Research Articles (SANBI)

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A 35-gene signature discriminates between rapidly- and slowly-progressing glioblastoma multiforme and predicts survival in known subtypes of the cancer
(BioMed Central, 2018) Fatai, Azeez A.; Gamieldien, Junaid
BACKGROUND: Gene expression can be employed for the discovery of prognostic gene or multigene signatures cancer. In this study, we assessed the prognostic value of a 35-gene expression signature selected by pathway and machine learning based methods in adjuvant therapy-linked glioblastoma multiforme (GBM) patients from the Cancer Genome Atlas. METHODS: Genes with high expression variance was subjected to pathway enrichment analysis and those having roles in chemoradioresistance pathways were used in expression-based feature selection. A modified Support Vector Machine Recursive Feature Elimination algorithm was employed to select a subset of these genes that discriminated between rapidly-progressing and slowly-progressing patients. RESULTS: Survival analysis on TCGA samples not used in feature selection and samples from four GBM subclasses, as well as from an entirely independent study, showed that the 35-gene signature discriminated between the survival groups in all cases (p < 0.05) and could accurately predict survival irrespective of the subtype. In a multivariate analysis, the signature predicted progression-free and overall survival independently of other factors considered. CONCLUSION: We propose that the performance of the signature makes it an attractive candidate for further studies to assess its utility as a clinical prognostic and predictive biomarker in GBM patients. Additionally, the signature genes may also be useful therapeutic targets to improve both progression-free and overall survival in GBM patients.
The African Coelecanth genome provides insights into tetrapod evolution
(Macmillan Publishers, 2013) Christoffels, Alan; Hesse, Uljana; Gamieldien, Junaid; Panji, Sumir; Picone, Barbara; Van Heusden, Peter
The discovery of a living coelacanth specimen in 1938 was remarkable, as this lineage of lobe-finned fish was thought to have become extinct 70 million years ago. The modern coelacanth looks remarkably similar to many of its ancient relatives, and its evolutionary proximity to our own fish ancestors provides a glimpse of the fish that first walked on land. Here we report the genome sequence of the African coelacanth, Latimeria chalumnae. Through a phylogenomic analysis, we conclude that the lungfish, and not the coelacanth, is the closest living relative of tetrapods. Coelacanth protein-coding genes are significantly more slowly evolving than those of tetrapods, unlike other genomic features. Analyses of changes in genes and regulatory elements during the vertebrate adaptation to land highlight genes involved in immunity, nitrogen excretion and the development of fins, tail, ear, eye, brain and olfaction. Functional assays of enhancers involved in the fin-to-limb transition and in the emergence of extra-embryonic tissues show the importance of the coelacanth genome as a blueprint for understanding tetrapod evolution.
Analyses of HIV-1 integrase sequences prior to South African national HIV-treatment program and available of integrase inhibitors in Cape Town, South Africa
(Nature Publishing Group, 2018) Brado, Dominik; Obasa, Adetayo Emmanuel; Ikomey, George Mondinde; Cloete, Ruben; Singh, Kamalendra; Engelbrecht, Susan; Neogi, Ujjwal; Jacobs, Graeme Brendon
HIV-Integrase (IN) has proven to be a viable target for highly specific HIV-1 therapy. We aimed to characterize the HIV-1 IN gene in a South African context and identify resistance-associated mutations (RAMs) against available first and second generation Integrase strand-transfer inhibitors (InSTIs). We performed genetic analyses on 91 treatment-naïve HIV-1 infected patients, as well as 314 treatmentnaive South African HIV-1 IN-sequences, downloaded from Los Alamos HIV Sequence Database. Genotypic analyses revealed the absence of major RAMs in the cohort collected before the broad availability of combination antiretroviral therapy (cART) and INSTI in South Africa, however, occurred at a rate of 2.85% (9/314) in database derived sequences. RAMs were present at IN-positions 66, 92, 143, 147 and 148, all of which may confer resistance to Raltegravir (RAL) and Elvitegravir (EVG), but are unlikely to affect second-generation Dolutegravir (DTG), except mutations in the Q148 pathway. Furthermore, protein modeling showed, naturally occurring polymorphisms impact the stability of the intasome-complex and therefore may contribute to an overall potency against InSTIs. Our data suggest the prevalence of InSTI RAMs, against InSTIs, is low in South Africa, but natural polymorphisms and subtype-specific differences may influence the effect of individual treatment regimens.
