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1.	Klionsky, Daniel J, et al. (författare) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). 2016 Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 12:1, s. 1-222 Tidskriftsartikel (refereegranskat)
2.	Klionsky, Daniel J., et al. (författare) Guidelines for the use and interpretation of assays for monitoring autophagy 2012 Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544 Forskningsöversikt (refereegranskat)abstract In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
3.	Markovic, Slobodan B., et al. (författare) Danube loess stratigraphy - Towards a pan-European loess stratigraphic model 2015 Ingår i: Earth-Science Reviews. - : Elsevier BV. - 0012-8252 .- 1872-6828. ; 148, s. 228-258 Tidskriftsartikel (refereegranskat)abstract The Danube River drainage basin is the second largest river catchment in Europe and contains a significant and extensive region of thick loess deposits that preserve a record of a wide variety of recent and past environments. Indeed, the Danube River and tributaries may themselves be responsible for the transportation of large volumes of silt that ultimately drive loess formation in the middle and lower reaches of this large catchment However, this vast loess province lacks a unified stratigraphic scheme. European loess research started in the late 17th century in the Danube Basin with the work of Count Luigi Ferdinand Marsigli. Since that time numerous investigations provided the basis for the pioneering stratigraphic framework proposed initially by Kukla (1970, 1977) in his correlations of loess with deep-sea sediments. Loess-palaeosol sequences in the middle and lower reaches of the Danube River basin were a key part of this framework and contain some of the longest and most complete continental climate records in Europe, covering more than the last million years. However, the very size of the Danube loess belt and the large number of countries it covers presents a major limiting factor in developing a unified approach that enables continental scale analysis of the deposits. Local loess-palaeosol stratigraphic schemes have been defined separately in different countries and the difficulties in correlating such schemes, which often change significantly with advances in age-dating, have limited the number of basin-wide studies. A unified basin-wide stratigraphic model would greatly alleviate these difficulties and facilitate research into the wider significance of these loess records. Therefore we review the existing stratigraphic schemes and define a new Danube Basin wide loess stratigraphy based around a synthetic type section of the Mosorin and Stari Slankamen sites in Serbia. We present a detailed comparison with the sedimentological and palaeoclimatic records preserved in sediments of the Chinese Loess Plateau, with the oxygen isotope records from deep-sea sediments, and with classic European Pleistocene stratigraphic subdivisions. The hierarchy of Danubian stratigraphic units is determined by climatically controlled environmental shifts, in a similar way to the Chinese loess stratigraphic scheme. A new unified Danube loess stratigraphic model has a number of advantages, including preventing confusion resulting from the use of multiple national schemes, a more transparent basis, and the potential to set Pleistocene palaeoenvironmental changes recorded in the Danube catchment area into a global context. The use of a very simple labelling system based on the well-established Chinese loess scheme facilitates interpretation of palaeoenvironmental information reported from the Danube Basin loess sites in a wider more accessible context that can be readily correlated world-wide. This stratigraphic approach also provides, for the first time, an appropriate framework for the development of an integrated, pan-European and potentially pan-Eurasian loess stratigraphic scheme.
4.	Adori, Csaba, et al. (författare) Critical role of somatostatin receptor 2 in the vulnerability of the central noradrenergic system : new aspects on Alzheimer's disease 2015 Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 129:4, s. 541-563 Tidskriftsartikel (refereegranskat)abstract Alzheimer's disease and other age-related neurodegenerative disorders are associated with deterioration of the noradrenergic locus coeruleus (LC), a probable trigger for mood and memory dysfunction. LC noradrenergic neurons exhibit particularly high levels of somatostatin binding sites. This is noteworthy since cortical and hypothalamic somatostatin content is reduced in neurodegenerative pathologies. Yet a possible role of a somatostatin signal deficit in the maintenance of noradrenergic projections remains unknown. Here, we deployed tissue microarrays, immunohistochemistry, quantitative morphometry and mRNA profiling in a cohort of Alzheimer's and age-matched control brains in combination with genetic models of somatostatin receptor deficiency to establish causality between defunct somatostatin signalling and noradrenergic neurodegeneration. In Alzheimer's disease, we found significantly reduced somatostatin protein expression in the temporal cortex, with aberrant clustering and bulging of tyrosine hydroxylase-immunoreactive afferents. As such, somatostatin receptor 2 (SSTR2) mRNA was highly expressed in the human LC, with its levels significantly decreasing from Braak stages III/IV and onwards, i.e., a process preceding advanced Alzheimer's pathology. The loss of SSTR2 transcripts in the LC neurons appeared selective, since tyrosine hydroxylase, dopamine beta-hydroxylase, galanin or galanin receptor 3 mRNAs remained unchanged. We modeled these pathogenic changes in Sstr2 (-/-) mice and, unlike in Sstr1 (-/-) or Sstr4 (-/-) genotypes, they showed selective, global and progressive degeneration of their central noradrenergic projections. However, neuronal perikarya in the LC were found intact until late adulthood (< 8 months) in Sstr2 (-/-) mice. In contrast, the noradrenergic neurons in the superior cervical ganglion lacked SSTR2 and, as expected, the sympathetic innervation of the head region did not show any signs of degeneration. Our results indicate that SSTR2-mediated signaling is integral to the maintenance of central noradrenergic projections at the system level, and that early loss of somatostatin receptor 2 function may be associated with the selective vulnerability of the noradrenergic system in Alzheimer's disease.
5.	Adori, Csaba, et al. (författare) Neuropeptide S- and Neuropeptide S receptor-expressing neuron populations in the human pons 2015 Ingår i: Frontiers in Neuroanatomy. - : Frontiers Media SA. - 1662-5129. ; 9 Tidskriftsartikel (refereegranskat)abstract Neuropeptide S (NPS) is a regulatory peptide with potent pharmacological effects. In rodents, NPS is expressed in a few pontine cell clusters. Its receptor (NPSR1) is, however, widely distributed in the brain. The anxiolytic and arousal promoting effects of NPS make the NPS NPSR1 system an interesting potential drug target in mood-related disorders. However, so far possible disease-related mechanisms involving NPS have only been studied in rodents. To validate the relevance of these animal studies for i.a. drug development, we have explored the distribution of NPS-expressing neurons in the human pons using in situ hybridization and stereological methods and we compared the distribution of NPS mRNA expressing neurons in the human and rat brain. The calculation revealed a total number of 22,317 +/- 2411 NPS mRNA-positive neurons in human, bilaterally. The majority of cells (84%) were located in the parabrachial area in human: in the extension of the medial and lateral parabrachial nuclei, in the Kolliker-Fuse nucleus and around the adjacent lateral lemniscus. In human, in sharp contrast to the rodents, only very few NPS-positive cells (5%) were found close to the locus coeruleus. In addition, we identified a smaller cell cluster (11% of all NPS cells) in the pontine central gray matter both in human and rat, which has not been described previously even in rodents. We also examined the distribution of NPSR1 mRNA-expressing neurons in the human pons. These cells were mainly located in the rostral laterodorsal tegmental nucleus, the cuneiform nucleus, the microcellular tegmental nucleus region and in the periaqueductal gray. Our results show that both NPS and NPSR1 in the human pons are preferentially localized in regions of importance for integration of visceral autonomic information and emotional behavior. The reported interspecies differences must, however, be considered when looking for targets for new pharmacotherapeutical interventions.
6.	Aktaa, Suleman, et al. (författare) European Society of Cardiology quality indicators for the care and outcomes of adults with pulmonary arterial hypertension. Developed in collaboration with the Heart Failure Association of the European Society of Cardiology 2023 Ingår i: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 25:4, s. 469-477 Tidskriftsartikel (refereegranskat)abstract Aims: To develop a suite of quality indicators (QIs) for the evaluation of the care and outcomes for adults with pulmonary arterial hypertension (PAH). Methods and results: We followed the European Society of Cardiology (ESC) methodology for the development of QIs. This included (i) the identification of key domains of care for the management of PAH, (ii) the proposal of candidate QIs following systematic review of the literature, and (iii) the selection of a set of QIs using a modified Delphi method. The process was undertaken in parallel with the writing of the 2022 ESC/European Respiratory Society (ERS) guidelines for the diagnosis and treatment of pulmonary hypertension and involved the Task Force chairs, experts in PAH, Heart Failure Association (HFA) members and patient representatives. We identified five domains of care for patients with PAH: structural framework, diagnosis and risk stratification, initial treatment, follow-up, and outcomes. In total, 23 main and one secondary QIs for PAH were selected. Conclusion: This document presents the ESC QIs for PAH, describes their development process and offers scientific rationale for their selection. The indicators may be used to quantify and improve adherence to guideline-recommended clinical practice and improve patient outcomes.
