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Clonal hematopoiesis (CH) is a common aging-associated condition with increased risk of hematologic malignancy. Knowledge of the mechanisms driving evolution from CH to overt malignancy has been hampered by a lack of in vivo models that orthogonally activate mutant alleles. Here, we develop independently regulatable mutations in DNA methyltransferase 3A (Dnmt3a) and nucleophosmin 1 (Npm1), observed in human CH and AML, respectively. We find Dnmt3a mutation expands hematopoietic stem and multipotent progenitor cells (HSC/MPPs), modeling CH. Induction of mutant Npm1 after development of Dnmt3a-mutant CH causes progression to myeloproliferative disorder (MPD), and more aggressive MPD is observed with longer latency between mutations. MPDs uniformly progress to acute myeloid leukemia (AML) following transplant, accompanied by a decrease in HSC/MPPs and an increase in myeloid-restricted progenitors, the latter of which propagate AML in tertiary recipient mice. At a molecular level, progression of CH to MPD is accompanied by selection for mutations activating Ras/Raf/MAPK signaling. Progression to AML is characterized by additional oncogenic signaling mutations (Ptpn11, Pik3r1, Flt3) and/or mutations in epigenetic regulators (Hdac1, Idh1, Arid1a). Together, our study demonstrates that Npm1 mutation drives evolution of Dnmt3a-mutant CH to AML and rate of disease progression is accelerated with longer latency of CH.

England's financial revolution in the eighteenth century has long been hailed as a key contributor to the world's first Industrial Revolution. Later, in the nineteenth century, roles change in standard narratives – finance turns from hero into villain, with Victorian economic “failure” a result of excessive financial development. This survey argues for the exact opposite. England's financial revolution was strictly limited to public finance, enabling an explosion of public borrowing that stifled economic activity in the century up to 1815. It was only afterwards that finance began to fulfill its promise, enabling the country's rise to become the undisputed workshop of the world by the 1850s. Finally, there is no evidence of Victorian failure through excessive capital exports. In sum, the English case eloquently demonstrates the risks of financial repression – and the vast benefits from repealing outdated rules and regulations.

The first edition of the European Leuke-miaNet (ELN) recommendations for diagnosis and management of acute myeloid leukemia (AML) in adults, published in 2010, has found broad acceptance by physicians and investigators caring for patients with AML. Recent advances, for example, in the discovery of the genomic landscape of the disease, in the development of assays for genetic testing and for detecting minimal residual disease (MRD), as well as in the development of novel antileukemic agents, prompted an international panel to provide updated evidence- and expert opinion-based recommendations. The recommendations include a revised version of the ELN genetic categories, a proposal for a response category based on MRD status, and criteria for progressive disease.

In nuclear medicine, the term theranostics describes the combination of therapy and diagnostic imaging. In practice, this concept dates back more than 50 years; however, among the most successful examples of theranostics are peptide receptor scintigraphy and peptide receptor radionuclide therapy of neuroendocrine tumors. The development of these modalities through the radiolabeling of somatostatin analogs with various radionuclides has led to a revolution in patient management and established a foundation for expansion of the theranostic principle into other oncology indications. This article provides a review of the evolution and development of the theranostic radionuclide approach to the management of neuroendocrine tumors, as described by the inventor of this technique, Eric P. Krenning, in an interview with Rachel Levine.

We describe a thermodynamic-motivated, information theoretic analysis of proteomic data collected from a series of 8 glioblastoma multiforme (GBM) tumors. GBMs are considered here as prototypes of heterogeneous cancers. That heterogeneity is viewed here as manifesting in different unbalanced biological processes that are associated with thermodynamic-like constraints. The analysis yields a molecular description of a stable steady state that is common across all tumors. It also resolves molecular descriptions of unbalanced processes that are shared by several tumors, such as hyperactivated phosphoprotein signaling networks. Further, it resolves unbalanced processes that provide unique classifiers of tumor subgroups. The results of the theoretical interpretation are compared against those of statistical multivariate methods and are shown to provide a superior level of resolution for identifying unbalanced processes in GBM tumors. The identification of specific constraints for each GBM tumor suggests tumor-specific combination therapies that may reverse this imbalance.

