A variety-specific analysis of climate change effects on California winegrapes.

California contains a broad geography over which climate conditions can be suitable for cultivating multiple varieties of winegrapes. However, climate change is projected to make winegrape cultivation more challenging across many of California's winegrowing regions. In order to understand the potential effects of climate change on winegrapes, this study models variety-specific phenology for six winegrape varieties and quantifies the change in phenology and viticulturally-important agroclimate metrics over 12 of California's American Viticultural Areas (AVAs) by the mid-21st century. Results show more rapid development for winegrapes with earlier budburst, flowering, veraison, and maturation across all varieties and AVAs. Cabernet Sauvignon shows the greatest change in phenology timing, while Chardonnay shows the least change. Likewise, the West Sonoma Coast AVA shows the greatest average change in phenology timing across varieties and development stages and Lodi AVA shows the least. Projected changes in agroclimatic metrics include an additional month of potentially damaging heat days (above 35 °C) in some AVAs, and decreases in frost days. These results have implications for numerous factors related to viticultural production, including water resources management and crop yield and quality, and underscore the need for California winegrape growers to improve their resilience to climate change by adopting strategies such as increasing soil health and water use efficiency and selecting cultivars suited for future climate conditions. By conducting climate effects analyses at the variety-specific and AVA scale, important information is provided to the winegrowing industry at a resolution that can support decision-making towards resilience.

Days alive and out of hospital for children born with single-ventricle heart disease.

BACKGROUND: This study describes the illness burden in the first year of life for children with single-ventricle heart disease, using the metric of days alive and out of hospital to characterize morbidity and mortality. METHODS: This is a retrospective single-centre study of single-ventricle patients born between 2005 and 2021 who had their initial operation performed at our institution. Patient demographics, anatomical details, and hospitalizations were extracted from our institutional single-ventricle database. Days alive and out of hospital were calculated by subtracting the number of days hospitalized from number of days alive during the first year of life. A multivariable linear regression with stepwise variable selection was used to determine independent risk factors associated with fewer days alive and out of hospital. RESULTS: In total, 437 patients were included. Overall median number of days alive and out of hospital in the first year of life for single-ventricle patients was 278 days (interquartile range 157-319 days). In a multivariable analysis, low birth weight (<2.5kg) (b = -37.55, p = 0.01), presence of a dominant right ventricle (b = -31.05, p = 0.01), moderate-severe dominant atrioventricular valve regurgitation at birth (b = -37.65, p < 0.05), index hybrid Norwood operation (b = -138.73, p < 0.01), or index heart transplant (b = -158.41, p < 0.01) were all independently associated with fewer days alive and out of hospital. CONCLUSIONS: Children with single-ventricle heart defects have significant illness burden in the first year of life. Identifying risk factors associated with fewer days alive and out of hospital may aid in counselling families regarding expectations and patient prognosis.

Induced Pluripotent Stem Cell-Based Modeling of Single-Ventricle Congenital Heart Diseases.

PURPOSE OF REVIEW: Congenital heart disease includes a wide variety of structural cardiac defects, the most severe of which are single ventricle defects (SVD). These patients suffer from significant morbidity and mortality; however, our understanding of the developmental etiology of these conditions is limited. Model organisms offer a window into normal and abnormal cardiogenesis yet often fail to recapitulate complex congenital heart defects seen in patients. The use of induced pluripotent stem cells (iPSCs) derived from patients with single-ventricle defects opens the door to studying SVD in patient-derived cardiomyocytes (iPSC-CMs) in a variety of different contexts, including organoids and chamber-specific cardiomyocytes. As the genetic and cellular causes of SVD are not well defined, patient-derived iPSC-CMs hold promise for uncovering mechanisms of disease development and serve as a platform for testing therapies. The purpose of this review is to highlight recent advances in iPSC-based models of SVD. RECENT FINDINGS: Recent advances in patient-derived iPSC-CM differentiation, as well as the development of both chamber-specific and non-myocyte cardiac cell types, make it possible to model the complex genetic and molecular architecture involved in SVD development. Moreover, iPSC models have become increasingly complex with the generation of 3D organoids and engineered cardiac tissues which open the door to new mechanistic insight into SVD development. Finally, iPSC-CMs have been used in proof-of-concept studies that the molecular underpinnings of SVD may be targetable for future therapies. While each platform has its advantages and disadvantages, the use of patient-derived iPSC-CMs offers a window into patient-specific cardiogenesis and SVD development. Advancement in stem-cell based modeling of SVD promises to revolutionize our understanding of the developmental etiology of SVD and provides a tool for developing and testing new therapies.

