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Here we evaluate five atmospheric reanalyses in an Arctic gateway during late summer. The reanalyses include ERA5, ERA-Interim, JRA-55, CFSv2 and MERRA-2. We use observations from 50 radiosondes launched in the Fram Strait around 79-80˚N, between 25 August – 11 September 2017. Crucially, data from 27 radiosondes were not transmitted to the Global Telecommunications System (GTS), and therefore not assimilated into any reanalysis. In most reanalyses, the magnitude of wind speed and humidity errors are similar for profiles with and without data assimilation. In cases without data assimilation, correlation coefficients (R) exceed 0.88 for temperature, wind speed and specific humidity, in all reanalyses. Overall, the newly released ERA5 has higher correlation coefficients than any other reanalyses as well as smaller biases and root mean square errors, for all three variables. The largest improvements identified in ERA5 are in its representation of the wind field, and temperature profiles over warm water.

Congenital heart disease (CHD) affects up to 1% of live births. However, a genetic diagnosis is not made in most cases. The purpose of this study was to assess the outcomes of genome sequencing (GS) of a heterogeneous cohort of CHD patients. Ninety-seven families with probands born with CHD requiring surgical correction were recruited for genome sequencing. At minimum, a proband–parents trio was sequenced per family. GS data were analyzed via a two-tiered method: application of a high-confidence gene screen (hcCHD), and comprehensive analysis. Identified variants were assessed for pathogenicity using the American College of Medical Genetics and Genomics–Association for Molecular Pathology (ACMG-AMP) guidelines. Clinically relevant genetic variants in known and emerging CHD genes were identified. The hcCHD screen identified a clinically actionable variant in 22% of families. Subsequent comprehensive analysis identified a clinically actionable variant in an additional 9% of families in genes with recent disease associations. Overall, this two-tiered approach provided a clinically relevant variant for 31% of families. Interrogating GS data using our two-tiered method allowed identification of variants with high clinical utility in a third of our heterogeneous cohort. However, association of emerging genes with CHD etiology, and development of novel technologies for variant assessment and interpretation, will increase diagnostic yield during future reassessment of our GS data.

Background Transplantation of hearts retrieved from donation after circulatory death (DCD) donors is an evolving clinical practice. Objectives The purpose of this study is to provide an update on the authors’ Australian clinical program and discuss lessons learned since performing the world’s first series of distantly procured DCD heart transplants. Methods The authors report their experience of 23 DCD heart transplants from 45 DCD donor referrals since 2014. Donor details were collected using electronic donor records (Donate Life, Australia) and all recipient details were collected from clinical notes and electronic databases at St. Vincent’s Hospital. Results Hearts were retrieved from 33 of 45 DCD donors. A total of 12 donors did not progress to circulatory arrest within the pre-specified timeframe. Eight hearts failed to meet viability criteria during normothermic machine perfusion, and 2 hearts were declined due to machine malfunction. A total of 23 hearts were transplanted between July 2014 and April 2018. All recipients had successful implantation, with mechanical circulatory support utilized in 9 cases. One case requiring extracorporeal membrane oxygenation subsequently died on the sixth post-operative day, representing a mortality of 4.4% over 4 years with a total follow-up period of 15,500 days for the entire cohort. All surviving recipients had normal cardiac function on echocardiogram and no evidence of acute rejection on discharge. All surviving patients remain in New York Heart Association functional class I with normal biventricular function. Conclusions DCD heart transplant outcomes are excellent. Despite a higher requirement for mechanical circulatory support for delayed graft function, primarily in recipients with ventricular assist device support, overall survival and rejection episodes are comparable to outcomes from contemporary brain-dead donors.

Background: \ud Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene.\ud \ud Objectives: \ud This study sought to test the association between the rs9349379 genotype and SCAD.\ud \ud Methods: \ud Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD.\ud \ud Results: \ud The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence.\ud \ud Conclusions: \ud The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD.

Pathological left ventricular hypertrophy (LVH) occurs in response to pressure overload and remains the single most important clinical predictor of cardiac mortality. The molecular pathways in the induction of pressure overload LVH are potential targets for therapeutic intervention. Current treatments aim to remove the pressure overload stimulus for LVH, but do not completely reverse adverse cardiac remodelling. Although numerous molecular signalling steps in the induction of LVH have been identified, the initial step by which mechanical stretch associated with cardiac pressure overload is converted into a chemical signal that initiates hypertrophic signalling remains unresolved. In this study, we show that selective deletion of transient receptor potential melastatin 4 (TRPM4) channels in mouse cardiomyocytes results in an approximately 50% reduction in the LVH induced by transverse aortic constriction. Our results suggest that TRPM4 channel is an important component of the mechanosensory signalling pathway that induces LVH in response to pressure overload and represents a potential novel therapeutic target for the prevention of pathological LVH.

Inflow forecasts play an essential role in the management of hydropower reservoirs. Forecasts help operators schedule power generation in advance to maximise economic value, mitigate downstream flood risk, and meet environmental requirements. The horizon of operational inflow forecasts is often limited in range to ~2 weeks ahead, marking the predictability barrier of deterministic weather forecasts. Reliable inflow forecasts in the sub-seasonal to seasonal (S2S) range would allow operators to take proactive action to mitigate risks of adverse weather conditions, thereby improving water management and increasing revenue. This study outlines a method of deriving skilful S2S inflow forecasts using a case study reservoir in the Scottish Highlands. We generate ensemble inflow forecasts by training a linear regression model for the observed inflow onto S2S ensemble precipitation predictions from the European Centre for Medium-range Weather Forecasting (ECMWF). Subsequently, post-processing techniques from Ensemble Model Output Statistics are applied to derive calibrated S2S probabilistic inflow forecasts, without the application of a separate hydrological model. We find the S2S probabilistic inflow forecasts hold skill relative to climatological forecasts up to 6 weeks ahead. The inflow forecasts hold greater skill during winter compared with summer. The forecasts, however, struggle to predict high summer inflows, even at short lead-times. The potential for the S2S probabilistic inflow forecasts to improve water management and deliver increased economic value is confirmed using a stylised cost model. While applied to hydropower forecasting, the results and methods presented here are relevant to broader fields of water management and S2S forecasting applications.

