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Results for “Functional Genomics”

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PubMed2002

Functional genomics reveals the sole sulphate transporter of the Mycobacterium tuberculosis complex and its relevance to the acquisition of sulphur in vivo.

Sulphur is essential for some of the most vital biological activities such as translation initiation and redox maintenance, and genes involved in sulphur metabolism have been implicated in virulence. Mycobacterium tuberculosis has three predicted genes for the prototrophic acquisition of sulphur as sulphate: cysA, part of an ABC transporter, and cysA2 and A3, SseC sulphotransferases. Screening for amino acid auxotrophs of Mycobacterium bovis BCG, obtained by transposon mutagenesis, was used to select methionine auxotrophs requiring a sulphur-containing amino acid for growth. We have characterized one of these auxotrophs as being disrupted in cysA. Both the cysA mutant and a previously identified mutant in an upstream gene, subI, were functionally characterized as being completely unable to take up sulphate. Complementation of the cysA mutant with the wild-type gene from M. tuberculosis restored prototrophy and the ability to take up sulphate with the functional characteristics of an ABC transporter. Hence, it appears that this is the sole locus encoding inorganic sulphur transport in the M. tuberculosis complex.

ATP-Binding Cassette Transporters↗
PubMed2006

Symmetric time warping, Boltzmann pair probabilities and functional genomics.

Given two time series, possibly of different lengths, time warping is a method to construct an optimal alignment obtained by stretching or contracting time intervals. Unlike pairwise alignment of amino acid sequences, classical time warping, originally introduced for speech recognition, is not symmetric in the sense that the time warping distance between two time series is not necessarily equal to the time warping distance of the reversal of the time series. Here we design a new symmetric version of time warping, and present a formal proof of symmetry for our algorithm as well as for one of the variants of Aach and Church [1]. We additionally design quadratic time dynamic programming algorithms to compute both the forward and backward Boltzmann partition functions for symmetric time warping, and hence compute the Boltzmann probability that any two time series points are aligned. In the future, with the availability of increasingly long and accurate time series gene expression data, our algorithm can provide a sense of biological significance for aligned time points - e.g. our algorithm could be used to provide evidence that expression values of two genes have higher Boltzmann probability (say) in the G1 and S phase than in G2 and M phases. Algorithms, source code and web interface, developed by the first author, are made publicly available via the Boltzmann Time Warping web server at bioinformatics.bc.edu/clotelab/.

Algorithms↗
PubMed2005

Gene expression analysis of peripheral blood leukocytes from discordant sib-pairs with schizophrenia and bipolar disorder reveals points of convergence between genetic and functional genomic approaches.

We performed global RNA transcript analysis and comprehensive gene group analysis of peripheral blood leukocyte (PBL) RNA from two groups of matched sib-pairs that were discordant for either schizophrenia (n = 33 sib-pairs) or bipolar disorder (n = 5 sib-pairs). The pairs chosen for these analyses were selected from families with known patterns of genetic linkage (5q for schizophrenia and 6q for bipolar disorder). At the single gene level, we obtained lists of the transcripts with the most significant changes in expression and from these lists determined those with the highest degree of predictive power for classifying subjects according to diagnosis in these samples. At the gene group level, we comprehensively analyzed pairwise expression changes of more than 4,000 functional groups and cytogenetic locations, and present a novel method of displaying these data that we term "cytogenomic" mapping. Verification of selected changes in expression was performed using quantitative real-time RT-PCR. Our results provide compelling evidence for the utility of analyzing PBL RNA for changes in expression in neuropsychiatric disorders.

Adult↗
PubMed2004

Candidate genes, pathways and mechanisms for bipolar (manic-depressive) and related disorders: an expanded convergent functional genomics approach.

Identifying genes for bipolar mood disorders through classic genetics has proven difficult. Here, we present a comprehensive convergent approach that translationally integrates brain gene expression data from a relevant pharmacogenomic mouse model (involving treatments with a stimulant--methamphetamine, and a mood stabilizer--valproate), with human data (linkage loci from human genetic studies, changes in postmortem brains from patients), as a bayesian strategy of crossvalidating findings. Topping the list of candidate genes, we have DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kDa) located at 17q12, PENK (preproenkephalin) located at 8q12.1, and TAC1 (tachykinin 1, substance P) located at 7q21.3. These data suggest that more primitive molecular mechanisms involved in pleasure and pain may have been recruited by evolution to play a role in higher mental functions such as mood. The analysis also revealed other high-probability candidates genes (neurogenesis, neurotrophic, neurotransmitter, signal transduction, circadian, synaptic, and myelin related), pathways and mechanisms of likely importance in pathophysiology.

