Genomic signatures for drylands adaptation at gene-rich regions in African zebu cattle.

BACKGROUND: Indigenous Sudanese cattle are mainly indicine/zebu (humped) type. They thrive in the harshest dryland environments characterised by high temperatures, long seasonal dry periods, nutritional shortages, and vector disease challenges. Here, we sequenced 60 indigenous Sudanese cattle from six indigenous breeds and analysed the data using three genomic scan approaches to unravel cattle adaptation to the African dryland region. RESULTS: We identified a set of gene-rich selective sweep regions, detected mostly on chromosomes 5, 7 and 19, shared across African and Gir zebu. These include genes involved in immune response, body size and conformation, and heat stress response. We also identified selective sweep regions unique to Sudanese zebu. Of these, a 250 kb selective sweep on chromosome 16 spans seven genes, including PLCH2, PEX10, PRKCZ, and SKI, which are involved in alternative adaptive metabolic strategies of insulin signalling, glucose homeostasis, and fat metabolism. CONCLUSIONS: Our results suggest that environmental adaptation may involve recent and ancient selection at gene-rich regions, which might be under a common regulatory genetic control, in zebu cattle.

Natural adaptation and human selection of northeast African sheep genomes.

African sheep manifest diverse but distinct physio-anatomical traits, which are the outcomes of natural- and human-driven selection. Here, we generated 34.8 million variants from 150 indigenous northeast African sheep genomes sequenced at an average depth of ∼54× for 130 samples (Ethiopia, Libya) and ∼20× for 20 samples (Sudan). These represented sheep from diverse environments, tail morphology and post-Neolithic introductions to Africa. Phylogenetic and model-based admixture analysis provided evidence of four genetic groups corresponding to altitudinal geographic origins, tail morphotypes and possible historical introduction and dispersal of the species into and across the continent. Running admixture at higher levels of K (6 ≤ K ≤ 25), revealed cryptic levels of genome intermixing as well as distinct genetic backgrounds in some populations. Comparative genomic analysis identified targets of selection that spanned conserved haplotype structures overlapping clusters of genes and gene families. These were related to hypoxia responses, ear morphology, caudal vertebrae and tail skeleton length, and tail fat-depot structures. Our findings provide novel insights underpinning morphological variation and response to human-driven selection and environmental adaptation in African indigenous sheep.

Giant ankyrin-G regulates cardiac function.

Cardiovascular disease (CVD) remains the most common cause of adult morbidity and mortality in developed nations. As a result, predisposition for CVD is increasingly important to understand. Ankyrins are intracellular proteins required for the maintenance of membrane domains. Canonical ankyrin-G (AnkG) has been shown to be vital for normal cardiac function, specifically cardiac excitability, via targeting and regulation of the cardiac voltage-gated sodium channel. Noncanonical (giant) AnkG isoforms play a key role in neuronal membrane biogenesis and excitability, with evidence for human neurologic disease when aberrant. However, the role of giant AnkG in cardiovascular tissue has yet to be explored. Here, we identify giant AnkG in the myocardium and identify that it is enriched in 1-week-old mice. Using a new mouse model lacking giant AnkG expression in myocytes, we identify that young mice displayed a dilated cardiomyopathy phenotype with aberrant electrical conduction and enhanced arrhythmogenicity. Structural and electrical dysfunction occurred at 1 week of age, when giant AnkG was highly expressed and did not appreciably change in adulthood until advanced age. At a cellular level, loss of giant AnkG results in delayed and early afterdepolarizations. However, surprisingly, giant AnkG cKO myocytes display normal INa, but abnormal myocyte contractility, suggesting unique roles of the large isoform in the heart. Finally, transcript analysis provided evidence for unique pathways that may contribute to the structural and electrical findings shown in giant AnkG cKO animals. In summary, we identify a critical role for giant AnkG that adds to the diversity of ankyrin function in the heart.

Artificial Intelligence and Machine Learning in Cancer Research: A Systematic and Thematic Analysis of the Top 100 Cited Articles Indexed in Scopus Database.