Pathological left ventricular hypertrophy (LVH) is a consequence of pressure overload caused by systemic hypertension or aortic stenosis and is a strong predictor of cardiac failure and mortality. Understanding the molecular pathways in the development of pathological LVH may lead to more effective treatment. Here, we show that the transient receptor potential cation channel subfamily melastatin 4 (TRPM4) ion channel is an important contributor to the mechanosensory transduction of pressure overload that induces LVH. In mice with pressure overload induced by transverse aortic constriction (TAC) for two weeks, cardiomyocyte TRPM4 expression was reduced, as compared to control mice. Cardiomyocyte-specific TRPM4 inactivation reduced by ~50% the degree of TAC-induced LVH, as compared with wild type (WT). In WT mice, TAC activated the CaMKIIδ-HDAC4-MEF2A but not the calcineurin-NFAT-GATA4 pathway. In TRPM4 knock-out mice, activation of the CaMKIIδ-HDAC4-MEF2A pathway by TAC was significantly reduced. However, consistent with a reduction in the known inhibitory effect of CaMKIIδ on calcineurin activity, reduction in the CaMKIIδ-HDAC4-MEF2A pathway was associated with partial activation of the calcineurin-NFAT-GATA4 pathway. These findings indicate that the TRPM4 channel and its cognate signalling pathway are potential novel therapeutic targets for the prevention of pathological pressure overload-induced LVH.Significance statementPathological left ventricular hypertrophy (LVH) occurs in response to pressure overload and remains the single most important clinical predictor of cardiac mortality. Preventing pressure overload LVH is a major goal of therapeutic intervention. Current treatments aim to remove the stimulus for LVH by lowering elevated blood pressure or replacing a stenotic aortic valve. However, neither of these interventions completely reverses adverse cardiac remodelling. Although numerous molecular signalling steps in the induction of LVH have been identified, the initial step by which mechanical stretch associated with cardiac pressure overload is converted into a chemical signal that initiates hypertrophic signalling, remains unresolved. Here, we demonstrate that the TRPM4 channel is a component of the mechanosensory transduction pathway that ultimately leads to LVH.

A developmental surge in thyroid hormone (T3) after postnatal day-10 (P10), in mice, results in a burst of cardiomyocyte proliferation. This finding remains controversial, which could arise from perceived homogeneity of myocardial sampling for immunoblotting and immunohistochemical studies, or from differences in enzymatic digestion efficiency for cardiomyocyte isolation used to determine total ventricular cardiomyocyte numbers. Using a highly efficient (>97%) method for cardiomyocyte isolation, we show that exogenous T3 administered in vivo to post-neonatal (after postnatal P6) mice increased cardiomyocyte numbers. Using S- and M-phase markers, and lineage-tracing tools to assay for cell cycle activation and cytokinesis, respectively, we show that the T3-mediated increase in cardiomyocytes is confined to cells of the left ventricular (LV) apex; such spatial heterogeneity also being observed during normal development, which might confound substantiation of developmental increases in cardiomyocyte proliferation. In these apical cardiomyocytes, T3 stimulates proliferative ERK1/2 signaling, whereas those in the LV base are tonically inhibited by expression of the nuclear phospho-ERK1/2-specific dual-specificity phosphatase, DUSP5. In P21 Dusp5–/– mice, cardiomyocyte endowment and LV mass are increased relative to age-matched wild-type controls, suggesting that DUSP5 regulates early heart growth. Identification of mechanisms regulating cardiomyocyte proliferation may allow development of cardiac regenerative therapies.

RationaleGq-coupled receptors are thought to play a critical role in the induction of left ventricular hypertrophy (LVH) secondary to pressure overload, although mechano-sensitive channel activation by a variety of mechanisms has also been proposed, and the relative importance of calcineurin- and calmodulin kinase II (CaMKII)-dependent hypertrophic pathways remains controversial.ObjectiveTo determine the mechanisms regulating the induction of LVH in response to mechanical pressure overload.Methods and ResultsTransgenic mice with cardiac-targeted inhibition of Gq-coupled receptors (GqI mice) and their non-transgenic littermates (NTL) were subjected to neurohumoral stimulation (continuous, subcutaneous angiotensin II (AngII) infusion for 14 days) or mechanical pressure overload (transverse aortic arch constriction (TAC) for 21 days) to induce LVH. Candidate signalling pathway activation was examined. As expected, LVH observed in NTL mice with AngII infusion was attenuated in heterozygous (GqI+/-) mice and absent in homozygous (GqI-/-) mice. In contrast, LVH due to TAC was unaltered by either heterozygous or homozygous Gq inhibition. Gene expression of atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and α-skeletal actin (α-SA) was increased 48 hours after AngII infusion or TAC in NTL mice; in GqI mice, the increases in ANP, BNP and α-SA in response to AngII were completely absent, as expected, but all three increased after TAC. Increased nuclear translocation of nuclear factor of activated T-cells c4 (NFATc4), indicating calcineurin pathway activation, occurred in NTL mice with AngII infusion but not TAC, and was prevented in GqI mice infused with AngII. Nuclear and cytoplasmic CaMKIIδ levels increased in both NTL and GqI mice after TAC but not AngII infusion, with increased cytoplasmic phospho- and total histone deacetylase 4 (HDAC4) and increased nuclear myocyte enhancer factor 2 (MEF2) levels.ConclusionCardiac Gq receptors and calcineurin activation are required for neurohumorally mediated LVH but are not required for LVH induced by mechanical pressure overload (TAC); the latter is mediated by activation of the CaMKII-HDAC4-MEF2 pathway.

Supplemental Digital Content is available in the text., Background: Spontaneous coronary artery dissection (SCAD) occurs when an epicardial coronary artery is narrowed or occluded by an intramural hematoma. SCAD mainly affects women and is associated with pregnancy and systemic arteriopathies, particularly fibromuscular dysplasia. Variants in several genes, such as those causing connective tissue disorders, have been implicated; however, the genetic architecture is poorly understood. Here, we aim to better understand the diagnostic yield of rare variant genetic testing among a cohort of SCAD survivors and to identify genes or gene sets that have a significant enrichment of rare variants. Methods: We sequenced a cohort of 384 SCAD survivors from the United Kingdom, alongside 13 722 UK Biobank controls and a validation cohort of 92 SCAD survivors. We performed a research diagnostic screen for pathogenic variants and exome-wide and gene-set rare variant collapsing analyses. Results: The majority of patients within both cohorts are female, 29% of the study cohort and 14% validation cohort have a remote arteriopathy. Four cases across the 2 cohorts had a diagnosed connective tissue disorder. We identified pathogenic or likely pathogenic variants in 7 genes (PKD1, COL3A1, SMAD3, TGFB2, LOX, MYLK, and YY1AP1) in 14/384 cases in the study cohort and in 1/92 cases in the validation cohort. In our rare variant collapsing analysis, PKD1 was the highest-ranked gene, and several functionally plausible genes were enriched for rare variants, although no gene achieved study-wide statistical significance. Gene-set enrichment analysis suggested a role for additional genes involved in renal function. Conclusions: By studying the largest sequenced cohort of SCAD survivors, we demonstrate that, based on current knowledge, only a small proportion have a pathogenic variant that could explain their disease. Our findings strengthen the overlap between SCAD and renal and connective tissue disorders, and we highlight several new genes for future validation.

The warming of our planet is changing the Arctic dramatically. The area covered by sea-ice is shrinking and the ice that is left is younger and thinner. We took part in an expedition to the Arctic, to study how these changes affect organisms living in and under the ice. Following this expedition, we found that storms can more easily break the thinner ice. Storms form cracks in the sea ice, allowing sunlight to pass into the water below, which makes algal growth possible. Algae are microscopic “plants” that grow in water or sea ice. Storms also brought thick heavy snow, which pushed the ice surface below the water. This flooded the snow and created slush. We discovered that this slush is another good habitat for algae. If Arctic sea ice continues to thin, and storms become more common, we expect that these algal habitats will become more important in the future.

