Data from collection and analysis of RNA sequencing data from pearl millet.

Pearl millet (Pennisetum glaucum, also known as Cenchrus americanus) is a cereal crop that has a C4 photosynthesis system and that can grow and develop seeds even under stressed conditions including drought-stressed, high temperature-stressed and nutrient-poor conditions. In previous studies, transcriptomes of pearl millet were studied by RNA sequencing (RNA-Seq) to understand mechanisms regulating its development and tolerance to such stressed conditions. Here, RNA-Seq reads from 565 pearl millet samples from 25 projects in the NCBI (National Center for Biotechnology Information) BioProject database were collected and mapped to the pearl millet reference genome to obtain read counts and transcripts per million (TPM) for each pearl millet gene. The count and TPM data for all the 565 samples as well as the attributes of those samples and projects were deposited in the figshare repository (https://doi.org/10.6084/m9.figshare.24902100).

Overexpression of a pearl millet WRKY transcription factor gene, PgWRKY74, in Arabidopsis retards shoot growth under dehydration and salinity-stressed conditions.

Pearl millet (Cenchrus americanus) is a cereal crop that can tolerate high temperatures, drought, and low-fertility conditions where other crops lose productivity. However, genes regulating this ability are largely unknown. Transcription factors (TFs) regulate transcription of their target genes, regulate downstream biological processes, and thus are candidates for regulators of such tolerance of pearl millet. PgWRKY74 encodes a group IIc WRKY TF in pearl millet and is downregulated by drought. PgWRKY74 may have a role in drought tolerance. The objective of this study was to gain insights into the physiological and biochemical functions of PgWRKY74. Yeast one-hybrid and gel shift assays were performed to examine transcriptional activation potential and deoxyribonucleic acid (DNA)-binding ability, respectively. Transgenic Arabidopsis thaliana plants overexpressing PgWRKY74-green fluorescent protein (GFP) fusion gene were generated and tested for growth and stress-responsive gene expression under mannitol and NaCl-stressed conditions. A construct with PgWRKY74 enabled yeast reporter cells to survive on test media in the yeast one-hybrid assays. The electrophoretic mobility of DNA with putative WRKY TF-binding motifs was lower in the presence of a recombinant PgWRKY74 protein than its absence. The PgWRKY74-GFP-overexpressing Arabidopsis plants exhibited smaller rosette areas than did wild-type plants under mannitol-stressed and NaCl-stressed conditions, and exhibited weaker expression of RD29B, which is induced by the stress-related phytohormone abscisic acid (ABA), under the mannitol-stressed condition. PgWRKY74 have transcriptional activation potential and DNA-binding ability, and can negatively regulate plant responses to mannitol and NaCl stresses, possibly by decreasing ABA levels or ABA sensitivity.

Data of RNA sequencing of pearl millet panicles treated with a high temperature.

Pearl millet (Pennisetum glaucum) is a cereal crop that can grow and set seeds even under drought, high temperatures and nutrient-poor conditions. Panicles of two pearl millet cultivars that differ in seed-setting rates were exposed to two different high-temperature treatments at three different developmental stages with three replicates, and RNA was prepared from these panicles. The resulting RNA samples were subjected to sequencing with the Illumina NovaSeq 6000 sequencer. The obtained data were 150-base-paired-end reads and were approximately 5 Gb/sample in total. These read data were deposited as those for a project in the NCBI (National Center for Biotechnology Information) BioProject database.

ORMDL3 regulates NLRP3 inflammasome activation by maintaining ER-mitochondria contacts in human macrophages and dictates ulcerative colitis patient outcome.