Genetic heterogeneity contributes to clinical outcome and progression of most tumors, but little is known about allelic diversity for epigenetic compartments, and almost no data exist for acute myeloid leukemia (AML). We examined epigenetic heterogeneity as assessed by cytosine methylation within defined genomic loci with four CpGs (epialleles), somatic mutations, and transcriptomes of AML patient samples at serial time points. We observed that epigenetic allele burden is linked to inferior outcome and varies considerably during disease progression. Epigenetic and genetic allelic burden and patterning followed different patterns and kinetics during disease progression. We observed a subset of AMLs with high epiallele and low somatic mutation burden at diagnosis, a subset with high somatic mutation and lower epiallele burdens at diagnosis, and a subset with a mixed profile, suggesting distinct modes of tumor heterogeneity. Genes linked to promoter-associated epiallele shifts during tumor progression showed increased single-cell transcriptional variance and differential expression, suggesting functional impact on gene regulation. Thus, genetic and epigenetic heterogeneity can occur with distinct kinetics likely to affect the biological and clinical features of tumors.

To design rational therapies for JAK2-driven hematological malignancies, we functionally dissected the key survival pathways downstream of hyperactive JAK2. In tumors driven by mutant JAK2, Stat1, Stat3, Stat5, and the Pi3k and Mek/Erk pathwayswere constitutively active, and gene expressionprofiling of TEL-JAK2 T-ALL cells revealed theupregulation of prosurvival Bcl-2 family genes. Combining the Bcl-2/Bcl-xL inhibitor ABT-737 with JAK2 inhibitors mediated prolonged disease regressions and cures in mice bearing primary human andmouse JAK2 mutant tumors. Moreover, combined targeting of JAK2 and Bcl-2/Bcl-xL was ableto circumvent and overcome acquired resistance to single-agent JAK2 inhibitor treatment. Thus, inhibiting the oncogenic JAK2 signaling network at two nodal points, at the initiating stage (JAK2) and the effector stage (Bcl-2/Bcl-xL), is highly effectiveand provides a clearly superior therapeutic benefitthan targeting just one node. Therefore, we have defined a potentially curative treatment for hematological malignancies expressing constitutively active JAK2.

To design rational therapies for JAK2-driven hematological malignancies, we functionally dissected the key survival pathways downstream of hyperactive JAK2. In tumors driven by mutant JAK2, Stat1, Stat3, Stat5, and the Pi3k and Mek/Erk pathways were constitutively active, and gene expression profiling of TEL-JAK2 T-ALL cells revealed the upregulation of prosurvival Bcl-2 family genes. Combining the Bcl-2/Bcl-xL inhibitor ABT-737 with JAK2 inhibitors mediated prolonged disease regressions and cures in mice bearing primary human and mouse JAK2 mutant tumors. Moreover, combined targeting of JAK2 and Bcl-2/Bcl-xL was able to circumvent and overcome acquired resistance to single-agent JAK2 inhibitor treatment. Thus, inhibiting the oncogenic JAK2 signaling network at two nodal points, at the initiating stage (JAK2) and the effector stage (Bcl-2/Bcl-xL), is highly effective and provides a clearly superior therapeutic benefit than targeting just one node. Therefore, we have defined a potentially curative treatment for hematological malignancies expressing constitutively active JAK2.

The marine-based Atlantic periphery of the last NW European Ice Sheet experienced significant advances and retreats of its marine sector during its existence. It therefore had considerable potential to intermittently inject freshwater or ice pulses to the North Atlantic. These European inputs had poorly known consequences for ocean circulation and climate. Here we examine the history of the western margin of the European Ice Sheet, from 34 to 15 cal ka BP, and use a combination of modelling and proxy evidence to explore the impact on the North Atlantic of the fresh water and iceberg injections that accompanied phases of retreat of the marine sector of the NW European Ice Sheet. We find that the lack of geographical synchronicity in the responses of the different components of the 3000 km long sector meant that the scale of the climate consequences of ice discharge most likely remained regional, except during the final deglaciation phase, around 17-15 cal ka BP. At this time, as the later component of the recently introduced concept of an extended Heinrich event H1, both proxy and modelling evidence suggest rapid sector collapse led to partial shut-down of the Atlantic overturning and a basin-wide cooling., AuthorCount:8

Isotope effects associated with gas phase N2 photolysis are used to interpret Martian atmospheric evolution, icy satellite atmospheric chemistry and meteorite isotopic anomalies from nebular N2 photochemistry. To interpret observations at the highest level, fundamental understanding of the precise wavelength dependency of the process must be known. In this paper VUV isotopic photodissociation effects are calculated as a function of wavelength at different wavelength slices in the 12.5-15 eV range. A very strong wavelength dependence is observed, which is significant for experiments. An observable effect is possible for the width of the beam profile at the advanced light source, ALS that may produce sufficient photolysis product for high precision isotopic analysis. A significantly more pronounced effect is predicted for a beam narrower by a factor of four providing a potential experimental test of the model. The spectrum is computed ab initio. It manifests two physical mechanisms for the isotope effect and they can be discriminated using a narrow beam. The fractionation is larger for the rarer heaviest isotopomer 15N15N and half as large for 15N14N., Comment: 10 pages, 3 figures, 22 references