Animal models of pressure overload are valuable for understanding hypertensive heart disease. We characterised a surgical model of pressure overload-induced hypertrophy in C57BL/6J mice produced by suprarenal aortic constriction (SAC). Compared to sham controls, at one week post-SAC systolic blood pressure was significantly elevated and left ventricular (LV) hypertrophy was evident by a 50% increase in the LV weight-to-tibia length ratio due to cardiomyocyte hypertrophy. As a result, LV end-diastolic wall thickness-to-chamber radius (h/R) ratio increased, consistent with the development of concentric hypertrophy. LV wall thickening was not sufficient to normalise LV wall stress, which also increased, resulting in LV systolic dysfunction with reductions in ejection fraction and fractional shortening, but no evidence of heart failure. Pathological LV remodelling was evident by the re-expression of fetal genes and coronary artery perivascular fibrosis, with ischaemia indicated by enhanced cardiomyocyte Hif1a expression. The expression of stem cell factor receptor, c-Kit, was low basally in cardiomyocytes and did not change following the development of robust hypertrophy, suggesting there is no role for cardiomyocyte c-Kit signalling in pathological LV remodelling following pressure overload.

The 'fight or flight' response to physiological stress involves sympathetic nervous system activation, catecholamine release and adrenergic receptor stimulation. In the heart, this induces positive inotropy, previously attributed to the β

The burden of cardiovascular disease in women is being increasingly appreciated. Nevertheless, both clinicians and the general public are largely unaware that cardiovascular disease is the leading cause of death worldwide in women in all countries and that outcomes after a heart attack are worse for women than men. Of note, certain types of cardiovascular disease have a predilection for women, including spontaneous coronary artery dissection (SCAD) and fibromuscular dysplasia (FMD). Although uncommon, SCAD is being increasingly recognised as the cause of an acute coronary syndrome (ACS) and can recur. It is a potentially fatal, under-diagnosed condition that affects relatively young women, who often have few traditional risk factors, and is the commonest cause of a myocardial infarction associated with pregnancy. In contrast, FMD often remains silent but when manifested can also cause major sequelae, including renal infarction, stroke, cervical artery dissection and gut infarction. Here we provide an update on the diagnosis, aetiology and management of these important disorders that overwhelmingly affect women.

Stimulating regeneration of complex tissues and organs after injury to effect complete structural and functional repair, is an attractive therapeutic option that would revolutionize clinical medicine. Compared to many metazoan phyla that show extraordinary regenerative capacity, which in some instances persists throughout life, regeneration in mammalians, particularly humans, is limited or absent. Here we consider recent insights in the elucidation of molecular mechanisms of regeneration that have come from studies of tissue homeostasis and injury repair in mammalian tissues that span the spectrum from little or no self-renewal, to those showing active cell turnover throughout life. These studies highlight the diversity of factors that constrain regeneration, including immune responses, extracellular matrix composition, age, injury type, physiological adaptation, and angiogenic and neurogenic capacity. Despite these constraints, much progress has been made in elucidating key molecular mechanisms that may provide therapeutic targets for the development of future regenerative therapies, as well as previously unidentified developmental paradigms and windows-of-opportunity for improved regenerative repair.

Oceanographic observations from the Eurasian Basin north of Svalbard collected between January and June 2015 from the N-ICE2015 drifting expedition are presented. The unique winter observations are a key contribution to existing climatologies of the Arctic Ocean, and show a ∼100m deep winter mixed layer likely due to high sea ice growth rates in local leads. Current observations for the upper ∼200m show mostly a barotropic flow, enhanced over the shallow Yermak Plateau. The two branches of inflowing Atlantic Water are partly captured, confirming that the outer Yermak Branch follows the perimeter of the plateau, and the inner Svalbard Branch the coast. Atlantic Water observed to be warmer and shallower than in the climatology, is found directly below the mixed layer down to 800m depth, and is warmest along the slope, while properties inside the basin are quite homogeneous. From late May onwards, the drift was continually close to the ice edge and a thinner surface mixed layer and shallower Atlantic Water coincided with significant sea ice melt being observed. This article is protected by copyright. All rights reserved.

Atmospheric measurements were made over Arctic sea ice north of Svalbard from winter to early summer (January–June) 2015 during the Norwegian Young Sea Ice (N-ICE2015) expedition. These measurements, which are available publicly, represent a comprehensive meteorological data set covering the seasonal transition in the Arctic Basin over the new, thinner sea ice regime. Winter was characterized by a succession of storms that produced short-lived (less than 48 h) temperature increases of 20 to 30 K at the surface. These storms were driven by the hemispheric scale circulation pattern with a large meridional component of the polar jet stream steering North Atlantic storms into the high Arctic. Nonstorm periods during winter were characterized by strong surface temperature inversions due to strong radiative cooling (“radiatively clear state”). The strength and depth of these inversions were similar to those during the Surface Heat Budget of the Arctic Ocean (SHEBA) campaign. In contrast, atmospheric profiles during the “opaquely cloudy state” were different to those from SHEBA due to differences in the synoptic conditions and location within the ice pack. Storm events observed during spring/summer were the result of synoptic systems located in the Barents Sea and the Arctic Basin rather than passing directly over N-ICE2015. These synoptic systems were driven by a large-scale circulation pattern typical of recent years, with an Arctic Dipole pattern developing during June. Surface temperatures became near-constant 0°C on 1 June marking the beginning of summer. Atmospheric profiles during the spring and early summer show persistent lifted temperature and moisture inversions that are indicative of clouds and cloud processes.

Near-surface air temperatures close to 0°C were observed in situ over sea ice in the central Arctic during the last three winter seasons. Here we use in situ winter (December–March) temperature observations, such as those from Soviet North Pole drifting stations and ocean buoys, to determine how common Arctic winter warming events are. Observations of winter warming events exist over most of the Arctic Basin. Temperatures exceeding -5°C were observed during >30% of winters from 1954 to 2010 by North Pole drifting stations or ocean buoys. Using the ERA-Interim record (1979–2016), we show that the North Pole (NP) region typically experiences 10 warming events (T2m > 10°C) per winter, compared with only five in the Pacific Central Arctic (PCA). There is a positive trend in the overall duration of winter warming events for both the NP region (4.25 days/decade) and PCA (1.16 days/decade), due to an increased number of events of longer duration.

