Sonic hedgehog guides post-crossing commissural axons both directly and indirectly by regulating Wnt activity

After midline crossing, axons of dorsolateral commissural neurons turn rostrally into the longitudinal axis of the spinal cord. In mouse, the graded distribution of Wnt4 attracts post-crossing axons rostrally. In contrast, in the chicken embryo, the graded distribution of Sonic hedgehog (Shh) guides post-crossing axons by a repulsive mechanism mediated by hedgehog-interacting protein. Based on these observations, we tested for a possible cooperation between the two types of morphogens. Indeed, we found that Wnts also act as axon guidance cues in the chicken spinal cord. However, in contrast to the mouse, Wnt transcription did not differ along the anteroposterior axis of the spinal cord. Rather, Wnt function was regulated by a gradient of the Wnt antagonist Sfrp1 (Secreted frizzled-related protein 1) that in turn was shaped by the Shh gradient. Thus, Shh affects post-crossing axon guidance both directly and indirectly by regulating Wnt function

WNT signalling in prostate cancer

Genome sequencing and gene expression analyses of prostate tumours have highlighted the potential importance of genetic and epigenetic changes observed in WNT signalling pathway components in prostate tumours-particularly in the development of castration-resistant prostate cancer. WNT signalling is also important in the prostate tumour microenvironment, in which WNT proteins secreted by the tumour stroma promote resistance to therapy, and in prostate cancer stem or progenitor cells, in which WNT-β-catenin signals promote self-renewal or expansion. Preclinical studies have demonstrated the potential of inhibitors that target WNT receptor complexes at the cell membrane or that block the interaction of β-catenin with lymphoid enhancer-binding factor 1 and the androgen receptor, in preventing prostate cancer progression. Some WNT signalling inhibitors are in phase I trials, but they have yet to be tested in patients with prostate cancer

Robot therapy for functional recovery of the upper limbs: a pilot study on patients after stroke.

Objective: To verify the possibility of administering robotaided therapy for the upper limbs in patients after stroke; to evaluate patients' degree of acceptance and compliance with the treatment; to establish if the treatment has an effect on motor impairment and functional outcome. Design: Quasi-experimental, uncontrolled study. Subjects: Fourteen patients with chronic hemiparesis after stroke. Methods: Patients were treated with a robotic system for the upper limbs (ReoGo TM ; Motorika Medical Ltd, Israel). Subjects performed the following assessment, at the start (T0), at the end of treatment (T1), and at the follow-up performed one month after the end of treatment (T2): Fugl-Meyer test (FM) for upper limbs; strength evaluation; Ashworth scale; visual analogue scale (VAS) for pain; Frenchay Arm test (FAT); Box and Block test (BB Functional Independence Measure (FIM TM ); ABILHAND Questionnaire; Timed Up and Go test (TUG); Euro-Quality of Life questionnaire and; a VAS for treatment satisfaction were administered to the subjects. Results: Total scores of FM, B&B, FAT and FIM TM showed a statistically significant improvement from T0 and T1 (FM p < 0.002, B&B p < 0.012, FAT p < 0.023, FIM TM p < 0.007) and from T0 and T2 (FM p < 0.003, B&B p < 0.011, FAT p < 0.024, FIM p < 0.027). No statistically significant differences were found between evaluations at T1 and T2 (FM p < 0.595, B&B p < 0.491, FAT p < 0.317, FIM p < 0.180). Conclusion: The sample was capable of completing the treatment and demonstrated good participant satisfaction. This pilot study led to the finding of a clinical improvement and excellent patient compliance. It can be hypothesized that the results are robot-dependent and that they were learned and then maintained. However, the study is limited in that a control group was not used. As such, it is desirable to continue this study with a control group, as well as by designing a prospective longitudinal randomized controlled trial study

cost of walking exertional dyspnoea and fatigue in individuals with multiple sclerosis not requiring assistive devices

n/

Myofibroblast-Derived SFRP1 as Potential Inhibitor of Colorectal Carcinoma Field Effect

Epigenetic changes of stromal-epithelial interactions are of key importance in the regulation of colorectal carcinoma (CRC) cells and morphologically normal, but genetically and epigenetically altered epithelium in normal adjacent tumor (NAT) areas. Here we demonstrated retained protein expression of well-known Wnt inhibitor, secreted frizzled-related protein 1 (SFRP1) in stromal myofibroblasts and decreasing epithelial expression from NAT tissues towards the tumor. SFRP1 was unmethylated in laser microdissected myofibroblasts and partially hypermethylated in epithelial cells in these areas. In contrast, we found epigenetically silenced myofibroblast-derived SFRP1 in CRC stroma. Our results suggest that the myofibroblast-derived SFRP1 protein might be a paracrine inhibitor of epithelial proliferation in NAT areas and loss of this signal may support tumor proliferation in CRC

