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Uncovering the trade-offs and synergy relationship of multiple ecosystem services (ESs) is important for scientific ecosystem management and the improvement of ecological service functions. In this study, we investigated the spatiotemporal changes of four typical ES types (i.e., water yield (WY), carbon storage (CS), soil conservation (SC), and habitat quality (HQ)) from 2001 to 2020 in the Han River Basin (HRB). Meanwhile, the trade-offs and synergies between paired ESs and the socioecological drivers of these ESs were further explored. The results showed that grassland, cropland, and bare land decreased by 12,141.3 km2, 624.09 km2, and 22.1 km2 during the study period, respectively, which can be attributed to their conversion to forests in the HRB. Temporally, the WY, CS, and SC all showed a continuously increasing trend. Spatially, WY and HQ exhibited bipolar clustering characteristics, with WY exhibiting low-value clustering in the upstream and high-value clustering in the downstream, while CS showed the clustering characteristics of a scattered distribution of cold and hot spots from 2001 to 2020. The spatial patterns of aggregation locations in CS and HQ were relatively similar, with clusters of higher ES values mainly distributed in the western and central regions and clusters of lower ES values mainly located in the eastern and southeastern regions, while the aggregation of WY was spatially concentrated. Overall, the CS showed a significant positive correlation with HQ, but a significant negative correlation with WY. Spatially, WY and HQ, CS, and SC showed a substantial trade-off relationship in the northwest and southeast parts of the study area, while HQ, CS, and SC mainly exhibited a synergistic relationship in most parts of the study area. Slope and temperature had high influencing factor coefficients on multiple ESs; the mixed effect of terrain and natural factors was significantly greater than the impact of a single factor on ESs, and terrain factors played an essential role in the changes in ESs. The findings can provide technical and theoretical support for integrated scientific ecosystem management and sustainable development at the local scale. [ABSTRACT FROM AUTHOR]

The description of boiling and condensation phenomena presents a challenging problem. We propose a Lagrangian incompressible–compressible mesh-free particle method for modeling multiphase flows involving boiling and condensation. This multiphase scheme combines the moving particle semi-implicit method with the smoothed particle hydrodynamics method, while incorporating a phase transformation model based on heat transfer to simulate gas–liquid phase transformation. Gas volume expansion and shrinkage are accounted for through particle splitting and merging techniques. Numerical investigations demonstrate the effectiveness and accuracy of this multiphase method and phase transformation model, including simulations of multiphase dam-break flow, rising bubble, Stefan problem, and sucking problem. Our approach successfully simulates the boiling growth and condensing collapse of vapor bubbles, which is validated against numerical and experimental results. Stable and relatively accurate simulations can be achieved for bubble collapse processes under different water subcooling degrees, gas overheating degrees, surface tension values, and bubble sizes. The complex process of boiling before condensation can be accurately reproduced. [ABSTRACT FROM AUTHOR]

The present paper addresses the experimental modeling of process parameters in laser surface texturing (LST) of medical needles. First, experiments were carried out based on Taguchi methodology. The laser process parameters considered during LST were the circumferential overlap, axial overlap and the overscan number. A second-order regression model of the machined depth for LST was developed based on the experimental results. Second, a predictive model for the machined depth based on least squares support vector machines (LS-SVM) with radial basis functions was constructed using the same experimental swatches. Grid search and leave-one-out cross-validation were used to determine the optimal parameters of the LS-SVM model. The comparison between the second-order regression model and the LS-SVM model was carried out. The experiments indicated that the LS-SVM model is capable of better predictions of the machined depth than the second-order regression model. The validity of the LS-SVM model has been checked through the creation of micro-channels with blended edges. It was found that the predicted profile was in a good agreement with the experimental profiles. The LS-SVM model can be used to predict machined geometry of the micro-channels on medical needles. [ABSTRACT FROM AUTHOR]