7.	Alafuzoff, Irina, et al. (författare) Assessment of alpha-synuclein pathology : a study of the BrainNet Europe Consortium. 2008 Ingår i: Journal of Neuropathology and Experimental Neurology. - : Oxford University Press (OUP). - 0022-3069 .- 1554-6578. ; 67:2, s. 125-43 Tidskriftsartikel (refereegranskat)abstract To determine the reliability of assessment of alpha-synuclein-immunoreactive (alphaS-IR) structures by neuropathologists, 28 evaluators from 17 centers of BrainNet Europe examined current methods and reproducibility of alphaS-IR evaluation using a tissue microarray (TMA) technique. Tissue microarray blocks were constructed of samples from the participating centers that contained alphaS-IR structures. Slides from these blocks were stained in each center and assessed for neuronal perikaryal inclusions, neurites, and glial cytoplasmic inclusions. The study was performed in 2 phases. First, the TMA slides were stained with the antibody of the center's choice. In this phase, 59% of the sections were of good or acceptable quality, and 4 of 9 antibodies used performed consistently. Differences in interpretation and categorization of alphaS-IR structures, however, led to differing results between the laboratories. Prior to the second phase, the neuropathologists participated in a training session on the evaluation of alphaS-IR structures. Based on the results of the first phase, selected antibodies using designated antigen retrieval methods were then applied to TMA slides in the second phase. When the designated methods of both staining and evaluation were applied, all 26 subsequently stained TMA sections evaluated were of good/acceptable quality, and a high level of concordance in the assessment of the presence or absence of specific alphaS-IR structures was achieved. A semiquantitative assessment of alphaS-IR neuronal perikaryal inclusions yielded agreements ranging from 49% to 82%, with best concordance in cortical core samples. These results suggest that rigorous methodology and dichotomized assessment (i.e. determining the presence or absence of alphaS-IR) should be applied, and that semiquantitative assessment can be recommended only for the cortical samples. Moreover, the study demonstrates that there are limitations in the scoring of alphaS-IR structures.
8.	Alafuzoff, Irina, et al. (författare) Assessment of beta-amyloid deposits in human brain : a study of the BrainNet Europe Consortium 2009 Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 117:3, s. 309-320 Tidskriftsartikel (refereegranskat)abstract beta-Amyloid (A-beta) related pathology shows a range of lesions which differ both qualitatively and quantitatively. Pathologists, to date, mainly focused on the assessment of both of these aspects but attempts to correlate the findings with clinical phenotypes are not convincing. It has been recently proposed in the same way as iota and alpha synuclein related lesions, also A-beta related pathology may follow a temporal evolution, i.e. distinct phases, characterized by a step-wise involvement of different brain-regions. Twenty-six independent observers reached an 81% absolute agreement while assessing the phase of A-beta, i.e. phase 1 = deposition of A-beta exclusively in neocortex, phase 2 = additionally in allocortex, phase 3 = additionally in diencephalon, phase 4 = additionally in brainstem, and phase 5 = additionally in cerebellum. These high agreement rates were reached when at least six brain regions were evaluated. Likewise, a high agreement (93%) was reached while assessing the absence/presence of cerebral amyloid angiopathy (CAA) and the type of CAA (74%) while examining the six brain regions. Of note, most of observers failed to detect capillary CAA when it was only mild and focal and thus instead of type 1, type 2 CAA was diagnosed. In conclusion, a reliable assessment of A-beta phase and presence/absence of CAA was achieved by a total of 26 observers who examined a standardized set of blocks taken from only six anatomical regions, applying commercially available reagents and by assessing them as instructed. Thus, one may consider rating of A-beta-phases as a diagnostic tool while analyzing subjects with suspected Alzheimer's disease (AD). Because most of these blocks are currently routinely sampled by the majority of laboratories, assessment of the A-beta phase in AD is feasible even in large scale retrospective studies.
9.	Alafuzoff, Irina, et al. (författare) Comorbidities. 2017 Ingår i: Handbook of Clinical Neurology. - 0072-9752 .- 2212-4152. ; 145, s. 573-577 Tidskriftsartikel (refereegranskat)abstract The term comorbidities or mixed pathologies is used when brain tissue, a surgical sample, or postmortem brain displays a mixture of protein alterations or other pathologies. Most of the alterations when seen in sufficient extent are considered causative, are related to a certain clinical phenotype, i.e., when hyperphosphorylated τ (HPτ) is observed in occipital cortex concomitant with β-amyloid (Aβ), the diagnosis is Alzheimer disease (AD). When HPτ is observed in hippocampal structures in a subject with extensive and widespread α-synuclein pathology, a Lewy body disease (LBD), the HPτ pathology is considered as a concomitant alteration. There are numerous reports indicating that when "concomitant" pathologies are seen in a subject with certain neurodegenerative diseases, the clinical phenotype might be altered. In addition there are those cases where many alterations are seen in a sparse extent, but jointly they lead to a clinical syndrome. Thus today it is not sufficient to confirm a certain pathology to be seen, i.e., AD- or LBD-related; in addition the concomitant aging-related alterations have to be looked for.
10.	Alafuzoff, Irina, et al. (författare) Inter-laboratory comparison of neuropathological assessments of beta-amyloid protein : a study of the BrainNet Europe consortium. 2008 Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 115:5, s. 533-46 Tidskriftsartikel (refereegranskat)abstract Amyloid-beta-protein (Abeta) is generally assessed by neuropathologists in diagnostics. This BrainNet Europe ( http://www.brainnet-europe.org/ ) (15 centres and 26 participants) study was carried out to investigate the reliability of such an assessment. In the first part of this trial, tissue microarray sections were stained with the antibody of each centre's choice. Reflecting the reality, seven antibodies and a plethora of pretreatment strategies were used. Ninety-two percent of the stainings were of good/acceptable quality and the estimation of presence of Abeta aggregates yielded good results. However, a poor agreement was reached particularly regarding quantitative (density) and qualitative (diffuse/cored plaques) results. During a joint meeting, the clone 4G8 was determined to label best the fleecy/diffuse plaques, and thus, this clone and the formic acid pretreatment technique were selected for the second part of this study. Subsequently, all stained sections were of good/acceptable quality and again a high level of concordance of the dichotomized (presence/absence) assessment of plaques and CAA was achieved. However, even when only one antibody was used, the type of Abeta-aggregates (diffuse/cored), type of vessel and Vonsattel grade, were not reliably assigned. Furthermore, the quantification of lesions was far from reliable. In line with the first trial, the agreement while assessing density (some, moderate and many) was unimpressive. In conclusion, we can confirm the utility of immunohistochemical detection of Abeta-protein in diagnostics and research. It is noteworthy that to reach reproducible results a dichotomized assessment of Abeta-immunoreactivity rather than quantification and assignment of various types of lesions should be applied, particularly when comparing results obtained by different neuropathologists.
11.	Alafuzoff, Irina, et al. (författare) Neuropathological assessments of the pathology in frontotemporal lobar degeneration with TDP43-positive inclusions : an inter-laboratory study by the BrainNet Europe consortium 2015 Ingår i: Journal of neural transmission. - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 122:7, s. 957-972 Tidskriftsartikel (refereegranskat)abstract The BrainNet Europe consortium assessed the reproducibility in the assignment of the type of frontotemporal lobar degeneration (FTLD) with TAR DNA-binding protein (TDP) 43 following current recommendations. The agreement rates were influenced by the immunohistochemical (IHC) method and by the classification strategy followed. p62-IHC staining yielded good uniform quality of stains, but the most reliable results were obtained implementing specific Abs directed against the hallmark protein TDP43. Both assessment of the type and the extent of lesions were influenced by the Abs and by the quality of stain. Assessment of the extent of the lesions yielded poor results repeatedly; thus, the extent of pathology should not be used in diagnostic consensus criteria. Whilst 31 neuropathologists typed 30 FTLD-TDP cases, inter-rater agreement ranged from 19 to 100 per cent, being highest when applying phosphorylated TDP43/IHC. The agreement was highest when designating Type C or Type A/B. In contrast, there was a poor agreement when attempting to separate Type A or Type B FTLD-TDP. In conclusion, we can expect that neuropathologist, independent of his/her familiarity with FTLD-TDP pathology, can identify a TDP43-positive FTLD case. The goal should be to state a Type (A, B, C, D) or a mixture of Types (A/B, A/C or B/C). Neuropathologists, other clinicians and researchers should be aware of the pitfalls whilst doing so. Agreement can be reached in an inter-laboratory setting regarding Type C cases with thick and long neurites, whereas the differentiation between Types A and B may be more troublesome.
