Search Results (15)

Background/Objectives: The Iroquois (IRX) family of homeobox genes regulates critical developmental processes, and emerging evidence suggests that their dysregulation contributes to cancer progression, particularly in relation to cancer stemness. Although their expression appears to be influenced by hormonal regulation, their potential roles in hormone-sensitive cancers remain incompletely understood. Methods: In this study, we performed a comprehensive, exploratory analysis of all six Iroquois genes (IRX1–IRX6) across prostate, breast, ovarian, and endometrial cancers. Using large-scale publicly available transcriptomic datasets, we systematically examined IRX gene expression patterns and their associations with tumour progression, prognosis, hormone regulation, drug response, and cancer stemness. Results:IRX3 and IRX5 were consistently elevated in estrogen-dependent tumours and IRX2 and IRX4 were notably upregulated in prostate cancer. Despite evidence of estrogen receptor 1 (ESR1) and androgen receptor (AR) binding near several IRX promoters, estrogen treatment assays showed that ESR1 binding at promoters alone was insufficient to induce IRX transcription. Clinically, IRX2 expression was associated with favourable outcomes in breast, endometrial, and ovarian cancers and showed correlations with stemness-related signatures in prostate cancer. Similarly, IRX4 expression was associated with stemness features in prostate and endometrial cancers. In addition, IRX6 expression showed associations with reduced sensitivity to abiraterone, suggesting a potential link with therapeutic resistance in these tumours. Conclusions: Collectively, these findings highlight the context-dependent expression patterns and clinical associations of IRX genes across hormone-driven cancers. While largely correlative, this study provides a framework for future functional investigations and suggests that selected IRXs may have potential utility as biomarkers for disease stratification and treatment response in hormone-sensitive cancers. Full article

Gastric cancer (GC) is the fifth leading cause of cancer-associated death worldwide, accounting for 768,793 related deaths and 1,089,103 new cases in 2020. Despite diagnostic advances, GC is often detected in late stages. Through a systematic literature search, this study focuses on the associations between the Iroquois gene family and GC. Accumulating evidence indicates that Iroquois genes are involved in the regulation of various physiological and pathological processes, including cancer. To date, information about Iroquois genes in GC is very limited. In recent years, the expression and function of Iroquois genes examined in different models have suggested that they play important roles in cell and cancer biology, since they were identified to be related to important signaling pathways, such as wingless, hedgehog, mitogen-activated proteins, fibroblast growth factor, TGFβ, and the PI3K/Akt and NF-kB pathways. In cancer, depending on the tumor, Iroquois genes can act as oncogenes or tumor suppressor genes. However, in GC, they seem to mostly act as tumor suppressor genes and can be regulated by several mechanisms, including methylation, microRNAs and important GC-related pathogens. In this review, we provide an up-to-date review of the current knowledge regarding Iroquois family genes in GC. Full article

Human heart development is governed by transcription factor (TF) networks controlling dynamic and temporal gene expression alterations. Therefore, to comprehensively characterize these transcriptional regulations, day-to-day transcriptomic profiles were generated throughout the directed cardiac differentiation, starting from three distinct human- induced pluripotent stem cell lines from healthy donors (32 days). We applied an expression-based correlation score to the chronological expression profiles of the TF genes, and clustered them into 12 sequential gene expression waves. We then identified a regulatory network of more than 23,000 activation and inhibition links between 216 TFs. Within this network, we observed previously unknown inferred transcriptional activations linking IRX3 and IRX5 TFs to three master cardiac TFs: GATA4, NKX2-5 and TBX5. Luciferase and co-immunoprecipitation assays demonstrated that these five TFs could (1) activate each other’s expression; (2) interact physically as multiprotein complexes; and (3) together, finely regulate the expression of SCN5A, encoding the major cardiac sodium channel. Altogether, these results unveiled thousands of interactions between TFs, generating multiple robust hypotheses governing human cardiac development. Full article

