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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 19 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2020

Unraveling the mechanism of recognition of the 3’ splice site of the adenovirus major late promoter intron by the alternative splicing factor PUF60

Pre-mRNA splicing is critical for achieving required amounts of a transcript at a given time and for regulating production of encoded protein. A given pre-mRNA may be spliced in many ways, or not at all, giving rise to multiple gene products. Numerous splicing factors are recruited to pre-mRNA splice sites to ensure proper splicing. One such factor, the 60 kDa poly(U)-binding splicing factor (PUF60), is recruited to sites that are not always spliced, but rather function as alternative splice sites. In this study, we characterized the interaction of PUF60 with a splice site from the adenovirus major late promoter (the AdML 3' splice site, AdML3’). We found that the PUF60–AdML3’ dissociation constants are in the micromolar range, with the binding affinity predominantly provided by PUF60’s two central RNA recognition motifs (RRMs). A 1.95 Å crystal structure of the two PUF60 RRMs in complex with AdML3’ revealed a dimeric organization placing two stretches of nucleic acid tracts in opposing directionalities, which can cause looping of nucleic acid and explain how PUF60 affects pre-mRNA geometry to effect splicing. Solution characterization of this complex by light-scattering and UV/Vis spectroscopy suggested a potential 2:1 (PUF60 2 :AdML3’) stoichiometry, consistent with the crystal structure. This work defines the sequence specificity of the alternative splicing factor PUF60 at the pre-mRNA 3’ splice site. Our observations suggest that control of pre-mRNA directionality is important in the early stage of spliceosome assembly, and advance our understanding of the molecular mechanism by which alternative and constitutive splicing factors differentiate among 3’ splice sites.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2019

Structures of neurexophilin–neurexin complexes reveal a regulatory mechanism of alternative splicing

Neurexins are presynaptic, cell-adhesion molecules that specify the functional properties of synapses via interactions with trans-synaptic ligands. Neurexins are extensively alternatively spliced at six canonical sites that regulate multifarious ligand interactions, but the structural mechanisms underlying alternative splicing-dependent neurexin regulation are largely unknown. Here, we determined high-resolution structures of the complex of neurexophilin-1 and the second laminin/neurexin/sex-hormone-binding globulin domain (LNS2) of neurexin-1 and examined how alternative splicing at splice site #2 (SS2) regulates the complex. Our data reveal a unique, extensive, neurexophilin–neurexin binding interface that extends the jelly-roll β-sandwich of LNS2 of neurexin-1 into neurexophilin-1. The SS2A insert of LNS2 augments this interface, increasing the binding affinity of LNS2 for neurexophilin-1. Taken together, our data reveal an unexpected architecture of neurexophilin–neurexin complexes that accounts for the modulation of binding by alternative splicing, which in turn regulates the competition of neurexophilin for neurexin binding with other ligands.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2019

tRNA ligase structure reveals kinetic competition between non-conventional mRNA splicing and mRNA decay

Yeast tRNA ligase (Trl1) is an essential trifunctional enzyme that catalyzes exon-exon ligation during tRNA biogenesis and the non-conventional splicing of HAC1 mRNA during the unfolded protein response (UPR). The UPR regulates the protein folding capacity of the endoplasmic reticulum (ER). ER stress activates Ire1, an ER-resident kinase/RNase, which excises an intron from HAC1 mRNA followed by exon-exon ligation by Trl1. The spliced product encodes for a potent transcription factor that drives the UPR. Here we report the crystal structure of Trl1 RNA ligase domain from Chaetomium thermophilum at 1.9 Å resolution. Structure-based mutational analyses uncovered kinetic competition between RNA ligation and degradation during HAC1 mRNA splicing. Incompletely processed HAC1 mRNA is degraded by Xrn1 and the Ski/exosome complex. We establish cleaved HAC1 mRNA as endogenous substrate for ribosome-associated quality control. We conclude that mRNA decay and surveillance mechanisms collaborate in achieving fidelity of non-conventional mRNA splicing during the UPR.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Stress-Induced Changes in Alternative Splicing Landscape in Rice: Functional Significance of Splice Isoforms in Stress Tolerance

