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Cavutilide (niferidil, refralon) is a new class III antiarrhythmic drug which effectively terminates persistent atrial fibrillation (AF; 84.6% of patients, mean AF duration 3 months) and demonstrates low risk of torsade de pointes (1.7%). ERG channels of rapid delayed rectifier current(IKr) are the primary target of cavutilide, but the particular reasons of higher effectiveness and lower proarrhythmic risk in comparison with other class III IKr blockers are unclear. The inhibition of hERG channels expressed in CHO-K1 cells by cavutilide was studied using whole-cell patch-clamp. The present study demonstrates high sensitivity of IhERG expressed in CHO-K1 cells to cavutilide (IC50 = 12.8 nM). Similarly to methanesulfonanilide class III agents, but unlike amiodarone and related drugs, cavutilide does not bind to hERG channels in their resting state. However, in contrast to dofetilide, cavutilide binds not only to opened, but also to inactivated channels. Moreover, at positive constantly set membrane potential (+ 60 mV) inhibition of IhERG by 100 nM cavutilide develops faster than at 0 mV and, especially, − 30 mV (τ of inhibition was 78.8, 103, and 153 ms, respectively). Thereby, cavutilide produces IhERG inhibition only when the cell is depolarized. During the same period of time, cavutilide produces greater block of IhERG when the cell is depolarized with 2 Hz frequency, if compared to 0.2 Hz. We suggest that, during the limited time after injection, cavutilide produces stronger inhibition of IKr in fibrillating atrium than in non-fibrillating ventricle. This leads to beneficial combination of antiarrhythmic effectiveness and low proarrhythmicity of cavutilide. [ABSTRACT FROM AUTHOR]

Sustainability outcomes are influenced by the laws and configurations of natural and engineered systems as well as activities in socio-economic systems. An important subset of human activity is the creation and implementation of institutions, formal and informal rules shaping a wide range of human behavior. Understanding these rules and codifying them in computational models can provide important missing insights into why systems function the way they do (static) as well as the pace and structure of transitions required to improve sustainability (dynamic). Here, we conduct a comparative synthesis of three modeling approaches--integrated assessment modeling, engineering-economic optimization, and agent-based modeling--with underexplored potential to represent institutions. We first perform modeling experiments on climate mitigation systems that represent specific aspects of heterogeneous institutions, including formal policies and institutional coordination, and informal attitudes and norms. We find measurable but uneven aggregate impacts, while more politically meaningful distributional impacts are large across various actors. Our results show that omitting institutions can influence the costs of climate mitigation and miss opportunities to leverage institutional forces to speed up emissions reduction. These experiments allow us to explore the capacity of each modeling approach to represent insitutions and to lay out a vision for the next frontier of endogenizing institutional change in sustainability science models. To bridge the gap between modeling, theories, and empirical evidence on social institutions, this research agenda calls for joint efforts between sustainability modelers who wish to explore and incorporate institutional detail, and social scientists studying the socio-political and economic foundations for sustainability transitions. [ABSTRACT FROM AUTHOR]

Economic costs of climate change are conventionally assessed at the aggregated global and national levels, while adaptation is local. When present, regionalised assessments are confined to direct damages, hindered by both data and models' limitations. This article goes beyond the aggregated analysis to explore direct and indirect economic consequences of sea level rise (SLR) at regional and sectoral levels in Europe. Using a dynamic computable general equilibrium model and novel datasets, we estimate the distribution of losses and gains across regions and sectors. A comparison of a high-end scenario against a no-climate-impact baseline suggests a GDP loss of 1.26% (€871.8 billion) for the whole EU&UK. Conversely our refined assessments show that some coastal regions lose 9.56–20.84% of GDP, revealing striking regional disparities. Inland regions grow due to the displaced demand from coastal areas, but the GDP gains are small (0–1.13%). While recovery benefits the construction sector, public services and industry face significant downturns. We show that prioritising recovery of critical sectors locally reduces massive regional GDP losses, at negligible costs to the overall European economy. Our analysis traces regional economic restructuring triggered by SLR, underscoring the necessity of region-specific adaptation policies that embrace uneven geographic impacts and unique sectoral profiles to inform resilient strategy design. [ABSTRACT FROM AUTHOR]

BACKGROUND: The three-ringed polycyclic aromatic hydrocarbon (PAH) phenanthrene (Phe) has been implicated in the cardiotoxicity of petroleum based pollution in aquatic systems, where it disrupts the contractile and electrical function of the fish heart. Phe is also found adsorbed to particulate matter and in the gas phase of air pollution, but to date, no studies have investigated the impact of Phe on mammalian cardiac function. OBJECTIVES: Our objectives were to determine the arrhythmogenic potential of acute Phe exposure on mammalian cardiac function and define the underlying mechanisms to provide insight into the toxicity risk to humans. METHODS: Ex vivo Langendorff-perfused mouse hearts were used to test the arrhythmogenic potential of Phe on myocardial function, and voltage and current-clamp recordings were used to define underlying cellular mechanisms in isolated cardiomyocytes. RESULTS: Mouse hearts exposed to ∼8 μM Phe for 15-min exhibited a significantly slower heart rate (푝=0.0006, 푁 =10 hearts), a prolonged PR interval (푝=0.036, 푁 =8 hearts), and a slower conduction velocity (푝=0.0143, 푁 =7 hearts). Whole-cell recordings from isolated cardiomyocytes revealed action potential (AP) duration prolongation (at 80% repolarization; 푝=0.0408, 푛=9 cells) and inhibition of key murine repolarizing currents- transient outward potassium current (I[sub to]) and ultrarapid potassium current (I[sub Kur])-following Phe exposure. A significant reduction in AP upstroke velocity (푝=0.0445, 푛=9 cells) and inhibition of the fast sodium current (I[sub Na]; 푝=0.001, 푛=8 cells) and calcium current (I[sub Ca]; 푝=0.0001) were also observed, explaining the slowed conduction velocity in intact hearts. Finally, acute exposure to ∼8 μM Phe significantly increased susceptibility to arrhythmias (푝=0.0455, 푁 =9 hearts). DISCUSSION: To the best of our knowledge, this is the first evidence of direct inhibitory effects of Phe on mammalian cardiac electrical activity at both the whole-heart and cell levels. This electrical dysfunction manifested as an increase in arrhythmia susceptibility due to impairment of both conduction and repolarization. Similar effects in humans could have serious health consequences, warranting greater regulatory attention and toxicological investigation into this ubiquitous PAH pollutant generated from fossil-fuel combustion. [ABSTRACT FROM AUTHOR]