The success of percutaneous procedures depends on the accuracy of the medical needle insertion. Reducing the insertion force and using better needle visualization during needle insertion can reduce needle placement errors. Surface texturing is frequently used to create micro-features on medical needle's tip portion to improve the visibility in ultrasound-guided percutaneous procedures. However, these micro-features usually increase the friction between the needle and tissue because of stress concentrations. This paper explores a method for creating micro-features with blended edges on echogenic needles and studies the friction behavior between textured echogenic needles and phantom tissue to identify blended texture patterns that would minimize the friction during needle insertion. Laser surface texturing was used to create regular micro-circumferential channels and micro-corner-cube-like dimples along the needle's axial direction. Variations of the overlap in the feed direction were used to blend the edges of micro-channels and micro-dimples with different fillet radii. Both needles with regular and blended surface textures were experimentally investigated through needle extraction experiments from phantom tissue. It was found that the blended textured needles with large fillet radii exhibit a much better friction behavior. [ABSTRACT FROM AUTHOR]

Pre-consolidated carbon fibre-reinforced polyphenylene sulphide (CF/PPS) laminates were thermoformed into V-shaped parts via designed out of autoclave thermoforming experiments. The different processing conditions tested in the experiment have resulted in final part angles whose differences ranged from 2.087 to 3.431° from the original mould angle. The test results show that processing conditions influenced finished part dimensions as the final sample angles were found to decrease relative to the tooling dimensions, as mould temperature increases. Higher mould temperature conditions produce thinner parts due to the thermal expansion of mould tools. The mould temperature of 170°C, which can produce parts with high degree of crystallinity as well as small size of crystal, has been established as the optimal thermoforming condition for CF/PPS composites. [ABSTRACT FROM PUBLISHER]

Abstract: Needle biopsy is a medical procedure to extract tissue for diagnosis of cancer and other diseases. The quality of tissue samples acquired by needle biopsy greatly depends on the cutting forces of the cannula. The reduction of cutting forces is crucial for obtaining good tissue samples. There exist many factors that influence the cutting forces, some of which include the cannula tip geometry, translation speed, and rotation speed. In the present paper, the effects of rotating the cannula on tissue cutting for needle biopsy are studied. A fracture-mechanics-based approach is used to analyze the cutting forces. Analysis has shown that the cutting forces decrease with the increases in the slice/push ratio defined as the ratio of speed component parallel to the cutting edge/speed perpendicular to the cutting edge. Experiments are performed to demonstrate this phenomenon. Mathematical models of the slice/push ratio for bevel tip cannulas are formulated. The results are used to determine the optimal cannula rotation/translation speed and the desired tip geometry for needle biopsy. It is shown that a minimal slice/push ratio of 2 is recommended. A cannula with a large bevel angle is more suitable for rotational needle biopsy. [Copyright &y& Elsevier]

Despite current treatment regimens, heart failure remains the leading cause of morbidity and mortality in the developed world due to the limited capacity of adult mammalian ventricular cardiomyocytes to divide and replace ventricular myocardium lost from ischaemia-induced infarct. Hence there is great interest to identify potential cellular sources and strategies to generate new ventricular myocardium. Past studies have shown that fish and amphibians and early postnatal mammalian ventricular cardiomyocytes can proliferate to help regenerate injured ventricles; however, recent studies have suggested that additional endogenous cellular sources may contribute to this overall ventricular regeneration. Here we have developed, in the zebrafish (Danio rerio), a combination of fluorescent reporter transgenes, genetic fate-mapping strategies and a ventricle-specific genetic ablation system to discover that differentiated atrial cardiomyocytes can transdifferentiate into ventricular cardiomyocytes to contribute to zebrafish cardiac ventricular regeneration. Using in vivo time-lapse and confocal imaging, we monitored the dynamic cellular events during atrial-to-ventricular cardiomyocyte transdifferentiation to define intermediate cardiac reprogramming stages. We observed that Notch signalling becomes activated in the atrial endocardium following ventricular ablation, and discovered that inhibiting Notch signalling blocked the atrial-to-ventricular transdifferentiation and cardiac regeneration. Overall, these studies not only provide evidence for the plasticity of cardiac lineages during myocardial injury, but more importantly reveal an abundant new potential cardiac resident cellular source for cardiac ventricular regeneration. [ABSTRACT FROM AUTHOR]