Improvements in yield and quality of rice are crucial for global food security. However, global rice production is substantially hindered by various biotic and abiotic stresses. Making further improvements in rice yield is a major challenge to the rice research community, which can be accomplished through developing abiotic stress-resilient rice varieties and engineering durable agrochemical-independent pathogen resistance in high-yielding elite rice varieties. This, in turn, needs increased understanding of the mechanisms by which stresses affect rice growth and development. Alternative splicing (AS), a post-transcriptional gene regulatory mechanism, allows rapid changes in the transcriptome and can generate novel regulatory mechanisms to confer plasticity to plant growth and development. Mounting evidence indicates that AS has a prominent role in regulating rice growth and development under stress conditions. Several regulatory and structural genes and splicing factors of rice undergo different types of stress-induced AS events, and the functional significance of some of them in stress tolerance has been defined. Both rice and its pathogens use this complex regulatory mechanism to devise strategies against each other. This review covers the current understanding and evidence for the involvement of AS in biotic and abiotic stress-responsive genes, and its relevance to rice growth and development. Furthermore, we discuss implications of AS for the virulence of different rice pathogens and highlight the areas of further research and potential future avenues to develop climate-smart and disease-resistant rice varieties.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2018

microRNA-mediated regulation of splicing factors SRSF1, SRSF2 and hnRNP A1 in context of their alternatively spliced 3′UTRs

Highlights: • A group of microRNAs contributes to the regulation of SRSF1, SRSF2 and hnRNP A1. • microRNAs targeting SRSF1 and SRSF2 are involved in a regulatory feedback loop. • microRNAs that regulate SRSF2 affect also the expression of apoptotic genes. • 3′UTR variants of SRSF1 and SRSF2 differ by the presence of miRNA-binding sites. SRSF1, SRSF2 and hnRNP A1 are splicing factors that regulate the expression of oncogenes and tumor suppressors. SRSF1 and SRSF2 contribute to the carcinogenesis in the kidney. Despite their importance, the mechanisms regulating their expression in cancer are not entirely understood. Here, we investigated the microRNA-mediated regulation of SRSF1, SRSF2 and hnRNP A1 in renal cancer. The expression of microRNAs predicted to target SRSF1, SRSF2 and hnRNP A1 was disturbed in renal tumors compared with controls. Using qPCR, Western blot/ICC and luciferase reporter system assays we identified microRNAs that contribute to the regulation of expression of SRSF1 (miR-10b-5p, miR-203a-3p), SRSF2 (miR-183-5p, miR-200c-3p), and hnRNP A1 (miR-135a-5p, miR-149-5p). Silencing of SRSF1 and SRSF2 enhanced the expression of their targeting microRNAs. miR-183-5p and miR-200c-3p affected the expression of SRSF2-target genes, TNFRSF1B, TNFRSF9, CRADD and TP53. 3′UTR variants of SRSF1 and SRSF2 differed by the presence of miRNA-binding sites. In conclusion, we identified a group of microRNAs that contribute to the regulation of expression of SRSF1, SRSF2 and hnRNP A1. The microRNAs targeting SRSF1 and SRSF2 are involved in a regulatory feedback loop. microRNAs miR-183-5p and miR-200c-3p that target SRSF2, affect the expression of genes involved in apoptotic regulation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Splicing dysregulation contributes to the pathogenicity of several F9 exonic point variants

Abstract Background Pre‐mRNA splicing is a complex process requiring the identification of donor site, acceptor site, and branch point site with an adjacent polypyrimidine tract sequence. Splicing is regulated by splicing regulatory elements (SREs) with both enhancer and suppressor functions. Variants located in exonic regions can impact splicing through dysregulation of native splice sites, SREs, and cryptic splice site activation. While splicing dysregulation is considered primary disease‐inducing mechanism of synonymous variants, its contribution toward disease phenotype of non‐synonymous variants is underappreciated. Methods In this study, we analyzed 415 disease‐causing and 120 neutral F9 exonic point variants including both synonymous and non‐synonymous for their effect on splicing using a series of in silico splice site prediction tools, SRE prediction tools, and in vitro minigene assays. Results The use of splice site and SRE prediction tools in tandem provided better prediction but were not always in agreement with the minigene assays. The net effect of splicing dysregulation caused by variants was context dependent. Minigene assays revealed that perturbed splicing can be found. Conclusion Synonymous variants primarily cause disease phenotype via splicing dysregulation while additional mechanisms such as translation rate also play an important role. Splicing dysregulation is likely to contribute to the disease phenotype of several non‐synonymous variants.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Survey of Aging and Monitoring Concerns for Cables and Splices Due to Cable Repair and Replacement