Antennal enriched odorant binding proteins are required for odor communication in glossina f. Fuscipes
(MPDI, 2021) Diallo, Souleymane; Shahbaaz, Mohd; Makwatta, JohnMark O.
Olfaction is orchestrated at different stages and involves various proteins at each step. For example, odorant-binding proteins (OBPs) are soluble proteins found in sensillum lymph that might encounter odorants before reaching the odorant receptors. In tsetse flies, the function of OBPs in olfaction is less understood. Here, we investigated the role of OBPs in Glossina fuscipes fuscipes olfaction, the main vector of sleeping sickness, using multidisciplinary approaches. Our tissue expression study demonstrated that GffLush was conserved in legs and antenna in both sexes, whereas GffObp44 and GffObp69 were expressed in the legs but absent in the antenna. GffObp99 was absent in the female antenna but expressed in the male antenna. Short odorant exposure induced a fast alteration in the transcription of OBP genes. Furthermore, we successfully silenced a specific OBP expressed in the antenna via dsRNAi feeding to decipher its function.
Application of an in silico approach identifies a genetic locus within ITGB2, and its interactions with HSPG2 and FGF9, to be associated with anterior cruciate ligament rupture risk
(Taylor and Francis Group, 2023) Dlamini, Senanile B.; Saunders, Colleen J.; Laguette, Mary-Jessica N.
We developed a Biomedical Knowledge Graph model that is phenotype and biological functionaware through integrating knowledge from multiple domains in a Neo4j, graph database. All known human genes were assessed through the model to identify potential new risk genes for anterior cruciate ligament (ACL) ruptures and Achilles tendinopathy (AT). Genes were prioritised and explored in a case–control study comparing participants with ACL ruptures (ACL-R), including a sub-group with non-contact mechanism injuries (ACL-NON), to uninjured control individuals (CON). After gene filtering, 3376 genes, including 411 genes identified through previous whole exome sequencing, were found to be potentially linked to AT and ACL ruptures. Four variants were prioritised: HSPG2:rs2291826A/G, HSPG2:rs2291827G/A, ITGB2:rs2230528C/T and FGF9:rs2274296C/T. The rs2230528 CC genotype was over-represented in the CON group compared to ACL-R (p < 0.001) and ACL-NON (p < 0.001) and the TT genotype and T allele were over-represented in the ACL-R group and ACL-NON compared to CON (p < 0.001) group.
Application of anin silicoapproach identifies a genetic locus withinITGB2,and itsinteractions withHSPG2 and FGF9,to be associated with anterior cruciateligament rupture risk
(Taylor and Francis Group, 2023) Dlamini, Senanile B.; Saunders, Colleen J.; Gamieldien, Junaid
We developed a Biomedical Knowledge Graph model that is phenotype and biological function-aware through integrating knowledge from multiple domains in a Neo4j, graph database. Allknown human genes were assessed through the model to identify potential new risk genes foranterior cruciate ligament (ACL) ruptures and Achilles tendinopathy (AT). Genes were prioritisedand explored in a case–control study comparing participants with ACL ruptures (ACL-R),including a sub-group with non-contact mechanism injuries (ACL-NON), to uninjured controlindividuals (CON). After genefiltering, 3376 genes, including 411 genes identified throughprevious whole exome sequencing, were found to be potentially linked to AT and ACL ruptures.Four variants were prioritised:HSPG2:rs2291826A/G,HSPG2:rs2291827G/A,ITGB2:rs2230528C/TandFGF9:rs2274296C/T. The rs2230528 CC genotype was over-represented in the CON groupcompared to ACL-R (p< 0.001) and ACL-NON (p< 0.001) and the TT genotype and T allele wereover-represented in the ACL-R group and ACL-NON compared to CON (p< 0.001) group. Severalsignificant differences in distributions were noted for the gene-gene interactions: (HSPG2:rs2291826, rs2291827 andITGB2:rs2230528) and (ITGB2:rs2230528 andFGF9:rs2297429).
