Alternative perspectives from economics and political economy now agree that work is set to disappear through the impact of mass automation. Some worry about the negative effects on unemployment and ...inequality, while others see the opportunity to extend free time. This paper confronts and criticises these perspectives. It addresses previous visions of an automated (‘workless’) future presented by Marx and Keynes and shows the enduring barriers to working less in capitalist society. It then questions whether work will be reduced by technological progress; rather, it argues that work will likely persist, despite and indeed because of the wider use of new technology. The threat to workers from technology is seen to come more from the erosion in the quality of work than from the loss of work. The paper argues that a better future for work and workers ultimately depends on broader changes in ownership.
Some economists now predict that technology will eliminate many millions of jobs and lead to a future without work. Much debate focuses on the accuracy of such a prediction—whether, or at what rate, ...jobs will disappear. But there is a wider question raised by this prediction, namely the merits or otherwise of automating work. Beyond estimating future job losses via automation, there is the normative issue of whether the quality of life would be enhanced in a world where machines replace humans in work. Economics makes particular assumptions about the value of work and the nature of well-being that can address this normative issue. But a deeper enquiry into the scope for living well in a possible automated future requires us to think beyond the limits of standard economic theory and to engage in matters of relevance to business ethicists. This paper shows how automation raises crucial concerns about work—its meaning and contribution to well-being—and how the ability to envisage a better future of work depends on bridging the gap between economics and business ethics. Overall, the paper aims to further understanding of automation as a possible mechanism to raise well-being within work and beyond it.
Age-related change in human haematopoiesis causes reduced regenerative capacity
, cytopenias
, immune dysfunction
and increased risk of blood cancer
, but the reason for such abrupt functional ...decline after 70 years of age remains unclear. Here we sequenced 3,579 genomes from single cell-derived colonies of haematopoietic cells across 10 human subjects from 0 to 81 years of age. Haematopoietic stem cells or multipotent progenitors (HSC/MPPs) accumulated a mean of 17 mutations per year after birth and lost 30 base pairs per year of telomere length. Haematopoiesis in adults less than 65 years of age was massively polyclonal, with high clonal diversity and a stable population of 20,000-200,000 HSC/MPPs contributing evenly to blood production. By contrast, haematopoiesis in individuals aged over 75 showed profoundly decreased clonal diversity. In each of the older subjects, 30-60% of haematopoiesis was accounted for by 12-18 independent clones, each contributing 1-34% of blood production. Most clones had begun their expansion before the subject was 40 years old, but only 22% had known driver mutations. Genome-wide selection analysis estimated that between 1 in 34 and 1 in 12 non-synonymous mutations were drivers, accruing at constant rates throughout life, affecting more genes than identified in blood cancers. Loss of the Y chromosome conferred selective benefits in males. Simulations of haematopoiesis, with constant stem cell population size and constant acquisition of driver mutations conferring moderate fitness benefits, entirely explained the abrupt change in clonal structure in the elderly. Rapidly decreasing clonal diversity is a universal feature of haematopoiesis in aged humans, underpinned by pervasive positive selection acting on many more genes than currently identified.
Abstract This paper re-examines the different visions of the future of working time offered by Marx and Keynes. While Marx and Keynes differed radically on some fundamental matters, they agreed that ...society would benefit from reducing work time. The idea of society using technology to curtail work hours was a central aspect of their respective visions of a better future. The paper compares Marx’s and Keynes’s visions. It also considers the fate of their visions as well as their relevance for modern debates on the future of work. The conclusion is that a critical political economy can learn from the different ideas of Marx and Keynes in supporting the case for reducing work hours in the present.
The molecular consequences of coding mutations can often be predicted simply from their effect on a gene’s sequence. Noncoding mutations require more work. In this issue of
Blood
,
Yang and ...colleagues
1
use 3D genomics to make an important contribution to the list of functional noncoding mutations in cancer. They show that microdeletions at 13q12.2 in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) eliminate the boundary of a topologically associated domain (TAD) at the
FLT3
locus, which results in higher expression of
FLT3
, an important driver gene in acute leukemias.
