Stochastic Analysis of Subcritical Amplification of Magnetic Energy in a Turbulent Dynamo

We present and analyze a simplified stochastic $\alpha \Omega -$dynamo model which is designed to assess the influence of additive and multiplicative noises, non-normality of dynamo equation, and nonlinearity of the $\alpha -$% effect and turbulent diffusivity, on the generation of a large-scale magnetic field in the subcritical case. Our model incorporates random fluctuations in the $\alpha -$parameter and additive noise arising from the small-scale fluctuations of magnetic and turbulent velocity fields. We show that the noise effects along with non-normality can lead to the stochastic amplification of the magnetic field even in the subcritical case. The criteria for the stochastic instability during the early kinematic stage are established and the critical value for the intensity of multiplicative noise due to $\alpha -$fluctuations is found. We obtain numerical solutions of non-linear stochastic differential equations and find the series of phase transitions induced by random fluctuations in the $\alpha -$parameter.Comment: 21pages,7 figure

Short- and Long-Term Effects of High-Intensity Interval Training vs. Moderate-Intensity Continuous Training on Left Ventricular Remodeling in Patients Early After ST-Segment Elevation Myocardial Infarction-The HIIT-EARLY Randomized Controlled Trial.

Aim Due to insufficient evidence on the safety and effectiveness of high-intensity interval training (HIIT) in patients early after ST-segment elevation myocardial infarction (STEMI), we aimed to compare short- and long-term effects of randomized HIIT or moderate-intensity continuous training (MICT) on markers of left ventricular (LV) remodeling in STEMI patients receiving optimal guideline-directed medical therapy (GDMT). Materials and Methods Patients after STEMI (<4 weeks) enrolled in a 12-week cardiac rehabilitation (CR) program were recruited for this randomized controlled trial (NCT02627586). During a 3-week run-in period with three weekly MICT sessions, GDMT was up-titrated. Then, the patients were randomized to HIIT or isocaloric MICT for 9 weeks. Echocardiography and cardiopulmonary exercise tests were performed after run-in (3 weeks), end of CR (12 weeks), and at 1-year follow-up. The primary outcome was LV end-diastolic volume index (LVEDVi) at the end of CR. Secondary outcomes were LV global longitudinal strain (GLS) and cardiopulmonary fitness. Results Seventy-three male patients were included, with the time between STEMI and start of CR and randomization being 12.5 ± 6.3 and 45.8 ± 10.8 days, respectively. Mixed models revealed no significant group × time interaction for LVEDVi at the end of CR (p = 0.557). However, there was a significantly smaller improvement in GLS at 1-year follow-up in the HIIT compared to the MICT group (p = 0.031 for group × time interaction). Cardiorespiratory fitness improved significantly from a median value of 26.5 (1st quartile 24.4; 3rd quartile 1.1) ml/kg/min at randomization in the HIIT and 27.7 (23.9; 31.6) ml/kg/min in the MICT group to 29.6 (25.3; 32.2) and 29.9 (26.1; 34.9) ml/kg/min at the end of CR and to 29.0 (26.6; 33.3) and 30.6 (26.0; 33.8) ml/kg/min at 1 year follow-up in HIIT and MICT patients, respectively, with no significant group × time interactions (p = 0.138 and 0.317). Conclusion In optimally treated patients early after STEMI, HIIT was not different from isocaloric MICT with regard to short-term effects on LVEDVi and cardiorespiratory fitness. The worsening in GLS at 1 year in the HIIT group deserves further investigation, as early HIIT may offset the beneficial effects of GDMT on LV remodeling in the long term

How do patients, politicians, physiotherapists and other health professionals view physiotherapy research in Switzerland? A qualitative study

