Multi-Formalism Modelling and Simulation: Application to Cardiac Modelling

Cardiovascular modelling has been a major research subject for the last decade. Different cardiac models have been developed at a cellular level as well as at the whole organ level. Most of these models are defined by a comprehensive cellular modelling using continuous formalisms or by a tissue-level modelling often based on discrete formalisms. Nevertheless, both views still suffer from difficulties that reduce their clinical applications: the first approach requires heavy computational resources while the second one is not able to reproduce certain pathologies. This paper presents an original methodology trying to gather advantages from both approaches, by means of a hybrid model mixing discrete and continuous formalisms. This method has been applied to define a hybrid model of cardiac action potential propagation on a 2D grid of endocardial cells, combining cellular automata and a set of cells defined by the Beeler-Reuter model. For simulations under physiological and ischemic conditions, results show that the action potential propagation as well as electrogram reconstructions are consistent with clinical diagnosis. Finally, the advantage of the proposed approach is discussed within the frame of cardiac modelling and simulation.     

Thematic review series: the immune system and atherogenesis. Molecular mechanisms regulating monocyte recruitment in atherosclerosis

Cardiovascular disease, a progressive disorder characterized by the accumulation of lipids in the artery wall, is a leading cause of death in Western societies. One of the initial events in atherogenesis involves the recruitment of inflammatory cells from the circulation into the developing lesion. Studies during the past decade have underscored the role of inflammatory mediators in disease initiation and progression. Critical progress has been made in our understanding of the complex mechanisms by which monocytes, macrophages, and T-cells accumulate in atherosclerotic plaques. Experimental research has identified several candidate adhesion proteins and chemokines that are critically involved in the recruitment process, and encouraging data provide a mechanistic framework for new therapeutic targets. This review provides an overview of our current understanding of the mechanisms that direct the recruitment of monocytes to, and their retention in, atherosclerotic lesions.     

Gene transfer to the vasculature: historical perspective and implication for future research objectives

Cardiovascular diseases are a major cause of fatality, disability, and economic burden in Western civilization. Although the pharmaceutical industry has delivered a plethora of drugs for treatment of diverse cardiovascular complaints, there remain many conditions for which pharmacological regimens are either nonexistent or largely ineffective. In contrast, remarkable progress has been made in the field of vascular gene transfer in the last decade. The vast majority of studies are preclinical, although a number of high profile vascular gene therapy clinical trials are in progress. In principle, vascular gene therapy represents an unprecedented opportunity to treat a host of cardiovascular diseases in humans although many scientific, clinical, and ethical obstacles remain. Here we discuss the rapid progress in preclinical vascular gene therapy, highlight the most appropriate gene delivery vectors, and discuss the advances toward the ultimate goal of an efficient and safe gene therapy for diverse cardiovascular diseases.     

Current methods for the maturation of induced pluripotent stem cellderived cardiomyocytes

Induced pluripotent stem cells(iPSCs) were first generated by Yamanaka and colleagues over a decade ago. Since then, iPSCs have been successfully differentiated into many distinct cell types, enabling tissue-, disease-, and patientspecific in vitro modelling. Cardiovascular disease is the greatest cause of mortality worldwide but encompasses rarer disorders of conduction and myocardial function for which a cellular model of study is ideal. Although methods to differentiate iPSCs into beating cardiomyocytes(iPSC-CMs) have recently been adequately optimized and commercialized, the resulting cells remain largely immature with regards to their structure and function,demonstrating fetal gene expression, disorganized morphology, reliance on predominantly glycolytic metabolism and contractile characteristics that differ from those of adult cardiomyocytes. As such, disease modelling using iPSC-CMs may be inaccurate and of limited utility. However, this limitation is widely recognized, and numerous groups have made substantial progress in addressing this problem. This review highlights successful methods that have been developed for the maturation of human iPSC-CMs using small molecules,environmental manipulation and 3-dimensional(3 D) growth approaches.     

