Expression Patterns of Protein Kinases Correlate with Gene Architecture and Evolutionary Rates

Protein kinase (PK) genes comprise the third largest superfamily that occupy ∼2% of the human genome. They encode regulatory enzymes that control a vast variety of cellular processes through phosphorylation of their protein substrates. Expression of PK genes is subject to complex transcriptional regulation which is not fully understood.Our comparative analysis demonstrates that genomic organization of regulatory PK genes differs from organization of other protein coding genes. PK genes occupy larger genomic loci, have longer introns, spacer regions, and encode larger proteins. The primary transcript length of PK genes, similar to other protein coding genes, inversely correlates with gene expression level and expression breadth, which is likely due to the necessity to reduce metabolic costs of transcription for abundant messages. On average, PK genes evolve slower than other protein coding genes. Breadth of PK expression negatively correlates with rate of non-synonymous substitutions in protein coding regions. This rate is lower for high expression and ubiquitous PKs, relative to low expression PKs, and correlates with divergence in untranslated regions. Conversely, rate of silent mutations is uniform in different PK groups, indicating that differing rates of non-synonymous substitutions reflect variations in selective pressure. Brain and testis employ a considerable number of tissue-specific PKs, indicating high complexity of phosphorylation-dependent regulatory network in these organs. There are considerable differences in genomic organization between PKs up-regulated in the testis and brain. PK genes up-regulated in the highly proliferative testicular tissue are fast evolving and small, with short introns and transcribed regions. In contrast, genes up-regulated in the minimally proliferative nervous tissue carry long introns, extended transcribed regions, and evolve slowly.PK genomic architecture, the size of gene functional domains and evolutionary rates correlate with the pattern of gene expression. Structure and evolutionary divergence of tissue-specific PK genes is related to the proliferative activity of the tissue where these genes are predominantly expressed. Our data provide evidence that physiological requirements for transcription intensity, ubiquitous expression, and tissue-specific regulation shape gene structure and affect rates of evolution

Retinoic Acid-Dependent Signaling Pathways and Lineage Events in the Developing Mouse Spinal Cord

Studies in avian models have demonstrated an involvement of retinoid signaling in early neural tube patterning. The roles of this signaling pathway at later stages of spinal cord development are only partly characterized. Here we use Raldh2-null mouse mutants rescued from early embryonic lethality to study the consequences of lack of endogenous retinoic acid (RA) in the differentiating spinal cord. Mid-gestation RA deficiency produces prominent structural and molecular deficiencies in dorsal regions of the spinal cord. While targets of Wnt signaling in the dorsal neuronal lineage are unaltered, reductions in Fibroblast Growth Factor (FGF) and Notch signaling are clearly observed. We further provide evidence that endogenous RA is capable of driving stem cell differentiation. Raldh2 deficiency results in a decreased number of spinal cord derived neurospheres, which exhibit a reduced differentiation potential. Raldh2-null neurospheres have a decreased number of cells expressing the neuronal marker β-III-tubulin, while the nestin-positive cell population is increased. Hence, in vivo retinoid deficiency impaired neural stem cell growth. We propose that RA has separable functions in the developing spinal cord to (i) maintain high levels of FGF and Notch signaling and (ii) drive stem cell differentiation, thus restricting both the numbers and the pluripotent character of neural stem cells

Making pathogens sociable: the emergence of high relatedness through limited host invasibility

Cooperation depends upon high relatedness, the high genetic similarity of interacting partners relative to the wider population. For pathogenic bacteria, which show diverse cooperative traits, the population processes that determine relatedness are poorly understood. Here, we explore whether within-host dynamics can produce high relatedness in the insect pathogen Bacillus thuringiensis. We study the effects of host/pathogen interactions on relatedness via a model of host invasion and fit parameters to competition experiments with marked strains. We show that invasibility is a key parameter for determining relatedness and experimentally demonstrate the emergence of high relatedness from well-mixed inocula. We find that a single infection cycle results in a bottleneck with a similar level of relatedness to those previously reported in the field. The bottlenecks that are a product of widespread barriers to infection can therefore produce the population structure required for the evolution of cooperative virulence

Resection of pediatric intracerebral tumors with the aid of intraoperative real-time 3-D ultrasound

PURPOSE: Intraoperative ultrasound (IOUS) has become a useful tool employed daily in neurosurgical procedures. In pediatric patients, IOUS offers a radiation-free and safe imaging method. This study aimed to evaluate the use of a new real-time 3-D IOUS technique (RT-3-D IOUS) in our pediatric patient cohort. MATERIAL AND METHODS: Over 24 months, RT-3-D IOUS was performed in 22 pediatric patients (8 girls and 14 boys) with various brain tumors. These lesions were localized by a standard navigation system followed by analyses before, intermittently during, and after neurosurgical resection using the iU22 ultrasound system (Philips, Bothell, USA) connected to the RT-3-D probe (X7-2). RESULTS: In all 22 patients, real-time 3-D ultrasound images of the lesions could be obtained during neurosurgical resection. Based on this imaging method, rapid orientation in the surgical field and the approach for the resection could be planned for all patients. In 18 patients (82%), RT-3-D IOUS revealed a gross total resection with a favorable neurological outcome. CONCLUSION: RT-3-D IOUS provides the surgeon with advanced orientation at the tumor site via immediate live two-plane imaging. However, navigation systems have yet to be combined with RT-3-D IOUS. This combination would further improve intraoperative localization