The purpose of this report is to survey aging and monitoring concerns for electrical cable splices in nuclear power plants (NPPs) in long term operation. As portions of existing electrical cable runs in nuclear are replaced over time due to localized events, the total number of splices in NPPs is expected to increase. Relative to cables, the body of knowledge regarding aging of splices and splices in combination with aging cables in nuclear service environments in long-term operations is low. A few reports have considered the aging of cable system components other than cables (Jacobus 1990; Nelson 1998; Villaran and Lofaro 2002), but the nuclear industry has two decades of operating experience since these were published to further enlighten this issue. Herein we discuss electrical cables and splices commonly found in U.S. nuclear power plants, their qualification in safety-related application, and methods for monitoring their health condition. Common environmental stresses that can give rise to cable and splice failure are discussed. The Nuclear Regulatory Commission (NRC) Licensee Event Reports (LER) database was used to identify documented issues of cable and splice failure. The trend in the resultant data over time is considered to see if failures are increasing as plants age. Observations and conclusions of this work include: 1. Cables and splices are highly reliable components. Occurrence rates for events of interest were low and nearly constant over the last 20 years. 2. Common-cause failure for evaluated cable events of interest was observed to primarily be associated with loose connections, which may manifest associated with workmanship issues, thermal cycling, and/or vibration. 3. Replacement of cables is more common than repair, leading to an increase in proportion of new generation cables in the plant over time. 4. Splices on degraded cables have been observed to be problematic. Due to aging NPP infrastructure, including electrical cables, it is expected that such issues will continue to increase. 5. Condition monitoring approaches, while shown to be fruitful for cables, have been shown to be insensitive to degradation of splice sleeves, which are critical to the continued performance of splices. Additional condition monitoring (CM) work is needed to evaluate methods which are sensitive to the degradation of splice components. 6. Extended Material Degradation Assessment (EMDA) knowledge gaps for electrical cables (Bernstein et al. 2014) have not been investigated for splices but may represent similar concerns such as for the accelerated aging process historically used in environmental qualification.

42 ENGINEERING↗
DOE OSTI2018

Engineered U7 snRNA mediates sustained splicing correction in erythroid cells from β-thalassemia/HbE patients

Highlights: • Defect of β{sup E}-globin pre-mRNA splicing was repaired by engineered splice-switching U7 snRNA. • Splice-switching oligonucleotide sequence was identified by a two-step tiling approach. • The engineered U7 snRNA improve pathology of erythroid cells from thalassemia patients. Repair of a splicing defect of β-globin pre-mRNA harboring hemoglobin E (HbE) mutation was successfully accomplished in erythroid cells from patients with β-thalassemia/HbE disorder by a synthetic splice-switching oligonucleotide (SSO). However, its application is limited by short-term effectiveness and requirement of lifelong periodic administration of SSO, especially for chronic diseases like thalassemias. Here, we engineered lentiviral vectors that stably express U7 small nuclear RNA (U7 snRNA) carrying the splice-switching sequence of the SSO that restores correct splicing of β{sup E}-globin pre-mRNA and achieves a long-term therapeutic effect. Using a two-step tiling approach, we systematically screened U7 snRNAs carrying splice-switching SSO sequences targeted to the cryptic 5′ splice site created by HbE mutation. We tested this approach and identified the most responsive element for mediating splicing correction in engineered U7 snRNAs in HeLa-β{sup E} cell model cell line. Remarkably, the U7 snRNA lentiviral vector (U7 βE4+1) targeted to this region effectively restored the correctly-spliced β{sup E}-globin mRNA for at least 5 months. Moreover, the effects of the U7 βE4+1 snRNA lentiviral vector were also evident as upregulation of the correctly-spliced β{sup E}-globin mRNA in erythroid progenitor cells from β-thalassemia/HbE patients treated with the vector, which led to improvements of pathologies in erythroid progenitor cells from thalassemia patients. These results suggest that the splicing correction of β{sup E}-globin pre-mRNA by the engineered U7 snRNA lentiviral vector provides a promising, long-term treatment for β-thalassemia/HbE.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Schizophyllum commune has an extensive and functional alternative splicing repertoire

Recent genome-wide studies have demonstrated that fungi possess the machinery to alternatively splice pre-mRNA. However, there has not been a systematic categorization of the functional impact of alternative splicing in a fungus. We investigate alternative splicing and its functional consequences in the model mushroom forming fungus Schizophyllum commune. Alternative splicing was demonstrated for 2,285 out of 12,988 expressed genes, resulting in 20% additional transcripts. Intron retentions were the most common alternative splicing events, accounting for 33% of all splicing events, and 43% of the events in coding regions. On the other hand, exon skipping events were rare in coding regions (1%) but enriched in UTRs where they accounted for 57% of the events. Specific functional groups, including transcription factors, contained alternatively spliced genes. Alternatively spliced transcripts were regulated differently throughout development in 19% of the 2,285 alternatively spliced genes. Notably, 69% of alternatively spliced genes have predicted alternative functionality by loss or gain of functional domains, or by acquiring alternative subcellular locations. S. commune exhibits more alternative splicing than any other studied fungus. Finally, taken together, alternative splicing increases the complexity of the S. commune proteome considerably and provides it with a rich repertoire of alternative functionality that is exploited dynamically.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

A Deep Exon Cryptic Splice Site Promotes Aberrant Intron Retention in a Von Willebrand Disease Patient

A translationally silent single nucleotide mutation in exon 44 (E44) of the von Willebrand factor (VWF) gene is associated with inefficient removal of intron 44 in a von Willebrand disease (VWD) patient. This intron retention (IR) event was previously attributed to reordered E44 secondary structure that sequesters the normal splice donor site. We propose an alternative mechanism: the mutation introduces a cryptic splice donor site that interferes with the function of the annotated site to favor IR. We evaluated both models using minigene splicing reporters engineered to vary in secondary structure and/or cryptic splice site content. Analysis of splicing efficiency in transfected K562 cells suggested that the mutation-generated cryptic splice site in E44 was sufficient to induce substantial IR. Mutations predicted to vary secondary structure at the annotated site also had modest effects on IR and shifted the balance of residual splicing between the cryptic site and annotated site, supporting competition among the sites. Further studies demonstrated that introduction of cryptic splice donor motifs at other positions in E44 did not promote IR, indicating that interference with the annotated site is context dependent. We conclude that mutant deep exon splice sites can interfere with proper splicing by inducing IR.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

The kinetics of pre-mRNA splicing in the Drosophila genome and the influence of gene architecture

Production of most eukaryotic mRNAs requires splicing of introns from pre-mRNA. The splicing reaction requires definition of splice sites, which are initially recognized in either intron-spanning (‘intron definition’) or exon-spanning (‘exon definition’) pairs. To understand how exon and intron length and splice site recognition mode impact splicing, we measured splicing rates genome-wide in Drosophila, using metabolic labeling/RNA sequencing and new mathematical models to estimate rates. We found that the modal intron length range of 60–70 nt represents a local maximum of splicing rates, but that much longer exon-defined introns are spliced even faster and more accurately. We observed unexpectedly low variation in splicing rates across introns in the same gene, suggesting the presence of gene-level influences, and we identified multiple gene level variables associated with splicing rate. Together our data suggest that developmental and stress response genes may have preferentially evolved exon definition in order to enhance the rate or accuracy of splicing.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2017

The kinetics of pre-mRNA splicing in the Drosophila genome and the influence of gene architecture

