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The multifactorial nature of Alzheimer’s disease necessitates the development of agents able to interfere with different relevant targets. A series of 22 tailored chromanones was conceptualized, synthesized and subjected to biological evaluation. We identified one representative bearing a linker-connected azepane moiety (compound 19) with balanced pharmacological properties. Compound 19 exhibited inhibitory activities against human acetyl-, butyrylcholinesterase and monoamine oxidase-B, as well as high affinity to both the 1 and 2 receptor. Our study provides a framework for the development of further chromanone-based multineurotarget agents.

The Front Cover illustrates the natural product andrographolide, which modulates the abundance of the transcription factor NRF2, a substrate of the E3 ligase KEAP1. Previous studies identified that this drug possessed anti-SARS-CoV-2 activity, but the mechanism of action remained unclear. The authors designed and synthesized novel andrographolide derivatives with a functional site to fine-tune physicochemical properties and for linker attachment. The team assayed this new set of compounds in a cell-based NRF2 reporter gene assay and determined their ability to decrease infectivity of virus-treated Vero-E6 cells. Data showed that NRF2 activation by compounds and inhibition of SARS-CoV-2 replication correlated well. The study opens new avenues to investigate natural products that target the KEAP1/NRF2 axis as anti-SARS-CoV-2 agents. More information can be found in the Research Article by Christian Steinebach et al.

Naturally occurring compounds represent a vast pool of pharmacologically active entities. One of such compounds is andrographolide, which is endowed with many beneficial properties, including the activity against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). To initiate a drug repurposing or hit optimization campaign, it is imperative to unravel the primary mechanism(s) of the antiviral action of andrographolide. Here, we showed by means of a reporter gene assay that andrographolide exerts its anti-SARS-CoV-2 effects by inhibiting the interaction between Kelch-like ECH-associated protein 1 (KEAP1) and nuclear factor erythroid 2-related factor 2 (NRF2) causing NRF2 upregulation. Moreover, we demonstrated that subtle structural modifications of andrographolide could lead to derivatives with stronger on-target activities and improved physicochemical properties. Our results indicate that further optimization of this structural class is warranted to develop novel COVID-19 therapies.

Background Although patients with Alzheimer’s disease and other cognitive-related neurodegenerative disorders may benefit from early detection, development of a reliable diagnostic test has remained elusive. The penetration of digital voice-recording technologies and multiple cognitive processes deployed when constructing spoken responses might offer an opportunity to predict cognitive status. Objective To determine whether cognitive status might be predicted from voice recordings of neuropsychological testing Design Comparison of acoustic and (para)linguistic variables from low-quality automated transcriptions of neuropsychological testing (n = 200) versus variables from high-quality manual transcriptions (n = 127). We trained a logistic regression classifier to predict cognitive status, which was tested against actual diagnoses. Setting Observational cohort study. Participants 146 participants in the Framingham Heart Study. Measurements Acoustic and either paralinguistic variables (e.g., speaking time) from automated transcriptions or linguistic variables (e.g., phrase complexity) from manual transcriptions. Results Models based on demographic features alone were not robust (area under the receiver-operator characteristic curve [AUROC] 0.60). Addition of clinical and standard acoustic features boosted the AUROC to 0.81. Additional inclusion of transcription-related features yielded an AUROC of 0.90. Conclusions The use of voice-based digital biomarkers derived from automated processing methods, combined with standard patient screening, might constitute a scalable way to enable early detection of dementia.

