Biology subjects

Abdullah, S.

Publications and source records attributed to Abdullah, S..

6 recordsLinked to original sources

bioRxiv2025

Genomic alterations in persistently infecting oncolytic Newcastle disease virus reveal mechanisms of viral persistence in bladder cancer cells

AbstractsNewcastle disease virus (NDV) is a promising oncolytic agent with a non-segmented, negative-sense single-stranded RNA (ssRNA) genome of approximately 15 kb. While NDV selectively replicates in and lyses a wide range of human cancer cells, a subset of these cells develop persistent infections, potentially compromising the therapeutic efficacy of NDV-based treatments. To investigate the molecular basis of persistent infection, we performed transcriptome profiling of TCCSUP bladder cancer cells persistently infected with the NDV AF2240 strain. Deep sequencing using Illumina HiSeq 2000 was conducted in triplicate, and the resulting viral and host reads were separated and analyzed. Using Integrative Genomic Viewer (IGV) software, we identified several nucleotide variants linked to persistence. Specifically, nucleotide alterations included a deletion at 359A[->]C and a substitution at 1653C[->]T within the nucleoprotein (NP) gene, as well as an insertion at 3338C[->]T in the matrix protein (M) gene. Additionally, a GGG base insertion was detected at position 2290 in the phosphoprotein (P) gene. Crucially, we observed truncations in the hemagglutinin-neuraminidase (HN) gene (nt 8263-8390) and the large polymerase (L) gene (nt 6203-6342). These mutations and truncations suggest significant disruptions in viral replication, assembly, and host cell attachment, potentially facilitating viral persistence in bladder cancer cells. Understanding these genomic alterations provides valuable insights into the mechanisms driving viral persistence and could inform strategies to optimize the oncolytic efficacy of NDV in cancer therapy.

genomics↗

bioRxiv2024

Population genomics reveals an ancient origin of heartworms in canids

Heartworms (Dirofilaria immitis) are parasitic nematodes that cause significant cardiopulmonary-associated morbidity and mortality in canids worldwide. The global spread of heartworms is believed to have occurred alongside the dispersal of domesticated dogs. To test this theory, we analysed the genomes of 127 specimens collected from mammalian carnivore hosts across four continents. Here we show distinct genetic differences between heartworms from different continents, indicating a more ancient dispersal in canid hosts than previously recognised. Using admixture analyses, we find an Asian origin for Australian heartworms, consistent with the arrival of dingoes thousands of years ago. Finally, the genetic relatedness between European and Central American heartworms suggests that modern dispersal, likely associated with human colonisation of the Americas by Europeans, occurred with domesticated dogs. This work sheds light on the population dynamics and deep evolutionary history of a globally widespread parasite of veterinary significance.

evolutionary biology↗

bioRxiv2024

Widespread occurrence of benzimidazole resistance SNPs in the canine hookworm, Ancylostoma caninum, in Australia

Canine hookworm (Ancylostoma caninum), a gastrointestinal nematode of domestic dogs, principally infects the small intestine of dogs and has the potential to cause zoonotic disease. In greyhounds and pet dogs in the USA, A. caninum has been shown to be resistant to multiple anthelmintics. We conducted a molecular survey of benzimidazole resistance in A. caninum from dogs at veterinary diagnostic centers in Australia and New Zealand. First, we implemented an internal transcribed spacer (ITS)-2 rDNA deep amplicon metabarcoding sequencing approach to ascertain the species of hookworms infecting dogs in the region. Then, we evaluated the frequency of the canonical F167Y and Q134H isotype-1 {beta}-tubulin mutations, which confer benzimidazole resistance, using the same sequencing approach. The most detected hookworm species in diagnostic samples was A. caninum (90%; 83/92); the related Northern hookworm (Uncinaria stenocephala) was identified in 11% (10/92) of the diagnostic samples. There was a single sample with coinfection by A. caninum and U. stenocephala. Both isotype-1 {beta}-tubulin mutations were present in A. caninum, 49% and 67% for Q134H and F167Y, respectively. Mutation F167Y in the isotype-1 {beta}-tubulin mutation was recorded in U. stenocephala for the first known time. Canonical benzimidazole resistance codons 198 and 200 mutations were absent. Egg hatch assays performed on a subset of the A. caninum samples showed significant correlation between 50% inhibitory concentration (IC50) to thiabendazole and F167Y, with an increased IC50 for samples with >75% F167Y mutation. We detected 14% of dogs with >75% F167Y mutation in A. caninum. Given that these samples were collected from dogs across various regions of Australia, the present study suggests that benzimidazole resistance in A. caninum is widespread. Therefore, to mitigate the risk of resistance selection and further spread, adoption of a risk assessment-based approach to limit unnecessary anthelmintic use should be a key consideration for future parasite control.

microbiology↗

bioRxiv2020

Analysis of PPI networks of transcriptomic expression identifies hub genes Associated with Newcastle disease virus persistent infection in bladder cancer