Winter time atmospheric observations from the 2015 Norwegian young sea-ICE campaign (N-ICE2015) are compared with data from the 1997-1998 Surface Heat Budget of the Arctic (SHEBA) campaign. Both datasets have a bimodal distribution of the net longwave radiative flux for January-February, with modal values of -40 W m-2 and 0 W m-2. These values correspond to the radiatively clear and opaquely cloudy states, respectively, and are likely to be representative of the wider Arctic. The new N-ICE2015 observations demonstrate that the two winter states operate in the Atlantic sector of the Arctic and regions of thin sea ice. We compare the N-ICE2015 and SHEBA data with ERA-Interim and output from the coupled Arctic regional climate model HIRHAM-NAOSIM. ERA-Interim simulates two Arctic winter states well and captures the timing of transitions from one state to the other, despite underestimating the cloud liquid water path. HIRHAM-NAOSIM has more cloud liquid water compared with ERA-Interim, but simulates the two states poorly. Our results demonstrate that models must simulate realistic synoptic forcing and temperature profiles to accurately capture the two Arctic winter states, and not only the presence of mixed-phase clouds. Using ERA-Interim, we find a positive trend in the number of opaquely cloudy days in the western Atlantic sector of the Arctic, and a strong correlation with the mean winter temperature over much of the Arctic Basin. Hence, the two Arctic winter states are important for understanding inter-annual variability in the Arctic. The N-ICE2015 dataset will help improve our understanding of these relationships.

Background There is increasing evidence that patients with spontaneous coronary artery dissection (SCAD) have an underlying genetic susceptibility (Goel et al JAMA Intern Med175:821–826, 2015). Moreover, in a collaborative study involving 1,055 SCAD cases and 7,190 controls, we recently reported the first risk allele for SCAD, a variant (rs9349379-A) in the PHACTR1/EDN1 genetic locus (Adlam et al J Amer Coll Cardiol73:58–66, 2019). Purpose We sought to determine the clinical characteristics and initial genetic data for 11 families, in which more than one member has had an episode of SCAD. Methods Participants were recruited largely via a social media platform. Informed consent was obtained in all cases for analysis of genetic information using whole genome sequencing, as well as collection of clinical information. SCAD was confirmed by review of coronary angiogram images and clinical data collected by phone interview, as well as review of specialist letters and hospital records. Results Of 235 participants recruited to date, 23 cases showed familial clustering involving sister-sister pairs in six families, three first-degree cousins in one family (picture), two first-degree cousins in two families, a mother-son pair, and a family with concordant monozygotic twins, that is both twins having had SCAD. In an additional family, SCAD is discordant in monozygotic twins. A comparison of symptoms, age at SCAD, clinical syndrome, cardiovascular risk factors, SCAD risk factors, environmental triggers, SCAD location, acute management, left ventricular function and recurrent SCAD events in these families versus isolated cases, will be presented. Three sister-sister pairs have undergone whole genome sequencing and these data sets are undergoing segregation analysis to identify rare variants that are present exclusively in affected family members. Family E Pedigree. Shaded circles represent first cousins affected with SCAD. The top number represents age (in years) of the SCAD event and the bottom number represents current age (in years). Conclusions To our knowledge, this is the largest assembly of SCAD cases with familial clustering reported to date. It provides strong evidence supporting an underlying genetic basis for SCAD, which most likely is a multi-genic disorder that also involves important gene-environment interactions.

The nomenclature of the Adrenoceptors has been agreed by the NC-IUPHAR Subcommittee on Adrenoceptors [58], see also [180]. Adrenoceptors, α1α1-Adrenoceptors are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. phenylephrine, methoxamine and cirazoline are agonists and prazosin and cirazoline antagonists considered selective for α1- relative to α2-adrenoceptors. [3H]prazosin and [125I]HEAT (BE2254) are relatively selective radioligands. S(+)-niguldipine also has high affinity for L-type Ca2+ channels. Fluorescent derivatives of prazosin (Bodipy PLprazosin- QAPB) are used to examine cellular localisation of α1-adrenoceptors. Selective α1-adrenoceptor agonists are used as nasal decongestants; antagonists to treat hypertension (doxazosin, prazosin) and benign prostatic hyperplasia (alfuzosin, tamsulosin). The α1- and β2-adrenoceptor antagonist carvedilol is used to treat congestive heart failure, although the contribution of α1-adrenoceptor blockade to the therapeutic effect is unclear. Several anti-depressants and anti-psychotic drugs are α1-adrenoceptor antagonists contributing to side effects such as orthostatic hypotension and extrapyramidal effects.Adrenoceptors, α2 α2-Adrenoceptors are activated by (-)-adrenaline and with lower potency by (-)-noradrenaline. brimonidine and talipexole are agonists and rauwolscine and yohimbine antagonists selective for α2- relative to α1-adrenoceptors. [3H]rauwolscine, [3H]brimonidine and [3H]RX821002 are relatively selective radioligands. There is species variation in the pharmacology of the α2A-adrenoceptor. Multiple mutations of α2-adrenoceptors have been described, some associated with alterations in function. Presynaptic α2-adrenoceptors regulate many functions in the nervous system. The α2-adrenoceptor agonists clonidine, guanabenz and brimonidine affect central baroreflex control (hypotension and bradycardia), induce hypnotic effects and analgesia, and modulate seizure activity and platelet aggregation. clonidine is an anti-hypertensive and counteracts opioid withdrawal. dexmedetomidine (also xylazine) is used as a sedative and analgesic in human and veterinary medicine with sympatholytic and anxiolytic properties. The α2-adrenoceptor antagonist yohimbine has been used to treat erectile dysfunction and mirtazapine as an anti-depressant. The α2B subtype appears to be involved in neurotransmission in the spinal cord and α2C in regulating catecholamine release from adrenal chromaffin cells.Adrenoceptors, ββ-Adrenoceptors are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. Isoprenaline is selective for β-adrenoceptors relative to α1- and α2-adrenoceptors, while propranolol (pKi 8.2-9.2) and cyanopindolol (pKi 10.0-11.0) are relatively β1 and β2 adrenoceptor-selective antagonists. (-)-noradrenaline, xamoterol and (-)-Ro 363 show selectivity for β1- relative to β2-adrenoceptors. Pharmacological differences exist between human and mouse β3-adrenoceptors, and the 'rodent selective' agonists BRL 37344 and CL316243 have low efficacy at the human β3-adrenoceptor whereas CGP 12177 and L 755507 activate human β3-adrenoceptors [88]. β3-Adrenoceptors are resistant to blockade by propranolol, but can be blocked by high concentrations of bupranolol. SR59230A has reasonably high affinity at β3-adrenoceptors, but does not discriminate well between the three β- subtypes whereas L 755507 is more selective. [125I]-cyanopindolol, [125I]-hydroxy benzylpindolol and [3H]-alprenolol are high affinity radioligands that label β1- and β2- adrenoceptors and β3-adrenoceptors can be labelled with higher concentrations (nM) of [125I]-cyanopindolol together with β1- and β2-adrenoceptor antagonists. [3H]-L-748337 is a β3-selective radioligand [474]. Fluorescent ligands such as BODIPY-TMR-CGP12177 can be used to track β-adrenoceptors at the cellular level [8]. Somewhat selective β1-adrenoceptor agonists (denopamine, dobutamine) are used short term to treat cardiogenic shock but, chronically, reduce survival. β1-Adrenoceptor-preferring antagonists are used to treat hypertension (atenolol, betaxolol, bisoprolol, metoprolol and nebivolol), cardiac arrhythmias (atenolol, bisoprolol, esmolol) and cardiac failure (metoprolol, nebivolol). Cardiac failure is also treated with carvedilol that blocks β1- and β2-adrenoceptors, as well as α1-adrenoceptors. Short (salbutamol, terbutaline) and long (formoterol, salmeterol) acting β2-adrenoceptor-selective agonists are powerful bronchodilators used to treat respiratory disorders. Many first generation β-adrenoceptor antagonists (propranolol) block both β1- and β2-adrenoceptors and there are no β2-adrenoceptor-selective antagonists used therapeutically. The β3-adrenoceptor agonist mirabegron is used to control overactive bladder syndrome.