12.	Alafuzoff, Irina, et al. (författare) Staging of neurofibrillary pathology in Alzheimer's disease : a study of the BrainNet Europe Consortium. 2008 Ingår i: Brain Pathology. - : Wiley. - 1015-6305 .- 1750-3639. ; 18:4, s. 484-96 Tidskriftsartikel (refereegranskat)abstract It has been recognized that molecular classifications will form the basis for neuropathological diagnostic work in the future. Consequently, in order to reach a diagnosis of Alzheimer's disease (AD), the presence of hyperphosphorylated tau (HP-tau) and beta-amyloid protein in brain tissue must be unequivocal. In addition, the stepwise progression of pathology needs to be assessed. This paper deals exclusively with the regional assessment of AD-related HP-tau pathology. The objective was to provide straightforward instructions to aid in the assessment of AD-related immunohistochemically (IHC) detected HP-tau pathology and to test the concordance of assessments made by 25 independent evaluators. The assessment of progression in 7-microm-thick sections was based on assessment of IHC labeled HP-tau immunoreactive neuropil threads (NTs). Our results indicate that good agreement can be reached when the lesions are substantial, i.e., the lesions have reached isocortical structures (stage V-VI absolute agreement 91%), whereas when only mild subtle lesions were present the agreement was poorer (I-II absolute agreement 50%). Thus, in a research setting when the extent of lesions is mild, it is strongly recommended that the assessment of lesions should be carried out by at least two independent observers.
13.	Alafuzoff, Irina, et al. (författare) Staging/typing of Lewy body related alpha-synuclein pathology : a study of the BrainNet Europe Consortium 2009 Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 117:6, s. 635-652 Tidskriftsartikel (refereegranskat)abstract When 22 members of the BrainNet Europe (BNE) consortium assessed 31 cases with alpha-synuclein (alphaS) immunoreactive (IR) pathology applying the consensus protocol described by McKeith and colleagues in 2005, the inter-observer agreement was 80%, being lowest in the limbic category (73%). When applying the staging protocol described by Braak and colleagues in 2003, agreement was only 65%, and in some cases as low as 36%. When modifications of these strategies, i.e., McKeith's protocol by Leverenz and colleagues from 2009, Braak's staging by Müller and colleagues from 2005 were applied then the agreement increased to 78 and 82%, respectively. In both of these modifications, a reduced number of anatomical regions/blocks are assessed and still in a substantial number of cases, the inter-observer agreement differed significantly. Over 80% agreement in both typing and staging of alphaS pathology could be achieved when applying a new protocol, jointly designed by the BNE consortium. The BNE-protocol assessing alphaS-IR lesions in nine blocks offered advantages over the previous modified protocols because the agreement between the 22 observers was over 80% in most cases. Furthermore, in the BNE-protocol, the alphaS pathology is assessed as being present or absent and thus the quality of staining and the assessment of the severity of alphaS-IR pathology do not alter the inter-observer agreement, contrary to other assessment strategies. To reach these high agreement rates an entity of amygdala-predominant category was incorporated. In conclusion, here we report a protocol for assessing alphaS pathology that can achieve a high inter-observer agreement for both the assignment to brainstem, limbic, neocortical and amygdala-predominant categories of synucleinopathy and the Braak stages.
14.	Andras, Toth, et al. (författare) ACROBOTER: a ceiling based crawling, hoisting and swinging service robot platform 2009 Ingår i: 23rd BCS Conference on Human-Computer Interaction. Konferensbidrag (refereegranskat)
15.	Antonios, Gregory, et al. (författare) N-truncated Abeta starting with position four : early intraneuronal accumulation and rescue of toxicity using NT4X-167, a novel monoclonal antibody 2013 Ingår i: Acta neuropathologica communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 1:1, s. 56- Tidskriftsartikel (refereegranskat)abstract BACKGROUND: The amyloid hypothesis in Alzheimer disease (AD) considers amyloid β peptide (Aβ) deposition causative in triggering down-stream events like neurofibrillary tangles, cell loss, vascular damage and memory decline. In the past years N-truncated Aβ peptides especially N-truncated pyroglutamate AβpE3-42 have been extensively studied. Together with full-length Aβ1-42 and Aβ1-40, N-truncated AβpE3-42 and Aβ4-42 are major variants in AD brain. Although Aβ4-42 has been known for a much longer time, there is a lack of studies addressing the question whether AβpE3-42 or Aβ4-42 may precede the other in Alzheimer's disease pathology.RESULTS: Using different Aβ antibodies specific for the different N-termini of N-truncated Aβ, we discovered that Aβ4-x preceded AβpE3-x intraneuronal accumulation in a transgenic mouse model for AD prior to plaque formation. The novel Aβ4-x immunoreactive antibody NT4X-167 detected high molecular weight aggregates derived from N-truncated Aβ species. While NT4X-167 significantly rescued Aβ4-42 toxicity in vitro no beneficial effect was observed against Aβ1-42 or AβpE3-42 toxicity. Phenylalanine at position four of Aβ was imperative for antibody binding, because its replacement with alanine or proline completely prevented binding. Although amyloid plaques were observed using NT4X-167 in 5XFAD transgenic mice, it barely reacted with plaques in the brain of sporadic AD patients and familial cases with the Arctic, Swedish and the presenilin-1 PS1Δ9 mutation. A consistent staining was observed in blood vessels in all AD cases with cerebral amyloid angiopathy. There was no cross-reactivity with other aggregates typical for other common neurodegenerative diseases showing that NT4X-167 staining is specific for AD.CONCLUSIONS: Aβ4-x precedes AβpE3-x in the well accepted 5XFAD AD mouse model underlining the significance of N-truncated species in AD pathology. NT4X-167 therefore is the first antibody reacting with Aβ4-x and represents a novel tool in Alzheimer research.
16.	Bell, Jeanne E, et al. (författare) Management of a twenty-first century brain bank : experience in the BrainNet Europe consortium. 2008 Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 115:5, s. 497-507 Tidskriftsartikel (refereegranskat)abstract Collections of human postmortem brains gathered in brain banks have underpinned many significant developments in the understanding of central nervous system (CNS) disorders and continue to support current research. Unfortunately, the worldwide decline in postmortem examinations has had an adverse effect on research tissue procurement, particularly from control cases (non-diseased brains). Recruitment to brain donor programmes partially addresses this problem and has been successful for dementing and neurodegenerative conditions. However, the collection of brains from control subjects, particularly from younger individuals, and from CNS disorders of sudden onset, remains a problem. Brain banks need to adopt additional strategies to circumvent such shortages. The establishment of brain bank networks allows data on, and access to, control cases and unusual CNS disorders to be shared, providing a larger resource for potential users. For the brain banks themselves, inclusion in a network fosters the sharing of protocols and development of best practice and quality control. One aspect of this collective experience concerns brain bank management, excellence in which is a prerequisite not only for gaining the trust of potential donors and of society in general, but also for ensuring equitable distribution to researchers of high quality tissue samples. This review addresses the legal, ethical and governance issues, tissue quality, and health and safety aspects of brain bank management and data management in a network, as well as the needs of users, brain bank staffing, donor programs, funding issues and public relations. Recent developments in research methodology present new opportunities for researchers who use brain tissue samples, but will require brain banks to adopt more complex protocols for tissue collection, preparation and storage, with inevitable cost implications for the future.