MotivationBladder cancer cells acquire persistent infection associated with oncolytic Newcastle disease virus (NDV) in which its molecular events are still unclear. This poses a potential problem for oncolytic virus application for cancer therapy. To unravel the molecular mechanism underlying the development of NDV persistent infection in bladder cancer, we used mRNA expression profile of the persistently infected bladder cancer cells to construct PPI network. ResultsBased on path and module exploring in the PPI network, the bridges were found mainly from pathways of p53 signalling, ECM-receptor interaction, and TGF-beta signalling by the upregulated mRNAs, to the antigen processing and presentation, protein processing in endoplasmic reticulum, completement and coagulation cascades by the downregulated mRNAs in NDV persistent TCCSUPPi cells. In persistent EJ28Pi cells comparatively, connections were identified mainly from pathways of renal carcinoma, viral carcinogenesis, Ras signalling and cell cycle by the upregulated mRNAs, to the Wnt signalling, HTLV-I infection and pathways in cancer by the downregulated mRNAs. This connection was mainly dependent on of RPL8- HSPA1A/HSPA4 in TCCSUPPi cells and EP300, PTPN11, RAC1 - TP53, SP1, CCND1 and XPO1 in EJ28Pi cells. Oncomine validation showed that the top hub genes identified in the network that includes RPL8, THBS1, F2 from TCCSUPPi and TP53 and RAC1 from EJ28Pi are involved in the development and progression of bladder cancer. Protein-drug interaction network, have identified several drugs targets that could be used to disconnect the linkages between modules and prevent bladder cancer cells from acquiring NDV persistent infection. This is the first time reporting the PPI network analysis of differentially expressed mRNAs of the NDV persistently infected bladder cancer cell lines which provide an insight into screening drugs that could be used together with NDV to manage bladder cancer resistance to therapy and progression.

bioinformatics↗

bioRxiv2020

Functional Transcriptome Analysis of Bladder Cancer Cell Lines Persistently Infected with Oncolytic Newcastle Disease Virus

BackgroundNewcastle disease virus (NDV) has been an attractive virotherapy agent that targets various type of human cancers while leaving normal cells unharmed. Wild-type NDV strain AF2240 has been found to persistently infect subpopulation of cancer cells in vitro, making the cells less susceptible to NDV-mediated oncolysis. It is proposed that transcriptome profiling of NDV persistently infected bladder cancer cell lines will provide insights to understand such occurrence by identifying specific pathways associated with NDV persistent infection due to transcriptomic dysregulation. ResultsTranscriptome profiling revealed a total of 63 and 134 differentially expressed genes (DEGs) from NDV persistently infected TCCSUPPi and EJ28Pi bladder cancer cells relative to their uninfected controls, respectively. Of the 63 DEGs identified for TCCSUPPi cells, 25 DEGs were upregulated (log2 fold-change [≥] 0) and 38 DEGs were downregulated (log2 fold-change [≤] 0). These genes were significantly enriched in the molecular function of calcium binding (GO:0005509) and DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227) and the enriched important upregulated pathways were mainly heme metabolism, TGF-beta signaling and spermatogenesis. As for EJ28Pi, 55 DEGs were upregulated (log2 fold-change [≥] 0) and 79 DEGs were downregulated (log2 fold-change [≤] 0). These DEGs resulted in significantly enriched molecular function such as protein domain specific binding (GO:0019904) and RNA polymerase II regulatory region sequence-specific DNA binding (GO:0000977). The enriched important upregulated pathways were allograft rejection, KRAS signaling up and interferon gamma response. Other important pathways that were downregulated in both the NDV-persistently infected cell lines were angiogenesis, apoptosis, and xenobiotic metabolism. ConclusionThe transcriptome profiles (RNA-Seq) of these cell lines suggest that evasion of apoptosis and increase in TGF-beta signaling and interferon gamma response activities are crucial for establishment of NDV persistent infection in bladder cancer cells. Findings from this study provide the molecular basis that warrant further study on how bladder cancer cells acquired NDV persistent infection. Resolving the mechanism of persistent infection will facilitate the application of NDV for more effective treatment of bladder cancer.

cancer biology↗

bioRxiv2020

Natural genetic diversity in the potato resistance gene RB confers suppression avoidance from Phytophthora effector IPI-O4

RB is a potato gene that provides resistance to a broad spectrum of genotypes of the late blight pathogen Phytophthora infestans. RB belongs to the CC-NB-LRR (coiled-coil, nucleotide-binding, leucine-rich repeat) class of resistance (R) genes, a major component of the plant immune system. It directly interacts with Class I and II IPI-O effectors from P. infestans to initiate a hypersensitive resistance response, but this activity is suppressed in the presence of the Class III effector IPI-O4. Using natural genetic variation of RB within potato wild relatives, we identified two amino acids in the CC domain that alter interactions needed for suppression of resistance by IPI-O4. We have found that separate modification of these amino acids in RB can diminish or enhance the resistance capability of this protein against P. infestans in both Nicotiana benthamiana and potato. Our results demonstrate that increased knowledge of the molecular mechanisms that determine resistance activation and R protein suppression by effectors can be utilized to tailor-engineer genes with the potential to provide increased durability.

plant biology↗