Concerns for widespread insecticide resistance and the unintended impacts of insecticides on nontarget organisms have generated a pressing need for mosquito control innovations. A yeast RNAi-based insecticide that targets a conserved site in mosquito Irx family genes, but which has not yet been identified in the genomes of nontarget organisms, was developed and characterized. Saccharomyces cerevisiae constructed to express short hairpin RNA (shRNA) matching the target site induced significant Aedes aegypti larval death in both lab trials and outdoor semi-field evaluations. The yeast also induced high levels of mortality in adult females, which readily consumed yeast incorporated into an attractive targeted sugar bait (ATSB) during simulated field trials. A conserved requirement for Irx function as a regulator of proneural gene expression was observed in the mosquito brain, suggesting a possible mode of action. The larvicidal and adulticidal properties of the yeast were also verified in Aedes albopictus, Anopheles gambiae, and Culexquinquefasciatus mosquitoes, but the yeast larvicide was not toxic to other nontarget arthropods. These results indicate that further development and evaluation of this technology as an ecofriendly control intervention is warranted, and that ATSBs, an emerging mosquito control paradigm, could potentially be enriched through the use of yeast-based RNAi technology. Full article

Adult American eels (Anguilla rostrata) are vulnerable to hydropower turbine mortality during outmigration from growth habitat in inland waters to the ocean where they spawn. Imaging sonar is a reliable and proven technology for monitoring of fish passage and migration; however, there is no efficient automated method for eel detection. We designed a deep learning model for automated detection of adult American eels from sonar data. The method employs convolution neural network (CNN) to distinguish between 14 images of eels and non-eel objects. Prior to image classification with CNN, background subtraction and wavelet denoising were applied to enhance sonar images. The CNN model was first trained and tested on data obtained from a laboratory experiment, which yielded overall accuracies of >98% for image-based classification. Then, the model was trained and tested on field data that were obtained near the Iroquois Dam located on the St. Lawrence River; the accuracy achieved was commensurate with that of human experts. Full article

Alternative splicing (AS) is tightly regulated to maintain genomic stability in humans. However, tumor growth, metastasis and therapy resistance benefit from aberrant RNA splicing. Iroquois-class homeodomain protein 4 (IRX4) is a TALE homeobox transcription factor which has been implicated in prostate cancer (PCa) as a tumor suppressor through genome-wide association studies (GWAS) and functional follow-up studies. In the current study, we characterized 12 IRX4 transcripts in PCa cell lines, including seven novel transcripts by RT-PCR and sequencing. They demonstrate unique expression profiles between androgen-responsive and nonresponsive cell lines. These transcripts were significantly overexpressed in PCa cell lines and the cancer genome atlas program (TCGA) PCa clinical specimens, suggesting their probable involvement in PCa progression. Moreover, a PCa risk-associated SNP rs12653946 genotype GG was corelated with lower IRX4 transcript levels. Using mass spectrometry analysis, we identified two IRX4 protein isoforms (54.4 kDa, 57 kDa) comprising all the functional domains and two novel isoforms (40 kDa, 8.7 kDa) lacking functional domains. These IRX4 isoforms might induce distinct functional programming that could contribute to PCa hallmarks, thus providing novel insights into diagnostic, prognostic and therapeutic significance in PCa management. Full article