Spontaneous coronary artery dissection (SCAD) is a non-atherosclerotic form of coronary artery disease of unknown cause that predominantly affects women (>90%; mean age 44–55 years) and can be fatal. The finding of familial clustering, including the concordant involvement of monozygotic twins, and its association with the PHACTR1/EDN1 genetic locus, indicate a genetic predisposition to its pathophysiology. A human induced pluripotent stem cell line (hiPSC) was generated from a patient who had survived an episode of SCAD. This disease-specific hiPSC line will be useful for the study of SCAD after differentiation into blood vessel-forming cells. Keywords: SCAD, Induced pluripotent stem cells, Disease modeling, Cardiovascular biology, Reprogramming

The ‘fight or flight’ response, involving sympathetic nervous system activation and catecholamine release, is central to survival. Resulting activation of adrenergic receptors (ARs) drives physiological responses, such as positive inotropy, which to date has been attributed solely to β 1 -AR/Gs/adenylyl cyclase/protein kinase A pathway-activation. We previously demonstrated that overexpression of the α 1A -AR is cardioprotective in rodents in the setting of pathological cardiac stress; a finding in agreement with studies of α 1A -AR inactivation. However, it remains unknown if α 1A -ARs also protect the heart from physiological stress. Using a tamoxifen-inducible, cardiomyocyte-specific α 1A -AR knockdown mouse model, we evaluated cardiac responses to swim exercise. Treatment of adult (8-12 week) mice with 4-OH tamoxifen (Tam) resulted in a 7.4 fold decrease (p1A -AR mRNA levels, with no compensatory changes in expression of β 1 -, β 2 - or α 2 -AR subtypes. A 90 minute, twice daily, four-week swim challenge induced eccentric cardiac hypertrophy, with Tam- and vehicle-treated mice displaying similar increases in heart weight/tibia length (mean increase: 1.4 and 1.6mg/mm, respectively; pIgf-1 mRNA increased 1.7 and 0.7 fold (p=0.004 vs sedentary mice), respectively, with no increase in Nppb , Myh7 or Acta1 mRNA. Cardiac function, assessed by micromanometry and echocardiography, showed increases in dP/dt min/EDV (mean: -117 vs -150 mmHg/s/μL; p=0.011), end-diastolic volume (mean: 76.9 vs 68.0μL; p=0.038) and end-systolic volume (mean: 29.4 vs 21.9μL; p=0.018), as well as a decrease in ejection fraction (mean: 63 vs 68%; p=0.046) in Tam- compared with vehicle-treated mice, respectively. Thus, despite a similar hypertrophic response, mice with cardiomyocyte-specific α 1A -AR inactivation showed an impaired contractile response to a sustained swim challenge. These findings are consistent with cardiomyocyte α 1A -ARs playing an important role in maintaining cardiac contractility in response to physiological stress.

Rapid changes are occurring in the Arctic, including a reduction in sea ice thickness and coverage and a shift towards younger and thinner sea ice. Snow and sea ice models are often used to study these ongoing changes in the Arctic, and are typically forced by atmospheric reanalyses in absence of observations. ERA5 is a new global reanalysis that will replace the widely used ERA-Interim (ERA-I). In this study, we compare the 2 m air temperature (T2M), snowfall (SF) and total precipitation (TP) from ERA-I and ERA5, and evaluate these products using buoy observations from Arctic sea ice for the years 2010 to 2016. We further assess how biases in reanalyses can influence the snow and sea ice evolution in the Arctic, when used to force a thermodynamic sea ice model. We find that ERA5 is generally warmer than ERA-I in winter and spring (0–1.2 ∘C), but colder than ERA-I in summer and autumn (0–0.6 ∘C) over Arctic sea ice. Both reanalyses have a warm bias over Arctic sea ice relative to buoy observations. The warm bias is smaller in the warm season, and larger in the cold season, especially when the T2M is below −25 ∘C in the Atlantic and Pacific sectors. Interestingly, the warm bias for ERA-I and new ERA5 is on average 3.4 and 5.4 ∘C (daily mean), respectively, when T2M is lower than −25 ∘C. The TP and SF along the buoy trajectories and over Arctic sea ice are consistently higher in ERA5 than in ERA-I. Over Arctic sea ice, the TP in ERA5 is typically less than 10 mm snow water equivalent (SWE) greater than in ERA-I in any of the seasons, while the SF in ERA5 can be 50 mm SWE higher than in ERA-I in a season. The largest increase in annual TP (40–100 mm) and SF (100–200 mm) in ERA5 occurs in the Atlantic sector. The SF to TP ratio is larger in ERA5 than in ERA-I, on average 0.6 for ERA-I and 0.8 for ERA5 along the buoy trajectories. Thus, the substantial anomalous Arctic rainfall in ERA-I is reduced in ERA5, especially in summer and autumn. Simulations with a 1-D thermodynamic sea ice model demonstrate that the warm bias in ERA5 acts to reduce thermodynamic ice growth. The higher precipitation and snowfall in ERA5 results in a thicker snowpack that allows less heat loss to the atmosphere. Thus, the larger winter warm bias and higher precipitation in ERA5, compared with ERA-I, result in thinner ice thickness at the end of the growth season when using ERA5; however the effect is small during the freezing period.

Published version, licensed by the CC BY 4.0, available at http://dx.doi.org/10.1038/s41598-019-45574-5 A large retreat of sea-ice in the ‘stormy’ Atlantic Sector of the Arctic Ocean has become evident through a series of record minima for the winter maximum sea-ice extent since 2015. Results from the Norwegian young sea ICE (N-ICE2015) expedition, a five-month-long (Jan-Jun) drifting ice station in first and second year pack-ice north of Svalbard, showcase how sea-ice in this region is frequently affected by passing winter storms. Here we synthesise the interdisciplinary N-ICE2015 dataset, including independent observations of the atmosphere, snow, sea-ice, ocean, and ecosystem. We build upon recent results and illustrate the different mechanisms through which winter storms impact the coupled Arctic sea-ice system. These short-lived and episodic synoptic-scale events transport pulses of heat and moisture into the Arctic, which temporarily reduce radiative cooling and henceforth ice growth. Cumulative snowfall from each sequential storm deepens the snow pack and insulates the sea-ice, further inhibiting ice growth throughout the remaining winter season. Strong winds fracture the ice cover, enhance ocean-ice-atmosphere heat fluxes, and make the ice more susceptible to lateral melt. In conclusion, the legacy of Arctic winter storms for sea-ice and the ice-associated ecosystem in the Atlantic Sector lasts far beyond their short lifespan.

