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.

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.

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.

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.

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.

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.

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.

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.

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.

Numerical simulation of cardiovascular dynamics with different types of VAD assistance.

A variety of methods by which mechanical circulatory support (MCS) can be provided have been described. However, the haemodynamic benefits of the different methods have not been adequately quantified. The aim of this paper is to compare the haemodynamic effects of six forms of MCS by numerical simulation. Three types of ventricular assist device (VAD) are studied: positive displacement; impeller and a novel reciprocating-valve design. Similarly, three pumping modes are modelled: constant flow; counterpulsation and copulsation. The cardiovascular system is modelled using an approach developed previously, using the concentrated parameter method by considering flow resistance, vessel elasticity and inertial effects of blood in individual conduit segments. The dynamic modelling of displacement and impeller pumps is represented by VAD inlet/outlet flow-rate changes. The dynamics of the reciprocating-valve pump is modelled with a specified displacement profile. Results show that in each simulation, the physiological variables of mean arterial pressure and systemic flow are adequately maintained. Modulation of the impeller pump flow profile produces a small (5 mmHg) oscillatory component to arterial pressure, whereas the displacement and reciprocating-valve pumps generate substantial arterial pressure and flow pulsatility. The impeller pump requires the least power input, the reciprocating valve pump slightly more, and the displacement pump the most. The in parallel configuration of the impeller and displacement pump designs with respect to the left ventricle provides near complete unloading and can cause the aortic valve to remain closed throughout the entire cardiac cycle with the attendant risk of aortic valve leaflet fusion following prolonged support. The in series configuration of the reciprocating-valve pump avoids this shortcoming but activation must be carefully synchronized to the cardiac cycle to allow adequate coronary perfusion. The reciprocating-valve pump is associated with haemodynamic advantages and a favourable power consumption.

Numerical simulation of cardiovascular dynamics with healthy and diseased heart valves.

This paper presents a new concentrated parameter model for cardiovascular dynamics that includes an innovative model of heart valve dynamics, which is embedded in the overall model of the four chambers of the heart and the systemic and pulmonary circulation loops. The heart chambers are described with a variable elastance model, and the systemic and pulmonary loops are described with modified Windkessel models. In modelling the heart valve dynamics, the various factors that influence the valve motion are examined, and the governing differential equation for valve motion is derived. The heart valve model includes the influence of the blood pressure effect, the friction effect from the tissue, and from blood motion. As improvement from previous works, the contribution of the blood vortex effect in the vicinity of the valve leaflets to valve motion is specially considered. The proposed model is then used in simulation of healthy and certain pathological conditions such as mitral valve stenosis and aortic regurgitation. The predicted results agree well with results illustrated in cardiology textbooks.

Effects of atrial contraction, atrioventricular interaction and heart valve dynamics on human cardiovascular system response.

Various simulation models of different complexity have been proposed to model the dynamic response of the human cardiovascular system. In a related paper we proposed an improved numerical model to study the dynamic response of the cardiovascular system, and the pressures, volumes and flow-rates in the four chambers of the heart, which included the effects of atrial contraction, atrioventricular interaction, and heart valve dynamics. This paper investigates the effects of each one of these aspects of the model on the overall dynamic system response. The dynamic response is studied under different situations, with and without including the effect of various features of the model, and these situations are studied and compared among themselves and to detailed aspects of expected healthy-system response. As an important contribution with potential clinical applications, this paper examines the corresponding effects of atrioventricular interaction, and heart valve opening and closing dynamics to the general system dynamic response. This isolation of physical cause-effect relationships is difficult to study with purely experimental methods. The simulation results agree well with results in the open literature. Comparison shows that introduction of these new features greatly improves the simulation accuracy of the effects of a, v and c waves, and in predicting regurgitant valve flow, the dichrotic notch, and E/A velocity ratio.

A concentrated parameter model for the human cardiovascular system including heart valve dynamics and atrioventricular interaction.

Numerical modeling of the human cardiovascular system has always been an active research direction since the 19th century. In the past, various simulation models of different complexities were proposed for different research purposes. In this paper, an improved numerical model to study the dynamic function of the human circulation system is proposed. In the development of the mathematical model, the heart chambers are described with a variable elastance model. The systemic and pulmonary loops are described based on the resistance-compliance-inertia concept by considering local effects of flow friction, elasticity of blood vessels and inertia of blood in different segments of the blood vessels. As an advancement from previous models, heart valve dynamics and atrioventricular interaction, including atrial contraction and motion of the annulus fibrosus, are specifically modeled. With these improvements the developed model can predict several important features that were missing in previous numerical models, including regurgitant flow on heart valve closure, the value of E/A velocity ratio in mitral flow, the motion of the annulus fibrosus (called the KG diaphragm pumping action), etc. These features have important clinical meaning and their changes are often related to cardiovascular diseases. Successful simulation of these features enhances the accuracy of simulations of cardiovascular dynamics, and helps in clinical studies of cardiac function.

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.

Numerical simulation of opening process in a bileaflet mechanical heart valve under pulsatile flow condition.

BACKGROUND AND AIM OF THE STUDY: Most previous computational fluid dynamics (CFD) studies of blood flow in mechanical heart valves (MHVs) have not efficiently addressed the important features of moving leaflet and blood-leaflet interaction. Herein, computationally efficient approaches were developed to study these features and to obtain better insight into the pulsatile flow field in bileaflet MHVs. METHODS: A simple and effective method to track the moving boundary was proposed, and an efficient method for calculating the blood-leaflet interaction applied. In this way, a CFD code was developed to study the pulsatile flow field around bileaflet MHVs. The CFD code was parallelized on a supercomputer to reduce turn-around time in the simulation. The solver was then used to study the opening process in a St. Jude Medical (SJM) size 29 bileaflet MHV. RESULTS: CFD results showed that, in the opening process, the flow field was consistently partitioned into two side channels and a central channel due to the presence of the two leaflets. In the flow field near the surface of the two leaflets, the fluid velocity followed the local surface velocity of the leaflets, thus showing a strong blood-leaflet interaction effect. Throughout the valve-opening process, peak velocities were always observed near the tips of the valve leaflet. The CFD simulation showed that the opening process took approximately 0.044 s, which compared well with experimental findings. CONCLUSION: The new computational approaches were efficient and able to address the moving leaflet and blood-leaflet interaction. The flow field in the opening process of a SJM 29 bileaflet MHV was successfully simulated using the developed solver.

Numerical simulation of a systemic flow test rig.

In this study, numerical simulation was carried out to investigate the dynamic response of a systemic flow test rig that is widely used for in vitro study of prosthesis in the cardiovascular system. In the system the physiological impedance of systemic circulation was modeled as a resistance-capacitance-resistance type. The system analysis was directly based on differential equations describing the system dynamics, and numerically solved using the fourth-order Runge-Kutta method. Results showed that pressure in the systemic circulation test rig could be successfully simulated with the developed model. From the numerical experiment, it was found that the maximum stroke of the driving mechanism, the flow coefficients and opening of the control valves, and the initial volume of air in the compliance strongly affect the dynamic performance of the test rig. The numerical method developed is a useful tool in the design and optimization of the system configuration.

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.