Bedeutung der MRT und FDG-PET in der Exploration des Entorhinalen Kortex in Zusammenhang mit der räumlichen Orientierung bei Patienten mit leichter kognitiver Beeinträchtigung

Background: The entorhinal cortex (ERC) has become a center of growing interest since the description of ERC neurons especially encoding for spatial navigation and spatial memory. In rodents, those cells are particularly found in the medial side of the ERC. Studies in humans are limited, in particular there is no study clearly identifying the homolog of the rodent medial ERC in humans so far. Objective: Brodmann areas (BA) 34 and 28 are major components of the ERC in humans. The aim of this study was to evaluate whether BA 34 or BA 28 might be considered the homolog to the medial ERC in rodents with respect to spatial navigation abilities, and to evaluate the role of MRI and FDG-PET in the exploration of both regions in relation to spatial orientation in patients with mild cognitive impairment (MCI). Methods: Patients with MCI from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were included if they had the entire visuospatial (VISSPAT) ability scores of the Everyday Cognition (ECog) test as well as high-resolution T1-weighted MRI and brain FDG-PET performed within 30 days of the ECog test. Grey matter volume and FDG uptake in each of ERC Brodmann areas (BA 34 and BA 28) were calculated from MRI and FDG-PET using predefined standard masks of BA 34 and BA 28. Regression and multivariate analyses of covariance were employed for statistical analyses. Results: The eligibility criteria were fulfilled by 379 MCI patients. Amongst all studied subdomains assessed by the ECog test, only spatial navigation performance, as characterized by the self-reported VISSPAT sum score, was correlated with the integrity of BA 34 (grey matter volume but not FDG uptake). None of the ECog subscores was correlated with BA 28 integrity (neither grey matter volume nor FDG uptake). Conclusion: Impairment of orientation skills and spatial memory in MCI is more strongly associated with atrophy of BA 34 compared to BA 28, suggesting that BA 34 rather than BA 28 is the human homolog of the rodent medial ERC with respect to spatial orientation abilities. Spatial orientation performance was not associated with glucose metabolism in BA 34, presumably due to higher between-subjects variability of (partial volume-corrected) FDG uptake in BA 34 used to characterize its glucose metabolism.Hintergrund: Der entorhinale Kortex (ERC) ist seit der Beschreibung von ERC- Neuronen, die insbesondere für die räumliche Navigation und das räumliche Gedächtnis kodieren, von zunehmenden Interesse. Bei Nagetieren befinden sich diese Zellen insbesondere im medialen Teil des ERC. Studien am Menschen sind begrenzt, insbesondere gibt es bisher keine Studie, die das Homolog des medialen ERC von Nagern beim Menschen eindeutig identifiziert. Ziel: Die Brodmann-Areale (BA) 34 und 28 sind wesentliche Bestandteile des ERC bei Menschen. Das Ziel dieser Studie war es zu testen, ob BA 34 oder BA 28 in Bezug auf die räumlichen Navigationsfähigkeiten als Homolog des medialen ERC bei Nagetieren angesehen werden können, und die Bedeutung der MRT und FDG-PET für die Exploration der beiden Hirnareale bei Patienten mit leichter kognitiver Beeinträchtigung zu evaluieren. Methoden: Patienten mit leichter kognitiver Beeinträchtigung aus der Alzheimer's Disease Neuroimaging Initiative (ADNI) wurden eingeschlossen, wenn sie einen vollständigen visuellen (VISSPAT) Fähigkeitsscore des Everyday Cognition (ECog)-Tests sowie hochauflösende T1-gewichtete MRT und FDG-PET Bilder des Gehirns aufwiesen, die innerhalb von 30 Tagen nach dem ECog-Test erstellt wurden. Das Volumen der grauen Substanz und die FDG-Aufnahme in BA 34 und BA 28 wurden aus MRT und FDG-PET Bildern unter Verwendung vordefinierter Standardmasken von BA 34 und BA 28 berechnet. Für die statistische Analyse wurden Regressions- und multivariate Kovarianzanalysen eingesetzt. Ergebnisse: Die Auswahlkriterien wurden von 379 MCI-Patienten erfüllt. Von allen durch den ECog-Test bewerteten Subdomänen korrelierte nur die räumliche Navigationsleistung aus dem selbst berichteten VISSPAT- Summenscore mit der Integrität von BA 34 (Volumen der grauen Hirnsubstanz, aber nicht FDG-Aufnahme). Keiner der ECog-Subscores war mit der BA 28- Integrität korreliert (weder das Volumen der grauen Substanz noch die FDG- Aufnahme). Schlussfolgerung: Die Beeinträchtigung der Orientierungsfähigkeit und des räumlichen Gedächtnisses bei MCI ist stärker mit einer Atrophie von BA 34 im Vergleich zu BA 28 verbunden, was darauf hindeutet, dass BA 34 und nicht BA 28 das menschliche Homolog des medialen ERC von Nagetieren in Bezug auf räumliche Navigationsfähigkeiten ist. Die räumliche Navigationsleistung war nicht mit dem Glukosestoffwechsel in BA 34 korreliert, vermutlich aufgrund der höheren Variabilität der (teilweise volumenkorrigierten) FDG-Aufnahme in BA 34, die zur Charakterisierung des Glukosestoffwechsels verwendet wurde

