Of autoregressive continuous time model parameters estimation

This article revisits a sequential approach to the estimation of the parameter in a first-order autoregressive model (AR(1)) with continuous time. There is provided a numerical study to get a results of sequential estimations of the parameter in first-order autoregressive model with continuous time and is computed a stopping rule and the optimal time of observations. Also there is provided a comparing analysis of estimation results with using the sequential approach both the optimal time of observations

Convergence of cMyc and β-catenin on Tcf7l1 enables endoderm specification.

The molecular machinery that directs formation of definitive endoderm from pluripotent stem cells is not well understood. Wnt/β-catenin and Nodal signalling have been implicated, but the requirements for lineage specification remain incompletely defined. Here, we demonstrate a potent effect of inhibiting glycogen synthase kinase 3 (GSK3) on definitive endoderm production. We find that downstream of GSK3 inhibition, elevated cMyc and β-catenin act in parallel to reduce transcription and DNA binding, respectively, of the transcriptional repressor Tcf7l1. Tcf7l1 represses FoxA2, a pioneer factor for endoderm specification. Deletion of Tcf7l1 is sufficient to allow upregulation of FoxA2 in the presence of Activin. In wild-type cells, cMyc contributes by reducing Tcf7l1 mRNA, while β-catenin acts on Tcf7l1 protein. GSK3 inhibition is further required for consolidation of endodermal fate via upregulation of Sox17, highlighting sequential roles for Wnt signalling. The identification of a cMyc/β-catenin-Tcf7l1-FoxA2 axis reveals a de-repression mechanism underlying endoderm induction that may be recapitulated in other developmental and patho-logical contexts.This study was funded by the Juvenile Diabetes Research Foundation International, the European Commission FP7 project BetaCellTherapy (agreement No. 241883), a core support grant from the Wellcome Trust and MRC to the Wellcome Trust – Medical Research Council Cambridge Stem Cell Institute, and a University of Edinburgh Chancellor’s Fellowship awarded to GM. GM was a JDRF advanced postdoctoral fellow. AS is a Medical Research Council Professor.This is the final version of the article. It was first available from Wiley via http://dx.doi.org/10.15252/embj.20159211

Remote Assessment of the Cardiovascular Function Using Camera-Based Photoplethysmography

Camera-based photoplethysmography (cbPPG) is a novel measurement technique that allows the continuous monitoring of vital signs by using common video cameras. In the last decade, the technology has attracted a lot of attention as it is easy to set up, operates remotely, and offers new diagnostic opportunities. Despite the growing interest, cbPPG is not completely established yet and is still primarily the object of research. There are a variety of reasons for this lack of development including that reliable and autonomous hardware setups are missing, that robust processing algorithms are needed, that application fields are still limited, and that it is not completely understood which physiological factors impact the captured signal. In this thesis, these issues will be addressed. A new and innovative measuring system for cbPPG was developed. In the course of three large studies conducted in clinical and non-clinical environments, the system’s great flexibility, autonomy, user-friendliness, and integrability could be successfully proven. Furthermore, it was investigated what value optical polarization filtration adds to cbPPG. The results show that a perpendicular filter setting can significantly enhance the signal quality. In addition, the performed analyses were used to draw conclusions about the origin of cbPPG signals: Blood volume changes are most likely the defining element for the signal's modulation. Besides the hardware-related topics, the software topic was addressed. A new method for the selection of regions of interest (ROIs) in cbPPG videos was developed. Choosing valid ROIs is one of the most important steps in the processing chain of cbPPG software. The new method has the advantage of being fully automated, more independent, and universally applicable. Moreover, it suppresses ballistocardiographic artifacts by utilizing a level-set-based approach. The suitability of the ROI selection method was demonstrated on a large and challenging data set. In the last part of the work, a potentially new application field for cbPPG was explored. It was investigated how cbPPG can be used to assess autonomic reactions of the nervous system at the cutaneous vasculature. The results show that changes in the vasomotor tone, i.e. vasodilation and vasoconstriction, reflect in the pulsation strength of cbPPG signals. These characteristics also shed more light on the origin problem. Similar to the polarization analyses, they support the classic blood volume theory. In conclusion, this thesis tackles relevant issues regarding the application of cbPPG. The proposed solutions pave the way for cbPPG to become an established and widely accepted technology

Intubation in Private Practice. And Its Perfection.

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The impact of HER2 phenotype of circulating tumor cells in metastatic breast cancer: a retrospective study in 107 patients