Abstract: Tissue cutting by a needle is greatly influenced by the geometry of its cutting edges. Yet, there are very few results in the technical literature that address the issues surrounding the relation between needle tip and cutting edge geometry and its cutting/insertion force. In the present paper, general mathematical models of the included and inclination angles of a needle''s cutting edge are formulated since they exert a profound influence on cutting behavior. Specific models for various tip geometries are developed to investigate four types of needle tips including one-plane, asymmetric three-plane, symmetric multi-plane, and symmetric three-curved-surface needles. The results show that the cutting edge of the one-plane needle has a very undesirable configuration. Asymmetric three-plane needles, such as the lancet and back bevel tip needles, can significantly improve the configuration of the cutting edge. Back bevel tip needles, in turn, offer even more desirable cutting edge geometry than lancet tip needles. In evaluating the cutting edge angles of multi-plane needles, it was shown that the included angle is limited by its tip geometry. To resolve this problem a needle formed by three curved surfaces was proposed. It was found that this new design has significant potential for reducing patient trauma as well as target accuracy during needle insertion. The proposed general approach provides the foundation for designing medical needles with specific cutting edge properties. [Copyright &y& Elsevier]

Exosomes released by cardiomyocytes are essential mediators of intercellular communications within the heart, and various exosomal proteins and miRNAs are associated with cardiovascular diseases. However, whether the endosomal sorting complex required for transport (ESCRT) and its key component Alix is required for exosome biogenesis within cardiomyocyte remains poorly understood. Super-resolution imaging was performed to investigate the subcellular location of Alix and multivesicular body (MVB) in primary cardiomyocytes. Cardiomyocyte-specific Alix-knockout mice were generated using AAV9/CRISPR/Cas9-mediated in vivo gene editing. A stable Alix-knockdown H9c2 cardiomyocyte line was constructed through lentiviral-mediated delivery of short hairpin RNA. In order to determine the role of Alix in controlling exosome biogenesis, exosomes from cardiomyocyte-specific Alix-knockout mice plasma and Alix-knockdown H9c2 culture medium were isolated and examined by western blot, NTA analysis and transmission electron microscopy. Biochemical and immunofluorescence analysis were performed to determine the role of ESCRT machinery in regulating MVB formation. Lastly, transverse aortic constriction (TAC)-induced cardiac pressure overload model was established to further explore the role of Alix-mediated exosome biogenesis under stress conditions. A significant proportion of Alix localized to the MVB membrane within cardiomyocytes. Genetic deletion of Alix in murine heart resulted in a reduction of plasma exosome content without affecting cardiac structure or contractile function. Consistently, the downregulation of Alix in H9c2 cardiomyocyte line also suppressed the biogenesis of exosomes. We found the defective ESCRT machinery and suppressed MVB formation upon Alix depletion caused compromised exosome biogenesis. Remarkably, TAC-induced cardiac pressure overload led to increased Alix, MVB levels, and elevated plasma exosome content, which could be totally abolished by Alix deletion. These results establish Alix as an essential and stress-sensitive regulator of cardiac exosome biogenesis and the findings may yield valuable therapeutic implications. [Display omitted] • Deletion of Alix in cardiomyocytes results in a reduction in plasma exosome content. • Defective ESCRT machinery and MVB formation are observed in the Alix -depleted heart. • Exosome biogenesis is enhanced in the pressure overload model. • Ablation of Alix mitigates the increased exosome formation in the stressed heart. [ABSTRACT FROM AUTHOR]