Depot specific expansion of orbital-adipose-tissue (OAT) in Graves’ Orbitopathy (GO) is associated with lipid metabolism signaling defects. We hypothesize that the unique adipocyte biology of OAT facilitates its expansion in GO. A comprehensive comparison of OAT and white-adipose-tissue (WAT) was performed by light/electron-microscopy, lipidomic and transcriptional analysis using ex vivo WAT, healthy OAT (OAT-H) and OAT from GO (OAT-GO). OAT-H/OAT-GO have a single lipid-vacuole and low mitochondrial number. Lower lipolytic activity and smaller adipocytes of OAT-H/OAT-GO, accompanied by similar essential linoleic fatty acid (FA) and (low) FA synthesis to WAT, revealed a hyperplastic OAT expansion through external FA-uptake via abundant SLC27A6 (FA-transporter) expression. Mitochondrial dysfunction of OAT in GO was apparent, as evidenced by the increased mRNA expression of uncoupling protein 1 (UCP1) and mitofusin-2 (MFN2) in OAT-GO compared to OAT-H. Transcriptional profiles of OAT-H revealed high expression of Iroquois homeobox-family (IRX-3&5), and low expression in HOX-family/TBX5 (essential for WAT/BAT (brown-adipose-tissue)/BRITE (BRown-in-whITE) development). We demonstrated unique features of OAT not presented in either WAT or BAT/BRITE. This study reveals that the pathologically enhanced FA-uptake driven hyperplastic expansion of OAT in GO is associated with a depot specific mechanism (the SLC27A6 FA-transporter) and mitochondrial dysfunction. We uncovered that OAT functions as a distinctive fat depot, providing novel insights into adipocyte biology and the pathological development of OAT expansion in GO. Full article

Iroquois homeobox (IRX) encodes members of homeodomain containing genes which are involved in development and differentiation. Since it has been reported that the IRX1 gene is localized in a lung cancer susceptibility locus, the epigenetic regulation and function of IRX1 was investigated in lung carcinogenesis. We observed frequent hypermethylation of the IRX1 promoter in non-small cell lung cancer (NSCLC) compared to small cell lung cancer (SCLC). Aberrant IRX1 methylation was significantly correlated with reduced IRX1 expression. In normal lung samples, the IRX1 promoter showed lower median DNA methylation levels (<10%) compared to primary adenocarcinoma (ADC, 22%) and squamous cell carcinoma (SQCC, 14%). A significant hypermethylation and downregulation of IRX1 was detected in ADC and SQCC compared to matching normal lung samples (p < 0.0001). Low IRX1 expression was significantly correlated with impaired prognosis of ADC patients (p = 0.001). Reduced survival probability was also associated with higher IRX1 promoter methylation (p = 0.02). Inhibition of DNA methyltransferase (DNMT) activity reactivated IRX1 expression in human lung cancer cell lines. Induced DNMT3A and EZH2 expression was correlated with downregulation of IRX1. On the cellular level, IRX1 exhibits nuclear localization and expression of IRX1 induced fragmented nuclei in cancer cells. Localization of IRX1 and induction of aberrant nuclei were dependent on the presence of the homeobox of IRX1. By data mining, we showed that IRX1 is negatively correlated with oncogenic pathways and IRX1 expression induces the proapoptotic regulator BAX. In conclusion, we report that IRX1 expression is significantly associated with improved survival probability of ADC patients. IRX1 hypermethylation may serve as molecular biomarker for ADC diagnosis and prognosis. Our data suggest that IRX1 acts as an epigenetically regulated tumor suppressor in the pathogenesis of lung cancer. Full article

The diagnosis of Parkinson’s disease (PD) is initiated after the occurrence of motor symptoms, such as resting tremors, rigidity, and bradykinesia. According to previous reports, non-motor symptoms, notably gastrointestinal dysfunction, could potentially be early biomarkers in PD patients as such symptoms occur earlier than motor symptoms. However, connecting PD to the intestine is methodologically challenging. Thus, we generated in vitro human intestinal organoids from PD patients and ex vivo mouse small intestinal organoids from aged transgenic mice. Both intestinal organoids (IOs) contained the human LRRK2 G2019S mutation, which is the most frequent genetic cause of familial and sporadic PD. By conducting comprehensive genomic comparisons with these two types of IOs, we determined that a particular gene, namely, Iroquois homeobox protein 2 (IRX2), showed PD-related expression patterns not only in human pluripotent stem cell (PSC)-derived neuroectodermal spheres but also in human PSC-derived neuronal cells containing dopaminergic neurons. We expected that our approach of using various cell types presented a novel technical method for studying the effects of multi-organs in PD pathophysiology as well as for the development of diagnostic markers for PD. Full article

