5 research outputs found
The role of Tet2 and Tet3 in the molecular programming of blood cell differentiation during zebrafish development
No full textDNA methylation is an epigenetic mark that regulates gene expression during cellular differentiation. Ten-eleven translocation (Tet) dioxygenase enzymes are involved in active demethylation and are required for hematopoietic stem cell (HSC) differentiation. HSCs arise from haemogenic endothelial cells (HECs) in arterial vessels, which depend on Notch signalling for their specification. Initially, the loss of HSC formation in tet2/tet3 double mutants was attributed to a failure in HEC formation caused by defective Notch signalling, despite normal vascular patterning and arterial specification. This study aimed to reinvestigate Notch signalling and HEC development in the ventral wall of the dorsal aorta (vDA) of tet2/tet3 double mutants to resolve these inconsistencies. Here, the Notch reporter transgene csl:mCherry was expressed in the endothelium of the vDA in the absence of Tet2 and Tet3. Confocal analysis of the gene trap line qmc551, which exhibits GFP expression in primitive red blood cells (prRBCs) and HECs of the vDA, demonstrated normal GFP expression in HECs of the vDA at 2 days post fertilisation (dpf). It also revealed a few GFP+ hematopoietic stem and progenitor cells (HSPCs) in the mesenchyme below the DA in tet2/tet3 double mutants. Whole-mount in situ hybridisation (WISH) experiments using the HEC marker growth factor independence 1aa (gfi1aa) revealed that, at 40 hours post fertilisation (hpf), gfi1aa expression persisted in the HECs of the vDA in tet2/tet3 double mutant embryos, contrasting with its typical downregulation in wild-type (WT) embryos at this stage. These findings suggest a defect in the endothelialto- hematopoietic transition (EHT), likely resulting from disrupted epigenetic programming of HECs in the absence of the two Tet proteins. In tet2/tet3 double mutant embryos, circulation appeared normal without evident shunts; however, blood flow velocity was reduced. To investigate the molecular programming underlying these defects, single-cell transcriptome analysis was performed on a cell population enriched for qmc551:GFP and Gata1a:dsRed single and doublepositive cells isolated from 2dpf WT and tet2/tet3 double mutant embryos. Transcriptomic analyses revealed significant downregulation of key endothelial genes, such as apelin, plvapb, casz1, and pecam1. These data suggest a critical role for Tet2 and Tet3 in endothelial programming and angiogenesis. The analysis also showed significant downregulation of erythroid genes in prRBCs. WISH experiments revealed increased gata1a expression in circulating prRBCs at 2 and 3dpf, indicating a late maturation defect in tet2/tet3 double mutant embryos. Additionally, reduced slc4a1a mRNA expression in mutants at 20hpf, prior to the onset of circulation, suggests delayed early differentiation of prRBCs. These findings indicate that the absence of both Tet2 and Tet3 leads to delayed erythroid development. In summary, this study elucidates the multifaceted roles of Tet2 and Tet3 proteins in regulating both primitive and definitive hematopoietic waves during zebrafish embryogenesis
The role of Tet2 and Tet3 in the molecular programming of blood cell differentiation during zebrafish development
No full textDNA methylation is an epigenetic mark that regulates gene expression during cellular differentiation. Ten-eleven translocation (Tet) dioxygenase enzymes are involved in active demethylation and are required for hematopoietic stem cell (HSC) differentiation. HSCs arise from haemogenic endothelial cells (HECs) in arterial vessels, which depend on Notch signalling for their specification. Initially, the loss of HSC formation in tet2/tet3 double mutants was attributed to a failure in HEC formation caused by defective Notch signalling, despite normal vascular patterning and arterial specification. This study aimed to reinvestigate Notch signalling and HEC development in the ventral wall of the dorsal aorta (vDA) of tet2/tet3 double mutants to resolve these inconsistencies. Here, the Notch reporter transgene csl:mCherry was expressed in the endothelium of the vDA in the absence of Tet2 and Tet3. Confocal analysis of the gene trap line qmc551, which exhibits GFP expression in primitive red blood cells (prRBCs) and HECs of the vDA, demonstrated normal GFP expression in HECs of the vDA at 2 days post fertilisation (dpf). It also revealed a few GFP+ hematopoietic stem and progenitor cells (HSPCs) in the mesenchyme below the DA in tet2/tet3 double mutants. Whole-mount in situ hybridisation (WISH) experiments using the HEC marker growth factor independence 1aa (gfi1aa) revealed that, at 40 hours post fertilisation (hpf), gfi1aa expression persisted in the HECs of the vDA in tet2/tet3 double mutant embryos, contrasting with its typical downregulation in wild-type (WT) embryos at this stage. These findings suggest a defect in the endothelialto- hematopoietic transition (EHT), likely resulting from disrupted epigenetic programming of HECs in the absence of the two Tet proteins. In tet2/tet3 double mutant embryos, circulation appeared normal without evident shunts; however, blood flow velocity was reduced. To investigate the molecular programming underlying these defects, single-cell transcriptome analysis was performed on a cell population enriched for qmc551:GFP and Gata1a:dsRed single and doublepositive cells isolated from 2dpf WT and tet2/tet3 double mutant embryos. Transcriptomic analyses revealed significant downregulation of key endothelial genes, such as apelin, plvapb, casz1, and pecam1. These data suggest a critical role for Tet2 and Tet3 in endothelial programming and angiogenesis. The analysis also showed significant downregulation of erythroid genes in prRBCs. WISH experiments revealed increased gata1a expression in circulating prRBCs at 2 and 3dpf, indicating a late maturation defect in tet2/tet3 double mutant embryos. Additionally, reduced slc4a1a mRNA expression in mutants at 20hpf, prior to the onset of circulation, suggests delayed early differentiation of prRBCs. These findings indicate that the absence of both Tet2 and Tet3 leads to delayed erythroid development. In summary, this study elucidates the multifaceted roles of Tet2 and Tet3 proteins in regulating both primitive and definitive hematopoietic waves during zebrafish embryogenesis
Liberal theory and Islam: (re)imagining the interaction of religion, law, state and society in Muslim contexts
No full textWithin the global phenomenon of the (re)emergence of religion into issues of public debate, one of the most salient issues confronting contemporary Muslim societies is how to relate the legal and political heritage that developed in pre-modern Islamic polities to the political order of the modern states in which Muslims now live.
This study seeks to develop a framework for addressing this issue by drawing upon two sources. The first is an interpretative understanding of the history of Muslim contexts emphasising, in particular, the diversity of views about what Islam mandates that have always been a part of Muslim experience and the distinction between political and religio-legal authority that developed in practice in these environments. The second source is a variety of contemporary liberal theory which this study develops and calls ‘justice as discourse’.
The central argument is that liberal theory, and justice as discourse in particular, though it may have emerged in a different social and cultural milieu, can be normatively useful in Muslim contexts for relating, religion, law, state and society. It is argued first, that Muslim contexts are facing issues similar to those out of which liberal theory emerged. Additionally, it is argued that both Muslim contexts and liberal theory are dynamic and continually developing and that this shared dynamism means that there may be space for convergence of the two. Just as Muslim contexts have developed historically (and continue to develop today) the same is the case with the requisites of liberal theory and this may allow for liberal choices to be made in a manner that is not a renunciation of Muslim heritage
The regulation of labour and the state in the Sudan : a study of the relationship between the stage of social and economic development and the autonomy of labour relations law
No full textThe thesis is a study of labour regulation and the State in the
Sudan in the light of a general theoretical conception of labour law and
the State. The first Chapter defines the concepts of analysis that are
used throughout the study, isolates the "essential" properties of the
Capitalist State and Law from the historically concrete forms which they
assume in a particular society and distinguishes between processes which
influence development of the form of law and others which influence its
sociological development. Drawing on the analysis in Chapter I, Chapter
II exposes the inter-relationship between the Sudanese social formation,
State and Law and the implication of this inter-relationship for both the
form and substance of labour relations law. Chapters III, IV and V are
specific verifications of the hypothesis regarding the inter-relationship
between the State and labour relations law in the Sudan and that
regarding the development of the "substance" and "ideology" of law in
general.
The thesis considers law as an empirically-founded discipline.
But, it distinguishes between various types of empirical facts about law
corresponding with respective semi-autonomous social levels at which law
asserts its existence. The research method followed describes the
empirical facts about law at the particular level and, in order to
determine the epistemological significance of these facts, analytically
relates them to empirical facts at other levels. Wherever used in the
thesis the term "theory" signifies either this methodological procedure of
analysing the inter-connection of empirical facts at a certain level and
their inter-relation with other facts at other levels, or the substantive
generalizations about law which findings at these various levels would
allow.
I consider my application of this methodology to the study of
labour rela tions law, the historical dimension this application introduces
in socio-economic analysis of this law, the criticism of certain Marxist
and other sociological conceptions of law it enables, and the
socio-histor ical relativity of the "substance" and "ideology" of law it
reveals as original contributions to the knowledge of labour law. The
compilation and evaluation within the framework of the thesis of
empirical materials on industrial relations in the Sudan are likewise
original contribution to the knowledge of Sudanese "labour law" and
labour law in general
SARS-CoV-2 vaccination modelling for safe surgery to save lives: data from an international prospective cohort study
No full textBackground: Preoperative SARS-CoV-2 vaccination could support safer elective surgery. Vaccine numbers are limited so this study aimed to inform their prioritization by modelling.
Methods: The primary outcome was the number needed to vaccinate (NNV) to prevent one COVID-19-related death in 1 year. NNVs were based on postoperative SARS-CoV-2 rates and mortality in an international cohort study (surgical patients), and community SARS-CoV-2 incidence and case fatality data (general population). NNV estimates were stratified by age (18-49, 50-69, 70 or more years) and type of surgery. Best- and worst-case scenarios were used to describe uncertainty.
Results: NNVs were more favourable in surgical patients than the general population. The most favourable NNVs were in patients aged 70 years or more needing cancer surgery (351; best case 196, worst case 816) or non-cancer surgery (733; best case 407, worst case 1664). Both exceeded the NNV in the general population (1840; best case 1196, worst case 3066). NNVs for surgical patients remained favourable at a range of SARS-CoV-2 incidence rates in sensitivity analysis modelling. Globally, prioritizing preoperative vaccination of patients needing elective surgery ahead of the general population could prevent an additional 58 687 (best case 115 007, worst case 20 177) COVID-19-related deaths in 1 year.
Conclusion: As global roll out of SARS-CoV-2 vaccination proceeds, patients needing elective surgery should be prioritized ahead of the general population