Pacemaker cardiomyocytes that create the sinoatrial node are essential for the initiation and maintenance of proper heart rhythm. However, illuminating developmental cues that direct their differentiation has remained particularly challenging due to the unclear cellular origins of these specialized cardiomyocytes. By discovering the origins of pacemaker cardiomyocytes, we reveal an evolutionarily conserved Wnt signaling mechanism that coordinates gene regulatory changes directing mesoderm cell fate decisions, which lead to the differentiation of pacemaker cardiomyocytes. We show that in zebrafish, pacemaker cardiomyocytes derive from a subset of Nkx2.5+ mesoderm that responds to canonical Wnt5b signaling to initiate the cardiac pacemaker program, including activation of pacemaker cell differentiation transcription factors Isl1 and Tbx18 and silencing of Nkx2.5. Moreover, applying these developmental findings to human pluripotent stem cells (hPSCs) notably results in the creation of hPSC-pacemaker cardiomyocytes, which successfully pace three-dimensional bioprinted hPSC-cardiomyocytes, thus providing potential strategies for biological cardiac pacemaker therapy. • Pacemaker cardiomyocytes derive from a subset of Nkx2.5+ mesoderm • Canonical Wnt5b signaling directs pacemaker cardiomyocyte differentiation in vivo • Wnt5b signaling promotes hPSC-pacemaker cardiomyocyte differentiation in vitro • hPSC-pacemaker cardiomyocytes can pace 3D bioprinted hPSC-cardiomyocytes Pacemaker cardiomyocytes are crucial for maintaining heart rate. Ren et al. show that these specialized cardiomyocytes originate from outlying Nkx2.5+ mesoderm that responds to canonical Wnt5b signaling in zebrafish. Applying these findings to human pluripotent stem cells (hPSCs) results in the generation of hPSC-pacemaker cardiomyocytes that can pace bioprinted hPSC-cardiomyocytes. [ABSTRACT FROM AUTHOR]

Evapotranspiration (E), a pivotal phenomenon inherent to hydrological and thermal dynamics, assumes a position of utmost importance within the intricate framework of the water–energy nexus. However, the quantitative study of E on a large scale for the "Grain for Green" projects under the backdrop of climate change is still lacking. Consequently, this study examined the interannual variations and spatial distribution patterns of E, transpiration (Et), and soil evaporation (Eb) in the Northern Foot of Yinshan Mountain (NFYM) between 2000 and 2020 and quantified the contributions of climate change and vegetation greening to the changes in E, Et, and Eb. Results showed that E (2.47 mm/a, p < 0.01), Et (1.30 mm/a, p < 0.01), and Eb (1.06 mm/a, p < 0.01) all exhibited a significant increasing trend during 2000–2020. Notably, vegetation greening emerged as the predominant impetus underpinning the augmentation of both E and Eb, augmenting their rates by 0.49 mm/a and 0.57 mm/a, respectively. In terms of Et, meteorological factors emerged as the primary catalysts, with temperature (Temp) assuming a predominant role by augmenting Et at a rate of 0.35 mm/a. Temp, Precipitation (Pre), and leaf area index (LAI) collectively dominated the proportional distribution of E, accounting for shares of 32.75%, 28.43%, and 25.01%, respectively. Within the spectrum of predominant drivers influencing Et, Temp exerted the most substantial influence, commanding the largest proportion at 33.83%. For Eb, the preeminent determinants were recognized as LAI and Temp, collectively constituting a substantial portion of the study area, accounting for 32.10% and 29.50%, respectively. The LAI exerted a pronounced direct influence on the Et, with no significant effects on E and bare Eb. Wind speed (WS) had a substantial direct impact on both E and Et. Pre exhibited a strong direct influence on E, Et, and Eb. Relative humidity (RH) significantly affected E directly. Temp primarily influenced Eb indirectly through radiation (Rad). Rad exerted a significant direct inhibitory effect on Eb. These findings significantly advanced our mechanistic understanding of how E and its components in the NFYM respond to climate change and vegetation greening, thus providing a robust basis for formulating strategies related to regional ecological conservation and water resources management, as well as supplying theoretical underpinnings for constructing sustainable vegetation restoration strategies involving water resources in the region. [ABSTRACT FROM AUTHOR]