Avihepadnavirus diversity in parrots is comparable to that found amongst all other avian species
(Elsevier, 2013) Piasecki, Tomasz; Harkins, Gordon William; Chrzastek, Klaudia; Julian, Laurel; Martin, Darren Patrick; Varsani, Arvind
Avihepadna viruses have previously been isolated from various species of duck ,goose, stork, heron and crane. Recently the first parrot avihepadna virus was isolated from a Ring-necked Parakeet in Poland. In this study, 41 psittacineliver samples archived in Poland over the last nine years were tested for presence of Parrot hepatitis B virus(PHBV). We cloned and sequenced PHBVisolates from 18 birds including a Crimson Rosella, an African grey parrot and sixteen Ring-necked Parakeets. PHBVisolates display a degree of diversity (478% genome wide pair wise identity) that is comparable to that found amongst all other avihepadna viruses (479% genome wide pair wise identity). The PHBV viruses can be subdivided into seven genetically distinct groups (tentatively named A-G) of which the two isolated of PHBV-Gare the most divergent sharing 79% genome wide pair wise identity with all their PHBVs. All PHBV isolates display classical avihepadnavirus genome architecture.
Blood pressure gradients and cardiovascular risk factors in urban and rural populations in Abia State South Eastern Nigeria using the WHO STEPwise approach
(Public Library of Science, 2013) Okpechi, Ikechi Gareth; Chukwuonye, Innocent Ijezie; Tiffin, Nicki; Madukwe, Okechukwu Ojoemelam; Onyeonoro, Ugochukwu Uchenna; Umeizudike, Theophilus Ifeanyichukwu; Ogah, Okechukwu Samuel; Onyeonoro, Ugochukwu Uchenna
Background: Developing countries of sub-Saharan Africa (SSA) face a double burden of non-communicable diseases (NCDs) and communicable diseases. As high blood pressure (BP) is a common global cardiovascular (CV) disorder associated with high morbidity and mortality, the relationship between gradients of BP and other CV risk factors was assessed in Abia State, Nigeria. Methods: Using the WHO STEPwise approach to surveillance of chronic disease risk factors, we conducted a populationbased cross-sectional survey in Abia state, Nigeria from August 2011 to March 2012. Data collected at various steps included: demographic and behavioral risk factors (Step 1); BP and anthropometric measurements (Step 2), and fasting blood cholesterol and glucose (Step 3). Results: Of the 2983 subjects with complete data for analysis, 52.1% were females and 53.2% were rural dwellers. Overall, the distribution of selected CV disease risk factors was diabetes (3.6%), hypertension (31.4%), cigarette smoking (13.3%), use of smokeless tobacco (4.8%), physical inactivity (64.2%) and being overweight or obese (33.7%). Presence of hypertension, excessive intake of alcohol, smoking (cigarette and smokeless tobacco) and physical inactivity occurred more frequently in males than in females (p,0.05); while low income, lack of any formal education and use of smokeless tobacco were seen more frequently in rural dwellers than in those living in urban areas (p,0.05). The frequency of selected CV risk factors increased as BP was graded from optimal, normal to hypertension; and high BP correlated with age, gender, smokeless tobacco, overweight or obesity, annual income and level of education. Conclusion: Given the high prevalence of hypertension in this part of Nigeria, there is an urgent need to focus on the reduction of preventable CV risk factors we have observed to be associated with hypertension, in order to effectively reduce the burden of NCDs in Africa.