Despite the growing calls to integrate realistic human behavior in sustainability science models, the representative rational agent prevails. This is especially problematic for climate change adaptation that relies on actions at various scales: from governments to individuals. Empirical evidence on individual adaptation to climate-induced hazards reveals diverse behavioral and social factors affecting economic considerations. Yet, implications of replacing the rational optimizer by realistic human behavior in nature-society systems models are poorly understood. Using an innovative evolutionary economic agent-based model we explore different framings regarding household adaptation behavior to floods, leveraging on behavioral data from a household survey in Miami, USA. We find that a representative rational agent significantly overestimates household adaptation diffusion and underestimates damages compared to boundedly rational behavior revealed from our survey. This "adaptation deficit" exhibited by a population of empirically informed agents is explained primarily by diverse "soft" adaptation constraints--awareness, social influences--rather than heterogeneity in financial constraints. Besides initial inequality disproportionally impacting low/medium adaptive capacity households post-flood, our findings suggest that even under a nearly complete adaptation diffusion, adaptation benefits are uneven, with late or less-efficient actions locking households to a path of higher damages, further exacerbating inequalities. Our exploratory modeling reveals that behavioral assumptions shape the uncertainty of physical factors, like exposure and objective effectiveness of flood-proofing measures, traditionally considered crucial in risk assessments. This unique combination of methods facilitates the assessment of cumulative and distributional effects of boundedly rational behavior essential for designing tailored climate adaptation policies, and for equitable sustainability transitions in general. [ABSTRACT FROM AUTHOR]

This assessment of the financial performance of PJSC Gazprom was carried out within the framework of modern theories of the cost of capital and capital structure: the Brusov–Filatova–Orekhova (BFO) theory and the Modigliani–Miller (MM) theory. Various methods for estimating the main parameter of both theories (BFO and MM), k0, the cost of equity, and WACC at zero leverage are discussed and applied. The analysis is based on data from official financial statements of PJSC Gazprom for the period from 2018 to 2022. Using the calculated values of k0, the main financial indicators were estimated, such as the cost of raising capital, the value of the company, and the cost of equity. The dependences of k0, k 0 * , WACC(L), V(L), and ke(L) of PJSC Gazprom on leverage level, L, for 2018–2022 were investigated. The results obtained are of forecast value, allowing a forecast of the values of financial indicators based on the particular capital structure of PJSC Gazprom. [ABSTRACT FROM AUTHOR]

Two modifications of a modern theory of capital structure—the Brusov–Filatova–Orekhova (BFO) theory—with variable income are considered: (1) with the income tax payments at the end of periods and (2) with advance income tax payments. BFO formulas for the WACC, and for company capitalization, V, were derived for these two cases. Using the obtained formulas, the dependence of the weighted average cost of capital, WACC; the discount rate; WACC–g (here, g, is the growth rate); company value, V; and the equity cost, ke, on the leverage level, L, at different values of g, at different values of the debt capital cost, kd, and at different values of company age, n, were studied. Comparing the results for cases (1) and (2) shows that case (2) is always preferable for both the company and the regulator. Recommendations have been developed for both parties to expand the practice of advance income tax payments. The managerial implications are as follows. Companies may choose to pay income tax either in advance or at the end of the reporting period in accordance with current results and tax laws. The developed methodology makes it possible to study companies with growing profits and companies with falling profits, which is very important in practice. It also allows the study of companies for which profits could rise and fall in different periods. [ABSTRACT FROM AUTHOR]

Ambitious climate mitigation policies face social and political resistance. One reason is that existing policies insufficiently capture the diversity of relevant insights from the social sciences about potential policy outcomes. We argue that agent‐based models can serve as a powerful tool for integration of elements from different disciplines. Having such a common platform will enable a more complete assessment of climate policies, in terms of criteria like effectiveness, equity and public support. This article is categorized under:Climate Models and Modeling > Knowledge Generation with ModelsThe Carbon Economy and Climate Mitigation > Policies, Instruments, Lifestyles, BehaviorPolicy and Governance > Multilevel and Transnational Climate Change Governance [ABSTRACT FROM AUTHOR]

Climate change effects are not uniform and have disproportionate impacts among different groups of people within communities. It is therefore important to understand the underlying issues of intersectionality for climate change adaptation and human well-being. This paper aims to measure human capabilities and freedom of choice by analyzing perceived climate change impacts and current climate change adaptation ability among ethnic and non-ethnic communities in Bangladesh. This study applies a range of participatory rural appraisal tools and key informant interviews to assess impacts of climate change when considering gender and ethnicity. Women in the coastal regions have less access to resources and services because of social capital and cultural practices and this directly or indirectly influences their adaptation to climate change. Women have limited or no participation in decision-making processes at family or community levels and this impacts their vulnerability and well-being. In consequence, women's capabilities must be focused on moderating their vulnerability and risk, and developing effective adaptation to the adverse impacts of climate change and natural hazards. [ABSTRACT FROM AUTHOR]