Somatic mutations in DNMT3A, which encodes a de novo DNA methyltransferase, are found in ∼30% of normal karyotype acute myeloid leukemia (AML) cases. Most mutations are heterozygous and alter R882 ...within the catalytic domain (most commonly R882H), suggesting the possibility of dominant-negative consequences. The methyltransferase activity of R882H DNMT3A is reduced by ∼80% compared with the WT enzyme. In vitro mixing of WT and R882H DNMT3A does not affect the WT activity, but coexpression of the two proteins in cells profoundly inhibits the WT enzyme by disrupting its ability to homotetramerize. AML cells with the R882H mutation have severely reduced de novo methyltransferase activity and focal hypomethylation at specific CpGs throughout AML cell genomes.
•AML cases with DNMT3A mutations at R882 exhibit focal hypomethylation•R882H DNMT3A is a dominant-negative inhibitor of WT DNMT3A•WT DNMT3A forms stable, active homotetramers•R882H DNMT3A dominantly disrupts DNMT3A tetramerization
Heterozygous DNMT3A R882H mutation is common in acute myeloid leukemia (AML). Russler-Germain et al. show that DNMT3AR882H inhibits wild-type DNMT3A activity in cells, but not in vitro, and that AML cells with the R882H mutation have reduced de novo methyltransferase activity and focal CpG hypomethylation.
Abstract
This article assesses the impact and probably limits of automation. It looks, in particular, at the case of the UK economy. The prospects for automation are seen as necessarily uncertain and ...potentially regressive in their effects, with technology likely to sustain a large number of low-quality jobs. The deep-seated problems of the UK economy—low-investment, low-productivity and low-real wages—are seen as key impediments to forms of automation that work for all in society. It is argued that, without wider institutional reform, the UK will be unable to reap the full potential of automation.
Adoptive immunotherapy with T cells expressing chimeric antigen receptors (CAR) has had limited success for solid tumors in early-phase clinical studies. We reasoned that introducing into CAR T cells ...an inducible costimulatory (iCO) molecule consisting of a chemical inducer of dimerization (CID)-binding domain and the MyD88 and CD40 signaling domains would improve and control CAR T-cell activation. In the presence of CID, T cells expressing HER2-CARζ and a MyD88/CD40-based iCO molecule (HER2ζ.iCO T cells) had superior T-cell proliferation, cytokine production, and ability to sequentially kill targets
relative to HER2ζ.iCO T cells without CID and T cells expressing HER2-CAR.CD28ζ. HER2ζ.iCO T cells with CID also significantly improved survival
in two xenograft models. Repeat injections of CID were able to further increase the antitumor activity of HER2ζ.iCO T cells
Thus, expressing MyD88/CD40-based iCO molecules in CAR T cells has the potential to improve the efficacy of CAR T-cell therapy approaches for solid tumors.
Inducible activation of MyD88 and CD40 in CAR T cells with a small-molecule drug not only enhances their effector function, resulting in potent antitumor activity in preclinical solid tumors, but also enables their remote control post infusion.
.
Modification of T cells with chimeric antigen receptors (CAR) has emerged as a promising treatment modality for human malignancies. Integration of co-stimulatory domains into CARs can augment the ...activation and function of genetically targeted T cells against tumors. However, the potential for insertional mutagenesis and toxicities due to the infused cells have made development of safe methods for removing transferred cells an important consideration. We have genetically modified human T cells with a lentiviral vector to express a CD20-CAR containing both CD28 and CD137 co-stimulatory domains, a "suicide gene" relying on inducible activation of caspase 9 (iC9), and a truncated CD19 selectable marker. Rapid expansion (2000 fold) of the transduced T cells was achieved in 28 days after stimulation with artificial antigen presenting cells. Transduced T cells exhibited effective CD20-specific cytotoxic activity in vitro and in a mouse xenograft tumor model. Activation of the iC9 suicide switch resulted in efficient removal of transduced T cells both in vitro and in vivo. Our work demonstrates the feasibility and promise of this approach for treating CD20(+) malignancies in a safe and more efficient manner. A phase I clinical trial using this approach in patients with relapsed indolent B-NHL is planned.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Approximately 25% of B‐cell acute lymphoblastic leukemia (B‐ALL) cases are defined by hyperdiploidy, with RAS mutations occurring in 30% of hyperdiploid B‐ALL patients. It is believed that ...hyperdiploidy is an in utero event with RAS mutations occurring postnatally, but clinical evidence of this is based on relatively few patients. We present a case of monozygotic, monochorionic twins who developed concordant hyperdiploid B‐ALL with identical chromosomal gains but different RAS mutations, adding further evidence that hyperdiploidy is occurring prenatally, with RAS mutations developing postnatally. Environmental exposures were reviewed with the family without identification of a clear association.
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