Genome-wide association studies in inflammatory bowel disease have identified risk loci in the orosomucoid-like protein 3/ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) gene to confer susceptibility to ulcerative colitis (UC), but the underlying functional relevance remains unexplored. Here, we found that a subpopulation of the UC patients who had higher disease activity shows enhanced expression of ORMDL3 compared to the patients with lower disease activity and the non-UC controls. We also found that the patients showing high ORMDL3 mRNA expression have elevated interleukin-1ß cytokine levels indicating positive correlation. Further, knockdown of ORMDL3 in the human monocyte-derived macrophages resulted in significantly reduced interleukin-1ß release. Mechanistically, we report for the first time that ORMDL3 contributes to a mounting inflammatory response via modulating mitochondrial morphology and activation of the NLRP3 inflammasome. Specifically, we observed an increased fragmentation of mitochondria and enhanced contacts with the endoplasmic reticulum (ER) during ORMDL3 over-expression, enabling efficient NLRP3 inflammasome activation. We show that ORMDL3 that was previously known to be localized in the ER also becomes localized to mitochondria-associated membranes and mitochondria during inflammatory conditions. Additionally, ORMDL3 interacts with mitochondrial dynamic regulating protein Fis-1 present in the mitochondria-associated membrane. Accordingly, knockdown of ORMDL3 in a dextran sodium sulfate -induced colitis mouse model showed reduced colitis severity. Taken together, we have uncovered a functional role for ORMDL3 in mounting inflammation during UC pathogenesis by modulating ER-mitochondrial contact and dynamics.

Circulating miR-let7a levels predict future diagnosis of chronic thromboembolic pulmonary hypertension.

Distinct patterns of circulating microRNAs (miRNAs) were found to be involved in misguided thrombus resolution. Thus, we aimed to investigate dysregulated miRNA signatures during the acute phase of pulmonary embolism (PE) and test their diagnostic and predictive value for future diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH). Microarray screening and subsequent validation in a large patient cohort (n = 177) identified three dysregulated miRNAs as potential biomarkers: circulating miR-29a and miR-720 were significantly upregulated and miR-let7a was significantly downregulated in plasma of patients with PE. In a second validation study equal expression patterns for miR-29a and miR-let7a regarding an acute event of recurrent venous thromboembolism (VTE) or deaths were found. MiR-let7a concentrations significantly correlated with echocardiographic and laboratory parameters indicating right ventricular (RV) dysfunction. Additionally, circulating miR-let7a levels were associated with diagnosis of CTEPH during follow-up. Regarding CTEPH diagnosis, ROC analysis illustrated an AUC of 0.767 (95% CI 0.54-0.99) for miR-let7a. Using logistic regression analysis, a calculated patient-cohort optimized miR-let7a cut-off value derived from ROC analysis of ≥ 11.92 was associated with a 12.8-fold increased risk for CTEPH. Therefore, miR-let7a might serve as a novel biomarker to identify patients with haemodynamic impairment and as a novel predictor for patients at risk for CTEPH.

Understanding genetic diversity in drought-adaptive hybrid parental lines in pearl millet.

Information on genetic diversity and population structure is helpful to strategize enhancing the genetic base of hybrid parental lines in breeding programs. The present study determined the population structure and genetic diversity of 109 pearl millet hybrid parental lines, known for their better adaptation and performance in drought-prone environments, using 16,472 single nucleotide polymorphic (SNP) markers generated from GBS (genotyping-by-sequencing) platforms. The SNPs were distributed uniformly across the pearl millet genome and showed considerable genetic diversity (0.337), expected heterozygosity (0.334), and observed heterozygosity (0.031). Most of the pairs of lines (78.36%) had Identity-by-State (IBS) based genetic distances of more than 0.3, indicating a significant amount of genetic diversity among the parental lines. Bayesian model-based population stratification, neighbor-joining phylogenetic analysis, and principal coordinate analysis (PCoA) differentiated all hybrid parental lines into two clear-cut major groups, one each for seed parents (B-lines) and pollinators (R-lines). Majority of parental lines sharing common parentages were found grouped in the same cluster. Analysis of molecular variance (AMOVA) revealed 7% of the variation among subpopulations, and 93% of the variation was attributable to within sub-populations. Chromosome 3 had the highest number of LD regions. Genomic LD decay distance was 0.69 Mb and varied across the different chromosomes. Genetic diversity based on 11 agro-morphological and grain quality traits also suggested that the majority of the B- and R-lines were grouped into two major clusters with few overlaps. In addition, the combined analysis of phenotypic and genotypic data showed similarities in the population grouping patterns. The present study revealed the uniqueness of most of the inbred lines, which can be a valuable source of new alleles and help breeders to utilize these inbred lines for the development of hybrids in drought-prone environments.

Musashi-2 causes cardiac hypertrophy and heart failure by inducing mitochondrial dysfunction through destabilizing Cluh and Smyd1 mRNA.