Carbonic anhydrase II based biosensing of carbon dioxide at high temperature: an analytical and MD simulation study
(OMICS International, 2018) Idrees, Danish; Anwer, Razique; Shahbaaz, Mohd; Sabela, Myalowenkosi; Khamees, Osama A. Al; Gourinath, Samudrala; Kumar, Manoj; Singh, M.P.; Qumaizi, Khalid I. Al
Concentration of carbon dioxide (CO2) in the atmosphere has increased significantly due to anthropogenic activities and attributed as a major factor to global warming. Its detection by biosensing methods will provide an alternative for the assessment of CO2 concentration. Biomineralization of CO2 is one of the available methods for the biological conversion of CO2 to carbonate using a highly active enzyme, carbonic anhydrase II (CAII). CAII was used for the carbonation reaction to convert CO2 to CaCO3. The precipitation of calcium carbonate (CaCO3) was promoted in the presence of the CAII at 325 K. CAII showed an enhanced formation of solid CaCO3 through the acceleration of CO2 hydration rate at 325 K. Furthermore, the electrocatalytic properties of glassy carbon electrode enable us to determine the reduction peak potential values of CO2 through cyclic voltammetry at –1.75 and 0.3 V at 325 K. Molecular dynamic (MD) simulations were performed each at 50 ns time scale provided a deeper insight into the molecular basis of the CAII interaction with CO2 at different temperatures, highlighted that the CAII can detect CO2 up to 325 K. We assume that CAII could be an effective and economical biosensor for biomineralization of CO2 at high temperature 325 K.
Careful governance of African biobanks
(Elsevier, 2020) Christoffels, Alan G.; Abayomi, Akin
The Sydney Statement is one of the first framing documents on the principles for guiding global health security. Framing matters because the funding pool for development assistance for health is finite and has plateaued over the past decade.2,3 Investments in global health security to prevent future catastrophes are subject to competing health priorities, such as scaling up the “most essential interventions” against ongoing epidemics of preventable morbidity and mortality in mothers, infants, and children in the Global South.4 Development assistance for health that prioritises global health security could overwhelm or detract attention from multiple competing health priorities.3
Castleman’s disease in the HIV-endemic setting
(Dovepress, 2018) Mahroug, Esam-Rajab; Sher-Locketz, Candice; Abayomi, Emmanuel-Akinola; Tomuleasa, Ciprian; Grewal, Ravnit
Castleman’s disease (CD), first described by Benjamin Castleman in 1954, is a giant or angiofollicular lymph node hyperplasia, described as a rare monotypic polyclonal B-cell lymphoproliferative disorder with an incompletely understood pathogenesis and variable clinical behavior. This study aimed to determine the incidence of CD diagnosis over an 11-year period. Additionally, the study aimed to describe the demographic, laboratory, and pathological features of CD. Methods: This is a retrospective study where the demographic and laboratory data were retrieved from the Tygerberg Academic Hospital (TAH) patient electronic records and Tygerberg Lymphoma Study Group (TLSG) and statistical analysis performed on the patients diagnosed with CD. Results: Fifty-four patients were diagnosed with CD during this period. The median age at presentation was 39 years (range: 9–58). HIV serology was available in 53 patients, of which 51 were HIV-positive and two were HIV-negative. The history of initiation of antiretroviral therapy at diagnosis was available in 43 patients (38 on treatment, four were not on treatment, and one defaulted treatment). The median CD4 count was 232.50 cells/μL (range: 2–883). The HIV viral load was performed in 43 patients at diagnosis, which was <49 HIV-1 RNA copies/ μL in more than half of the patients (58%). Diagnosis was made on lymph node biopsies in 53 patients, with one case diagnosed on a spleen biopsy. Kaposi sarcoma was found on the same tissue biopsy in 13 cases. A bone marrow biopsy was performed in 31 patients. The predominant features noted were a disorganized hypercellular marrow with plasmocytosis. Conclusion: CD is a rare polyclonal B-cell lymphoproliferative disorder. However, we demonstrated a significant increase in the incidence of HIV-associated multicentric CD over the last decade in our area in South Africa.
