39 research outputs found

    Logistik: Hur pÄverkar Just-In-Time pÄ lönsamheten av ett företag?

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    Ett företag har som grunduppgift att hÄllas verksamt genom att ekonomiskt prestera bÀttre för varje Är. Logistik Àr det verksamhetsomrÄde som stÄr för majoriteten av ett företags kostnader. Kostnader i sig Àr en dÄlig sak för företag, men det Àr Àven en möjlighet för logistiken att sÀnka dessa kostnader, vilket i sin tur Àr bra för företagets lön-samhet. Just-In-Time (JIT) Àr en produktions- och styrfilosofi inom logistiken, dÀr det huvudsakliga mÄlet Àr att minska lagernivÄerna och att eliminera allt onödigt. Syftet med denna studie Àr att finna ett samband mellan JIT och lönsamhet ur ett logistiskt perspektiv. Vid studien anvÀnds DuPont-modellen som definition av lönsamhet samt som ett jÀmförelseverktyg dÀr sex olika finansiella faktorer mÀts. Metoden för studien Àr kvalitativ i form av en litteraturstudie. Materialet som analyseras hÀmtas endast frÄn Arcadas databaser och analysen av materialet sker i form av innehÄllsanalys. Resultaten av materialet som analyserades Àr vÀldigt blandat. MÄnga studier pÄpekar att det rÄder brist pÄ forskning inom detta ÀmnesomrÄdet, vilket Àven kan vara orsaken till dessa blandade resultat. Det gÄr dock att urskilja tre finansiella mÄtt frÄn DuPont-modellen som pÄver-kas positivt av JIT. Dessa Àr: intÀkter, kostnader och lager. Ingen studie visade att JIT skulle ha negativ inverkan pÄ ett företags lönsamhet. Andra intressanta faktorer som JIT hade en positiv inverkan pÄ Àr operativa prestanda, t.ex. minskade ledtider

    Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

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    Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased AÎČ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

    Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by <i>HLA-DRB1*04</i> subtypes

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    Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased AÎČ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.</p

    Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

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    Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased AÎČ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

    Plos Med

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    Background The Δ4 allele of apolipoprotein E (APOE) gene and increasing age are two of the most important known risk factors for developing Alzheimer disease (AD). The diagnosis of AD based on clinical symptoms alone is known to have poor specificity; recently developed diagnostic criteria based on biomarkers that reflect underlying AD neuropathology allow better assessment of the strength of the associations of risk factors with AD. Accordingly, we examined the global and age-specific association between APOE genotype and AD by using the A/T/N classification, relying on the cerebrospinal fluid (CSF) levels of ÎČ-amyloid peptide (A, ÎČ-amyloid deposition), phosphorylated tau (T, pathologic tau), and total tau (N, neurodegeneration) to identify patients with AD. Methods and findings This case–control study included 1,593 white AD cases (55.4% women; mean age 72.8 [range = 44–96] years) with abnormal values of CSF biomarkers from nine European memory clinics and the American Alzheimer’s Disease Neuroimaging Initiative (ADNI) study. A total of 11,723 dementia-free controls (47.1% women; mean age 65.6 [range = 44–94] years) were drawn from two longitudinal cohort studies (Whitehall II and Three-City), in which incident cases of dementia over the follow-up were excluded from the control population. Odds ratio (OR) and population attributable fraction (PAF) for AD associated with APOE genotypes were determined, overall and by 5-year age categories. In total, 63.4% of patients with AD and 22.6% of population controls carried at least one APOE Δ4 allele. Compared with non-Δ4 carriers, heterozygous Δ4 carriers had a 4.6 (95% confidence interval 4.1–5.2; p < 0.001) and Δ4/Δ4 homozygotes a 25.4 (20.4–31.2; p < 0.001) higher OR of AD in unadjusted analysis. This association was modified by age (p for interaction < 0.001). The PAF associated with carrying at least one Δ4 allele was greatest in the 65–70 age group (69.7%) and weaker before 55 years (14.2%) and after 85 years (22.6%). The protective effect of APOE Δ2 allele for AD was unaffected by age. Main study limitations are that analyses were based on white individuals and AD cases were drawn from memory centers, which may not be representative of the general population of patients with AD. Conclusions In this study, we found that AD diagnosis based on biomarkers was associated with APOE Δ4 carrier status, with a higher OR than previously reported from studies based on only clinical AD criteria. This association differs according to age, with the strongest effect at 65–70 years. These findings highlight the need for early interventions for dementia prevention to mitigate the effect of APOE Δ4 at the population level

    Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

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    11 pĂĄginas, 4 figuras, 2 tablas. Datasets en su material suplementario. This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2302720120/-/DCSupplemental.Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased AÎČ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.This work was supported by the Michael J. Fox Foundation grant MJFF-020161 (E.M., Z.G.-O.), NIH and National Institute of Aging grants AG060747 (M.D.G.), AG066206 (Z.H.), AG066515 (Z.H., M.D.G.), the European Union’s Horizon 2020 research and innovation program under the Marie SkƂodowska-Curie (grant agreement No. 890650, Y.L.G.), the Alzheimer’s Association (AARF-20-683984, M.E.B.), and the Iqbal Farrukh and Asad Jamal Fund, a grant from the EU Joint Programme—Neurodegenerative Disease Research (European Alzheimer DNA BioBank, EADB; JPND), the Japan Agency for Medical Research and Development JP21dk0207045 (T.I.), JP21dk020704 (K.O., S.N.), JP21km040550 (K.O.), the Einstein Center for Neurosciences in Berlin (S.M.Y.), the Swedish Research Council (#2018-02532, H.Z.), the European Research Council (#681712, H.Z.), and the Swedish State Support for Clinical Research (#ALFGBG-720931, H.Z.). Inserm UMR1167 is also funded by the Inserm, Institut Pasteur de Lille, Lille MĂ©tropole CommunautĂ© Urbaine, and the French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD). Additional funders of individual investigators and institutions who contributed to data collection and genotyping are provided in SI Appendix.Peer reviewe

    Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

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    Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased AÎČ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

    IntĂ©rĂȘt de la crĂ©ation d'une unitĂ© post urgence au CHRU de Lille

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    LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

    Etude de peptides amyloïdogéniques dérivés de la tropoélastine humaine par simulations numériques

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    Ce travail de thÚse porte sur l étude de peptides dérivés de la tropoélastine par simulations de dynamique moléculaire en solvant explicite. Ces peptides sont issus des exons 7, 28 et 30 et possÚdent une séquence consensus XGGZG (X, Z = Valine, Leucine) identifiée expérimentalement comme responsable de la formation d assemblages supramoléculaire ayant des propriétés amyloïdes. Nous montrons tout d abord que le motif minimal XGGZG et (XGGZG) adoptent un grand nombre de coudes quel que soit la permutation entre valine et leucine et que localement les résidus non glycine présentent une conformation de type polyproline II dans des proportions significatives. L étude des répétitions (XGGZG)3 fait apparaßtre des structures allant du feuillet b antiparallÚle pour (VGGVG)3 à de l hélice a et 310 pour (LGGLG)3. Les répétitions (VGGLG) 3 et (LGGVG)3 donnent pour leur part à la fois des structures comportant de faibles proportions d hélices ou de feuillets. Des résultats équivalents sont obtenus sur les exons 28 et 30 entiers, ainsi que sur le peptide comprenant les 17 premier résidus de l exon 30. La création d un plancher poly(VGGVG) de brins b virtuellement infini nous permet de montrer qu en sa présence, des peptides VGGVG peuvent s organiser parallÚlement ou perpendiculairement à ce dernier. Enfin, es simulations préliminaires distinctes ont été menées afin d évaluer le rÎle du cholestérol dans les phénomÚnes d agrégation ou dynamiques des peptides dérivés de la tropélastine. Des études de l effet biologique des peptides ont été débutées et sont une perspectives intéressantes de ce travail.This work deals with the study of tropoelastin-derived peptides by molecular dynamics simulations in explicit solvent. These peptides are identified in exons 7, 28 and 30 possess a consensus sequence XGGZG (X, Z = Valine, Leucine) described experimentally as responsible for the formation of supramolecular assemblies with amyloid properties. We first show that the minimal motif XGGZG and (XGGZG) adopt a large number of turns, independently of the permutation of valine and leucine residues. Locally, non-glycine residues exhibit polyproline-II conformation in significant proportions. The study of (XGGZG)3 show that it gives rise to structure form antiparallel b sheets for (VGGVG)3 to a and 310 helices for (LGGLG)3. (VGGLG)3 and (LGGVG)3 sequences give rise to both structures in small proportions. Equivalent results are obtained on the entire exons 28 and 30, and the peptide including the first 17 residues of exon 30. The construction of a poly(VGGVG) plan with virtually infinite b strand allows us to show that in contact with it, VGGVG peptides can organize parallel or perpendicularly to the plan. Finally, separate preliminary simulations were conducted to evaluate the role of cholesterol in the phenomena of aggregation and dynamics to tropoelastin-derived peptides. Studies of the biological effect of these peptides were initiated and are an interesting perspective of this work.REIMS-BU Sciences (514542101) / SudocSudocFranceF

    Mesoscopic Rigid Body Modelling of the Extracellular Matrix Self-Assembly

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    The extracellular matrix (ECM) plays an important role in supporting tissues and organs. It even has a functional role in morphogenesis and differentiation by acting as a source of active molecules (matrikines). Many diseases are linked to dysfunction of ECM components and fragments or changes in their structures. As such it is a prime target for drugs. Because of technological limitations for observations at mesoscopic scales, the precise structural organisation of the ECM is not well-known, with sparse or fuzzy experimental observables. Based on the Unity3D game and physics engines, along with rigid body dynamics, we propose a virtual sandbox to model large biological molecules as dynamic chains of rigid bodies interacting together to gain insight into ECM components behaviour in the mesoscopic range. We have preliminary results showing how parameters such as fibre flexibility or the nature and number of interactions between molecules can induce different structures in the basement membrane. Using the Unity3D game engine and virtual reality headset coupled with haptic controllers, we immerse the user inside the corresponding simulation. Untrained users are able to navigate a complex virtual sandbox crowded with large biomolecules models in a matter of seconds
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