Radiocommunications Agency

In nature, key molecular processes such as communication, replication, and enzyme catalysis all rely on a delicate balance between molecular and supramolecular chirality. Here we report the design, synthesis, and operation of a reversible, photoresponsive, self-assembling molecular system in which molecular and supramolecular chirality communicate. It shows exceptional stereoselectivity upon aggregation of the molecules during gel formation with the solvent. This chirality is locked by photochemical switching, a process that is subsequently used to induce an inverted chiral supramolecular assembly as revealed by circular dichroism spectroscopy. The optical switching between different chiral aggregated states and the interplay of molecular and supramolecular chirality offer attractive new prospects for the development of molecular memory systems and smart functional materials.

<p>Eliminated without a trace: The fastest click reaction, the highly selective inverse-electron-demand Diels-Alder reaction, has been modified to enable selective bioorthogonal release. Thus, the click reaction of a tetrazine with a drug-bound trans-cyclooctene caused the instantaneous release of the drug and CO<sub>2</sub> (see scheme). One possible application is the chemically triggered release, and thereby activation, of a drug from a tumor-bound antibody-drug conjugate.</p>

Current antibody-drug conjugates (ADCs) target internalising receptors on cancer cells leading to intracellular drug release. Typically, only a subset of patients with solid tumours has sufficient expression of such a receptor, while there are suitable non-internalising receptors and stroma targets. Here, we demonstrate potent therapy in murine tumour models using a non-internalising ADC that releases its drugs upon a click reaction with a chemical activator, which is administered in a second step. This was enabled by the development of a diabody-based ADC with a high tumour uptake and very low retention in healthy tissues, allowing systemic administration of the activator 2 days later, leading to efficient and selective activation throughout the tumour. In contrast, the analogous ADC comprising the protease-cleavable linker used in the FDA approved ADC Adcetris is not effective in these tumour models. This first-in-class ADC holds promise for a broader applicability of ADCs across patient populations.

The last decades of neuroscience research have produced immense progress in the methods available to understand brain structure and function. Social, cognitive, clinical, affective, economic, communication, and developmental neurosciences have begun to map the relationships between neuro-psychological processes and behavioral outcomes, yielding a new understanding of human behavior and promising interventions. However, a limitation of this fast moving research is that most findings are based on small samples of convenience. Furthermore, our understanding of individual differences may be distorted by unrepresentative samples, undermining findings regarding brain-behavior mechanisms. These limitations are issues that social demographers, epidemiologists, and other population scientists have tackled, with solutions that can be applied to neuroscience. By contrast, nearly all social science disciplines, including social demography, sociology, political science, economics, communication science, and psychology, make assumptions about processes that involve the brain, but have incorporated neural measures to differing, and often limited, degrees; many still treat the brain as a black box. In this article, we describe and promote a perspective--population neuroscience--that leverages interdisciplinary expertise to (i) emphasize the importance of sampling to more clearly define the relevant populations and sampling strategies needed when using neuroscience methods to address such questions; and (ii) deepen understanding of mechanisms within population science by providing insight regarding underlying neural mechanisms. Doing so will increase our confidence in the generalizability of the findings. We provide examples to illustrate the population neuroscience approach for specific types of research questions and discuss the potential for theoretical and applied advances from this approach across areas.

The use of a bioorthogonal reaction for the selective cleavage of tumor-bound antibody-drug conjugates (ADCs) would represent a powerful new tool for ADC therapy, as it would not rely on the currently used intracellular biological activation mechanisms, thereby expanding the scope to noninternalizing cancer targets. Here we report that the recently developed inverse-electron-demand Diels-Alder pyridazine elimination reaction can provoke rapid and self-immolative release of doxorubicin from an ADC in vitro and in tumor-bearing mice.