Production of most eukaryotic mRNAs requires splicing of introns from pre-mRNA. The splicing reaction requires definition of splice sites, which are initially recognized in either intron-spanning (‘intron definition’) or exon-spanning (‘exon definition’) pairs. To understand how exon and intron length and splice site recognition mode impact splicing, we measured splicing rates genome-wide in Drosophila , using metabolic labeling/RNA sequencing and new mathematical models to estimate rates. We found that the modal intron length range of 60–70 nt represents a local maximum of splicing rates, but that much longer exon-defined introns are spliced even faster and more accurately. Here, we observed unexpectedly low variation in splicing rates across introns in the same gene, suggesting the presence of gene-level influences, and we identified multiple gene level variables associated with splicing rate. Together our data suggest that developmental and stress response genes may have preferentially evolved exon definition in order to enhance the rate or accuracy of splicing.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

RNA Splicing Events in Circulation Distinguish Individuals With and Without New-onset Type 1 Diabetes

Context: Alterations in RNA splicing may influence protein isoform diversity that contributes to or reflects the pathophysiology of certain diseases. Whereas specific RNA splicing events in pancreatic islets have been investigated in models of inflammation in vitro, how RNA splicing in the circulation correlates with or is reflective of type 1 diabetes (T1D) disease pathophysiology in humans remains unexplored. Objective: To use machine learning to investigate if alternative RNA splicing events differ between individuals with and without new-onset T1D and to determine if these splicing events provide insight into T1D pathophysiology. Methods: RNA deep sequencing was performed on whole blood samples from 2 independent cohorts: a training cohort consisting of 12 individuals with new-onset T1D and 12 age- and sex-matched nondiabetic controls and a validation cohort of the same size and demographics. Machine learning analysis was used to identify specific isoforms that could distinguish individuals with T1D from controls. Results: Distinct patterns of RNA splicing differentiated participants with T1D from unaffected controls. Notably, certain splicing events, particularly involving retained introns, showed significant association with T1D. Machine learning analysis using these splicing events as features from the training cohort demonstrated high accuracy in distinguishing between T1D subjects and controls in the validation cohort. Gene Ontology pathway enrichment analysis of the retained intron category showed evidence for a systemic viral response in T1D subjects. Conclusion: Alternative RNA splicing events in whole blood are significantly enriched in individuals with new-onset T1D and can effectively distinguish these individuals from unaffected controls. Further, our findings also suggest that RNA splicing profiles offer the potential to provide insights into disease pathogenesis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2010

Mechanism of protein splicing of the Pyrococcus abyssi lon protease intein

Research highlights: {yields} The Pyrococcus abyssi lon protease intein promotes efficient protein splicing. {yields} Inteins with mutations that interfere with individual steps of splicing do not promote unproductive side reactions. {yields} The intein splices with Lys in place of the highly conserved penultimate His. {yields} The intein is flanked by a Gly-rich region at its C terminus that may increase the efficiency of the third step of splicing, Asn cyclization coupled to peptide bond cleavage. -- Abstract: Protein splicing is a post-translational process by which an intervening polypeptide, the intein, excises itself from the flanking polypeptides, the exteins, coupled to ligation of the exteins. The lon protease of Pyrococcus abyssi (Pab) is interrupted by an intein. When over-expressed as a fusion protein in Escherichia coli, the Pab lon protease intein can promote efficient protein splicing. Mutations that block individual steps of splicing generally do not lead to unproductive side reactions, suggesting that the intein tightly coordinates the splicing process. The intein can splice, although it has Lys in place of the highly conserved penultimate His, and mutants of the intein in the C-terminal region lead to the accumulation of stable branched-ester intermediate.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Cell survival: Interplay between hypoxia and pre-mRNA splicing