Vegetation net primary productivity (NPP) serves as a crucial and intuitive indicator for assessing ecosystem health. However, the nonlinear dynamics and influencing factors operating at various time scales are not yet fully understood. Here, the ensemble empirical mode decomposition (EEMD) method was used to analyze the spatiotemporal patterns of NPP and its association with hydrothermal factors and anthropogenic activities across different temporal scales for the Yellow River Basin (YRB) from 2000 to 2020. The results indicate that: (1) the annual average NPP was 236.37 g C/m2 in the YRB and increased at rates of 4.64 g C/m2/a1 (R2 = 0.86, p < 0.01) during 2000 to 2020. Spatially, nonlinear analysis indicates that 72.77% of the study area exhibits a predominantly increasing trend in NPP, while 25.17% exhibits a reversing trend. (2) On a 3-year time scale, warming has resulted in an increase in NPP in the majority of areas of the study area (69.49%). As the time scale widens, the response of vegetation to climate change becomes more prominent; especially under the long-term trend, the percentage areas of the correlation between vegetation and precipitation and temperature increased with significance, reaching 48.21% and 11.57%, respectively. (3) Through comprehensive time analysis and multivariate regression analysis, it was confirmed that both human activities and climate factors had comparable impacts on vegetation growth. Among different vegetation types, climate was still the main factor affecting grassland NPP, and only 15.74% of grassland was affected by human activities. For shrubland, forest, and farmland, human activity was a dominating factor for vegetation NPP change. There are still few studies on vegetation change using nonlinear methods in the Yellow River Basin, and most studies have not considered the effect of time scale on vegetation evolution. The findings highlight the significance of multi-time scale analysis in understanding the vegetation dynamics and providing scientific guidance for future vegetation restoration and conservation efforts. [ABSTRACT FROM AUTHOR]

Grasslands, a vital ecosystem and component of the global carbon cycle, play a significant role in evaluating ecosystem health and monitoring the global carbon balance. In this study, based on the Carnegie–Ames–Stanford Approach (CASA) model, we estimated the Net Primary Productivity (NPP) of grasslands in northern Shaanxi from 2000 to 2020. Employing trend analysis, stability analysis, multiple regression analysis, and residual analysis, the research examined the dynamic changes of grassland NPP and its response to climatic and human factors. Key findings include: (1) Grassland NPP showed a significant increasing trend during 2000–2020, with high-coverage grasslands showing a higher rate of increase than medium and low-coverage grasslands. (2) Most grasslands (>90%) exhibited unstable growth and high NPP fluctuation. (3) While temperature, precipitation, and radiation undulate, the trends were not significant. Rainfall and radiation emerged as dominant factors affecting NPP, with temperature suppressing NPP increase to some extent. (4) Policies like returning farmland to grassland had a positive impact on grassland recovery, vegetation productivity, and regional ecosystem health. [ABSTRACT FROM AUTHOR]

Autophagy has stabilizing functions for cardiomyocytes. Recent studies indicate that an impairment in the autophagy pathway can seriously affect morphology and function, potentially leading to heart failure. However, the role and the underlying mechanism of the endosomal sorting complex required for transport (ESCRT) family protein, in particular the AAA-ATPase vacuolar protein sorting 4a (Vps4a), in regulating myocardial autophagy remains unclear. In the present study, cardiomyocyte-specific Vps4a knockout mice were generated by crossing Vps4aflox/flox (Vps4afl/fl) with Myh6-cre transgenic mice. As a result, we observed a partially dilated left ventricular (LV) chamber, a significant increase in heart weight to body weight ratio (HW/BW), and heart weight to tibial length ratio (HW/TL), hypertrophic cardiomyopathy and early lethality starting at 3 months of age. Hematoxylin-eosin (HE), immunofluorescence assay (IFA), and Western blot (WB) revealed autophagosome accumulation in cardiomyocytes. A transcriptome-based analysis and autophagic flux tracking by AAV-RFP-GFP-LC3 showed that the autophagic flux was blocked in Vps4a knockout cardiomyocytes. In addition, we provided in vitro evidence demonstrating that Vps4a and LC3 were partially co-localized in cardiomyocytes, and the knockdown of Vps4a led to the accumulation of autophagosomes in cardiomyocytes. Similarly, the transfection of cardiomyocytes with adenovirus (Adv) mCherry-GFP-LC3 further indicated that the autophagic flux was blocked in cells with deficient levels of Vps4a. Finally, an electron microscope (EM) showed that the compromised sealing of autophagosome blocked the autophagic flux in Vps4a-depleted cardiomyocytes. These findings revealed that Vps4a contributed to the sealing of autophagosomes in cardiomyocytes. Therefore, we demonstrated that Vps4a deletion could block the autophagic flux, leading to the accumulation of degradation substances and compromised cardiac function. Overall, this study provides insights into a new theoretical basis for which autophagy may represent a therapeutic target for cardiovascular diseases. [ABSTRACT FROM AUTHOR]