17.	Borg Hammer, Anne Sofie, et al. (författare) Hypodiploidy has unfavorable impact on survival in pediatric acute myeloid leukemia : An I-BFM Study Group collaboration 2023 Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 7:6, s. 1045-1055 Tidskriftsartikel (refereegranskat)abstract Hypodiploidy, defined as modal numbers (MNs) 45 or lower, has not been independently investigated in pediatric acute myeloid leukemia (AML) but is a well-described high-risk factor in pediatric acute lymphoblastic leukemia. We aimed to characterize and study the prognostic impact of hypodiploidy in pediatric AML. In this retrospective cohort study, we included children below 18 years of age with de novo AML and a hypodiploid karyotype diagnosed from 2000 to 2015 in 14 childhood AML groups from the International Berlin-Frankfurt-Münster (I-BFM) framework. Exclusion criteria comprised constitutional hypodiploidy, monosomy 7, composite karyotype, and t(8;21) with concurring sex chromosome loss. Hypodiploidy occurred in 81 patients (1.3%) with MNs, 45 (n = 66); 44 (n = 10) and 43 (n = 5). The most frequently lost chromosomes were chromosome 9 and sex chromosomes. Five-year event-free survival (EFS) and overall survival (OS) were 34% and 52%, respectively, for the hypodiploid cohort. Children with MN≤44 (n = 15) had inferior EFS (21%) and OS (33%) compared with children with MN = 45 (n = 66; EFS, 37%; OS, 56%). Adjusted hazard ratios (HRs) were 4.9 (P = .001) and 6.1 (P = .003). Monosomal karyotype or monosomy 9 had particular poor OS (43% and 15%, respectively). Allogeneic stem cell transplantation (SCT) in first complete remission (CR1) (n = 18) did not mitigate the unfavorable outcome of hypodiploidy (adjusted HR for OS was 1.5; P = .42). We identified pediatric hypodiploid AML as a rare subgroup with an inferior prognosis even in the patients treated with SCT in CR1.
18.	Cinege, Gyöngyi, et al. (författare) Broad Ultrastructural and Transcriptomic Changes Underlie the Multinucleated Giant Hemocyte Mediated Innate Immune Response against Parasitoids 2022 Ingår i: Journal of Innate Immunity. - : S. Karger. - 1662-811X .- 1662-8128. ; 14:4, s. 335-354 Tidskriftsartikel (refereegranskat)abstract Multinucleated giant hemocytes (MGHs) represent a novel type of blood cell in insects that participate in a highly efficient immune response against parasitoid wasps involving isolation and killing of the parasite. Previously, we showed that circulating MGHs have high motility and the interaction with the parasitoid rapidly triggers encapsulation. However, structural and molecular mechanisms behind these processes remained elusive. Here, we used detailed ultrastructural analysis and live cell imaging of MGHs to study encapsulation in Drosophila ananassae after parasitoid wasp infection. We found dynamic structural changes, mainly driven by the formation of diverse vesicular systems and newly developed complex intracytoplasmic membrane structures, and abundant generation of giant cell exosomes in MGHs. In addition, we used RNA sequencing to study the transcriptomic profile of MGHs and activated plasmatocytes 72 h after infection, as well as the uninduced blood cells. This revealed that differentiation of MGHs was accompanied by broad changes in gene expression. Consistent with the observed structural changes, transcripts related to vesicular function, cytoskeletal organization, and adhesion were enriched in MGHs. In addition, several orphan genes encoding for hemolysin-like proteins, pore-forming toxins of prokaryotic origin, were expressed at high level, which may be important for parasitoid elimination. Our results reveal coordinated molecular and structural changes in the course of MGH differentiation and parasitoid encapsulation, providing a mechanistic model for a powerful innate immune response.
19.	Cinege, Gyöngyi, et al. (författare) Distinctive features of Zaprionus indianus hemocyte differentiation and function revealed by transcriptomic analysis 2023 Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 14 Tidskriftsartikel (refereegranskat)abstract Background: Insects have specialized cell types that participate in the elimination of parasites, for instance, the lamellocytes of the broadly studied species Drosophila melanogaster. Other drosophilids, such as Drosophila ananassae and the invasive Zaprionus indianus, have multinucleated giant hemocytes, a syncytium of blood cells that participate in the encapsulation of the eggs or larvae of parasitoid wasps. These cells can be formed by the fusion of hemocytes in circulation or originate from the lymph gland. Their ultrastructure highly resembles that of the mammalian megakaryocytes.Methods: Morphological, protein expressional, and functional features of blood cells were revealed using epifluorescence and confocal microscopy. The respective hemocyte subpopulations were identified using monoclonal antibodies in indirect immunofluorescence assays. Fluorescein isothiocyanate (FITC)-labeled Escherichia coli bacteria were used in phagocytosis tests. Gene expression analysis was performed following mRNA sequencing of blood cells.Results: D. ananassae and Z. indianus encapsulate foreign particles with the involvement of multinucleated giant hemocytes and mount a highly efficient immune response against parasitoid wasps. Morphological, protein expressional, and functional assays of Z. indianus blood cells suggested that these cells could be derived from large plasmatocytes, a unique cell type developing specifically after parasitoid wasp infection. Transcriptomic analysis of blood cells, isolated from naïve and wasp-infected Z. indianus larvae, revealed several differentially expressed genes involved in signal transduction, cell movements, encapsulation of foreign targets, energy production, and melanization, suggesting their role in the anti-parasitoid response. A large number of genes that encode proteins associated with coagulation and wound healing, such as phenoloxidase activity factor-like proteins, fibrinogen-related proteins, lectins, and proteins involved in the differentiation and function of platelets, were constitutively expressed. The remarkable ultrastructural similarities between giant hemocytes and mammalian megakaryocytes, and presence of platelets, and giant cell-derived anucleated fragments at wound sites hint at the involvement of this cell subpopulation in wound healing processes, in addition to participation in the encapsulation reaction.Conclusion: Our observations provide insights into the broad repertoire of blood cell functions required for efficient defense reactions to maintain the homeostasis of the organism. The analysis of the differentiation and function of multinucleated giant hemocytes gives an insight into the diversification of the immune mechanisms.
20.	Cinege, G., et al. (författare) Genes encoding cuticular proteins are components of the Nimrod gene cluster in Drosophila 2017 Ingår i: Insect Biochemistry and Molecular Biology. - : Elsevier BV. - 0965-1748 .- 1879-0240. ; 87, s. 45-54 Tidskriftsartikel (refereegranskat)abstract The Nimrod gene cluster, located on the second chromosome of Drosophila melanogaster, is the largest synthenic unit of the Drosophila genome. Nimrod genes show blood cell specific expression and code for phagocytosis receptors that play a major role in fruit fly innate immune functions. We previously identified three homologous genes (vajk-1, vajk-2 and vajk-3) located within the Nimrod cluster, which are unrelated to the Nimrod genes, but are homologous to a fourth gene (vajk-4) located outside the cluster. Here we show that, unlike the Nimrod candidates, the Vajk proteins are expressed in cuticular structures of the late embryo and the late pupa, indicating that they contribute to cuticular barrier functions. © 2017 Elsevier Ltd
21.	Crary, John F., et al. (författare) Primary age-related tauopathy (PART) : a common pathology associated with human aging 2014 Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 128:6, s. 755-766 Tidskriftsartikel (refereegranskat)abstract We recommend a new term, "primary age-related tauopathy" (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer's disease (AD), in the absence of amyloid (A beta) plaques. For these "NFT+/A beta-aEuroe brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex). Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as "tangle-only dementia" and "tangle-predominant senile dementia", are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of A beta accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed.
22.	Eros, Nora, et al. (författare) Large B-cell lymphoma of the leg in a patient with multiple malignant tumours. 2003 Ingår i: Acta dermato-venereologica. - : Medical Journals Sweden AB. - 0001-5555. ; 83:5, s. 354-7 Tidskriftsartikel (refereegranskat)abstract A patient who had primary gastric B-cell non-Hodgkin's lymphoma, invasive ductal breast cancer and a basocellular carcinoma of the forehead in her medical history was studied. Three years after polychemotherapy and irradiation of the breast cancer, a rapidly enlarging, ulcerated violaceous tumour developed on the patient's left leg. The tumour was identified by the histopathological, immunohistochemical and immunoglobulin gene rearrangement analyses as a cutaneous large B-cell lymphoma. No signs of extracutaneous involvement were detectable. Despite surgical excision, interferon-alpha2b treatment and chlorambucil + prednisone chemotherapy, a relapse occurred in the previously affected site, whereafter the patient received radiotherapy. She was lost to follow-up, and died approximately 14 months after the surgical intervention without autopsy. We discuss the clinical and histologic features and outcome of the large B-cell lymphoma of the leg, its coincidence with other diseases, and the uncommon occurrence of primary multiple malignant tumours.
