Cardiac lymphatics in health and disease

The lymphatic vasculature, which accompanies the blood vasculature in most organs, is indispensable in the maintenance of tissue fluid homeostasis, immune cell trafficking, and nutritional lipid uptake and transport, as well as in reverse cholesterol transport. In this Review, we discuss the physiological role of the lymphatic system in the heart in the maintenance of cardiac health and describe alterations in lymphatic structure and function that occur in cardiovascular pathology, including atherosclerosis and myocardial infarction. We also briefly discuss the role that immune cells might have in the regulation of lymphatic growth (lymphangiogenesis) and function. Finally, we provide examples of how the cardiac lymphatics can be targeted therapeutically to restore lymphatic drainage in the heart to limit myocardial oedema and chronic inflammation.Peer reviewe

Investigating the role of Prox1 in cardiac and skeletal muscle development and disease

Restricted expression of contractile protein gene isoforms contributes to the functional distinction between cardiac and skeletal striated muscle types, with these genes often misregulated in myopathic disease. The homeobox transcription factor Prox1 is expressed in both cardiac and skeletal muscle, and ablation of Prox1 specifically within cardiomyocytes resulted in the abnormal upregulation of the fast-twitch skeletal isoforms of the contractile protein genes troponin T (Tnnt3), troponin I (Tnni2), and MyLC 1 (Myl1) from early in heart development. Similar loss of function studies in skeletal muscle using a Myf5-driven Cre revealed overexpression of these same fast-twitch genes specifically in slow-twitch skeletal muscle, identifying Prox1 as the first transcription factor known to directly repress a program of fast-twitch skeletal genes across both cardiac and skeletal striated muscle types. Furthermore, loss of Prox1 expression in skeletal muscle was sufficient to cause a switch from a slow to a fast-twitch fibre-type, which has not previously been reported following knockout of a single transcription factor. Intriguingly, aberrant expression of Tnnt3, Tnni2, and Myl1 has been observed in other muscle-specific knockout models, including HDAC1/2 and miR-208a (cardiac), and Sox6 and miR-208b/miR-499 (skeletal), where the transcription factor directly responsible for their misexpression remains to be demonstrated. Recent work has revealed a lack of conservation in the regulation of these genes from the zebrafish, suggesting that in the mouse this role may be fulfilled by Prox1. This study has additionally uncovered novel putative regulatory relationships between Prox1 and miRNAs implicated in cardiac and/or skeletal muscle development, function, or disease, using a high-throughput in vitro screen. Herein is also the first description of the heart phenotype of survived cardiac-specific Prox1 knockouts, which develop severe dilated cardiomyopathy that is fatal within the first 14 weeks of life. Consequently, these mice model the functional impact of loss of Prox1 function on the adult heart, including the effect of ectopic fast-twitch contractile protein gene expression, and the molecular pathways that underlie the development of dilated cardiomyopathy. An improved understanding of the function of Prox1 in the developing and adult heart may provide new opportunities for therapeutic intervention

Loss of Prox1 in striated muscle causes slow to fast skeletal muscle fiber conversion and dilated cardiomyopathy.

Correct regulation of troponin and myosin contractile protein gene isoforms is a critical determinant of cardiac and skeletal striated muscle development and function, with misexpression frequently associated with impaired contractility or disease. Here we reveal a novel requirement for Prospero-related homeobox factor 1 (Prox1) during mouse heart development in the direct transcriptional repression of the fast-twitch skeletal muscle genes troponin T3, troponin I2, and myosin light chain 1. A proportion of cardiac-specific Prox1 knockout mice survive beyond birth with hearts characterized by marked overexpression of fast-twitch genes and postnatal development of a fatal dilated cardiomyopathy. Through conditional knockout of Prox1 from skeletal muscle, we demonstrate a conserved requirement for Prox1 in the repression of troponin T3, troponin I2, and myosin light chain 1 between cardiac and slow-twitch skeletal muscle and establish Prox1 ablation as sufficient to cause a switch from a slow- to fast-twitch muscle phenotype. Our study identifies conserved roles for Prox1 between cardiac and skeletal muscle, specifically implicated in slow-twitch fiber-type specification, function, and cardiomyopathic disease

Loss of Prox1 in striated muscle causes slow to fast skeletal muscle fiber conversion and dilated cardiomyopathy.

