Strategiskt beslutsfattande vid påtvingade förändringar - en fallstudie av studentnationerna i Lund

En kvalitativ fallstudie där syftet har varit att undersöka hur tjänsteorganisationer i stabila miljöer strategiskt hanterar en omvälvande extern förändring och vilka problem de ställs inför i samband med detta

The value of a common approach to lean

Thesis (S.M.)--Massachusetts Institute of Technology, Sloan School of Management; and, (S.M.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering; in conjunction with the Leaders for Manufacturing Program at MIT, 2004.Includes bibliographical references (p. 83-84).ABB is a world leader in power and automation technologies working to enable utility and industry customers to improve operations. Competition in these markets is increasing and in order to retain their competitive position, ABB must strive to improve their operations by reducing costs and delivery times. Most ABB factories still operate on push principles with long throughput time, high inventories, and high overhead In order to remain competitive these factories have decided to transform their businesses reduce costs and increase speed. The strategy to achieve this in the power technologies distribution transformer (PTDT) factories is to develop a standard approach to lean manufacturing for implementation in factories around the world. The thesis will describe standard approaches to lean proposed by academics and used by other leading companies; analyzing at the frameworks used including implementation practices, tools, and results. With an understanding of how other companies implement lean manufacturing techniques, this thesis will then describe the creation of a standard approach to lean for ABB PTDT factories, examining the methodology of the approach including the implementation process, common production practices, tools used, and evaluation techniques. Two case studies will be used to describe the implementation of these lean manufacturing techniques at the Monselice, Italy and Zaragoza, Spain factories. Using the Monselice and Zaragoza case studies, along with results seen by other companies, this thesis will analyze the benefits of a standard approach to lean as it relates to the creation of a corporate culture; improvements in implementation results, and increasing ease of implementation.by Michelle Elisabeth Bernson.S.M

Graphene oxide sheets and quantum dots inhibit alpha-synuclein amyloid formation by different mechanisms

Aggregation and amyloid formation of the 140-residue presynaptic and intrinsically disordered protein alpha-synuclein (alpha-syn) is a pathological hallmark of Parkinson\u27s disease (PD). Understanding how alpha-syn forms amyloid fibrils, and investigations of agents that can prevent their formation is therefore important. We demonstrate herein that two types of graphene oxide nanoparticles (sheets and quantum dots) inhibit alpha-syn amyloid formation by different mechanisms mediatedviadifferential interactions with both monomers and fibrils. We have used thioflavin-T fluorescence assays and kinetic analysis, circular dichroism, dynamic light scattering, fluorescence spectroscopy and atomic force microscopy to asses the kinetic nature and efficiency of this inhibitory effect. We show that the two types of graphene oxide nanoparticles alter the morphology of alpha-syn fibrils, disrupting their interfilament assembly and the resulting aggregates therefore consist of single protofilaments. Our results further show that graphene oxide sheets reduce the aggregation rate of alpha-syn primarily by sequestering of monomers, thereby preventing primary nucleation and elongation. Graphene quantum dots, on the other hand, interact less avidly with both monomers and fibrils. Their aggregation inhibitory effect is primarily related to adsorption of aggregated species and reduction of secondary processes, and they can thus not fully prevent aggregation. This fine-tuned and differential effect of graphene nanoparticles on amyloid formation shows that rational design of these nanomaterials has great potential in engineering materials that interact with specific molecular events in the amyloid fibril formation process. The findings also provide new insight into the molecular interplay between amyloidogenic proteins and graphene-based nanomaterials in general, and opens up their potential use as agents to manipulate fibril formation

Impact of killer-immunoglobulin-like receptor and human leukocyte antigen genotypes on the efficacy of immunotherapy in acute myeloid leukemia

Interactions between killer-immunoglobulin-like receptors (KIRs) and their HLA class I ligands are instrumental in natural killer (NK) cell regulation and protect normal tissue from NK cell attack. Human KIR haplotypes comprise genes encoding mainly inhibitory receptors (KIR A) or activating and inhibitory receptors (KIR B). A substantial fraction of humans lack ligands for inhibitory KIRs (iKIRs), that is, a 'missing ligand' genotype. KIR B/x and missing ligand genotypes may thus give rise to potentially autoreactive, unlicensed NK cells. Little is known regarding the impact of such genotypes in untransplanted acute myeloid leukemia (AML). For this study, NK cell phenotypes and KIR/HLA genotypes were determined in 81 AML patients who received immunotherapy with histamine dihydrochloride and low-dose IL-2 for relapse prevention (NCT01347996). We observed that presence of unlicensed NK cells impacted favorably on clinical outcome, in particular among patients harboring functional NK cells reflected by high expression of the natural cytotoxicity receptor (NCR) NKp46. Genotype analyses suggested that the clinical benefit of high NCR expression was restricted to patients with a missing ligand genotype and/or a KIR B/x genotype. These data imply that functional NK cells are significant anti-leukemic effector cells in patients with KIR/HLA genotypes that favor NK cell autoreactivity