This article summarizes the contributions in research on tissue cutting with needles. The geometry of the needle's cutting edges was analytically defined and expressions for the inclination and rake angles of hollow and solid needles and trocars have been derived. Based on the semi-empirical method, finite element model and the fracture mechanics approach, force models of needle insertion were developed. The relationship between the needle's tip geometry and insertion force was established and used in several applications. It was shown, for example, that the cutting edge of the lancet needle can be optimally designed to minimize insertion force or bevel length. The cutting mechanics in rotary needle insertion was investigated along with the exploration of improvements of needle biopsy performance by decreasing the needle cutting and friction forces. The deflections of the needle during insertion were measured to develop a strategy for guiding the needle to the right position in brachytherapy and drug delivery. From an overall perspective, fundamental advances and application problems based on the cutting mechanics of soft tissue for needle were highlighted to lay the foundation for developments of biomedical device and improvements of healthcare procedures. [ABSTRACT FROM PUBLISHER]

[Display omitted] • Vegetation in China showed a significant greening trend from 2001 to 2020. • Differences in the EVI patterns along four climate zones were characterized. • EVI was more sensitive to rainfall in the tropics and temperate regions. • This study is significant for the scientific management of cross climate zone ecosystems. Vegetation growth is sensitive to climate change. The complex climate types of China pose great challenges to the sustainable management of vegetation on global change. Therefore, this study used Enhanced Vegetation Index (EVI) as an indicator to explore the spatiotemporal dynamics of vegetation and their driving factors in different climatic zones of China to provide theoretical support for sustainable vegetation management in different climate zones in the future. The results showed that vegetation exhibited considerable clustering patterns in the country, with high and low values concentrated in the eastern and western regions, respectively. From 2001 to 2020, both at regional and pixel scales, vegetation in China showed a significant greening trend. EVI displayed a noticeable increase within temperate and subtropical areas. The only exception is observed in the eastern coastal area of the North China Plain and Yangtze River Delta region, which experienced evident degradation trend. During this period, China's climate showed an overall trend towards warming and humidification with drying trends observed mainly over the western regions. The impact of climate changes resulted in EVI dynamics that vary over time and space. The vegetation change in China was mainly derived by changes in precipitation and radiation rather than temperature, especially in temperate and subfrigid regions. Precipitation was the main driving factor for vegetation greening in tropical and temperate regions, while radiation and temperature were the dominant climate factor for vegetation greening in subfrigid and subtropical regions, respectively. When precipitation was no longer a limiting factor for vegetation growth, the effect of temperature or radiation increases. In addition, the positive impact of precipitation on plant growth in temperate regions was much greater than that of radiation and temperature, and this difference was much greater than in tropical, subtropical, and subfrigid regions. [ABSTRACT FROM AUTHOR]

Mitochondrial flash (mitoflash) is a highly-conserved, universal, and physiological mitochondrial activity in isolated mitochondria, intact cells, and live organisms. Here we investigated developmental and disease-related remodeling of mitoflash activity in zebrafish skeletal muscles. In transgenic zebrafish expressing the mitoflash reporter cpYFP, in vivo imaging revealed that mitoflash frequency and unitary properties underwent multiphasic and muscle type-specific changes, accompanying mitochondrial morphogenesis from 2 to 14 dpf. In particular, short (S)-type mitoflashes predominated in early muscle formation, then S-, transitory (T)- and regular (R)-type mitoflashes coexisted during muscle maturation, followed by a switch to R-type mitoflashes in mature skeletal muscles. In early development of muscular dystrophy, we found accelerated S- to R-type mitoflash transition and reduced mitochondrial NAD(P)H amidst a remarkable cell-to-cell heterogeneity. This study not only unravels a profound functional and morphological remodeling of mitochondria in developing and diseased skeletal muscles, but also underscores mitoflashes as a useful reporter of mitochondrial function in milieu of live animals under physiological and pathophysiological conditions. [ABSTRACT FROM AUTHOR]