Am 20. Januar 2021 wird Joe Biden als der 46. Präsident der USA ins Weiße Haus einziehen. Mit dem Machtwechsel in Washington werden in Deutschland und in Europa große Erwartungen und Hoffnungen verbunden. Viele versprechen sich eine Entspannung der transatlantischen Beziehungen sowie die Rückkehr der USA zum Multilateralismus und einer regelbasierten internationalen Ordnung. Auch in der Wirtschaftspolitik wird mit Veränderungen gerechnet, die vor allem der Handels- und der Klimapolitik positive Impulse verleihen würden. Sind die Hoffnungen auf eine neue politische Ära berechtigt? Philipp Hauber, Institut für Weltwirtschaft, Kiel, rechnet mit erheblichen Veränderungen in der Wirtschaftspolitik. Die Agenda von Joe Biden sehe weitreichende Ausgaben vor allem in den Bereichen Infrastruktur, erneuerbare Energien und Bildung vor, die zum Teil durch Steuererhöhungen finanziert werden sollen. Stormy-Annika Mildner, Aspen Institute, Berlin, geht davon aus, dass Biden zwar die „America-first“-Politik von Trump nicht fortsetzen werde, allerdings werde seine Handelspolitik ebenfalls protektionistische Elemente enthalten. Zudem gehöre Handel nicht zu seinen Top-Prioritäten. Umso wichtiger sei es, dass die Handelspartner der USA – allen voran die EU – nicht auf Angebote warten, sondern den USA aktiv Angebote unterbreiten. Galina Kolev und Jürgen Matthes, Institut der deutschen Wirtschaft, Köln, sehen vor allem eine Änderung im Ton bei der Handelspolitik. Jedoch dürfte auch unter Joe Biden der wirtschafts- und handelspolitische Kurs der USA weiterhin von dem Grundsatz “America first” geprägt sein. Sonja Peterson, Institut für Weltwirtschaft, Kiel, geht davon aus, dass sich die USA mit Joe Biden wieder den Zielen des Pariser Klimaabkommens verpflichtet fühlen. Denn er habe für die USA ambitionierte und angemessene langfristige Ziele – u. a. Treibhausgasneutralität bis 2050 – angekündigt. Reimund Schwarze, Universität Leipzig, sieht ebenfalls positive Zeichen für die internationale

Polyploidy often confers emergent properties, such as the higher fibre productivity and quality of tetraploid cottons than diploid cottons bred for the same environments. Here we show that an abrupt five-to sixfold ploidy increase approximately 60million years (Myr) ago, and allopolyploidy reuniting divergent Gossypium genomes approximately 1-2 Myr ago, conferred about 30-36-fold duplication of ancestral angiosperm (flowering plant) genes in elite cottons (Gossypium hirsutum and Gossypium barbadense), genetic complexity equalled only by Brassica among sequenced angiosperms. Nascent fibre evolution, before allopolyploidy, is elucidated by comparison of spinnable-fibred Gossypium herbaceum A and non-spinnable Gossypium longicalyx F genomes to one another and the outgroup D genome of non-spinnable Gossypium raimondii. The sequence of a G. hirsutum A t D t (in which t' indicates tetraploid) cultivar reveals many non-reciprocal DNA exchanges between subgenomes that may have contributed to phenotypic innovation and/or other emergent properties such as ecological adaptation by polyploids. Most DNA-level novelty in G. hirsutum recombines alleles from the D-genome progenitor native to its New World habitat and the Old World A-genome progenitor in which spinnable fibre evolved. Coordinated expression changes in proximal groups of functionally distinct genes, including a nuclear mitochondrial DNA block, may account for clusters of cotton-fibre quantitative trait loci affecting diverse traits. Opportunities abound for dissecting emergent properties of other polyploids, particularly angiosperms, by comparison to diploid progenitors and outgroups. © 2012 Macmillan Publishers Limited. All rights reserved.

