Palladium-Catalyzed Sequential Cross-Coupling/Annulation of ortho-Vinyl Bromobenzene with Aryl Bromide: Bimetallic Pathway versus Pd(II)-Pd(IV) Pathway: A DFT Investigation.

The palladium-catalyzed sequential cross-coupling/annulation of ortho-vinyl bromobenzenes with aryl bromides generating phenanthrenes was characterized by density functional theory (DFT). The Pd(II)-Pd(IV) pathway (Path V) is shown to be less probable than the bimetallic pathway (Path I), the latter proceeding via the following six steps: oxidative addition, vinyl-C(sp2)-H activation, Pd(II)-Pd(II) transmetalation, C-C coupling, aryl-C(sp2)-H activation, and reductive elimination. The aryl-C(sp2)-H activation process acts as the rate-determining step (RDS) of the entire chemical transformation, with an activation free energy barrier of ca. 27.4-28.8 kcal·mol-1, in good agreement with the corresponding experimental data (phenanthrenes' yields of ca. 65-90% at 130 °C after 5 h of reaction). The K2CO3 additive effectively reduces the activation free energy barrier of the RDS through direct participation in the reaction while preferentially modulating the charge distributions and increasing the stability of corresponding intermediates and complexes along the reaction path. Furthermore, bonding and electronic structure analyses of the key structures indicate that the chemo- and regioselectivities of the reaction are strongly influenced by both electronic effects and steric hindrance.

Transcriptomic analysis reveals ozone treatment delays kiwifruit postharvest softening by modulating cell wall metabolism.

Kiwifruit ripening and senescence after harvesting are closely related to its economic value. Transcriptome analysis and biochemical parameters were used to investigate the differences in gene expression levels and the potential regulation of cell wall metabolism in kiwifruit treated with ozone, thereby regulating fruit softening and prolonging postharvest life. Compared to the control group, the activities of the cell wall modification enzyme were lower under ozone treatment, the content of polysaccharide in the cell wall of primary pectin and cellulose was higher, and the content of soluble pectin was lower. Meanwhile, ozone treatment delayed the degradation of the cell wall mesosphere during storage. A total of 20 pectinesterase (PE)-related genes were identified by sequencing analysis. The data analysis and quantitative polymerase chain reaction results confirmed that cell wall modifying enzyme genes played an important role in softening and senescence after harvesting, which may reduce or induce the expression of certain genes affecting cell wall metabolism. Ozone treatment not only regulates active genes such as xyloglucan endo glycosyltransferase/hydrolase, cellulose synthase, polygalacturonase, and PE to maintain the quality of fruit after harvest but also acts synergically with cell wall modifying enzymes to inhibit the degradation of cell wall, resulting in changes in the ultrastructure of cell wall, thereby reducing the hardness of kiwifruit. In addition, according to the results of cis-acting elements, cell wall degradation is also related to downstream hormone signaling, especially PE-related genes. These results provide a theoretical basis for studying the mechanism of firmness and cell wall metabolism difference of kiwifruit and also lay a good foundation for further research.

Ozone treatment modulates reactive oxygen species levels in kiwifruit through the antioxidant system: Insights from transcriptomic analysis.

Owing to its easy decomposition and residue-free properties, ozone has been used as an effective and environmentally friendly physical preservation method for maintaining the post-harvest quality of fruits. This study aimed to investigate the effects of ozone treatment on the levels of oxidative stress markers and the status of the antioxidant defense system in refrigerated kiwifruit. Additionally, the study aimed to identify the differences in gene expression levels and potential regulatory effects from the transcriptional level. The results showed that ozone treatment reduced the respiration rate, maintained the fruit hardness and storage quality, and inhibited the ripening and senescence of kiwifruit. Ozone treatment activated antioxidant enzymes (superoxide dismutase, peroxidase, and catalase) and ascorbate-glutathione cycle to prevent the increase of reactive oxygen species levels (H2O2, O2-•) and malonaldehyde content, maintaining lower membrane lipid peroxidation and reactive oxygen species (ROS) accumulation than the control treatment. Further analysis showed that the regulatory ability of ROS in kiwifruit treated with ozone was not only related to the synergistic effect of enzyme activity and gene expression related to the antioxidant oxidase system and the ascorbate-glutathione (ASA-GSH) cycle but also related to downstream hormone signaling. This study provides a foundation for understanding the potential effects of ozone treatment on the antioxidant cycle of kiwifruit and provides valuable insights into the molecular basis and related key genes involved in regulating ROS to delay aging in kiwifruit.

Comparison of stenosis models for usage in the estimation of pressure gradient across aortic coarctation.