Outlook on sponge reproduction science in the last ten years: are we far from where we should be?

To comprehend the state of the art of sponge reproduction science (SRS), we quantified and analyzed the trends in SRS in the last decade, aiming to answer three questions: (i) Were there fewer SRS works presented during the last sponge conference? (ii) Did the number of SRS publications decline in the last decade? (iii) Does the number of abstracts at sponge conferences influence overall SRS publications? In addition, we checked whether the SRS community has answered Ereskovsky’s ‘five important questions’, enabling us to advance SRS enough to be considered as a fourth period of this scientific field. We found that SRS was less represented at the last sponge conference, despite an increase in the number of publications during the last decade. Moreover, the number of abstracts presented at sponge conferences contributed to a small portion (25%) of the published works in this area during the last decade. In addition, we found that two of the five Ereskovsky’s questions are still mostly not answered. Thus, we conclude that SRS is healthy and advancing steadily, especially in some subareas (e.g. developmental biology and life history). There are still much to advance, but this is still a strong field of biological science research.     

Drosophila melanogaster: the model organism

In the 20th century, there were two decades during which Drosophila melanogaster was the most significant model organism and each decade led to the establishment of new scientific disciplines. The first decade was roughly from 1910 and during this period a small group at Columbia University, headed by Thomas Hunt Morgan, established the rules of transmission genetics with which we are all familiar. In the second decade, roughly from 1970, many of the principles and techniques of the earlier period were used to determine the genetic control of basic aspects of the biology of organisms, notably their development and their behaviour. In this review I will show that it was not only the genius of the research workers (five were awarded Nobel Prizes and it has been argued, with justification, that at least one more should have been awarded) but also the special features of D. melanogaster that led to these advances. While Drosophila is still a significant model organism, the advent of molecular biology permits the investigation of organisms less amenable to genetic analysis, but the principles applied in these investigations were in the main principles laid down during the earlier work on Drosophila.     

Skeletal muscle mechanics in osteoporotic and nonosteoporotic postmenopausal women

The purpose of this study was to evaluate single-joint, dynamic muscle function of osteoporotic (OST) and nonosteoporotic (N-OST) women. Knee flexor and extensor function in postmenopausal women (6th decade OST,n = 15; 7th decade OST,n = 10; 6th decade N-OST,n = 6; 7th decade N-OST,n = 5) were evaluated at five angular velocities from 60° · s^–1 to 300° · s^–1. All subject groups had similar anthropometric measurements, but the 6th decade N-OST group were more physically active than the age-matched OST group. The OST and N-OST women produced peak torque at similar knee angles. The 6th decade N-OST women produced significantly greater knee extensor mean peak torque and angle specific torque, and mean work than any of the other three groups (P<0.05). However, knee flexor function was equivalent throughout the groups for most comparisons, except those between the 6th decade N-OST and 7th decade OST. While previous research has shown an early loss of flexor muscle function in ageing women, our data indicated that women with osteoporosis also experience a deterioration in quadriceps muscle function not encountered within the N-OST subjects. It is possible that such a change is precipitated by reduced physical activity, and may mirror deterioration in bone mineral content.     

Quantitative phosphoproteomics by mass spectrometry: past, present, and future

Protein phosphorylation-mediated signaling networks regulate much of the cellular response to external stimuli, and dysregulation in these networks has been linked to multiple disease states. Significant advancements have been made over the past decade to enable the analysis and quantification of cellular protein phosphorylation events, but comprehensive analysis of the phosphoproteome is still lacking, as is the ability to monitor signaling at the network level while comprehending the biological implications of each phosphorylation site. In this review we highlight many of the technological advances over the past decade and describe some of the latest applications of these tools to uncover signaling networks in a variety of biological settings. We finish with a concise discussion of the future of the field, including additional advances that are required to link protein phosphorylation analysis with biological insight.     