Animals↗
PubMed2003

A functional genomic analysis of cell morphology using RNA interference.

BACKGROUND: The diversity of metazoan cell shapes is influenced by the dynamic cytoskeletal network. With the advent of RNA-interference (RNAi) technology, it is now possible to screen systematically for genes controlling specific cell-biological processes, including those required to generate distinct morphologies. RESULTS: We adapted existing RNAi technology in Drosophila cell culture for use in high-throughput screens to enable a comprehensive genetic dissection of cell morphogenesis. To identify genes responsible for the characteristic shape of two morphologically distinct cell lines, we performed RNAi screens in each line with a set of double-stranded RNAs (dsRNAs) targeting 994 predicted cell shape regulators. Using automated fluorescence microscopy to visualize actin filaments, microtubules and DNA, we detected morphological phenotypes for 160 genes, one-third of which have not been previously characterized in vivo. Genes with similar phenotypes corresponded to known components of pathways controlling cytoskeletal organization and cell shape, leading us to propose similar functions for previously uncharacterized genes. Furthermore, we were able to uncover genes acting within a specific pathway using a co-RNAi screen to identify dsRNA suppressors of a cell shape change induced by Pten dsRNA. CONCLUSIONS: Using RNAi, we identified genes that influence cytoskeletal organization and morphology in two distinct cell types. Some genes exhibited similar RNAi phenotypes in both cell types, while others appeared to have cell-type-specific functions, in part reflecting the different mechanisms used to generate a round or a flat cell morphology.

Animals↗
PubMed2004

Functional genomic analysis of the response of HIV-1-infected lymphatic tissue to antiretroviral therapy.

Highly active antiretroviral therapy (HAART) curtails human immunodeficiency virus type 1 (HIV-1) replication in lymphatic tissues and partially reverses the pathological damage associated with infection, but the genes that mediate these pathological and reparative processes remain largely unknown. To identify these genes, we used microarrays to profile gene expression in serial lymph node biopsy specimens obtained before and after treatment. We discovered approximately 200 treatment-responsive genes, many of them known mediators and moderators of immune activation and defenses, particularly innate defense genes, which, surprisingly, were expressed at all stages of HIV-1 infection. Most of the rest of the treatment-responsive genes we categorized as mediators of trafficking, reformation of active follicles, and tissue repair. We propose a model in which nearly counterbalanced functions of mediators and moderators of immune activation and defenses account for the slow dynamics of HIV-1 infection before treatment. This model suggests that there could be a role for anti-inflammatory agents, alone or in combination with HAART, in treating HIV-1 infection by tipping this balance to mitigate pathology.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Functional genomics reveals a family of eukaryotic oxidation protection genes.

Reactive oxygen species (ROS) are toxic compounds produced by normal metabolic processes. Their reactivity with cellular components is a major stress for aerobic cells that results in lipid, protein, and DNA damage. ROS-mediated DNA damage contributes to spontaneous mutagenesis, and cells deficient in repair and protective mechanisms have elevated levels of spontaneous mutations. In Escherichia coli a large number of genes are involved in the repair of oxidative DNA damage and its prevention by detoxification of ROS. In humans, the genes required for these processes are not well defined. In this report we describe the human OXR1 (oxidation resistance) gene discovered in a search for human genes that function in protection against oxidative damage. OXR1 is a member of a conserved family of genes found in eukaryotes but not in prokaryotes. We also outline the procedures developed to identify human genes involved in the prevention and repair of oxidative damage that were used to identify the human OXR1 gene. This procedure makes use of the spontaneous mutator phenotype of E. coli oxidative repair-deficient mutants and identifies genes of interest by screening for antimutator activity resulting from cDNA expression.

Amino Acid Sequence↗
PubMed2005

Functional genomics of maize submergence tolerance and cloning of the related gene Sicyp51.