Isotope effects associated with gas phase N2 photolysis are used to interpret Martian atmospheric evolution, icy satellite atmospheric chemistry and meteorite isotopic anomalies from nebular N2 photochemistry. To interpret observations at the highest level, fundamental understanding of the precise wavelength dependency of the process must be known. In this paper VUV isotopic photodissociation effects are calculated as a function of wavelength at different wavelength slices in the 12.5-15 eV range. A very strong wavelength dependence is observed, which is significant for experiments. An observable effect is possible for the width of the beam profile at the advanced light source, ALS that may produce sufficient photolysis product for high precision isotopic analysis. A significantly more pronounced effect is predicted for a beam narrower by a factor of four providing a potential experimental test of the model. The spectrum is computed ab initio. It manifests two physical mechanisms for the isotope effect and they can be discriminated using a narrow beam. The fractionation is larger for the rarer heaviest isotopomer 15N15N and half as large for 15N14N., Comment: 10 pages, 3 figures, 22 references

The Atlantic-Mediterranean exchange of water at Gibraltar represents a significant heat and freshwater sink for the North Atlantic and is a major control on the heat, salt and freshwater budgets of the Mediterranean Sea. Consequently, an understanding of the response of the exchange system to external changes is vital to a full comprehension of the hydrographic responses in both ocean basins. Here, we use a synthesis of empirical (oxygen isotope, planktonic foraminiferal assemblage) and modeling (analytical and general circulation) approaches to investigate the response of the Gibraltar Exchange system to Atlantic freshening during Heinrich Stadials (HSs). HSs display relatively flat W-E surface hydrographic gradients more comparable to the Late Holocene than the Last Glacial Maximum. This is significant, as it implies a similar state of surface circulation during these periods and a different state during the Last Glacial Maximum. During HS1, the gradient may have collapsed altogether, implying very strong water column stratification and a single thermal and delta O-18(water) condition in surface water extending from southern Portugal to the eastern Alboran Sea. Together, these observations imply that inflow of Atlantic water into the Mediterranean was significantly increased during HS periods compared to background glacial conditions. Modeling efforts confirm that this is a predictable consequence of freshening North Atlantic surface water with iceberg meltwater and indicate that the enhanced exchange condition would last until the cessation of anomalous freshwater supply into to the northern North Atlantic. The close coupling of dynamics at Gibraltar Exchange with the Atlantic freshwater system provides an explanation for observations of increased Mediterranean Outflow activity during HS periods and also during the last deglaciation. This coupling is also significant to global ocean dynamics, as it causes density enhancement of the Atlantic water column via the G

The Atlantic-Mediterranean exchange of water at Gibraltar represents a significant heat and freshwater sink for the North Atlantic and is a major control on the heat, salt and freshwater budgets of the Mediterranean Sea. Consequently, an understanding of the response of the exchange system to external changes is vital to a full comprehension of the hydrographic responses in both ocean basins. Here, we use a synthesis of empirical (oxygen isotope, planktonic foraminiferal assemblage) and modeling (analytical and general circulation) approaches to investigate the response of the Gibraltar Exchange system to Atlantic freshening during Heinrich Stadials (HSs). HSs display relatively flat W-E surface hydrographic gradients more comparable to the Late Holocene than the Last Glacial Maximum. This is significant, as it implies a similar state of surface circulation during these periods and a different state during the Last Glacial Maximum. During HS1, the gradient may have collapsed altogether, implying very strong water column stratification and a single thermal and delta O-18(water) condition in surface water extending from southern Portugal to the eastern Alboran Sea. Together, these observations imply that inflow of Atlantic water into the Mediterranean was significantly increased during HS periods compared to background glacial conditions. Modeling efforts confirm that this is a predictable consequence of freshening North Atlantic surface water with iceberg meltwater and indicate that the enhanced exchange condition would last until the cessation of anomalous freshwater supply into to the northern North Atlantic. The close coupling of dynamics at Gibraltar Exchange with the Atlantic freshwater system provides an explanation for observations of increased Mediterranean Outflow activity during HS periods and also during the last deglaciation. This coupling is also significant to global ocean dynamics, as it causes density enhancement of the Atlantic water column via the G

