The role of miRNA regulation in fetal cardiomyocytes, cardiac maturation and the risk of heart disease in adults

Myocardial infarction is a primary contributor towards the global burden of cardiovascular disease. Rather than repairing the existing damage of myocardial infarction, current treatments only address the symptoms of the disease and reducing the risk of a secondary infarction. Cardiac regenerative capacity is dependent on cardiomyocyte proliferation, which concludes soon after birth in humans and precocial species such as sheep. Human fetal cardiac tissue has some ability to repair following tissue damage, whereas a fully matured human heart has minimal capacity for cellular regeneration. This is in contrast to neonatal mice and adult zebrafish hearts, which retain the ability to undergo cardiomyocyte proliferation and can regenerate cardiac tissue after birth. In mice and zebrafish models, microRNAs (miRNAs) have been implicated in the regulation of genes involved in cardiac cell cycle progression and regeneration. However, the significance of miRNA regulation in cardiomyocyte proliferation for humans and other large mammals, where the timing of heart development in relation to birth is similar, remains unclear. miRNAs may be valuable targets for therapies that promote cardiac repair after injury. Therefore, elucidating the role of specific miRNAs in large animals, where heart development closely resembles that of humans, remains vitally important for identifying therapeutic targets that may be translated into clinical practice focussed on tissue repair.Mitchell C. Lock, Ross L. Tellam, Kimberley J. Botting, Kimberley C.W.Wang, Joseph B. Selvanayagam, Doug A. Brooks, Mike Seed and Janna L. Morriso

Mechanism of interferon stimulated gene induction in HIV-1 infected macrophages

Viruses manipulate the complex interferon and interferon stimulated gene (ISG) system in different ways. We have previously shown that HIV inhibits type I and III interferons in its key target cells but directly stimulates a subset of >20 ISGs in macrophages and dendritic cells many of which are antiviral. Here we examined the mechanism of induction of ISGs and showed this occurred in two phases. The first phase was transient (0-24hpi) induced mainly by extracellular vesicles, and one of its component proteins HSP90α, contained within the HIV inoculum. The second dominant and persistent phase (>48hpi) was induced via newly transcribed HIV RNA and sensed via RIGI, as shown by the reduction in ISG expression after the knock down of the RIGI adaptor, MAVS, by siRNA and the inhibition of both the initiation and elongation of HIV transcription, by shRNA transcriptional silencing. We further defined the induction pathway, showing sequential HIV RNA stimulation via Tat, RIGI, MAVS, IRF1 and IRF7 also identified by siRNA knockdown. IRF1 also plays a key role in the first phase. We also showed that the ISGs, IFITs 1-3 inhibited HIV production, measured as extracellular infectious virus. All induced antiviral ISGs probably lead to restriction of HIV replication in macrophages, contributing to a persistent, non-cytopathic infection while the inhibition of interferon facilitates spread to adjacent cells. Both may influence the size of macrophage HIV reservoirs in vivo. Elucidating the mechanisms of ISG induction may help devise immunotherapeutic strategies to limit the size of these reservoirs. IMPORTANCE HIV, like other viruses, manipulates the antiviral interferon and interferon stimulated gene (ISG) system to facilitate its initial infection and establishment of viral reservoirs. HIV specifically inhibits all type l and lll interferons in its target cells, including, macrophages, dendritic cells and T cells. It also induces a subset of over 20 ISGs of differing composition in each cell target. This occurs in two temporal phases in macrophages. Extracellular vesicles contained within the inoculum induced the first and transient phase of ISGs. Newly transcribed HIV RNA induced the second and dominant ISG phase and here the full induction pathway is defined. Therefore, HIV nucleic acids, which are potent inducers of interferon and ISGs, are initially concealed and antiviral ISGs are not fully induced until replication is well established. Theses antiviral ISGs may contribute to the persistent infection in macrophages and to the establishment of viral reservoirs in vivo.Najla Nasr, Abdullateef A. Alshehri, Thomas K. Wright, Maryam Shahid, Bonnie M. Heiner, Andrew N. Harman, Rachel A. Botting, Karla J. Helbig, Michael R. Beard, Kazuo Suzuki, Anthony D. Kelleher, Paul Hertzog, Anthony L. Cunningha

Improving pregnancy outcomes in humans through studies in sheep

Experimental studies that are relevant to human pregnancy rely on the selection of appropriate animal models as an important element in experimental design. Consideration of the strengths and weaknesses of any animal model of human disease is fundamental to effective and meaningful translation of preclinical research. Studies in sheep have made significant contributions to our understanding of the normal and abnormal development of the fetus. As a model of human pregnancy, studies in sheep have enabled scientists and clinicians to answer questions about the etiology and treatment of poor maternal, placental and fetal health and to provide an evidence base for translation of interventions into the clinic. The aim of this review is to highlight the advances in perinatal human medicine that have been achieved following translation of research using the pregnant sheep and fetus.Janna L. Morrison, Mary J. Berry, Kimberley J. Botting, Jack R. T. Darby ... Kathryn L. Gatford ... Claire T. Roberts ... et al

Growth impairment in very low birthweight children at 12 years: correlation with perinatal and outcome variables.

