Motif co-regulation and co-operativity are common mechanisms in transcriptional, post-transcriptional and post-translational regulation

A substantial portion of the regulatory interactions in the higher eukaryotic cell are mediated by simple sequence motifs in the regulatory segments of genes and (pre-)mRNAs, and in the intrinsically disordered regions of proteins. Although these regulatory modules are physicochemically distinct, they share an evolutionary plasticity that has facilitated a rapid growth of their use and resulted in their ubiquity in complex organisms. The ease of motif acquisition simplifies access to basal housekeeping functions, facilitates the co-regulation of multiple biomolecules allowing them to respond in a coordinated manner to changes in the cell state, and supports the integration of multiple signals for combinatorial decision-making. Consequently, motifs are indispensable for temporal, spatial, conditional and basal regulation at the transcriptional, post-transcriptional and post-translational level. In this review, we highlight that many of the key regulatory pathways of the cell are recruited by motifs and that the ease of motif acquisition has resulted in large networks of co-regulated biomolecules. We discuss how co-operativity allows simple static motifs to perform the conditional regulation that underlies decision-making in higher eukaryotic biological systems. We observe that each gene and its products have a unique set of DNA, RNA or protein motifs that encode a regulatory program to define the logical circuitry that guides the life cycle of these biomolecules, from transcription to degradation. Finally, we contrast the regulatory properties of protein motifs and the regulatory elements of DNA and (pre-)mRNAs, advocating that co-regulation, co-operativity, and motif-driven regulatory programs are common mechanisms that emerge from the use of simple, evolutionarily plastic regulatory modules

A 1-Kbit EEPROM in SIMOX technology for high-temperature applications up to 250 deg C

A 1-Kbit high-temperature EEPROM memory module has been developed in a 1.6µm thin-film SIMOX technology. The memory array is based on single-poly EEPROM cells, which are erased and programmed by Fowler-Nordheim tunneling. Operation at elevated temperatures is achieved by a special array design, suitable for elimination of cell-disturb problems caused by temperature-induced leakage currents of the select transistors. High-voltage switching is done without PMOS transistors in order to avoid leakage currents due to the backgate effect. The memory module is designed for 5-V-only operation and offers an access time of 260 ns at an operating temperature of 250 °C. At 250 °C, data retention of 3000 h and an endurance of 10000 erase/program cycles has been achieved. The area of the 1-Kbit memory module is 0.89 x 2.71 mm²

A MOS switched capacitor ladder filter in SIMOX technology for high temperature applications up to 300 degrees Celsius

This paper describes techniques and methods used to realize a seventh order switched capacitor low pass filter in SIMOX technology. The filter has bessel characteristic and a 3dB-bandwidth of 20Hz at a clock frequency of 100kHz. Special design of transistors and transmission gates results in drastically reduced leakage currents. The power supply voltage is 10V. The temperature range is extended up to 300øC. Experimental results of this filter are presented

JUVENILE OSSIFYING FIBROMA - AN ANALYSIS OF 33 CASES WITH EMPHASIS ON HISTOPATHOLOGICAL ASPECTS

Juvenile ossifying fibroma (JOF) is a maxillofacial fibro-osseous lesion that may show cell-rich osteoid strands or psammoma-like ossicles. Whether both types are variants of a single entity or different lesions under the same diagnostic label is a subject of debate. This problem was investigated by analyzing a series of 33 patients with lesions having one or bath of the above histological appearances. It was concluded that osteoid strands define a unique fibro-osseous lesion but that lesions with psammoma-like ossicles fall within the morphological spectrum of cemento-ossifying fibroma. Therefore the term juvenile ossifying fibroma should be reserved for the lesion with the osteoid strands

K-ras Mutation Subtypes in NSCLC and Associated Co-occuring Mutations in Other Oncogenic Pathways

Introduction: Although KRAS mutations in NSCLC have been considered mutually exclusive driver mutations for a long time, there is now growing evidence that KRAS-mutated NSCLC represents a genetically heterogeneous subgroup. We sought to determine genetic heterogeneity with respect to cancer-related co-mutations and their correlation with different KRAS mutation subtypes. Methods: Diagnostic samples from 4507 patients with NSCLC were analyzed by next-generation sequencing by using a panel of 14 genes and, in a subset of patients, fluorescence in situ hybridization. Next-generation sequencing with an extended panel of 14 additional genes was performed in 101 patients. Molecular data were correlated with clinical data. Whole-exome sequencing was performed in two patients. Results: We identified 1078 patients with KRAS mutations, of whom 53.5% had at least one additional mutation. Different KRAS mutation subtypes showed different patterns of co-occurring mutations. Besides mutations in tumor protein p53 gene (TP53) (39.4%), serine/threonine kinase 11 gene (STK11) (19.8%), kelch like ECH associated protein 1 gene (KEAP1) (12.9%), and ATM serine/threonine kinase gene (ATM) (11.9%), as well as MNNG HOS Transforming gene (MET) amplifications (15.4%) and erb-b2 receptor tyrosine kinase 2 gene (ERBB2) amplifications (13.8%, exclusively in G12C), we found rare co-occurrence of targetable mutations in EGFR (1.2%) and BRAF (1.2%). Whole-exome sequencing of two patients with co-occurring phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA) mutation revealed clonality of mutated KRAS in one patient and subclonality in the second, suggesting different evolutionary backgrounds. Conclusion: KRAS-mutated NSCLC represents a genetically heterogeneous subgroup with a high frequency of co-occurring mutations in cancer-associated pathways, partly associated with distinct KRAS mutation subtypes. This diversity might have implications for understanding the variability of treatment outcome in KRAS-mutated NSCLC and for future trial design. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc