Bridging the great divide? Making sense of the human rights-CSR relationship in UK multinational companies

Human rights (HR) and corporate social responsibility (CSR) are both fields of knowledge and research that have been shaped by, and examine, the role of multi-national enterprises in society. Whilst scholars have highlighted the overlapping nature of CSR and HR, our understanding of this relationship within business practice remains vague and under-researched. To explore the interface between CSR and HR, this paper presents empirical data from a qualitative study involving 22 international businesses based in the UK. Through an analysis based on sensemaking, the paper examines how and where CSR and HR overlap, contrast and shape one another, and the role that companies’ international operations has on this relationship. The findings reveal a complex and multi-layered relationship between the two, and concludes that in contrast to management theory, companies have bridged the ‘great divide’ in varying degrees most notably in their implementation strategies

My contemporaries in 20^<th> century.

De novo copy number variations (CNVs) identified in the 1210B2 iPSC-derived NSPCs. (XLSX 39 kb

Combining Chimeric Mice with Humanized Liver, Mass Spectrometry, and Physiologically-Based Pharmacokinetic Modeling in Toxicology

Species differences exist in terms of drug oxidation activities, which are mediated mainly by cytochrome P450 (P450) enzymes. To overcome the problem of species extrapolation, transchromosomic mice containing a human P450 3A cluster or chimeric mice transplanted with human hepatocytes have been introduced into the human toxicology research area. In this review, drug metabolism and disposition mediated by humanized livers in chimeric mice are summarized in terms of biliary/urinary excretions of phthalate and bisphenol A and plasma clearances of the human cocktail probe drugs caffeine, warfarin, omeprazole, metoprolol, and midazolam. Simulation of human plasma concentrations of the teratogen thalidomide and its human metabolites is possible with a simplified physiologically based pharmacokinetic model based on data obtained in chimeric mice, in accordance with reported clinical thalidomide concentrations. In addition, <i>in vivo</i> nonspecific hepatic protein binding parameters of metabolically activated ¹⁴C-drug candidate and hepatotoxic medicines in humanized liver mice can be analyzed by accelerator mass spectrometry and are useful for predictions in humans

Simulation of Human Plasma Concentrations of Thalidomide and Primary 5‑Hydroxylated Metabolites Explored with Pharmacokinetic Data in Humanized TK-NOG Mice

Plasma concentrations of thalidomide and primary 5-hydroxylated metabolites including 5,6-dihydroxythalidomide and glutathione (GSH) conjugate(s) were investigated in chimeric mice with highly “humanized” liver cells harboring cytochrome <i>P450 3A5*1</i>. Following oral administration of thalidomide (100 mg/kg), plasma concentrations of GSH conjugate(s) of 5-hydroxythalidomide were higher in humanized mice than in controls. Simulation of human plasma concentrations of thalidomide were achieved with a simplified physiologically based pharmacokinetic model in accordance with reported thalidomide concentrations. The results indicate that the pharmacokinetics in humans of GSH conjugate and/or catechol primary 5-hydroxylated thalidomide contributing <i>in vivo</i> activation can be estimated for the first time

Assessment of Protein Binding of 5‑Hydroxythalidomide Bioactivated in Humanized Mice with Human <i>P450 3A</i>-Chromosome or Hepatocytes by Two-Dimensional Electrophoresis/Accelerator Mass Spectrometry

Bioactivation of 5-hydroxy-[<i>carbonyl</i>-¹⁴C]­thalidomide, a known metabolite of thalidomide, by human artificial or native cytochrome P450 3A enzymes, and nonspecific binding in livers of mice was assessed using two-dimensional electrophoresis combined with accelerator mass spectrometry. The apparent major target proteins were liver microsomal cytochrome <i>c</i> oxidase subunit 6B1 and ATP synthase subunit α in mice containing humanized <i>P450 3A</i> genes or transplanted humanized liver. Liver cytosolic retinal dehydrogenase 1 and glutathione transferase A1 were targets in humanized mice with P450 3A and hepatocytes, respectively. 5-Hydroxythalidomide is bioactivated by human P450 3A enzymes and trapped with proteins nonspecifically in humanized mice

The Adult Livers of Immunodeficient Mice Support Human Hematopoiesis: Evidence for a Hepatic Mast Cell Population that Develops Early in Human Ontogeny