Regulation of RNA stability and translation by RNA-binding proteins (RBPs) is a crucial process altering gene expression. Musashi family of RBPs comprising Msi1 and Msi2 is known to control RNA stability and translation. However, despite the presence of MSI2 in the heart, its function remains largely unknown. Here, we aim to explore the cardiac functions of MSI2. We confirmed the presence of MSI2 in the adult mouse, rat heart, and neonatal rat cardiomyocytes. Furthermore, Msi2 was significantly enriched in the heart cardiomyocyte fraction. Next, using RNA-seq data and isoform-specific PCR primers, we identified Msi2 isoforms 1, 4, and 5, and two novel putative isoforms labeled as Msi2 6 and 7 to be expressed in the heart. Overexpression of Msi2 isoforms led to cardiac hypertrophy in cultured cardiomyocytes. Additionally, Msi2 exhibited a significant increase in a pressure-overload model of cardiac hypertrophy. We selected isoforms 4 and 7 to validate the hypertrophic effects due to their unique alternative splicing patterns. AAV9-mediated overexpression of Msi2 isoforms 4 and 7 in murine hearts led to cardiac hypertrophy, dilation, heart failure, and eventually early death, confirming a pathological function for Msi2. Using global proteomics, gene ontology, transmission electron microscopy, seahorse, and transmembrane potential measurement assays, increased MSI2 was found to cause mitochondrial dysfunction in the heart. Mechanistically, we identified Cluh and Smyd1 as direct downstream targets of Msi2. Overexpression of Cluh and Smyd1 inhibited Msi2-induced cardiac malfunction and mitochondrial dysfunction. Collectively, we show that Msi2 induces hypertrophy, mitochondrial dysfunction, and heart failure.

Progress in the design of portable colorimetric chemical sensing devices.

The need for precise determination of heavy metals, anions, biomolecules, pesticides, drugs, and other substances is vital across clinical, environmental, and food safety domains. Recent years have seen significant progress in portable colorimetric chemical sensing devices, revolutionizing on-the-spot analysis. This review offers a comprehensive overview of these advancements, covering handheld colorimetry, RGB-based colorimetry, paper-based colorimetry, and wearable colorimetry devices. It explores the underlying principles, functional materials (chromophoric reagents/dyes and nanoparticles), detection mechanisms, and their applications in environmental monitoring, clinical care, and food safety. Noble metal nanoparticles (NPs) have arisen as promising substitutes in the realm of sensing materials. They display notable advantages, including heightened sensitivity, the ability to fine-tune their plasmonic characteristics for improved selectivity, and the capacity to induce visible color changes, and simplifying detection. Integration of NPs fabricated paper device with smartphones and wearables facilitates reagent-free, cost-effective, and portable colorimetric sensing, enabling real-time analysis and remote monitoring.

Probing Molecular Diversity and Ultrastructure of Brain Cells with Fluorescent Aptamers.

Detergent-free immunolabeling has been proven feasible for correlated light and electron microscopy, but its application is restricted by the availability of suitable affinity reagents. Here we introduce CAptVE, a method using slow off-rate modified aptamers for cell fluorescence labeling on ultrastructurally reconstructable electron micrographs. CAptVE provides labeling for a wide range of biomarkers, offering a pathway to integrate molecular analysis into recent approaches to delineate neural circuits via connectomics.

Plasma proteome of growing tumors.

Early detection of cancer is vital for the best chance of successful treatment, but half of all cancers are diagnosed at an advanced stage. A simple and reliable blood screening test applied routinely would therefore address a major unmet medical need. To gain insight into the value of protein biomarkers in early detection and stratification of cancer we determined the time course of changes in the plasma proteome of mice carrying transplanted human lung, breast, colon, or ovarian tumors. For protein measurements we used an aptamer-based assay which simultaneously measures ~ 5000 proteins. Along with tumor lineage-specific biomarkers, we also found 15 markers shared among all cancer types that included the energy metabolism enzymes glyceraldehyde-3-phosphate dehydrogenase, glucose-6-phophate isomerase and dihydrolipoyl dehydrogenase as well as several important biomarkers for maintaining protein, lipid, nucleotide, or carbohydrate balance such as tryptophanyl t-RNA synthetase and nucleoside diphosphate kinase. Using significantly altered proteins in the tumor bearing mice, we developed models to stratify tumor types and to estimate the minimum detectable tumor volume. Finally, we identified significantly enriched common and unique biological pathways among the eight tumor cell lines tested.