Cellular and molecular targets of waterbuck repellent blend odors in antennae of glossina fuscipes fuscipes newstead, 1910
(Frontiers Media S.A., 2020) Diallo, Souleymane; Shahbaaz, Mohd; Torto, Baldwyn
Insects that transmit many of the world’s deadliest animal diseases, for instance trypanosomosis, find their suitable hosts and avoid non-preferred hosts mostly through olfactory cues. The waterbuck repellent blend (WRB) comprising geranylacetone, guaiacol, pentanoic acid, and d-octalactone derived from waterbuck skin odor is a repellent to some savannah-adapted tsetse flies and reduces trap catches of riverine species. However, the cellular and molecular mechanisms associated with detection and coding of the repellent odors remain to be elucidated. Here, we demonstrated that WRB inhibited blood feeding in both Glossina pallidipes Austen, 1903 and Glossina fuscipes fuscipes Newstead, 1910. Using the DREAM (Deorphanization of Receptors based on Expression Alterations in odorant receptor mRNA levels) technique, combined with ortholog comparison and molecular docking, we predicted the putative odorant receptors (ORs) for the WRB in G. f. fuscipes, a non-model insect.
Challenges of biobanking in South Africa to facilitate indigenous research in an environment burdened with human immunodeficiency virus, tuberculosis, and emerging non-communicable diseases
(Mary Ann Liebert, Inc., 2013) Abayomi, Akin; Christoffels, Alan; Grewal, Ravnit; Karam, Locunda A.; Rossouw, Catherine; Staunton, Ciara; Swanepoel, Carmen; van Rooyen, Beverley
The high burden of infectious diseases and the growing problem of noncommunicable and metabolic disease syndromes in South Africa (SA) forces a more focused research approach to facilitate cutting-edge scientific growth and public health development. Increased SA research on these diseases and syndromes and the collection of associated biospecimens has ensured a plethora of biobanks created by individuals, albeit without the foresight of prospective and collective use by other local and international researchers. As the need for access to high-quality specimens in statistically relevant numbers has increased, so has the necessity for the development of national human biobanks in SA and across the Continent. The prospects of achieving sustainable centralized biobanks are still an emerging and evolving concept, primarily and recently driven by the launch of the H3Africa consortium, which includes the development of harmonized and standardized biobanking operating procedures. This process is hindered by a myriad of complex societal considerations and ethico-legal challenges. Efforts to consolidate and standardize biological sample collections are further compromised by the lack of full appreciation by national stakeholders of the biological value inherent in these collections, and the availability of high quality human samples with well-annotated data for future scientific research and development. Inadequate or nonexistent legislative structures that specifically regulate the storage, use, dispersal, and disposal of human biological samples are common phenomena and pose further challenges. Furthermore, concerns relating to consent for unspecific future uses, as well as access to information and data protection, are all new paradigms that require further consideration and public engagement. This article reviews important fundamental issues such as governance, ethics, infrastructure, and bioinformatics that are important foundational prerequisites for the establishment and evolution of successful human biobanking in South Africa.
Changes in subcutaneous adipose tissue microRNA expression in response to exercise training in African women with obesity
(Nature Research, 2022) Pheiffer, Carmen; Dias, Stephanie; Pretorius, Ashley
The mechanisms that underlie exercise-induced adaptations in adipose tissue have not been elucidated, yet, accumulating studies suggest an important role for microRNAs (miRNAs). This study aimed to investigate miRNA expression in gluteal subcutaneous adipose tissue (GSAT) in response to a 12-week exercise intervention in South African women with obesity, and to assess depot-specific differences in miRNA expression in GSAT and abdominal subcutaneous adipose tissue (ASAT). In addition, the association between exercise-induced changes in miRNA expression and metabolic risk was evaluated. Women underwent 12-weeks of supervised aerobic and resistance training (n = 19) or maintained their regular physical activity during this period (n = 12). Exercise-induced miRNAs were identified in GSAT using Illumina sequencing, followed by analysis of differentially expressed miRNAs in GSAT and ASAT using quantitative real-time PCR. Associations between the changes (pre- and postexercise training) in miRNA expression and metabolic parameters were evaluated using Spearman’s correlation tests.