<div><p>The liver plays a vital role in hematopoiesis during mammalian prenatal development but its hematopoietic output declines during the perinatal period. Nonetheless, hepatic hematopoiesis is believed to persist into adulthood. We sought to model human adult-liver hematopoiesis by transplantation of fetal and neonatal hematopoietic stem cells (HSCs) into adult immunodeficient mice. Livers were found to be engrafted with human cells consisting primarily of monocytes and B-cells with lesser contributions by erythrocytes, T-cells, NK-cells and mast-cells. A resident population of CD117⁺⁺CD203c⁺ mast cells was also documented in human midgestation liver, indicating that these cells comprise part of the liver's resident immune cell repertoire throughout human ontogeny. The murine liver was shown to support human multilineage hematopoiesis up to 321 days after transplant. Evidence of murine hepatic hematopoiesis was also found in common mouse strains as old as 2 years. Human HSC engraftment of the murine liver was demonstrated by detection of high proliferative-potential colony-forming cells in clonal cultures, observation of CD38⁻CD34⁺⁺ and CD133⁺CD34⁺⁺ cells by flow cytometry, and hematopoietic reconstitution of secondary transplant recipients of chimeric liver cells. Additionally, chimeric mice with both hematopoietic and endothelial reconstitution were generated by intrasplenic injection of immunodeficient mice with liver specific expression of the urokinase-type plasminogen activator (uPA) transgene. In conclusion, the murine liver is shown to be a hematopoietic organ throughout adult life that can also support human hematopoiesis in severely immunodeficient strains. Further humanization of the murine liver can be achieved in mice harboring an uPA transgene, which support engraftment of non-hematopoietic cells types. Thus, offering a model system to study the interaction of diverse human liver cell types that regulate hematopoiesis and immune function in the liver.</p></div

Human hematopoiesis in the livers of mice transplanted with fetal cells.

<p>(A) Hematopoietic precursors are present in the liver of a mouse analyzed 130 days after being transplanted with 1×10⁶ hFL cells. Filled arrows identify CD38⁻CD34⁺⁺ and CD133⁺CD34⁺⁺ cells, possible HSCs, whereas open arrows point to committed progenitors. (B) Various committed hematopoietic progenitor populations are evident in the liver including B-cell progenitors and myeloid progenitors shown from among CD19⁻ human cells.The bottom row of data shows immature erythroid cells that express low levels of CD235a and high levels of CD71 as indicated by the arrows. Data are from 4 pooled livers analyzed 148 days after transplantation with 2×10⁵ Lin⁻ hFL cells. (C) HPP-CFC and LPP-CFC responsive to human-specific cytokines were assayed from the light-density livers cells harvested from 5 transplanted and 1 untransplanted NOD-SCID mice. Mice were analyzed 30 days after transplant with 1×10⁷ hFBM cells of 23 weeks' gestation. Lines indicate the total number of CD34^+/++ and CD133⁺CD34⁺⁺ cells (right axis) shown on top of a bar chart of colony numbers (left axis). (D) A photomicrograph of representative myeloid colonies grown from liver cells shows both a large HPP-CFC-derived colony and smaller LPP-CFC-derived colonies. The size of the colonies can be gauged from the 2 mm grid shown in the background.</p

Mature human blood cells in the murine liver.

<p>(A) Significantly more light-density liver cells were recovered from 3 mice transplanted with CD34⁺⁺CD38⁻ hFL cells than from untransplanted NSG mice. (B) Myeloid, lymphoid and erythroid engraftment observed 68-166 days after transplantation with hFBM or Lin⁻ LDFL cells. (C) Distribution of T-cell subsets among CD3⁺ T-cells in mice transplanted with hFBM cells. The numbers (n) of animals evaluated are indicate in the 3 box plots. (D) Flow cytometric analysis of light-density liver cells pooled from 3 NSG mice transplanted with CD34⁺⁺CD38⁻ hFL cells were analyzed 144 days after transplantation showing multilineage hematopoietic engraftment. T-cell subsets were evaluated by gating on CD3⁺ cells as indicated. CD56⁺ NK cells were defined by a low side-light scatter gate (not shown) and their lack of CD3 expression. Numbers shown in the graphs represent the percentages of gated events among all CD59⁺ human cells.</p

Hematopoietic reconstitution of uPA-NOG mice.

<p>(A) Adult mice were transplanted with erythrocyte-depleted hFL cells by intra-splenic injection. No irradiation was used for pre-transplant cytoablation. Engraftment was evaluated 75 - 82 days after transplant. Digested liver cell suspensions were separated into quickly-settling high-density and the remaining, low-density, cells. The light-density cells were analyzed for hematopoietic reconstitution. Note the presence of CD19⁺ B-cells, CD33⁺ myeloid cells, possible immature erythroid elements (arrow, CD71⁺⁺CD235a⁺ cells) and CD34⁺ hematopoietic stem (CD38⁻CD133⁺) and progenitor cells (CD38⁺CD133⁻). (B) Multilineage hematopoietic engraftment was also observed in the BM of a uPA-NOG mouse. (C) High-density cells isolated from uPA-NOG transplanted mice contained CD45⁻CD14⁺ cells likely representing liver endothelial cells as well as CD45⁺ hematopoietic cells (C). The same population of CD45⁻CD14⁺ cells was much less prevalent in NSG mice.</p

Hematopoietic reconstitution following transplantation of chimeric liver cells.

<p>(A) Phenotypic analysis of light density liver cells pooled from 9 mice harvested 89 days after transplant with hFBM cells reveals evidence of CD38⁻CD34⁺⁺ and CD133⁺CD34⁺⁺ cells. These cells were used for transplantation into secondary recipients. (B) An example of the multilineage reconstitution of the BM of a secondary recipient 69 days after transplantation with chimeric liver cells. Arrows identify CD38⁻CD34⁺⁺ and CD133⁺CD34⁺⁺ candidate HSCs and CD7⁺⁺CD56⁺ NK cells.</p