Ectopic Wnt/Beta–Catenin Signaling Induces Neurogenesis in the Spinal Cord and Hindbrain Floor Plate

The most ventral structure of the developing neural tube, the floor plate (FP), differs in neurogenic capacity along the neuraxis. The FP is largely non-neurogenic at the hindbrain and spinal cord levels, but generates large numbers of dopamine (mDA) neurons at the midbrain levels. Wnt1, and other Wnts are expressed in the ventral midbrain, and Wnt/beta catenin signaling can at least in part account for the difference in neurogenic capacity of the FP between midbrain and hindbrain levels. To further develop the hypothesis that canonical Wnt signaling promotes mDA specification and FP neurogenesis, we have generated a model wherein beta–catenin is conditionally stabilized throughout the FP. Here, we unambiguously show by fate mapping FP cells in this mutant, that the hindbrain and spinal cord FP are rendered highly neurogenic, producing large numbers of neurons. We reveal that a neurogenic hindbrain FP results in the altered settling pattern of neighboring precerebellar neuronal clusters. Moreover, in this mutant, mDA progenitor markers are induced throughout the rostrocaudal axis of the hindbrain FP, although TH+ mDA neurons are produced only in the rostral aspect of rhombomere (r)1. This is, at least in part, due to depressed Lmx1b levels by Wnt/beta catenin signaling; indeed, when Lmx1b levels are restored in this mutant, mDA are observed not only in rostral r1, but also at more caudal axial levels in the hindbrain, but not in the spinal cord. Taken together, these data elucidate both patterning and neurogenic functions of Wnt/beta catenin signaling in the FP, and thereby add to our understanding of the molecular logic of mDA specification and neurogenesis

New Mediterranean biodiversity records (March 2016)

In this Collective Article on “New Mediterranean Biodiversity Records”, we present additional records of species found in the Mediterranean Sea. These records refer to eight different countries mainly throughout the northern part of the basin, and include 28 species, belonging to five Phyla. The findings per country include the following species: Spain: Callinectes sapidus and Chelidonura fulvipunctata; Monaco: Aplysia dactylomela; Italy: Charybdis (Charybdis) feriata, Carcharodon carcharias, Seriola fasciata, and Siganus rivulatus; Malta: Pomacanthus asfur; Croatia: Lagocephalus sceleratus and Pomadasys incisus; Montenegro: Lagocephalus sceleratus; Greece: Amathia (Zoobotryon) verticillata, Atys macandrewii, Cerithium scabridum, Chama pacifica, Dendostrea cf. folium, Ergalatax junionae, Septifer cumingii, Syphonota geographica, Syrnola fasciata, Oxyu- richthys petersi, Scarus ghobban, Scorpaena maderensis, Solea aegyptiaca and Upeneus pori; Turkey: Lobotes surinamensis, Ruvettus pretiosus and Ophiocten abyssicolum. In the current article, the presence of Taractes rubescens (Jordan & Evermann, 1887) is recorded for the first time in the Mediterranean from Italy. The great contribution of citizen scientists in monitoring biodiversity records is reflected herein, as 10% of the authors are citizen scientists, and contributed 37.5% of the new findings.peer-reviewe

MEDLEM database, a data collection on large elasmobranchs in the Mediterranean and Black Seas

The Mediterranean Large Elasmobranchs Monitoring (MEDLEM) database contains more than 3,000 records (with more than 4,000 individuals) of large elasmobranch species from 21 different countries around the Mediterranean and Black seas, observed from 1666 to 2017. The principal species included in the archive are the devil ray (1,868 individuals), the basking shark (935 individuals), the blue shark (622 individuals), and the great white shark (342 individuals). In the last decades, other species such as the thresher shark (187 individuals), the shortfin mako (180 individuals), and the spiny butterfly ray (138) were reported with increasing frequency. This was possibly due to increased public awareness on the conservation status of sharks, and the consequent development of new monitoring programs. MEDLEM does not have homogeneous reporting coverage throughout the Mediterranean and Black seas and it should be considered as a database of observed species presence. Scientific monitoring efforts in the south-eastern Mediterranean and Black seas are generally lower than in the northern sectors and the absence of some species in our database does not imply their actual absence in these regions. However, the available data allowed us to analyse the frequency and spatial distribution of records, the size frequencies for a few selected the available data allowed us to analyse the frequency and spatial distribution of records, the size frequencies for a few selected species, the overall area coverage, and which species are involved as bycatch by different fishing gears

Mouse Transgenesis Identifies Conserved Functional Enhancers and cis-Regulatory Motif in the Vertebrate LIM Homeobox Gene Lhx2 Locus