Non-invasive estimation of the pressure gradient in cardiovascular stenosis has much clinical importance in assisting the diagnosis and treatment of stenotic diseases. In this research, a systematic comparison is conducted to investigate the accuracy of a group of stenosis models against the MRI- and catheter-measured patient data under the aortic coarctation condition. Eight analytical stenosis models, including six from the literature and two proposed in this study, are investigated to examine their prediction accuracy against the clinical data. The two improved models proposed in this study consider comprehensively the Poiseuille loss, the Bernoulli loss in its exact form, and the entrance effect, of the blood flow. Comparison of the results shows that one of the proposed models demonstrates a cycle-averaged mean prediction error of -0.15 ± 3.03 mmHg, a peak-to-peak prediction error of -1.8 ± 6.89 mmHg, which is the best among the models studied.

Mock circulatory test rigs for the in vitro testing of artificial cardiovascular organs.

In vitro study plays an important role in the experimental study of cardiovascular dynamics. An essential hardware facility that mimics the blood flow changes and provides the required test conditions, a mock circulatory test rig (MCTR), is imperative for the execution of in vitro study. This paper examines the current MCTRs in use for the testing of artificial cardiovascular organs. Various aspects of the MCTRs are surveyed, including the necessity of in vitro study, the building of MCTRs, relevant standards, general system structure (e.g., the motion and driving, fluid, measurement subsystems), classification, motion driving mechanism of MCTRs, and the considerations for the modelling of the physiological impedance of MCTRs. Examples of the steady and pulsatile flow types of the MCTRs are introduced. Recent developments in MCTRs are inspected and possible future design improvements suggested. This study will help researchers in the design, construction, analysis, and selection of MCTRs for cardiovascular research.

Patient-specific non-invasive estimation of pressure gradient across aortic coarctation using magnetic resonance imaging.

BACKGROUND: Non-invasive estimation of the pressure gradient in aortic coarctation has much clinical importance in assisting the diagnosis and treatment of the disease. Previous researchers applied computational fluid dynamics for the prediction of the pressure gradient in aortic coarctation. The accuracy of the prediction was satisfactory but the procedure was time-consuming and resource-demanding. METHOD: In this research a magnetic resonance imaging (MRI)-based non-invasive modeling procedure is implemented to predict the pressure gradient in 14 patient cases of aortic coarctation. Multi-cycle patient flow and pressure data are processed to produce the flow and pressure conditions in the patient cases. Bernoulli equation-based friction loss model combined with the inertial effect of the blood flow in the vessel segments are applied to model the pressure gradient in the aortic coarctation. The model-predicted pressure gradient data are then compared with the catheter in vivo measurement data for validation. RESULTS: The MRI-based model prediction technique produces results that are consistent with those from the catheter measurement, based on the criteria of both the cycle-averaged instantaneous pressure gradient and the peak-to-peak pressure gradient. CONCLUSION: This study suggests that the MRI-based non-invasive modeling procedure has much potential to be applied in clinical practice for the prediction of the pressure gradient in aortic coarctation patients.

Structure and motion design of a mock circulatory test rig.

Mock circulatory test rig (MCTR) is the essential and indispensable facility in the cardiovascular in vitro studies. The system configuration and the motion profile of the MCTR design directly influence the validity, precision, and accuracy of the experimental data collected. Previous studies gave the schematic but never describe the structure and motion design details of the MCTRs used, which makes comparison of the experimental data reported by different research groups plausible but not fully convincing. This article presents the detailed structure and motion design of a sophisticated MCTR system, and examines the important issues such as the determination of the ventricular motion waveform, modelling of the physiological impedance, etc., in the MCTR designing. The study demonstrates the overall design procedures from the system conception, cardiac model devising, motion planning, to the motor and accessories selection. This can be used as a reference to aid researchers in the design and construction of their own in-house MCTRs for cardiovascular studies.

Impeller-pump model derived from conservation laws applied to the simulation of the cardiovascular system coupled to heart-assist pumps.