Characterizing the emergence and persistence of drug resistant mutations in HIV-1 subtype C infections using 454 ultra deep pyrosequencing
(BioMed Central -The Open Access Publisher, 2013) Bansode, Vijay; McCormack, Grace P.; Shrestha, Ram K.; Travers, Simon A.; Crampin, Amelia C.; Ngwira, Bagrey; French, Neil; Glynn, Judith R.
BACKGROUND: The role of HIV-1 RNA in the emergence of resistance to antiretroviral therapies (ARTs) is well documented while less is known about the role of historical viruses stored in the proviral DNA. The primary focus of this work was to characterize the genetic diversity and evolution of HIV drug resistant variants in an individual’s provirus during antiretroviral therapy using next generation sequencing. METHODS: Blood samples were collected prior to antiretroviral therapy exposure and during the course of treatment from five patients in whom drug resistance mutations had previously been identified using consensus sequencing. The spectrum of viral variants present in the provirus at each sampling time-point were characterized using 454 pyrosequencing from multiple combined PCR products. The prevalence of viral variants containing drug resistant mutations (DRMs) was characterized at each time-point. RESULTS: Low abundance drug resistant viruses were identified in 14 of 15 sampling time-points from the five patients. In all individuals DRMs against current therapy were identified at one or more of the sampling time-points. In two of the five individuals studied these DRMs were present prior to treatment exposure and were present at high prevalence within the amplified and sequenced viral population. DRMs to drugs other than those being currently used were identified in four of the five individuals. CONCLUSION: The presence of DRMs in the provirus, regardless of their observed prevalence did not appear to have an effect on clinical outcomes in the short term suggesting that the drug resistant viral variants present in the proviral DNA do not appear to play a role in the short term in facilitating the emergence of drug resistance.
Chromosomal-level assembly of the Asian seabass genome using long sequence reads and multi-layered scaffolding
(Public Library of Science, 2016) Vij, Shubha; Van Heusden, Peter; Christoffels, Alan; Mbandi, Stanley K.; Mwangi, Sarah
We report here the ~670 Mb genome assembly of the Asian seabass (Lates calcarifer), a tropical marine teleost. We used long-read sequencing augmented by transcriptomics, optical and genetic mapping along with shared synteny from closely related fish species to derive a chromosome-level assembly with a contig N50 size over 1 Mb and scaffold N50 size over 25 Mb that span ~90% of the genome. The population structure of L. calcarifer species complex was analyzed by re-sequencing 61 individuals representing various regions across the species’ native range. SNP analyses identified high levels of genetic diversity and confirmed earlier indications of a population stratification comprising three clades with signs of admixture apparent in the South-East Asian population. The quality of the Asian seabass genome assembly far exceeds that of any other fish species, and will serve as a new standard for fish genomics.
The combat-tb workbench: Making powerful Mycobacterium tuberculosis bioinformatics accessible
(American Society for Microbiology, 2022) van Heusden, Peter; Mashologu, Ziphozakhe; Lose, Thoba
Whole-genome sequencing (WGS) is a powerful method for detecting drug resistance, genetic diversity, and transmission dynamics of Mycobacterium tuberculosis. Implementation of WGS in public health microbiology laboratories is impeded by a lack of user-friendly, automated, and semiautomated pipelines. We present the COMBAT-TB Workbench, a modular, easy-to-install application that provides a web-based environment for Mycobacterium tuberculosis bioinformatics. The COMBAT-TB Workbench is built using two main software components: the IRIDA platform for its web-based user interface and data management capabilities and the Galaxy bioinformatics workflow platform for workflow execution.