Neointimal hyperplasia, stimulated by injury and certain vascular diseases, promotes artery obstruction and tissue ischemia. In vascular smooth muscle cell (VSMCs), multiple modulators of protein handling machinery regulate intimal hyperplasia. These include elements of the VSMC unfolded protein response to endoplasmic reticulum stress (UPRER), and transglutaminase 2 (TG2), which catalyzes post-translational protein modification. Previous results for deficiency of UPRER-specific mediator XBP1, and of TG2, have been significant, but in multiple instances contradictory, for effects on cultured VSMC function, and, using multiple models, for neointimal hyperplasia in vivo. Here, we engineered VSMC-specific deficiency of XBP1, and studied cultured VSMCs, and neointimal hyperplasia in response to carotid artery ligation in vivo. Intimal area almost doubled in Xbp1fl/fl SM22α-CRE+ mice 21 days post-ligation. Cultured murine Xbp1 deficient VSMCs migrated more in response to platelet derived growth factor (PDGF) than control VSMCs, and had an increased level of inositol-requiring enzyme 1α (Ire1α), a PDGF receptor-binding UPRER transmembrane endonuclease whose substrates include XBP1. Cultured XBP1-deficient VSMCs demonstrated decreased levels of TG2 protein, in association with increased TG2 polyubiquitination, but with increased TG transamidation catalytic activity. Moreover, IRE1α, and TG2-specific transamidation cross-links were increased in carotid artery neointima in Xbp1fl/fl SM22α-CRE+ mice. Cultured TG2-deficient VSMCs had decreased XBP1 associated with increased IRE1α, and increased migration in response to PDGF. Neointimal hyperplasia also was significantly increased in Tgm2fl/fl SM22α-CRE+ mice at 21 days after carotid ligation. In conclusion, a VSMC regulatory circuit between XBP1 and TG2 limits neointimal hyperplasia in response to carotid ligation.

The ‘CoINPocket’ approach identifies pharmacological similarities between G protein–coupled receptors. On the basis of predicted pharmacological similarity to a few phylogenetically unrelated receptors, the approach identified surrogate ligands for the orphan receptor GPR37L1. Understanding the pharmacological similarity of G protein–coupled receptors (GPCRs) is paramount for predicting ligand off-target effects, drug repurposing, and ligand discovery for orphan receptors. Phylogenetic relationships do not always correctly capture pharmacological similarity. Previous family-wide attempts to define pharmacological relationships were based on three-dimensional structures and/or known receptor–ligand pairings, both unavailable for orphan GPCRs. Here, we present GPCR–CoINPocket, a novel contact-informed neighboring pocket metric of GPCR binding-site similarity that is informed by patterns of ligand–residue interactions observed in crystallographically characterized GPCRs. GPCR–CoINPocket is applicable to receptors with unknown structure or ligands and accurately captures known pharmacological relationships between GPCRs, even those undetected by phylogeny. When applied to orphan receptor GPR37L1, GPCR–CoINPocket identified its pharmacological neighbors, and transfer of their pharmacology aided in discovery of the first surrogate ligands for this orphan with a 30% success rate. Although primarily designed for GPCRs, the method is easily transferable to other protein families.

miRNAs play critical roles in heart disease. In addition to differential miRNA expression, miRNA-mediated control is also affected by variable miRNA processing or alternative 3'-end cleavage and polyadenylation (APA) of their mRNA targets. To what extent these phenomena play a role in the heart remains unclear. We sought to explore miRNA processing and mRNA APA in cardiomyocytes, and whether these change during cardiac hypertrophy. Thoracic aortic constriction (TAC) was performed to induce hypertrophy in C57BL/6J mice. RNA extracted from cardiomyocytes of sham-treated, pre-hypertrophic (2 days post-TAC), and hypertrophic (7 days post-TAC) mice was subjected to small RNA- and poly(A)-test sequencing (PAT-Seq). Differential expression analysis matched expectations; nevertheless we identified ~400 mRNAs and hundreds of noncoding RNA loci as altered with hypertrophy for the first time. Although multiple processing variants were observed for many miRNAs, there was little change in their relative proportions during hypertrophy. PAT-Seq mapped ~48,000 mRNA 3'-ends, identifying novel 3' untranslated regions (3'UTRs) for over 7000 genes. Importantly, hypertrophy was associated with marked changes in APA with a net shift from distal to more proximal mRNA 3'-ends, which is predicted to decrease overall miRNA repression strength. We independently validated several examples of 3'UTR proportion change and showed that alternative 3'UTRs associate with differences in mRNA translation. Our work suggests that APA contributes to altered gene expression with the development of cardiomyocyte hypertrophy and provides a rich resource for a systems-level understanding of miRNA-mediated regulation in physiological and pathological states of the heart.

GPCRs are the most successful pharmaceutical targets in history. Nevertheless, the pharmacology of many GPCRs remains inaccessible as their endogenous or exogenous modulators have not been discovered. Tools that explore the physiological functions and pharmacological potential of these 'orphan' GPCRs, whether they are endogenous and/or surrogate ligands, are therefore of paramount importance. Rates of receptor deorphanization determined by traditional reverse pharmacology methods have slowed, indicating a need for the development of more sophisticated and efficient ligand screening approaches. Here, we discuss the use of structure-based ligand discovery approaches to identify small molecule modulators for exploring the function of orphan GPCRs. These studies have been buoyed by the growing number of GPCR crystal structures solved in the past decade, providing a broad range of template structures for homology modelling of orphans. This review discusses the methods used to establish the appropriate signalling assays to test orphan receptor activity and provides current examples of structure-based methods used to identify ligands of orphan GPCRs. Linked Articles This article is part of a themed section on Molecular Pharmacology of G Protein-Coupled Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.20/issuetoc.

Congenital heart disease (CHD) affects up to 1% of live births. However, a genetic diagnosis is not made in most cases. The purpose of this study was to assess the outcomes of genome sequencing (GS) of a heterogeneous cohort of CHD patients.Ninety-seven families with probands born with CHD requiring surgical correction were recruited for genome sequencing. At minimum, a proband-parents trio was sequenced per family. GS data were analyzed via a two-tiered method: application of a high-confidence gene screen (hcCHD), and comprehensive analysis. Identified variants were assessed for pathogenicity using the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines.Clinically relevant genetic variants in known and emerging CHD genes were identified. The hcCHD screen identified a clinically actionable variant in 22% of families. Subsequent comprehensive analysis identified a clinically actionable variant in an additional 9% of families in genes with recent disease associations. Overall, this two-tiered approach provided a clinically relevant variant for 31% of families.Interrogating GS data using our two-tiered method allowed identification of variants with high clinical utility in a third of our heterogeneous cohort. However, association of emerging genes with CHD etiology, and development of novel technologies for variant assessment and interpretation, will increase diagnostic yield during future reassessment of our GS data.