AIM: To compare the growth of very low birthweight (VLBW) children in early adolescence with that of their normal birthweight peers; to examine the role of factors contributing to growth-parental height, perinatal variables, bone maturity and sexual maturation; to examine the correlation between head growth and cognitive and educational outcome. METHODS: Standing and sitting heights, weight, occipito-frontal circumference (OFC), skinfold thicknesses and pubertal staging were assessed in 137 VLBW children and 160 controls at 11-13.5 years of age. Ninety six (70%) of the VLBW children had their bone age assessed using the TW2 method. Reported parental heights were obtained by questionnaire. All children had standardised tests of cognitive and educational ability. Perinatal data had been collected prospectively as part of a longitudinal study. RESULTS: VLBW children had lower heights, weight, and OFC. Skinfold thicknesses were no different. The children's short stature was not accounted for by difference in parental height, degree of pubertal development, or by retarded bone age. Indeed, the TW2 RUS score was significantly advanced in the VLBW children. Using the bone ages to predict final adult height, 17% have a predicted height below the third centile and 33% below the tenth. Weight was appropriate for height, but there was a residual deficiency in OFC measurements after taking height into account. In the VLBW group smaller head size was associated with lower IQ and mathematics and reading scores. CONCLUSIONS: Growth problems persist in VLBW children and final heights may be even more abnormal than present heights suggest. VLBW children have smaller OFCs than expected from their short stature alone and this may be associated with poorer educational and cognitive outcomes

Sponge spicule assemblages from the Cambrian (Series 2?3) of North Greenland (Laurentia) : systematics and biogeography

Isolated microscopic spicules from disarticulated scleritomes demonstrate the presence of a diverse sponge fauna otherwise not evident from the macrofossil record in carbonate successions deposited during the un-named Cambrian Series 2 and Cambrian Series 3 (Miaolingian) in North Greenland. Most of the spicule morphotypes are not recognised from faunas of articulated sponges known from contemporaneous siliciclastic strata elsewhere. Assemblages are described in terms of four Cambrian stages and contain numerous spicule morphotypes not previously recorded from Laurentia. Many of the spicules can be correlated worldwide, however, extending current knowledge of the biogeographic distribution of sponge spicule-based taxa in the Cambrian. In particular, similar Cambrian Stage 4 (Series 2) and Miaolingian assemblages (Wuliuan, Drumian and Guzhangian stages) faunas are recorded from tropical palaeolatitudes in Australia, South China, Siberia and Laurentia, although this may in part reflect a methodology focused on the preparation of the carbonate samples that dominate these successions. New spicule-based taxa: Eiffelia floriformis n. sp., Australispongia? inuak n. sp., Celtispongia dorte n. gen. n. sp., Sanningasoqia borealis n. gen. n. sp., Speciosuspongia inughuitorum n. sp., Sulukispicula gelidae n. gen. n. sp

The earliest ostracods: The geological evidence

The oldest assumed ostracods appear in the fossil record from the Tremadocian Paltodus deltifer conodont Biozone. Although geographically widespread these early ostracods have no obvious Cambrian antecedents. Their first appearance at ca. 485 Ma contrasts with molecular evidence that suggests a much earlier (latest Proterozoic or Cambrian) origin for ostracods. Some Cambrian bivalved arthropods such as Altajanella and Vojbokalina, conventionally referred to the Bradoriida, have carapace morphologies that resemble Ordovician palaeocopid ostracods, though such a relationship is unproven without soft part anatomy. Evidence from preserved soft anatomy demonstrates that Bradoriida, such as Kunmingella, and Phosphatocopida, essentially the Cambrian 'ostracod' record of traditional usage, belong outside the Eucrustacea. Early Ordovician ostracods appeared first in shallow marine, oxygenated environments on shelf margins, in a similar setting to other elements of the 'Paleozoic fauna'. Their biodiversity was low (3 named genera and ca. 12 species), though some taxa such as Nanopsis and Eopilla achieved widespread dispersal between major Ordovician palaeocontinents. As bradoriids were largely extinct by the Late Cambrian, ostracods do not appear to have directly competed with them for shallow marine environments. The rapid colonisation of these settings by ostracods may have been facilitated by the available ecospace vacated by Bradoriida

Factors influencing grapevine vigour and the potential for control with partial rootzone drying

Maintaining the most cost-effective balance between vegetative and reproductive growth is one of the most testing problems in modern viticulture. Grapevines which exhibit excessive vegetative vigour are likely to produce less fruit of reduced quality, and vines with inadequate vigour may be compromised in terms of their yield potential. The requirement for techniques to better manage excess vigour has become more acute in recent years with the increased use of irrigation, adoption of vigour-imparting rootstocks and the expansion of vineyards into cooler geographic regions. A number of strategies may be used to control vine vigour. Chemical growth regulators, although capable of reducing shoot vigour, have never received acceptance due to undesirable side effects and concerns over chemical residues. Devigorating rootstocks, likewise, may have the potential to control vigour but none are in wide commercial use. Restriction of the effective root volume, achieved through manipulation of planting densities, competition by cover crops, regulation of the soil volume wetted by drip irrigation or regulation of water availability can all achieve a degree of devigoration but often at the expense of fruit yield. Manipulation of vines through pruning and trellis design are probably the most commonly used methods for the control of shoot vigour. A high number of nodes retained at pruning combined with trellises which allow open canopies have proved successful. Advances in the understanding of the physiological factors influencing shoot growth and transpiration have allowed the development of novel irrigation methods for the control of vine vigour. These techniques exploit the fact that chemical signals originating in the roots are primarily responsible for the control of shoot growth and transpiration. Stimulation of the production of these signals through partial drying of the root system results in a significant reduction in shoot growth and water-use while maintaining crop yield and improving fruit quality. These new techniques, in combination with appropriate pruning and trellising methods, are providing new viticultural tools for controlling vine vigour and water-use efficiency