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01 02 In contrast to previous attempts to examine adaptation to climate change in developing countries, the authors focus on how individuals and broader social groups adjust their aspirations, mental states, social values and behaviour as well as practices in response to changes in their personal and social circumstances. Employing a unique blend of cross-disciplinary work from economics, psychology, sociology and philosophy, this innovative book draws on quantitative and qualitative techniques. The three sections deal with conceptual issues, empirical studies and specific topics (gender, disability, migration) relating to adaptation in developing countries. It includes detailed case studies of adaptation in China, Ethiopia, India and South Africa and underlines the case for listening to the poor by suggesting that people who become worse off are less likely to lower their aspirations – or restrict their values – than is commonly thought by some philosophers and social scientists. 16 02 No other book focuses on adaptation in the context of developing countries. The available work on adaptation is scattered across a wide range of disciplines mostly in the form of journal papers or single chapters in edited volumes. The available empirical work either focuses on case studies of Western countries or international datasets which under-represent developing countries. The only book that deals specifically with adaptation is Adaptation Level Theory: A Symposium (H. M. Apley, Academic Press, 1971). This book is dated and is concerned with psychological theory rather than cross disciplinary work on adaptation in poor countries. The nearest competing books in psychology/ economics include works like Well-Being: The Foundations of Hedonic Psychology (Daniel Khaneman et al, 1999, Sage) Culture and Subjective Well-Being (Ed Diener et al, 2000, MIT) Happiness: Lessons from a New Science (Richard Layard, 2006, Penguin)   In political economy/philosophy and international development the nearest competing works include Sour Grapes: Studies in the Subversion of Rationality (Jon Elster, 1983, Cambridge University Press) Commodities and Capabilities (Amartya Sen, 1985, Blackwell) Women and Human Development (Martha Nussbaum, 2000, Cambridge University Press). With the exception of Elster's book (which is largely concerned with one particular form of adaptation), these volumes typically include a single chapter on adaptation. 31 02 World-leading academics investigate 'adaptation', in its various guises and forms including gender, disability and migration, in the context of economic and social development in poor countries 02 02 The first book to examine in detail the ways in which people adapt their understanding and behaviours towards poverty as a direct result to their experiences of poverty in developing countries, including world-leading academics and case studies from China, India, Ethiopia and South Africa. 19 02 Examines in detail how people adapt their understanding and behaviours towards poverty when experiencing it firsthand in developing countries Written byinternationally reputed academicsfrom the UK, Australia, Germany, and India Includes country case studies from China, India, Ethiopia, and South Africa 08 02 'Economics is venturing into a new world previously inhabited by psychologists, the extent to which people adapt in various ways to changing circumstances. Better knowledge of adaptation is fundamental to advancing our understanding of human behavior and feelings of well-being. This volume is a welcome and valuable contribution to an important and much-neglected subject.' – Richard A. Easterlin, Professor of Economics, University of Southern California, USA 'This book breaks new ground by bringing together theoretical and empirical perspectives on the problem of adaptation, using case studies in India, China and Africa. Clear, insightful and methodical, it will become essential reading for all those interested in the increasingly important question of how to interpret subjective measures of well-being, especially in a development context.' – Tania Burchardt, Deputy Director, Centre for the Analysis of Social Exclusion, London School of Economics and Political Science, UK 'Is adaptation of deprived people to their often abysmal circumstances a healthy reaction which improves the quality of their lives? Or does it inhibit action to improve the situation – by them and by others? This fascinating book explores such issues conceptually and empirically, and is especially pertinent today when 'happiness' is being promoted as the new metric of development.' - Frances Stewart, University of Oxford, UK '...covers interesting themes that are of importance to those interested in the dynamics of subjective well-being (SWB), whether from a theoretical, empirical or policymaking perspective, which is a great achievement indeed...There is no doubt that anyone can learn a lot from reading this book. The range of topics covered is so broad that even experts in the field can enhance their knowledge as they also add new insights and open up novel perspectives for future research...the editor is certainly to be lauded for having succeeded in publishing a book that may also be read by non-specialists. For all these reasons, I expect Adaptation, Poverty and Development. The Dynamics of Subjective Well-Being to be well received by its readers.' - Claudia Tello, University of Barcelona, European Journal of Development Research 13 02 DAVID A. CLARK Honorary Fellow and Research Associate at theBrooks World Poverty Institute of the University of Manchester, UK, and Visiting Fellow at the Centre for Analysis of Social Exclusion of London School of Economics and Political Science, UK. Previous publications include The Elgar Companion to Development Studies and Visions of Development: A Study of Human Values . 04 02 Adaptation and Development – Issues, Evidence and Policy Relevance PART I: ADAPTATION AND DEVELOPMENT: CONCEPTS AND ISSUES Utilitarianism, 'Adaptation' and Paternalism; M.Qizilbash Adaptation: Implications for Development in Theory and Practice PART II: ADAPTATION AND DEVELOPMENT: THREE CASE STUDIES Aspirations, Adaptation and Subjective Well-Being of Rural-Urban Migrants in China; J.Knight & R.Gunatilaka A Multidimensional Analysis of Adaptation in a Developing Country Context; A.Barr Adaptation, Poverty and Subjective Well-Being: Evidence from South India; D.Neff PART III: ADAPTATION AND DEVELOPMENT: SPECIFIC ISSUES Subjective Well-being, Disability and Adaptation: A Case Study from Rural Ethiopia; M.Fafchamps & B.Kebede Adaptation of the Rural Working Class in India: A Case Study of Migrant Workers; B.Reddy & W.Olsen

Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease of the synovial joints with a global prevalence of 1%, causing pain, work instability and disability. The condition's genetic aetiology is complex, and genome-wide association studies have highlighted over 100 susceptibility loci. The vast majority of implicated variants are noncoding, posing a major challenge in defining genetic mechanisms of cell-mediated immune dysregulation. The precise contribution to this process of epigenetic factors at a cellular level, such as the addition of methyl groups to DNA, also remains to be deciphered. By conducting comprehensive molecular profiling of circulating immune cells from early arthritis patients, my project aimed to elucidate mechanisms of genetic risk and prioritise causal disease genes in RA. To address this, genomewide DNA methylation, transcriptome and genotype data were available from peripheral blood CD4+ T cells and B cells of treatment-naïve early arthritis patients. Firstly, a comparison of DNA methylation between patients with early RA and those with other arthropathies was undertaken. Subsequently, the capacity of RA-associated variants to influence DNA methylation by mapping methylation quantitative trait loci (meQTLs) was confirmed. Here, it was observed that disease variants preferentially modified DNA methylation at sites mapping to lymphocyte enhancers and regions flanking transcription start sites, as well as positions bound by the NFκB transcription factor. By integrating transcriptomic data and employing a statistical approach to infer causality, loci were identified at which genetically conferred modifications in DNA methylation regulate transcription of genes including FCRL3, ANKRD55, IL6ST, and JAZF1 in CD4+ T cells. Finally, in vitro assays were used to validate meQTLs at loci of interest, and to confirm regulatory mechanisms. This work highlights genes and pathways of potential relevance to lymphocyte-mediated pathology in early RA and, potentially, other immune mediated diseases. It has implications for the functional interpretation of genome/epigenome-wide association studies.

Abstract This paper introduces a new volume on Adaptation, Poverty and Development: The Dynamics of Subjective Well-Being (Clark, 2012), sponsored by the ESRC Global Poverty Research Group (Universities of Manchester and Oxford) and the Brooks World Poverty Institute (University of Manchester). The book draws on conceptual and empirical work and utilises a range of methodologies to investigate 'adaptation' - in its various guises and forms - in the context of economic and social development in poor countries. This paper is divided into five parts. Following a brief introduction, Section 2 reviews some key concepts and issues associated with adaptation from across diverse and fragmented literatures. Section 3 provides a brief overview of existing theories and empirical evidence. Section 4 considers the rationale and contribution of the book and places it in the context of existing work. And Section 5 provides a brief introduction to the structure, contents, key findings and policy conclusions of the book.

Visions of Development: A Study of Human Values by David Alexander Clark is reviewed.