My essay considers the history of collecting the art of Haudenosaunee (Iroquois) artists in the twentieth century. For decades Native visual and material culture was viewed under the guise of ‘crafts.’ I look back to the work of Lewis Henry Morgan on Haudenosaunee material culture. His writings helped establish a specific notion of Haudenosaunee material culture within the scholarly field of anthropology in the nineteenth century. At that point two-dimensional arts did not play a substantial role in Haudenosaunee visual culture, even though both Tuscarora and Seneca artists had produced drawings and paintings then. I investigate the turn toward collecting two-dimensional Haudenosaunee representational art, where before there was only craft. I locate this turn at the beginning of Franklin Delano Roosevelt’s administration in the 1930s. It was at this point that Seneca anthropologist Arthur C. Parker recruited Native crafts people and painters working in two-dimensional art forms to participate in a Works Progress Administration-sponsored project known as the Seneca Arts Program. Thereafter, museum collectors began purchasing and displaying paintings by the artists: Jesse Cornplanter, Sanford Plummer, and Ernest Smith. I argue that their representation in museum collections opened the door for the contemporary Haudenosaunee to follow. Full article

Bama minipigs are a local pig breed that is unique to China and has a high development and utilization value. However, its high fat content, low feed utilization rate, and slow growth rate have limited its popularity and utilization. Compared with the long breeding cycle and high cost of traditional genetic breeding of pigs, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) endonuclease 9 system (CRISPR/Cas9)-mediated gene editing can cost-effectively implement targeted mutations in animal genomes, thereby providing a powerful tool for rapid improvement of the economic traits of Bama minipigs. The iroquois homeobox 3 (IRX3) gene has been implicated in human obesity. Mouse experiments have shown that knocking out IRX3 significantly enhances basal metabolism, reduces fat content, and controls body mass and composition. This study aimed to knock out IRX3 using the CRISPR/Cas9 gene editing method to breed Bama minipigs with significantly reduced fat content. First, the CRISPR/Cas9 gene editing method was used to efficiently obtain IRX3^-/- cells. Then, the gene-edited cells were used as donor cells to produce surviving IRX3^-/- Bama minipigs using somatic cell cloning. The results show that the use of IRX3^-/- cells as donor cells for the production of somatic cell-cloned pigs results in a significant decrease in the average live litter size and a significant increase in the average number of stillbirths. Moreover, the birth weight of surviving IRX3^-/- somatic cell-cloned pigs is significantly lower, and viability is poor such that all piglets die shortly after birth. Therefore, the preliminary results of this study suggest that IRX3 may have important biological functions in pigs, and IRX3 should not be used as a gene editing target to reduce fat content in Bama minipigs. Moreover, this study shows that knocking out IRX3 does not favor the survival of pigs, and whether targeted regulation of IRX3 in the treatment of human obesity will also induce severe adverse consequences requires further investigation. Full article

Public museums and art galleries in Canada are highly authoritative, and trusted knowledge and identity mobilising institutions, whose exhibitions are frequently a ‘blank page’ of erasure, silencing, and marginalisation, in terms of women’s histories, experiences, and contributions. Feminist exhibitions are a response to this, but few in Canada have been explored as practices of feminist community adult education. I begin to address this gap with an analysis of two feminist exhibitions: In Defiance: Indigenous Women Define Themselves, curated by Mohawk-Iroquois artist, Lindsay Katsitsakatste Delaronde, at the Legacy Gallery, University of Victoria; and Fashion Victims: The Pleasures & Perils of Dress in the 19th Century, curated by Ryerson Professor Alison Matthews David, at the Bata Shoe Museum, Toronto. Although dissimilar in form, focus, and era, these exhibitions act as powerful intentional pedagogical processes of disruption and reclamation, using images and storytelling to animate, re-write and reimagine the ‘blank pages’ of particular and particularised histories and identities. Through the centrality of women’s bodies and practices of violence, victimization, and women’s power, these exhibitions encourage the feminist oppositional imagination, dialogic looking, gender consciousness, and a visual literacy of hope and possibility. Yet, as women’s stories become audible through the very representational vehicles and institutional spaces used to silence them, challenges remain. Full article