In this study, SSH (Suppression Subtractive Hybridization) and cDNA microarray were used to identify genes associated with waterlogging response of maize roots. Mo17 and Hz32 are two maize inbred lines with differential tolerance to hypoxia. Seedlings of the inbred lines with two leaves were submerged in hypoxia buffer. SSH libraries were constructed with cDNA samples from roots. Both forward and reverse subtractions were performed for each inbred line, and 105 positive clones induced by hypoxia were selected by differential screening. The treated and control message RNA were hybridized with the cDNA microarray of Mo17, sequentially, 57 of 3-fold differentially expressed clones were obtained. A total of 162 positive clones were all sequenced. Bioinformatics analysis showed these positive clones represent 85 TUGs, including genes involved in several biochemistry pathways, such as glycolysis, protection, signal transduction, cell construction and energy metabolism and 41 EST with unknown function. Comparison between Mo17 and Hz32 indicates that genes related to hypoxia tolerance have different expression patterns in submerged roots. Several positive clones' expression patterns were revealed by Northern or RT-PCR, and a new gene (Sicyp51), which may contribute to hypoxia tolerance, was identified.

Cell Hypoxia↗
PubMed2004

RNAi knock-down mice: an emerging technology for post-genomic functional genetics.

RNA interference (RNAi) has been extensively used for sequence-specific silencing of gene function in mammalian cells. The latest major breakthrough in the application of RNAi technology came from experiments demonstrating RNAi-mediated gene repression in mice and rats. After more than two decades of functional mouse research aimed at developing and continuously improving transgenic and knock-out technology, the advent of RNAi knock-down mice represents a valuable new alternative for studying gene function in vivo. In this review we provide some basic insight as to how RNAi can induce gene silencing to then focus on recent findings concerning the applicability of RNAi for regulating gene function in the mouse. Reviewed topics will include delivery methods for RNAi-mediating molecules, a comparison between traditional knock-out and innovative transgenic RNAi technology and the generation of graded RNAi knock-down phenotypes. Apart from the exciting possibilities RNAi provides for studying gene function in mice, we discuss several caveats and limitations to be considered. Finally, we present prospective strategies as to how RNAi technology might be applied for generating conditional and tissue-restricted knock-down mice.

Alleles↗
PubMed2006

Functional genomic analysis of herpes simplex virus type 1 counteraction of the host innate response.

Herpes simplex virus type 1 (HSV-1) mutants lacking the ICP34.5 gene are severely attenuated in mouse models and have a significant growth defect in confluent mouse embryo fibroblasts. Previously, ICP34.5 was demonstrated to have a crucial role in evading the innate immune response to infection by mediating the dephosphorylation of eIF2alpha, a translation initiation factor phosphorylated by PKR during the antiviral response. To further understand the role of ICP34.5 in evasion of the antiviral response, we used transcriptional profiling to examine host cell gene expression in both wild-type and ICP34.5-null virus-infected mouse embryo fibroblasts over a time course of infection. Our study revealed that cells responded to infection within 3 h through PKR-dependent eIF2alpha phosphorylation and that the majority of up-regulated genes at 3 h postinfection were involved in the antiviral response. HSV-1 counters this response through early expression of ICP34.5 and dephosphorylation of eIF2alpha. By 12 h postinfection, the differences between the number and functional classification of genes differentially up- and down-regulated between wild-type and ICP34.5-null virus-infected cells were maximal. Specifically, in wild-type virus-infected cells, the majority of changed genes were involved in metabolic and biosynthetic processes, while in ICP34.5-null virus-infected cells, mostly antiviral genes were up-regulated. Further, ICP34.5-null virus-infected cells produced greater amounts of beta interferon than wild-type virus-infected cells. These results indicate that ICP34.5 expression and function at early times postinfection have a pivotal role in the ability of HSV-1 to gain control of the host cell and maintain an environment for successful viral replication.

Animals↗
PubMed2003

Functional genomics of P450s.