The clinical utility of pediatric cardiomyopathy genetic testing: From diagnosis to a precision medicine-based approach to care.

BACKGROUND: Pediatric-onset cardiomyopathies are rare yet cause significant morbidity and mortality in affected children. Genetic testing has a major role in the clinical evaluation of pediatric-onset cardiomyopathies, and identification of a variant in an associated gene can be used to confirm the clinical diagnosis and exclude syndromic causes that may warrant different treatment strategies. Further, risk-predictive testing of first-degree relatives can assess who is at-risk of disease and requires continued clinical follow-up. AIM OF REVIEW: In this review, we seek to describe the current role of genetic testing in the clinical diagnosis and management of patients and families with the five major cardiomyopathies. Further, we highlight the ongoing development of precision-based approaches to diagnosis, prognosis, and treatment. KEY SCIENTIFIC CONCEPTS OF REVIEW: Emerging application of genotype-phenotype correlations opens the door for genetics to guide a precision medicine-based approach to prognosis and potentially for therapies. Despite advances in our understanding of the genetic etiology of cardiomyopathy and increased accessibility of clinical genetic testing, not all pediatric cardiomyopathy patients have a clear genetic explanation for their disease. Expanded genomic studies are needed to understand the cause of disease in these patients, improve variant classification and genotype-driven prognostic predictions, and ultimately develop truly disease preventing treatment.

Comparing mechanistic and empirical approaches to modeling the thermal niche of almond.

Delineating locations that are thermally viable for cultivating high-value crops can help to guide land use planning, agronomics, and water management. Three modeling approaches were used to identify the potential distribution and key thermal constraints on on almond cultivation across the southwestern United States (US), including two empirical species distribution models (SDMs)-one using commonly used bioclimatic variables (traditional SDM) and the other using more physiologically relevant climate variables (nontraditional SDM)-and a mechanistic model (MM) developed using published thermal limitations from field studies. While models showed comparable results over the majority of the domain, including over existing croplands with high almond density, the MM suggested the greatest potential for the geographic expansion of almond cultivation, with frost susceptibility and insufficient heat accumulation being the primary thermal constraints in the southwestern US. The traditional SDM over-predicted almond suitability in locations shown by the MM to be limited by frost, whereas the nontraditional SDM showed greater agreement with the MM in these locations, indicating that incorporating physiologically relevant variables in SDMs can improve predictions. Finally, opportunities for geographic expansion of almond cultivation under current climatic conditions in the region may be limited, suggesting that increasing production may rely on agronomical advances and densifying current almond plantations in existing locations.

Survival after partial heart transplantation in a piglet model.

Partial heart transplantation (PHT) is a novel surgical approach that involves transplantation of only the part of the heart containing a valve. The rationale for this approach is to deliver growing heart valve implants that reduce the need for future re-operations in children. However, prior to clinical application of this approach, it was important to assess it in a preclinical model. To investigate PHT short-term outcomes and safety, we performed PHT in a piglet model. Yorkshire piglets (n = 14) were used for PHT of the pulmonary valve. Donor and recipient pairs were matched based on blood types. The piglets underwent PHT at an average age of 44 days (range 34-53). Post-operatively, the piglets were monitored for a period of two months. Of the 7 recipient piglets, one mortality occurred secondary to anesthesia complications while undergoing a routine echocardiogram on post-operative day 19. All piglets had appropriate weight gain and laboratory findings throughout the post-operative period indicating a general state of good health and rehabilitation after undergoing PHT. We conclude that PHT has good short-term survival in the swine model. PHT appears to be safe for clinical application.

Surgical Protocol for Partial Heart Transplantation in Growing Piglets.

