Human gene control by vital oncogenes: revisiting a theoretical model and its implications for targeted cancer therapy

An important assumption of our current understanding of the mechanisms of carcinogenesis has been the belief that clarification of the cancer process would inevitably reveal some of the crucial mechanisms of normal human gene regulation. Since the momentous work of Bishop and Varmus, both the molecular and the biochemical processes underlying the events in the development of cancer have become increasingly clear. The identification of cellular signaling pathways and the role of protein kinases in the events leading to gene activation have been critical to our understanding not only of normal cellular gene control mechanisms, but also have clarified some of the important molecular and biochemical events occurring within a cancer cell. We now know that oncogenes are dysfunctional proto-oncogenes and that dysfunctional tumor suppressor genes contribute to the cancer process. Furthermore, Weinstein and others have hypothesized the phenomenon of oncogene addiction as a distinct characteristic of the malignant cell. It can be assumed that cancer cells, indeed, become dependent on such vital oncogenes. The products of these vital oncogenes, such as c-myc, may well be the Achilles heel by which targeted molecular therapy may lead to truly personalized cancer therapy. The remaining problem is the need to introduce relevant molecular diagnostic tests such as genome microarray analysis and proteomic methods, especially protein kinase identification arrays, for each individual patient. Genome wide association studies on cancers with gene analysis of single nucleotide and other mutations in functional proto-oncogenes will, hopefully, identify dysfunctional proto-oncogenes and allow the development of more specific targeted drugs directed against the protein products of these vital oncogenes. In 1984 Willis proposed a molecular and biochemical model for eukaryotic gene regulation suggesting how proto-oncogenes might function within the normal cell. That model predicted the existence of vital oncogenes and can now be used to hypothesize the biochemical and molecular mechanisms that drive the processes leading to disruption of the gene regulatory machinery, resulting in the transformation of normal cells into cancer.     

Gold Catalysis: β‐Ketonaphthalenes via Molecular Gymnastics of 1,6‐Diyne‐4‐en‐3‐ols

1,6‐Diyne‐4‐en‐3‐ols with one terminal alkyne were applied as test substrates for a possible dual catalyzed cyclization. Instead of a dual catalysis cycle, naphthyl ketone derivatives were obtained as single products. The regioselectivity of the obtained products is unprecedented. Instead of the expected naphthyl ketones bearing the keto group in the α‐position, the keto group is positioned in the ß‐position of the naphthyl skeleton by a complex rearrangement of the starting materials.     

A digitally temperature-compensated crystal oscillator

The base frequency of oscillators used in the Global System for Mobile Communication (GSM) network or Global Positioning System (GPS) receiver applications needs to be very stable with respect to temperature and supply-voltage variations. One approach to obtain extremely good frequency stability is the use of oven-stabilized crystal oscillators. With this kind of oscillator, a frequency stability versus temperature of a few ppb versus the standard temperature range can be achieved. In this paper, a digitally compensated crystal oscillator is described. The system provides a frequency stability of (Δf)/f<1.5 ppm for a temperature range of -40°C to 90°C compared to about ±20 ppm for a noncompensated crystal. The core of the system is an application-specified integrated circuit (ASIC) fabricated in a standard 0.8-μm CMOS process. The power consumption for the oscillator running at 13 MHz is 100 mW. The final device equipped with the ASIC, crystal blank, and a few external components fits into a 14×9×3 mm³ package     

Effektiver Algorithmus zur Lösung von inversen Aufgabenstellungen – Anwendung in der Geomechanik

Effective algorithm for solving inverse problems – geomechanical application. When working with numerical models, it is essential to determine model parameters which are as realistic as possible. Optimization techniques are being employed more and more frequently for solving this task. However, using these methods may lead to very high time costs – in particular, if rather complicated forward calculations are involved. In this paper, we present a class of methods that allows estimating the solution of this kind of optimization problems based on relatively few sampling points. We put very weak constraints on the sampling point distribution; hence, they may be taken from previous forward calculations as well as from alternative sources. Starting from an introduction into the theoretical approach, a strategy for speeding up inverse optimization problems is introduced which is illustrated by an example geomechanics.     

Bestimmung thermophysikalischer Parameter von Baustoffen

Determination of thermophysical parameters of building materials Heat transfer in construction elements is defined by the material‐sensitive parameters thermal conductivity and specific heat respectively the heat storage capacity. Many proposals exist for the measurement of these quantities. In this paper the mentioned parameters are determined out from time constants of the measured signals of temperature and heat flow density. The duration of the measurement lies in the medium‐minute range.     