COMBAT-TB-NeoDB: Fostering tuberculosis research through integrative analysis using graph database technologies
(Oxford University Press, 2020) Lose, Thoba; van Heusden, Peter A.; Christoffels, Alan G.
Tuberculosis (TB) is a significant global health threat, with onethird of the population infected with its causative agent Mycobacterium tuberculosis (M.tb). Globally, researchers have been responding with a plethora of heterogeneous TB databases with each focusing on different subsets of TB data and present limited options for data integration thus impeding the chances of integrative analysis. Although each database can provide answers to certain questions in its scope, it falls short in answering questions that require federated queries across multiple domains of biological knowledge.
Comparative analysis of testis and ovary transcriptomes in zebrafish by combining experimental and computational tools
(Wiley, 2004) Li, Yang; Chia, Jer, M; Bartfai, Richard; Christoffels, Alan; Yue, Gen, H; Ding, Ke; Ho, Mei, Y; Hill, James, A; Stupka, Elia; Orban, Laszlo
Studies on the zebrafish model have contributed to our understanding of several important developmental processes, especially those that can be easily studied in the embryo. However, knowledge on late events such as gonad differentiation in the zebrafish is still limited. Here an analysis on the gene sets is expressed in the adult zebrafish testis and ovary in an attempt to identify genes with potential role in (zebra)fish gonad development and function. We produced 10 533 expressed sequence tags (ESTs) from zebrafish testis or ovary and downloaded an additional 23 642 gonad-derived sequences from the zebrafish EST database. We clustered these sequences together with over 13 000 kidney-derived zebrafish ESTs to study partial transcriptomes for these three organs. We searched for genes with gonad-specific expression by screening macroarrays containing at least 2600 unique cDNA inserts with testis-, ovary- and kidney-derived cDNA probes. Clones hybridizing to only one of the two gonad probes were selected, and subsequently screened with computational tools to identify 72 genes with potentially testis-specific and 97 genes with potentially ovary-specific expression, respectively. PCR-amplification confirmed gonad-specificity for 21 of the 45 clones tested (all without known function). Our study, which involves over 47 000 EST sequences and specialized cDNA arrays, is the first analysis of adult organ transcriptomes of zebrafish at such a scale. The study of genes expressed in adult zebrafish testis and ovary will provide useful information on regulation of gene expression in teleost gonads and might also contribute to our understanding of the development and differentiation of reproductive organs in vertebrates.
Computational approaches for the design of novel anticancer compounds based on pyrazolo[3,4-d]pyrimidine derivatives as trap1 inhibitor
(MPDI, 2021) Ali, Amen; Abdellattif, Magda H; Shahbaaz, Mohd
In the present in-silico study, various computational techniques were applied to determine potent compounds against TRAP1 kinase. The pharmacophore hypothesis DHHRR_1 consists of important features required for activity. The 3D QSAR study showed a statistically significant model with R2 = 0.96 and Q2 = 0.57. Leave one out (LOO) cross-validation (R2 CV = 0.58) was used to validate the QSAR model. The molecular docking study showed maximum XP docking scores (−11.265, −10.532, −10.422, −10.827, −10.753 kcal/mol) for potent pyrazole analogs (42, 46, 49, 56, 43), respectively, with significant interactions with amino acid residues (ASP 594, CYS 532, PHE 583, SER 536) against TRAP1 kinase receptors (PDB ID: 5Y3N). Furthermore, the docking results were validated using the 100 ns MD simulations performed for the selected five docked complexes. The selected inhibitors showed relatively higher binding affinities than the TRAP1 inhibitor molecules present in the literature. The ZINC database was used for a virtual screening study that screened ZINC05297837, ZINC05434822, and ZINC72286418, which showed similar binding interactions to those shown by potent ligands. Absorption, distribution, metabolism, and excretion (ADME) analysis showed noticeable results. The results of the study may be helpful for the further development of potent TRAP1 inhibitors.

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