Partial heart transplantation is a new approach to deliver growing heart valve implants. Partial heart transplants differ from heart transplants because only the part of the heart containing the necessary heart valve is transplanted. This allows partial heart transplants to grow, similar to the valves in heart transplants. However, the transplant biology of partial heart transplantation remains unexplored. This is a critical barrier to progress of the field. Without knowledge about the specific transplant biology of partial heart transplantation, children with partial heart transplants are empirically treated like children with heart transplants because the valves in heart transplants are known to grow. In order to progress the field, an animal model for partial heart transplantation is necessary. Here, we contribute our surgical protocol for partial heart transplantation in growing piglets. All aspects of partial heart transplantation, including the donor procedure, the recipient procedure, and recipient perioperative care are described in detail. There are important nuances in the conduct of virtually all aspects of open heart surgery that differs in piglets from humans. Our surgical protocol, which is based on our experience with 34 piglets, will allow other investigators to leverage our experience to seek fundamental knowledge about the nature of partial heart transplants. This is significant because the partial heart transplant model in piglets is complex and very resource intensive.

One gene, two modes of inheritance, four diseases: A systematic review of the cardiac manifestation of pathogenic variants in JPH2-encoded junctophilin-2.

Rare variants in JPH2 have been associated with a range of cardiac disease, including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmias, and sudden cardiac death (SCD); however, our understanding of how variants in JPH2 correspond to specific modes of inheritance and correlate clinical phenotypes has not been comprehensively explored. In this systematic review, we assess current case reports and series that describe patients with JPH2 variants and cardiac disease. We identified a total of 61 variant-positive individuals, approximately 80% of whom had some form of cardiac disease, including 47% HCM, 18% DCM, and 14% arrhythmia/SCD. In analyzing the 24 probands described in the studies, we found that autosomal recessive, loss-of-function variants are associated with severe, early onset DCM, while autosomal dominant missense variants are associated with a wider range of cardiac disease, including HCM, arrhythmia, SCD, and cardiac conduction disease.

Use of microaxial flow pumps in adolescents.

Objectives: The Impella 5.5 has been successfully used in the adult population; however, safety and efficacy data in patients aged less than 18 years are limited. Methods: Six pediatric patients, aged 13 to 16 years and weighing 45 to 113 kg, underwent axillary artery graft placement and attempted placement of the Impella 5.5 device at our institution between August 2020 and March 2023. Results: Indications for implantation were heart failure secondary to myocarditis (2), rejection of prior orthotopic heart transplant, idiopathic dilated cardiomyopathy (2), and heart failure after transposition of the great arteries repair. Placement was unsuccessful in a 13.8-year-old female patient due to prohibitively acute angulation of the right subclavian artery, and venoarterial extracorporeal membrane oxygenation cannulation was performed via the axillary graft. In 5 patients with successful Impella 5.5 placement, median duration of support was 13.5 days (range, 7-42 days). One experienced cardiac arrest secondary to coagulation-associated device failure, requiring temporary HeartMate3 implantation. Four patients were bridged to transplant; 3 patients received a transplant directly from Impella 5.5, and 1 patient received a transplant after HeartMate3. The final patient received the HeartMate3 on Impella day 42 and is awaiting transplant. Conclusions: Although exact size cutoffs and anatomy are still being determined, our experience provides a framework for use of the Impella 5.5 in adolescents.

DiscoVari: A Web-Based Precision Medicine Tool for Predicting Variant Pathogenicity in Cardiomyopathy- and Channelopathy-Associated Genes.

BACKGROUND: With genetic testing advancements, the burden of incidentally identified cardiac disease-associated gene variants is rising. These variants may carry a risk of sudden cardiac death, highlighting the need for accurate diagnostic interpretation. We sought to identify pathogenic hotspots in sudden cardiac death-associated genes using amino acid-level signal-to-noise (S:N) analysis and develop a web-based precision medicine tool, DiscoVari, to improve variant evaluation. METHODS: The minor allele frequency of putatively pathogenic variants was derived from cohort-based cardiomyopathy and channelopathy studies in the literature. We normalized disease-associated minor allele frequencies to rare variants in an ostensibly healthy population (Genome Aggregation Database) to calculate amino acid-level S:N. Amino acids with S:N above the gene-specific threshold were defined as hotspots. DiscoVari was built using JavaScript ES6 and using open-source JavaScript library ReactJS, web development framework Next.js, and JavaScript runtime NodeJS. We validated the ability of DiscoVari to identify pathogenic variants using variants from ClinVar and individuals clinically evaluated at the Duke University Hospitals with cardiac genetic testing. RESULTS: We developed DiscoVari as an internet-based tool for S:N-based variant hotspots. Upon validation, a higher proportion of ClinVar likely pathogenic/pathogenic variants localized to DiscoVari hotspots (43.1%) than likely benign/benign variants (17.8%; P<0.0001). Further, 75.3% of ClinVar variants reclassified to likely pathogenic/pathogenic were in hotspots, compared with 41.3% of those reclassified as variants of uncertain significance (P<0.0001) and 23.4% of those reclassified as likely benign/benign (P<0.0001). Of the clinical cohort variants, 73.1% of likely pathogenic/pathogenic were in hotspots, compared with 0.0% of likely benign/benign (P<0.01). CONCLUSIONS: DiscoVari reliably identifies disease-susceptible amino acid residues to evaluate variants by searching amino acid-specific S:N ratios.