Competitive snoopy caching

In a snoopy cache multiprocessor system, each processor has a cache in which it stores blocks of data. Each cache is connected to a bus used to communicate with the other caches and with main memory. Each cache monitors the activity on the bus and in its own processor and decides which blocks of data to keep and which to discard. For several of the proposed architectures for snoopy caching systems, we present new on-line algorithms to be used by the caches to decide which blocks to retain and which to drop in order to minimize communication over the bus. We prove that, for any sequence of operations, our algorithms' communication costs are within a constant factor of the minimum required for that sequence; for some of our algorithms we prove that no on-line algorithm has this property with a smaller constant.A preliminary and condensed version of this paper appeared in theProceedings of the 27th Annual Symposium on the Foundations of Computer Science, IEEE, 1986.This author received support from an IBM doctoral fellowship, and did part of this work while a research student associate at IBM Almaden Research Center.     

ARDEA—An MAV with skills for future planetary missions

We introduce a prototype flying platform for planetary exploration: autonomous robot design for extraterrestrial applications (ARDEA). Communication with unmanned missions beyond Earth orbit suffers from time delay, thus a key criterion for robotic exploration is a robot's ability to perform tasks without human intervention. For autonomous operation, all computations should be done on‐board and Global Navigation Satellite System (GNSS) should not be relied on for navigation purposes. Given these objectives ARDEA is equipped with two pairs of wide‐angle stereo cameras and an inertial measurement unit (IMU) for robust visual‐inertial navigation and time‐efficient, omni‐directional 3D mapping. The four cameras cover a $240^{°}$ vertical field of view, enabling the system to operate in confined environments such as caves formed by lava tubes. The captured images are split into several pinhole cameras, which are used for simultaneously running visual odometries. The stereo output is used for simultaneous localization and mapping, 3D map generation and collision‐free motion planning. To operate the vehicle efficiently for a variety of missions, ARDEA's capabilities have been modularized into skills which can be assembled to fulfill a mission's objectives. These skills are defined generically so that they are independent of the robot configuration, making the approach suitable for different heterogeneous robotic teams. The diverse skill set also makes the micro aerial vehicle (MAV) useful for any task where autonomous exploration is needed. For example terrestrial search and rescue missions where visual navigation in GNSS‐denied indoor environments is crucial, such as partially collapsed man‐made structures like buildings or tunnels. We have demonstrated the robustness of our system in indoor and outdoor field tests.     

Towards Resilient Rotterdam? Key conditions for a networked approach to managing urban infrastructure risks

Critical infrastructures are increasingly recognized to be playing important roles in urban resilience theory and practice. However, little is known about which governance challenges result from making them an integral part of urban resilience policies and what role city administrations play or could play in the resulting governance arrangements. We address these shortcomings in the scholarly literature by analysing the case of the Dutch city of Rotterdam, which has positioned itself as a front runner with regard to urban resilience. We find that the city administration is limited in its authority and depends on decisions made by other public and private actors, particularly those relating to the integrated management of interconnected infrastructure networks such as those for water and energy provision. We therefore argue that institutionalizing resilience will strongly depend on city administrations’ institutional capacity to manage networks more effectively. For this, we derive key conditions for institutional adjustments in current governance arrangements. Necessary adjustments include redefining roles and responsibilities for cross‐territorial risk management, cross‐sectoral and cross‐departmental budgeting of resilience measures, and integrating local actions and measures with those at regional and national levels of government. Our conclusions call for national and supranational legal reforms to establish uniform procedural rules for urban risk management and contingency planning to provide guidance for municipalities on how to enhance the resilience of their cities and infrastructures.     

Effect of target peak power density on the phase formation,microstructure evolution,and mechanical properties of Cr2AlC MAX-phase coatings

The applicability of Cr₂AlC MAX-phases as protective coatings in energy conversion or aerospace applications requires a dense, single-phase structure. Therefore, we study the effect of target power density and substrate bias on phase formation, microstructure evolution, and mechanical properties of Cr₂AlC coatings utilizing direct current (DCMS) and high-power pulsed magnetron sputtering (HPPMS). Generally, HPPMS results in coatings with superior density and hence larger elastic moduli compared to DCMS, indicating that ion bombardment by ionized film-forming species is beneficial. However, decreasing the substrate bias to ?200 V for DCMS and ?100 V for HPPMS favors the ion bombardment induced formation of the disordered (Cr,Al)₂C_x solid solution. It is evident that there is an optimum moderate ion energy for the formation of dense Cr₂AlC coatings. Too low energy results in the formation of under-dense coatings. Too high energy yields the formation of (Cr,Al)₂C_x in addition to Cr₂AlC.