title: Grainyhead-like 2 is required for morphological integrity of mouse embryonic stem cells and orderly formation of inner ear-like organoids

authors: Forrester-Gauntlett, Blaise

abstract: Mutations in the transcription factor gene grainyhead-like 2 (GRHL2) are associated with progressive non-syndromic sensorineural deafness autosomal dominant type 28 (DFNA28) in humans. Since complete loss of Grhl2 is lethal in mouse embryos, we studied its role during inner ear pathology and hearing loss in vitro. To this end, we generated different homozygous deletions to knockout Grhl2 in mouse embryonic stem cells (Grhl2-KO ESCs), including some mimicking naturally occurring truncations in the dimerisation domain related to human DFNA28. Under naïve culture conditions, Grhl2-KO cells in suspension were more heterogenous in size and larger than wild-type controls. Adherent Grhl2-KO cells were also larger, with a less uniform shape, flattened, less circular morphology, forming loose monolayer colonies with poorly defined edges. These changes correlated with lower expression of epithelial cadherin Cdh1 but no changes in tight junction markers (Ocln, Tjp2) or other Grhl isoforms (Grhl1, Grhl3). Clonogenicity from single cells, proliferation rates of cell populations and proliferation markers were reduced in Grhl2-KO ESCs. We next induced stepwise directed differentiation of Grhl2-KO ESCs along an otic pathway, giving rise to three-dimensional inner ear-like organoids (IELOs). Quantitative morphometry revealed that Grhl2-KO cells initially formed larger IELOs with a less compacted structure, more eccentric shape and increased surface area. These morphological changes persisted for up to one week. They were partially rescued by forced cell aggregation and fully restored by stably overexpressing exogenous Grhl2 in Grhl2-KO ESCs, indicating that Grhl2 alters cell-cell interactions. On day 8, aggregates were transferred into minimal maturation medium to allow self-guided organogenesis for another two weeks. During this period, Grhl2-KO cells and wild-type controls developed similarly, expressing neural, neuronal and sensory hair cell markers, while maintaining their initial differences in size and shape. In summary, Grhl2 is required for morphological maintenance of ESCs and orderly formation of IELOs, consistent with an essential role in organising epithelial integrity during inner ear development. Our findings validate quantitative morphometry as a useful, non-invasive screening method for molecular phenotyping of candidate mutations during organoid development.

text: Grainyhead-like 2 is required for morphological integrity of mouse embryonic stem cells and orderly formation of inner ear-like organoids Mutations in the transcription factor gene grainyhead-like 2 (GRHL2) are associated with progressive non-syndromic sensorineural deafness autosomal dominant type 28 (DFNA28) in humans. Since complete loss of Grhl2 is lethal in mouse embryos, we studied its role during inner ear pathology and hearing loss in vitro. To this end, we generated different homozygous deletions to knockout Grhl2 in mouse embryonic stem cells (Grhl2-KO ESCs), including some mimicking naturally occurring truncations in the dimerisation domain related to human DFNA28. Under naïve culture conditions, Grhl2-KO cells in suspension were more heterogenous in size and larger than wild-type controls. Adherent Grhl2-KO cells were also larger, with a less uniform shape, flattened, less circular morphology, forming loose monolayer colonies with poorly defined edges. These changes correlated with lower expression of epithelial cadherin Cdh1 but no changes in tight junction markers (Ocln, Tjp2) or other Grhl isoforms (Grhl1, Grhl3). Clonogenicity from single cells, proliferation rates of cell populations and proliferation markers were reduced in Grhl2-KO ESCs. We next induced stepwise directed differentiation of Grhl2-KO ESCs along an otic pathway, giving rise to three-dimensional inner ear-like organoids (IELOs). Quantitative morphometry revealed that Grhl2-KO cells initially formed larger IELOs with a less compacted structure, more eccentric shape and increased surface area. These morphological changes persisted for up to one week. They were partially rescued by forced cell aggregation and fully restored by stably overexpressing exogenous Grhl2 in Grhl2-KO ESCs, indicating that Grhl2 alters cell-cell interactions. On day 8, aggregates were transferred into minimal maturation medium to allow self-guided organogenesis for another two weeks. During this period, Grhl2-KO cells and wild-type controls developed similarly, expressing neural, neuronal and sensory hair cell markers, while maintaining their initial differences in size and shape. In summary, Grhl2 is required for morphological maintenance of ESCs and orderly formation of IELOs, consistent with an essential role in organising epithelial integrity during inner ear development. Our findings validate quantitative morphometry as a useful, non-invasive screening method for molecular phenotyping of candidate mutations during organoid development.