Properly functionalized dithienylethenes show promise for light-induced switching processes. To prevent cis/trans isomerization from competing with conrotatory 6π-electron ring closure, the ethene segment is usually incorporated in a (perfluorinated) cyclopentene. In the present article syntheses of perhydrocyclopentene 1 and perfluorocyclopentene 2 are described, which are amenable for large-scale conversions. Both compounds have chloro substituents at the 5-position of the thiophene rings to allow further functionalization. The conversion of the chloro substituents of 1 to formyl, carboxylate, boronyl, and hydrogen groups by halogen/lithium exchange at room temperature is described, and examples are given of further elaboration of 1 and 2 by attachment, both in a symmetrical as well as unsymmetrical fashion, of additional functionality by condensation, Friedel−Crafts or Suzuki reactions. The newly prepared thienylperhydrocyclopentene derivatives show reversible photochromism if the substituents at the 5-postions allow for conjugation with the thiophene π-system. (© Wiley-VCH Verlag GmbH & Co KGaA, 69451 Weinheim, Germany, 2003)

A century ago Wilhelm Ostwald received the Nobel Prize for Chemistry. Although Ostwald was never significantly involved with the phenomenon of chirality, one of his discoveries, Ostwald ripening, is thought to be involved in a recently discovered method in which grinding-induced attrition is used to transform racemic conglomerates virtually quantitatively into a single enantiomer. In this Minireview the basic concepts developed by Ostwald will be introduced, followed by a summary of the current status of grinding-induced asymmetric transformations. We will see how close Ostwald himself came to discovering this technique.

Change of heart: A solution-phase enantiomeric excess that has the handedness of the minor population of the solid phase is observed during grinding of a slurry of racemic conglomerate crystals. This excess is the driving force for a net flux of molecules from crystals of the minor handedness to crystals of the major handedness, thus explaining the complete deracemization of the solid phase (see picture: blue: S form, red: R form).

In 1977, Wegner conjectured that the chromatic number of the square of every planar graph G with maximum degree ∆ ≥ 8 is at most ⌈ 3 2 ∆ ⌉ + 1. We show that it is at most ∆ (1 + o(1)).

The reversible photoconversion of self-assembling dithienylcyclopentene photochromic switches between an aggregated and nonaggregated state is manifest at the macroscopic level by a fully reversible sol–gel phase transition and results in spatially confined structure formation in an inhomogeneous optical field. The reversibility of aggregation is exploited in dynamic pattern formation (see images).

Insights into the mechanism of attrition-enhanced deracemization and resolution of solid enantiomorphic chiral compounds are obtained by crystal size and solubility measurements and by isotopic labeling experiments. Together these results help to deconvolute the various chemical and physical rate processes contributing to the phenomenon. Crystal size measurements highlight a distinct correlation between the stochastic, transient growth of crystals and the emergence of a single solid enantiomorph under attrition conditions. The rapid mass transfer of molecules between the solution and solid phases under attrition is demonstrated, and the concept of a crystal-size-induced solubility driving force is exploited to overcome the stochastic nature of the crystal growth and dissolution processes. Extension to non-racemizing conditions provides a novel methodology for chiral resolution. Implications both for practical chiral separations and for the origin of biological homochirality are discussed.

Abstract The radio astronomy satellite HALCA was launched by the Institute of Space and Astronautical Science in 1997 February to participate in Very Long Baseline Interferometry (VLBI) observations with arrays of ground radio telescopes. HALCA is the main element of the VLBI Space Observatory Programme (VSOP), a complex international endeavor involving over 25 ground radio telescopes, five tracking stations and three correlators. Simultaneous observations with HALCA's 8 meter diameter radio telescope and ground radio telescopes synthesize a radio telescope over twice the size of the Earth, enabling the highest resolution 1.6 GHz and 5 GHz images to be made.

The bioorthogonal cleavage of allylic carbamates from trans-cyclooctene (TCO) upon reaction with tetrazine is widely used to release amines. We disclose herein that this reaction can also cleave TCO esters, carbonates, and surprisingly, ethers. Mechanistic studies demonstrated that the elimination is mainly governed by the formation of the rapidly eliminating 1,4-dihydropyridazine tautomer, and less by the nature of the leaving group. In contrast to the widely used p-aminobenzyloxy linker, which affords cleavage of aromatic but not of aliphatic ethers, the aromatic, benzylic, and aliphatic TCO ethers were cleaved as efficiently as the carbamate, carbonate, and esters. Bioorthogonal ether release was demonstrated by the rapid uncaging of TCO-masked tyrosine in serum, followed by oxidation by tyrosinase. Finally, tyrosine uncaging was used to chemically control cell growth in tyrosine-free medium.