Background Over 100 mammalian G protein-coupled receptors are yet to be matched with endogenous ligands; these so-called orphans are prospective drug targets for the treatment of disease. GPR37L1 is one such orphan, abundant in the brain and detectable as mRNA in the heart and kidney. GPR37L1 ablation was reported to cause hypertension and left ventricular hypertrophy, and thus, we sought to further define the role of GPR37L1 in blood pressure homeostasis. Methods We investigated the cardiovascular effects of GPR37L1 using wild-type (GPR37L1wt/wt) and null (GPR37L1KO/KO) mice established on a C57BL/6J background, both under baseline conditions and during AngII infusion. We profiled GPR37L1 tissue expression, examining the endogenous receptor by immunoblotting and a β-galactosidase reporter mouse by immunohistochemistry. Results GPR37L1 protein was abundant in the brain but not detectable in the heart and kidney. We measured blood pressure in GPR37L1wt/wt and GPR37L1KO/KO mice and found that deletion of GPR37L1 causes a female-specific increase in systolic, diastolic, and mean arterial pressures. When challenged with short-term AngII infusion, only male GPR37L1KO/KO mice developed exacerbated left ventricular hypertrophy and evidence of heart failure, while the female GPR37L1KO/KO mice were protected from cardiac fibrosis. Conclusions Despite its absence in the heart and kidney, GPR37L1 regulates baseline blood pressure in female mice and is crucial for cardiovascular compensatory responses in males. The expression of GPR37L1 in the brain, yet absence from peripheral cardiovascular tissues, suggests this orphan receptor is a hitherto unknown contributor to central cardiovascular control. Electronic supplementary material The online version of this article (10.1186/s13293-018-0173-y) contains supplementary material, which is available to authorized users.

Background: Congenital heart disease (CHD)—structural abnormalities of the heart that arise during embryonic development—is the most common inborn malformation, affecting ≤1% of the population. However, currently, only a minority of cases can be explained by genetic abnormalities. The goal of this study was to identify disease-causal genetic variants in 30 families affected by CHD. Methods: Whole-exome sequencing was performed with the DNA of multiple family members. We utilized a 2-tiered whole-exome variant screening and interpretation procedure. First, we manually curated a high-confidence list of 90 genes known to cause CHD in humans, identified predicted damaging variants in genes on this list, and rated their pathogenicity using American College of Medical Genetics and Genomics-Association for Molecular Pathology guidelines. RESULTS: In 3 families (10%), we found pathogenic variants in known CHD genes TBX5, TFAP2B, and PTPN11, explaining the cardiac lesions. Second, exomes were comprehensively analyzed to identify additional predicted damaging variants that segregate with disease in CHD candidate genes. In 10 additional families (33%), likely disease-causal variants were uncovered in PBX1, CNOT1, ZFP36L2, TEK, USP34, UPF2, KDM5A, KMT2C, TIE1, TEAD2, and FLT4. Conclusions: The pathogenesis of CHD could be explained using our high-confidence CHD gene list for variant filtering in a subset of cases. Furthermore, our unbiased screening procedure of family exomes implicates additional genes and variants in the pathogenesis of CHD, which suggest themselves for functional validation. This 2-tiered approach provides a means of (1) identifying clinically actionable variants and (2) identifying additional disease-causal genes, both of which are essential for improving the molecular diagnosis of CHD., Background: Congenital heart disease (CHD), structural abnormalities of the heart that arise during embryonic development, are the most common inborn malformations, affecting up to 1% of the population. However, currently only a minority of cases can be explained by genetic abnormalities. The goal of this study was to identify disease-causal genetic variants in 30 families affected by CHD. Methods and Results: Whole-exome sequencing was performed with the DNA of multiple family members. We utilized a two-tiered whole-exome variant screening and interpretation procedure. Firstly, we manually curated a high-confidence list of 90 genes known to cause CHD in humans, identified predicted-damaging variants in genes on this list, and rated their pathogenicity using ACMG-AMP guidelines. In three families (10%), we found pathogenic variants in known CHD genes TBX5, TFAP2B, and PTPN11, explaining the cardiac lesions. Secondly, exomes were comprehensively analyzed to identify additional predicted-damaging variants that segregate with disease in CHD candidate genes. In ten additional families (33%), likely disease-causal variants were uncovered in PBX1, CNOT1, ZFP36L2, TEK, USP34, UPF2, KDM5A, KMT2C, TIE1, TEAD2, and FLT4. Conclusions: The etiology of CHD could be explained using our high-confidence CHD genes list for variant filtering in a subset of cases. Furthermore, our unbiased screening procedure of family exomes implicates additional genes and variants in the pathogenesis of CHD, that suggest themselves for functional validation. This two-tiered approach provides a means of (1) identifying clinically actionable variants and (2) identifying additional disease-causal genes, both of which are essential for improving the molecular diagnosis of CHD.

We have previously demonstrated that adult transgenic C57BL/6J mice with CM-restricted overexpression of the dominant negative W v mutant protein (dn-c-kit-Tg) respond to pressure overload with robust cardiomyocyte (CM) cell cycle entry. Here, we tested if outcomes after myocardial infarction (MI) due to coronary artery ligation are improved in this transgenic model. Compared to non-transgenic littermates (NTLs), adult male dn-c-kit-Tg mice displayed CM hypertrophy and concentric left ventricular (LV) hypertrophy in the absence of an increase in workload. Stroke volume and cardiac output were preserved and LV wall stress was markedly lower than that in NTLs, leading to a more energy-efficient heart. In response to MI, infarct size in adult (16-week old) dn-c-kit-Tg hearts was similar to that of NTL after 24 h but was half that in NTL hearts 12 weeks post-MI. Cumulative CM cell cycle entry was only modestly increased in dn-c-kit-Tg hearts. However, dn-c-kit-Tg mice were more resistant to infarct expansion, adverse LV remodelling and contractile dysfunction, and suffered no early death from LV rupture, relative to NTL mice. Thus, pre-existing cardiac hypertrophy lowers wall stress in dn-c-kit-Tg hearts, limits infarct expansion and prevents death from myocardial rupture.

Objective— Stimulation of cardiac α 1A -adrenergic receptors (α 1A -AR) has been proposed for treatment of heart failure, since it increases myocardial contractility. We investigated a different mechanism, induction of angiogenesis. Approach and Results— Four to 6 weeks after permanent coronary artery occlusion, transgenic rats with cardiomyocyte-specific α 1A -adrenergic receptor overexpression had less remodeling than their nontransgenic littermates, with less fibrosis, hypertrophy and lung weight, and preserved left ventricular ejection fraction and wall stress (all P −1 g −1 ; P 1A -agonist, resulting in angiogenesis. Conditioned medium from cultured cardiomyocytes treated with an α 1A agonist enhanced human umbilical vein endothelial cell tubule formation, which was blocked by an anti–vascular endothelial growth factor-A antibody. Moreover, improved cardiac function, blood flow, and increased capillary density after chronic coronary artery occlusion in transgenic rats were blocked by either a mitogen ERK kinase (MEK) or a vascular endothelial growth factor-A inhibitor. Conclusion— Cardiomyocyte-specific overexpression of the α 1A -adrenergic receptors resulted in enhanced MEK-dependent cardiomyocyte vascular endothelial growth factor-A expression, which stimulates angiogenesis via a paracrine mechanism involving heterocellular cardiomyocyte/endothelial cell signaling, protecting against remodeling and heart failure after chronic coronary artery occlusion.