CLUH functions as a negative regulator of inflammation in human macrophages and determines ulcerative colitis pathogenesis.

Altered mitochondrial function without a well-defined cause has been documented in patients with ulcerative colitis (UC). In our efforts to understand UC pathogenesis, we observed reduced expression of clustered mitochondrial homolog (CLUH) only in the active UC tissues compared with the unaffected areas from the same patient and healthy controls. Stimulation with bacterial Toll-like receptor (TLR) ligands similarly reduced CLUH expression in human primary macrophages. Further, CLUH negatively regulated secretion of proinflammatory cytokines IL-6 and TNF-α and rendered a proinflammatory niche in TLR ligand-stimulated macrophages. CLUH was further found to bind to mitochondrial fission protein dynamin related protein 1 (DRP1) and regulated DRP1 transcription in human macrophages. In the TLR ligand-stimulated macrophages, absence of CLUH led to enhanced DRP1 availability for mitochondrial fission, and a smaller dysfunctional mitochondrial pool was observed. Mechanistically, this fissioned mitochondrial pool in turn enhanced mitochondrial ROS production and reduced mitophagy and lysosomal function in CLUH-knockout macrophages. Remarkably, our studies in the mouse model of colitis with CLUH knockdown displayed exacerbated disease pathology. Taken together, this is the first report to our knowledge explaining the role of CLUH in UC pathogenesis, by means of regulating inflammation via maintaining mitochondrial-lysosomal functions in the human macrophages and intestinal mucosa.

Loss-of-function of triacylglycerol lipases are associated with low flour rancidity in pearl millet [Pennisetum glaucum (L.) R. Br.].

Pearl millet is an important cereal crop of semi-arid regions since it is highly nutritious and climate resilient. However, pearl millet is underutilized commercially due to the rapid onset of hydrolytic rancidity of seed lipids post-milling. We investigated the underlying biochemical and molecular mechanisms of rancidity development in the flour from contrasting inbred lines under accelerated aging conditions. The breakdown of storage lipids (triacylglycerols; TAG) was accompanied by free fatty acid accumulation over the time course for all lines. The high rancidity lines had the highest amount of FFA by day 21, suggesting that TAG lipases may be the cause of rancidity. Additionally, the high rancidity lines manifested substantial amounts of volatile aldehyde compounds, which are characteristic products of lipid oxidation. Lipases with expression in seed post-milling were sequenced from low and high rancidity lines. Polymorphisms were identified in two TAG lipase genes (PgTAGLip1 and PgTAGLip2) from the low rancidity line. Expression in a yeast model system confirmed these mutants were non-functional. We provide a direct mechanism to alleviate rancidity in pearl millet flour by identifying mutations in key TAG lipase genes that are associated with low rancidity. These genetic variations can be exploited through molecular breeding or precision genome technologies to develop elite pearl millet cultivars with improved flour shelf life.

Human Resource Demand Prediction and Configuration Model Based on Grey Wolf Optimization and Recurrent Neural Network.

Business development is dependent on a well-structured human resources (HR) system that maximizes the efficiency of an organization's human resources input and output. It is tough to provide adequate instructions for HR's unique task. In a time when the domestic labor market is still maturing, it is difficult for companies to make successful adjustments in HR structures to meet fluctuations in demand for human resources caused by shifting corporate strategies, operations, and size. Data on corporate human resources are often insufficient or inaccurate, which creates substantial nonlinearity and uncertainty when attempting to predict staffing needs, since human resource demand is influenced by numerous variables. The aim of this research is to predict the human resource demand using novel methods. Recurrent neural networks (RNNs) and grey wolf optimization (GWO) are used in this study to develop a new quantitative forecasting method for HR demand prediction. Initially, we collect the dataset and preprocess using normalization. The features are extracted using principal component analysis (PCA) and the proposed RNN with GWO effectively predicts the needs of HR. Moreover, organizations may be able to estimate personnel demand based on current circumstances, making forecasting more relevant and adaptive and enabling enterprises to accomplish their objectives via efficient human resource planning.

RIPK3-MLKL signaling activates mitochondrial CaMKII and drives intrarenal extracellular matrix production during CKD.