Shaken and stirred: The emergence of single chirality in the solid state during grinding of a slurry has been kinetically studied for a phenylglycine amide (see scheme). The insight obtained into the underlying process of attrition-enhanced Ostwald ripening enables the definition of suitable conditions to increase the deracemization rate drastically. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Abstract We prove that for any planar graph G with maximum degree Δ, it holds that the chromatic number of the square of G satisfies χ( G 2 ) ≤ 2Δ + 25. We generalize this result to integer labelings of planar graphs involving constraints on distances one and two in the graph. © 2002 Wiley Periodicals, Inc. J Graph Theory 42: 110–124, 2003

In the past 5 years radiofrequency personal exposure meters have been used to characterize the exposure during daily activities. We found from calibration tests for the 12 frequency bands of the EME Spy 121 exposimeter in a Gigahertz Transverse Electromagnetic cell and an Open Area Test Site, that these measurements tend to underestimate the actual exposure. Therefore, a maximum frequency-dependent correction factor of 1.1-1.6 should be applied to the electric field. This correction factor consists of three multipliers correcting for calibration, elevation arrival angle, and influence of the body. The calibration correction factor should be determined per exposimeter, as the maximum range of response between exposimeters in a frequency band is 2.4 dB. Since the range of response for different elevation angles could reach 10.2 dB, a strict protocol for wearing the exposimeter during fieldwork should be followed to be able to compare and combine measurements made by different persons in the same microenvironments. Because the influence of the body depends on the azimuth angle of arrival, it may lead to an over- or underestimation. Thus, the body correction factor is an average over the angles and should only be applied in activities involving movement through the full 360° range of random angles of arrival.

Die schnellste Klick-Reaktion, die hoch selektive Diels-Alder-Reaktion mit inversem Elektronenbedarf, wurde so modifiziert, dass sie selektive bioorthogonale Freisetzungen ermöglicht. Auf diese Weise führte die Reaktion eines Tetrazins mit einem wirkstoffgebundenen trans-Cycloocten zur augenblicklichen Freisetzung des Wirkstoffs und von CO2 (siehe Schema). Eine mögliche Anwendung ist die chemisch ausgelöste Freisetzung und Aktivierung eines Wirkstoffs aus einem tumorgebundenen Antikörper-Wirkstoff-Konjugat. As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Beim Mahlen einer Aufschlämmung eines kristallinen racemischen Konglomerats beobachtet man einen Enantiomerenüberschuss in der Lösungsphase, der die Händigkeit der Minderpopulation in den Festkörpern aufweist. Dieser Überschuss ist die treibende Kraft für einen Netto-Molekülfluss von den Kristallen der Minderpopulation hin zu denen der Hauptpopulation, was die vollständige Deracemisierung der Festphase erklärt (siehe Bild; blau: S-Form, rot: R-Form). Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

High-throughput screening (HTS) represents a major cornerstone of drug discovery. The availability of an innovative, relevant and high-quality compound collection to be screened often dictates the final fate of a drug discovery campaign. Given that the chemical space to be sampled in research programs is practically infinite and sparsely populated, significant efforts and resources need to be invested in the generation and maintenance of a competitive compound collection. The European Lead Factory (ELF) project is addressing this challenge by leveraging the diverse experience and know-how of academic groups and small and medium enterprises (SMEs) engaged in synthetic and/or medicinal chemistry. Here, we describe the novelty, diversity, structural complexity, physicochemical characteristics and overall attractiveness of this first batch of ELF compounds for HTS purposes.

Geschüttelt und gerührt: Die Entstehung einer einheitlichen Chiralität im Festzustand beim Vermahlen einer Aufschlämmung wurde am Beispiel eines Phenylglycinamids kinetisch untersucht (siehe Schema). Die Ergebnisse geben Einblick in den zugrundeliegenden Prozess der abriebverstärkten Ostwald-Reifung, woraus optimale Reaktionsbedingungen zur Beschleunigung der Deracemisierung abgeleitet wurden. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.