The purpose of this review is to analyze all existing theories of the capital structure (with their advantages and disadvantages) in order to understand all aspects of the problem and make correct management decisions in practice. The role of the capital structure is that the correct determination of the optimal capital structure allows the company's management to maximize the capitalization of the company and the long-term goal of the function of any company. The review examines the state of the capital structure and capital cost theory from the middle of the last century, when the first quantitative theory was created, to the present. The two main theories, Modigliani–Miller (MM) and Brusov–Filatova–Orekhova (BFO), are discussed and analyzed, as well as their numerous modifications and generalizations. Additionally, discussed is the latest stage in the development of the theory of capital structure, which began a couple of years ago and is associated with the adaptation of the two main theories of capital structure (Brusov–Filatova–Orekhova and Modigliani–Miller) to establish the practice of the function of companies. This generalization takes into account the real conditions of the work of the companies. It was noted that taking into account some effects that are present in economic practice (such as variable income, frequent payments of tax on income, advance payments of tax on income, etc.) brings both theories closer, and even the Modigliani–Miller theory, with all its many limitations, becomes more applicable in economic practice. However, it should be remembered that the Modigliani–Miller theory is only true for perpetual companies, while the BFO theory is valid for companies of any age, and from this point of view, they never coincide. [ABSTRACT FROM AUTHOR]

As climate change increases the probability and severity of natural hazards, the need for coordinated adaptation at all levels of society intensifies. Governmental‐level adaptation measures are essential, but insufficient in the face of growing risks, necessitating complementary action from households. Apprehending the drivers of household adaptation is critical if governments are to stimulate protective behavior effectively. While past work has focused on the behavioral drivers of household adaptation, little attention has been paid to understanding the relationships between adaptation measures themselves—both previously undergone and additionally (planned) intended adaptation(s). Using survey data (N = 4,688) from four countries—the United States, China, Indonesia, and the Netherlands—we utilize protection motivation theory to account for the behavioral drivers of household adaptation to the most devastating climate‐driven hazard: flooding. We analyze how past and additionally intended adaptations involving structural modification to one's home affect household behavior. We find that both prior adaptations and additionally intended adaptation have a positive effect on intending a specific adaptation. Further, we note that once links between adaptations are accounted for, the effect that worry has on motivating specific actions, substantially lessens. This suggests that while threat appraisal is important in initially determining if households intend to adapt, it is households' adaptive capacity that determines how. Our analysis reveals that household structural modifications may be nonmarginal. This could indicate that past action and intention to pursue one action trigger intentions for other adaptations, a finding with implications for estimating the speed and scope of household adaptation diffusion. [ABSTRACT FROM AUTHOR]

The development of interatrial septum (IAS) is a complicated process, which continues during postnatal life. The hypertrophic signals in developing heart are mediated among others by α-adrenergic pathways. These facts suggest the presence of specific electrophysiological features in developing IAS. This study was aimed to investigate the electrical activity in the tissue preparations of IAS from rat heart in normal conditions and under stimulation of adrenoreceptors. Intracellular recording of electrical activity revealed less negative level of resting membrane potential in IAS if compared to myocardium of left atrium. In normal conditions, non-paced IAS preparations were quiescent, but noradrenaline (10−5 M) and phenylephrine (10−5 M) induced spontaneous action potentials, which could be abolished by α1-blocker prazosin (10−5 M), but not β1-blocker atenolol (10−5 M). Optical mapping showed drastic phenylephrine-induced slowing of conduction in adult rat IAS. The α1-dependent ectopic automaticity of IAS myocardium might be explained by immunohistochemical data indicating the presence of transcription factor GATA4 and abundant α1A-adrenoreceptors in myocytes from adult rat IAS. An elevated sensitivity to adrenergic stimulation due to involvement of α1-adrenergic pathways may underlie increased proarrhythmic potential of adult IAS at least in rats. [ABSTRACT FROM AUTHOR]

To expand the applicability in practice of the modern theory of cost and capital structure, the theory of Brusov–Filatova–Orekhova (BFO), which is valid for companies of arbitrary age, is generalized for the case of variable income. The generalized theory of capital structure can be successfully applied in corporate finance, business valuation, banking, investments, ratings, etc. income. A generalized Brusov–Filatova–Orekhova formula for the weighted average cost of capital, WACC, is derived using a formula in MS Excel, where the role of the discount rate shifts from WACC to WACC–g (here g is the growth rate) for financially dependent companies and k0–g for financially independent companies is shown. A decrease in the real discount rates of WACC–g and k0–g with g ensures an increase in the company's capitalization with g. The tilt of the equity cost curve, ke(L), increases with g. Since the cost of equity justifies the amount of dividends, this should change the dividend policy of the company. It turns out that for the growth rate g < g*, the tilt of the curve ke(L) becomes negative. This qualitatively new effect, discovered here for the first time, can significantly change the principles of the dividend policy of the company. The obtained results are compared with the results of the MM theory with variable income. [ABSTRACT FROM AUTHOR]