The Atlantic‐Mediterranean exchange of water at Gibraltar represents a significant heat and freshwater sink for the North Atlantic and is a major control on the heat, salt and freshwater budgets of the Mediterranean Sea. Consequently, an understanding of the response of the exchange system to external changes is vital to a full comprehension of the hydrographic responses in both ocean basins. Here, we use a synthesis of empirical (oxygen isotope, planktonic foraminiferal assemblage) and modeling (analytical and general circulation) approaches to investigate the response of the Gibraltar Exchange system to Atlantic freshening during Heinrich Stadials (HSs). HSs display relatively flat W–E surface hydrographic gradients more comparable to the Late Holocene than the Last Glacial Maximum. This is significant, as it implies a similar state of surface circulation during these periods and a different state during the Last Glacial Maximum. During HS1, the gradient may have collapsed altogether, implying very strong water column stratification and a single thermal and d18Owater condition in surface water extending from southern Portugal to the eastern Alboran Sea. Together, these observations imply that inflow of Atlantic water into the Mediterranean was significantly increased during HS periods compared to background glacial conditions. Modeling efforts confirm that this is a predictable consequence of freshening North Atlantic surface water with iceberg meltwater and indicate that the enhanced exchange condition would last until the cessation of anomalous freshwater supply into to the northern North Atlantic. The close coupling of dynamics at Gibraltar Exchange with the Atlantic freshwater system provides an explanation for observations of increased Mediterranean Outflow activity during HS periods and also during the last deglaciation. This coupling is also significant to global ocean dynamics, as it causes density enhancement of the Atlantic water column via the Gibraltar

The Atlantic-Mediterranean exchange of water at Gibraltar represents a significant heat and freshwater sink for the North Atlantic and is a major control on the heat, salt and freshwater budgets of the Mediterranean Sea. Consequently, an understanding of the response of the exchange system to external changes is vital to a full comprehension of the hydrographic responses in both ocean basins. Here, we use a synthesis of empirical (oxygen isotope, planktonic foraminiferal assemblage) and modeling (analytical and general circulation) approaches to investigate the response of the Gibraltar Exchange system to Atlantic freshening during Heinrich Stadials (HSs). HSs display relatively flat W-E surface hydrographic gradients more comparable to the Late Holocene than the Last Glacial Maximum. This is significant, as it implies a similar state of surface circulation during these periods and a different state during the Last Glacial Maximum. During HS1, the gradient may have collapsed altogether, implying very strong water column stratification and a single thermal and delta O-18(water) condition in surface water extending from southern Portugal to the eastern Alboran Sea. Together, these observations imply that inflow of Atlantic water into the Mediterranean was significantly increased during HS periods compared to background glacial conditions. Modeling efforts confirm that this is a predictable consequence of freshening North Atlantic surface water with iceberg meltwater and indicate that the enhanced exchange condition would last until the cessation of anomalous freshwater supply into to the northern North Atlantic. The close coupling of dynamics at Gibraltar Exchange with the Atlantic freshwater system provides an explanation for observations of increased Mediterranean Outflow activity during HS periods and also during the last deglaciation. This coupling is also significant to global ocean dynamics, as it causes density enhancement of the Atlantic water column via the G

The Atlantic‐Mediterranean exchange of water at Gibraltar represents a significant heat and freshwater sink for the North Atlantic and is a major control on the heat, salt and freshwater budgets of the Mediterranean Sea. Consequently, an understanding of the response of the exchange system to external changes is vital to a full comprehension of the hydrographic responses in both ocean basins. Here, we use a synthesis of empirical (oxygen isotope, planktonic foraminiferal assemblage) and modeling (analytical and general circulation) approaches to investigate the response of the Gibraltar Exchange system to Atlantic freshening during Heinrich Stadials (HSs). HSs display relatively flat W–E surface hydrographic gradients more comparable to the Late Holocene than the Last Glacial Maximum. This is significant, as it implies a similar state of surface circulation during these periods and a different state during the Last Glacial Maximum. During HS1, the gradient may have collapsed altogether, implying very strong water column stratification and a single thermal and d18Owater condition in surface water extending from southern Portugal to the eastern Alboran Sea. Together, these observations imply that inflow of Atlantic water into the Mediterranean was significantly increased during HS periods compared to background glacial conditions. Modeling efforts confirm that this is a predictable consequence of freshening North Atlantic surface water with iceberg meltwater and indicate that the enhanced exchange condition would last until the cessation of anomalous freshwater supply into to the northern North Atlantic. The close coupling of dynamics at Gibraltar Exchange with the Atlantic freshwater system provides an explanation for observations of increased Mediterranean Outflow activity during HS periods and also during the last deglaciation. This coupling is also significant to global ocean dynamics, as it causes density enhancement of the Atlantic water column via the Gibraltar