Highlights • Shelf sediment iron source concentrated around coastal margins. • No large iron flux from sediments on shallow submerged plateaus in the open ocean. • Horizontal advection of iron more important than upwelling of iron at ocean fronts. • Western boundary currents major supply mechanism of iron for Sub-Antarctic Zone. Abstract Primary productivity is limited by the availability of iron over large areas of the global ocean. Changes in the supply of iron to these regions could have major impacts on primary productivity and the carbon cycle. However, source regions and supply mechanisms of iron to the global oceans remain poorly constrained. Shelf sediments are considered one of the largest sources of dissolved iron to the global ocean, and a large shelf sediment iron flux is prescribed in many biogeochemical models over all areas of bathymetry shallower than 1000 m. Here, we infer the likely location of shelf sediment iron sources in the Southern Ocean, by identifying where satellite chlorophyll concentrations are enhanced over shallow bathymetry (2 mg m−3 are only found within 50 km of a continental or island coastline. These results suggest that sedimentary iron sources only exist on continental and island shelves. Large sedimentary iron fluxes do not seem present on seamounts and submerged plateaus. Large chlorophyll blooms develop where the western boundary currents detach from the continental shelves, and turn eastward into the Sub-Antarctic Zone. Chlorophyll concentrations are enhanced along contours of sea surface height extending off the continental shelves, as shown by the trajectories of virtual water parcels in satellite altimetry data. These analyses support the hypothesis that bioavailable iron from continental shelves is entrained into western boundary currents, and advected into the Sub-Antarctic Zone along the Dynamical Subtropical Front. Our results indicate that upwelling at fronts in the open ocean is unlikely to deliver iron to the ocean surface from deep sources. Finally, we hypothesise how a reduction in sea level may have altered the distribution of shelf sediment iron sources in the Southern Ocean and increased export production over the Sub-Antarctic Zone during glacial intervals.

Urban metabolism provides a framework to understand resource flows into cities and waste flows out. Its potential has been hampered by the lack of good disaggregated data. This article presents energy-use findings for the residential sector for the city of Los Angeles based on census-block–level aggregation of address-level electricity use obtained from the Los Angeles Department of Water and Power. City or county billing data by customer class over time can enable empirical tracking of energy conservation and efficiency programs by different customer classes, and matched to census information and county tax assessor data about building vintage, size, and type can provide information important for rate setting, for example, or energy conservation and efficiency program investments. We report on median electricity demand and corresponding greenhouse gas emissions and expenditures at three geographical aggregations: city council district (15 in total); neighborhood (114 in total); and census block group (2,538 in total). We find that the ratio of median annual demand between highest- and lowest-tier users is 26 at the census-block group level, but only 2.2 at the city council district level, demonstrating that spatial aggregation significantly masks the degree of variation that may be observed. We also show how such data can enable the description of energy to develop energy disclosure thresholds that reflect a city's morphology. In contrast to New York City's 50,000-square-foot reporting threshold, to capture half of Los Angeles’ electricity consumption, the threshold for reporting would have to be 5,000 square feet.

Summary Background Orthotopic heart transplantation is the gold-standard long-term treatment for medically refractive end-stage heart failure. However, suitable cardiac donors are scarce. Although donation after circulatory death has been used for kidney, liver, and lung transplantation, it is not used for heart transplantation. We report a case series of heart transplantations from donors after circulatory death. Methods The recipients were patients at St Vincent's Hospital, Sydney, Australia. They received Maastricht category III controlled hearts donated after circulatory death from people younger than 40 years and with a maximum warm ischaemic time of 30 min. We retrieved four hearts through initial myocardial protection with supplemented cardioplegia and transferred to an Organ Care System (Transmedics) for preservation, resuscitation, and transportation to the recipient hospital. Findings Three recipients (two men, one woman; mean age 52 years) with low transpulmonary gradients ( Interpretation Strict limitations on donor eligibility, optimised myocardial protection, and use of a portable ex-vivo organ perfusion platform can enable successful, distantly procured orthotopic transplantation of hearts donated after circulatory death. Funding NHMRC, John T Reid Charitable Trust, EVOS Trust Fund, Harry Windsor Trust Fund.

The shortage of donors in cardiac transplantation may be alleviated by the use of allografts from donation after circulatory death (DCD) donors. We have previously shown that hearts exposed to 30 min warm ischemic time and then flushed with Celsior supplemented with agents that activate ischemic postconditioning pathways, show complete recovery on a blood-perfused ex vivo working heart apparatus. In this study, these findings were assessed in a porcine orthotopic heart transplant model. DCD hearts were preserved with either normothermic ex vivo perfusion (NEVP) using a clinically approved device, or with standard cold storage (CS) for 4 h. Orthotopic transplantation into recipient animals was subsequently undertaken. Five of six hearts preserved with NEVP demonstrated favorable lactate profiles during NEVP and all five could be weaned off cardiopulmonary bypass posttransplant, compared with 0 of 3 hearts preserved with CS (p

SUMMARYThe interstitial and perivascular spaces of the mammalian heart contain a highly interactive tissue community essential for cardiac homeostasis, repair and regeneration. Mesenchymal cells (fibroblasts) are one of the most abundant cell types, playing key roles as sentinels, tissue architects, paracrine signaling hubs and lineage precursors, and are linked to heart disease through their roles in inflammation and fibrosis. Platelet-derived growth factors (PDGFs) are secreted by several cell types involved in cardiac injury and repair, and are recognized mitogens for cardiac fibroblasts and mesenchymal stem cells. However, their roles are complex and investigations of their impact on heart repair have produced contrasting outcomes, leaving therapeutic potential uncertain. Here, we use new approaches and tools, including single cell RNA sequencing, to explore cardiac fibroblast heterogeneity and how PDGF receptor α (PDGFRα) signaling impacts fibroblasts during heart repair. Short-term systemic delivery of PDGF-AB to mice from the time of myocardial infarction (MI) led to enhanced anatomical and functional recovery. Underpinning these benefits was a priming effect, in which PDGF-AB accelerated exit of fibroblasts from quiescence and induced a higher translational biosynthetic capacity in both fibroblasts and macrophages without triggering fibrosis. Our study highlights the significant biosynthetic heterogeneity and plasticity in cardiac fibroblast populations, and suggests a rationale for a novel therapeutic approach to cardiac injury involving controlled stimulation of fibroblast activation.

Malignant paratesticular tumors are rare. We describe the first documented case of a paratesticular serous ovarian type epithelial tumor (OTET) associated with abdominal metastasis and its treatment.