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Article ; Online: Business, Human Rights and the Environment—Using Macro Legal Analysis to Develop a Legal Framework That Coherently Addresses the Root Causes of Corporate Human Rights Violations and Environmental Degradation

Stephen J. Turner

Sustainability, Vol 13, Iss 12709, p

2021 Volume 12709

Abstract: This article applies ‘macro’ legal analysis to the challenge of legal reform related to corporate responsibility for human rights violations and degradation of the environment. It recognises that the approaches from different communities of lawyers to ... ...

Abstract	This article applies ‘macro’ legal analysis to the challenge of legal reform related to corporate responsibility for human rights violations and degradation of the environment. It recognises that the approaches from different communities of lawyers to the negative impacts on human rights and the environment caused by companies, sometimes operate in isolation from each other, are not always mutually supportive, can lead to a fragmentation of effort, and may not address the root causes of the problem. In particular, this article analyses the extent to which existing approaches tend to address symptoms of the issues, rather than the root causes themselves. It makes the case that in this regard specific root causes exist within the frameworks of corporate law in all jurisdictions and various aspects of international economic law too. To carry out the study, it employs macro legal analysis, a methodology not previously applied in this field, as a means of developing an understanding of the legal frameworks that, it argues, influence corporate decision making that can affect human rights and the environment. It undertakes an analysis that incorporates relevant corporate law, World Trade Organisation (WTO) law, international investment law, the law relating to multilateral development banks (MDBs), and international insurance law. By using this form of anlaysis it is possible to show how legal frameworks can operate in unison, reinforcing each other providing a cumulative effect that can influence corporate decision makers. Finally, based on the results of the analysis, it suggests a possible strategy of macro-level reforms that could be applied to the re-design of relevant legal frameworks to better facilitate the full protection of human rights and to achieve net zero degradation of the environment. As a result it seeks to demonstrate how this approach can be strategically applied by both human rights and environmental lawyers as a common pathway towards effective legal reform.
Keywords	corporate responsibility ; environmental ; social ; governance ; business and human rights ; macro legal analysis ; Environmental effects of industries and plants ; TD194-195 ; Renewable energy sources ; TJ807-830 ; Environmental sciences ; GE1-350
Subject code	340
Language	English
Publishing date	2021-11-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Running to Stand Still

Taylah J. Bennett / Vibha A. V. Udupa / Stephen J. Turner

International Journal of Molecular Sciences, Vol 21, Iss 9773, p

Naive CD8 + T Cells Actively Maintain a Program of Quiescence

2020 Volume 9773

Abstract: CD8 + T cells play a pivotal role in clearing intracellular pathogens and combatting tumours. Upon infection, naïve CD8 + T cells differentiate into effector and memory cells, and this program is underscored by large-scale and coordinated changes in the ... ...

Abstract	CD8 + T cells play a pivotal role in clearing intracellular pathogens and combatting tumours. Upon infection, naïve CD8 + T cells differentiate into effector and memory cells, and this program is underscored by large-scale and coordinated changes in the chromatin architecture and gene expression. Importantly, recent evidence demonstrates that the epigenetic mechanisms that regulate the capacity for rapid effector function of memory T cells are shared by innate immune cells such as natural killer (NK) cells. Thus, it appears that the crucial difference between innate and adaptive immunity is the presence of the naïve state. This important distinction raises an intriguing new hypothesis, that the naïve state was evolutionary installed to restrain a default program of effector and memory differentiation in response to antigen recognition. We argue that the hallmark of adaptive T immunity is therefore the naïve program, which actively maintains CD8 + T cell quiescence until receipt of appropriate activation signals. In this review, we examine the mechanistic control of naïve CD8 + T cell quiescence and summarise the multiple levels of restraint imposed in naïve cells in to limit spontaneous and inappropriate activation. This includes epigenetic mechanisms and transcription factor (TF) regulation of gene expression, in addition to novel inhibitory receptors, abundance of RNA, and protein degradation.
Keywords	CD8 + T cell ; naïve T cell ; memory T cell ; transcription factors ; epigenetics ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	333
Language	English
Publishing date	2020-12-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: 3D Single Molecule Super-Resolution Microscopy of Whole Nuclear Lamina

Ashley M. Rozario / Alison Morey / Cade Elliott / Brendan Russ / Donna R. Whelan / Stephen J. Turner / Toby D. M. Bell

Frontiers in Chemistry, Vol

2022 Volume 10

Abstract: Single molecule (SM) super-resolution microscopies bypass the diffraction limit of conventional optical techniques and provide excellent spatial resolutions in the tens of nanometers without overly complex microscope hardware. SM imaging using optical ... ...