The Atlantic‐Mediterranean exchange of water at Gibraltar represents a significant heat and freshwater sink for the North Atlantic and is a major control on the heat, salt and freshwater budgets of the Mediterranean Sea. Consequently, an understanding of the response of the exchange system to external changes is vital to a full comprehension of the hydrographic responses in both ocean basins. Here, we use a synthesis of empirical (oxygen isotope, planktonic foraminiferal assemblage) and modeling (analytical and general circulation) approaches to investigate the response of the Gibraltar Exchange system to Atlantic freshening during Heinrich Stadials (HSs). HSs display relatively flat W–E surface hydrographic gradients more comparable to the Late Holocene than the Last Glacial Maximum. This is significant, as it implies a similar state of surface circulation during these periods and a different state during the Last Glacial Maximum. During HS1, the gradient may have collapsed altogether, implying very strong water column stratification and a single thermal and d18Owater condition in surface water extending from southern Portugal to the eastern Alboran Sea. Together, these observations imply that inflow of Atlantic water into the Mediterranean was significantly increased during HS periods compared to background glacial conditions. Modeling efforts confirm that this is a predictable consequence of freshening North Atlantic surface water with iceberg meltwater and indicate that the enhanced exchange condition would last until the cessation of anomalous freshwater supply into to the northern North Atlantic. The close coupling of dynamics at Gibraltar Exchange with the Atlantic freshwater system provides an explanation for observations of increased Mediterranean Outflow activity during HS periods and also during the last deglaciation. This coupling is also significant to global ocean dynamics, as it causes density enhancement of the Atlantic water column via the Gibraltar

The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.

We assess the impact of bank deregulation on the distribution of income in the United States. From the 1970s through the 1990s, most states removed restrictions on intrastate branching, which intensified bank competition and improved bank performance. Exploiting the cross-state, cross-time variation in the timing of branch deregulation, we find that deregulation materially tightened the distribution of income by boosting incomes in the lower part of the income distribution while having little impact on incomes above the median. The results suggest that regulatory impediment to competition among banks during the 20th century were disproportionally harmful to lower income workers.

Acute megakaryoblastic leukemia (AMKL) is a form of acute myeloid leukemia (AML) associated with a poor prognosis. The genetics and pathophysiology of AMKL are not well understood. We generated a knockin mouse model of the one twenty-two-megakaryocytic acute leukemia (OTT-MAL) fusion oncogene that results from the t(1;22)(p13;q13) translocation specifically associated with a subtype of pediatric AMKL. We report here that OTT-MAL expression deregulated transcriptional activity of the canonical Notch signaling pathway transcription factor recombination signal binding protein for immunoglobulin kappa J region (RBPJ) and caused abnormal fetal megakaryopoiesis. Furthermore, cooperation between OTT-MAL and an activating mutation of the thrombopoietin receptor myeloproliferative leukemia virus oncogene (MPL) efficiently induced a short-latency AMKL that recapitulated all the features of human AMKL, including megakaryoblast hyperproliferation and maturation block, thrombocytopenia, organomegaly, and extensive fibrosis. Our results establish that concomitant activation of RBPJ (Notch signaling) and MPL (cytokine signaling) transforms cells of the megakaryocytic lineage and suggest that specific targeting of these pathways could be of therapeutic value for human AMKL.

Although research shows that financial development accelerates aggregate economic growth, economists have not resolved conflicting theoretical predictions and ongoing policy disputes about the cross-firm distributional effects of financial development. Using cross-industry, cross-country data, the results are consistent with the view that financial development exerts a disproportionately positive effect on small firms. These results have implications for understanding the political economy of financial sector reform.

By studying intrastate branch banking reform in the United States, this paper provides evidence that financial markets substantively influence the distribution of income. From the 1970s through the 1990s, most states removed restrictions on intrastate branching, which intensified bank competition and improved efficiency. Exploiting the cross-state, cross-time variation in the timing of bank deregulation, we evaluate the impact of liberalizing intrastate branching restrictions on the distribution of income. We find that branch deregulation significantly reduced income inequality by boosting the incomes of lower income workers. The reduction in income inequality is fully accounted for by a reduction in earnings inequality among salaried workers.