Redox-Dependent Copper Ion Modulation of Amyloid-β (1-42) Aggregation In Vitro

Plaque deposits composed of amyloid-β (Aβ) fibrils are pathological hallmarks of Alzheimer’s disease (AD). Although copper ion dyshomeostasis is apparent in AD brains and copper ions are found co-deposited with Aβ peptides in patients’ plaques, the molecular effects of copper ion interactions and redox-state dependence on Aβ aggregation remain elusive. By combining biophysical and theoretical approaches, we here show that Cu2+\ua0(oxidized) and Cu+\ua0(reduced) ions have opposite effects on the assembly kinetics of recombinant Aβ(1-42) into amyloid fibrils in vitro. Cu2+\ua0inhibits both the unseeded and seeded aggregation of Aβ(1-42) at pH 8.0. Using mathematical models to fit the kinetic data, we find that Cu2+\ua0prevents fibril elongation. The Cu2+-mediated inhibition of Aβ aggregation shows the largest effect around pH 6.0 but is lost at pH 5.0, which corresponds to the pH in lysosomes. In contrast to Cu2+, Cu+\ua0ion binding mildly catalyzes the Aβ(1-42) aggregation via a mechanism that accelerates primary nucleation, possibly via the formation of Cu+-bridged Aβ(1-42) dimers. Taken together, our study emphasizes redox-dependent copper ion effects on Aβ(1-42) aggregation and thereby provides further knowledge of putative copper-dependent mechanisms resulting in AD

Amyloid formation of fish β-parvalbumin involves primary nucleation triggered by disulfide-bridged protein dimers

Amyloid formation involves the conversion of soluble protein species to an aggregated state. Amyloid fibrils of β-parvalbumin, a protein abundant in fish, act as an allergen but also inhibit the in vitro assembly of the Parkinson protein α-synuclein. However, the intrinsic aggregation mechanism of β-parvalbumin has not yet been elucidated. We performed biophysical experiments in combination with mathematical modeling of aggregation kinetics and discovered that the aggregation of β-parvalbumin is initiated by the formation of dimers stabilized by disulfide bonds and then proceeds via primary nucleation and fibril elongation processes. Dimer formation is accelerated by H2O2 and hindered by reducing agents, resulting in faster and slower aggregation rates, respectively. Purified β-parvalbumin dimers readily assemble into amyloid fibrils with similar morphology as those formed when starting from monomer solutions. Furthermore, addition of preformed dimers accelerates the aggregation reaction of monomers. Aggregation of purified β-parvalbumin dimers follows the same kinetic mechanism as that of monomers, implying that the rate-limiting primary nucleus is larger than a dimer and/or involves structural conversion. Our findings demonstrate a folded protein system in which spontaneously formed intermolecular disulfide bonds initiate amyloid fibril formation by recruitment of monomers. This dimer-induced aggregation mechanism may be of relevance for human amyloid diseases in which oxidative stress is often an associated hallmark

Role of regulatory T cells in acute myeloid leukemia patients undergoing relapse-preventive immunotherapy

Regulatory T cells (Tregs) have been proposed to dampen functions of anti-neoplastic immune cells and thus promote cancer progression. In a phase IV trial (Re:Mission Trial, NCT01347996, http://www.clinicaltrials.gov ) 84 patients (age 18-79) with acute myeloid leukemia (AML) in first complete remission (CR) received ten consecutive 3-week cycles of immunotherapy with histamine dihydrochloride (HDC) and low-dose interleukin-2 (IL-2) to prevent relapse of leukemia in the post-consolidation phase. This study aimed at defining the features, function and dynamics of Foxp3+CD25highCD4+ Tregs during immunotherapy and to determine the potential impact of Tregs on relapse risk and survival. We observed a pronounced increase in Treg counts in peripheral blood during initial cycles of HDC/IL-2. The accumulating Tregs resembled thymic-derived natural Tregs (nTregs), showed augmented expression of CTLA-4 and suppressed the cell cycle proliferation of conventional T cells ex vivo. Relapse of AML was not prognosticated by Treg counts at onset of treatment or after the first cycle of immunotherapy. However, the magnitude of Treg induction was diminished in subsequent treatment cycles. Exploratory analyses implied that a reduced expansion of Tregs in later treatment cycles and a short Treg telomere length were significantly associated with a favorable clinical outcome. Our results suggest that immunotherapy with HDC/IL-2 in AML entails induction of immunosuppressive Tregs that may be targeted for improved anti-leukemic efficiency