Intrarenal extracellular matrix production or kidney fibrosis is a prevalent feature of all forms of chronic kidney disease (CKD). The transforming growth factor-beta (TGFß) is believed to be a major driver of extracellular matrix production. Nevertheless, anti-TGFß therapies have consistently failed to reduce extracellular matrix production in CKD patients indicating the need for novel therapeutic strategies. We have previously shown that necroinflammation contributes to acute kidney injury. Here, we show that chronic/persistent necroinflammation drives intrarenal extracellular matrix production during CKD. We found that renal expression of receptor-interacting protein kinase-1 (RIPK1), RIPK3, and mixed lineage kinase domain-like (MLKL) increases with the production of intrarenal extracellular matrix and declined kidney function in both humans and mice. Furthermore, we found that TGFß exposure induces the translocation of RIPK3 and MLKL to mitochondria resulting in mitochondrial dysfunction and ROS production. Mitochondrial ROS activates the serine-threonine kinase calcium/calmodulin-dependent protein kinases-II (CaMKII) that increases phosphorylation of Smad2/3 and subsequent production of alpha-smooth muscle actin (αSMA), collagen (Col) 1α1, etc. in response to TGFß during the intrarenal extracellular matrix production. Consistent with this, deficiency or knockdown of RIPK3 or MLKL as well as pharmacological inhibition of RIPK1, RIPK3, and CaMKII prevents the intrarenal extracellular matrix production in oxalate-induced CKD and unilateral ureteral obstruction (UUO). Together, RIPK1, RIPK3, MLKL, CaMKII, and Smad2/3 are molecular targets to inhibit intrarenal extracellular matrix production and preserve kidney function during CKD.

Pharmacognostical and phytochemical screening of root and fruit of Ficus semicordata Buch.-Ham. Ex Sm. - An extra pharmacopoeial drug.

Introduction: Root and fruits of Bhumi Udumbara (Ficus semicordata Buch.-Ham. ex Sm.) are traditionally used in the treatment of aphthous complaints, leprosy, headache, abdominal diseases, bladder ailments, visceral obstruction, and various disorders. Aim: Present study reports the microscopic including powder microscopy, physiochemical and preliminary phytochemical characters of root and fruit of F. semicordata. Materials and methods: Root and fruit of the plant, after proper authentication, were evaluated following standard pharmacopoeial recommended procedures. Results: Striking characters of the F. semicordata root is the presence of profusely branched root-like structures, nearer to the trunk, and reaches the ground as a supporting root (aerial root or false root). The diagrammatic section of the root, circular in outline, made up of an outer cork, followed by cortex, vascular bundle, and central pseudo pith. Fruit is shortly peduncled, in pairs or clusters, globose in shape, hispid and warted surface, reddish brown in color. Loss on drying at 110°C was found to be 10.54% and 11.73% of root and fruit respectively. High-performance thin-layer chromatography results showed 2 peaks at 254 and 366 nm of root and 3 peaks at 254 and 1 peak at 366 nm of fruit respectively. Conclusion: F. semicordata is a small or medium-sized evergreen tree, bears a supporting root (aerial root or false root) nearer to the trunk region. Root reddish brown in color with smooth surface, prominent nodes, and internodes, presence of fruits over nodes and internodes is the key identifying character. Stone cells found in root and the presence of pollen grains, simple starch grains, and compound starch grains in fruit are the diagnostic characteristics of F. semicordata.

Understanding Heterosis, Genetic Effects, and Genome Wide Associations for Forage Quantity and Quality Traits in Multi-Cut Pearl Millet.