23.	Ferrara, Francesco, et al. (författare) The Right Heart International Network (RIGHT-NET) : Rationale, Objectives, Methodology, and Clinical Implications 2018 Ingår i: Heart Failure Clinics. - : Elsevier BV. - 1551-7136. ; 14:3, s. 443-465 Forskningsöversikt (refereegranskat)abstract The Right Heart International Network is a multicenter international study aiming to prospectively collect exercise Doppler echocardiography tests of the right heart pulmonary circulation unit (RHPCU) in large cohorts of healthy subjects, elite athletes, and individuals at risk of or with overt pulmonary hypertension. It is going to provide standardization of exercise stress echocardiography of RHPCU and explore the full physiopathologic response.
24.	Giaccone, Giorgio, et al. (författare) New lexicon and criteria for the diagnosis of Alzheimer's disease 2011 Ingår i: Lancet Neurology. - 1474-4422 .- 1474-4465. ; 10:4, s. 298-299 Tidskriftsartikel (refereegranskat)
25.	Hettyey, Attila, et al. (författare) Does testis weight decline towards the Subarctic? : a case study on the common frog, Rana temporaria 2005 Ingår i: Die Naturwissenschaften. - 0028-1042 .- 1432-1904. ; 92:4, s. 188-192 Tidskriftsartikel (refereegranskat)abstract Interpopulation comparisons of variation in resource availability and in allocation patterns along altitudinal and latitudinal gradients allow insights into the mechanisms shaping the life history of animals. Patterns of between-population differences in female life history traits have been studied intensively across a wide range of taxa, but similar investigations in males have remained scarce. To study if testis weight-a measure of reproductive investment-varies on a geographical scale in anurans, we focussed on the variation in relative testis weight (RelTW) and asymmetry in 22 populations of the common frog Rana temporaria along a 1,600-km latitudinal transect across the Scandinavian peninsula. We found that RelTW decreased towards the north. Body mass and body length both had independent positive effects on testes mass. We found evidence for directional asymmetry (DA) in testis weight with the right testis being larger than the left. The level of DA in testis weight was not related to latitude, but both body mass and testes mass had independent positive effects on asymmetry. We discuss the northwards decrease in RelTW in terms of a decreased reproductive investment as a possible consequence of harsher environmental conditions, and perhaps also, weaker sexual selection in the north than in the south.
26.	Horvath, Istvan, et al. (författare) Co-aggregation of pro-inflammatory S100A9 with alpha-synuclein in Parkinson's disease : ex vivo and in vitro studies 2018 Ingår i: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 15 Tidskriftsartikel (refereegranskat)abstract Background: Chronic neuroinflammation is a hallmark of Parkinson's disease (PD) pathophysiology, associated with increased levels of pro-inflammatory factors in PD brain tissues. The pro-inflammatory mediator and highly amyloidogenic protein S100A9 is involved in the amyloid-neuroinflammatory cascade in Alzheimer's disease. This is the first report on the co-aggregation of alpha-synuclein (alpha-syn) and S100A9 both in vitro and ex vivo in PD brain. Methods: Single and sequential immunohistochemistry, immunofluorescence, scanning electron and atomic force (AFM) microscopies were used to analyze the ex vivo PD brain tissues for S100A9 and alpha-syn location and aggregation. In vitro studies revealing S100A9 and alpha-syn interaction and co-aggregation were conducted by NMR, circular dichroism, Thioflavin-T fluorescence, AFM, and surface plasmon resonance methods. Results: Co-localized and co-aggregated S100A9 and alpha-syn were found in 20% Lewy bodies and 77% neuronal cells in the substantia nigra; both proteins were also observed in Lewy bodies in PD frontal lobe (Braak stages 4-6). Lewy bodies were characterized by ca. 10-23 mu m outer diameter, with S100A9 and alpha-syn being co-localized in the same lamellar structures. S100A9 was also detected in neurons and blood vessels of the aged patients without PD, but in much lesser extent. In vitro S100A9 and alpha-syn were shown to interact with each other via the alpha-syn C-terminus with an apparent dissociation constant of ca. 5 mu M. Their co-aggregation occurred significantly faster and led to formation of larger amyloid aggregates than the self-assembly of individual proteins. S100A9 amyloid oligomers were more toxic than those of alpha-syn, while co-aggregation of both proteins mitigated the cytotoxicity of S100A9 oligomers. Conclusions: We suggest that sustained neuroinflammation promoting the spread of amyloidogenic S100A9 in the brain tissues may trigger the amyloid cascade involving alpha-syn and S100A9 and leading to PD, similar to the effect of S100A9 and A beta co-aggregation in Alzheimer's disease. The finding of S100A9 involvement in PD may open a new avenue for therapeutic interventions targeting S100A9 and preventing its amyloid self-assembly in affected brain tissues.
27.	Humbert, Marc, et al. (författare) 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension 2023 Ingår i: The European respiratory journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 61:1 Tidskriftsartikel (refereegranskat)
28.	Imrefi, Ildikó, et al. (författare) Poaceascoma zborayi sp. nov. and Agrorhizomyces patris gen. et spec. nov. : Two novel dark septate endophytes colonizing wheat (Triticum aestivum) roots from a cropland in Hungary 2024 Ingår i: Mycological progress. - : Springer. - 1617-416X .- 1861-8952. ; 23:1 Tidskriftsartikel (refereegranskat)abstract In this study, we investigated two distinct new phylogenetic lineages of root-colonizing dark septate endophytic fungi colonizing wheat (Triticum aestivum) roots from a long-term agricultural experimental site in Hungary. According to four-locus (internal transcribed spacer, partial large and small subunit regions of nuclear ribosomal DNA, and partial translation elongation factor 1-alpha) phylogenetic analyses, the isolates belong to the Lentitheciaceae and Didymosphaeriaceae of the Pleosporales (Dothideomycetes). We studied the morphology and culture characteristics of the strains. We carried out in vitro resynthesis pot experiments with their original hosts and found no overall negative effect of the inoculation with different isolates of the new taxa. One of the lineages belonged to the genus Poaceascoma (Lentitheciaceae) and represented a novel species described here as Poaceascoma zborayi. We could describe conidia-like structures from this species. Isolates of the other lineage represented a monotypic novel genus in the Didymosphaeriaceae. Accordingly, the new genus, Agrorhizomyces, represented by the species A. patris, is introduced. Sterile, globose structures resembling immature sporocarps were detected. Sequence similarity searches indicated that P. zborayi might be widely distributed, while no sequence similar to A. patris was found outside the sampling area.
29.	Jadhav, Santosh, et al. (författare) A walk through tau therapeutic strategies 2019 Ingår i: Acta Neuropathologica Communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 7:1 Forskningsöversikt (refereegranskat)abstract Tau neuronal and glial pathologies drive the clinical presentation of Alzheimer's disease and related human tauopathies. There is a growing body of evidence indicating that pathological tau species can travel from cell to cell and spread the pathology through the brain. Throughout the last decade, physiological and pathological tau have become attractive targets for AD therapies. Several therapeutic approaches have been proposed, including the inhibition of protein kinases or protein-3-O-(N-acetyl-beta-D-glucosaminyl)-L-serine/threonine Nacetylglucosaminyl hydrolase, the inhibition of tau aggregation, active and passive immunotherapies, and tau silencing by antisense oligonucleotides. New tau therapeutics, across the board, have demonstrated the ability to prevent or reduce tau lesions and improve either cognitive or motor impairment in a variety of animal models developing neurofibrillary pathology. The most advanced strategy for the treatment of human tauopathies remains immunotherapy, which has already reached the clinical stage of drug development. Tau vaccines or humanised antibodies target a variety of tau species either in the intracellular or extracellular spaces. Some of them recognise the amino-terminus or carboxy-terminus, while others display binding abilities to the proline-rich area or microtubule binding domains. The main therapeutic foci in existing clinical trials are on Alzheimer's disease, progressive supranuclear palsy and non-fluent primary progressive aphasia. Tau therapy offers a new hope for the treatment of many fatal brain disorders. First efficacy data from clinical trials will be available by the end of this decade.