INTRODUCTION: Cancer is a major public health problem and a global leading cause of death where the screening, diagnosis, prediction, survival estimation, and treatment of cancer and control measures are still a major challenge. The rise of Artificial Intelligence (AI) and Machine Learning (ML) techniques and their applications in various fields have brought immense value in providing insights into advancement in support of cancer control. METHODS: A systematic and thematic analysis was performed on the Scopus database to identify the top 100 cited articles in cancer research. Data were analyzed using RStudio and VOSviewer.Var1.6.6. RESULTS: The top 100 articles in AI and ML in cancer received a 33 920 citation score with a range of 108 to 5758 times. Doi Kunio from the USA was the most cited author with total number of citations (TNC = 663). Out of 43 contributed countries, 30% of the top 100 cited articles originated from the USA, and 10% originated from China. Among the 57 peer-reviewed journals, the "Expert Systems with Application" published 8% of the total articles. The results were presented in highlight technological advancement through AI and ML via the widespread use of Artificial Neural Network (ANNs), Deep Learning or machine learning techniques, Mammography-based Model, Convolutional Neural Networks (SC-CNN), and text mining techniques in the prediction, diagnosis, and prevention of various types of cancers towards cancer control. CONCLUSIONS: This bibliometric study provides detailed overview of the most cited empirical evidence in AI and ML adoption in cancer research that could efficiently help in designing future research. The innovations guarantee greater speed by using AI and ML in the detection and control of cancer to improve patient experience.

Protein Phosphatase 2A Regulates Cardiac Na+ Channels.

RATIONALE: Voltage-gated Na+ channel ( INa) function is critical for normal cardiac excitability. However, the Na+ channel late component ( INa,L) is directly associated with potentially fatal forms of congenital and acquired human arrhythmia. CaMKII (Ca2+/calmodulin-dependent kinase II) enhances INa,L in response to increased adrenergic tone. However, the pathways that negatively regulate the CaMKII/Nav1.5 axis are unknown and essential for the design of new therapies to regulate the pathogenic INa,L. OBJECTIVE: To define phosphatase pathways that regulate INa,L in vivo. METHODS AND RESULTS: A mouse model lacking a key regulatory subunit (B56α) of the PP (protein phosphatase) 2A holoenzyme displayed aberrant action potentials after adrenergic stimulation. Unbiased computational modeling of B56α KO (knockout) mouse myocyte action potentials revealed an unexpected role of PP2A in INa,L regulation that was confirmed by direct INa,L recordings from B56α KO myocytes. Further, B56α KO myocytes display decreased sensitivity to isoproterenol-induced induction of arrhythmogenic INa,L, and reduced CaMKII-dependent phosphorylation of Nav1.5. At the molecular level, PP2A/B56α complex was found to localize and coimmunoprecipitate with the primary cardiac Nav channel, Nav1.5. CONCLUSIONS: PP2A regulates Nav1.5 activity in mouse cardiomyocytes. This regulation is critical for pathogenic Nav1.5 late current and requires PP2A-B56α. Our study supports B56α as a novel target for the treatment of arrhythmia.

Survey of antibodies to Rift Valley fever virus and associated risk factors in one-humped camels (Camelus dromedarius) slaughtered in Maiduguri abattoir, Borno State, Nigeria.

Rift Valley fever (RVF) is an emerging mosquito-borne zoonosis that threatens public health and animal agriculture in the endemic areas causing devastating epizootics characterized by abortion storms and high mortalities, especially in newborn animals. A cross-sectional study was conducted to determine the seroprevalence and investigate risk factors associated with exposure to the virus in camels slaughtered in Maiduguri abattoir, Borno State of Nigeria. Camels presented for slaughtered were sampled and data on age, sex, source or origin, utility, presence of post-mortem lesions, body weights and body condition score were collected. Blood samples were collected and sera were harvested and stored at - 20 °C until tested. The sera were tested using a commercial ELISA kit based on the manufacturer's instructions. The overall seroprevalence in the study was 20.7% (95% CI, 13.6-30.0). The analysis showed no significant differences between the presence of antibodies and variables that included the sex of camels (χ2 = 0.015, df = 1, p = 0.904) and the presence of post-mortem lesion on the carcass (χ2 = 0.009, df = 1, p = 0.925). There were significant differences between presence of antibodies and three variables that included the age (χ2 = 4.89, df = 1, p = 0.027), the source (χ2 = 7.077, df = 2, p = 0.029) and the main utility (χ2 = 8.057, df = 3, p = 0.045) of the camels. It was concluded that camels presented for slaughter at the Maiduguri abattoir have evidence of exposure to the RVF virus and maybe means of transmission of the virus. Regular monitoring and control of transboundary animal movements were recommended in the study area.