Human beings are an active component of every terrestrial ecosystem on Earth. Although our local impact on the evolution of these ecosystems has been undeniable and extensively documented, it remains unclear precisely how our activities are altering them, in part because ecosystems are dynamic systems structured by complex, non-linear feedback processes and cascading effects. We argue that it is only by studying human–environment interactions over timescales that greatly exceed the lifespan of any individual human (i.e., the deep past or longue durée), we can hope to fully understand such processes and their implications. In this article, we identify some of the key challenges faced in integrating long-term datasets with those of other areas of sustainability science, and suggest some useful ways forward. Specifically, we (a) highlight the potential of the historical sciences for sustainability science, (b) stress the need to integrate theoretical frameworks wherein humans are seen as inherently entangled with the environment, and (c) propose formal computational modelling as the ideal platform to overcome the challenges of transdisciplinary work across large, and multiple, geographical and temporal scales. Our goal is to provide a manifesto for an integrated scientific approach to the study of socio-ecological systems over the long term. [ABSTRACT FROM AUTHOR]

In practice, profit tax payments are (1) made more frequently than annually and (2) can be made in advance. To study the influence of these two factors on the financial indicators of a company, we generalized the Brusov–Filatova–Orekhova (BFO) theory for the case of advance profit tax payments with an arbitrary frequency for the first time. Using modified BFO formulae, we showed that all financial indicators of a company, such as company value, the weighted average cost of capital (WACC) and equity cost (ke), depend on the frequency of the profit tax payments. We found that the WACC increased with the payments and the company value decreased with the payments. This meant that more infrequent payments could be beneficial for the company. The tilt angle of the equity cost (ke(L)) also increased with the payments. Depending on the age of the company, the equity cost either decreased with L for all payment frequencies or increased for some frequencies. We compared the obtained results to those that we described recently for profit tax payments at the end of the financial period and found them to be totally different. We found that in spite the fact that the WACC decreased with the payments and the company value increased with the payments, the WACC value in this case turned out to be bigger and the company value turned out to be smaller than in the case of advance profit tax payments of any frequency. This underlined the importance of advance profit tax payments. Regulator recommendations were also developed to encourage the practice of advance profit tax payments due to the understanding of the benefits of this for both parties: the companies and the state. A new effect was discovered: the decrease in equity cost with an increase in the level of leverage (L). [ABSTRACT FROM AUTHOR]

The modern capital cost and capital structure theory—the Brusov–Filatova–Orekhova (BFO) theory and its perpetuity limit, the Modigliani–Miller theory—describe the case of the payments of income tax at the end of the year. However, in practice, companies could make these payments in advance. Recently, the Modigliani–Miller theory has been modified for the case of advanced payments of income tax and has shown that the obtained results are quite different from ones in the "classical" Modigliani–Miller theory. In the current paper, for the first time, we modify the Brusov–Filatova–Orekhova (BFO) theory for the case of advanced payments of income tax and show that the impact of the transition to advance payments is much more significant than in the case of a perpetuity limit (the MM theory) and even leads to a qualitatively new effect in the dependence of equity cost on leverage. An important conclusion drawn in this paper is that the tax shield is very important, and the way it is formed (payments at the end of the year or in advance) leads to very important consequences, changing all the financial indicators of the company, such as the cost of raising capital and company value and radically changing the company's dividend policy. [ABSTRACT FROM AUTHOR]

Both main theories of capital cost and capital structure—the Brusov–Filatova–Orekhova (BFO) theory and its perpetuity limit, the Modigliani–Miller theory—consider the payments of tax on profit once per year, while in real economy these payments are made more frequently (semi-annual, quarterly, monthly etc.). Recently the Modigliani–Miller theory has been generalized by us for the case of tax on profit payments with an arbitrary frequency. Here for the first time, we generalized the Brusov–Filatova–Orekhova (BFO) theory for this case. The main purpose of the paper is bringing the BFO theory closer to economic practice, taking into account one of the features of the real functioning of companies, the frequent payments of tax on profit. We derive modified BFO formulas and show that: (1) All BFO formulas change; (2) all main financial parameters of the company, such as company value, V, equity cost, ke, and the weighted average cost of capital, WACC, depend on the tax on profit payments frequency. The increase of the frequency of payments of income tax leads to a decrease in the cost of attracting capital, WACC, and increase in the capitalization of the company, V. At a certain age n of the company and at certain frequency of tax on profit payments p, a qualitatively new anomalous effect takes place: the equity cost, ke(L), decreases with an increase in the level of leverage L. This radically changes the company′s dividend policy, since the economically justified amount of the dividends is equal to the cost of equity. For both parties–for the company and for the tax regulator more frequent payments of tax on profit are beneficial: for the company, because this increases the company capitalization, and for the tax regulator, because earlier payments are beneficial for it due to the time value of money. [ABSTRACT FROM AUTHOR]

The mechanoelectrical feedback (MEF) mechanism in the heart that plays a significant role in the occurrence of arrhythmias, involves cation flux through cation nonselective stretch‐activated channels (SACs). It is well known that nitric oxide (NO) can act as a regulator of MEF. Here we addressed the possibility of SAC's regulation along NO‐dependent and NO‐independent pathways, as well as the possibility of S‐nitrosylation of SACs. In freshly isolated rat ventricular cardiomyocytes, using the patch‐clamp method in whole‐cell configuration, inward nonselective stretch‐activated cation current ISAC was recorded through SACs, which occurs during dosed cell stretching. NO donor SNAP, α1‐subunit of sGC activator BAY41‐2272, sGC blocker ODQ, PKG blocker KT5823, PKG activator 8Br‐cGMP, and S‐nitrosylation blocker ascorbic acid, were employed. We concluded that the physiological concentration of NO in the cell is a necessary condition for the functioning of SACs. An increase in NO due to SNAP in an unstretched cell causes the appearance of a Gd3+‐sensitive nonselective cation current, an analog of ISAC, while in a stretched cell it eliminates ISAC. The NO‐independent pathway of sGC activation of α subunit, triggered by BAY41‐2272, is also important for the regulation of SACs. Since S‐nitrosylation inhibitor completely abolishes ISAC, this mechanism occurs. The application of BAY41‐2272 cannot induce ISAC in a nonstretched cell; however, the addition of SNAP on its background activates SACs, rather due to S‐nitrosylation. ODQ eliminates ISAC, but SNAP added on the background of stretch increases ISAC in addition to ODQ. This may be a result of the lack of NO as a result of inhibition of NOS by metabolically modified ODQ. KT5823 reduces PKG activity and reduces SACs phosphorylation, leading to an increase in ISAC. 8Br‐cGMP reduces ISAC by activating PKG and its phosphorylation. These results demonstrate a significant contribution of S‐nitrosylation to the regulation of SACs. [ABSTRACT FROM AUTHOR]