30.	Jellinger, Kurt A., et al. (författare) PART, a distinct tauopathy, different from classical sporadic Alzheimer disease 2015 Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 129:5, s. 757-762 Tidskriftsartikel (refereegranskat)
31.	Juhász, Annamária, et al. (författare) A subthalamicus mag célkoordinátáinak összehasonlítása 1 és 3 Tesla MR-vizsgálattal mély agyi stimulációs műtétek tervezése során : [Comparison of subthalamic nucleus planning coordinates in 1Tesla and 3Tesla MRI for deep brain stimulation targeting] 2018 Ingår i: Ideggyogyaszati Szemle. - : Literatura Medica Kiado. - 0019-1442 .- 2498-6208. ; 71:11-12, s. 405-410 Tidskriftsartikel (refereegranskat)abstract Background and purpose: Deep brain stimulation (DBS) involves placing electrodes within specific deep brain nuclei. For movement disorders the most common indications are tremors, Parkinsons disease and dystonias. Surgeons mostly employ MR imaging for preoperative target selection. MR field geometrical distortion may contribute to target-selection error in the MR scan which can contribute to error in electrode placement.Methods: In this paper we compared the STN target planning coordinates in six parkinsonian DBS patients. Each patient underwent target planning in 1T and 3T MRI. We statistically compared and analysed the target-, and the fiducial coordinates in two different magnetic fileds.Results: The target coordinates showed no significant differences (Mann-Whitney test, p > 0.05), however we found significant difference in fiducial coordinates (p < 0.01), in 3T MRI it was more pronounced (mean ± SD: 0.8 ± 0.3 mm) comparing to 1T (mean ± SD: 0.4 ± 0.2 mm).Conclusion: Preliminary results showed no significant differences in planning of target coordinates comparing 1T to 3T magnetic fields.
32.	Kovacs, Gabor G., et al. (författare) Aging-related tau astrogliopathy (ARTAG) : harmonized evaluation strategy 2016 Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 131:1, s. 87-102 Tidskriftsartikel (refereegranskat)abstract Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, but poorly characterized feature of the aging brain. Its etiology is uncertain, but its presence is sufficiently ubiquitous to merit further characterization and classification, which may stimulate clinicopathological studies and research into its pathobiology. This paper aims to harmonize evaluation and nomenclature of aging-related tau astrogliopathy (ARTAG), a term that refers to a morphological spectrum of astroglial pathology detected by tau immunohistochemistry, especially with phosphorylation-dependent and 4R isoform-specific antibodies. ARTAG occurs mainly, but not exclusively, in individuals over 60 years of age. Tau-immunoreactive astrocytes in ARTAG include thorn-shaped astrocytes at the glia limitans and in white matter, as well as solitary or clustered astrocytes with perinuclear cytoplasmic tau immunoreactivity that extends into the astroglial processes as fine fibrillar or granular immunopositivity, typically in gray matter. Various forms of ARTAG may coexist in the same brain and might reflect different pathogenic processes. Based on morphology and anatomical distribution, ARTAG can be distinguished from primary tauopathies, but may be concurrent with primary tauopathies or other disorders. We recommend four steps for evaluation of ARTAG: (1) identification of five types based on the location of either morphologies of tau astrogliopathy: subpial, subependymal, perivascular, white matter, gray matter; (2) documentation of the regional involvement: medial temporal lobe, lobar (frontal, parietal, occipital, lateral temporal), subcortical, brainstem; (3) documentation of the severity of tau astrogliopathy; and (4) description of subregional involvement. Some types of ARTAG may underlie neurological symptoms; however, the clinical significance of ARTAG is currently uncertain and awaits further studies. The goal of this proposal is to raise awareness of astroglial tau pathology in the aged brain, facilitating communication among neuropathologists and researchers, and informing interpretation of clinical biomarkers and imaging studies that focus on tau-related indicators.
33.	Kovacs, Gabor G., et al. (författare) An antibody with high reactivity for disease-associated α-synuclein reveals extensive brain pathology 2012 Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 124:1, s. 37-50 Tidskriftsartikel (refereegranskat)abstract α-Synuclein is the major protein associated with Lewy body dementia, Parkinson's disease and multiple system atrophy. Since α-synuclein is present in the brain in physiological conditions as a presynaptic protein, it is crucial to characterize disease-associated modifications to develop an in vivo biomarker. With the aim to develop antibodies showing high specificity and sensitivity for disease-associated α-synuclein, synthetic peptides containing different amino acid sequences were used for immunization of mice. After generation of α-synuclein aggregates, ELISA and immunoblotting were used to test the specificity of antibodies. Tissue microarray sections originating from different human α-synucleinopathies were used to compare immunostaining with other, commercially available antibodies. Immunization of mice with the peptide TKEGVVHGVATVAE (amino acid 44-57 of α-synuclein) resulted in the generation of a monoclonal antibody (5G4), which was able to bind aggregated α-synuclein preparation in sandwich ELISA or coated on magnetic beads. 5G4 proved to be superior to other antibodies in comparative immunohistochemical studies by revealing more widespread and distinct α-synuclein pathology. Immunoblotting of human brain tissue revealed an additional band seen in dementia with Lewy bodies, whereas the band representing monomeric α-synuclein was very weak or lacking. In summary, the 5G4 antibody is most promising for re-evaluation of archival material and may offer new perspective for the development of in vivo diagnostic assays for detecting disease-associated α-synuclein in body fluids.
34.	Kovacs, Gabor G, et al. (författare) Concomitant pathologies II : neurodegenerative conditions 2015 Ingår i: Neuropathology of neurodegenerative diseases A practical guide. - : Cambridge University Press. - 9781107588660 - 9781107674202 ; , s. 292-298 Bokkapitel (refereegranskat)abstract Introduction The term “mixed or concomitant” pathologies in neurodegenerative disease means that, in addition to the hallmark lesions of a neurodegenerative disease entity, further pathological alterations can be observed in the same brain. The term mixed pathology was originally used when describing accompanying vascular pathology. Later, Lewy body pathology was also described as concomitant pathology when seen together with other neurodegenerative diseases. Currently, we classify neurodegenerative diseases according to the predominant protein that shows pathological depositions in the brain. During the diagnostic process, detecting hallmark lesions of a certain disease, like neuritic plaques in the cortex, spongiform change in the cortex, globose tangles in the brainstem nuclei or Lewy bodies in the brainstem or cortex, can lead to negligence of further lesions or performance of further stains. However, deposition of multiple proteins, in addition to co-occurrence of non-neurodegenerative pathology (e.g. vascular, metabolic), is a frequent event. In fact, overlapping neurodegeneration may be more the rule than the exception. This concept is supported by observations in genetic forms of neurodegenerative disorders where various proteins may show pathological deposits in the same brain [1–3]. Complex constellations of clinical symptoms (movement disorders and cognitive decline) may associate with the accompanying presence of diverse neurodegenerative disorders. There are several factors determining overlap between neurodegenerative disorders as proposed by Armstrong et al. [4]): (i) historical factors, which means that the original descriptions of key disorders were based on the descriptions of relatively small numbers of cases; furthermore, the original investigators interpreted these as ‘syndromes’ rather than distinct diseases; (ii) disease heterogeneity; (iii) age-related changes;(iv) apolipoprotein ɛ genotype, especially in cases with significant Aβ deposition but without further features of Alzheimer’s disease (AD); (v) co-occurrence of common diseases, like AD and Parkinson’s disease (PD), as both are more likely to occur in the elderly and thus are more likely to co-occur.
35.	Kovacs, Gabor G., et al. (författare) Heroin abuse exaggerates age-related deposition of hyperphosphorylated tau and p62-positive inclusions 2015 Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 36:11, s. 3100-3107 Tidskriftsartikel (refereegranskat)abstract The observation of increased hyperphosphorylated tau levels correlating with microglial activation in opiate abusers has been interpreted as predisposition to accelerated Alzheimer diseaseerelated changes. The present study focused on evaluating additional neurodegeneration-related proteins, including a-synuclein and TDP-43, and p62-positive deposits. We performed a systematic mapping of protein deposits in the brains of 27 individuals with documented heroin addiction (age: 19-40 years) and compared with 11 controls (age: 15-40 years). We confirm previous findings that heroin addiction associates with tau hyperphosphorylation in predilection brain areas for aging and Alzheimer disease. Furthermore, we show that this occurs also in areas implicated in the molecular disturbances and in vivo neuronal networks related to heroin abuse. There was, however, no presence of amyloid-beta deposits. We extend previous findings by showing the lack of TDP-43 or alpha-synuclein pathology and emphasize the independent effect of the duration of drug use on the appearance of age-related p62-positive neuritic profiles. These observations provide unique insights about neuropathological alterations in the brains of young heroin addicts and have implications about brain aging and the influences of environmental and toxic factors.
