Transcriptional Down Regulation of Spermatogenesis Genes in Drosophila Interspecies Hybrids

In Drosophila, crossing two closely related species can generate viable but sterile male offspring,typically an outcome of postzygotic reproductive isolation. Hybrids between species of the Drosophila simulans clade show disruption mainly after the meiosis stage of the spermatogenesis pathway, which eventually affects the production of mature sperm. Whole genome investigations (using microarray) of the clade identified that misregulation in sterile hybrids was caused by post-meiotic breakdown. However, either the use of non species-specific genomic platforms or the choice of tissue sampling (whole bodies rather than testes) has made the results of previous investigations prone to ambiguity.Down regulation of spermatogenesis genes specific to interspecies hybrid testes was further supported by lack of differences in gene expression in hybrid ovaries (interspecific), hybrid whole body samples (interspecific) and hybrid testes (intrapsecific) when compared to their respective parental species. However a preliminary protein assay did not suggest a difference in expression between D. mauritiana and interspecies sterile hybrid for bam and sa. These results suggest that misregulation in hybrid sterile males is solely transcriptional and exclusive to testes in interspecies hybrids. The results presented in this thesis do not support down regulation driven by hybrid male sterility. It is possible that transcriptional down regulation of spermatogenesis genes in interspecific hybrids could be the result of rapid divergence experienced by the male genome among the closely related species of Drosophila (i.e. the male sex drive hypothesis). Alternatively, allometric changes due to subtle testes-specific developmental abnormalities in sterile interspecific hybrids, as suggested by morphological analysis, might also contribute to differences in gene expression.Master of Science in Biolog

Third chromosome candidate genes for conspecific sperm precedence between D. simulans and D. mauritiana

<p>Abstract</p> <p>Background</p> <p>Male - female incompatibilities can be critical in keeping species as separate and discrete units. Premating incompatibilities and postzygotic hybrid sterility/inviability have been widely studied as isolating barriers between species. In recent years, a number of studies have brought attention to postmating prezygotic barriers arising from male - male competition and male - female interactions. Yet little is known about the genetic basis of postmating prezygotic isolation barriers between species.</p> <p>Results</p> <p>Using <it>D. simulans </it>lines with mapped introgressions of <it>D. mauritiana </it>into their third chromosome, we find at least two <it>D. mauritiana </it>introgressions causing male breakdown in competitive paternity success. Eighty one genes within the mapped introgressed regions were identified as broad-sense candidates on the basis of male reproductive tract expression and male-related function. The list of candidates was narrowed down to five genes based on differences in male reproductive tract expression between <it>D. simulans </it>and <it>D. mauritiana</it>. Another ten genes were confirmed as candidates using evidence of adaptive gene coding sequence diversification in the <it>D. simulans </it>and/or <it>D. mauritiana </it>lineage. Our results show a complex genetic basis for conspecific sperm precedence, with evidence of gene interactions between at least two third chromosome loci. Pleiotropy is also evident from correlation between conspecific sperm precedence and female induced fecundity and the identification of candidate genes that might exert an effect through genetic conflict and immunity.</p> <p>Conclusions</p> <p>We identified at least two loci responsible for conspecific sperm precedence. A third of candidate genes within these two loci are located in the 89B cytogenetic position, highlighting a possible major role for this chromosome position during the evolution of species specific adaptations to postmating prezygotic reproductive challenges.</p

A novel ZEB1/HAS2 positive feedback loop promotes EMT in breast cancer

10.18632/oncotarget.14563Oncotarget8711530-1154

Evaluation of SMA-RL71, a curcumin analogue nanomicelle as a drug in xenograft models of triple negative breast cancer