Cardiac Beriberi: Two Modes of Presentation

Two patients suffering from cardiovascular beriberi presented with different clinical manifestations. One had the classical features of a high cardiac output with raised jugular venous pressure and gross oedema. The other was in fulminating heart failure with clinical evidence of a low cardiac output but no peripheral oedema. The latter type of beriberi (shoshin) is rare. Cardiovascular beriberi has a high mortality when untreated. Both patients responded dramatically to thiamine, and this emphasizes the importance of considering thiamine deficiency as a cause of heart failure even when the cardiac output is low.     

Decade of the brain. An agenda for the nineties.

On July 25, 1989, President George Bush, in response to reports written by the National Advisory Councils of the National Institute of Neurological Disorders and Stroke and the National Institute of Mental Health and at the urging of Congress, signed a presidential declaration designating the 1990s to be the "Decade of the Brain" and called on the United States to observe the decade with appropriate activities. At mid-decade, scientific accomplishment has been spectacular; however, both public support and increases in research resources have been minimal. It can be anticipated that scientific progress will continue to be impressive for the remainder of the decade, but many research opportunities will either not be addressed or will be postponed. At mid-decade, the time has come to re-evaluate the research agenda and the public strategy for the remainder of the decade.     

Analysis of diversification: combining phylogenetic and taxonomic data

The estimation of diversification rates using phylogenetic data has attracted a lot of attention in the past decade. In this context, the analysis of incomplete phylogenies (e.g. phylogenies resolved at the family level but unresolved at the species level) has remained difficult. I present here a likelihood-based method to combine partly resolved phylogenies with taxonomic (species-richness) data to estimate speciation and extinction rates. This method is based on fitting a birth-and-death model to both phylogenetic and taxonomic data. Some examples of the method are presented with data on birds and on mammals. The method is compared with existing approaches that deal with incomplete phylogenies. Some applications and generalizations of the approach introduced in this paper are further discussed.     

Cognitive neuroscience

The last decade of the 20th century has seen the development of cognitive neuroscience as an effort to understand how the brain represents mental events. We review the areas of emotional and motor memory, vision, and higher mental processes as examples of this new understanding. Progress in all of these areas has been swift and impressive, but much needs to be done to reveal the mechanisms of cognition at the local circuit and molecular levels. This work will require new methods for controlling gene expression in higher animals and in studying the interactions between neurons at multiple levels.     

Temperature, growth rate, and body size in ectotherms: fitting pieces of a life-history puzzle

The majority of ectotherms grow slower but mature at a larger body size in colder environments. This phenomenon has puzzled biologists because classic theories of life-history evolution predict smaller sizes at maturity in environments that retard growth. During the last decade, intensive theoretical and empirical research has generated some plausible explanations based on nonadaptive or adaptive plasticity. Nonadaptive plasticity of body size is hypothesized to result from thermal constraints on cellular growth that cause smaller cells at higher temperatures, but the generality of this theory is poorly supported. Adaptive plasticity is hypothesized to result from greater benefits or lesser costs of delayed maturation in colder environments. These theories seem to apply well to some species but not others. Thus, no single theory has been able to explain the generality of temperature-size relationships in ectotherms. We recommend a multivariate theory that focuses on the coevolution of thermal reaction norms for growth rate and size at maturity. Such a theory should incorporate functional constraints on thermal reaction norms, as well as the natural covariation between temperature and other environmental variables.     

Association of brain-type natriuretic protein and cardiac troponin I with incipient cardiovascular disease in chimpanzees (Pan troglodytes)