Defining new mechanistic roles for αII spectrin in cardiac function.

Spectrins are cytoskeletal proteins essential for membrane biogenesis and regulation and serve critical roles in protein targeting and cellular signaling. αII spectrin (SPTAN1) is one of two α spectrin genes and αII spectrin dysfunction is linked to alterations in axon initial segment formation, cortical lamination, and neuronal excitability. Furthermore, human αII spectrin loss-of-function variants cause neurological disease. As global αII spectrin knockout mice are embryonic lethal, the in vivo roles of αII spectrin in adult heart are unknown and untested. Here, based on pronounced alterations in αII spectrin regulation in human heart failure we tested the in vivo roles of αII spectrin in the vertebrate heart. We created a mouse model of cardiomyocyte-selective αII spectrin-deficiency (cKO) and used this model to define the roles of αII spectrin in cardiac function. αII spectrin cKO mice displayed significant structural, cellular, and electrical phenotypes that resulted in accelerated structural remodeling, fibrosis, arrhythmia, and mortality in response to stress. At the molecular level, we demonstrate that αII spectrin plays a nodal role for global cardiac spectrin regulation, as αII spectrin cKO hearts exhibited remodeling of αI spectrin and altered ß-spectrin expression and localization. At the cellular level, αII spectrin deficiency resulted in altered expression, targeting, and regulation of cardiac ion channels NaV1.5 and KV4.3. In summary, our findings define critical and unexpected roles for the multifunctional αII spectrin protein in the heart. Furthermore, our work provides a new in vivo animal model to study the roles of αII spectrin in the cardiomyocyte.

Abnormal myocardial expression of SAP97 is associated with arrhythmogenic risk.

Synapse-associated protein 97 (SAP97) is a scaffolding protein crucial for the functional expression of several cardiac ion channels and therefore proper cardiac excitability. Alterations in the functional expression of SAP97 can modify the ionic currents underlying the cardiac action potential and consequently confer susceptibility for arrhythmogenesis. In this study, we generated a murine model for inducible, cardiac-targeted Sap97 ablation to investigate arrhythmia susceptibility and the underlying molecular mechanisms. Furthermore, we sought to identify human SAP97 (DLG1) variants that were associated with inherited arrhythmogenic disease. The murine model of cardiac-specific Sap97 ablation demonstrated several ECG abnormalities, pronounced action potential prolongation subject to high incidence of arrhythmogenic afterdepolarizations and notable alterations in the activity of the main cardiac ion channels. However, no DLG1 mutations were found in 40 unrelated cases of genetically elusive long QT syndrome (LQTS). Instead, we provide the first evidence implicating a gain of function in human DLG1 mutation resulting in an increase in Kv4.3 current (Ito) as a novel, potentially pathogenic substrate for Brugada syndrome (BrS). In conclusion, DLG1 joins a growing list of genes encoding ion channel interacting proteins (ChIPs) identified as potential channelopathy-susceptibility genes because of their ability to regulate the trafficking, targeting, and modulation of ion channels that are critical for the generation and propagation of the cardiac electrical impulse. Dysfunction in these critical components of cardiac excitability can potentially result in fatal cardiac disease.NEW & NOTEWORTHY The gene encoding SAP97 (DLG1) joins a growing list of genes encoding ion channel-interacting proteins (ChIPs) identified as potential channelopathy-susceptibility genes because of their ability to regulate the trafficking, targeting, and modulation of ion channels that are critical for the generation and propagation of the cardiac electrical impulse. In this study we provide the first data supporting DLG1-encoded SAP97's candidacy as a minor Brugada syndrome susceptibility gene.

Association of genotype III of dengue virus serotype 3 with disease outbreak in Eastern Sudan, 2019.