Impact of Ventricular Dominance on Long-Term Fontan Outcomes: A 25-year Single-institution Study.

BACKGROUND: The long-term impact of ventricular dominance on Fontan outcomes is controversial. This study examined this issue in a 25-year cohort. METHODS: Patients undergoing the Fontan operation at a single institution (Duke University Medical Center, Durham, NC) from October 1998 to February 2022 were reviewed. Primary outcomes were transplant-free survival and Fontan failure (death, heart transplantation, takedown, protein-losing enteropathy, or plastic bronchitis). Secondary outcomes included hospital and intensive care lengths of stay. Kaplan-Meier methodology compared outcomes by ventricular dominance. Multiphase parametric risk hazard analysis identified risk factors for primary outcomes. RESULTS: There were 195 patients (104 right ventricular dominant) included in the study. Baseline characteristics were comparable. Perioperative survival was similar (right ventricular dominant, 98%; non-right ventricular dominant, 100%; P = .51). The proportion of patients experiencing death or heart transplantation was 8.7%, and the rate of Fontan failure was 11.8% during a median follow-up of 4.5 years (interquartile range, 0.3-9.8 years). Right ventricular-dominant patients had reduced transplant-free survival (10-year estimates: 80% [95% CI, 70%-91%] vs 92% [95% CI, 83%-100%]; P = .04) and freedom from Fontan failure (73% [95% CI, 62%-86%] vs 92% [95% CI, 83%-100%]; P = .04). Multiphase hazard modeling resolved 2 risk phases. The early phase spanned from surgery to approximately 6 months afterward. The late phase spanned from approximately 6 months after surgery onward. In multivariable analysis, right ventricular dominance was an independent risk factor for death or heart transplantation (parameter estimate, 1.3 ± 0.6; P = .04) and Fontan failure (1.1 ± 0.5; P = .04) during the second phase, with no significant first-phase risk factors. CONCLUSIONS: Right ventricular dominance was associated with long-term complications after Fontan procedures, including mortality, heart transplantation, and Fontan failure. This cohort may benefit from heightened surveillance in a multidisciplinary Fontan clinic after the perioperative period.

PRDM16 Deletion Is Associated With Sex-dependent Cardiomyopathy and Cardiac Mortality: A Translational, Multi-Institutional Cohort Study.

BACKGROUND: 1p36 deletion syndrome can predispose to pediatric-onset cardiomyopathy. Deletion breakpoints are variable and may delete the transcription factor PRDM16. Early studies suggest that deletion of PRDM16 may underlie cardiomyopathy in patients with 1p36 deletion; however, the prognostic impact of PRDM16 loss is unknown. METHODS: This retrospective cohort included subjects with 1p36 deletion syndrome from 4 hospitals. Prevalence of cardiomyopathy and freedom from death, cardiac transplantation, or ventricular assist device were analyzed. A systematic review cohort was derived for further analysis. A cardiac-specific Prdm16 knockout mouse (Prdm16 conditional knockout) was generated. Echocardiography was performed at 4 and 6 to 7 months. Histology staining and qPCR were performed at 7 months to assess fibrosis. RESULTS: The retrospective cohort included 71 patients. Among individuals with PRDM16 deleted, 34.5% developed cardiomyopathy versus 7.7% of individuals with PRDM16 not deleted (P=0.1). In the combined retrospective and systematic review cohort (n=134), PRDM16 deletion-associated cardiomyopathy risk was recapitulated and significant (29.1% versus 10.8%, P=0.03). PRDM16 deletion was associated with increased risk of death, cardiac transplant, or ventricular assist device (P=0.04). Among those PRDM16 deleted, 34.5% of females developed cardiomyopathy versus 16.7% of their male counterparts (P=0.2). We find sex-specific differences in the incidence and the severity of contractile dysfunction and fibrosis in female Prdm16 conditional knockout mice. Further, female Prdm16 conditional knockout mice demonstrate significantly elevated risk of mortality (P=0.0003). CONCLUSIONS: PRDM16 deletion is associated with a significantly increased risk of cardiomyopathy and cardiac mortality. Prdm16 conditional knockout mice develop cardiomyopathy in a sex-biased way. Patients with PRDM16 deletion should be assessed for cardiac disease.