Previous numerical models of impeller pumps for ventricular assist devices utilize curve-fitted polynomials to simulate experimentally-obtained pressure difference versus flow rate characteristics of the pumps, with pump rotational speed as a parameter. In this paper the numerical model for the pump pressure difference versus flow rate characteristics is obtained by analytic derivation. The mass, energy and angular momentum conservation laws are applied to the working fluid passing through the impeller geometry and coupled with the turbomachine's velocity diagram. This results in the construction of a pressure difference versus flow rate characteristic for the specific pump geometry, with pump rotational speed as parameter. Overall this model allows modifications of the pump geometry, so that the pump avoids undesirable operating conditions, such as regurgitant flow. The HeartMate III centrifugal pump is used as an example to demonstrate the application of the technique. The parameterised numerical model for HeartMate III derived by this technique is coupled with a numerical model for the human cardiovascular system, and the combination is used to investigate the cardiovascular response under different conditions of impeller pump support. Conditions resulting in regurgitant pump flow, the pump resulting in aortic valve closure and taking over completely the pumping action from the diseased heart, and inner ventricular wall suction at pump inlet are predicted by the model. The simulation results suggest that for normal HeartMate III operation the pump speed should be maintained between 3,100 and 4,500 rpm to avoid regurgitant pump flow and ventricular suction. To obtain optimal overall cardiovascular system plus pump response, the pump operating speed should be 3,800 rpm.

Construction of lumped-parameter cardiovascular models using the CellML language.

Lumped-parameter models are widely used by cardiovascular researchers in the analysis of the circulatory dynamics. However, portability and model exchange have always been a problem, with different researchers implement the model differently. To improve the situation, in this study, a group of lumped-parameter cardiovascular system models with different levels of complexity have been implemented using the CellML mark-up language. The models have been curated and made publicly available in the CellML model repository, and the purpose of this paper is to provide further technical details to support the usage of these models by the research community. The developed models are validated and tested under the OpenCell environment as part of the curation process. Simulation results agree well with typical published data on cardiovascular system response.

Computer model for the cardiovascular system: development of an e-learning tool for teaching of medical students.

BACKGROUND: This study combined themes in cardiovascular modelling, clinical cardiology and e-learning to create an on-line environment that would assist undergraduate medical students in understanding key physiological and pathophysiological processes in the cardiovascular system. METHODS: An interactive on-line environment was developed incorporating a lumped-parameter mathematical model of the human cardiovascular system. The model outputs were used to characterise the progression of key disease processes and allowed students to classify disease severity with the aim of improving their understanding of abnormal physiology in a clinical context. Access to the on-line environment was offered to students at all stages of undergraduate training as an adjunct to routine lectures and tutorials in cardiac pathophysiology. Student feedback was collected on this novel on-line material in the course of routine audits of teaching delivery. RESULTS: Medical students, irrespective of their stage of undergraduate training, reported that they found the models and the environment interesting and a positive experience. After exposure to the environment, there was a statistically significant improvement in student performance on a series of 6 questions based on cardiovascular medicine, with a 33% and 22% increase in the number of questions answered correctly, p < 0.0001 and p < 0.001 respectively. CONCLUSIONS: Considerable improvement was found in students' knowledge and understanding during assessment after exposure to the e-learning environment. Opportunities exist for development of similar environments in other fields of medicine, refinement of the existing environment and further engagement with student cohorts. This work combines some exciting and developing fields in medical education, but routine adoption of these types of tool will be possible only with the engagement of all stake-holders, from educationalists, clinicians, modellers to, most importantly, medical students.

Are greenhouse gas emissions from international shipping a type of marine pollution?

Whether greenhouse gas emissions from international shipping are a type of marine pollution is a controversial issue and is currently open to debate. This article examines the current treaty definitions of marine pollution, and applies them to greenhouse gas emissions from ships. Based on the legal analysis of treaty definitions and relevant international and national regulation on this issue, this article asserts that greenhouse gas emissions from international shipping are a type of 'conditional' marine pollution.

Closing the loop: modelling of heart failure progression from health to end-stage using a meta-analysis of left ventricular pressure-volume loops.

INTRODUCTION: The American Heart Association (AHA)/American College of Cardiology (ACC) guidelines for the classification of heart failure (HF) are descriptive but lack precise and objective measures which would assist in categorising such patients. Our aim was two fold, firstly to demonstrate quantitatively the progression of HF through each stage using a meta-analysis of existing left ventricular (LV) pressure-volume (PV) loop data and secondly use the LV PV loop data to create stage specific HF models. METHODS AND RESULTS: A literature search yielded 31 papers with PV data, representing over 200 patients in different stages of HF. The raw pressure and volume data were extracted from the papers using a digitising software package and the means were calculated. The data demonstrated that, as HF progressed, stroke volume (SV), ejection fraction (EF%) decreased while LV volumes increased. A 2-element lumped parameter model was employed to model the mean loops and the error was calculated between the loops, demonstrating close fit between the loops. The only parameter that was consistently and statistically different across all the stages was the elastance (Emax). CONCLUSIONS: For the first time, the authors have created a visual and quantitative representation of the AHA/ACC stages of LVSD-HF, from normal to end-stage. The study demonstrates that robust, load-independent and reproducible parameters, such as elastance, can be used to categorise and model HF, complementing the existing classification. The modelled PV loops establish previously unknown physiological parameters for each AHA/ACC stage of LVSD-HF, such as LV elastance and highlight that it this parameter alone, in lumped parameter models, that determines the severity of HF. Such information will enable cardiovascular modellers with an interest in HF, to create more accurate models of the heart as it fails.