Downregulation of HLA Class I Renders Inflammatory Neutrophils More Susceptible to NK Cell-Induced Apoptosis

Neutrophils are potent effector cells and contain a battery of harmful substances and degrading enzymes. A silent neutrophil death, i.e., apoptosis, is therefore of importance to avoid damage to the surrounding tissue and to enable termination of the acute inflammatory process. There is a pile of evidence supporting the role for pro-inflammatory cytokines in extending the life-span of neutrophils, but relatively few studies have been devoted to mechanisms actively driving apoptosis induction in neutrophils. We have previously demonstrated that natural killer (NK) cells can promote apoptosis in healthy neutrophils. In this study, we set out to investigate how neutrophil sensitivity to NK cell-mediated cytotoxicity is regulated under inflammatory conditions. Using in vitro-activated neutrophils and a human skin chamber model that allowed collection of in vivo-transmigrated neutrophils, we performed a comprehensive characterization of neutrophil expression of ligands to NK cell receptors. These studies revealed a dramatic downregulation of HLA class I molecules in inflammatory neutrophils, which was associated with an enhanced susceptibility to NK cell cytotoxicity. Collectively, our data shed light on the complex regulation of interactions between NK cells and neutrophils during an inflammatory response and provide further support for a role of NK cells in the resolution phase of inflammation

Opioid Overdoses Among High-Risk Medicaid Members: Healthcare Cost, Service Utilization, and Risk Factor Analysis

Research Objective: Identify risk factors associated with opioid overdoses among three high-risk populations of Medicaid members related to cost and service utilization. Study Design: Repeated cross-sectional study using five years of Massachusetts Medicaid (MassHealth) claims and state agency data. Population Studied: MassHealth members aged 11-64 years considered to be high-risk (homeless, unstably housed, and/or criminal justice-involved) and in need of support services, especially those with extensive behavioral health (BH) needs. These three populations were identified as being particularly vulnerable to non-fatal and/or fatal opioid overdoses. Principal Findings: MassHealth members who were both justice-involved and unstably housed were at much higher risk of an opioid overdose than the MassHealth population overall, especially those with a substance use disorder (SUD) or a serious mental illness (SMI). Experiencing both homelessness and justice involvement substantially compounded members’ non-fatal overdose risk, regardless of BH diagnosis. Co-occurring SUD/SMI was a key driver of high overdose prevalence, particularly among the justice-involved. Compared to MassHealth members in general, those with justice involvement and unstable housing had costs that were 50-65% higher; members who experienced homelessness had triple the costs. Healthcare service use both before and after an overdose was relatively low, including the timeframe between multiple non-fatal overdoses. In multivariate analyses, all three high-risk factors (i.e., populations) were significantly related to an increased opioid overdose risk after controlling for additional risk factors (BH diagnoses, chronic medical conditions, and demographic characteristics). Males and whites were more likely to have an opioid overdose; those with diabetes or hypertension were less likely. These results were similar when assessing various opioid overdose outcomes (non-fatal and/or fatal). Conclusions: These findings helped inform MassHealth’s understanding of its members’ experiences regarding medical and BH services, especially among high-risk populations with an opioid overdose. The identification of risk factors most predictive of a subsequent overdose may help address the needs of these high-risk groups. For most of the populations studied, prevalence of co-occurring BH diagnoses was much higher than MassHealth members in general and appeared to impact opioid overdose rates. Most members received services for 1-2 months in both the pre- and post-overdose periods; service use was relatively low in the year following a non-fatal overdose, suggesting retention was also low. Multivariate analyses consistently showed that gender and race were significantly associated with increased overdose risk. Implications for Policy or Practice: Understanding opioid overdose risk factors and identifying service utilization gaps and missed opportunities are important. As payment reforms evolve under the umbrella of accountable care organizations, BH community partnership models are key for collaborating with healthcare and social service providers, and community resources for care management, care coordination, and referrals to support services. Our study initially developed an in-depth descriptive analysis of individuals with SUD, SMI, or both identified as being at high risk for an opioid overdose. Understanding service trajectory and outcomes through additional analyses was critical for planning and prioritizing appropriate services. As payors are actively making decisions about effective systems of care, they are particularly interested in understanding the need for community-based and residential services, particularly for those with housing instability and/or criminal justice involvement