Pearl millet is an important food and fodder crop cultivated in the arid and semi-arid regions of Africa and Asia, and is now expanding to other regions for forage purpose. This study was conducted to better understand the forage quantity and quality traits to enhance the feed value of this crop. Two sets of pearl millet hybrids (80 single cross hybrids in Set-I and 50 top cross hybrids in Set-II) along with their parents evaluated multi-locationally for the forage-linked traits under multi-cut (two cuts) system revealed significant variability for the forage traits in the hybrids and parents. The mean better parent heterosis (BPH) for total dry forage yield (TDFY) was 136% across all the single cross hybrids and 57% across all the top cross hybrids. The mean BPH for in vitro organic matter digestibility (IVOMD) varied from -11 to 7% in the single cross hybrids and -13 to 11% in the top cross hybrids across cuts. The findings of TDFY and IVOMD heterosis in these sets indicated the potential of improvement of the hybrid cultivars for forage quantity and quality in forage pearl millet. The parental lines single cross parent (SCP)-L02, SCP-L06, and top cross parent (TCP)-T08 found superior in the forage quantity and quality traits can be utilized in the future breeding programs. Most of the forage traits were found to be controlled by using the non-additive gene action. A diverse panel of 105 forage-type hybrid parents (Set-III) genotyped following genotyping by sequencing (GBS) and phenotyped for crude protein (CP) and IVOMD under multi-cuts for 2 years identified one stable significant single nucleotide polymorphism (SNP) on LG4 for CP, and nine SNPs for IVOMD distributed across all the linkage groups except on LG2. The identified loci, once validated, then could be used for the forage quality traits improvement in pearl millet through marker-assisted selection.

Comprehensive analysis of NAC transcription factor family uncovers drought and salinity stress response in pearl millet (Pennisetum glaucum).

BACKGROUND: Pearl millet (Pennisetum glaucum) is a cereal crop that possesses the ability to withstand drought, salinity and high temperature stresses. The NAC [NAM (No Apical Meristem), ATAF1 (Arabidopsis thaliana Activation Factor 1), and CUC2 (Cup-shaped Cotyledon)] transcription factor family is one of the largest transcription factor families in plants. NAC family members are known to regulate plant growth and abiotic stress response. Currently, no reports are available on the functions of the NAC family in pearl millet. RESULTS: Our genome-wide analysis found 151 NAC transcription factor genes (PgNACs) in the pearl millet genome. Thirty-eight and 76 PgNACs were found to be segmental and dispersed duplicated respectively. Phylogenetic analysis divided these NAC transcription factors into 11 groups (A-K). Three PgNACs (- 073, - 29, and - 151) were found to be membrane-associated transcription factors. Seventeen other conserved motifs were found in PgNACs. Based on the similarity of PgNACs to NAC proteins in other species, the functions of PgNACs were predicted. In total, 88 microRNA target sites were predicted in 59 PgNACs. A previously performed transcriptome analysis suggests that the expression of 30 and 42 PgNACs are affected by salinity stress and drought stress, respectively. The expression of 36 randomly selected PgNACs were examined by quantitative reverse transcription-PCR. Many of these genes showed diverse salt- and drought-responsive expression patterns in roots and leaves. These results confirm that PgNACs are potentially involved in regulating abiotic stress tolerance in pearl millet. CONCLUSION: The pearl millet genome contains 151 NAC transcription factor genes that can be classified into 11 groups. Many of these genes are either upregulated or downregulated by either salinity or drought stress and may therefore contribute to establishing stress tolerance in pearl millet.

Telomerase therapy attenuates cardiotoxic effects of doxorubicin.

Doxorubicin is one of the most potent chemotherapeutic agents. However, its clinical use is restricted due to the severe risk of cardiotoxicity, partially attributed to elevated production of reactive oxygen species (ROS). Telomerase canonically maintains telomeres during cell division but is silenced in adult hearts. In non-dividing cells such as cardiomyocytes, telomerase confers pro-survival traits, likely owing to the detoxification of ROS. Therefore, we hypothesized that pharmacological overexpression of telomerase may be used as a therapeutic strategy for the prevention of doxorubicin-induced cardiotoxicity. We used adeno-associated virus (AAV)-mediated gene therapy for long-term expression of telomerase in in vitro and in vivo models of doxorubicin-induced cardiotoxicity. Overexpression of telomerase protected the heart from doxorubicin-mediated apoptosis and rescued cardiac function, which was accompanied by preserved cardiomyocyte size. At the mechanistic level, we observed altered mitochondrial morphology and dynamics in response to telomerase expression. Complementary in vitro experiments confirmed the anti-apoptotic effects of telomerase overexpression in human induced pluripotent stem cell-derived cardiomyocytes after doxorubicin treatment. Strikingly, elevated levels of telomerase translocated to the mitochondria upon doxorubicin treatment, which helped to maintain mitochondrial function. Thus, telomerase gene therapy could be a novel preventive strategy for cardiotoxicity by chemotherapy agents such as the anthracyclines.