From stability to chaos in last-passage percolation

We study the transition from stability to chaos in a dynamic last passage percolation model on $\mathbb{Z}^d$ with random weights at the vertices. Given an initial weight configuration at time $0$, we perturb the model over time in such a way that the weight configuration at time $t$ is obtained by resampling each weight independently with probability $t$. On the cube $[0,n]^d$, we study geodesics, that is, weight-maximizing up-right paths from $(0,0, \dots, 0)$ to $(n,n, \dots, n)$, and their passage time $T$. Under mild conditions on the weight distribution, we prove a phase transition between stability and chaos at $t \asymp \frac{1}{n}\mathrm{Var}(T)$. Indeed, as $n$ grows large, for small values of $t$, the passage times at time $0$ and time $t$ are highly correlated, while for large values of $t$, the geodesics become almost disjoint.Comment: 12 pages. A video summary may be found at https://youtu.be/Y29t_KUzv7

Anaerobic Digestion of Animal Manure and Influence of Organic Loading Rate and Temperature on Process Performance, Microbiology, and Methane Emission From Digestates

Biogas production from manure is of particular value in regard of lowering greenhouse gas emissions and enhancing nutrient re-circulation. However, the relatively low energy content and the characteristics of manure often result in low degradation efficiency, and the development of operating strategies is required to improve the biogas yield and the economic benefits. In this study, the potential to enhance the performance of two full-scale biogas plants operating with cattle manure, in mono-digestion or combined with poultry manure, was investigated. Four continuously fed laboratory-scale reactors were operated in sets of two, in which the temperature in one reactor in each set was increased from 37-42 degrees C to 52 degrees C. The potential to increase the capacity was thereafter assessed by increasing the organic loading rate (OLR), from ca 3 to 5 kg volatile solids (VS)/ m(3) and day. The processes were evaluated with both chemical and microbiological parameters, and in addition, the residual methane potential (RMP) was measured to evaluate the risk of increased methane emissions from the digestate. The results showed that both processes could be changed from mesophilic to themophilic temperature without major problems and with a similar shift in the microbial community profile to a typical thermophilic community, e.g., an increase in the relative abundance of the phylum Firmicutes. However, the temperature increase in the reactor co-digesting cattle and poultry manure caused a slight accumulation of fatty acids (2 g/l) and reduced the specific methane production, most likely due to ammonia inhibition (0.4-0.7 g NH3/l). Still, during operation at higher OLR, thermophilic as compared to mesophilic temperature slightly increased the methane yield and specific methane production, in both investigated processes. However, the higher OLR decreased the overall degree of degradation in all processes, and this showed a positive correlation with increased RMP values. Chemical analyses suggested that high RMP values (40-98 Nml gVS(-1)) were related to the degradation of cellulose, hemicellulose, and volatile fatty acid enriched in the digestate. Conclusively, increased temperature and load can increase the methane yield from manure but can result in less efficient degradation and increased risks for methane emissions during storage and handling of the digestate

Integrating perspectives of patients, healthcare professionals, system developers and academics in the co-design of a digital information tool

Background Patients diagnosed with cancer who are due to commence radiotherapy, often, despite the provision of a considerable amount of information, report a range of unmet information needs about the treatment process. Factors such as inadequate provision of information, or the stressful situation of having to deal with information about unfamiliar things, may influence the patient’s ability to comprehend the information. There is a need to further advance the format in which such information is presented. The composition of information should be tailored according to the patient’s individual needs and style of learning. Method and findings The PD methodology is frequently used when a technology designed artefact is the desired result of the process. This research is descriptive of its kind and provides a transparent description of the co-design process used to develop an innovative digital information tool employing PD methodology where several stakeholders participated as co-designers. Involving different stakeholders in the process in line with recommended PD activities enabled us to develop a digital information tool that has the potential to be relevant and user-friendly for the ultimate consumer. Conclusions Facilitating collaboration, structured PD activities can help researchers, healthcare professionals and patients to co-design patient information that meets the end users’ needs. Furthermore, it can enhance the rigor of the process, ensure the relevance of the information, and finally have a potential to employ a positive effect on the reach of the related digital information tool