Derivation of aortic distensibility and pulse wave velocity by image registration with a physics-based regularisation term.

Analysis of the cardiovascular system represents a classical problem in which the solid and fluid phases interact intimately, and so is a rich field of application for state-of-the-art fluid-solid interaction (FSI) analyses. In this paper, we focus on the human aorta. Solution of the full FSI problem requires knowledge of the material properties of the wall and information on vessel support. We show that variation of distensibility along the aorta can be obtained from four-dimensional image data using image registration. If pressure data at one point in the vessel are available, these can be converted to absolute values. Alternatively, values of pulse wave velocity along the vessel can be obtained. The quality of the extracted data is improved by the incorporation into the registration of a regularisation term based on the one-dimensional wave equation. The method has been validated using simulated data. For idealised vessels, the accuracy with which the distensibility and wave velocity can be extracted is high (1%-2%). The method is applied to six clinical datasets from patients with mild coarctation, for which it is shown that wave velocity along the aorta is relatively constant.

Accuracy vs. computational time: translating aortic simulations to the clinic.

State of the art simulations of aortic haemodynamics feature full fluid-structure interaction (FSI) and coupled 0D boundary conditions. Such analyses require not only significant computational resource but also weeks to months of run time, which compromises the effectiveness of their translation to a clinical workflow. This article employs three computational fluid methodologies, of varying levels of complexity with coupled 0D boundary conditions, to simulate the haemodynamics within a patient-specific aorta. The most comprehensive model is a full FSI simulation. The simplest is a rigid walled incompressible fluid simulation while an alternative middle-ground approach employs a compressible fluid, tuned to elicit a response analogous to the compliance of the aortic wall. The results demonstrate that, in the context of certain clinical questions, the simpler analysis methods may capture the important characteristics of the flow field.

Importance of realistic LVAD profiles for assisted aortic simulations: evaluation of optimal outflow anastomosis locations.

Left ventricular assist devices (LVADs) are carefully designed, but the significance of the implantation configuration and interaction with the vasculature is complex and not fully determined. The present study employs computational fluid dynamics to investigate the importance of applying a realistic LVAD profile when evaluating assisted aortic flow fields and subsequently compares a number of potential anastomosis locations in a patient-specific aortic geometry. The outflow profile of the Berlin Heart INCOR® device was provided by Berlin Heart GmbH (Berlin, Germany) and the cannula was attached at a number of locations on the aorta. Simulations were conducted to compare a flat profile against the real LVAD profile. The results illustrate the importance of applying an LVAD profile. It not only affects the magnitude and distribution of oscillatory shear index, but also the distribution of flow to the great arteries. The ascending aorta was identified as the optimal location for the anastomosis.

Review of zero-D and 1-D models of blood flow in the cardiovascular system.

BACKGROUND: Zero-dimensional (lumped parameter) and one dimensional models, based on simplified representations of the components of the cardiovascular system, can contribute strongly to our understanding of circulatory physiology. Zero-D models provide a concise way to evaluate the haemodynamic interactions among the cardiovascular organs, whilst one-D (distributed parameter) models add the facility to represent efficiently the effects of pulse wave transmission in the arterial network at greatly reduced computational expense compared to higher dimensional computational fluid dynamics studies. There is extensive literature on both types of models. METHOD AND RESULTS: The purpose of this review article is to summarise published 0D and 1D models of the cardiovascular system, to explore their limitations and range of application, and to provide an indication of the physiological phenomena that can be included in these representations. The review on 0D models collects together in one place a description of the range of models that have been used to describe the various characteristics of cardiovascular response, together with the factors that influence it. Such models generally feature the major components of the system, such as the heart, the heart valves and the vasculature. The models are categorised in terms of the features of the system that they are able to represent, their complexity and range of application: representations of effects including pressure-dependent vessel properties, interaction between the heart chambers, neuro-regulation and auto-regulation are explored. The examination on 1D models covers various methods for the assembly, discretisation and solution of the governing equations, in conjunction with a report of the definition and treatment of boundary conditions. Increasingly, 0D and 1D models are used in multi-scale models, in which their primary role is to provide boundary conditions for sophisticate, and often patient-specific, 2D and 3D models, and this application is also addressed. As an example of 0D cardiovascular modelling, a small selection of simple models have been represented in the CellML mark-up language and uploaded to the CellML model repository http://models.cellml.org/. They are freely available to the research and education communities. CONCLUSION: Each published cardiovascular model has merit for particular applications. This review categorises 0D and 1D models, highlights their advantages and disadvantages, and thus provides guidance on the selection of models to assist various cardiovascular modelling studies. It also identifies directions for further development, as well as current challenges in the wider use of these models including service to represent boundary conditions for local 3D models and translation to clinical application.