Plant systems utilize a diverse array of cytochrome P450 monooxygenases (P450s) in their biosynthetic and detoxicative pathways. Those P450s in biosynthetic pathways play critical roles in the synthesis of lignins, UV protectants, pigments, defense compounds, fatty acids, hormones, and signaling molecules. Those in catabolic pathways participate in the breakdown of endogenous compounds and toxic compounds encountered in the environment. Because of their roles in this wide diversity of metabolic processes, plant P450 proteins and transcripts can serve as downstream reporters for many different biochemical pathways responding to chemical, developmental, and environmental cues. This review focuses initially on defining P450 biochemistries, nomenclature systems, and the relationships between genes in the extended P450 superfamily that exists in all plant species. Subsequently, it focuses on outlining the many approaches being used to assign function to individual P450 proteins and gene loci. The examples of assigned P450 activities that are spread throughout this review highlight the importance of understanding and utilizing P450 sequences as markers for linking biochemical pathway responses to physiological processes.

Cytochrome P-450 Enzyme System↗
PubMed2005

Sequencing and analysis of common bean ESTs. Building a foundation for functional genomics.

Although common bean (Phaseolus vulgaris) is the most important grain legume in the developing world for human consumption, few genomic resources exist for this species. The objectives of this research were to develop expressed sequence tag (EST) resources for common bean and assess nodule gene expression through high-density macroarrays. We sequenced a total of 21,026 ESTs derived from 5 different cDNA libraries, including nitrogen-fixing root nodules, phosphorus-deficient roots, developing pods, and leaves of the Mesoamerican genotype, Negro Jamapa 81. The fifth source of ESTs was a leaf cDNA library derived from the Andean genotype, G19833. Of the total high-quality sequences, 5,703 ESTs were classified as singletons, while 10,078 were assembled into 2,226 contigs producing a nonredundant set of 7,969 different transcripts. Sequences were grouped according to 4 main categories, metabolism (34%), cell cycle and plant development (11%), interaction with the environment (19%), and unknown function (36%), and further subdivided into 15 subcategories. Comparisons to other legume EST projects suggest that an entirely different repertoire of genes is expressed in common bean nodules. Phaseolus-specific contigs, gene families, and single nucleotide polymorphisms were also identified from the EST collection. Functional aspects of individual bean organs were reflected by the 20 contigs from each library composed of the most redundant ESTs. The abundance of transcripts corresponding to selected contigs was evaluated by RNA blots to determine whether gene expression determined by laboratory methods correlated with in silico expression. Evaluation of root nodule gene expression by macroarrays and RNA blots showed that genes related to nitrogen and carbon metabolism are integrated for ureide production. Resources developed in this project provide genetic and genomic tools for an international consortium devoted to bean improvement.

Carbon↗
PubMed2002

DNA-bound lipids of normal and tumor cells: retrospective and outlooks for functional genomics.

By very soft phenol method, the high-molecular-mass natural DNA complexes (10(8)-10(9) Da), which contain 1-3% specific lipids, were isolated from different eukaryotic and prokaryotic cells. Two pools of DNA-bound lipids were isolated: loosely bound (extracted with 35% ethanol) and tightly bound lipids (extracted after additional treatment DNAse I). The composition of these two lipid pools of different sources (rat thymus, liver, regenerating liver, loach sperm, pigeon erythrocytes, Zajdel ascites hepatoma, Ehrlich ascites carcinoma, sarcoma 37, Escherichia coli B, T2 phage) was studied. The DNA-bound lipid pools consist of neutral lipids (NL) and phospholipids (PL), moreover NL is always in a few fold more than PL. The composition of these lipid pools of eukaryotes distinguishes between themselves, mainly, by free cholesterol (minor fraction), cardiolipin (major fraction), and by phosphatidylcholine. Only the tightly bound lipid pool was present in T2 phage DNA. The dramatic redistribution effect between all fractions of NL pools (free and ester cholesterol, free fatty acids, diglycerides) was observed in DNA synthesis phase of cell cycle on the background of the unchanged composition of PL pools. Comparative analysis of DNA-bound lipid pools of normal and cancer cells was carried out. The DNA-bound lipid pools of transformed cells significantly differ from the same normal cells both by PL composition (cardiolipin) and by the presence of additional fractions (mono- and triglycerides) as well. The possible functions of DNA-bound lipid pools, especially of cardiolipin and cholesterol at the attachment of DNA loops to the nuclear matrix, DNA replicon organization, replication, and transcription are discussed.

Animals↗
PubMed2006

Human arsenic methyltransferase (AS3MT) pharmacogenetics: gene resequencing and functional genomics studies.