BACKGROUND: Dengue fever (DF) is an arthropod-borne disease caused by dengue virus (DENV). DENV is a member of the genus Flavivirus in the family Flaviviridae. Recently, DENV has been reported as an important emerging infectious viral pathogen in Sudan. Multiple outbreaks and sporadic cases of DF have been frequently reported in the eastern region of Sudan. The present study was conducted to confirm DENV outbreak in Kassala State, eastern Sudan, 2019, and to provide some information on the molecular characterization of the DENV isolate associated with the disease outbreak. METHODS: A hundred serum samples were collected during the outbreak from residents of Kassala State, Sudan, 2019. ELISA was used to detect DENV non structural protein NS1 (DENV-NS1) in acute phase sera sampled during the disease outbreak. RT-PCR assays were used to amplify a fragment of the capsid/pre-membrane region (CprM) of the viral polyprotein gene. The PCR products of the amplified CprM region of the viral polyprotein gene were purified and partial sequences were generated and used to confirm the specificity of DENV sequences and to identify the virus serotype. Phylogenetic tree was constructed to determine the genotype of DENV associated with the outbreak. RESULTS: Using DENV-NS1 ELISA assay, DENV infection was confirmed in 23% sampled sera. The detection of DENV RNA was made possible using group-specific RT-PCR assay. The virus was serotyped as DENV serotype 3 (DENV-3) using DENV serotype-specific RT-PCR assay. Phylogenetic analysis of the partial CprM sequences of the viral polyprotein gene indicates that the virus belonged to genotype III of DENV-3. CONCLUSION: The scientific data presented in this investigation confirmed that genotype III of DENV-3 was associated with the disease outbreak in eastern Sudan, 2019. The study represents the first report on molecular characterization of DENV-3 in Sudan.

Ecologically controlling insect and mite pests of tea plants with microbial pesticides: a review.

Insect and mite pests are damaging stressors that are threatening the cultivation of tea plants, which result in enormous crop loss. Over the years, the effectiveness of synthetic pesticides has allowed for its prominent application as a control strategy. However, the adverse effects of synthetic pesticides in terms of pesticide residue, environmental contamination and insect pest resistance have necessitated the need for alternative strategies. Meanwhile, microbial pesticides have been applied to tackle the damaging activities of the insect and mite pests of tea plants, and their performances were scientifically adjudged appreciable and environmental friendly. Herein, entomopathogenic microbes that were effective against tea geometrid (Ectropis obliqua Prout), tea green leafhopper (Empoasca onukii Matsuda), paraguay tea ampul (Gyropsylla spegazziniana), tea mosquito bug (Helopeltis theivora Waterhouse) and red spider mite (Oligonychus coffea Nietner) have been reviewed. The current findings revealed that microbial pesticides were effective and showed promising performances against these pests. Overall, this review has provided the basic and integrative information on the integrated pest management (IPM) tool(s) that can be utilized towards successful control of the aforementioned insect and mite pests.

SCN5A variant that blocks fibroblast growth factor homologous factor regulation causes human arrhythmia.

Nav channels are essential for metazoan membrane depolarization, and Nav channel dysfunction is directly linked with epilepsy, ataxia, pain, arrhythmia, myotonia, and irritable bowel syndrome. Human Nav channelopathies are primarily caused by variants that directly affect Nav channel permeability or gating. However, a new class of human Nav channelopathies has emerged based on channel variants that alter regulation by intracellular signaling or cytoskeletal proteins. Fibroblast growth factor homologous factors (FHFs) are a family of intracellular signaling proteins linked with Nav channel regulation in neurons and myocytes. However, to date, there is surprisingly little evidence linking Nav channel gene variants with FHFs and human disease. Here, we provide, to our knowledge, the first evidence that mutations in SCN5A (encodes primary cardiac Nav channel Nav1.5) that alter FHF binding result in human cardiovascular disease. We describe a five*generation kindred with a history of atrial and ventricular arrhythmias, cardiac arrest, and sudden cardiac death. Affected family members harbor a novel SCN5A variant resulting in p.H1849R. p.H1849R is localized in the central binding core on Nav1.5 for FHFs. Consistent with these data, Nav1.5 p.H1849R affected interaction with FHFs. Further, electrophysiological analysis identified Nav1.5 p.H1849R as a gain-of-function for INa by altering steady-state inactivation and slowing the rate of Nav1.5 inactivation. In line with these data and consistent with human cardiac phenotypes, myocytes expressing Nav1.5 p.H1849R displayed prolonged action potential duration and arrhythmogenic afterdepolarizations. Together, these findings identify a previously unexplored mechanism for human Nav channelopathy based on altered Nav1.5 association with FHF proteins.

Physicochemical properties associated with the presence of Burkholderia pseudomallei in small ruminant farm water supplies in Peninsular Malaysia.