36.	Kovacs, Gabor G., et al. (författare) Mixed brain pathologies in dementia : the BrainNet Europe consortium experience 2008 Ingår i: Dementia and Geriatric Cognitive Disorders. - : S. Karger AG. - 1420-8008 .- 1421-9824. ; 26:4, s. 343-350 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Dementia results from heterogeneous diseases of the brain. Mixed disease forms are increasingly recognized. METHODS: We performed a survey within brain banks of BrainNet Europe to estimate the proportion of mixed disease forms underlying dementia and age- and gender-specific influences. RESULTS: Data collected in 9 centres from 3,303 individuals were analysed. The proportion of patients with mixed diagnoses among all cases with Alzheimer disease (AD), vascular pathology (VP), argyrophilic grain dementia (AGD), and synucleinopathies, such as Lewy body dementia (LBD), Parkinson disease (PD) and synuclein pathology only in the amygdala, was 53.3%. Mixed pathology was more frequently reported with LBD, PD, AGD, and VP than with AD. The percentage of mixed diagnoses for AGD and VP significantly differed between centres. In patients younger than 75 years, synucleinopathies, and pure forms of AD, VP, and AGD were more frequent in men. Above 75 years of age, more women had pure AD and pure AGD. CONCLUSIONS: The most obvious neuropathological alteration should not terminate the diagnostic procedure since copathology is likely to be found. Neuropathological interpretation of AGD and VP has not been sufficiently established in a consensus. Pure forms of synucleinopathies are unlikely sole substrates for dementia.
37.	Kovacs, Gabor G., et al. (författare) Multisite Assessment of Aging-Related Tau Astrogliopathy (ARTAG) 2017 Ingår i: Journal of Neuropathology and Experimental Neurology. - : Oxford University Press (OUP). - 0022-3069 .- 1554-6578. ; 76:7, s. 605-619 Tidskriftsartikel (refereegranskat)abstract Aging-related tau astrogliopathy (ARTAG) is a recently introduced terminology. To facilitate the consistent identification of ARTAG and to distinguish it from astroglial tau pathologies observed in the primary frontotemporal lobar degeneration tauopathies we evaluated how consistently neuropathologists recognize (1) different astroglial tau immunoreactivities, including those of ARTAG and those associated with primary tauopathies (Study 1); (2) ARTAG types (Study 2A); and (3) ARTAG severity (Study 2B). Microphotographs and scanned sections immunostained for phosphorylated tau (AT8) were made available for download and preview. Percentage of agreement and kappa values with 95% confidence interval (CI) were calculated for each evaluation. The overall agreement for Study 1 was > 60% with a kappa value of 0.55 (95% CI 0.433-0.645). Moderate agreement (> 90%, kappa 0.48, 95% CI 0.457-0.900) was reached in Study 2A for the identification of ARTAG pathology for each ARTAG subtype (kappa 0.37-0.72), whereas fair agreement (kappa 0.40, 95% CI 0.341-0.445) was reached for the evaluation of ARTAG severity. The overall assessment of ARTAG showed moderate agreement (kappa 0.60, 95% CI 0.534-0.653) among raters. Our study supports the application of the current harmonized evaluation strategy for ARTAG with a slight modification of the evaluation of its severity.
38.	Kovacs, Gabor G, et al. (författare) Neuropathology of the hippocampus in FTLD-Tau with Pick bodies : A study of the BrainNet Europe Consortium 2013 Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 39:2, s. 166-178 Tidskriftsartikel (refereegranskat)abstract Aims: Frontotemporal lobar degeneration with Pick bodies (Pick's disease) is characterized by the presence of tau immunoreactive spherical structures in the cytoplasm of neurons. In view of confusion about the molecular pathology of Pick's disease, we aimed to evaluate the spectrum of tau pathology and concomitant neurodegeneration-associated protein depositions in the characteristically affected hippocampus. Methods: We evaluated immunoreactivity for tau (AT8, 3R, 4R), α-synuclein, TDP43, p62, and ubiquitin in the hippocampus, entorhinal and temporal cortex in 66 archival cases diagnosed neuropathologically as Pick's disease. Results: Mean age at death was 68.2 years (range 49 to 96). Fifty-two (79%) brains showed 3R immunoreactive spherical inclusions in the granule cells of the dentate gyrus. These typical cases presented mainly with the behavioural variant of FTD, followed by progressive aphasia, mixed syndromes or early memory disturbance. α-Synuclein immunoreactivity was seen only in occasional spherical tau-positive inclusions, TDP-43 IR was absent, and 4R IR was present only as neurofibrillary tangles in pyramidal neurons. Aβ immunoreactivity was observed in 16 cases; however, the overall level of Alzheimer's disease-related alterations was mainly low or intermediate (n = 3). Furthermore, we identified six cases with unclassifiable tauopathy. Conclusions: 1) Pick's disease may occur also in elderly patients and is characterized by a relatively uniform pathology with 3R tau inclusions particularly in the granule cells of dentate gyrus; 2) even minor deviation from these morphological criteria suggests a different disorder; and 3) immunohistological revision of archival cases expands the spectrum of tauopathies that require further classification.
39.	Kovacs, Gabor G, et al. (författare) Preface. 2017 Ingår i: Handbook of Clinical Neurology. - 0072-9752 .- 2212-4152. ; 145, s. 9- Tidskriftsartikel (refereegranskat)
40.	Kovacs, Gabor, et al. (författare) Graphite electrodes modified with Neurospora crassa cellobiose dehydrogenase: Comparative electrochemical characterization under direct and mediated electron transfer 2012 Ingår i: Bioelectrochemistry. - : Elsevier BV. - 1878-562X .- 1567-5394. ; 88, s. 84-91 Tidskriftsartikel (refereegranskat)abstract The electrochemical characterization of a class II cellobiose dehydrogenase (CDH), from the ascomycete fungus Neurospora crassa. adsorbed on graphite (G), was performed in regard to direct (DET) and mediated electron transfer (MET). The effects of the applied potential, mediator (1,4 benzoquinone) concentration and flow carrier pH on the amperometric response of the G/CDH modified electrodes were investigated under flow conditions. From the calibration curves, recorded at two pH values (5.2 and 7.0) for nine different sugars, the kinetic and the analytical parameters were evaluated under DET and MET operation modes. These results together with those obtained from long term operational stability measurements showed that: (i) for all nine investigated sugars the sensitivity was higher for MET than for DET and for pH 5.2 compared to pH 7.0; (ii) irrespective of DET or MET operation mode, the sensitivity of the new enzyme towards the investigated sugars decreased in the following sequence: cellobiose > lactose > (cellotriose approximate to cellopentaose) > > (maltotriose approximate to maltotetraose approximate to maltopentaose) > (maltose approximate to glucose); (iii) for all tested substrates, the apparent CDH affinity was roughly higher in DET than in MET operation mode. (C) 2012 Elsevier B.V. All rights reserved.
41.	Lachmann, Ingolf, et al. (författare) New monoclonal antibody 5G4 suitable for specific detection of disease-associated alpha-synuclein in the human brain 2012 Ingår i: Prion. - 1933-6896. ; 6:4 Suppl 1, s. 83-83 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
42.	Lai, Ian-Lin, et al. (författare) Gas outflow and dust transport of comet 67P/Churyumov-Gerasimenko 2016 Ingår i: Monthly notices of the Royal Astronomical Society. - : OXFORD UNIV PRESS. - 0035-8711 .- 1365-2966. ; 462, s. S533-S546 Tidskriftsartikel (refereegranskat)abstract Because of the diurnal thermal cycle and the irregular shape of the nucleus, gas outflow of comet 67P/Churyumov-Gerasimenko could be highly anisotropic as indicated by the colliminated dust jet structures on the sunlit side. Based on the OSIRIS imaging observations of the outgassing effect, a simple model of surface sublimation can be constructed by taking into account the dependence on the solar insolation. With preliminary information on the time variability of the global gas production rate, a sequence of gas coma models can be generated at different epochs before and after perihelion. We also investigate different patterns of dust particle dynamics under the influences of nuclear rotation and gas drag. From these considerations, a consistent picture of the spatial distribution of dusty materials across the surface of comet 67P as it moves around the perihelion can be developed. It is found that because of the redeposition of the ejected dust from the Southern hemisphere to the Northern hemisphere during the southern summer season the Hapi region could gain up to 0.4 m while the Wosret region would lose up to 1.8 m of dust mantle per orbit.