Triple negative breast cancer (TNBC) is a subtype of ER (-) cancer that currently has no treatment options. A novel drug formulation of the most potent curcumin analogue (RL71), compared to the analogues synthesised by other laboratories, styrene-co-maleic acid - 3,5-bis (3,4,5-trimethoxybenzylidene)-1 methylpiperidin-4-one (SMA-RL71) was tested for its anti-cancer activity in an animal model of breast cancer. In the dose response study 15 mg/kg, 10 mg/kg and 5 mg/kg of SMA-RL71 and 10 mg/kg of RL71 was injected into the tail vein of female SCID mice inoculated with MDA-MB-231 cells. None of the treatments produced a statistically significant decrease in tumour volume. Since SMA-RL71 15 mg/kg caused necrosis of the tail, a time course study was performed using SMA-RL71 10 mg/kg at different time points to test if tumour suppression could be achieved with multiple injections of the drug. Mice were randomly grouped after tumour inoculation and dosed with SMA-RL71 10 mg/kg (2 weeks), SMA-RL71 10 mg/kg (3 weeks), RL71 10 mg/kg (2 weeks), and RL71 10 mg/kg (3 weeks) via the tail vein, twice weekly (every 3-4 days). Tumour volume and body weight were determined twice weekly and tumour weight was determined at necropsy. Toxicity was determined from the organ weight at the time of necropsy. Compared to control, there was a 46% decrease (P < 0.001) in tumour volume in the mice dosed with SMA-RL71 10 mg/kg for 2 weeks from day 24. Furthermore, on day 31 when the mice were sacrificed, there was a 43% decrease (P < 0.0001) in tumour weight. All mice gained a similar amount of weight at the end of each study. However, an increase in the weight of the spleen, liver and kidney were observed in the mice dosed with SMA-RL71. HPLC was optimised for the detection of RL71 in plasma, using curcumin as an internal standard. In summary, 15% SMA-RL71 10 mg/kg twice weekly for two weeks suppressed the growth of TNBC tumours without any significant loss in body weight

Evaluation of SMA-RL71, a curcumin analogue nanomicelle as a drug in xenograft models of triple negative breast cancer

Triple negative breast cancer (TNBC) is a subtype of ER (-) cancer that currently has no treatment options. A novel drug formulation of the most potent curcumin analogue (RL71), compared to the analogues synthesised by other laboratories, styrene-co-maleic acid - 3,5-bis (3,4,5-trimethoxybenzylidene)-1 methylpiperidin-4-one (SMA-RL71) was tested for its anti-cancer activity in an animal model of breast cancer. In the dose response study 15 mg/kg, 10 mg/kg and 5 mg/kg of SMA-RL71 and 10 mg/kg of RL71 was injected into the tail vein of female SCID mice inoculated with MDA-MB-231 cells. None of the treatments produced a statistically significant decrease in tumour volume. Since SMA-RL71 15 mg/kg caused necrosis of the tail, a time course study was performed using SMA-RL71 10 mg/kg at different time points to test if tumour suppression could be achieved with multiple injections of the drug. Mice were randomly grouped after tumour inoculation and dosed with SMA-RL71 10 mg/kg (2 weeks), SMA-RL71 10 mg/kg (3 weeks), RL71 10 mg/kg (2 weeks), and RL71 10 mg/kg (3 weeks) via the tail vein, twice weekly (every 3-4 days). Tumour volume and body weight were determined twice weekly and tumour weight was determined at necropsy. Toxicity was determined from the organ weight at the time of necropsy. Compared to control, there was a 46% decrease (P < 0.001) in tumour volume in the mice dosed with SMA-RL71 10 mg/kg for 2 weeks from day 24. Furthermore, on day 31 when the mice were sacrificed, there was a 43% decrease (P < 0.0001) in tumour weight. All mice gained a similar amount of weight at the end of each study. However, an increase in the weight of the spleen, liver and kidney were observed in the mice dosed with SMA-RL71. HPLC was optimised for the detection of RL71 in plasma, using curcumin as an internal standard. In summary, 15% SMA-RL71 10 mg/kg twice weekly for two weeks suppressed the growth of TNBC tumours without any significant loss in body weight

Exploiting replicative stress in gynecological cancers as a therapeutic strategy

10.1136/ijgc-2020-001277INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER3081224-123

Revisiting the miR-200 Family: A Clan of Five Siblings with Essential Roles in Development and Disease

Over two decades of studies on small noncoding RNA molecules illustrate the significance of microRNAs (miRNAs/miRs) in controlling multiple physiological and pathological functions through post-transcriptional and spatiotemporal gene expression. Among the plethora of miRs that are essential during animal embryonic development, in this review, we elaborate the indispensable role of the miR-200 family (comprising miR-200a, -200b, 200c, -141, and -429) in governing the cellular functions associated with epithelial homeostasis, such as epithelial differentiation and neurogenesis. Additionally, in pathological contexts, miR-200 family members are primarily involved in tumor-suppressive roles, including the reversal of the cancer-associated epithelial–mesenchymal transition dedifferentiation process, and are dysregulated during organ fibrosis. Moreover, recent eminent studies have elucidated the crucial roles of miR-200s in the pathophysiology of multiple neurodegenerative diseases and tissue fibrosis. Lastly, we summarize the key studies that have recognized the potential use of miR-200 members as biomarkers for the diagnosis and prognosis of cancers, elaborating the application of these small biomolecules in aiding early cancer detection and intervention