Approaches to link RNA secondary structures with splicing regulation

In higher eukaryotes, alternative splicing is usually regulated by protein factors, which bind to the pre-mRNA and affect the recognition of splicing signals. There is recent evidence that the secondary structure of the pre-mRNA may also play an important role in this process, either by facilitating or by hindering the interaction with factors and small nuclear ribonucleoproteins (snRNPs) that regulate splicing. Moreover, the secondary structure could play a fundamental role in the splicing of yeast species, which lack many of the regulatory splicing factors present in metazoans. This review describes the steps in the analysis of the secondary structure of the pre-mRNA and its possible relation to splicing. As a working example, we use the case of yeast and the problem of the recognition of the 3-prime splice site.Comment: 21 pages, 7 figure

Convergence of density expansions of correlation functions and the Ornstein-Zernike equation

We prove absolute convergence of the multi-body correlation functions as a power series in the density uniformly in their arguments. This is done by working in the context of the cluster expansion in the canonical ensemble and by expressing the correlation functions as the derivative of the logarithm of an appropriately extended partition function. In the thermodynamic limit, due to combinatorial cancellations, we show that the coeffi- cients of the above series are expressed by sums over some class of two-connected graphs. Furthermore, we prove the convergence of the density expansion of the “direct correlation function” which is based on a completely different approach and it is valid only for some inte- gral norm. Precisely, this integral norm is suitable to derive the Ornstein-Zernike equation. As a further outcome, we obtain a rigorous quantification of the error in the Percus-Yevick approximation

A Gene in the Process of Endosymbiotic Transfer

BACKGROUND: The endosymbiotic birth of organelles is accompanied by massive transfer of endosymbiont genes to the eukaryotic host nucleus. In the centric diatom Thalassiosira pseudonana the Psb28 protein is encoded in the plastid genome while a second version is nuclear-encoded and possesses a bipartite N-terminal presequence necessary to target the protein into the diatom complex plastid. Thus it can represent a gene captured during endosymbiotic gene transfer. METHODOLOGY/PRINCIPAL FINDINGS: To specify the origin of nuclear- and plastid-encoded Psb28 in T. pseudonana we have performed extensive phylogenetic analyses of both mentioned genes. We have also experimentally tested the intracellular location of the nuclear-encoded Psb28 protein (nuPsb28) through transformation of the diatom Phaeodactylum tricornutum with the gene in question fused to EYFP. CONCLUSIONS/SIGNIFICANCE: We show here that both versions of the psb28 gene in T. pseudonana are transcribed. We also provide experimental evidence for successful targeting of the nuPsb28 fused with EYFP to the diatom complex plastid. Extensive phylogenetic analyses demonstrate that nucleotide composition of the analyzed genes deeply influences the tree topology and that appropriate methods designed to deal with a compositional bias of the sequences and the long branch attraction artefact (LBA) need to be used to overcome this obstacle. We propose that nuclear psb28 in T. pseudonana is a duplicate of a plastid localized version, and that it has been transferred from its endosymbiont

Reduced prefrontal gyrification in obsessive–compulsive disorder

Structural magnetic resonance imaging (MRI) studies reveal evidence for brain abnormalities in obsessive–compulsive disorder (OCD), for instance, reduction of gray matter volume in the prefrontal cortex. Disturbances of gyrification in the prefrontal cortex have been described several times in schizophrenia pointing to a neurodevelopmental etiology, while gyrification has not been studied so far in OCD patients. In 26 OCD patients and 38 healthy control subjects MR-imaging was performed. Prefrontal cortical folding (gyrification) was measured bilaterally by an automated version of the automated-gyrification index (A-GI), a ratio reflecting the extent of folding, from the slice containing the inner genu of the corpus callosum up to the frontal pole. Analysis of covariance (ANCOVA, independent factor diagnosis, covariates age, duration of education) demonstrated that compared with control subjects, patients with OCD displayed a significantly reduced A-GI in the left hemisphere (p = 0.021) and a trend for a decreased A-GI in the right hemisphere (p = 0.076). Significant correlations between prefrontal lobe volume and A-GI were only observed in controls, but not in OCD patients. In conclusion, prefrontal hypogyrification in OCD patients may be a structural correlate of the impairment in executive function of this patient group and may point to a neurodevelopmental origin of this disease

Visual Exploration and Object Recognition by Lattice Deformation

Mechanisms of explicit object recognition are often difficult to investigate and require stimuli with controlled features whose expression can be manipulated in a precise quantitative fashion. Here, we developed a novel method (called “Dots”), for generating visual stimuli, which is based on the progressive deformation of a regular lattice of dots, driven by local contour information from images of objects. By applying progressively larger deformation to the lattice, the latter conveys progressively more information about the target object. Stimuli generated with the presented method enable a precise control of object-related information content while preserving low-level image statistics, globally, and affecting them only little, locally. We show that such stimuli are useful for investigating object recognition under a naturalistic setting – free visual exploration – enabling a clear dissociation between object detection and explicit recognition. Using the introduced stimuli, we show that top-down modulation induced by previous exposure to target objects can greatly influence perceptual decisions, lowering perceptual thresholds not only for object recognition but also for object detection (visual hysteresis). Visual hysteresis is target-specific, its expression and magnitude depending on the identity of individual objects. Relying on the particular features of dot stimuli and on eye-tracking measurements, we further demonstrate that top-down processes guide visual exploration, controlling how visual information is integrated by successive fixations. Prior knowledge about objects can guide saccades/fixations to sample locations that are supposed to be highly informative, even when the actual information is missing from those locations in the stimulus. The duration of individual fixations is modulated by the novelty and difficulty of the stimulus, likely reflecting cognitive demand

Antiangiogenic agents in the treatment of recurrent or newly diagnosed glioblastoma: Analysis of single-agent and combined modality approaches

Surgical resection followed by radiotherapy and temozolomide in newly diagnosed glioblastoma can prolong survival, but it is not curative. For patients with disease progression after frontline therapy, there is no standard of care, although further surgery, chemotherapy, and radiotherapy may be used. Antiangiogenic therapies may be appropriate for treating glioblastomas because angiogenesis is critical to tumor growth. In a large, noncomparative phase II trial, bevacizumab was evaluated alone and with irinotecan in patients with recurrent glioblastoma; combination treatment was associated with an estimated 6-month progression-free survival (PFS) rate of 50.3%, a median overall survival of 8.9 months, and a response rate of 37.8%. Single-agent bevacizumab also exceeded the predetermined threshold of activity for salvage chemotherapy (6-month PFS rate, 15%), achieving a 6-month PFS rate of 42.6% (p < 0.0001). On the basis of these results and those from another phase II trial, the US Food and Drug Administration granted accelerated approval of single-agent bevacizumab for the treatment of glioblastoma that has progressed following prior therapy. Potential antiangiogenic agents-such as cilengitide and XL184-also show evidence of single-agent activity in recurrent glioblastoma. Moreover, the use of antiangiogenic agents with radiation at disease progression may improve the therapeutic ratio of single-modality approaches. Overall, these agents appear to be well tolerated, with adverse event profiles similar to those reported in studies of other solid tumors. Further research is needed to determine the role of antiangiogenic therapy in frontline treatment and to identify the optimal schedule and partnering agents for use in combination therapy