Multipotent adult progenitor cells are a bone marrow-derived, allogeneic, cell therapy product that modulates the immune system, and represents a promising therapy for acute stroke. We aimed to identify the highest, well-tolerated, and safest single dose of multipotent adult progenitor cells, and if they were efficacious as a treatment for stroke recovery. We did a phase 2, randomised, double-blind, placebo-controlled, dose-escalation trial of intravenous multipotent adult progenitor cells in 33 centres in the UK and the USA. We used a computer-generated randomisation sequence and interactive voice and web response system to assign patients aged 18–83 years with moderately severe acute ischaemic stroke and a National Institutes of Health Stroke Scale (NIHSS) score of 8–20 to treatment with intravenous multipotent adult progenitor cells (400 million or 1200 million cells) or placebo between 24 h and 48 h after symptom onset. Patients were ineligible if there was a change in NIHSS of four or more points during at least a 6 h period between screening and randomisation, had brainstem or lacunar infarct, a substantial comorbid disease, an inability to undergo an MRI scan, or had a history of splenectomy. In group 1, patients were enrolled and randomly assigned in a 3:1 ratio to receive 400 million cells or placebo and assessed for safety through 7 days. In group 2, patients were randomly assigned in a 3:1 ratio to receive 1200 million cells or placebo and assessed for safety through the first 7 days. In group 3, patients were enrolled, randomly assigned, and stratified by baseline NIHSS score to receive 1200 million cells or placebo in a 1:1 ratio within 24–48 h. Patients, investigators, and clinicians were masked to treatment assignment. The primary safety outcome was dose-limiting toxicity effects. The primary efficacy endpoint was global stroke recovery, which combines dichotomised results from the modified Rankin scale, change in NIHSS score from baseline, and Barthel index at day 90. Analysis was by intention to treat (ITT) including all patients in groups 2 and 3 who received the investigational agent or placebo. This study is registered with ClinicalTrials.gov, number NCT01436487. The study was done between Oct 24, 2011, and Dec 7, 2015. After safety assessments in eight patients in group 1, 129 patients were randomly assigned (67 to receive multipotent adult progenitor cells and 62 to receive placebo) in groups 2 and 3 (1200 million cells). The ITT populations consisted of 65 patients who received multipotent adult progenitor cells and 61 patients who received placebo. There were no dose-limiting toxicity events in either group. There were no infusional or allergic reactions and no difference in treatment-emergent adverse events between the groups (64 [99%] of 65 patients in the multipotent adult progenitor cell group vs 59 [97%] of 61 in the placebo group). There was no difference between the multipotent adult progenitor cell group and placebo groups in global stroke recovery at day 90 (odds ratio 1·08 [95% CI 0·55–2·09], p=0·83). Administration of multipotent adult progenitor cells was safe and well tolerated in patients with acute ischaemic stroke. Although no significant improvement was observed at 90 days in neurological outcomes with multipotent adult progenitor cells treatment, further clinical trials evaluating the efficacy of the intervention in an earlier time window after stroke (<36 h) are planned. Athersys Inc.

Mcl-1 is a member of the Bcl-2 family of proteins that promotes cell survival by preventing induction of apoptosis in many cancers. High expression of Mcl-1 causes tumorigenesis and resistance to anticancer therapies highlighting the potential of Mcl-1 inhibitors as anticancer drugs. Here, we describe AZD5991, a rationally designed macrocyclic molecule with high selectivity and affinity for Mcl-1 currently in clinical development. Our studies demonstrate that AZD5991 binds directly to Mcl-1 and induces rapid apoptosis in cancer cells, most notably myeloma and acute myeloid leukemia, by activating the Bak-dependent mitochondrial apoptotic pathway. AZD5991 shows potent antitumor activity in vivo with complete tumor regression in several models of multiple myeloma and acute myeloid leukemia after a single tolerated dose as monotherapy or in combination with bortezomib or venetoclax. Based on these promising data, a Phase I clinical trial has been launched for evaluation of AZD5991 in patients with hematological malignancies (NCT03218683). High expression of Mcl-1 promotes tumorigenesis and resistance to anticancer therapies. Here they report a macrocyclic molecule with high selectivity and affinity for Mcl-1 that exhibits potent anti-tumor effects as single agent and in combination with bortezomib or venetoclax in preclinical models of multiple myeloma and acute myeloid leukemia.