Protein Function Prediction using Phylogenomics, Domain Architecture Analysis, Data Integration, and Lexical Scoring

“As the number of sequenced genomes rapidly grows, the overwhelming majority of protein products can only be annotated computationally.” (Radivojac, Clark, Oron, et al. 2013) With this goal, three new protein function annotation tools were developed, which produce trustworthy and concise protein annotations, are easy to obtain and install, and are capable of processing large sets of proteins with reasonable computational resource demands. Especially for high throughput analysis e.g. on genome scale, these tools improve over existing tools both in ease of use and accuracy. They are dubbed: • Automated Assignment of Human Readable Descriptions (AHRD) (github.com/groupschoof/AHRD; Hallab, Klee, Srinivas, and Schoof 2014), • AHRD on gene clusters, and • Phylogenetic predictions of Gene Ontology (GO) terms with specific calibrations (PhyloFun v2). “AHRD” assigns human readable descriptions (HRDs) to query proteins and was developed to mimic the decision making process of an expert curator. To this end it processes the descriptions of reference proteins obtained by searching selected databases with BLAST (Altschul, Madden, Schaffer, et al. 1997). Here, the trust a user puts into results found in each of these databases can be weighted separately. In the next step the descriptions of the found homologous proteins are filtered, removing accessions, species information, and finally discarding uninformative candidate descriptions like e.g. “putative protein”. Afterwards a dictionary of meaningful words is constructed from those found in the remaining candidates. In this, another filter is applied to ignore words, not conveying information like e.g. the word “protein” itself. In a lexical approach each word is assigned a score based on its frequency in all candidate descriptions, the sequence alignment quality associated with the candidate reference proteins, and finally the already mentioned trust put into the database the reference was obtained from. Subsequently each candidate description is assigned a score, which is computed from the respective scores of the meaningful words contained in that candidate. Also incorporated into this score is the description’s frequency among all regarded candidates. In the final step the highest scoring description is assigned to the query protein. The performance of this lexical algorithm, implemented in “AHRD”, was subsequently compared with that of competitive methods, which were Blast2GO and “best Blast”, where the latter “best Blast” simply passes the description of the best scoring hit to the query protein. To enable this comparison of performance, and in lack of a robust evaluation procedure, a new method to measure the accuracy of textual human readable protein descriptions was developed and applied with success. In this, the accuracy of each assigned competitive description was inferred with the frequently used “F-measure”, the harmonic mean of precision and recall, which we computed regarding meaningful words appearing in both the reference and the assigned descriptions as true positives. The results showed that “AHRD” not only outperforms its competitors by far, but also is very robust and thus does not require its users to use carefully selected parameters. In fact, AHRD’s robustness was demonstrated through cross validation and use of three different reference sets. The second annotation tool “AHRD on gene clusters” uses conserved protein domains from the InterPro database (Apweiler, Attwood, Bairoch, et al. 2000) to annotate clusters of homologous proteins. In a first step the domains found in each cluster are filtered, such that only the most informative are retained. For example are family descriptions discarded, if more detailed sub-family descriptions are also found annotated to members of the cluster. Subsequently, the most frequent candidate description is assigned, favoring those of type “family” over “domain”. Finally the third tool “PhyloFun (v2)” was developed to annotate large sets of query proteins with terms from the Gene Ontology. This work focussed on extending the “Belief propagation” (Pearl 1988) algorithm implemented in the “Sifter” annotation tool (Engelhardt, Jordan, Muratore, and Brenner 2005; Engelhardt, Jordan, Srouji, and Brenner 2011). Jöcker had developed a phylogenetic pipeline generating the input that was fed into the Sifter program. This pipeline executes stringent sequence similarity