A surprisingly small number of signalling pathways generate a plethora of cellular responses ranging from the acquisition of multiple cell fates to proliferation, differentiation, morphogenesis and cell death. These diverse responses may be due to the dose-dependent activities of signalling factors, or to intrinsic differences in the response of cells to a given signal—a phenomenon called differential cellular competence. In this review, we focus on temporal and spatial differences in competence for Hedgehog (HH) signalling, a signalling pathway that is reiteratively employed in embryos and adult organisms. We discuss the upstream signals and mechanisms that may establish differential competence for HHs in a range of different tissues. We argue that the changing competence for HH signalling provides a four-dimensional framework for the interpretation of the signal that is essential for the emergence of functional anatomy. A number of diseases—including several types of cancer—are caused by malfunctions of the HH pathway. A better understanding of what provides differential competence for this signal may reveal HH-related disease mechanisms and equip us with more specific tools to manipulate HH signalling in the clinic. Full article

This article examines how Native places are made, named, and reconstructed after colonization through storytelling. Storying the land is a process whereby the land is invested with the moral and spiritual perspectives specific to Native American communities. As seen in the oral traditions and written literature of Native American storytellers and authors, the voices of indigenous people retrace and remap cartographies for the land after colonization through storytelling. This article shows that the Americas were storied by Native American communities long before colonial contact beginning in the fifteenth century and demonstrates how the land continues to be storied in the present as a method of decolonization and cultural survivance. The article examines manifestations of the oral tradition in multiple forms, including poetry, interviews, fiction, photography, and film, to demonstrate that the land itself, through storytelling, becomes a repository of the oral tradition. The article investigates oral narratives from precontact and postcolonial time periods and across numerous nations and geographical regions in the Americas, including stories from the Mayan Popol Vuh; Algonkian; Western Apache; Hopi; Haudenosaunee/Iroquois; and Laguna Pueblo stories; and the contemporary poetry and fiction of Joy Harjo (Mvskoke/Creek Nation) and Leslie Marmon Silko (Laguna Pueblo). Full article

Background and objective: North Carolina macular dystrophy (NCMD) is a very rare autosomal dominant hereditary disease. Up to date there are three types of NCMD described and consequently named macular dystrophy, retinal: MCDR1, MCDR2 and MCDR3. The aim of this study was to perform linkage and copy number variation analysis for the family affected by NCMD followed by the selected candidate gene sequencing.
Materials and methods: This study concerned a 3-generation, non-consanguineous Latvian family with NCMD. Genome-wide scan, copy number variation and non-parametric linkage analysis was performed. Analysis resolved the locus of interest to the 5p15.33 region. Two of the genes, iroquois homeobox 2 (IRX2) and iroquois homeobox 4 (IRX4), were selected and sanger sequencing was performed.
Results: Linkage analysis indicated a region on chromosome 5 for the analyzed family, corresponding to a genetic locus previously described for MCDR3 (5p15-p13). Chromosomal aberrations were not identified in the affected family members. An upstream intron variant (NM_001278634: c.-139G > A (rs6876836)) in IRX4 gene segregated with NCMD phenotype in the analyzed family.
Conclusions: It is unlikely to be the causative mutation of NCMD due to its high minor allele frequency 0.3532. Therefore, the role of IRX2 and IRX4 genes in the pathogenesis of NCMD has not been proved. Considerable variability in visual acuity between individuals of the same age group in all the families examined was noted. No overlap between NCMD grade and family generation was seen in the family described in the present study. Full article