Oral appliance therapy versus nasal continuous positive airway pressure in obstructive sleep apnea : A randomized, placebo-controlled trial on temporomandibular side-effects

Purpose To assess the differences in the frequency of clinical signs of temporomandibular disorder (TMD) pain and mandibular function impairment between mandibular advancement device (MAD) and nasal continuous positive airway pressure (nCPAP) therapies in obstructive sleep apnea (OSA) patients at baseline and after 6 month of treatment. Methods This study concerns a secondary analysis of a randomized placebo-controlled trial in which different treatment effects of an objectively titrated MAD were compared with those of nCPAP and an intra-oral placebo appliance in a parallel design. Sixty-four mild to severe OSA patients (52.0 +/- 9.6 years) were randomly assigned to these three groups. All patients underwent a shortened functional examination of their masticatory system at baseline and after 6 months to establish the presence of clinical signs of TMD pain. Mandibular function impairment was assessed with a questionnaire. Results Clinical signs of TMD pain were only rarely present at baseline and therapy evaluation. No significant differences were found between the three groups in the (low) frequency of clinical signs of TMD pain at both time points (p = .401-.176). In addition, the (low) scores of mandibular function impairment did not differ between the three groups either, neither at baseline (p = .744) nor after 6 months (p = .359). Conclusions A low frequency of clinical signs of TMD pain in mild to severe OSA patients was found after 6 months, regardless of treatment with MAD or nCPAP. In addition, no difference in mandibular function impairment was observed between the different treatment modalities.Peer reviewe

Oral appliance therapy versus nasal continuous positive airway pressure in obstructive sleep apnea : a randomized, placebo-controlled trial on psychological distress

The aim of this randomized placebo-controlled trail was to compare the effects of an objectively titrated mandibular advancement device (MAD) with those of nasal continuous positive airway pressure (nCPAP) and an intraoral placebo device on symptoms of psychological distress in OSA patients. In a parallel design, 64 mild/moderate OSA patients (52.0 +/- 9.6 years) were randomly assigned to an objectively titrated MAD, nCPAP, or an intraoral placebo appliance. All patients filled out the Symptom Checklist-90-Revised twice: one before treatment and one after 6 months of treatment. The Symptom Checklist-90-Revised is a multidimensional symptom inventory designed to measure symptomatic psychological distress over the past week. Linear mixed model analyses were performed to study differences between the therapy groups for the different dimensions of the Symptom Checklist-90-Revised over time. The MAD group showed significant improvements over time in the dimensions "somatization," "insufficiency of thinking and acting," "agoraphobia," "anxiety," "sleeping problems," and "global severity index" (F = 4.14-16.73, P = 0.048-0.000). These improvements in symptoms of psychological distress were, however, not significantly different from those observed in the nCPAP and placebo groups (P = 0.374-0.953). There is no significant difference between MAD, nCPAP, and an intraoral placebo appliance in their beneficial effects on symptoms of psychological distress. The improvement in psychological distress symptoms in mild/moderate OSA patients under MAD or nCPAP treatment may be explained by a placebo effect.Peer reviewe