Characterization of sedation and anesthesia complications in patients with alternating hemiplegia of childhood.

BACKGROUND: Alternating hemiplegia of childhood (AHC) pathophysiology suggests predisposition to sedation and anesthesia complications. GOALS: Hypotheses: 1) AHC patients experience high rates of sedation-anesthesia complications. 2) ATP1A3 mutation genotype positivity, age, and AHC severity correlate with more severe complications. 3) Prior short QTc correlates with cardiac rhythm complications. METHODS: Analysis of 34 consecutive AHC patients who underwent sedation or anesthesia. Classification of complications: mild (not requiring intervention), moderate (intervention), severe (intervention, risk for permanent injury or potential life-threatening emergency). STATISTICS: Fisher Exact test, Spearman correlations. RESULTS: These patients underwent 129 procedures (3.79 ± 2.75 procedures/patient). Twelve (35%) experienced complications during at least one procedure. Fourteen/129 procedures (11%) manifested one or more complications (2.3% mild, 7% moderate, 1.6% severe). Of the total 20 observed complications, six (33.3%) were severe: apneas (2), seizures (2), bradycardia (1), ventricular fibrillation that responded to resuscitation (1). Moderate complications: non-life-threatening bradycardias, apneas, AHC spells or seizures. Complications occurred during sedation or anesthesia and during procedures or recovery periods. Patients with disease-associated ATP1A3 variants were more likely to have moderate or severe complications. There was no correlation between complications and age or AHC severity. Presence of prior short QTc correlated with cardiac rhythm complications. After this series was analyzed, another patient had severe recurrent laryngeal dystonia requiring tracheostomy following anesthesia with intubation. CONCLUSIONS: During sedation or anesthesia, AHC patients, particularly those with ATP1A3 variants and prior short QTc, are at risk for complications consistent with AHC pathophysiology. Increased awareness is warranted during planning, performance, and recovery from such procedures.

Advancing the scholarship and practice of stakeholder engagement in working landscapes: a co-produced research agenda.

Participatory approaches to science and decision making, including stakeholder engagement, are increasingly common for managing complex socio-ecological challenges in working landscapes. However, critical questions about stakeholder engagement in this space remain. These include normative, political, and ethical questions concerning who participates, who benefits and loses, what good can be accomplished, and for what, whom, and by who. First, opportunities for addressing justice, equity, diversity, and inclusion interests through engagement, while implied in key conceptual frameworks, remain underexplored in scholarly work and collaborative practice alike. A second line of inquiry relates to research-practice gaps. While both the practice of doing engagement work and scholarly research on the efficacy of engagement is on the rise, there is little concerted interplay among 'on-the-ground' practitioners and scholarly researchers. This means scientific research often misses or ignores insight grounded in practical and experiential knowledge, while practitioners are disconnected from potentially useful scientific research on stakeholder engagement. A third set of questions concerns gaps in empirical understanding of the efficacy of engagement processes and includes inquiry into how different engagement contexts and process features affect a range of behavioral, cognitive, and decision-making outcomes. Because of these gaps, a cohesive and actionable research agenda for stakeholder engagement research and practice in working landscapes remains elusive. In this review article, we present a co-produced research agenda for stakeholder engagement in working landscapes. The co-production process involved professionally facilitated and iterative dialogue among a diverse and international group of over 160 scholars and practitioners through a yearlong virtual workshop series. The resulting research agenda is organized under six cross-cutting themes: (1) Justice, Equity, Diversity, and Inclusion; (2) Ethics; (3) Research and Practice; (4) Context; (5) Process; and (6) Outcomes and Measurement. This research agenda identifies critical research needs and opportunities relevant for researchers, practitioners, and policymakers alike. We argue that addressing these research opportunities is necessary to advance knowledge and practice of stakeholder engagement and to support more just and effective engagement processes in working landscapes. Supplementary Information: The online version contains supplementary material available at 10.1007/s42532-022-00132-8.