Abstract	Single molecule (SM) super-resolution microscopies bypass the diffraction limit of conventional optical techniques and provide excellent spatial resolutions in the tens of nanometers without overly complex microscope hardware. SM imaging using optical astigmatism is an efficient strategy for visualizing subcellular features in 3D with a z-range of up to ∼1 µm per acquisition. This approach however, places high demands on fluorophore brightness and photoswitching resilience meaning that imaging entire cell volumes in 3D using SM super-resolution remains challenging. Here we employ SM astigmatism together with multiplane acquisition to visualize the whole nuclear lamina of COS-7 and T cells in 3D. Nuclear lamina provides structural support to the nuclear envelope and participates in vital nuclear functions including internuclear transport, chromatin organization and gene regulation. Its position at the periphery of the nucleus provides a visible reference of the nuclear boundary and can be used to quantify the spatial distribution of intranuclear components such as histone modifications and transcription factors. We found Alexa Fluor 647, a popular photoswitchable fluorophore, remained viable for over an hour of continuous high laser power exposure, and provided sufficient brightness detectable up to 8 µm deep into a cell, allowing us to capture the entire nuclear lamina in 3D. Our approach provides sufficient super-resolution detail of nuclear lamina morphology to enable quantification of overall nuclear dimensions and local membrane features.
Keywords	astigmatism ; multiplane imaging ; T cell ; nuclear envelope ; convex hull ; Chemistry ; QD1-999
Subject code	570
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: UL34 Deletion Restricts Human Cytomegalovirus Capsid Formation and Maturation

Declan L. Turner / Rachel M. Templin / Adele A. Barugahare / Brendan E. Russ / Stephen J. Turner / Georg Ramm / Rommel A. Mathias

International Journal of Molecular Sciences, Vol 23, Iss 5773, p

2022 Volume 5773

Abstract: Over 50% of the world’s population is infected with Human Cytomegalovirus (HCMV). HCMV is responsible for serious complications in the immuno-compromised and is a leading cause of congenital birth defects. The molecular function of many HCMV proteins ... ...

Abstract	Over 50% of the world’s population is infected with Human Cytomegalovirus (HCMV). HCMV is responsible for serious complications in the immuno-compromised and is a leading cause of congenital birth defects. The molecular function of many HCMV proteins remains unknown, and a deeper understanding of the viral effectors that modulate virion maturation is required. In this study, we observed that UL34 is a viral protein expressed with leaky late kinetics that localises to the nucleus during infection. Deletion of UL34 from the HCMV genome (ΔUL34) did not abolish the spread of HCMV. Instead, over >100-fold fewer infectious virions were produced, so we report that UL34 is an augmenting gene. We found that ΔUL34 is dispensable for viral DNA replication, and its absence did not alter the expression of IE1, MCP, gB, UL26, UL83, or UL99 proteins. In addition, ΔUL34 infections were able to progress through the replication cycle to form a viral assembly compartment; however, virion maturation in the cytoplasm was abrogated. Further examination of the nucleus in ΔUL34 infections revealed replication compartments with aberrant morphology, containing significantly less assembled capsids, with almost none undergoing subsequent maturation. Therefore, this work lays the foundation for UL34 to be further investigated in the context of nuclear organization and capsid maturation during HCMV infection.
Keywords	HCMV ; herpesvirus ; UL34 ; replication compartment ; capsid maturation ; genome packaging ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	570
Language	English
Publishing date	2022-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Epigenetic and transcriptional regulation of CCL17 production by glucocorticoids in arthritis

Tanya J. Lupancu / Kevin M.C. Lee / Mahtab Eivazitork / Cecil Hor / Andrew J. Fleetwood / Andrew D. Cook / Moshe Olshansky / Stephen J. Turner / Richard de Steiger / Keith Lim / John A. Hamilton / Adrian A. Achuthan

iScience, Vol 26, Iss 10, Pp 108079- (2023)

2023

Abstract: Summary: Glucocorticoids (GCs) are potent anti-inflammatory agents and are broadly used in treating rheumatoid arthritis (RA) patients, albeit with adverse side effects associated with long-term usage. The negative consequences of GC therapy provide an ... ...