year: 2023-01-01

title: Relevance of corporate governance practices in charitable organisations: A case study of registered charities in New Zealand

authors: Reddy, Krishna

subjects: allocative efficiency

abstract: Purpose – The purpose of this paper is to examine whether the registered charities in New Zealand have adopted the principle-based corporate governance practices similar to those adopted by the publicly-listed companies and the effect corporate governance practices have on their financial performance measured by technical efficiency, allocative efficiency and quick ratio. The paper addresses four important questions: how registered charities in New Zealand are managed and controlled; whether the funds donated to registered charities are utilised effectively; the nature of the corporate governance practiced by registered charities in New Zealand; and the nature of compliance to the Charities Act 2005. 
Design/methodology/approach – Panel data for the registered charities over the period 2008-2010 are analysed using ordinary least squares (OLS) regression and Tobit model regression. Technical efficiency, allocative efficiency and quick ratio are used as the dependent variables. 
Findings – The findings indicate that there is no reporting requirement for the registered charities under the Charities Act 2005 to report detailed information regarding the board make-up, board committees, board meetings, etc. and therefore, registered charities have not reported such information. The results show also that board gender diversity is an important corporate governance mechanism to mitigate agency problem in charitable organisations in New Zealand. However, large board size and large donors have potential to increase agency costs in charitable organisations in New Zealand. 
Research limitations/implications – Caution should be exercised when interpreting and generalising the paper's results, as this study is a case study of registered charities in New Zealand and data comprised only large charities that have revenue over NZ$20?m. It should also be noted that there was a small sample size, which may have had a bearing on the results. 
Practical implications – This study offers insights for policy makers and practitioners interested in adopting similar corporate governance practices within their country. 
Social implications – Within New Zealand, issues relating to management and control of charitable organisations are better understood and as a consequence, development of sector-wise standards could be initiated. 
Originality/value – This research is novel as it investigates the nature of corporate governance practices relating to the registered charities in New Zealand. The availability of data provided by Charities Commission made this research possible.

text: Relevance of corporate governance practices in charitable organisations: A case study of registered charities in New Zealand Purpose – The purpose of this paper is to examine whether the registered charities in New Zealand have adopted the principle-based corporate governance practices similar to those adopted by the publicly-listed companies and the effect corporate governance practices have on their financial performance measured by technical efficiency, allocative efficiency and quick ratio. The paper addresses four important questions: how registered charities in New Zealand are managed and controlled; whether the funds donated to registered charities are utilised effectively; the nature of the corporate governance practiced by registered charities in New Zealand; and the nature of compliance to the Charities Act 2005. 
Design/methodology/approach – Panel data for the registered charities over the period 2008-2010 are analysed using ordinary least squares (OLS) regression and Tobit model regression. Technical efficiency, allocative efficiency and quick ratio are used as the dependent variables. 
Findings – The findings indicate that there is no reporting requirement for the registered charities under the Charities Act 2005 to report detailed information regarding the board make-up, board committees, board meetings, etc. and therefore, registered charities have not reported such information. The results show also that board gender diversity is an important corporate governance mechanism to mitigate agency problem in charitable organisations in New Zealand. However, large board size and large donors have potential to increase agency costs in charitable organisations in New Zealand. 
Research limitations/implications – Caution should be exercised when interpreting and generalising the paper's results, as this study is a case study of registered charities in New Zealand and data comprised only large charities that have revenue over NZ$20?m. It should also be noted that there was a small sample size, which may have had a bearing on the results. 
Practical implications – This study offers insights for policy makers and practitioners interested in adopting similar corporate governance practices within their country. 
Social implications – Within New Zealand, issues relating to management and control of charitable organisations are better understood and as a consequence, development of sector-wise standards could be initiated. 
Originality/value – This research is novel as it investigates the nature of corporate governance practices relating to the registered charities in New Zealand. The availability of data provided by Charities Commission made this research possible.

year: 2013

title: Overcoming ‘Being’ in Favour of Knowledge: The fixing effect of ‘mātauranga’

authors: Mika, Carl Te Hira

subjects: knowledge

abstract: It is common to hear Māori discuss primordial states of Being, yet in colonisation those very central beliefs are forced into weaker utterances. In this process those utterances merely conform to a colonised agenda. ‘Mātauranga’, a tidy term that overwhelmingly refers to an epistemological knowing of the world, colludes nicely with its English equivalent, ‘knowledge’, to further colonise those core contemplations of Being. Its plausibility relies on an orderly regard of things in the world. In education, historical and current practices of schooling pave the way for things in the world so that they amount to mātauranga for Māori, and even the term ‘ako’ will conspire in its own way. Both Novalis and Heidegger have the ability to identify subtly colonising philosophies, and may even propose some theoretical solutions for Māori.

text: Overcoming ‘Being’ in Favour of Knowledge: The fixing effect of ‘mātauranga’ It is common to hear Māori discuss primordial states of Being, yet in colonisation those very central beliefs are forced into weaker utterances. In this process those utterances merely conform to a colonised agenda. ‘Mātauranga’, a tidy term that overwhelmingly refers to an epistemological knowing of the world, colludes nicely with its English equivalent, ‘knowledge’, to further colonise those core contemplations of Being. Its plausibility relies on an orderly regard of things in the world. In education, historical and current practices of schooling pave the way for things in the world so that they amount to mātauranga for Māori, and even the term ‘ako’ will conspire in its own way. Both Novalis and Heidegger have the ability to identify subtly colonising philosophies, and may even propose some theoretical solutions for Māori.

year: 2012