Arsenic contaminates ground water worldwide. Methylation is an important reaction in the biotransformation of arsenic. We set out to study the pharmacogenetics of human arsenic methyltransferase (AS3MT, previously CYT19). After cloning the human AS3MT cDNA, we annotated the human gene and resequenced its 5'-flanking region, exons, and splice junctions using 60 DNA samples from African-American (AA) and 60 samples from Caucasian-American (CA) subjects. We observed 26 single nucleotide polymorphisms (SNPs), including 3 non-synonymous cSNPs, as well as a variable number of tandem repeats in exon 1 within an area encoding the cDNA 5'-untranslated region. The nonsynonymous cSNPs included T860C (M287T) with frequencies of 10.8 and 10% in AA and CA subjects, respectively, as well as C517T (A173W) in one AA and C917T (T306I) in one CA sample. Haplotype analysis showed that Ile(306) was linked to Thr(287), so this double variant allozyme was also studied functionally. After expression in COS-1 cells and correction for transfection efficiency, the Trp(173) allozyme displayed 31%, Thr(287) 350%, Ile(306) 4.8%, and Thr(287)/Ile(306) 6.2% of the activity of the wild type (WT) allozyme, with 20, 190, 4.4, and 7.9% of the level of WT immunoreactive protein, respectively. Apparent K(m) values for S-adenosyl-l-methionine were 4.6, 3.1, and 11 mum for WT, Trp(173), and Thr(287) allozymes, with K(m) values for sodium arsenite with the same allozymes of 11.8, 8.9, and 4.5mum. The Ile(306) and Thr(287)/Ile(306) allozymes expressed too little activity for inclusion in the substrate kinetic studies. Expression of reporter gene constructs for the 5'-flanking region and the variable number of tandem repeats in the 5'-untranslated region demonstrated cell line-dependent variation in reporter gene expression, with shorter repeats associated with increased transcription in HepG2 cells. These results raise the possibility that inherited variation in AS3MT may contribute to variation in arsenic metabolism and, perhaps, arsenic-dependent carcinogenesis in humans.

5' Untranslated Regions↗
PubMed2006

Functional genomics of stress response in Pseudomonas putida KT2440.

The metabolically versatile soil bacterium Pseudomonas putida has to cope with numerous abiotic stresses in its habitats. The stress responses of P. putida KT2440 to 4 degrees C, pH 4.5, 0.8 M urea, and 45 mM sodium benzoate were analyzed by determining the global mRNA expression profiles and screening for stress-intolerant nonauxotrophic Tn5 transposon mutants. In 392 regulated genes or operons, 36 gene regions were differentially expressed by more than 2.5-fold, and 32 genes in 23 operons were found to be indispensable for growth during exposure to one of the abiotic stresses. The transcriptomes of the responses to urea, benzoate, and 4 degrees C correlated positively with each other but negatively with the transcriptome of the mineral acid response. The CbrAB sensor kinase, the cysteine synthase CysM, PcnB and VacB, which control mRNA stability, and BipA, which exerts transcript-specific translational control, were essential to cope with cold stress. The cyo operon was required to cope with acid stress. A functional PhoP, PtsP, RelA/SpoT modulon, and adhesion protein LapA were necessary for growth in the presence of urea, and the outer membrane proteins OmlA and FepA and the phosphate transporter PstBACS were indispensable for growth in the presence of benzoate. A lipid A acyltransferase (PP0063) was a mandatory component of the stress responses to cold, mineral acid, and benzoate. Adaptation of the membrane barrier, uptake of phosphate, maintenance of the intracellular pH and redox status, and translational control of metabolism are key mechanisms of the response of P. putida to abiotic stresses.

Bacterial Outer Membrane Proteins↗
PubMed2005

Paracoccidioides brasiliensis translation and protein fate machineries revealed by functional genome analysis.