Correct regulation of troponin and myosin contractile protein gene isoforms is a critical determinant of cardiac and skeletal striated muscle development and function, with misexpression frequently associated with impaired contractility or disease. Here we reveal a novel requirement for Prospero-related homeobox factor 1 (Prox1) during mouse heart development in the direct transcriptional repression of the fast-twitch skeletal muscle genes troponin T3, troponin I2, and myosin light chain 1. A proportion of cardiac-specific Prox1 knockout mice survive beyond birth with hearts characterized by marked overexpression of fast-twitch genes and postnatal development of a fatal dilated cardiomyopathy. Through conditional knockout of Prox1 from skeletal muscle, we demonstrate a conserved requirement for Prox1 in the repression of troponin T3, troponin I2, and myosin light chain 1 between cardiac and slow-twitch skeletal muscle and establish Prox1 ablation as sufficient to cause a switch from a slow- to fast-twitch muscle phenotype. Our study identifies conserved roles for Prox1 between cardiac and skeletal muscle, specifically implicated in slow-twitch fiber-type specification, function, and cardiomyopathic disease

Flank-Collapse on Ta’u Island, Samoan Archipelago: Timing and Hazard Implications

A discrepancy between the cartographic depiction of Ta\u27u Island, Samoan archipelago, in 1849 and its present geomorphology, leads to the impression that a massive collapse involving an estimated 30 km3 occurred on the island\u27s southern flank less than 170 years ago. It is likely that this flank-collapse, whenever it occurred, generated a tsunami with regional impacts. Here we apply exposure dating to the remnant landslide scarp using the cosmogenic nuclide 36Cl, to show that the flank-collapse occurred 22.4 1.8 ka during the last glacial maximum (LGM). The collapse may have been triggered due to volcanic-related processes, but it is also possible that climatic-eustatic sea-level during the LGM may have played a role in influencing failure of the flank. We confirm that the initial cartographic depiction of Ta\u27u in 1849 was incorrect, and that this prehistoric landslide-tsunami was not a societal hazard at the time of its occurrence. This is because the Samoan and surrounding Island Nations were only inhabited about 3 ka or so. Nevertheless, we suggest that geomorphic features similar to the Ta\u27u flank-collapse on analogous islands and seamounts in the Pacific likely represent signatures of landslide-tsunamis in the past. We conclude that there is a need to identify and date other such features in the Pacific, in order to further improve our spatial and geochronological understanding of these events. There is also a need to identify flank features that have not yet failed, and assess the likelymechanisms that could potentially trigger failure. By doing this, we can start assessing with more confidence the hazard potential of similar flank-collapses in future-a risk that is presently under-represented

Epistatic rescue of Nkx2.5 adult cardiac conduction disease phenotypes by prospero-related homeobox protein 1 and HDAC3.

RATIONALE: Nkx2.5 is one of the most widely studied cardiac-specific transcription factors, conserved from flies to man, with multiple essential roles in both the developing and adult heart. Specific dominant mutations in NKX2.5 have been identified in adult congenital heart disease patients presenting with conduction system anomalies and recent genome-wide association studies implicate the NKX2.5 locus, as causative for lethal arrhythmias ("sudden cardiac death") that occur at a frequency in the population of 1 in 1000 per annum worldwide. Haploinsufficiency for Nkx2.5 in the mouse phenocopies human conduction disease pathology yet the phenotypes, described in both mouse and man, are highly pleiotropic, implicit of unknown modifiers and/or factors acting in epistasis with Nkx2.5/NKX2.5. OBJECTIVE: To identify bone fide upstream genetic modifier(s) of Nkx2.5/NKX2.5 function and to determine epistatic effects relevant to the manifestation of NKX2.5-dependent adult congenital heart disease. METHODS AND RESULTS: A study of cardiac function in prospero-related homeobox protein 1 (Prox1) heterozygous mice, using pressure-volume loop and micromannometry, revealed rescue of hemodynamic parameters in Nkx2.5(Cre/+); Prox1(loxP/+) animals versus Nkx2.5(Cre/+) controls. Anatomic studies, on a Cx40(EGFP) background, revealed Cre-mediated knock-down of Prox1 restored the anatomy of the atrioventricular node and His-Purkinje network both of which were severely hypoplastic in Nkx2.5(Cre/+) littermates. Steady state surface electrocardiography recordings and high-speed multiphoton imaging, to assess Ca(2+) handling, revealed atrioventricular conduction and excitation-contraction were also normalized by Prox1 haploinsufficiency, as was expression of conduction genes thought to act downstream of Nkx2.5. Chromatin immunoprecipitation on adult hearts, in combination with both gain and loss-of-function reporter assays in vitro, revealed that Prox1 recruits the corepressor HDAC3 to directly repress Nkx2.5 via a proximal upstream enhancer as a mechanism for regulating Nkx2.5 function in adult cardiac conduction. CONCLUSIONS: Here we identify Prox1 as a direct upstream modifier of Nkx2.5 in the maintenance of the adult conduction system and rescue of Nkx2.5 conduction disease phenotypes. This study is the first example of rescue of Nkx2.5 function and establishes a model for ensuring electrophysiological function within the adult heart alongside insight into a novel Prox1-HDAC3-Nkx2.5 signaling pathway for therapeutic targeting in conduction disease