Burkholderia pseudomallei causes melioidosis, a life-threatening infection in both humans and animals. Water is an important reservoir of the bacteria and may serve as a source of environmental contamination leading to infection. B. pseudomallei has an unusual ability to survive in water for a long period. This paper investigates physicochemical properties of water associated with the presence of B. pseudomallei in water supply in small ruminant farms in Peninsular Malaysia. Physicochemical properties of water samples taken from small ruminant farms that included temperature, pH, dissolved oxygen (DO2), optical density (OD), and chemical oxygen demand (COD) were measured after which the samples were cultured for B. pseudomallei. Multivariable logistic regression model revealed that slightly acidic water pH and higher COD level were significantly associated with the likelihood of the B. pseudomallei presence in the water.

Epidemiology of Measles Cases in South Darfur State, Sudan, 2011-2015.

Case-based surveillance measles data was defined according to World Health Organization (WHO) guidelines. A total of 511 measles cases were studied from 2011 to 2015 in Southern Darfur State, Sudan and 58.1% of cases were confirmed from Nyala city. About 43.4% of cases were males, 56.6% of cases were female, and 47.7% were children under five years old. Similarity, within February to June, the cases increased by 8.0% in children vaccinated through measles campaign, and 5.3% in children that used child vaccination card and 78.7% in unvaccinated one. The epidemiologically linked (EPI-Linked) measles cases declined from 2011 to 2015; consequently, Measles still remain to be a significant challenge in south Darfur state, Sudan.

Eps15 Homology Domain-containing Protein 3 Regulates Cardiac T-type Ca2+ Channel Targeting and Function in the Atria.

Proper trafficking of membrane-bound ion channels and transporters is requisite for normal cardiac function. Endosome-based protein trafficking of membrane-bound ion channels and transporters in the heart is poorly understood, particularly in vivo. In fact, for select cardiac cell types such as atrial myocytes, virtually nothing is known regarding endosomal transport. We previously linked the C-terminal Eps15 homology domain-containing protein 3 (EHD3) with endosome-based protein trafficking in ventricular cardiomyocytes. Here we sought to define the roles and membrane protein targets for EHD3 in atria. We identify the voltage-gated T-type Ca(2+) channels (CaV3.1, CaV3.2) as substrates for EHD3-dependent trafficking in atria. Mice selectively lacking EHD3 in heart display reduced expression and targeting of both Cav3.1 and CaV3.2 in the atria. Furthermore, functional experiments identify a significant loss of T-type-mediated Ca(2+) current in EHD3-deficient atrial myocytes. Moreover, EHD3 associates with both CaV3.1 and CaV3.2 in co-immunoprecipitation experiments. T-type Ca(2+) channel function is critical for proper electrical conduction through the atria. Consistent with these roles, EHD3-deficient mice demonstrate heart rate variability, sinus pause, and atrioventricular conduction block. In summary, our findings identify CaV3.1 and CaV3.2 as substrates for EHD3-dependent protein trafficking in heart, provide in vivo data on endosome-based trafficking pathways in atria, and implicate EHD3 as a key player in the regulation of atrial myocyte excitability and cardiac conduction.

Voltage-Gated Sodium Channel Phosphorylation at Ser571 Regulates Late Current, Arrhythmia, and Cardiac Function In Vivo.

BACKGROUND: Voltage-gated Na(+) channels (Nav) are essential for myocyte membrane excitability and cardiac function. Nav current (INa) is a large-amplitude, short-duration spike generated by rapid channel activation followed immediately by inactivation. However, even under normal conditions, a small late component of INa (INa,L) persists because of incomplete/failed inactivation of a subpopulation of channels. Notably, INa,L is directly linked with both congenital and acquired disease states. The multifunctional Ca(2+)/calmodulin-dependent kinase II (CaMKII) has been identified as an important activator of INa,L in disease. Several potential CaMKII phosphorylation sites have been discovered, including Ser571 in the Nav1.5 DI-DII linker, but the molecular mechanism underlying CaMKII-dependent regulation of INa,L in vivo remains unknown. METHODS AND RESULTS: To determine the in vivo role of Ser571, 2 Scn5a knock-in mouse models were generated expressing either: (1) Nav1.5 with a phosphomimetic mutation at Ser571 (S571E), or (2) Nav1.5 with the phosphorylation site ablated (S571A). Electrophysiology studies revealed that Ser571 regulates INa,L but not other channel properties previously linked to CaMKII. Ser571-mediated increases in INa,L promote abnormal repolarization and intracellular Ca(2+) handling and increase susceptibility to arrhythmia at the cellular and animal level. Importantly, Ser571 is required for maladaptive remodeling and arrhythmias in response to pressure overload. CONCLUSIONS: Our data provide the first in vivo evidence for the molecular mechanism underlying CaMKII activation of the pathogenic INa,L. Relevant for improved rational design of potential therapies, our findings demonstrate that Ser571-dependent regulation of Nav1.5 specifically tunes INa,L without altering critical physiological components of the current.