Cardiovascular disease (CVD) is the primary cause of morbidity and mortality in chimpanzees, but its etiology and clinical presentations remain poorly understood. The disease in chimpanzees differs sufficiently from that in humans that simple extrapolation from human findings are inadequate to guide clinical diagnoses. Nevertheless, the burden of disease posed by CVD made it important to attempt to identify specific chimpanzees at risk of developing CVD to allow clinical intervention prior to clinical presentation of advanced disease. We screened 4 CVD biomarkers used in human and veterinary medicine to identify markers with prognostic value in chimpanzees. Biomarkers included complete lipid panel, C-reactive protein, brain-type natriuretic protein, and cardiac troponin I. Serum levels of brain-type natriuretic protein differed between chimpanzees with CVD and heart-healthy controls. Cardiac troponin I gave mixed results. C-reactive protein and lipid panel values were not informative for cardiovascular disease, although total cholesterol, LDL-cholesterol, and triglycerides increased significantly with decade of life. Values of braintype natriuretic protein exceeding 163 mg/mL had a specificity of 90.5% for CVD, whereas levels of cardiac troponin I above the threshold of detection (0.20 ng/mL) appeared to be clinically relevant. More extensive clinical studies are recommended to validate these specific values. We conclude that brain-type natriuretic protein and possibly cardiac troponin I are useful diagnostic biomarkers for incipient CVD processes in chimpanzees.     

Clinical transplantation: current problems, possible solutions

I have attempted to summarize the progress that has been made in organ transplantation in the past 50 years since the first identical twin transplant. For those who have worked long in this area its success has been remarkable. We currently expect patients to survive the operation and more than 90% of the graft to be functioning at a year with the half-life of the graft beyond 10 years, with some patients surviving into the fifth decade after kidney transplantation with grafts from unrelated donors and the fourth decade for liver transplants. Now the main stumbling block is shortage of organ donors and this is unlikely to be solved easily. There has been a considerable increase in donations from living volunteers and also the worry of immoral and illegal practices.In the future, we can expect considerable advances in immunosuppression with more effective, less toxic drugs and in some patients induction therapy that may approach tolerance so that no maintenance therapy will eventually be needed. Cell transplantation is likely to be developed as treatment for the clinic in the next 5-10 years, but developments of transplantation from animal to man still remains unsolved and unlikely to be successful in the clinic in the near future.     

Cardiovascular effects of growth hormone treatment: potential risks and benefits

Growth hormone (GH) and insulin-like growth factor-I are involved in heart development and in maintaining cardiac structure and performance. Cardiovascular disease has been reported to reduce life expectancy both in GH deficiency (GHD) and in GH excess. Patients with GHD suffer from abnormalities of left ventricular performance, i.e. reduced diastolic filling and impaired response to peak exercise. Patients with GHD also have increased intima-media thickness at the common carotid arteries, associated with a higher occurrence of atherosclerotic plaques, which may further aggravate the haemodynamic conditions. This may contribute to increased cardiovascular and cerebrovascular risk. These cardiovascular abnormalities can be reversed, at least partially, with GH replacement therapy. In recent years, GH therapy has been used to increase cardiac mass in ischaemic or dilated cardiomyopathy, but the results have produced contradictory data.     

A comprehensive resilience assessment of Mexican tree species and their relationship with drought events over the last century

The resilience of forests to drought events has become a major natural resource sustainability concern, especially in response to climate change. Yet, little is known about the legacy effects of repeated droughts, and tree species ability to respond across environmental gradients. In this study, we used a tree-ring database (121 sites) to evaluate the overall resilience of tree species to drought events in the last century. We investigated how climate and geography affected the response at the species level. We evaluated temporal trends of resilience using a predictive mixed linear modeling approach. We found that pointer years (e.g., tree growth reduction) occurred during 11.3% of the 20th century, with an average decrease in tree growth of 66% compared to the previous period. The occurrence of pointer years was associated with negative values of the Standardized Precipitation Index (SPI, 81.6%) and Palmer Drought Severity Index (PDSI, 77.3%). Tree species differed in their resilience capacity, however, species inhabiting xeric conditions were less resistant but with higher recovery rates (e.g., Abies concolor, Pinus lambertiana, and Pinus jeffreyi). On average, tree species needed 2.7 years to recover from drought events, with extreme cases requiring more than a decade to reach pre-drought tree growth rates. The main abiotic factor related to resilience was precipitation, confirming that some tree species are better adapted to resist the effects of droughts. We found a temporal variation for all tree resilience indices (scaled to 100), with a decreasing resistance (−0.56 by decade) and resilience (−0.22 by decade), but with a higher recovery (+1.72 by decade) and relative resilience rate (+0.33 by decade). Our results emphasize the importance of time series of forest resilience, particularly by distinguishing the species-level response in the context of legacy of droughts, which are likely to become more frequent and intense under a changing climate.     