As availability of precision therapies expands, a well-validated circulating cell-free DNA (cfDNA)-based comprehensive genomic profiling assay has the potential to provide considerable value as a complement to tissue-based testing to ensure potentially life-extending therapies are administered to patients most likely to benefit. Additional data supporting the clinical validity of cfDNA-based testing is necessary to inform optimal use of these assays in the clinic. The FoundationOne.sup.® Liquid CDx assay is a pan-cancer cfDNA-based comprehensive genomic profiling assay that was recently approved by FDA. Validation studies included >7,500 tests and >30,000 unique variants across >300 genes and >30 cancer types. Clinical validity results across multiple tumor types are presented. Additionally, results demonstrated a 95% limit of detection of 0.40% variant allele fraction for select substitutions and insertions/deletions, 0.37% variant allele fraction for select rearrangements, 21.7% tumor fraction for copy number amplifications, and 30.4% TF for copy number losses. The limit of detection for microsatellite instability and blood tumor mutational burden were also determined. The false positive variant rate was 0.013% (approximately 1 in 8,000). Reproducibility of variant calling was 99.59%. In comparison with an orthogonal method, an overall positive percent agreement of 96.3% and negative percent agreement of >99.9% was observed. These study results demonstrate that FoundationOne Liquid CDx accurately and reproducibly detects the major types of genomic alterations in addition to complex biomarkers such as microsatellite instability, blood tumor mutational burden, and tumor fraction. Critically, clinical validity data is presented across multiple cancer types.

Global mean sea level has been steadily rising over the last century, is projected to increase by the end of this century, and will continue to rise beyond the year 2100 unless the current global mean temperature trend is reversed. Inertia in the climate and global carbon system, however, causes the global mean temperature to decline slowly even after greenhouse gas emissions have ceased, raising the question of how much sea-level commitment is expected for different levels of global mean temperature increase above preindustrial levels. Although sea-level rise over the last century has been dominated by ocean warming and loss of glaciers, the sensitivity suggested from records of past sea levels indicates important contributions should also be expected from the Greenland and Antarctic Ice Sheets. Uncertainties in the paleo-reconstructions, however, necessitate additional strategies to better constrain the sea-level commitment. Here we combine paleo-evidence with simulations from physical models to estimate the future sea-level commitment on a multimillennial time scale and compute associated regional sea-level patterns. Oceanic thermal expansion and the Antarctic Ice Sheet contribute quasi-linearly, with 0.4 m °C ⁻¹ and 1.2 m °C ⁻¹ of warming, respectively. The saturation of the contribution from glaciers is overcompensated by the nonlinear response of the Greenland Ice Sheet. As a consequence we are committed to a sea-level rise of approximately 2.3 m °C ⁻¹ within the next 2,000 y. Considering the lifetime of anthropogenic greenhouse gases, this imposes the need for fundamental adaptation strategies on multicentennial time scales.

Homeostatic temperature regulation is fundamental to mammalian physiology and is controlled by acute and chronic responses of local, endocrine and nervous regulators. Here, we report that loss of the heparan sulfate proteoglycan, syndecan-1, causes a profoundly depleted intradermal fat layer, which provides crucial thermogenic insulation for mammals. Mice without syndecan-1 enter torpor upon fasting and show multiple indicators of cold stress, including activation of the stress checkpoint p38α in brown adipose tissue, liver and lung. The metabolic phenotype in mutant mice, including reduced liver glycogen, is rescued by housing at thermoneutrality, suggesting that reduced insulation in cool temperatures underlies the observed phenotypes. We find that syndecan-1, which functions as a facultative lipoprotein uptake receptor, is required for adipocyte differentiation in vitro. Intradermal fat shows highly dynamic differentiation, continuously expanding and involuting in response to hair cycle and ambient temperature. This physiology probably confers a unique role for Sdc1 in this adipocyte sub-type. The PPARγ agonist rosiglitazone rescues Sdc1-/- intradermal adipose tissue, placing PPARγ downstream of Sdc1 in triggering adipocyte differentiation. Our study indicates that disruption of intradermal adipose tissue development results in cold stress and complex metabolic pathology.