Abstract	Summary: Glucocorticoids (GCs) are potent anti-inflammatory agents and are broadly used in treating rheumatoid arthritis (RA) patients, albeit with adverse side effects associated with long-term usage. The negative consequences of GC therapy provide an impetus for research into gaining insights into the molecular mechanisms of GC action. We have previously reported that granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced CCL17 has a non-redundant role in inflammatory arthritis. Here, we provide molecular evidence that GCs can suppress GM-CSF-mediated upregulation of IRF4 and CCL17 expression via downregulating JMJD3 expression and activity. In mouse models of inflammatory arthritis, GC treatment inhibited CCL17 expression and ameliorated arthritic pain-like behavior and disease. Significantly, GC treatment of RA patient peripheral blood mononuclear cells ex vivo resulted in decreased CCL17 production. This delineated pathway potentially provides new therapeutic options for the treatment of many inflammatory conditions, where GCs are used as an anti-inflammatory drug but without the associated adverse side effects.
Keywords	Orthopedics ; Molecular mechanism of gene regulation ; Epigenetics ; Science ; Q
Subject code	616
Language	English
Publishing date	2023-10-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Pediatric glioma histone H3.3 K27M/G34R mutations drive abnormalities in PML nuclear bodies

Hsiao P. J. Voon / Linda Hii / Andrew Garvie / Maheshi Udugama / Brian Krug / Caterina Russo / Anderly C. Chüeh / Roger J. Daly / Alison Morey / Toby D. M. Bell / Stephen J. Turner / Joseph Rosenbluh / Paul Daniel / Ron Firestein / Jeffrey R. Mann / Philippe Collas / Nada Jabado / Lee H. Wong

Genome Biology, Vol 24, Iss 1, Pp 1-

2023 Volume 27

Abstract: Abstract Background Point mutations in histone variant H3.3 (H3.3K27M, H3.3G34R) and the H3.3-specific ATRX/DAXX chaperone complex are frequent events in pediatric gliomas. These H3.3 point mutations affect many chromatin modifications but the exact ... ...

Abstract	Abstract Background Point mutations in histone variant H3.3 (H3.3K27M, H3.3G34R) and the H3.3-specific ATRX/DAXX chaperone complex are frequent events in pediatric gliomas. These H3.3 point mutations affect many chromatin modifications but the exact oncogenic mechanisms are currently unclear. Histone H3.3 is known to localize to nuclear compartments known as promyelocytic leukemia (PML) nuclear bodies, which are frequently mutated and confirmed as oncogenic drivers in acute promyelocytic leukemia. Results We find that the pediatric glioma-associated H3.3 point mutations disrupt the formation of PML nuclear bodies and this prevents differentiation down glial lineages. Similar to leukemias driven by PML mutations, H3.3-mutated glioma cells are sensitive to drugs that target PML bodies. We also find that point mutations in IDH1/2—which are common events in adult gliomas and myeloid leukemias—also disrupt the formation of PML bodies. Conclusions We identify PML as a contributor to oncogenesis in a subset of gliomas and show that targeting PML bodies is effective in treating these H3.3-mutated pediatric gliomas.
Keywords	Histone variant H3.3 ; Pediatric glioma ; PML bodies ; Arsenic trioxide ; Biology (General) ; QH301-705.5 ; Genetics ; QH426-470
Subject code	616
Language	English
Publishing date	2023-12-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Tuning antiviral CD8 T-cell response via proline-altered peptide ligand vaccination.