Conduction spectroscopy measures the current I through a nanosystem as a function of the voltage V between two electrodes. The differential conductance, dI/dV, has peaks that can be assigned to resonance conditions with different electronic levels of the system. Between these increments, the current has roughly constant plateaus. We discuss how measurements of the current vs. voltage can be used to perform Boolean operations and hence construct finite state logic machines and combinational circuits. The inputs to the device are the source–drain voltage, including its sign, and a gate voltage applied in a manner analogous to optical Stark spectroscopy. As simple examples, we describe a two-state set–reset machine (a machine whose output depends on the input and also on its present state) and a full adder circuit (a circuit that requires three inputs and provides two outputs).

Conduction spectroscopy measures the current I through a nanosystem as a function of the voltage V between two electrodes. The differential conductance, dI/dV, has peaks that can be assigned to resonance conditions with different electronic levels of the system. Between these increments, the current has roughly constant plateaus. We discuss how measurements of the current vs. voltage can be used to perform Boolean operations and hence construct finite state logic machines and combinational circuits. The inputs to the device are the source–drain voltage, including its sign, and a gate voltage applied in a manner analogous to optical Stark spectroscopy. As simple examples, we describe a two-state set–reset machine (a machine whose output depends on the input and also on its present state) and a full adder circuit (a circuit that requires three inputs and provides two outputs).

Two experiments exploring the effects of social category membership on real-life helping behavior are reported. In Study 1, intergroup rivalries between soccer fans are used to examine the role of identity in emergency helping. An injured stranger wearing an in-group team shirt is more likely to be helped than when wearing a rival team shirt or an unbranded sports shirt. In Study 2, a more inclusive social categorization is made salient for potential helpers. Helping is extended to those who were previously identified as out-group members but not to those who do not display signs of group membership. Taken together, the studies show the importance of both shared identity between bystander and victim and the inclusiveness of salient identity for increasing the likelihood of emergency intervention.

Two experiments exploring the effects of social category membership on real-life helping behavior are reported. In Study 1, intergroup rivalries between soccer fans are used to examine the role of identity in emergency helping. An injured stranger wearing an in-group team shirt is more likely to be helped than when wearing a rival team shirt or an unbranded sports shirt. In Study 2, a more inclusive social categorization is made salient for potential helpers. Helping is extended to those who were previously identified as out-group members but not to those who do not display signs of group membership. Taken together, the studies show the importance of both shared identity between bystander and victim and the inclusiveness of salient identity for increasing the likelihood of emergency intervention.

In T-cell acute lymphoblastic leukemia (T-ALL), transcription factors are known to be deregulated by chromosomal translocations, but mutations in protein tyrosine kinases have only rarely been identified(1-3). Here we describe the extrachromosomal (episomal)(4) amplification of ABL1 in 5 of 90 (5.6%) individuals with T-ALL, an aberration that is not detectable by conventional cytogenetics. Molecular analyses delineated the amplicon as a 500-kb region from chromosome band 9q34, containing the oncogenes ABL1 and NUP214 (refs.(5,6)). We identified a previously undescribed mechanism for activation of tyrosine kinases in cancer: the formation of episomes resulting in a fusion between NUP214 and ABL1. We detected the NUP214-ABL1 transcript in five individuals with the ABL1 amplification, in 5 of 85 (5.8%) additional individuals with T-ALL and in 3 of 22 T-ALL cell lines. The constitutively phosphorylated tyrosine kinase NUP214-ABL1 is sensitive to the tyrosine kinase inhibitor imatinib(7,8). The recurrent cryptic NUP214-ABL1 rearrangement is associated with increased HOX expression(1) and deletion of CDKN2A(9), consistent with a multistep pathogenesis of T-ALL. NUP214-ABL1 expression defines a new subgroup of individuals with T-ALL who could benefit from treatment with imatinib.

