent-physician encounters were assessed using six-point Likert scales.</p> <p>Results</p> <p>Both forms of training were highly accepted (RP 5.32 ± .41, SP 5.51 ± .44, n.s.; 6 = very good, 1 = very poor) and perceived to be highly realistic (RP 5.60 ± .38, SP 5.53 ± .36, n.s.; 6 = highly realistic, 1 = unrealistic). Regarding perceived effects, participation was seen to be significantly more worthwhile in the SP group (RP 5.17 ± .37, SP 5.50 ± .43; p < .003; 6 = totally agree, 1 = don't agree at all). Both training methods were perceived as useful for training communication skills (RP 5.01 ± .68, SP 5.34 ± .47; 6 = totally agree; 1 = don't agree at all) and were considered to be moderately applicable for future parent-physician encounters (RP 4.29 ± 1.08, SP 5.00 ± .89; 6 = well prepared, 1 = unprepared), with usefulness and applicability both being rated higher in the SP group (p < .032 and p < .009).</p> <p>Conclusions</p> <p>RP and SP represent comparably valuable tools for the training of specific communication skills from the student perspective. Both provide highly realistic training scenarios and warrant inclusion in medical curricula. Given the expense of SP, deciding which method to employ should be carefully weighed up. From the perspective of the students in our study, SP were seen as a more useful and more applicable tool than RP. We discuss the potential of RP to foster a greater empathic appreciation of the patient perspective.</p

Global Genomic Analysis of SARS-CoV-2 RNA Dependent RNA Polymerase Evolution and Antiviral Drug Resistance.

A variety of antiviral treatments for COVID-19 have been investigated, involving many repurposed drugs. Currently, the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp, encoded by nsp12-nsp7-nsp8) has been targeted by numerous inhibitors, e.g., remdesivir, the only provisionally approved treatment to-date, although the clinical impact of these interventions remains inconclusive. However, the potential emergence of antiviral resistance poses a threat to the efficacy of any successful therapies on a wide scale. Here, we propose a framework to monitor the emergence of antiviral resistance, and as a proof of concept, we address the interaction between RdRp and remdesivir. We show that SARS-CoV-2 RdRp is under purifying selection, that potential escape mutations are rare in circulating lineages, and that those mutations, where present, do not destabilise RdRp. In more than 56,000 viral genomes from 105 countries from the first pandemic wave, we found negative selective pressure affecting nsp12 (Tajima's D = -2.62), with potential antiviral escape mutations in only 0.3% of sequenced genomes. Potential escape mutations included known key residues, such as Nsp12:Val473 and Nsp12:Arg555. Of the potential escape mutations involved globally, in silico structural models found that they were unlikely to be associated with loss of stability in RdRp. No potential escape mutation was found in a local cohort of remdesivir treated patients. Collectively, these findings indicate that RdRp is a suitable drug target, and that remdesivir does not seem to exert high selective pressure. We anticipate our framework to be the starting point of a larger effort for a global monitoring of drug resistance throughout the COVID-19 pandemic

Search for a vector-like quark T′ → tH via the diphoton decay mode of the Higgs boson in proton-proton collisions at s \sqrt{s} = 13 TeV

A search for the electroweak production of a vector-like quark T′, decaying to a top quark and a Higgs boson is presented. The search is based on a sample of proton-proton collision events recorded at the LHC at = 13 TeV, corresponding to an integrated luminosity of 138 fb−1. This is the first T′ search that exploits the Higgs boson decay to a pair of photons. For narrow isospin singlet T′ states with masses up to 1.1 TeV, the excellent diphoton invariant mass resolution of 1–2% results in an increased sensitivity compared to previous searches based on the same production mechanism. The electroweak production of a T′ quark with mass up to 960 GeV is excluded at 95% confidence level, assuming a coupling strength κT = 0.25 and a relative decay width Γ/MT′ < 5%

Combined searches for the production of supersymmetric top quark partners in proton–proton collisions at √s=13Te

A combination of searches for top squark pair production using proton–proton collision data at a center-of-mass energy of 13TeV at the CERN LHC, corresponding to an integrated luminosity of 137fb$^{-1}$ collected by the CMS experiment, is presented. Signatures with at least 2 jets and large missing transverse momentum are categorized into events with 0, 1, or 2 leptons. New results for regions of parameter space where the kinematical properties of top squark pair production and top quark pair production are very similar are presented. Depending on the model, the combined result excludes a top squark mass up to 1325GeV for a massless neutralino, and a neutralino mass up to 700GeV for a top squark mass of 1150GeV. Top squarks with masses from 145 to 295GeV, for neutralino masses from 0 to 100GeV, with a mass difference between the top squark and the neutralino in a window of 30GeV around the mass of the top quark, are excluded for the first time with CMS data. The results of theses searches are also interpreted in an alternative signal model of dark matter production via a spin-0 mediator in association with a top quark pair. Upper limits are set on the cross section for mediator particle masses of up to 420GeV