Deconvoluting kinase inhibitor induced cardiotoxicity

Many drugs designed to inhibit kinases have their clinical utility limited by cardiotoxicity-related label warnings or prescribing restrictions. While this liability is widely recognized, designing safer kinase inhibitors (KI) requires knowledge of the causative kinase(s). Efforts to unravel the kinases have encountered pharmacology with nearly prohibitive complexity. At therapeutically relevant concentrations, KIs show promiscuity distributed across the kinome. Here, to overcome this complexity, 65 KIs with known kinome-scale polypharmacology profiles were assessed for effects on cardiomyocyte (CM) beating. Changes in human iPSC-CM beat rate and amplitude were measured using label-free cellular impedance. Correlations between beat effects and kinase inhibition profiles were mined by computation analysis (Matthews Correlation Coefficient) to identify associated kinases. Thirty kinases met criteria of having (1) pharmacological inhibition correlated with CM beat changes, (2) expression in both human-induced pluripotent stem cell-derived cardiomyocytes and adult heart tissue, and (3) effects on CM beating following single gene knockdown. A subset of these 30 kinases were selected for mechanistic follow up. Examples of kinases regulating processes spanning the excitation–contraction cascade were identified, including calcium flux (RPS6KA3, IKBKE) and action potential duration (MAP4K2). Finally, a simple model was created to predict functional cardiotoxicity whereby inactivity at three sentinel kinases (RPS6KB1, FAK, STK35) showed exceptional accuracy in vitro and translated to clinical KI safety data. For drug discovery, identifying causative kinases and introducing a predictive model should transform the ability to design safer KI medicines. For cardiovascular biology, discovering kinases previously unrecognized as influencing cardiovascular biology should stimulate investigation of underappreciated signaling pathways

Human iPSC modelling of a familial form of atrial fibrillation reveals a gain of function of I-f and I-CaL in patient-derived cardiomyocytes

Aims: Atrial fibrillation (AF) is the most common type of cardiac arrhythmias, whose incidence is likely to increase with the aging of the population. It is considered a progressive condition, frequently observed as a complication of other cardiovascular disorders. However, recent genetic studies revealed the presence of several mutations and variants linked to AF, findings that define AF as a multifactorial disease. Due to the complex genetics and paucity of models, molecular mechanisms underlying the initiation of AF are still poorly understood. Here we investigate the pathophysiological mechanisms of a familial form of AF, with particular attention to the identification of putative triggering cellular mechanisms, using patient's derived cardiomyocytes (CMs) differentiated from induced pluripotent stem cells (iPSCs). Methods and results: Here we report the clinical case of three siblings with untreatable persistent AF whose whole-exome sequence analysis revealed several mutated genes. To understand the pathophysiology of this multifactorial form of AF we generated three iPSC clones from two of these patients and differentiated these cells towards the cardiac lineage. Electrophysiological characterization of patient-derived CMs (AF-CMs) revealed that they have higher beating rates compared to control (CTRL)-CMs. The analysis showed an increased contribution of the If and ICaL currents. No differences were observed in the repolarizing current IKr and in the sarcoplasmic reticulum calcium handling. Paced AF-CMs presented significantly prolonged action potentials and, under stressful conditions, generated both delayed after-depolarizations of bigger amplitude and more ectopic beats than CTRL cells. Conclusions: Our results demonstrate that the common genetic background of the patients induces functional alterations of If and ICaL currents leading to a cardiac substrate more prone to develop arrhythmias under demanding conditions. To our knowledge this is the first report that, using patient-derived CMs differentiated from iPSC, suggests a plausible cellular mechanism underlying this complex familial form of AF

High-resolution macromolecular crystallography at the FemtoMAX beamline with time-over-threshold photon detection

Protein dynamics contribute to protein function on different time scales. Ultrafast X-ray diffraction snapshots can visualize the location and amplitude of atom displacements after perturbation. Since amplitudes of ultrafast motions are small, high-quality X-ray diffraction data is necessary for detection. Diffraction from bovine trypsin crystals using single femtosecond X-ray pulses was recorded at FemtoMAX, which is a versatile beamline of the MAX IV synchrotron. The time-over-threshold detection made it possible that single photons are distinguishable even under short-pulse low-repetition-rate conditions. The diffraction data quality from FemtoMAX beamline enables atomic resolution investigation of protein structures. This evaluation is based on the shape of the Wilson plot, cumulative intensity distribution compared with theoretical distribution, I/σ, Rmerge /Rmeas and CC1/2 statistics versus resolution. The FemtoMAX beamline provides an interesting alternative to X-ray free-electron lasers when studying reversible processes in protein crystals