A novel framework for studying the impact of binding energy distributions on the chemistry of dust grains

The evaporation of molecules from dust grains is crucial to understanding some key aspects of the star- and the planet-formation processes. During the heating phase, the presence of young protostellar objects induces molecules to evaporate from the dust surface into the gas phase, enhancing its chemical complexity. Similarly, in circumstellar discs, the position of the so-called snow lines is determined by evaporation, with important consequences for the formation of planets. The amount of molecules that are desorbed depends on the interaction between the species and the grain surface, which is controlled by the binding energy. Recent theoretical and experimental works point towards a distribution of values for this parameter instead of the single value often employed in astrochemical models.We present a new "multi-binding energy" framework to assess the effects that a distribution of binding energies has on the amount of species bound to the grains. We find that the efficiency of the surface chemistry is significantly influenced by this process, with crucial consequences on the theoretical estimates of the desorbed species

A novel framework to study the impact of binding energy distributions on the chemistry of dust grains

The evaporation of molecules from dust grains is crucial to understand some key aspects of the star- and the planet-formation processes. During the warm-up phase the presence of young protostellar objects induces molecules to evaporate from the dust surface into the gas phase, enhancing its chemical complexity. Similarly, in circumstellar disks, the position of the so-called snow-lines is determined by evaporation, with important consequences for the formation of planets. The amount of molecules that are desorbed depends on the interaction between the species and the grain surface, which is controlled by the binding energy. Recent theoretical and experimental works point towards a distribution of values for this parameter instead of the single value often employed in astrochemical models.We present here a new "multi-binding energy" framework, to assess the effects that a distribution of binding energies has on the amount of species bound to the grains. We find that the efficiency of the surface chemistry is significantly influenced by this process with crucial consequences on the theoretical estimates of the desorbed species.Comment: Accepted A&

Identification of critical paralog groups with indispensable roles in the regulation of signaling flow

Extensive cross-talk between signaling pathways is required to integrate the myriad of extracellular signal combinations at the cellular level. Gene duplication events may lead to the emergence of novel functions, leaving groups of similar genes - termed paralogs - in the genome. To distinguish critical paralog groups (CPGs) from other paralogs in human signaling networks, we developed a signaling network-based method using cross-talk annotation and tissue-specific signaling flow analysis. 75 CPGs were found with higher degree, betweenness centrality, closeness, and ‘bowtieness’ when compared to other paralogs or other proteins in the signaling network. CPGs had higher diversity in all these measures, with more varied biological functions and more specific post-transcriptional regulation than non-critical paralog groups (non-CPG). Using TGF-beta, Notch and MAPK pathways as examples, SMAD2/3, NOTCH1/2/3 and MEK3/6-p38 CPGs were found to regulate the signaling flow of their respective pathways. Additionally, CPGs showed a higher mutation rate in both inherited diseases and cancer, and were enriched in drug targets. In conclusion, the results revealed two distinct types of paralog groups in the signaling network: CPGs and non-CPGs. Thus highlighting the importance of CPGs as compared to non-CPGs in drug discovery and disease pathogenesis

The Wnt Receptor Ryk Reduces Neuronal and Cell Survival Capacity by Repressing FOXO Activity During the Early Phases of Mutant Huntingtin Pathogenicity

The Wnt receptor Ryk is an evolutionary-conserved protein important during neuronal differentiation through several mechanisms, including γ-secretase cleavage and nuclear translocation of its intracellular domain (Ryk-ICD). Although the Wnt pathway may be neuroprotective, the role of Ryk in neurodegenerative disease remains unknown. We found that Ryk is up-regulated in neurons expressing mutant huntingtin (HTT) in several models of Huntington's disease (HD). Further investigation in Caenorhabditis elegans and mouse striatal cell models of HD provided a model in which the early-stage increase of Ryk promotes neuronal dysfunction by repressing the neuroprotective activity of the longevity-promoting factor FOXO through a noncanonical mechanism that implicates the Ryk-ICD fragment and its binding to the FOXO co-factor β-catenin. The Ryk-ICD fragment suppressed neuroprotection by lin-18/Ryk loss-of-function in expanded-polyQ nematodes, repressed FOXO transcriptional activity, and abolished β-catenin protection of mutant htt striatal cells against cell death vulnerability. Additionally, Ryk-ICD was increased in the nucleus of mutant htt cells, and reducing γ-secretase PS1 levels compensated for the cytotoxicity of full-length Ryk in these cells. These findings reveal that the Ryk-ICD pathway may impair FOXO protective activity in mutant polyglutamine neurons, suggesting that neurons are unable to efficiently maintain function and resist disease from the earliest phases of the pathogenic process in HD. © 2014 Tourette et al