Conflicting values: ecosystem services and invasive tree management

Tree species have been planted widely beyond their native ranges to provide or enhance ecosystem services such as timber and fibre production, erosion control, and aesthetic or amenity benefits. At the same time, non-native tree species can have strongly negative impacts on ecosystem services when they naturalize and subsequently become invasive and disrupt or transform communities and ecosystems. The dichotomy between positive and negative effects on ecosystem services has led to significant conflicts over the removal of non-native invasive tree species worldwide. These conflicts are often viewed in only a local context but we suggest that a global synthesis sheds important light on the dimensions of the phenomenon. We collated examples of conflict surrounding the control or management of tree invasions where conflict has caused delay, increased cost, or cessation of projects aimed at invasive tree removal. We found that conflicts span a diverse range of taxa, systems and countries, and that most conflicts emerge around three areas: urban and near-urban trees; trees that provide direct economic benefits; and invasive trees that are used by native species for habitat or food. We suggest that such conflict should be seen as a normal occurrence in invasive tree removal. Assessing both positive and negative effects of invasive species on multiple ecosystem services may provide a useful framework for the resolution of conflicts

Conservation of fragmented grasslands as part of the urban green infrastructure: how important are species diversity, functional diversity and landscape functionality?

Natural remnants, such as fragmented grasslands form an integral part of the urban green infrastructure in the Grassland biome of South Africa. Nearly 30 % of natural grasslands are transformed with only 1 % formally conserved. Since grassland habitats are globally regarded as a biodiversity conservation priority, protection should be accorded outside formal conservation areas as well. However, urban grassland fragments are often regarded as highly transformed, and are therefore targeted for development rather than conservation. The aim of this study was to compare plant species composition, −diversity and -functional diversity, as well as the fine-scale biophysical landscape functionality of grassland fragments in urban and exurban areas in the vulnerable Rand Highveld Grassland vegetation type in the Tlokwe Municipal area of South Africa. Thirty selected grassland fragments were investigated along an urbanisation (urban-exurban) gradient that was quantified using several demographic- and physical variables as well as landscape metrics, each reflecting a pattern or process associated with urbanisation. Plant species composition, −diversity, and -life history traits were determined in randomly selected sample plots. Functional diversity indices were also calculated to describe the composition and distribution of plant functional traits in the selected grassland fragments. Additionally, landscape functionality, in terms of how effectively the landscape is functioning as a biophysical system, was determined using the Landscape Function Analysis (LFA) method. LFA provides information such as fine-scale resource conserving patchiness, soil surface stability, infiltration, and nutrient cycling. The fine-scale biophysical landscape function of urban and exurban landscapes are comparable, indicating that urban grassland fragments are worthy of conservation on a biophysical landscape function scale. However, differences in plant species diversity, functional trait composition, and plant functional diversity were evident

Impacts of climate change on the amphibians and reptiles of Southeast Asia

10.1007/s10531-010-9782-4Biodiversity and Conservation1941043-1062BONS