Adil Doganay Duru / Renhua Sun / Eva B Allerbring / Jesseka Chadderton / Nadir Kadri / Xiao Han / Kaliroi Peqini / Hannes Uchtenhagen / Chaithanya Madhurantakam / Sara Pellegrino / Tatyana Sandalova / Per-Åke Nygren / Stephen J Turner / Adnane Achour

PLoS Pathogens, Vol 16, Iss 5, p e

2020 Volume 1008244

Abstract: Viral escape from CD8+ cytotoxic T lymphocyte responses correlates with disease progression and represents a significant challenge for vaccination. Here, we demonstrate that CD8+ T cell recognition of the naturally occurring MHC-I-restricted LCMV- ... ...

Abstract	Viral escape from CD8+ cytotoxic T lymphocyte responses correlates with disease progression and represents a significant challenge for vaccination. Here, we demonstrate that CD8+ T cell recognition of the naturally occurring MHC-I-restricted LCMV-associated immune escape variant Y4F is restored following vaccination with a proline-altered peptide ligand (APL). The APL increases MHC/peptide (pMHC) complex stability, rigidifies the peptide and facilitates T cell receptor (TCR) recognition through reduced entropy costs. Structural analyses of pMHC complexes before and after TCR binding, combined with biophysical analyses, revealed that although the TCR binds similarly to all complexes, the p3P modification alters the conformations of a very limited amount of specific MHC and peptide residues, facilitating efficient TCR recognition. This approach can be easily introduced in peptides restricted to other MHC alleles, and can be combined with currently available and future vaccination protocols in order to prevent viral immune escape.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2020-05-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Tuning antiviral CD8 T-cell response via proline-altered peptide ligand vaccination

Adil Doganay Duru / Renhua Sun / Eva B. Allerbring / Jesseka Chadderton / Nadir Kadri / Xiao Han / Hannes Uchtenhagen / Chaithanya Madhurantakam / Sara Pellegrino / Tatyana Sandalova / Per-Åke Nygren / Stephen J. Turner / Adnane Achour

Abstract: AbstractViral escape from CD8+ cytotoxic T lymphocyte responses correlates with disease progression and represents a significant challenge for vaccination. Here, we demonstrate that CD8+ T cell recognition of the naturally occurring MHC-I-restricted LCMV- ...

Abstract	AbstractViral escape from CD8+ cytotoxic T lymphocyte responses correlates with disease progression and represents a significant challenge for vaccination. Here, we demonstrate that CD8+ T cell recognition of the naturally occurring MHC-I-restricted LCMV-associated immune escape variant Y4F is restored following vaccination with a proline-altered peptide ligand (APL). The APL increases MHC/peptide (pMHC) complex stability, rigidifies the peptide and facilitates T cell receptor (TCR) recognition through reduced entropy costs. Structural analyses of pMHC complexes before and after TCR binding, combined with biophysical analyses, revealed that although the TCR binds similarly to all complexes, the p3P modification alters the conformations of a very limited amount of specific MHC and peptide residues, facilitating efficient TCR recognition. This approach can be easily introduced in peptides restricted to other MHC alleles, and can be combined with currently available and future vaccination protocols in order to prevent viral immune escape.Author SummaryViral escape mutagenesis correlates often with disease progression and represents a major hurdle for vaccination-based therapies. Here, we have designed and developed a novel generation of altered epitopes that re-establish and enhance significantly CD8+ T cell recognition of a naturally occurring viral immune escape variant. Biophysical and structural analyses provide a clear understanding of the molecular mechanisms underlying this reestablished recognition. We believe that this approach can be implemented to currently available or novel vaccination approaches to efficiently restore T cell recognition of virus escape variants to control disease progression.
Keywords	covid19
Publisher	biorxiv
Document type	Article ; Online
DOI	10.1101/862144
Database	COVID19

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Article ; Online: Activation and In Vivo Evolution of the MAIT Cell Transcriptome in Mice and Humans Reveals Tissue Repair Functionality

Timothy S.C. Hinks / Emanuele Marchi / Maisha Jabeen / Moshe Olshansky / Ayako Kurioka / Troi J. Pediongco / Bronwyn S. Meehan / Lyudmila Kostenko / Stephen J. Turner / Alexandra J. Corbett / Zhenjun Chen / Paul Klenerman / James McCluskey

Cell Reports, Vol 28, Iss 12, Pp 3249-3262.e

2019 Volume 5

Abstract: Summary: Mucosal-associated invariant T (MAIT) cells are MR1-restricted innate-like T cells conserved across mammalian species, including mice and humans. By sequencing RNA from sorted MR1-5-OP-RU tetramer+ cells derived from either human blood or murine ...