Physiological control of an in-series connected pulsatile VAD: numerical simulation study.

This paper investigates ventricular assist device (VAD)-assisted cardiovascular dynamics under proportion-integration-differentiation (PID) feedback control. Previously, we have studied the cardiovascular responses under the support of an in-series connected reciprocating-valve VAD through numerical simulation, and no feedback control was applied in the VAD. In this research, we explore the contribution of the VAD control on the circulatory dynamics assisted by the reciprocating-valve VAD, in response to the changing physiological conditions. The classical PID control algorithm is implemented to regulate the VAD stroke beat-to-beat, based on the error signal between the expected and the realistic mean aortic pressures. Simulation results show that under the PID VAD control, physiological variables such as left atrial, ventricular and systemic arterial pressures, cardiac output and ventricular volumes are satisfactorily maintained in the physiological ranges. With the online PID feedback control, operation of the reciprocating-valve VAD can be satisfactorily regulated to accommodate metabolic requirements under various physiological conditions including normal resting and exercise situations.

Computational modelling and evaluation of cardiovascular response under pulsatile impeller pump support.

This study presents a numerical simulation of cardiovascular response in the heart failure condition under the support of a Berlin Heart INCOR impeller pump-type ventricular assist device (VAD). The model is implemented using the CellML modelling language. To investigate the potential of using the Berlin Heart INCOR impeller pump to produce physiologically meaningful arterial pulse pressure within the various physiological constraints, a series of VAD-assisted cardiovascular cases are studied, in which the pulsation ratio and the phase shift of the VAD motion profile are systematically changed to observe the cardiovascular responses in each of the studied cases. An optimization process is proposed, including the introduction of a cost function to balance the importance of the characteristic cardiovascular variables. Based on this cost function it is found that a pulsation ratio of 0.35 combined with a phase shift of 200° produces the optimal cardiovascular response, giving rise to a maximal arterial pulse pressure of 12.6 mm Hg without inducing regurgitant pump flow while keeping other characteristic cardiovascular variables within appropriate physiological ranges.

Numerical modeling of hemodynamics with pulsatile impeller pump support.

There is significant interest in the development and application of variable speed impeller-pump type ventricular assist devices designed to generate pulsatile blood flow. However, no study has so far been carried out to investigate the systemic cardiovascular response to various aspects of pump motion. In this article, a numerical model is constructed for the simulation of the cardiovascular response in the heart failure condition under representative cases of pulsatile impeller pump support. The native cardiovascular model is based on a previously validated model, and the impeller pump is modeled by directly fitting the pressure-flow curves that describe the pump characteristics. The model developed is applied to study circulatory dynamics under different degrees of phase shift and pulsation ratio in the pump motion profile. The characteristic variables are discussed as criteria for the evaluation of system response for comparison of the pulsatile flows. Simulation results show that a constant pump speed is the most efficient work mode for the rotary pump, and with the application of either a phase shift of 75% and a pulsation ratio of 0.5, or a phase shift of 42% and a pulsation ratio of 0.55, it is possible to generate arterial pulse pressure with the maximal magnitude of about 28 mmHg. However, this is achieved at the cost of reduced cardiac output and pump efficiency.

Numerical simulation of global hydro-dynamics in a pulsatile bioreactor for cardiovascular tissue engineering.

Previous numerical simulations of the hydro-dynamic response in the various bioreactor designs were mostly concentrated on the local flow field analysis using computational fluid dynamics, which cannot provide the global hydro-dynamics information to assist the bioreactor design. In this research, a mathematical model is developed to simulate the global hydro-dynamic changes in a pulsatile bioreactor design by considering the flow resistance, the elasticity of the vessel and the inertial effect of the media fluid in different parts of the system. The developed model is used to study the system dynamic response in a typical pulsatile bioreactor design for the culturing of cardiovascular tissues. Simulation results reveal the detailed pressure and flow-rate changes in the different positions of the bioreactor, which are very useful for the evaluation of hydro-dynamic performance in the bioreactor designed. Typical pressure and flow-rate changes simulated agree well with the published experimental data, thus validates the mathematical model developed. The proposed mathematical model can be used for design optimization of other pulsatile bioreactors that work under different experimental conditions and have different system configurations.