searches in a database of selected reference proteins, and reconstruct a phylogenetic tree from the found orthologs and inparalogs. This tree is than used by the Sifter program and interpreted as a “Bayesian Network” into which the GO term annotations of the homologous reference proteins are fed as “diagnostic evidence” (Pearl 1988). Subsequently the current strength of belief, the probability of this evidence being also the true state of ancestral tree nodes, is then spread recursively through the tree towards its root, and then vice versa towards the tips. These, of course, include the query protein, which in the final step is annotated with those GO terms that have the strongest belief. Note that during this recursive belief propagation a given GO term’s annotation probability depends on both the length of the currently processed branch, as well as the type of evolutionary event that took place. This event can be one of “speciation” or “duplication”, such that function mutation becomes more likely on longer branches and particularly after “duplication” events. A particular goal in extending this algorithm was to base the annotation probability of a given GO term not on a preconceived model of function evolution among homologous proteins as implemented in Sifter, but instead to compute these GO term annotation probabilities based on empirical measurements. To achieve this, calibrations were computed for each GO term separately, and reference proteins annotated with a given GO term were investigated such that the probability of function loss could be assessed empirically for decreasing sequence homology among related proteins. A second goal was to overcome errors in the identification of the type of evolutionary events. These errors arose from missing knowledge in terms of true species trees, which, in version 1 of the PhyloFun pipeline, are compared with the actual protein trees in order to tell “duplication” from “speciation” events (Zmasek and Eddy 2001). As reliable reference species trees are sparse or in many cases not available, the part of the algorithm incorporating the type of evolutionary event was discarded. Finally, the third goal postulated for the development of PhyloFun’s version 2 was to enable easy installation, usage, and calibration on latest available knowledge. This was motivated by observations made during the application of the first version of PhyloFun, in which maintaining the knowledge-base was almost not feasible. This obstacle was overcome in version 2 of PhyloFun by obtaining required reference data directly from publicly available databases. The accuracy and performance of the new PhyloFun version 2 was assessed and compared with selected competitive methods. These were chosen based on their widespread usage, as well as their applicability on large sets of query proteins without them surpassing reasonable time and computational resource requirements. The measurement of each method’s performance was carried out on a “gold standard”, obtained from the Uniprot/Swissprot public database (Boeckmann, Bairoch, Apweiler, et al. 2003), of 1000 selected reference proteins, all of which had GO term annotations made by expert curators and mostly based on experimental verifications. Subsequently the performance assessment was executed with a slightly modified version of the “Critical Assessment of Function Annotation experiment (CAFA)” experiment (Radivojac, Clark, Oron, et al. 2013). CAFA compares the performance of different protein function annotation tools on a worldwide scale using a provided set of reference proteins. In this, the predictions the competitors deliver are evaluated using the already introduced “F-measure”. Our performance evaluation of PhyloFun’s protein annotations interestingly showed that PhyloFun outperformed all of its competitors. Its use is recommended furthermore by the highly accurate phylogenetic trees the pipeline computes for each query and the found homologous reference proteins. In conclusion, three new premium tools addressing important matters in the computational prediction of protein function were developed and, in two cases, their performance assessed. Here, both AHRD and PhyloFun (v2) outperformed their competitors. Further arguments for the usage of all three tools are, that they are easy to install and use, as well as being reasonably resource demanding. Because of these results the publications of AHRD and PhyloFun (v2) are in preparation, even while AHRD already is applied by different researchers worldwide