Exploiting recombinant antibodies in point-of-care (POC) diagnostics: the combinatorial advantage

Antibodies are ubiquitously deployed on in vitro diagnostic (IVD) platforms for detecting a panoply of analytes indicative of environmental and food contamination, residue adulteration and both veterinary and medical diagnostics. In the clinical realm, rapid and accurate determination of disease status is paramount. The significance of immunodiagnostic performance cannot be overemphasized and in many cases reliable diagnosis informs medical intervention which can mean the difference between patient recovery and demise. Cardiovascular disease (CVD) is the single biggest cause of adult mortality in the western world and principal burden on the healthcare services. Although the troponin (Tn) family, in particular troponin I (TnI), are regarded as the gold standard for diagnosis of myocardial damage, over the last decade much research has focused on the identification of alternative cardiac biomarker molecules that can either supplant or complement TnI metrics to add value to cardiac risk stratification criteria. In particular, markers that appear earlier than TnI in the pathophyisiology of cardiac disease are highly sought after. The subject?of this addendum represents part of a broader challenge to deliver novel rapid point-of-care (POC) diagnostics to provide a chip-based multi-plexed platform for more comprehensive profiling of cardiac status with additive diagnostic and prognostic value.?Specifically, it outlines proof-of-concept direct myeloperoxidase (MPO) detection, demonstrates the benefits of using recombinant antibodies in POC diagnostics and describes optimized strategies for generation of superior candidate antibody panels.     

HUPO 2011: The new Cardiovascular Initiative - integrating proteomics and cardiovascular biology in health and disease

A newly reorganized HUPO Cardiovascular Initiative was announced at the HUPO 2011 Cardiovascular Initiative Workshop at Geneva. The new initiative is now part of the biology- and disease-driven component of the HUPO Human Proteome Project (B/D-HPP). Here we report the recent achievements and future directions of the initiative, and offer a perspective on the present challenges of cardiovascular proteomics and its integration with the cardiovascular biology community at large.     

Local snow melt and temperature—but not regional sea ice—explain variation in spring phenology in coastal Arctic tundra

The Arctic is undergoing dramatic environmental change with rapidly rising surface temperatures, accelerating sea ice decline and changing snow regimes, all of which influence tundra plant phenology. Despite these changes, no globally consistent direction of trends in spring phenology has been reported across the Arctic. While spring has advanced at some sites, spring has delayed or not changed at other sites, highlighting substantial unexplained variation. Here, we test the relative importance of local temperatures, local snow melt date and regional spring drop in sea ice extent as controls of variation in spring phenology across different sites and species. Trends in long‐term time series of spring leaf‐out and flowering (average span: 18 years) were highly variable for the 14 tundra species monitored at our four study sites on the Arctic coasts of Alaska, Canada and Greenland, ranging from advances of 10.06 days per decade to delays of 1.67 days per decade. Spring temperatures and the day of spring drop in sea ice extent advanced at all sites (average 1°C per decade and 21 days per decade, respectively), but only those sites with advances in snow melt (average 5 days advance per decade) also had advancing phenology. Variation in spring plant phenology was best explained by snow melt date (mean effect: 0.45 days advance in phenology per day advance snow melt) and, to a lesser extent, by mean spring temperature (mean effect: 2.39 days advance in phenology per °C). In contrast to previous studies examining sea ice and phenology at different spatial scales, regional spring drop in sea ice extent did not predict spring phenology for any species or site in our analysis. Our findings highlight that tundra vegetation responses to global change are more complex than a direct response to warming and emphasize the importance of snow melt as a local driver of tundra spring phenology.