Aim: This study is aimed at investigation of electrophysiological effects of α1‐adrenoreceptor (α1‐AR) stimulation in the rat superior vena cava (SVC) myocardium, which is one of the sources of proarrhythmic activity. Methods: α1‐ARs agonists (phenylephrine—PHE or norepinephrine in presence of atenolol—NE + ATL) were applied to SVC and atrial tissue preparations or isolated cardiomyocytes, which were examined using optical mapping, glass microelectrodes or whole‐cell patch clamp. α1‐ARs distribution was evaluated using immunofluorescence. Kir2.X mRNA and protein level were estimated using RT‐PCR and Western blotting. Results: PHE or NE + ATL application caused a significant suppression of the conduction velocity (CV) of excitation and inexcitability in SVC, an increase in the duration of electrically evoked action potentials (APs), a decrease in the maximum upstroke velocity (dV/dtmax) and depolarization of the resting membrane potential (RMP) in SVC to a greater extent than in atria. The effects induced by α1‐ARs activation in SVC were attenuated by protein kinase C inhibition (PKC). The whole‐cell patch clamp revealed PHE‐induced suppression of outward component of IK1 inward rectifier current in isolated SVC, but not atrial myocytes. These effects can be mediated by α1A subtype of α‐ARs found in abundance in rat SVC. The basal IK1 level in SVC was much lower than in atria as a result of the weaker expression of Kir2.2 channels. Conclusion: Therefore, the reduced density of IK1 in rat SVC cardiomyocytes and sensitivity of this current to α1A‐AR stimulation via PKC‐dependent pathways might lead to proarrhythmic conduction in SVC myocardium by inducing RMP depolarization, AP prolongation, CV and dV/dtmax decrease. [ABSTRACT FROM AUTHOR]

The twofold aim of this paper is to provide an overview of the current state of resilience research with regard to climate change in the social sciences and propose a research agenda. Resilience research among social scientists is characterized by much more diversity today than a few decades ago. Different definitions and understandings of resilience appear in publications during the last 10 years. Resilience research increasingly bears the mark of social constructivism, a relative newcomer compared to the more long-standing tradition of naturalism. There are also approaches that are indebted to both "naturalism" and "constructivism", which, of course, come in many varieties. Based on our overview of recent scholarship, which is far from being exhaustive, we have identified six research avenues that arguably deserve continued attention. They combine naturalist and constructivist insights and approaches so that human agency, reflexivity, and considerations of justice and equity are incorporated into systems thinking research or supplement such research. Ultimately, we believe that the overarching challenge for future research is to ensure that resilience to climate change does not compromise sustainability and considerations of justice (including environmental, climate, and energy justice). [ABSTRACT FROM AUTHOR]

Small G-proteins of Rho family modulate the activity of several classes of ion channels, including K+ channels Kv1.2, Kir2.1, and ERG; Ca2+ channels; and epithelial Na+ channels. The present study was aimed to check the RhoA potential regulatory effects on Na+ current (INa) transferred by Na+ channel cardiac isoform NaV1.5 in heterologous expression system and in native rat cardiomyocytes. Whole-cell patch-clamp experiments showed that coexpression of NaV1.5 with the wild-type RhoA in CHO-K1 cell line caused 2.7-fold decrease of INa density with minimal influence on steady-state activation and inactivation. This effect was reproduced by the coexpression with a constitutively active RhoA, but not with a dominant negative RhoA. In isolated ventricular rat cardiomyocytes, a 5-h incubation with the RhoA activator narciclasine (5 × 10−6 M) reduced the maximal INa density by 38.8%. The RhoA-selective inhibitor rhosin (10−5 M) increased the maximal INa density by 25.3%. Experiments with sharp microelectrode recordings in isolated right ventricular wall preparations showed that 5 × 10−6 M narciclasine induced a significant reduction of action potential upstroke velocity after 2 h of incubation. Thus, RhoA might be considered as a potential negative regulator of sodium channels cardiac isoform NaV1.5. [ABSTRACT FROM AUTHOR]

Recent advances in fluorescence microscopy have made it possible to measure the fluctuations of nascent (actively transcribed) RNA. These closely reflect transcription kinetics, as opposed to conventional measurements of mature (cellular) RNA, whose kinetics is affected by additional processes downstream of transcription. Here, we formulate a stochastic model which describes promoter switching, initiation, elongation, premature detachment, pausing, and termination while being analytically tractable. We derive exact closed-form expressions for the mean and variance of nascent RNA fluctuations on gene segments, as well as of total nascent RNA on a gene. We also obtain exact expressions for the first two moments of mature RNA fluctuations and approximate distributions for total numbers of nascent and mature RNA. Our results, which are verified by stochastic simulation, uncover the explicit dependence of the statistics of both types of RNA on transcriptional parameters and potentially provide a means to estimate parameter values from experimental data. [ABSTRACT FROM AUTHOR]