Employment among Patients on Dialysis: An Unfulfilled Promise

Comment on : Employment among Patients Starting Dialysis in the United States. [Clin J Am Soc Nephrol. 2018

Codage et classification non supervisée d'un corpus maya : extraire des contextes pour situer l'inconnu par rapport au connu

International audienceL'écriture logosyllabique des anciens Mayas comprend plus de 500 signes et est en bonne partie déchiffrée, avec des degrés de certitude divers. Nous avons appliqué au codex de Dresde, l'un des trois seuls manuscrits qui nous soient parvenus, codé sous LATEX avec le système mayaTEX, notre méthode de représentation graduée, par apprentissage non supervisé hybride entre clustering et analyse factorielle oblique, sous la métrique de Hellinger, afin d'obtenir une image nuancée des thèmes traités : les individus statistiques sont les 212 segments de folio du codex, et leurs attributs sont les 1687 bigrammes de signes extraits. Pour comparaison, nous avons introduit dans cette approche endogène un élément exogène, la décomposition en éléments des signes composites, pour préciser plus finement les contenus. La rétro-visualisation dans le texte original des résultats et expressions dégagées éclaire la signification de certains glyphes peu compris, en les situant dans des contextes clairement interprétables

Processing a Mayan Corpus for Enhancing our Knowledge of Ancient Scripts

International audienceThe ancient Maya writing comprises more than 500 signs, either syllabic or semantic, and is largely deciphered, with a variable degree of reliability. We applied to the Dresden Codex, one of the only three manuscripts that reached us, encoded for LATEX with the mayaTEX package, our graded representation method of hybrid non-supervised learning, intermediate between clustering and oblique factor analysis, and following Hellinger metrics, in order to obtain a nuanced image of themes dealt with: the statistical entities are the 214 codex segments, and their attributes are the 1687 extracted bigrams of signs. For comparison, we introduced in this approach an exogenous element, i.e. the splitting of the composed signs into their elements, for a finer elicitation of the contents. The results are visualized as a set of "thematic concordances": for each homogeneous semantic context, the most salient bigrams or sequences of bigrams are displayed in their textual environment, which sheds a new light on the meaning of some little understood glyphs, placing them in clearly understandable contexts

Method for Characterization of Material Loss from Modular Head-Stem Taper Surfaces of Hip Replacement Devices

Assessment of the head-stem taper junction requires the estimation of material loss from the taper surfaces of both femoral head and stem. This paper describes a method for the measurement and analysis of material loss from the modular taper junction of hip replacements, in particular femoral stem tapers where generally the entire taper surface has been engaged. In such cases no direct unworn datum is readily identifiable to assess material loss. The highly anisotropic topology of some stem designs poses additional challenges to the measurement and analysis process. Estimation of material loss of retrieved femoral stems is further complicated by retrieval damage or surface deposits often present on the taper surface. The femoral head tapers typically exhibit areas of pristine surface attributed to the difference in taper length compared to the engaging stem. These areas can be selected as unworn when employed in the analysis process, provided they do not show surface damage or deposits. Measurement of the taper surfaces has been performed using a Talyrond (Ametek, Inc., US) out-of-roundness measurement instrument equipped with a 5µm diamond tip stylus. Vertical axial traces were employed to digitize the surface of the taper. Measurement data has been analyzed using a multi stage process that has been specifically adapted for stem tapers. The underlying stem taper geometry is determined by means of a morphological filter to remove the high aspect ratio microstructure. This paper presents a study of 40 retrieved LHMoM hip replacements that have been analyzed to ascertain the material loss at the modular taper junction. The purpose of this study was to ascertain the viability of characterizing material loss from the stem taper junction and to provide insight into the overall material loss contribution

Acculturation to the global consumer culture and ethnic identity : an empirical study in Lebanon

Today's world is affected in all its aspects, including consumers' behaviors and attitudes, by the activities representing globalization. With respect to global media, technology, and traveling activities, the whole world is becoming one single market, containing diverse cultures, with similar consumer needs. A wide body of research has demonstrated that culture significantly affects consumer behavior. Thus it is important for marketing managers to examine the effects of global consumer culture on today's consumers' consumption patterns. This helps them know when and where to standardize or localize their marketing strategies and plans of actions regarding consumer behavior, communication, and retailing, and when, where, and how to blend both standardization and adaptation. With fast developing economies, international business activities have been growing very fast recently in the Middle-East in general; therefore, in order to extend the research boundaries and break the North American bias in the literature, Lebanon is the focus of the present's study to connect acculturation to global consumer culture (AGCC) and ethnic identity (EID) to consumer behavior. In addition, the present study links AGCC and EID to other constructs such as ethnocentrism (CET), materialism (MAT), religiosity (REL), demographics, and Schwartz's Value Dimensions (SVD). It turns out that the Lebanese population is slightly acculturated above average score to the global consumer culture, yet still very attached to their traditions. Moreover, AGCC and EID are negatively related, where the former construct positively affects global food and consumption, while the latter influences (a) positively local food and clothing consumption and (b) negatively luxury good consumption. In addition, AGCC shows a (1) negative relationship with CET and a positive relationship with MAT respectively, while EID shows positive relationships with each of CET, MAT, and REL. As to SVD, AGCC is found to be positively related to openness to change, self-transcendence, and self-enhancement, while EID is found to be positively related to conservation, self-transcendence, and self-enhancement. The study concludes that marketing managers should adapt their strategies for culture-bound products and standardize their strategies for culture-free products (except for luxury goods) in Lebanon. Limitations and directions for future research are highlighted as well