The vertebrate Lhx2 is a member of the LIM homeobox family of transcription factors. It is essential for the normal development of the forebrain, eye, olfactory system and liver as well for the differentiation of lymphoid cells. However, despite the highly restricted spatio-temporal expression pattern of Lhx2, nothing is known about its transcriptional regulation. In mammals and chicken, Crb2, Dennd1a and Lhx2 constitute a conserved linkage block, while the intervening Dennd1a is lost in the fugu Lhx2 locus. To identify functional enhancers of Lhx2, we predicted conserved noncoding elements (CNEs) in the human, mouse and fugu Crb2-Lhx2 loci and assayed their function in transgenic mouse at E11.5. Four of the eight CNE constructs tested functioned as tissue-specific enhancers in specific regions of the central nervous system and the dorsal root ganglia (DRG), recapitulating partial and overlapping expression patterns of Lhx2 and Crb2 genes. There was considerable overlap in the expression domains of the CNEs, which suggests that the CNEs are either redundant enhancers or regulating different genes in the locus. Using a large set of CNEs (810 CNEs) associated with transcription factor-encoding genes that express predominantly in the central nervous system, we predicted four over-represented 8-mer motifs that are likely to be associated with expression in the central nervous system. Mutation of one of them in a CNE that drove reporter expression in the neural tube and DRG abolished expression in both domains indicating that this motif is essential for expression in these domains. The failure of the four functional enhancers to recapitulate the complete expression pattern of Lhx2 at E11.5 indicates that there must be other Lhx2 enhancers that are either located outside the region investigated or divergent in mammals and fishes. Other approaches such as sequence comparison between multiple mammals are required to identify and characterize such enhancers

Cognitive and Psychological Reactions of the General Population Three Months After the 2011 Tohoku Earthquake and Tsunami

BACKGROUND: The largest earthquake on record in Japan (magnitude 9.0) occurred on March 11, 2011, and the subsequent tsunami devastated the Pacific coast of Northern Japan. These further triggered the Fukushima I nuclear power plant accidents. Such a hugely complex disaster inevitably has negative psychological effects on general populations as well as on the direct victims. While previous disaster studies enrolled descriptive approaches focusing on direct victims, the structure of the psychological adjustment process of people from the general population has remained uncertain. The current study attempted to establish a path model that sufficiently reflects the early psychological adaptation process of the general population to large-scale natural disasters. METHODS AND FINDINGS: Participants from the primary disaster area (n = 1083) and other areas (n = 2372) voluntarily participated in an online questionnaire study. By constructing path models using a structural equation model procedure (SEM), we examined the structural relationship among psychological constructs known related to disasters. As post-traumatic stress symptoms (PTS) were significantly more present in people in the primarily affected area than in those in secondary- or non-affected areas, the path models were constructed for the primary victims. The parsimoniously depicted model with the best fit was achieved for the psychological-adjustment centered model with quality of life (QoL) as a final outcome. CONCLUSION: The paths to QoL via negative routes (from negative cognitive appraisal, PTS, and general stress) were dominant, suggesting the importance of clinical intervention for reducing negative cognitive appraisal, and for caring for general stress and PTS to maintain QoL at an early stage of psychological adaptation to a disaster. The model also depicted the presence of a positive route where positive cognitive appraisal facilitates post-traumatic growth (PTG) to achieve a higher QoL, suggesting the potential importance of positive psychological preventive care for unexpected natural disasters

Impact of Safety-Related Dose Reductions or Discontinuations on Sustained Virologic Response in HCV-Infected Patients: Results from the GUARD-C Cohort.

BACKGROUND: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. METHODS: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively. RESULTS: SVR24 rates were 46.1% (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1, 2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced ≥1 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with ≥1 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not ≥5. CONCLUSIONS: In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginterferon alfa-2a/ribavirin.This study was sponsored by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Support for third-party writing assistance for this manuscript, furnished by Blair Jarvis MSc, ELS, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd, Basel, Switzerland

Impact of safety-related dose reductions or discontinuations on sustained virologic response in HCV-infected patients: Results from the GUARD-C Cohort

Background: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. Methods: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively. Results: SVR24 rates were 46.1 % (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1,2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced 651 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with 651 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not 655. Conclusions: In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginter-feron alfa-2a/ribavirin

Integrin signalling regulates the expansion of neuroepithelial progenitors and neurogenesis via Wnt7a and Decorin

Development of the cerebral cortex requires regulation of proliferation and differentiation of neural stem cells and a diverse range of progenitors. Recent work suggests a role for extracellular matrix (ECM) and the major family of ECM receptors, the integrins. Here we show that enhancing integrin beta-1 signalling, by expressing a constitutively active integrin beta-1 (CA*β1) in the embryonic chick mesencephalon, enhances neurogenesis and increases the number of mitotic cells dividing away from the ventricular surface, analogous to sub-apical progenitors in mouse. Only non-integrin-expressing neighbouring cells (lacking CA*β1) contributed to the increased neurogenesis. Transcriptome analysis reveals upregulation of Wnt7a within the CA*β1 cells and upregulation of the ECM protein Decorin in the neighbouring non-expressing cells. Experiments using inhibitors in explant models and genetic knock-downs in vivo reveal an integrin-Wnt7a-Decorin pathway that promotes proliferation and differentiation of neuroepithelial cells, and identify Decorin as a novel neurogenic factor in the central nervous system