Background: In metastatic breast cancer (MBC), antigen profiles of metastatic tissue and primary tumor differ in up to 20 % of patients. Reassessment of predictive markers, including human epidermal growth factor receptor 2 (HER2) expression, might help to optimize MBC treatment. While tissue sampling is invasive and often difficult to repeat, circulating tumor cell (CTC) analysis requires only a blood sample and might provide an easy-to-repeat, real-time “liquid biopsy” approach. The present retrospective study was conducted to compare HER2 expression in primary tumors, metastatic tissue, and circulating tumor cells (CTCs) from MBC patients and to analyze the potential impact of HER2 overexpression by CTCs on progression-free (PFS) and overall survival (OS) in MBC. Methods: CTC-positive (five or more CTCs/7.5 mL blood; CellSearch®, Janssen Diagnostics) MBC patients starting a new line of systemic treatment were eligible for the study. HER2 status of CTCs was determined by immunofluorescence (CellSearch®). HER2 status of primary (PRIM) and metastatic (MET) tumor tissue was determined by immunohistochemistry. Data were analyzed using descriptive statistics and Kaplan–Meier plots. Results: One hundred seven patients (median age (range) 57 (33–81) years) were included. 100/107 (93 %) patients were followed-up for a median [95 % confidence interval (CI)] of 28.5 [25.1–40.1] months. Of 37/107 (35 %) CTC-HER2-positive patients only 10 (27 %) were PRIM-HER2-positive. 6/46 (13 %) patients were MET-HER2-positive; only 2/10 (20 %) CTC-HER2-positive patients were MET-HER2-positive. Overall accuracy between CTC-HER2 expression and PRIM-HER2 and MET-HER2 status was 69 % and 74 %, respectively. Kaplan–Meier plots of PFS and OS by CTC-HER2 status revealed significantly longer median [95 % CI] PFS of CTC-HER2-positive versus CTC-HER2-negative patients (7.4 [4.7–13.7] versus 4.34 [3.5–5.9] months; p = 0.035). CTC-HER2-positive status showed no significant difference for OS (13.7 [7.7–30.0] versus 8.7 [5.9–15.3] months; p = 0.287). Conclusions: HER2 status can change during the course of breast cancer. CTC phenotyping may serve as an easy-to-perform “liquid biopsy” to reevaluate HER2 status and potentially guide treatment decisions. Further, prospective studies are needed

Survival of pancreatic cancer cells lacking KRAS function

Activating mutations in the proto-oncogene KRAS are a hallmark of pancreatic ductal adenocarcinoma (PDAC), an aggressive malignancy with few effective therapeutic options. Despite efforts to develop KRAS-targeted drugs, the absolute dependence of PDAC cells on KRAS remains incompletely understood. Here we model complete KRAS inhibition using CRISPR/Cas-mediated genome editing and demonstrate that KRAS is dispensable in a subset of human and mouse PDAC cells. Remarkably, nearly all KRAS deficient cells exhibit phosphoinositide 3-kinase (PI3K)-dependent mitogen-activated protein kinase (MAPK) signaling and induced sensitivity to PI3K inhibitors. Furthermore, comparison of gene expression profiles of PDAC cells retaining or lacking KRAS reveal a role of KRAS in the suppression of metastasis-related genes. Collectively, these data underscore the potential for PDAC resistance to even the very best KRAS inhibitors and provide insights into mechanisms of response and resistance to KRAS inhibition

Urban Cultural Heritage in Delhi, India: An Asset for the Future or a Neglected Resource?

The attractiveness of cities and their national and international competitiveness are partly determined by “soft” and “intangible" factors: cultural, social, and individual aspects are becoming the basis for the “unique competitive edge” that cities have and play a crucial role with regard to the creation of identity. In Delhi, every epoch of the city’s rich history has left its traces, and the Indian capital has numerous monuments, gardens, historic areas, and ancient buildings as a result. Affected by globalization and urbanization, Delhi has been increasingly turning into a globalized metropolis, which has had a major impact on its urban fabric. Framed against the backdrop of the changing concepts and perception of urban heritage, this article focuses on the question of how Delhi’s unique urban heritage should be safeguarded. The responsibility for this task does not lie with the authorities alone, but is embedded in the complex structure of public, private, individual, and collective stakeholders acting at different levels with their respective interests. These diverse stakeholders act within the scope of a differentiated set of rules and legislation. Thus, safeguarding urban heritage and integrating it into the urban planning process requires laws and regulations specifically relevant to cultural heritage and not just planning instruments. The institutional and legal framework of heritage protection in Delhi, its implementation, and the complex challenges that go with this are investigated

Residual Policy Learning for Vehicle Control of Autonomous Racing Cars

The development of vehicle controllers for autonomous racing is challenging because racing cars operate at their physical driving limit. Prompted by the demand for improved performance, autonomous racing research has seen the proliferation of machine learning-based controllers. While these approaches show competitive performance, their practical applicability is often limited. Residual policy learning promises to mitigate this by combining classical controllers with learned residual controllers. The critical advantage of residual controllers is their high adaptability parallel to the classical controller's stable behavior. We propose a residual vehicle controller for autonomous racing cars that learns to amend a classical controller for the path-following of racing lines. In an extensive study, performance gains of our approach are evaluated for a simulated car of the F1TENTH autonomous racing series. The evaluation for twelve replicated real-world racetracks shows that the residual controller reduces lap times by an average of 4.55 % compared to a classical controller and zero-shot generalizes to new racetracks.Comment: Submitted to IEEE Intelligent Vehicles Symposium 202

New outcomes of Lewis base addition to diboranes(4): electronic effects override strong steric disincentives

Two surprising new outcomes of the reaction of Lewis bases with dihalodiboranes(4) are presented, including sp2–sp3 diboranes in which the Lewis base unit is bound to a highly sterically congested boron atom, and a rearranged double base adduct. The results provide a fuller understanding of the reactivity of diboranes, a poorly-understood class of molecule of critical importance to synthetic organic chemistry