43.	Lau, Heather H. C., et al. (författare) The G51D SNCA mutation generates a slowly progressive alpha-synuclein strain in early-onset Parkinson's disease 2023 Ingår i: Acta neuropathologica communications. - : BioMed Central (BMC). - 2051-5960. ; 11:1 Tidskriftsartikel (refereegranskat)abstract Unique strains of a-synuclein aggregates have been postulated to underlie the spectrum of clinical and pathological presentations seen across the synucleinopathies. Whereas multiple system atrophy (MSA) is associated with a predominance of oligodendroglial a-synuclein inclusions, a-synuclein aggregates in Parkinson's disease (PD) preferentially accumulate in neurons. The G51D mutation in the SNCA gene encoding a-synuclein causes an aggressive, early-onset form of PD that exhibits clinical and neuropathological traits reminiscent of both PD and MSA. To assess the strain characteristics of G51D PD a-synuclein aggregates, we performed propagation studies in M83 transgenic mice by intracerebrally inoculating patient brain extracts. The properties of the induced a-synuclein aggregates in the brains of injected mice were examined using immunohistochemistry, a conformational stability assay, and by performing a-synuclein seed amplification assays. Unlike MSA-injected mice, which developed a progressive motor phenotype, G51D PD-inoculated animals remained free of overt neurological illness for up to 18 months post-inoculation. However, a subclinical synucleinopathy was present in G51D PD-inoculated mice, characterized by the accumulation of a-synuclein aggregates in restricted regions of the brain. The induced a-synuclein aggregates in G51D PD-injected mice exhibited distinct properties in a seed amplification assay and were much more stable than those present in mice injected with MSA extract, which mirrored the differences observed between human MSA and G51D PD brain samples. These results suggest that the G51D SNCA mutation specifies the formation of a slowly propagating a-synuclein strain that more closely resembles a-synuclein aggregates associated with PD than MSA.
44.	Lee, Jui-Chi, et al. (författare) Geomorphological mapping of comet 67P/Churyumov-Gerasimenko's Southern hemisphere 2016 Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 462, s. S573-S592 Tidskriftsartikel (refereegranskat)abstract In 2015 May, the Southern hemisphere of comet 67P/Churyumov-Gerasimenko became visible by the OSIRIS cameras on-board the Rosetta spacecraft. The resolution was high enough to carry out a detailed analysis of the surface morphology, which is quite different from the Northern hemisphere. Previous works show that fine particle deposits are the most extensive geological unit in the Northern hemisphere. In contrast, the Southern hemisphere is dominated by outcropping consolidated terrain. In this work, we provide geomorphological maps of the Southern hemisphere with the distinction of both geological units and linear features. The geomorphological maps described in this study allow us to gain a better understanding of the processes shaping the comet nucleus and the distribution of primary structures such as fractures and strata.
45.	Liptak, Gyorgy, et al. (författare) Traffic Reaction Model 2021 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract In this paper a novel non-negative finite volume discretization scheme is proposed for certain first order nonlinear partial differential equations describing conservation laws arising in traffic flow modelling. The spatially discretized model is shown to preserve several fundamentally important analytical properties of the conservation law (e.g., conservativeness, capacity) giving rise to a set of (second order) polynomial ODEs. Furthermore, it is shown that the discretized traffic flow model is formally kinetic and that it can be interpreted in a compartmental context. As a consequence, traffic networks can be represented as reaction graphs. It is shown that the model can be equipped with on- and off- ramps in a physically meaningful way, still preserving the advantageous properties of the discretization. Numerical case studies include empirical convergence tests, and the stability analysis presented in the paper paves the way to scalable observer and controller design.
46.	Mackenzie, Ian R. A., et al. (författare) Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration : an update 2010 Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 119:1, s. 1-4 Tidskriftsartikel (refereegranskat)
47.	Mackenzie, Ian R. A., et al. (författare) Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration : consensus recommendations 2009 Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 117:1, s. 15-18 Tidskriftsartikel (refereegranskat)
48.	Maksuti, Silia, 1989-, et al. (författare) Automated and Secure Onboarding for System of Systems 2021 Ingår i: IEEE Access. - : IEEE. - 2169-3536. ; 9, s. 111095-111113 Tidskriftsartikel (refereegranskat)abstract The Internet of Things (IoT) is rapidly changing the number of connected devices and the way they interact with each other. This increases the need for an automated and secure onboarding procedure for IoT devices, systems and services. Device manufacturers are entering the market with internet connected devices, ranging from small sensors to production devices, which are subject of security threats specific to IoT. The onboarding procedure is required to introduce a new device in a System of Systems (SoS) without compromising the already onboarded devices and the underlying infrastructure. Onboarding is the process of providing access to the network and registering the components for the first time in an IoT/SoS framework, thus creating a chain of trust from the hardware device to its hosted software systems and their provided services. The large number and diversity of device hardware, software systems and running services raises the challenge to establish a generic onboarding procedure. In this paper, we present an automated and secure onboarding procedure for SoS. We have implemented the onboarding procedure in the Eclipse Arrowhead framework. However, it can be easily adapted for other IoT/SoS frameworks that are based on Service-oriented Architecture (SoA) principles. The automated onboarding procedure ensures a secure and trusted communication between the new IoT devices and the Eclipse Arrowhead framework. We show its application in a smart charging use case and perform a security assessment.
49.	Massironi, Matteo, et al. (författare) Two independent and primitive envelopes of the bilobate nucleus of comet 67P 2015 Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 526:7573, s. 402-405 Tidskriftsartikel (refereegranskat)abstract The factors shaping cometary nuclei are still largely unknown, but could be the result of concurrent effects of evolutionary(1,2) and primordial processes(3,4). The peculiar bilobed shape of comet 67P/Churyumov-Gerasimenko may be the result of the fusion of two objects that were once separate or the result of a localized excavation by outgassing at the interface between the two lobes(5). Here we report that the comet's major lobe is enveloped by a nearly continuous set of strata, up to 650 metres thick, which are independent of an analogous stratified envelope on the minor lobe. Gravity vectors computed for the two lobes separately are closer to perpendicular to the strata than those calculated for the entire nucleus and adjacent to the neck separating the two lobes. Therefore comet 67P/Churyumov-Gerasimenko is an accreted body of two distinct objects with 'onion-like' stratification, which formed before they merged. We conclude that gentle, low-velocity collisions occurred between two fully formed kilometre-sized cometesimals in the early stages of the Solar System. The notable structural similarities between the two lobes of comet 67P/Churyumov-Gerasimenko indicate that the early-forming cometesimals experienced similar primordial stratified accretion, even though they formed independently.
50.	McAleese, Kirsty E., et al. (författare) Post-mortem assessment in vascular dementia : advances and aspirations 2016 Ingår i: BMC Medicine. - : Springer Science and Business Media LLC. - 1741-7015. ; 14 Tidskriftsartikel (refereegranskat)abstract Background: Cerebrovascular lesions are a frequent finding in the elderly population. However, the impact of these lesions on cognitive performance, the prevalence of vascular dementia, and the pathophysiology behind characteristic in vivo imaging findings are subject to controversy. Moreover, there are no standardised criteria for the neuropathological assessment of cerebrovascular disease or its related lesions in human post-mortem brains, and conventional histological techniques may indeed be insufficient to fully reflect the consequences of cerebrovascular disease. Discussion: Here, we review and discuss both the neuropathological and in vivo imaging characteristics of cerebrovascular disease, prevalence rates of vascular dementia, and clinico-pathological correlations. We also discuss the frequent comorbidity of cerebrovascular pathology and Alzheimer's disease pathology, as well as the difficult and controversial issue of clinically differentiating between Alzheimer's disease, vascular dementia and mixed Alzheimer's disease/vascular dementia. Finally, we consider additional novel approaches to complement and enhance current post-mortem assessment of cerebral human tissue. Conclusion: Elucidation of the pathophysiology of cerebrovascular disease, clarification of characteristic findings of in vivo imaging and knowledge about the impact of combined pathologies are needed to improve the diagnostic accuracy of clinical diagnoses.

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