Sustainable change: long-term efforts toward developing a learning organization

Globalization and intensified competition require organizations to change and adapt to dynamic environments in order to stay competitive. This article describes a longitudinal action research study supporting the strategic change of a trading company. The strategic change was accompanied by planned changes in organizational structures and processes, management systems, emerging changes in leadership, and organization members’ attitudes and behaviors, and it was supported by management development activities. Longitudinal data over a 4-year period including participant observation and interviews reveal that a systemic approach, a learning and becoming perspective toward change, trust, an appropriate role perception, and the specific use of management instruments contribute to sustained change that resulted in performance improvements and a move toward a learning organization. We conclude with implications for strategic change and suggestions for further research in this area

Plasmonic excitations in noble metals: The case of Ag

The delicate interplay between plasmonic excitations and interband transitions in noble metals is described by means of {\it ab initio} calculations and a simple model in which the conduction electron plasmon is coupled to the continuum of electron-hole pairs. Band structure effects, specially the energy at which the excitation of the $d$-like bands takes place, determine the existence of a subthreshold plasmonic mode, which manifests itself in Ag as a sharp resonance at 3.8 eV. However, such a resonance is not observed in the other noble metals. Here, this different behavior is also analyzed and an explanation is provided.Comment: 9 pages, 8 figure

Exatidão dos dados do sistema de vigilância epidemiológica da malária no estado do Amazonas

The Epidemiological Surveillance System for Malaria (SIVEP-Malaria) is the Brazilian governmental program that registers all information about compulsory reporting of detected cases of malaria by all medical units and medical practitioners. The objective of this study is to point out the main sources of errors in the SIVEP-Malaria database by applying a data cleaning method to assist researchers about the best way to use it and to report the problems to authorities. The aim of this study was to assess the quality of the data collected by the surveillance system and its accuracy. The SIVEP-Malaria data base used was for the state of Amazonas, Brazil, with data collected from 2003 to 2014. A data cleaning method was applied to the database to detect and remove erroneous records. It was observed that the collecting procedure of the database is not homogeneous among the municipalities and over the years. Some of the variables had different data collection periods, missing data, outliers and inconsistencies. Variables depending on the health agents showed a good quality but those that rely on patients were often inaccurate. We showed that a punctilious preprocessing is needed to produce statistically correct data from the SIVEP-Malaria data base. Fine spatial scale and multi-temporal analysis are of particular concern due to the local concentration of uncertainties and the data collecting seasonality observed. This assessment should help to enhance the quality of studies and the monitoring of the use of the SIVEP database.O Sistema de Vigilância Epidemiológica de Malária (SIVEP-Malária) é um programa governamental brasileiro que arquiva automaticamente todas as informações sobre casos de malária registrados em todas as unidades de saúde e consultórios medicos. O objetivo deste estudo foi avaliar a qualidade dos dados coletados pelo sistema de vigilância e sua precisão. Foram utilizados os dados do SIVEP-Malária para o estado do Amazonas, Brasil, de 2003 a 2014. Um método de limpeza de dados foi aplicado para detectar e remover registros errôneos. Observamos que a coleta de dados não é homogênea entre os municipios e ao longo dos anos. Algumas variaveis tinham diferentes padrões de coleta, falta de dados, dados discrepantes e inconsistências. Dados que dependem do agente de saúde possuem boa qualidade mas aqueles que dependem dos pacientes são frequentemente imprecisos. Mostramos que um pre-processamento meticuloso é necessário para produzir dados estatisticamente corretos a partir do SIVEP-Malária. Analises em escala espacial detalhada ou multi-temporais são particularmente afetadas devido à concentração local de incertezas e a sazonalidade observada na coleta de dados. Esta avaliação deve auxiliar a melhorar os estudos e monitoramentos que fazem uso dos dados do SIVEP

CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice

Neuroinflammation and microglial activation are significant processes in Alzheimer's disease pathology. Recent genome-wide association studies have highlighted multiple immune-related genes in association with Alzheimer's disease, and experimental data have demonstrated microglial proliferation as a significant component of the neuropathology. In this study, we tested the efficacy of the selective CSF1R inhibitor JNJ-40346527 (JNJ-527) in the P301S mouse tauopathy model. We first demonstrated the anti-proliferative effects of JNJ-527 on microglia in the ME7 prion model, and its impact on the inflammatory profile, and provided potential CNS biomarkers for clinical investigation with the compound, including pharmacokinetic/pharmacodynamics and efficacy assessment by TSPO autoradiography and CSF proteomics. Then, we showed for the first time that blockade of microglial proliferation and modification of microglial phenotype leads to an attenuation of tau-induced neurodegeneration and results in functional improvement in P301S mice. Overall, this work strongly supports the potential for inhibition of CSF1R as a target for the treatment of Alzheimer's disease and other tau-mediated neurodegenerative diseases