Ankyrin-G coordinates intercalated disc signaling platform to regulate cardiac excitability in vivo.

RATIONALE: Nav1.5 (SCN5A) is the primary cardiac voltage-gated Nav channel. Nav1.5 is critical for cardiac excitability and conduction, and human SCN5A mutations cause sinus node dysfunction, atrial fibrillation, conductional abnormalities, and ventricular arrhythmias. Further, defects in Nav1.5 regulation are linked with malignant arrhythmias associated with human heart failure. Consequently, therapies to target select Nav1.5 properties have remained at the forefront of cardiovascular medicine. However, despite years of investigation, the fundamental pathways governing Nav1.5 membrane targeting, assembly, and regulation are still largely undefined. OBJECTIVE: Define the in vivo mechanisms underlying Nav1.5 membrane regulation. METHODS AND RESULTS: Here, we define the molecular basis of an Nav channel regulatory platform in heart. Using new cardiac-selective ankyrin-G(-/-) mice (conditional knock-out mouse), we report that ankyrin-G targets Nav1.5 and its regulatory protein calcium/calmodulin-dependent kinase II to the intercalated disc. Mechanistically, ßIV-spectrin is requisite for ankyrin-dependent targeting of calcium/calmodulin-dependent kinase II-δ; however, ßIV-spectrin is not essential for ankyrin-G expression. Ankyrin-G conditional knock-out mouse myocytes display decreased Nav1.5 expression/membrane localization and reduced INa associated with pronounced bradycardia, conduction abnormalities, and ventricular arrhythmia in response to Nav channel antagonists. Moreover, we report that ankyrin-G links Nav channels with broader intercalated disc signaling/structural nodes, as ankyrin-G loss results in reorganization of plakophilin-2 and lethal arrhythmias in response to ß-adrenergic stimulation. CONCLUSIONS: Our findings provide the first in vivo data for the molecular pathway required for intercalated disc Nav1.5 targeting/regulation in heart. Further, these new data identify the basis of an in vivo cellular platform critical for membrane recruitment and regulation of Nav1.5.

EHD3-dependent endosome pathway regulates cardiac membrane excitability and physiology.

RATIONALE: Cardiac function is dependent on the coordinate activities of membrane ion channels, transporters, pumps, and hormone receptors to tune the membrane electrochemical gradient dynamically in response to acute and chronic stress. Although our knowledge of membrane proteins has rapidly advanced during the past decade, our understanding of the subcellular pathways governing the trafficking and localization of integral membrane proteins is limited and essentially unstudied in vivo. In the heart, to our knowledge, there are no in vivo mechanistic studies that directly link endosome-based machinery with cardiac physiology. OBJECTIVE: To define the in vivo roles of endosome-based cellular machinery for cardiac membrane protein trafficking, myocyte excitability, and cardiac physiology. METHODS AND RESULTS: We identify the endosome-based Eps15 homology domain 3 (EHD3) pathway as essential for cardiac physiology. EHD3-deficient hearts display structural and functional defects including bradycardia and rate variability, conduction block, and blunted response to adrenergic stimulation. Mechanistically, EHD3 is critical for membrane protein trafficking, because EHD3-deficient myocytes display reduced expression/localization of Na/Ca exchanger and L-type Ca channel type 1.2 with a parallel reduction in Na/Ca exchanger-mediated membrane current and Cav1.2-mediated membrane current. Functionally, EHD3-deficient myocytes show increased sarcoplasmic reticulum [Ca], increased spark frequency, and reduced expression/localization of ankyrin-B, a binding partner for EHD3 and Na/Ca exchanger. Finally, we show that in vivo EHD3-deficient defects are attributable to cardiac-specific roles of EHD3 because mice with cardiac-selective EHD3 deficiency demonstrate both structural and electric phenotypes. CONCLUSIONS: These data provide new insight into the critical role of endosome-based pathways in membrane protein targeting and cardiac physiology. EHD3 is a critical component of protein trafficking in heart and is essential for the proper membrane targeting of select cellular proteins that maintain excitability.