Background. Since 2002, the professional education for Swiss physiotherapists has been upgraded to a tertiary educational level. With this change, the need for research related to professional practice has become more salient. The elaboration of research priorities is seen as a possible way to determine the profession’s needs, to help coordinate research collaborations and to address expectations regarding physiotherapy. There is still limited evidence about stakeholders’ views with regard to physiotherapy research. The objective of this study was to investigate key stakeholders’ opinions about research in physiotherapy in Switzerland. Methods. Focus groups with patients, health professionals, researchers and representatives of public health organizations were conducted, and semi-structured interviews were conducted with politicians, health insurers and medical doctors from three linguistic regions in Switzerland. An interview guide was elaborated. Data were transcribed and analysed using inductive content analysis (Atlas-ti 6W). Results. Eighteen focus groups and 23 interviews/written commentaries included 134 participants with various research experiences and from different settings. Fourteen categories were defined reflecting three themes: identity, interdisciplinarity and visibility. Stakeholders had positive views about the profession and perceived physiotherapists’ important role now and in the future. Yet, they also felt that physiotherapy was not sufficiently recognized in society and not visible enough. A stronger professional identity would be key to enhancing interdisciplinary work. Conclusions. Results of this qualitative study provide insights into key aspects for moving the physiotherapy profession forward. Identity is at the heart of physiotherapy, not necessarily in terms of research priorities but in the definition of domains of competence and future positioning. Identity is also tightly connected to Interdisciplinarity as this might threaten the existence of the profession. Stakeholders outside the profession insist on the importance of visibility. The results of this study can help stakeholders reflect on the future of physiotherapy and elaborate research priorities. Keywords interdisciplinary; physiotherapy; policy; qualitative research; research prioritie

Head and neck paragangliomas: clinical and molecular genetic classification

Head and neck paragangliomas are tumors arising from specialized neural crest cells. Prominent locations are the carotid body along with the vagal, jugular, and tympanic glomus. Head and neck paragangliomas are slowly growing tumors, with some carotid body tumors being reported to exist for many years as a painless lateral mass on the neck. Symptoms depend on the specific locations. In contrast to paraganglial tumors of the adrenals, abdomen and thorax, head and neck paragangliomas seldom release catecholamines and are hence rarely vasoactive. Petrous bone, jugular, and tympanic head and neck paragangliomas may cause hearing loss. The internationally accepted clinical classifications for carotid body tumors are based on the Shamblin Class I–III stages, which correspond to postoperative permanent side effects. For petrous-bone paragangliomas in the head and neck, the Fisch classification is used. Regarding the molecular genetics, head and neck paragangliomas have been associated with nine susceptibility genes: NF1, RET, VHL, SDHA, SDHB, SDHC, SDHD, SDHAF2 (SDH5), and TMEM127. Hereditary HNPs are mostly caused by mutations of the SDHD gene, but SDHB and SDHC mutations are not uncommon in such patients. Head and neck paragangliomas are rarely associated with mutations of VHL, RET, or NF1. The research on SDHA, SDHAF2 and TMEM127 is ongoing. Multiple head and neck paragangliomas are common in patients with SDHD mutations, while malignant head and neck paraganglioma is mostly seen in patients with SDHB mutations. The treatment of choice is surgical resection. Good postoperative results can be expected in carotid body tumors of Shamblin Class I and II, whereas operations on other carotid body tumors and other head and neck paragangliomas frequently result in deficits of the cranial nerves adjacent to the tumors. Slow growth and the tendency of hereditary head and neck paragangliomas to be multifocal may justify less aggressive treatment strategies

Multiplexed pancreatic genome engineering and cancer induction by transfection-based CRISPR/Cas9 delivery in mice

Mouse transgenesis has provided fundamental insights into pancreatic cancer, but is limited by the long duration of allele/model generation. Here we show transfection-based multiplexed delivery of CRISPR/Cas9 to the pancreas of adult mice, allowing simultaneous editing of multiple gene sets in individual cells. We use the method to induce pancreatic cancer and exploit CRISPR/Cas9 mutational signatures for phylogenetic tracking of metastatic disease. Our results demonstrate that CRISPR/Cas9-multiplexing enables key applications, such as combinatorial gene-network analysis, in vivo synthetic lethality screening and chromosome engineering. Negative-selection screening in the pancreas using multiplexed-CRISPR/Cas9 confirms the vulnerability of pancreatic cells to Brca2-inactivation in a Kras-mutant context. We also demonstrate modelling of chromosomal deletions and targeted somatic engineering of inter-chromosomal translocations, offering multifaceted opportunities to study complex structural variation, a hallmark of pancreatic cancer. The low-frequency mosaic pattern of transfection-based CRISPR/Cas9 delivery faithfully recapitulates the stochastic nature of human tumorigenesis, supporting wide applicability for biological/preclinical research

Multiplexed pancreatic genome engineering and cancer induction by transfection-based CRISPR/Cas9 delivery in mice.