The Public Repository of Xenografts enables discovery and randomized phase II-like trials in mice

More than 90% of drugs with preclinical activity fail in human trials, largely due to insufficient efficacy. We hypothesized that adequately powered trials of patient-derived xenografts (PDX) in mice could efficiently define therapeutic activity across heterogeneous tumors. To address this hypothesis, we established a large, publicly available repository of well-characterized leukemia and lymphoma PDXs that undergo orthotopic engraftment, called the Public Repository of Xenografts (PRoXe). PRoXe includes all de-identified information relevant to the primary specimens and the PDXs derived from them. Using this repository, we demonstrate that large studies of acute leukemia PDXs that mimic human randomized clinical trials can characterize drug efficacy and generate transcriptional, functional, and proteomic biomarkers in both treatment-naive and relapsed/refractory disease

Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Volume I. Introduction to DUNE

The preponderance of matter over antimatter in the early universe, the dynamics of the supernovae that produced the heavy elements necessary for life, and whether protons eventually decay—these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our universe, its current state, and its eventual fate. The Deep Underground Neutrino Experiment (DUNE) is an international world-class experiment dedicated to addressing these questions as it searches for leptonic charge-parity symmetry violation, stands ready to capture supernova neutrino bursts, and seeks to observe nucleon decay as a signature of a grand unified theory underlying the standard model. The DUNE far detector technical design report (TDR) describes the DUNE physics program and the technical designs of the single- and dual-phase DUNE liquid argon TPC far detector modules. This TDR is intended to justify the technical choices for the far detector that flow down from the high-level physics goals through requirements at all levels of the Project. Volume I contains an executive summary that introduces the DUNE science program, the far detector and the strategy for its modular designs, and the organization and management of the Project. The remainder of Volume I provides more detail on the science program that drives the choice of detector technologies and on the technologies themselves. It also introduces the designs for the DUNE near detector and the DUNE computing model, for which DUNE is planning design reports. Volume II of this TDR describes DUNE\u27s physics program in detail. Volume III describes the technical coordination required for the far detector design, construction, installation, and integration, and its organizational structure. Volume IV describes the single-phase far detector technology. A planned Volume V will describe the dual-phase technology

History of clinical transplantation

How transplantation came to be a clinical discipline can be pieced together by perusing two volumes of reminiscences collected by Paul I. Terasaki in 1991-1992 from many of the persons who were directly involved. One volume was devoted to the discovery of the major histocompatibility complex (MHC), with particular reference to the human leukocyte antigens (HLAs) that are widely used today for tissue matching.1 The other focused on milestones in the development of clinical transplantation.2 All the contributions described in both volumes can be traced back in one way or other to the demonstration in the mid-1940s by Peter Brian Medawar that the rejection of allografts is an immunological phenomenon.3,4 © 2008 Springer New York

Longitudinal analysis reveals that delayed bystander CD8+ T cell activation and early immune pathology distinguish severe COVID-19 from mild disease.

The kinetics of the immune changes in COVID-19 across severity groups have not been rigorously assessed. Using immunophenotyping, RNA sequencing and serum cytokine analysis, we analyzed serial samples from 207 SARS-CoV2-infected individuals with a range of disease severities over 12 weeks from symptom onset. An early robust bystander CD8+ T cell immune response, without systemic inflammation, characterized asymptomatic or mild disease. Hospitalized individuals had delayed bystander responses and systemic inflammation that was already evident near symptom onset, indicating that immunopathology may be inevitable in some individuals. Viral load did not correlate with this early pathological response, but did correlate with subsequent disease severity. Immune recovery is complex, with profound persistent cellular abnormalities in severe disease correlating with altered inflammatory responses, with signatures associated with increased oxidative phosphorylation replacing those driven by cytokines tumor necrosis factor (TNF) and interleukin (IL)- 6. These late immunometabolic and immune defects may have clinical implication