Adaptation is an essential part of climate change policy. In areas where impacts are likely to be severe, migration is considered to be an adaptation option. In Bangladesh coastal areas migration due to climate change is contingent on people's freedom of choice at individual and household level. Following Amartya Sen's capability approach, we argue that there should be a line drawn between migrations by free choice versus forced migration. Sen's capability approach focuses on the importance of people's freedom of choice to act, and the ability to achieve what they consider valuable in their life. In this paper, we use an extensive empirical work engaging 22 focus groups discussions (8–12 individuals in each group) and 14 Key Informants Interviews in South-West Bangladesh to elicit how freedom of choice changes with the economic class and social status of an individual. Using these data we apply Sen's capability approach to understand the role of the freedom of choice when considering migration as an adaptation option. We argue that the capability approach is essential in revealing a thin border between migration as a (planned) adaptation option and forced migration. [ABSTRACT FROM AUTHOR]

Since the 1970s, Holling's socio-ecological systems (SES) approach has been a most predominant theoretical force in resilience research in the context of the climate crisis. From Holling's approach, however, two contrasting scientific approaches to resilience have developed, namely, naturalism and constructivism. While naturalist resilience research takes SES as complex systems marked by non-linearity and evolutionary changes, constructivist resilience research focuses on the embeddedness of SES in heterogenous contexts. In naturalist resilience research resilience is defined as a system property, while in constructivist resilience research resilience is politically loaded and historically contingent. The aim of this paper is to review and structure current developments in resilience research in the field of climate change studies, in terms of the approaches, definitions, models and commitments that are typical for naturalism and constructivism; identify the key tension between naturalist and constructivist resilience research in terms of the widely discussed issue of adaptation and transformation, and discuss its implications for sustainable development; and propose a research agenda of topics distilled from the adaptation-transformation tension between naturalist and constructivist resilience research. [ABSTRACT FROM AUTHOR]

In the last decade, instigated by the Paris agreement and United Nations Climate Change Conferences (COP22 and COP23), the efforts to limit temperature increase to 1.5 °C above pre-industrial levels are expanding. The required reductions in greenhouse gas emissions imply a massive decarbonization worldwide with much involvement of regions, cities, businesses, and individuals in addition to the commitments at the national levels. Improving end-use efficiency is emphasized in previous IPCC reports (IPCC 2014). Serving as the primary 'agents of change' in the transformative process towards green economies, households have a key role in global emission reduction. Individual actions, especially when amplified through social dynamics, shape green energy demand and affect investments in new energy technologies that collectively can curb regional and national emissions. However, most energy-economics models—usually based on equilibrium and optimization assumptions—have a very limited representation of household heterogeneity and treat households as purely rational economic actors. This paper illustrates how computational social science models can complement traditional models by addressing this limitation. We demonstrate the usefulness of behaviorally rich agent-based computational models by simulating various behavioral and climate scenarios for residential electricity demand and compare them with the business as usual (SSP2) scenario. Our results show that residential energy demand is strongly linked to personal and social norms. Empirical evidence from surveys reveals that social norms have an essential role in shaping personal norms. When assessing the cumulative impacts of these behavioral processes, we quantify individual and combined effects of social dynamics and of carbon pricing on individual energy efficiency and on the aggregated regional energy demand and emissions. The intensity of social interactions and learning plays an equally important role for the uptake of green technologies as economic considerations, and therefore in addition to carbon-price policies (top-down approach), implementing policies on education, social and cultural practices can significantly reduce residential carbon emissions. [ABSTRACT FROM AUTHOR]

Modern societies are exposed to a myriad of risks ranging from disease to natural hazards and technological disruptions. Exploring how the awareness of risk spreads and how it triggers a diffusion of coping strategies is prominent in the research agenda of various domains. It requires a deep understanding of how individuals perceive risks and communicate about the effectiveness of protective measures, highlighting learning and social interaction as the core mechanisms driving such processes. Methodological approaches that range from purely physics-based diffusion models to data-driven environmental methods rely on agent-based modeling to accommodate context-dependent learning and social interactions in a diffusion process. Mixing agent-based modeling with data-driven machine learning has become popularity. However, little attention has been paid to the role of intelligent learning in risk appraisal and protective decisions, whether used in an individual or a collective process. The differences between collective learning and individual learning have not been sufficiently explored in diffusion modeling in general and in agent-based models of socio-environmental systems in particular. To address this research gap, we explored the implications of intelligent learning on the gradient from individual to collective learning, using an agent-based model enhanced by machine learning. Our simulation experiments showed that individual intelligent judgement about risks and the selection of coping strategies by groups with majority votes were outperformed by leader-based groups and even individuals deciding alone. Social interactions appeared essential for both individual learning and group learning. The choice of how to represent social learning in an agent-based model could be driven by existing cultural and social norms prevalent in a modeled society. [ABSTRACT FROM AUTHOR]

Federally regulated or insured lenders in the United States are mandated to require flood insurance on properties that are located in areas at high risk of flooding. Despite the existence of this mandatory flood insurance requirement, take‐up rates for flood insurance have been low, and the federal government's exposure to uninsured property losses from flooding remains substantial. Meanwhile, the value of capital at risk varies significantly with flood events and changing risk perceptions, which necessitates mechanisms that stabilize these dynamics. In this article we discuss how a scenario of complete insurance uptake, under various risk attitudes, affects the value of properties in the 100‐year and 500‐year flood zones. Our results indicate that an increase in flood insurance uptake may provide such a mechanism by lowering the value of capital at risk in the flood zone consistently, independent of homeowners' risk attitudes. We apply an empirical adaptive agent‐based model to examine the capitalization of insurance costs, risk premiums, and their interaction in housing prices. Our approach combines widely‐used empirical hedonic analysis with the computational economic framework. We highlight the usefulness of our method in capturing the marginal implicit price of homeowners' preferences that may change over time and separately assess the effect of various factors and policies on property values, illustrating the agent‐based modeling as a valuable complement to traditional hedonic analysis. [ABSTRACT FROM AUTHOR]