The translational and post-translational modification machineries of Paracoccidioides brasiliensis were assessed by means of comparative analyses of PbAESTs (P. brasiliensis assembled expressed sequence tags) with sequences deposited on different databases. Of the 79 sequences corresponding to cytosolic ribosomal proteins, we were able to find 78 in the P. brasiliensis transcriptome. Nineteen of the 27 Saccharomyces cerevisiae genes related to translation initiation were also found. All eukaryotic elongation factors were detected in P. brasiliensis transcriptome, with eEF1A as one of the most expressed genes. Translation termination is performed, in eukaryotes, by factors 1 and 3 (eRF1, eRF3). In P. brasiliensis transcriptome it was possible to identify eRF3, but not eRF1. Sixteen PbAESTs showing aminoacyl-tRNA synthetase-predicted activities were found in our analyses, but no cysteinyl-, leucyl-, asparagyl- and arginyl-tRNA synthetases were detected. Among the mitochondrial ribosomal proteins, we have found 20 and 18 orthologs to S. cerevisiae large and small ribosomal subunit proteins, respectively. We have also found three PbAESTs similar to Neurospora crassa mitochondrial ribosomal genes, with no similarity with S. cerevisiae genes. Although orthologs to S. cerevisiae mitochondrial EF-Tu, EF-G and RF1 have been found in P. brasiliensis transcriptome, no sequences corresponding to functional EF-Ts were detected. In addition, 64 and 28 PbAESTs associated to protein modification and degradation, respectively, were found. These results suggest that these machineries are well conserved in P. brasiliensis, when compared to other organisms.

Expressed Sequence Tags↗
PubMed2004

Functional genomic analysis of Arabidopsis thaliana glycoside hydrolase family 1.

In plants, Glycoside Hydrolase (GH) Family 1 beta -glycosidases are believed to play important roles in many diverse processes including chemical defense against herbivory, lignification, hydrolysis of cell wall-derived oligosaccharides during germination, and control of active phytohormone levels. Completion of the Arabidopsis thaliana genome sequencing project has enabled us, for the first time, to determine the total number of Family 1 members in a higher plant. Reiterative database searches revealed a multigene family of 48 members that includes eight probable pseudogenes. Manual reannotation and analysis of the entire family were undertaken to rectify existing misannotations and identify phylogenetic relationships among family members. Forty-seven members (designated BGLU1 through BGLU47 ) share a common evolutionary origin and were subdivided into approximately 10 subfamilies based on phylogenetic analysis and consideration of intron-exon organizations. The forty-eighth member of this family ( At3g06510; sfr2 ) is a beta -glucosidase-like gene that belongs to a distinct lineage. Information pertaining to expression patterns and potential functions of Arabidopsis GH Family 1 members is presented. To determine the biological function of all family members, we intend to investigate the substrate specificity of each mature hydrolase after its heterologous expression in the Pichia pastoris expression system. To test the validity of this approach, the BGLU44 -encoded hydrolase was expressed in P. pastoris and purified to homogeneity. When tested against a wide range of natural and synthetic substrates, this enzyme showed a preference for beta -mannosides including 1,4- beta -D-mannooligosaccharides, suggesting that it may be involved in A. thaliana in degradation of mannans, galactomannans, or glucogalactomannans. Supporting this notion, BGLU44 shared high sequence identity and similar gene organization with tomato endosperm beta -mannosidase and barley seed beta -glucosidase/ beta -mannosidase BGQ60.

Arabidopsis↗
PubMed2002

[Functional genomics of pressure-loaded cardiomyocytes: etomoxir in heart failure?].

BACKGROUND: Drugs for counteracting the neuroendocrine activation in heart failure can reduce the adverse remodelling of the extracellular matrix of the heart. Progression of heart failure can, however, often not be prevented and the question arises whether important pharmacological targets remain unidentified. Promising are drugs targeted at ventricular diastolic dysfunction which is a marker of early progression of heart failure. PATHOPHYSIOLOGY: Left ventricular dysfunction is characteristic of overloaded hypertrophied hearts with molecular structures that are not adapted to the increased Ca2+ diffusion distances. Thus, the Ca(2+)-pump (SERCA2) of sarcoplasmic reticulum is inadequately expressed leading to a reduced force development and relaxation of hypertrophied cardiomyocytes. ETOMOXIR: Drugs in development (CPT-1 inhibitor/PPARalpha activator) that increase glucose oxidation can enhance SERCA2 expression. The lead compound etomoxir had a selective influence on the contraction and relaxation rate of pressure-overloaded hearts. The functional parameters were correlated with the proportion of alpha-myosin heavy chains. Since viral or inflammatory injury of the heart can also induce a fetal phenotype, metabolic modulators such as etomoxir represent a promising therapeutic approach also for cardiomyopathies with inadequate SERCA2 expression.

Animals↗