Polyploidy often confers emergent properties, such as the higher fibre productivity and quality of tetraploid cottons than diploid cottons bred for the same environments. Here we show that an abrupt five-to sixfold ploidy increase approximately 60million years (Myr) ago, and allopolyploidy reuniting divergent Gossypium genomes approximately 1-2 Myr ago, conferred about 30-36-fold duplication of ancestral angiosperm (flowering plant) genes in elite cottons (Gossypium hirsutum and Gossypium barbadense), genetic complexity equalled only by Brassica among sequenced angiosperms. Nascent fibre evolution, before allopolyploidy, is elucidated by comparison of spinnable-fibred Gossypium herbaceum A and non-spinnable Gossypium longicalyx F genomes to one another and the outgroup D genome of non-spinnable Gossypium raimondii. The sequence of a G. hirsutum A t D t (in which t' indicates tetraploid) cultivar reveals many non-reciprocal DNA exchanges between subgenomes that may have contributed to phenotypic innovation and/or other emergent properties such as ecological adaptation by polyploids. Most DNA-level novelty in G. hirsutum recombines alleles from the D-genome progenitor native to its New World habitat and the Old World A-genome progenitor in which spinnable fibre evolved. Coordinated expression changes in proximal groups of functionally distinct genes, including a nuclear mitochondrial DNA block, may account for clusters of cotton-fibre quantitative trait loci affecting diverse traits. Opportunities abound for dissecting emergent properties of other polyploids, particularly angiosperms, by comparison to diploid progenitors and outgroups. © 2012 Macmillan Publishers Limited. All rights reserved.

In times of scarce resources and increasing demands, an optimum IT support requires a greater service orientation and a more systematic description and management. While IT Service Management (ITSM) previously in the industry has become a standard, there are so far, only few best practice examples at universities and research institutions. The essential characteristic of this paradigm shift in the way of IT provisioning is to align IT with the specific business processes of the organization. This paper proposes an approach to ITSM for research institutes that achieves an IT and business alignment in the context of an IT service orientation, based on ITIL v3. Starting with a description of the business processes in the context of research institutions the required IT services structure can be derived. A draft of a generic business process map providing the basis for the definition and design of IT services has been found. The resulting IT service and IT function catalogues combine the business and technical view. This provides the first step towards the development of a standardized and efficient implementation reference model for ITSM in the research area. The goal of this ongoing project is to develop a practical framework for the ITSM of research institutes and an IT management information system prototype.

In times of scarce resources and increasing demands, an optimum IT support requires a greater service orientation and a more systematic description and management. While IT Service Management (ITSM) previously in the industry has become a standard, there are so far, only few best practice examples at universities and research institutions. The essential characteristic of this paradigm shift in the way of IT provisioning is to align IT with the specific business processes of the organization. This paper proposes an approach to ITSM for research institutes that achieves an IT and business alignment in the context of an IT service orientation, based on ITIL v3. Starting with a description of the business processes in the context of research institutions the required IT services structure can be derived. A draft of a generic business process map providing the basis for the definition and design of IT services has been found. The resulting IT service and IT function catalogues combine the business and technical view. This provides the first step towards the development of a standardized and efficient implementation reference model for ITSM in the research area. The goal of this ongoing project is to develop a practical framework for the ITSM of research institutes and an IT management information system prototype.

The linear complementarity problem and the piecewise linear system are the two principal models in complementary pivot and fixed point theory. It is shown that the path following methods for solving each are conceptually equivalent. (Author), Sponsored in part by Grant NSF-MCS78-02096.

Some theorems are given which relate to approximating and establishing the existence of solutions to systems F(x) = y of n equations in n unknowns, for various y, in a region of euclidean n-space (E sup n). They generalize known theorems. Viewing complementarity problems and fixed-point problems as examples, known results or generalization of known results are obtained., Sponsored in part by Chicago Univ., Ill. Graduate School of Business, and Rensselaer Polytechnic Inst., Troy, N.Y. Dept. of Mathematical Sciences.

A differentiable function on a convex set K is said to be K-flat if its gradient vanishes at each of its zeros belonging to K. K-flatness of quadratic forms implies their constrained semi-definiteness. This furnishes a useful characterization of positive semi-definite matrices (when K is the whole space) and 'copositive-plus' matrices (when K is the non-negative orthant). Parallel comparisions between these classes of matrices are made. (Author), Prepared in cooperation with Rensselaer Polytechnic Inst., Troy, N. Y., Grants NSF-GP-6339, AF-AFOSR-339-64.