Machine learning (ML) algorithms steer agent decisions in agent-based models (ABMs), serving as a vehicle for implementing behaviour changes during simulation runs. However, when training an ML algorithm, obtaining large sets of micro-level human behaviour data is often problematic. Information on human behaviour is often collected via surveys of relatively small sample sizes. This paper presents a methodology for training a learning algorithm to guide agent behaviour in a spatial ABM using a limited survey data sample. We apply different implementation strategies using survey data and Bayesian networks (BNs). By being grounded in probabilistic directed graphical models, BNs stand out among other learning algorithms in that they can be based on expert knowledge and/or known datasets. This paper presents four alternative implementations of data-driven BNs to support agent decisions in a spatial ABM. We differentiate between training BNs prior to, or during the simulation runs, using only survey data or a combination of survey data and expert knowledge. The four different implementations are then illustrated using a spatial ABM of cholera diffusion for Kumasi, Ghana. The results indicate that a balance between expert knowledge and survey data provides the best control over the learning process of the agents and produces the most realistic agent behaviour. [ABSTRACT FROM AUTHOR]

The following study examined the impact of IL-2 on Ca2+ channel activity in the event of several hours' incubation in IL-2. The right ventricle free wall for action potential measurements was isolated and perfused with Tyrode solution. The whole-cell voltage clamp experiments were performed on enzymatically isolated single cardiomyocytes. The whole-cell voltage clamp recording of Ca2+ currents was performed using the Cs+-based pipette and bath solutions. The protocol with depolarizing prepulse (− 40 mV) was used to inactivate both Na+ current and Ca2+T-type current. The L-type Ca2+ current was elicited by a series of 250 ms depolarizing square pulses with 10 mV increments. At the 15th minute of continuous recording, the peak density at 0 mV was − 3.036 ± 0.3015 pA/pF under IL-2 and − 3.008 ± 0.3452 pA/pF in control conditions. The IL-2 in moderate concentration (1 ng/mL) has no acute effects on ICa.L in rat ventricular cells. In contrast, to the lack of acute effects, the long-term incubation with IL-2 (2 h or more) produced a prominent enhancement of Ca2+L-type current. In rat, ventricular myocardium IL-2 (1 ng/mL) produced a very gradual prolongation of subendocardial APs which reached a maximal extent after 3-4 h of treatment. The patch clamp study shows an IL-2-induced ICa.L current activation, while the action potential studies on multicellular ventricular preparations suggest an IL-2-induced L-type Ca2+ channel participation in the development of AP. [ABSTRACT FROM AUTHOR]

The purpose of this study was to examine the effects of interferon-γ (IFN-γ) on calcium movement in rat ventricular myocytes. L-type Ca2+ currents (ICa,L) were recorded with the whole-cell configuration of the patch-clamp techniques. IFN-γ induces current density reduction at the test potential of 0 mV by 47.6 ± 7.4%. Heparin, a selective inhibitor of inositol-1,4,5-triphosphate (IP3)-induced Ca2+ release, applied via a patch pipette, induced an ICa,L amplitude decrease of about 46 ± 5.6%. The addition of IFN-γ to heparin-treated cells has no effect on ICa,L. Ryanodine induced an ICa,L current amplitude decrease of 35.1 ± 6.2%. The addition of IFN-γ to ryanodine-treated cells caused an additional ICa,L inhibiting of 17.6 ± 4.8%. Both cyclopiazonic acid (CPA), a specific SERCA inhibitor, and a combination of CPA and ryanodine caused a significant reduction of the ICa,L amplitudes. Subsequent addition of IFN-γ inhibited ICa,L for an additional 16.3 ± 4.4%. The employment of chelerythrine in this study prevented IFN-γ-induced L-type Ca2+ channel inhibition in only 10 min from the start of perfusion. Proposed mechanisms of regulation involved IFN-γ-induced IP3-sensitive Ca2+ release probably by a Ca2+-dependent translocation of PKC from the cytoplasm to the cell membrane as the obligatory first step of the IFN-γ-induced PKC-dependent L-type Ca2+ channel inhibition. [ABSTRACT FROM AUTHOR]

The immunological profiles of human specific IgE (sIgE) and specific IgG4 (sIgG4) vary by genetic predisposition, living conditions in different geographical locations and patient’s age. The aim of our study was to analyze sIgE and sIgG4 patterns and their age-dependent changes in patients from the Moscow region. For identifying sIgE and sIgG4 profiles the blood samples from 513 patients aged 6 months to 17 years who were showing symptoms of allergic diseases were analyzed using microarrays containing 31 allergens. The highest sIgE prevalence was observed for birch pollen (32%) among pollen allergens, cat dander (24%) among indoor allergens, and egg whites (21%) among food allergens. The most common sIgG4 response was developed toward egg whites (80% of patients). Age-related elevation was identified for patients with increased sIgE to pollen allergens and indoor allergens (cat or dog dander and house dust mites). For each allergen, the proportion of cases with significant levels of sIgG4 appeared to increase with patients’ age. The data on allergen-specific sIgE and sIgG4 prevalence show both general trends and some local special aspects that are indicative for the Moscow region. This information should be useful in terms of epidemiology of allergic diseases. [ABSTRACT FROM AUTHOR]

