Tumor Reliance on Cytosolic versus Mitochondrial One-Carbon Flux Depends on Folate Availability

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Cellular and molecular mechanisms of cerebellar granule cell migration

The real-time observation of cell movement in brain slice preparations reveals that in the developing brain, postmitotic neurons alter their shape concomitantly with changes in the mode, direction, tempo, and rate of migration as they traverse different cortical layers. Although it has been hypothesized that orchestrated activities of multiple external cues and cell-cell contact are essential for controlling the cortical-layer-specific changes in cell migration, signaling mechanisms and external guidance cues related to the alteration of neuronal cell migration remain to be determined. In this article, we will first review recent studies on position-specific changes in granule cell behavior through different migratory terrains of the developing cerebellar cortex. We will then present possible roles for the coordinated activity of Ca²⁺ channels, NMDA type of glutamate receptors, and intracellular Ca²⁺ fluctuations in controlling cerebellar granule cell movement. Furthermore, we will discuss the crucial roles of brain-derived neurotrophic factor (BDNF), neuregulin (NRG), stromal cell-derived factor 1α (SDF-1α), ephrin-B2, and EphB2 receptor in providing directional cues promoting granule cell migration from the external granular layer (EGL) to the internal granular layer (IGL). Finally, we will demonstrate that endogenous somatostatin controls the migration of granule cells in a cortical layer-specific manner: Endogenous somatostatin accelerates granule cell movement near the birthplace within the EGL, but significantly slows down the movement near their final destination within the IGL.     

Brk/Protein Tyrosine Kinase 6 Phosphorylates p27KIP1, Regulating the Activity of Cyclin D–Cyclin-Dependent Kinase 4

Cyclin D and cyclin-dependent kinase 4 (cdk4) are overexpressed in a variety of tumors, but their levels are not accurate indicators of oncogenic activity because an accessory factor such as p27^Kip1 is required to assemble this unstable dimer. Additionally, tyrosine (Y) phosphorylation of p27 (pY88) is required to activate cdk4, acting as an “on/off switch.” We identified two SH3 recruitment domains within p27 that modulate pY88, thereby modulating cdk4 activity. Via an SH3-PXXP interaction screen, we identified Brk (breast tumor-related kinase) as a high-affinity p27 kinase. Modulation of Brk in breast cancer cells modulates pY88 and increases resistance to the cdk4 inhibitor PD 0332991. An alternatively spliced form of Brk (Alt Brk) which contains its SH3 domain blocks pY88 and acts as an endogenous cdk4 inhibitor, identifying a potentially targetable regulatory region within p27. Brk is overexpressed in 60% of breast carcinomas, suggesting that this facilitates cell cycle progression by modulating cdk4 through p27 Y phosphorylation. p27 has been considered a tumor suppressor, but our data strengthen the idea that it should also be considered an oncoprotein, responsible for cyclin D-cdk4 activity.     

Effects of desipramine on the antioxidant status in rat tissues at carrageenan‐induced paw inflammation

The pathogenesis of many diseases and different pathological conditions, including inflammation, is associated with excess production of reactive oxygen species (ROS). The present study aimed to investigate the effects of the antidepressant desipramine (DES) on carrageenan (CG)‐induced inflammation, as well as on the endogenous levels of cell enzyme and non‐enzyme antioxidants in rat liver and spleen, 4 and 24 h after CG injection. The intra‐plantar CG injection into the right hind paw resulted in a time‐dependent increase in the paw volume; the maximum of CG‐induced edema peak was in 2–4 h. A single DES dose of 20 mg·kg^?1, administered 30 min before CG, had no effect on paw edema, whereas the higher drug dose used (50 mg·kg^?1) suppressed the edematous response to CG. The latter drug dose protected CG‐induced decrease of glutathione (non‐enzyme antioxidant) in the liver; it did not affect CG‐unchanged activities of superoxide dismutase, glutathione peroxidase (enzyme antioxidants) and glucose‐6‐phosphate dehydrogenase (enzyme, important for the activity of glutathione‐conjugated antioxidant enzymes) in both liver and spleen. The drug showed an efficient antioxidant capacity in ROS‐generating chemical systems; it was higher than that of fluoxetine (another type of antidepressant). The present results suggest that the good antioxidant activity of DES might contribute to its beneficial effects in liver injuries. Copyright © 2011 John Wiley & Sons, Ltd.     

Attraction of willow warblers to sawfly‐damaged mountain birches: novel function of inducible plant defences?

Plants wounded by invertebrate herbivores emit volatile compounds which invertebrate predators and parasitoids can utilize in locating herbivore prey or hosts. We studied the possibility that an analogical phenomenon might operate between plants and avian insectivores. We show that foliar damage by sawfly larvae on the mountain birch led a passerine bird (willow warbler) to prefer intact branches from trees with introduced larvae over intact branches from control trees. Besides olfaction, the UV vision of birds offers a possible mechanism, as some herbivore‐inducible leaf compounds, e.g. surface flavonoids, have UV spectral maxima well within the range of birds’ UV vision.     

Two-phase importance sampling for inference about transmission trees

There has been growing interest in the statistics community to develop methods for inferring transmission pathways of infectious pathogens from molecular sequence data. For many datasets, the computational challenge lies in the huge dimension of the missing data. Here, we introduce an importance sampling scheme in which the transmission trees and phylogenies of pathogens are both sampled from reasonable importance distributions, alleviating the inference. Using this approach, arbitrary models of transmission could be considered, contrary to many earlier proposed methods. We illustrate the scheme by analysing transmissions of Streptococcus pneumoniae from household to household within a refugee camp, using data in which only a fraction of hosts is observed, but which is still rich enough to unravel the within-household transmission dynamics and pairs of households between whom transmission is plausible. We observe that while probability of direct transmission is low even for the most prominent cases of transmission, still those pairs of households are geographically much closer to each other than expected under random proximity.