Section Extension from Hyperbolic Geometry of Punctured Disk and Holomorphic Family of Flat Bundles

The construction of sections of bundles with prescribed jet values plays a fundamental role in problems of algebraic and complex geometry. When the jet values are prescribed on a positive dimensional subvariety, it is handled by theorems of Ohsawa-Takegoshi type which give extension of line bundle valued square-integrable top-degree holomorphic forms from the fiber at the origin of a family of complex manifolds over the open unit 1-disk when the curvature of the metric of line bundle is semipositive. We prove here an extension result when the curvature of the line bundle is only semipositive on each fiber with negativity on the total space assumed bounded from below and the connection of the metric locally bounded, if a square-integrable extension is known to be possible over a double point at the origin. It is a Hensel-lemma-type result analogous to Artin's application of the generalized implicit function theorem to the theory of obstruction in deformation theory. The motivation is the need in the abundance conjecture to construct pluricanonical sections from flatly twisted pluricanonical sections. We also give here a new approach to the original theorem of Ohsawa-Takegoshi by using the hyperbolic geometry of the punctured open unit 1-disk to reduce the original theorem of Ohsawa-Takegoshi to a simple application of the standard method of constructing holomorphic functions by solving the d-bar equation with cut-off functions and additional blowup weight functions

Challenges for Optimizing Real-World Evidence in Alzheimer’s Disease: The ROADMAP Project

ROADMAP is a public-private advisory partnership to evaluate the usability of multiple data sources, including real-world evidence, in the decision-making process for new treatments in Alzheimer’s disease, and to advance key concepts in disease and pharmacoeconomic modeling. ROADMAP identified key disease and patient outcomes for stakeholders to make informed funding and treatment decisions, provided advice on data integration methods and standards, and developed conceptual cost-effectiveness and disease models designed in part to assess whether early treatment provides long-term benefit

A practical drug discovery project at the undergraduate level

A practical drug discovery project for third-year undergraduates is described. No previous knowledge of medicinal chemistry is assumed. Initial lecture-workshops cover the basic principles; then students are asked to improve the profile of a weakly potent, poorly soluble PI3K inhibitor (1). Compound array design, molecular modelling and screening data analysis are followed by laboratory work in which each student, as part of a team, attempts to synthesise at least two target compounds. The project benefits from significant industrial support, including lectures, student mentoring and consumables. The aim is to make the learning experience as close as possible to real-life industrial situations. Forty-eight target compounds have been prepared, the best of which (5b, 5j, 6b and 6ap) improved the potency and aqueous solubility of the lead compound (1) by 100-1000 fold and 10-fold, respectively

Exploiting bacterial DNA gyrase as a drug target: current state and perspectives

DNA gyrase is a type II topoisomerase that can introduce negative supercoils into DNA at the expense of ATP hydrolysis. It is essential in all bacteria but absent from higher eukaryotes, making it an attractive target for antibacterials. The fluoroquinolones are examples of very successful gyrase-targeted drugs, but the rise in bacterial resistance to these agents means that we not only need to seek new compounds, but also new modes of inhibition of this enzyme. We review known gyrase-specific drugs and toxins and assess the prospects for developing new antibacterials targeted to this enzyme

High performance hybrid construction system with timber and steel

In nur fünf Monaten wurde in Lenzburg (CH) mit einem neu ent-wickelten Hochleistungs-Hybridbausystem ein energieeffizien-tes Mehrfamilienhaus mit 20 preisgünstigen Mietwohnungen realisiert.Das Prinzip des Hochleistungs-Hybridbausystems sieht bezugs-fertig hergestellte kubische Wohnraummodule aus einer Holz-leichtbaukonstruktion vor, welche auf der Baustelle in eine vor-gängig montierte Stahlskelettkonstruktion eingefügt werden. Im Gegensatz zur üblichen Raummodulbauweise, bei der die Module aufeinandergestapelt werden, konnten durch das Ent-wurfsprinzip der sich selbst tragenden Holzbaumodule die Wanddicken reduziert und damit wesentlich materialoptimiert werden. Die Stahlskelettkonstruktion ermöglicht, die Wanddi-cke der Stahlhohlprofile optimal auf die Anzahl der Geschosse anzupassen. Die Stahlskelettstützen bleiben in ihren Außen-abmessung bei vier- bis achtgeschossigen Gebäuden immer gleich und ermöglichen eine max. Standardisierung bei der Detailausbildung. Eines der Schlüsselelemente der Entwick-lungsarbeit war die konsequent ausgebildete Schallentkopp-lung zwischen Wohnraummodul und Stahlskelett. Sämtliche Auflagerdetails, Stabilisierungsanschlüsse und Verbindungen zwischen Modul und Skelett sind durch Elastomerlager schall-technisch entkoppelt.In just five months, an energy-efficient apartment building with 20 low-priced rental apartments was built in Lenzburg (Switzer-land) using a newly developed high-performance hybrid con-struction system.The principle of the high-performance hybrid construction system envisages cubic living space modules made of a light-weight timber construction and manufactured ready to move, which are inserted into a previously assembled steel skeleton construction on site. In contrast to the usual room module con-struction method, in which the modules are stacked on top of each other, the present design principle of the self-supporting timber construction modules allows a reduction of wall thick-nesses and thus a considerable optimization of material use. The steel skeleton construction enables an optimal adaptation of wall thickness of the steel hollow sections to the number of floors. The external dimensions of the steel skeleton support remain always the same for four to eight story buildings and allow a maximum standardization in the detail design. One of the key elements of the development work is the consistently developed sound decoupling between the living space module and the steel skeleton. All support details, stabilisation connec-tions and connections between module and skeleton are sound decoupled by elastomer layers