Genetic Etiology of Left-Sided Obstructive Heart Lesions: A Story in Development.

Congenital heart disease is the most common congenital defect observed in newborns. Within the spectrum of congenital heart disease are left-sided obstructive lesions (LSOLs), which include hypoplastic left heart syndrome, aortic stenosis, bicuspid aortic valve, coarctation of the aorta, and interrupted aortic arch. These defects can arise in isolation or as a component of a defined syndrome; however, nonsyndromic defects are often observed in multiple family members and associated with high sibling recurrence risk. This clear evidence for a heritable basis has driven a lengthy search for disease-causing variants that has uncovered both rare and common variants in genes that, when perturbed in cardiac development, can result in LSOLs. Despite advancements in genetic sequencing platforms and broadening use of exome sequencing, the currently accepted LSOL-associated genes explain only 10% to 20% of patients. Further, the combinatorial effects of common and rare variants as a cause of LSOLs are emerging. In this review, we highlight the genes and variants associated with the different LSOLs and discuss the strengths and weaknesses of the present genetic associations. Furthermore, we discuss the research avenues needed to bridge the gaps in our current understanding of the genetic basis of nonsyndromic congenital heart disease.

Impacts of large-scale teleconnection indices on chill accumulation for specialty crops in California.

Although the impacts of teleconnection indices on climate metrics such as precipitation and temperature in California have been widely studied, less attention has been given to the impact on integrated climate indices such as chill accumulation. This study investigates the linkages between large-scale teleconnections and winter chill accumulation for specialty crops in California, which may enable more effective and dynamic adaptation to in-season climate variability. Three large-scale teleconnection indices were selected: Oceanic Nino Index (ONI), Pacific-North American teleconnection pattern (PNA), and Pacific Decadal Oscillation (PDO) index to assess their effects on chill accumulation. The Chill Hours Model and Dynamic Model are adopted to calculate chill accumulation in Chill Hours (CH) and Chill Portions (CP) from November to January. Three major crop-producing regions, including the Central Coast, Sacramento Valley, and San Joaquin Valley, are used as the focused regions. Our results suggest CP generally has a stronger response to teleconnection patterns than CH in California. The correlations between chill accumulation and teleconnections are generally weaker during the summer than other seasons, and significant correlation can be observed 2-10 months before the start of the chill accumulation period. Among the three teleconnection indices, ONI is most weakly correlated to chill accumulation in focused regions, while PDO shows the strongest positive correlation and explains up to 39% variability of CP. PNA presents the most widespread negative correlation with chill accumulation. When aggregated to different teleconnection modes, +3.6 above-average CP is expected during ONI positive mode; +2.3 above-average CP is expected during PDO positive mode, while +2.1 above-average CP is expected during PNA negative mode. This study provides insights on early-season chill prediction and feasible management and adaptation strategies, and the methodology presented here can be used to develop decision support tools of risk control for agricultural producers and policymakers.

Cardiac retinoic acid levels decline in heart failure.

Although low circulating levels of the vitamin A metabolite, all-trans retinoic acid (ATRA), are associated with increased risk of cardiovascular events and all-cause mortality, few studies have addressed whether cardiac retinoid levels are altered in the failing heart. Here, we showed that proteomic analyses of human and guinea pig heart failure (HF) were consistent with a decline in resident cardiac ATRA. Quantitation of the retinoids in ventricular myocardium by mass spectrometry revealed 32% and 39% ATRA decreases in guinea pig HF and in patients with idiopathic dilated cardiomyopathy (IDCM), respectively, despite ample reserves of cardiac vitamin A. ATRA (2 mg/kg/d) was sufficient to mitigate cardiac remodeling and prevent functional decline in guinea pig HF. Although cardiac ATRA declined in guinea pig HF and human IDCM, levels of certain retinoid metabolic enzymes diverged. Specifically, high expression of the ATRA-catabolizing enzyme, CYP26A1, in human IDCM could dampen prospects for an ATRA-based therapy. Pertinently, a pan-CYP26 inhibitor, talarozole, blunted the impact of phenylephrine on ATRA decline and hypertrophy in neonatal rat ventricular myocytes. Taken together, we submit that low cardiac ATRA attenuates the expression of critical ATRA-dependent gene programs in HF and that strategies to normalize ATRA metabolism, like CYP26 inhibition, may have therapeutic potential.