In T-cell acute lymphoblastic leukemia (T-ALL), transcription factors are known to be deregulated by chromosomal translocations, but mutations in protein tyrosine kinases have only rarely been identified. Here we describe the extrachromosomal (episomal) amplification of ABL1 in 5 of 90 (5.6%) individuals with T-ALL, an aberration that is not detectable by conventional cytogenetics. Molecular analyses delineated the amplicon as a 500-kb region from chromosome band 9q34, containing the oncogenes ABL1 and NUP214 (refs. 5,6). We identified a previously undescribed mechanism for activation of tyrosine kinases in cancer: the formation of episomes resulting in a fusion between NUP214 and ABL1. We detected the NUP214-ABL1 transcript in five individuals with the ABL1 amplification, in 5 of 85 (5.8%) additional individuals with T-ALL and in 3 of 22 T-ALL cell lines. The constitutively phosphorylated tyrosine kinase NUP214-ABL1 is sensitive to the tyrosine kinase inhibitor imatinib. The recurrent cryptic NUP214-ABL1 rearrangement is associated with increased HOX expression and deletion of CDKN2A, consistent with a multistep pathogenesis of T-ALL. NUP214-ABL1 expression defines a new subgroup of individuals with T-ALL who could benefit from treatment with imatinib., Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S., SCOPUS: ar.j, info:eu-repo/semantics/published

In T-cell acute lymphoblastic leukemia (T-ALL), transcription factors are known to be deregulated by chromosomal translocations, but mutations in protein tyrosine kinases have only rarely been identified. Here we describe the extrachromosomal (episomal) amplification of ABL1 in 5 of 90 (5.6%) individuals with T-ALL, an aberration that is not detectable by conventional cytogenetics. Molecular analyses delineated the amplicon as a 500-kb region from chromosome band 9q34, containing the oncogenes ABL1 and NUP214 (refs. 5,6). We identified a previously undescribed mechanism for activation of tyrosine kinases in cancer: the formation of episomes resulting in a fusion between NUP214 and ABL1. We detected the NUP214-ABL1 transcript in five individuals with the ABL1 amplification, in 5 of 85 (5.8%) additional individuals with T-ALL and in 3 of 22 T-ALL cell lines. The constitutively phosphorylated tyrosine kinase NUP214-ABL1 is sensitive to the tyrosine kinase inhibitor imatinib. The recurrent cryptic NUP214-ABL1 rearrangement is associated with increased HOX expression and deletion of CDKN2A, consistent with a multistep pathogenesis of T-ALL. NUP214-ABL1 expression defines a new subgroup of individuals with T-ALL who could benefit from treatment with imatinib., Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S., SCOPUS: ar.j, info:eu-repo/semantics/published

This paper begins by problematizing the `taken for granted' status of Newtonian linear time at the heart of (social) psychology. Borrowing from Adam, the paper makes a distinction between an `events in time' and `time in events' approach to social psychology. It argues that a `time in events' approach helps to reveal the importance of multiple times for social psychological theories and practices. To demonstrate this approach, it considers some of the multiple times that are relevant for analysing the concept of `identity'. It also explores the multiple times of the research encounter. In doing so, it suggests that traditional dichotomies in social psychology between synchronic and diachronic methods, and between experimental and qualitative methods, can be dissolved by this focus on the temporal. The paper concludes with some observations about the importance of time for thinking about social psychology as a knowledge-producing practice.

This paper begins by problematizing the `taken for granted' status of Newtonian linear time at the heart of (social) psychology. Borrowing from Adam, the paper makes a distinction between an `events in time' and `time in events' approach to social psychology. It argues that a `time in events' approach helps to reveal the importance of multiple times for social psychological theories and practices. To demonstrate this approach, it considers some of the multiple times that are relevant for analysing the concept of `identity'. It also explores the multiple times of the research encounter. In doing so, it suggests that traditional dichotomies in social psychology between synchronic and diachronic methods, and between experimental and qualitative methods, can be dissolved by this focus on the temporal. The paper concludes with some observations about the importance of time for thinking about social psychology as a knowledge-producing practice.

This perspective examines quantum dot (QD) superlattices as model systems for achieving a general understanding of the electronic structure of solids and devices built from nanoscale components. QD arrays are artificial two-dimensional solids, with novel optical and electric properties, which can be experimentally tuned. The control of the properties is primarily by means of the selection of the composition and size of the individual QDs and secondly, through their packing. The freedom of the architectural design is constrained by nature insisting on diversity. Even the best synthesis and separation methods do not yield dots of exactly the same size nor is the packing in the self-assembled array perfectly regular. A series of experiments, using both spectroscopic and electrical probes, has characterized the effects of disorder for arrays of metallic dots. We review these results and the corresponding theory. In particular, we discuss temperature-dependent transport experiments as the next step in the characterization of these arrays.

