Homology of ciliary bands in Spiralian Trochophores

A number of hypotheses have been presented regarding the originsof the metazoans and, more specifically, the Bilateria. Usingvarious phylogenetic analyses, characteristics have been mappedon phylogenetic trees to infer ancestral body plans and lifehistory strategies of those ancestors. Many arguments on theevolution of the Bilateria are based on the presumed homologyof certain characteristics of extant larva and adults, includingvarious ciliated bands involved in feeding and locomotion. Thisarticle considers a recent study indicating that the second,downstream-collecting, ciliated band in the veliger larva ofthe gastropod mollusc, Crepidula fornicata, is actually derivedfrom secondary trochoblasts (derived from second quartet micromeres),that normally form part of the prototrochal band found in otherspiralian phyla (Hejnol et al. 2007). Despite previous arguments,these new findings suggest that the second ciliated band inthe veliger larva is not homologous to the metatroch found inthe trochophore larva of some other spiralians, such as theannelid, Polygordius lacteus. In the latter case, the metatrochwas reported to be formed by a different set of lineage precursors(derived from third quartet micromeres) (Woltereck 1904). Thesefindings have important implications for the interpretationof various hypotheses related to the evolution of metazoan phyla.     

Upregulation of miR-24 is associated with a decreased DNA damage response upon etoposide treatment in highly differentiated CD8(+) T cells sensitizing them to apoptotic cell death

The life-long homeostasis of memory CD8(+) T cells as well as persistent viral infections have been shown to facilitate the accumulation of highly differentiated CD8(+) CD28(-) T cells, a phenomenon that has been associated with an impaired immune function in humans. However, the molecular mechanisms regulating homeostasis of CD8(+) CD28(-) T cells have not yet been elucidated. In this study, we demonstrate that the miR-23～24～27 cluster is up-regulated during post-thymic CD8(+) T-cell differentiation in humans. The increased expression of miR-24 in CD8(+) CD28(-) T cells is associated with decreased expression of the histone variant H2AX, a protein that plays a key role in the DNA damage response (DDR). Following treatment with the classic chemotherapeutic agent etoposide, a topoisomerase II inhibitor, apoptosis was increased in CD8(+) CD28(-) when compared to CD8(+) CD28(+) T cells and correlated with an impaired DDR in this cell type. The reduced capacity of CD8(+) CD28(-) T cell to repair DNA was characterized by the automated fluorimetric analysis of DNA unwinding (FADU) assay as well as by decreased phosphorylation of H2AX at Ser139, of ATM at Ser1981, and of p53 at Ser15. Interleukin (IL)-15 could prevent etoposide-mediated apoptosis of CD8(+) CD28(-) T cells, suggesting a role for IL-15 in the survival and the age-dependent accumulation of CD8(+) CD28(-) T cells in humans.     

Immunocytochemistry of the neuromuscular systems of Loxosomella vivipara and L. parguerensis (Entoprocta: Loxosomatidae)

Little detailed information exists on the anatomy of the nervous system and the musculature of Entoprocta. Herein we describe the distribution of the neurotransmitters RFamide and serotonin as well as the myo-anatomy of adults and asexually produced budding stages of the solitary entoproct species Loxosomella vivipara and L. parguerensis using immunocytochemistry and epifluorescence as well as confocal microscopy. The development of the RFamidergic and serotonergic nervous system starts in early budding stages. In the adults, RFamide is present in the bilateral symmetric cerebral ganglion, a pair of oral nerves that innervate two pairs of nerve cell clusters in the heel of the foot, a pair of aboral nerves, the paired lateral nerves, the calyx nerves, the atrial ring nerve, the tentacle nerves, the stomach nerves, and the rectal nerves. Serotonin is only found in the cerebral ganglion, the oral nerves, and in the tentacle nerves. Some differences in the distribution of both neurotransmitters were found between L. vivipara and L. parguerensis and are most obvious in the differing number of large serotonergic perikarya associated with the oral nerves. Nerves arising from the cerebral ganglion and running in a ventral direction have not been described for Entoprocta before, and the homology of these to the ventral nerve cords of other Spiralia is considered possible. The body musculature of both Loxosomella species comprises longitudinal and diagonal muscles in the foot, the stalk, and the calyx. We found several circular muscles in the calyx. The stalk and parts of the foot and the calyx are surrounded by a fine outer layer of ring muscles. In addition to the congruent details regarding the myo-anatomy of both species, species-specific muscle structures could be revealed. The comparison of our data with recent findings of the myo-anatomy of two Loxosoma species indicates that longitudinal and diagonal body muscles, atrial ring muscles, tentacle muscles, esophageal and rectal ring muscles, as well as intestinal and anal sphincters are probably part of the ancestral entoproct muscle bauplan.     