The histidine-rich Ca-binding protein (HRC) is located in the lumen of the sarcoplasmic reticulum (SR) and exhibits high-capacity Ca-binding properties. Overexpression of HRC in the heart resulted in impaired SR Ca uptake and depressed relaxation through its interaction with SERCA2a. However, the functional significance of HRC in overall regulation of calcium cycling and contractility is not currently well defined. To further elucidate the role of HRC in vivo under physiological and pathophysiological conditions, we generated and characterized HRC-knockout (KO) mice. The KO mice were morphologically and histologically normal compared to wild-type (WT) mice. At the cellular level, ablation of HRC resulted in significantly enhanced contractility, Ca transients, and maximal SR Ca uptake rates in the heart. However, after-contractions were developed in 50 % of HRC-KO cardiomyocytes, compared to 11 % in WT mice under stress conditions of high-frequency stimulation (5 Hz) and isoproterenol application. A parallel examination of the electrical activity revealed significant increases in the occurrence of Ca spontaneous SR Ca release and delayed afterdepolarizations with ISO in HRC-KO, compared to WT cells. The frequency of Ca sparks was also significantly higher in HRC-KO cells with ISO, consistent with the elevated SR Ca load in the KO cells. Furthermore, HRC-KO cardiomyocytes showed significantly deteriorated cell contractility and Ca-cycling caused possibly by depressed SERCA2a expression after transverse-aortic constriction (TAC). Also HRC-null mice exhibited severe cardiac hypertrophy, fibrosis, pulmonary edema and decreased survival after TAC. Our results indicate that ablation of HRC is associated with poorly regulated SR Ca-cycling, and severe pathology under pressure-overload stress, suggesting an essential role of HRC in maintaining the integrity of cardiac function. [ABSTRACT FROM AUTHOR]

Aims Junctin and triadin are calsequestrin-binding proteins that regulate sarcoplasmic reticulum (SR) Ca2+ release by interacting with the ryanodine receptor. The levels of these proteins are significantly down-regulated in failing human hearts. However, the significance of such decreases is currently unknown. Here, we addressed the functional role of these accessory proteins in the heart's responses to ischaemia/reperfusion (I/R) injury. Methods and results Isolated mouse hearts were subjected to global I/R, and contractile parameters were assessed in wild-type (WT), junctin-knockout (JKO), and triadin-knockout (TKO) hearts. Both JKO and TKO were associated with significantly depressed post-I/R contractile recovery. However, ablation of triadin resulted in the most severe post-I/R phenotype. The additional contractile impairment of TKO hearts was not related to a mitochondrial death pathway, but attributed to endoplasmic reticulum (ER) stress-mediated apoptosis. Activation of the X-box-binding protein-1 and transcriptional up-regulation of C/EBP-homologous protein (CHOP) provided a molecular mechanism of caspase-12-dependent apoptosis in myocytes. In addition, elevation of cytosolic Ca2+ during reperfusion was associated with the activation of calpain proteases and troponin I breakdown. Accordingly, treatment with the calpain inhibitor MDL-28170 significantly ameliorated post-I/R impairment of contractile recovery in intact hearts. Conclusion These findings indicate that deficiency of either junctin or triadin impairs the contractile recovery in post-ischaemic hearts, which appears to be primarily attributed to increased ER stress and activation of calpain. [ABSTRACT FROM PUBLISHER]

Summary: In quiescent cells, mitochondria are the primary source of reactive oxygen species (ROS), which are generated by leakiness of the electron transport chain (ETC). High levels of ROS can trigger cell death, whereas lower levels drive diverse and important cellular functions. We show here by employing a newly developed mitochondrial matrix-targeted superoxide indicator, that individual mitochondria undergo spontaneous bursts of superoxide generation, termed “superoxide flashes.” Superoxide flashes occur randomly in space and time, exhibit all-or-none properties, and provide a vital source of superoxide production across many different cell types. Individual flashes are triggered by transient openings of the mitochondrial permeability transition pore stimulating superoxide production by the ETC. Furthermore, we observe a flurry of superoxide flash activity during reoxygenation of cardiomyocytes after hypoxia, which is inhibited by the cardioprotective compound adenosine. We propose that superoxide flashes could serve as a valuable biomarker for a wide variety of oxidative stress-related diseases. [Copyright &y& Elsevier]