Projected impacts of climate change on the range and phenology of three culturally-important shrub species.

Climate change is shifting both the habitat suitability and the timing of critical biological events, such as flowering and fruiting, for plant species across the globe. Here, we ask how both the distribution and phenology of three food-producing shrubs native to northwestern North America might shift as the climate changes. To address this question, we compared gridded climate data with species location data to identify climate variables that best predicted the current bioclimatic niches of beaked hazelnut (Corylus cornuta), Oregon grape (Mahonia aquifolium), and salal (Gaultheria shallon). We also developed thermal-sum models for the timing of flowering and fruit ripening for these species. We then used multi-model ensemble future climate projections to estimate how species range and phenology may change under future conditions. Modelling efforts showed extreme minimum temperature, climate moisture deficit, and mean summer precipitation were predictive of climatic suitability across all three species. Future bioclimatic niche models project substantial reductions in habitat suitability across the lower elevation and southern portions of the species' current ranges by the end of the 21st century. Thermal-sum phenology models for these species indicate that flowering and the ripening of fruits and nuts will advance an average of 25 days by the mid-21st century, and 36 days by the late-21st century under a high emissions scenario (RCP 8.5). Future changes in the climatic niche and phenology of these important food-producing species may alter trophic relationships, with cascading impacts on regional ecosystems.

Extreme heat effects on perennial crops and strategies for sustaining future production.

Extreme heat events will challenge agricultural production and raise the risk of food insecurity. California is the largest agricultural producer in the United States, and climate change and extreme heat may significantly affect the state's food production. This paper provides a summary of the current literature on crop responses to extreme heat, with a focus on perennial agriculture in California. We highlight contemporary trends and future projections in heat extremes, and the range of plant responses to extreme heat exposure, noting the variability in plant tolerance and response across season, crop, and cultivar. We also review practices employed to mitigate heat damage and the capacity for those practices to serve as adaptation options in a warmer and drier future. Finally, we discuss current and future research directions aimed at increasing the adaptive capacity of perennial agriculture to the increased heat exposure anticipated with climate change. Collectively, the literature reviewed makes clear the need to understand crop responses and tolerances to heat within the context of climate change and climate extremes in order to sustain crop production, preserve agricultural communities, and bolster food security at local, national, and global scales.

A 7000-year record of floods and ecological feedbacks in Weeks Bay, Alabama, USA.

Climate change, sea-level rise, and human activities present major concerns for coastal environments. Paleoenvironmental records allow us to extend the instrumented record and study recent environmental impacts in a long-term context with natural pre-industrial conditions. Here, we investigate grain size, stable carbon (δ13C) and nitrogen (δ15N) isotopes, elemental composition, and diatom abundance in sediments to construct a 7000-year paleoenvironmental history of Weeks Bay, Alabama, a NOAA National Estuarine Research Reserve. Four major floods of the Fish River since 1986 CE are independently identified in the Weeks Bay sediment record, validating the bay setting as an archive of flood events. Thirty-four flood events were identified over the last 5000 years, with two periods of intense flood activity coinciding with the Medieval Climate Anomaly and the Little Ice Age, indicating association of relatively short-term climate events and enhanced storm activity. Further, multiple paleoenvironmental proxies indicate marine conditions during formation of the bay ~6600 calendar years Before Present (cal yr BP) and a brackish transition as the estuary became restricted ~2000 cal yr BP. High total organic carbon/nitrogen values indicate nitrogen limitation in Weeks Bay. Increase in organic content, diatoms, and redox- and nutrient-associated elemental proxies over the last 300 years, with dramatic increase in algal abundance since the 1980s, strongly suggest that human activities (i.e. land clearing, agriculture) increased ecological feedbacks in the bay. Comparing past and present environmental conditions of coastal estuaries advances our understanding of estuarine response to climate change and sea level, floods, and human activities, which is important for environmental management and wetland conservation policy.