The complexity of quantifying ecosystem services in monetary terms has long been a challenging issue for economists and ecologists. Many case specific valuation studies have been carried out in various parts of theWorld. Yet, a coherent review on the valuation of coastal ecosystem services (CES), which systematically describes fundamental concepts, analyzes reported applications, and addresses the issue of climate change (CC) impacts on the monetary value of CES is still lacking. Here, we take a step towards addressing this knowledge gap by pursuing a coherent review that aims to provide policy makers and researchers in multidisciplinary teams with a summary of the state-of-the-art and a guideline on the process of economic valuation of CES and potential changes in these values due to CC impacts. The article highlights the main concepts of CES valuation studies and offers a systematic analysis of the best practices by analyzing two global scale and 30 selected local and regional case studies, in which different CES have been valued. Our analysis shows that coral reefs and mangroves are among the most frequently valued ecosystems, while sea-grass beds are the least considered ones. Currently, tourism and recreation services as well as storm protection are two of the most considered services representing higher estimated value than other CES. In terms of the valuation techniques used, avoided damage, replacement and substitute cost method as well as stated preference method are among the most commonly used valuation techniques. Following the above analysis, we propose a methodological framework that provides step-wise guidance and better insight into the linkages between climate change impacts and the monetary value of CES. This highlights two main types of CC impacts on CES: one being the climate regulation services of coastal ecosystems, and the other being the monetary value of services, which is subject to substantial uncertainty. Finally, a systematic four-step approach is proposed to effectively monetize potential CC driven variations in the value of CES. [ABSTRACT FROM AUTHOR]

Property prices are affected by changing market conditions, incomes and preferences of people. Price trends in natural hazard zones may shift significantly and abruptly after a disaster signalling structural systemic changes in property markets. It challenges accurate market assessments of property prices and capital at risk after major disasters. A rigorous prediction of property prices in this case should ideally be done based only on the most recent sales, which are likely to form a rather small dataset. Hedonic analysis has been long used to understand how various factors contribute to the housing price formation. Yet, the robustness of its assessment is undermined when the analysis needs to be performed on relatively small samples. The purpose of this study is to suggest a model that can be widely applicable and quickly calibrated in a changing environment. We systematically study four statistical models: starting from a typical standard hedonic function and gradually changing its functional specification by reducing the hedonic analysis to some basic property characteristics and applying kriging to control for neighbourhood effects. Across different sample sizes we find that the latter performs consistently better in the out-of-sample predictions than other traditional price prediction methods. We present the specific improvements to the traditional spatial hedonic model that enhance the model’s prediction accuracy. The improved model can be used to monitor price changes in risk-prone areas, accounting for changes in flood risk and at the same time controlling for autonomous market responses to flood risk. [ABSTRACT FROM AUTHOR]

Human migration is increasingly seen as a promising climate change adaptation and flood risk reduction strategy. The purpose of this paper is to investigate how spatial differences in flood risk, due to differences in flood protection, reduce the mobility of vulnerable households through a credit constraint mechanism. Using an equilibrium model with two households types and endogenous sorting, we show how spatial differences in flood protection lead to clustering of vulnerable households in a risky region, in a real-world setting of common United States (US) flood zones. We find clustering effects of some size for flood zones with return periods of less than 30 years. [ABSTRACT FROM AUTHOR]

Diadenosine pentaphosphate (Ap5A) belongs to the family of diadenosine polyphosphates, endogenously produced compounds that affect vascular tone and cardiac performance when released from platelets. The previous findings indicate that Ap5A shortens action potentials (APs) in rat myocardium via activation of purine P2 receptors. The present study demonstrates alternative mechanism of Ap5A electrophysiological effects found in guinea pig myocardium. Ap5A (10 M) shortens APs in guinea pig working atrial myocardium and slows down pacemaker activity in the sinoatrial node. P1 receptors antagonist DPCPX (10 M) or selective GIRK channels blocker tertiapin (10 M) completely abolished all Ap5A effects, while P2 blocker PPADS (10 M) was ineffective. Patch-clamp experiments revealed potassium inward rectifier current activated by Ap5A in guinea pig atrial myocytes. The current was abolished by DPCPX or tertiapin and therefore was considered as potassium acetylcholine-dependent inward rectifier ( I ). Thus, unlike rat, in guinea pig atrium Ap5A produces activation of P1 receptors and subsequent opening of KACh channels leading to negative effects on cardiac electrical activity. [ABSTRACT FROM AUTHOR]

Electrophysiological effects produced by selective activation of M3 cholinoreceptors were studied in isolated left atrium preparations from rat using the standard sharp glass microelectrode technique. The stimulation of M3 receptors was obtained by application of muscarinic agonist pilocarpine (10 M) in the presence of selective M2 antagonist methoctramine (10 M). Stimulation of M3 receptors induced marked reduction of action potential duration by 14.4 ± 2.4% and 16.1 ± 2.5% of control duration measured at 50 and 90% of repolarization, respectively. This effect was completely abolished by selective M3 blocker 4-DAMP (10 M). In isolated myocytes obtained from the rat left atrium, similar pharmacological stimulation of M3 receptors led to suppression of peak L-type calcium current by 13.9 ± 2.6% of control amplitude (measured at +10 mV), but failed to affect K currents I , I , and I . In the absence of M2 blocker methoctramine, pilocarpine (10 M) produced stronger attenuation of I and induced an increase in I . This additive inward rectifier current could be abolished by highly selective blocker of K3.1/3.4 channels tertiapin-Q (10 M) and therefore was identified as I . Thus, in the rat atrial myocardium activation of M3 receptors leads to shortening of action potentials via suppression of I , but does not enhance the major potassium currents involved in repolarization. Joint stimulation of M2 and M3 receptors produces stronger action potential shortening due to M2-mediated activation of I [ABSTRACT FROM AUTHOR]