A Systematic Review of MicroRNA in Glioblastoma Multiforme: Micro-modulators in the Mesenchymal Mode of Migration and Invasion

Glioblastoma multiforme (GBM) is an incurable form of brain cancer with a very poor prognosis. Because of its highly invasive nature, it is impossible to remove all tumor cells during surgical resection, making relapse inevitable. Further research into the regulatory mechanism underpinning GBM pathogenesis is therefore warranted, and over the past decade, there has been an increased focus on the functional role of microRNA (miRNA). This systematic review aims to present a comprehensive overview of all the available literature on the expression profiles and function of miRNA in GBM. Here, we have reviewed 163 papers and identified 253 upregulated, 95 downregulated, and 17 disputed miRNAs with respect to expression levels; 85 % of these miRNAs have not yet been functionally characterized. A focus in this study has been 26 interesting miRNAs involved in the mesenchymal mode of migration and invasion, demonstrating the importance of miRNAs in the context of the cellular niche. Both oncogenic and tumor-suppressive miRNAs were found to affect target genes involved in cell migration, cytoskeletal rearrangement, invasiveness, and angiogenesis. Clearly, the distinct functional properties of these miRNAs need further investigation and might hold a great potential in future molecular therapies targeting GBM.     

Microtubule-associated Proteins 1 (MAP1) Promote Human Immunodeficiency Virus Type I (HIV-1) Intracytoplasmic Routing to the Nucleus

After cell entry, HIV undergoes rapid transport toward the nucleus using microtubules and microfilaments. Neither the cellular cytoplasmic components nor the viral proteins that interact to mediate transport have yet been identified. Using a yeast two-hybrid screen, we identified four cytoskeletal components as putative interaction partners for HIV-1 p24 capsid protein: MAP1A, MAP1S, CKAP1, and WIRE. Depletion of MAP1A/MAP1S in indicator cell lines and primary human macrophages led to a profound reduction in HIV-1 infectivity as a result of impaired retrograde trafficking, demonstrated by a characteristic accumulation of capsids away from the nuclear membrane, and an overall defect in nuclear import. MAP1A/MAP1S did not impact microtubule network integrity or cell morphology but contributed to microtubule stabilization, which was shown previously to facilitate infection. In addition, we found that MAP1 proteins interact with HIV-1 cores both in vitro and in infected cells and that interaction involves MAP1 light chain LC2. Depletion of MAP1 proteins reduced the association of HIV-1 capsids with both dynamic and stable microtubules, suggesting that MAP1 proteins help tether incoming viral capsids to the microtubular network, thus promoting cytoplasmic trafficking. This work shows for the first time that following entry into target cells, HIV-1 interacts with the cytoskeleton via its p24 capsid protein. Moreover, our results support a role for MAP1 proteins in promoting efficient retrograde trafficking of HIV-1 by stimulating the formation of stable microtubules and mediating the association of HIV-1 cores with microtubules.     

Bloch Equations-Based Reconstruction of Myocardium T1 Maps from Modified Look-Locker Inversion Recovery Sequence

Modified Look-Locker Inversion recovery (MOLLI) sequence is increasingly performed for myocardial T1 mapping but is known to underestimate T1 values. The aim of the study was to quantitatively analyze several sources of errors when T1 maps are derived using standard post-processing of the sequence and to propose a reconstruction approach that takes into account inversion efficacy (η), T2 relaxation during balanced steady-state free-precession readouts and B1+ inhomogeneities. Contributions of the different sources of error were analyzed using Bloch equations simulations of MOLLI sequence. Bloch simulations were then combined with the acquisition of fast B1+ and T2 maps to derive more accurate T1 maps. This novel approach was evaluated on phantoms and on five healthy volunteers. Simulations show that T2 variations, B1+ heterogeneities and inversion efficiency represent major confounders for T1 mapping when MOLLI is processed with standard 3-parameters fitting. In vitro data indicate that T1 values are accurately derived with the simulation approach and in vivo data suggest that myocardium T1 are 15% underestimated when processed with the standard 3-parameters fitting. At the cost of additional acquisitions, this method might be suitable in clinical research protocols for precise tissue characterization as it decorrelates T1 and T2 effects on parametric maps provided by MOLLI sequence and avoids inaccuracies when B1+ is not homogenous throughout the myocardium.     