Abstract	Summary: Mucosal-associated invariant T (MAIT) cells are MR1-restricted innate-like T cells conserved across mammalian species, including mice and humans. By sequencing RNA from sorted MR1-5-OP-RU tetramer+ cells derived from either human blood or murine lungs, we define the basic transcriptome of an activated MAIT cell in both species and demonstrate how this profile changes during the resolution of infection and during reinfection. We observe strong similarities between MAIT cells in humans and mice. In both species, activation leads to strong expression of pro-inflammatory cytokines and chemokines as well as a strong tissue repair signature, recently described in murine commensal-specific H2-M3-restricted T cells. Transcriptomes of MAIT cells and H2-M3-specific CD8+ T cells displayed the most similarities to invariant natural killer T (iNKT) cells when activated, but to γδ T cells after the resolution of infection. These data define the requirements for and consequences of MAIT cell activation, revealing a tissue repair phenotype expressed upon MAIT cell activation in both species. : Mucosal-associated invariant T (MAIT) cells are implicated in antibacterial and antiviral immunity. Using RNA sequencing of human MAIT cells stimulated with their cognate ligand and murine MAIT cells stimulated by acute Legionella infection, Hinks et al. report that activation leads to expression of a strong tissue repair signature in both species. Keywords: mucosal-associated invariant T cell, T cell, transcriptome, MHC-related protein 1, activation, lung, human, mouse, riboflavin, tissue repair
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2019-09-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Regulation of H3K4me3 at Transcriptional Enhancers Characterizes Acquisition of Virus-Specific CD8+ T Cell-Lineage-Specific Function

Brendan E. Russ / Moshe Olshansky / Jasmine Li / Michelle L.T. Nguyen / Linden J. Gearing / Thi H.O. Nguyen / Matthew R. Olson / Hayley A. McQuilton / Simone Nüssing / Georges Khoury / Damian F.J. Purcell / Paul J. Hertzog / Sudha Rao / Stephen J. Turner

Cell Reports, Vol 21, Iss 12, Pp 3624-

2017 Volume 3636

Abstract: Summary: Infection triggers large-scale changes in the phenotype and function of T cells that are critical for immune clearance, yet the gene regulatory mechanisms that control these changes are largely unknown. Using ChIP-seq for specific histone post- ... ...

Abstract	Summary: Infection triggers large-scale changes in the phenotype and function of T cells that are critical for immune clearance, yet the gene regulatory mechanisms that control these changes are largely unknown. Using ChIP-seq for specific histone post-translational modifications (PTMs), we mapped the dynamics of ∼25,000 putative CD8+ T cell transcriptional enhancers (TEs) differentially utilized during virus-specific T cell differentiation. Interestingly, we identified a subset of dynamically regulated TEs that exhibited acquisition of a non-canonical (H3K4me3+) chromatin signature upon differentiation. This unique TE subset exhibited characteristics of poised enhancers in the naive CD8+ T cell subset and demonstrated enrichment for transcription factor binding motifs known to be important for virus-specific CD8+ T cell differentiation. These data provide insights into the establishment and maintenance of the gene transcription profiles that define each stage of virus-specific T cell differentiation. : Russ et al. demonstrate that a subset of poised transcriptional enhancers found in naive virus-specific CD8+ T cells acquire a non-canonical chromatin signature upon differentiation. These data provide the genomic location for T cell lineage-specific transcription factor binding that is necessary for virus-specific T cell differentiation. Keywords: CD8+ T cell, influenza, chromatin, epigenetics, transcription factor
Keywords	Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2017-12-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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