This perspective examines quantum dot (QD) superlattices as model systems for achieving a general understanding of the electronic structure of solids and devices built from nanoscale components. QD arrays are artificial two-dimensional solids, with novel optical and electric properties, which can be experimentally tuned. The control of the properties is primarily by means of the selection of the composition and size of the individual QDs and secondly, through their packing. The freedom of the architectural design is constrained by nature insisting on diversity. Even the best synthesis and separation methods do not yield dots of exactly the same size nor is the packing in the self-assembled array perfectly regular. A series of experiments, using both spectroscopic and electrical probes, has characterized the effects of disorder for arrays of metallic dots. We review these results and the corresponding theory. In particular, we discuss temperature-dependent transport experiments as the next step in the characterization of these arrays.

Research established that the organic material of the coccoliths consists of proteins, glycoproteins, and polysaccharides are found in preparations of isolated coccoliths. It was determined that the organic material affects crystal nucleation, post-nucleation crystal growth, and the architecture of the crystals. Results were obtained by light and scanning electron microscopy. It was determined that the coccoliths organic material contains to a-binding proteins and to isolated and purify the proteins. We demonstrated that these protein have specific effects of the growth and form of crystals formed in solution as determined by a combination of light and scanning electron microscopy and atomic force microscopy.

Bystander apathy is a long established phenomenon in social psychology which has yet to be translated into practical strategies for increasing bystander intervention. This paper argues that the traditional paradigm is hampered by a focus on the physical co-presence of others rather than an analysis of the social meanings inherent in (non) intervention. The testimony provided by 38 bystanders at the trial of two ten year old boys for the murder of two and a half year old James Bulger is analysed. It is argued that their failure to intervene can be attributed to the fact that they assumed - or were told - that the three boys were brothers. The way in which this category of ‘ the family’ served to prohibit or deflect intervention is analysed. This approach is contrasted with a traditional bystander apathy account of the bystanders actions in the Bulger case. It is argued that bystander (non) intervention phenomenon should be analysed in terms of the construction of social categories in local contexts.

Objectives: This paper describes two experiments which develop a Self Categorisation Theory (SCT) (Turner, Hogg, Oakes, Reicher and Wetherell 1987) approach to the way people make sense of their symptoms. The first experiment builds upon a study by Levine and Reicher (1996) in which it is proposed that symptoms are evaluated, not against preexisting illness representations, but by reference to their impact on situationally salient identities. The second experiment extends the SCT perspective on symptom evaluation to argue that the identities that are instrumental in assigning meaning to symptoms are themselves situationally constructed. Design and Methods: In the first experiment 40 female secretaries, defined either in terms of a ‘secretary’ identity or in terms of a ‘gender’ identity, were asked to evaluate a number of scenarios which describe different illnesses or injuries. In the second experiment 40 men from a rugby club were asked to evaluate a number of scenarios relating to illness and injuries. The identity from which scenarios were evaluated was held constant, but the comparison groups (or frame of reference) was manipulated. Results: Overall, the results of the first study provide clear evidence that the significance ascribed to scenarios depends on which identity is salient. The results from the second study provide clear evidence that the significance ascribed by male subjects to the scenarios was a function of the comparison groups they believed they were being compared to. Conclusions: Taken together, these two experiments provide strong evidence for the viability of an SCT approach to symptom evaluation.

Objectives: This paper describes two experiments which develop a Self Categorisation Theory (SCT) (Turner, Hogg, Oakes, Reicher and Wetherell 1987) approach to the way people make sense of their symptoms. The first experiment builds upon a study by Levine and Reicher (1996) in which it is proposed that symptoms are evaluated, not against preexisting illness representations, but by reference to their impact on situationally salient identities. The second experiment extends the SCT perspective on symptom evaluation to argue that the identities that are instrumental in assigning meaning to symptoms are themselves situationally constructed. Design and Methods: In the first experiment 40 female secretaries, defined either in terms of a ‘secretary’ identity or in terms of a ‘gender’ identity, were asked to evaluate a number of scenarios which describe different illnesses or injuries. In the second experiment 40 men from a rugby club were asked to evaluate a number of scenarios relating to illness and injuries. The identity from which scenarios were evaluated was held constant, but the comparison groups (or frame of reference) was manipulated. Results: Overall, the results of the first study provide clear evidence that the significance ascribed to scenarios depends on which identity is salient. The results from the second study provide clear evidence that the significance ascribed by male subjects to the scenarios was a function of the comparison groups they believed they were being compared to. Conclusions: Taken together, these two experiments provide strong evidence for the viability of an SCT approach to symptom evaluation.