RNA splicing takes place in the nucleus and occurs either co- or post-transcriptionally. Noncoding sequences (introns) in nuclear mRNA precursors (pre-mRNA) are removed by dedicated splicing machinery. The coding sequences (exons) are joined to generate the mature mRNA that is exported to the cytoplasm and translated into protein. Splicing events are tissue-specific. This process plays an important role in cellular differentiation and organism development. The splicing machinery heavily contributes to biological complexity and especially to the ability of cells to adapt to different developmental stages and altered cellular conditions. A striking change has been observed in alternative splicing pattern of genes and alterations in splicing factor expression under pathologic conditions especially in human cancers. Cancer cells are often confronted with a significant reduction in oxygen availability, which is a major reason for changeover of major cellular processes. Hypoxic regions have been identified within all solid tumors and their presence has been linked to malignant progression, metastasis, resistance to therapy, and poor clinical outcomes following treatment. Cellular responses to hypoxia are mediated by hypoxia inducible transcription factors (HIFs). This review focuses on currently available data how pre-mRNAs splicing contributes to cellular adaptation to hypoxic conditions, to genes which alternative splicing is regulated dependent on hypoxia and how regulation of alternative splicing under hypoxic conditions is achieved.

60 APPLIED LIFE SCIENCES↗
NASA NTRSDate not supplied

Conserved Function of RNA Binding Motif Protein48 (RBM48) and Armadillo Repeat Containing 7 (ARMC7) in Maize and Human U12 Splicing

Splicing of pre-mRNA is fundamental for genes containing introns. Emerging data points to a deeply conserved role of this process in eukaryotic cell differentiation and proliferation. The vast majority of introns termed U2-type introns are spliced by a major spliceosome; however, there also exist rare and more conserved U12-type introns that are spliced by a minor spliceosome. Mutations that disrupt U12 splicing inhibit cell differentiation in both maize endosperm and human blood cells. However, the mechanism underlying this process is not well understood. The maize RNA Binding Motif Protein 48 (RBM48) plays an essential role as a U12 splicing factor and is required for proper maize kernel development. Using human cell lines, CRISPR-Cas9 knockdown of RBM48 demonstrated a conserved function in human U12 intron splicing. RBM48 and Armadillo Repeat Containing 7 (ARMC7) protein interact in both maize and human as part of the activated minor spliceosome. Here we show RBM48 and ARMC7 co-localization in the nucleus of human cell lines. Vertebrate ARMC7 is normally localized in the cytosol, whereas RBM48 is found in the nucleus. Our data suggests that the interaction plays a role in regulating ARMC7 localization or the efficiency of U12 intron splicing. We also performed comprehensive transcriptome profiling and identified a common subset of conserved Minor Intron Containing Genes (MIGs) impacted in both human and maize RBM48 knockout mutants. Of importance, the vast majority of these MIGs are associated with developmental defects in both plants and animals. This suggests that aberrant splicing of these targets has a high likelihood of mediating abnormal cell phenotypes. These data support evolutionarily conserved U12 splicing mechanisms between maize and humans with both RBM48 and ARMC7 having roles in the activated spliceosome.

maize↗
DOE OSTI2018

An important class of intron retention events in human erythroblasts is regulated by cryptic exons proposed to function as splicing decoys

During terminal erythropoiesis, the splicing machinery in differentiating erythroblasts executes a robust intron retention (IR) program that impacts expression of hundreds of genes. We studied IR mechanisms in the SF3B1 splicing factor gene, which expresses ~50% of its transcripts in late erythroblasts as a nuclear isoform that retains intron 4. RNA-seq analysis of nonsense-mediated decay (NMD)-inhibited cells revealed previously undescribed splice junctions, rare or not detected in normal cells, that connect constitutive exons 4 and 5 to highly conserved cryptic cassette exons within the intron. Minigene splicing reporter assays showed that these cassettes promote IR. Genome-wide analysis of splice junction reads demonstrated that cryptic noncoding cassettes are much more common in large (>1 kb) retained introns than they are in small retained introns or in nonretained introns. Functional assays showed that heterologous cassettes can promote retention of intron 4 in the SF3B1 splicing reporter. Although many of these cryptic exons were spliced inefficiently, they exhibited substantial binding of U2AF1 and U2AF2 adjacent to their splice acceptor sites. We propose that these exons function as decoys that engage the intron-terminal splice sites, thereby blocking cross-intron interactions required for excision. Developmental regulation of decoy function underlies a major component of the erythroblast IR program.

59 BASIC BIOLOGICAL SCIENCES↗