Mouse transgenesis has provided fundamental insights into pancreatic cancer, but is limited by the long duration of allele/model generation. Here we show transfection-based multiplexed delivery of CRISPR/Cas9 to the pancreas of adult mice, allowing simultaneous editing of multiple gene sets in individual cells. We use the method to induce pancreatic cancer and exploit CRISPR/Cas9 mutational signatures for phylogenetic tracking of metastatic disease. Our results demonstrate that CRISPR/Cas9-multiplexing enables key applications, such as combinatorial gene-network analysis, in vivo synthetic lethality screening and chromosome engineering. Negative-selection screening in the pancreas using multiplexed-CRISPR/Cas9 confirms the vulnerability of pancreatic cells to Brca2-inactivation in a Kras-mutant context. We also demonstrate modelling of chromosomal deletions and targeted somatic engineering of inter-chromosomal translocations, offering multifaceted opportunities to study complex structural variation, a hallmark of pancreatic cancer. The low-frequency mosaic pattern of transfection-based CRISPR/Cas9 delivery faithfully recapitulates the stochastic nature of human tumorigenesis, supporting wide applicability for biological/preclinical research

Interlaboratory study on rheological properties of cement pastes and reference substances: comparability of measurements performed with different rheometers and measurement geometries

This paper presents the results of an interlaboratory study of the rheological properties of cement paste and ultrasound gel as reference substance. The goal was to quantify the comparability and reproducibility of measurements of the Bingham parameters yield stress and plastic viscosity when measured on one specific paste composition and one particular ultrasound gel in different laboratories using different rheometers and measurement geometries. The procedures for both in preparing the cement paste and carrying out the rheological measurements on cement paste and ultrasound gel were carefully defined for all of the study’s participants. Different conversion schemes for comparing the results obtained with the different measurement setups are presented here and critically discussed. The procedure proposed in this paper ensured a reasonable comparability of the results with a coefficient of variation for the yield stress of 27% and for the plastic viscosity of 24%, despite the individual measurement series’ having been performed in different labs with different rheometers and measurement geometries

Bcl3 Couples Cancer Stem Cell Enrichment With Pancreatic Cancer Molecular Subtypes

[Background & Aims]: The existence of different subtypes of pancreatic ductal adenocarcinoma (PDAC) and their correlation with patient outcome have shifted the emphasis on patient classification for better decision-making algorithms and personalized therapy. The contribution of mechanisms regulating the cancer stem cell (CSC) population in different subtypes remains unknown. [Methods]: Using RNA-seq, we identified B-cell CLL/lymphoma 3 (BCL3), an atypical nf-κb signaling member, as differing in pancreatic CSCs. To determine the biological consequences of BCL3 silencing in vivo and in vitro, we generated bcl3-deficient preclinical mouse models as well as murine cell lines and correlated our findings with human cell lines, PDX models, and 2 independent patient cohorts. We assessed the correlation of bcl3 expression pattern with clinical parameters and subtypes. [Results]: Bcl3 was significantly down-regulated in human CSCs. Recapitulating this phenotype in preclinical mouse models of PDAC via BCL3 genetic knockout enhanced tumor burden, metastasis, epithelial to mesenchymal transition, and reduced overall survival. Fluorescence-activated cell sorting analyses, together with oxygen consumption, sphere formation, and tumorigenicity assays, all indicated that BCL3 loss resulted in CSC compartment expansion promoting cellular dedifferentiation. Overexpression of BCL3 in human PDXs diminished tumor growth by significantly reducing the CSC population and promoting differentiation. Human PDACs with low BCL3 expression correlated with increased metastasis, and BCL3-negative tumors correlated with lower survival and nonclassical subtypes. [Conclusions]: We demonstrate that bcl3 impacts pancreatic carcinogenesis by restraining CSC expansion and by curtailing an aggressive and metastatic tumor burden in PDAC across species. Levels of BCL3 expression are a useful stratification marker for predicting subtype characterization in PDAC, thereby allowing for personalized therapeutic approaches.This work was supported by the Deutsche Forschungsgemeinschaft (grants AL 1174/4-1, AL1174/4-2, and Collaborative Research Center 1321 “Modeling and Targeting Pancreatic Cancer” to Hana Algül; SFB824 Z2 to Katja Steiger), the Deutsche Krebshilfe (grant 111646 to Hana Algül), a Ramon y Cajal Merit Award from the Ministerio de Economía y Competitividad, Spain (to Bruno Sainz Jr), a Coordinated Grant from Fundación Asociación Española Contra el Cáncer (GC16173694BARB to Bruno Sainz Jr), funding from The Fero Foundation (to Bruno Sainz Jr), and a Proyecto de Investigacion de Salud, ISCIII, Spain (no. PI18/00757 to Bruno Sainz Jr). Jiaoyu Ai is supported by the “China Scholarship Council” grant program