Integral strategy for evaluation of fecal indicator performance in bird-influenced saline inland waters

Wild birds are an important nonpoint source of fecal contamination of surface waters, but their contribution to fecal pollution is mostly difficult to estimate. Thus, to evaluate the relation between feces production and input of fecal indicator bacteria (FIB) into aquatic environments by wild waterfowl, we introduced a new holistic approach for evaluating the performance of FIB in six shallow saline habitats. For this, we monitored bird abundance, fecal pellet production, and the abundance of FIB concomitantly with a set of environmental variables over a 9-month period. For estimating fecal pellet production, a new protocol of fecal pellet counting was introduced, which was called fecal taxation (FTX). We could show that, over the whole range of investigated habitats, bird abundance, FTX values, and FIB abundance were highly significantly correlated and could demonstrate the good applicability of the FTX as a meaningful surrogate parameter for recent bird abundances and fecal contamination by birds in shallow aquatic ecosystems. Presumptive enterococci (ENT) were an excellent surrogate parameter of recent fecal contamination in these saline environments for samples collected at biweekly to monthly sampling intervals while presumptive Escherichia coli and fecal coliforms (FC) were often undetectable. Significant negative correlations with salinity indicated that E. coli and FC survival was hampered by osmotic stress. Statistical analyses further revealed that fecal pollution-associated parameters represented one system component independent from other environmental variables and that, besides feces production, rainfall, total suspended solids (direct), and trophy (indirect) had significant positive effects on ENT concentrations. Our holistic approach of linking bird abundance, feces production, and FIB detection with environmental variables may serve as a powerful model for application to other aquatic ecosystems.     

Polythiophenes inhibit prion propagation by stabilizing prion protein (PrP) aggregates

Luminescent conjugated polymers (LCPs) interact with ordered protein aggregates and sensitively detect amyloids of many different proteins, suggesting that they may possess antiprion properties. Here, we show that a variety of anionic, cationic, and zwitterionic LCPs reduced the infectivity of prion-containing brain homogenates and of prion-infected cerebellar organotypic cultured slices and decreased the amount of scrapie isoform of PrP(C) (PrP(Sc)) oligomers that could be captured in an avidity assay. Paradoxically, treatment enhanced the resistance of PrP(Sc) to proteolysis, triggered the compaction, and enhanced the resistance to proteolysis of recombinant mouse PrP(23-231) fibers. These results suggest that LCPs act as antiprion agents by transitioning PrP aggregates into structures with reduced frangibility. Moreover, ELISA on cerebellar organotypic cultured slices and in vitro conversion assays with mouse PrP(23-231) indicated that poly(thiophene-3-acetic acid) may additionally interfere with the generation of PrP(Sc) by stabilizing the conformation of PrP(C) or of a transition intermediate. Therefore, LCPs represent a novel class of antiprion agents whose mode of action appears to rely on hyperstabilization, rather than destabilization, of PrP(Sc) deposits.     

Analysis of the fibroblast growth factor system reveals alterations in a mouse model of spinal muscular atrophy

The monogenetic disease Spinal Muscular Atrophy (SMA) is characterized by a progressive loss of motoneurons leading to muscle weakness and atrophy due to severe reduction of the Survival of Motoneuron (SMN) protein. Several models of SMA show deficits in neurite outgrowth and maintenance of neuromuscular junction (NMJ) structure. Survival of motoneurons, axonal outgrowth and formation of NMJ is controlled by neurotrophic factors such as the Fibroblast Growth Factor (FGF) system. Besides their classical role as extracellular ligands, some FGFs exert also intracellular functions controlling neuronal differentiation. We have previously shown that intracellular FGF-2 binds to SMN and regulates the number of a subtype of nuclear bodies which are reduced in SMA patients. In the light of these findings, we systematically analyzed the FGF-system comprising five canonical receptors and 22 ligands in a severe mouse model of SMA. In this study, we demonstrate widespread alterations of the FGF-system in both muscle and spinal cord. Importantly, FGF-receptor 1 is upregulated in spinal cord at a pre-symptomatic stage as well as in a mouse motoneuron-like cell-line NSC34 based model of SMA. Consistent with that, phosphorylations of FGFR-downstream targets Akt and ERK are increased. Moreover, ERK hyper-phosphorylation is functionally linked to FGFR-1 as revealed by receptor inhibition experiments. Our study shows that the FGF system is dysregulated at an early stage in SMA and may contribute to the SMA pathogenesis.