A small molecule accelerates neuronal differentiation in the adult rat

Adult neurogenesis occurs in mammals and provides a mechanism for continuous neural plasticity in the brain. However, little is known about the molecular mechanisms regulating hippocampal neural progenitor cells (NPCs) and whether their fate can be pharmacologically modulated to improve neural plasticity and regeneration. Here, we report the characterization of a small molecule (KHS101) that selectively induces a neuronal differentiation phenotype. Mechanism of action studies revealed a link of KHS101 to cell cycle exit and specific binding to the TACC3 protein, whose knockdown in NPCs recapitulates the KHS101-induced phenotype. Upon systemic administration, KHS101 distributed to the brain and resulted in a significant increase in neuronal differentiation in vivo. Our findings indicate that KHS101 accelerates neuronal differentiation by interaction with TACC3 and may provide a basis for pharmacological intervention directed at endogenous NPCs.     

Development of GABAergic inputs controls the contribution of maturing neurons to the adult hippocampal network

New neurons are continuously generated in the dentate gyrus (DG) in the adult hippocampus, and new granule cells (GCs) have been shown to be necessary for several aspects of learning and memory. Nonetheless, the limited information available regarding the anatomical and physiological development of synaptic inputs onto maturing neurons has restricted our understanding of how new GCs affect cognition. Here, we use photostimulation to demonstrate the time course by which anatomically isolated inhibitory inputs develop onto maturing GCs. We then show that the gradual development of inhibition is sufficient in a computational model to drive learning of novel information in young neurons. Finally, we validate this model observation by using slice physiology to show how inhibition regulates firing probability and plasticity in young GCs. Combined, these data demonstrate that the unique connectivity of immature GCs affords them a functional role that is different from mature neurons in the DG circuit, a distinction that potentially underlies many of the proposed functions of new neurons in the hippocampal network.     

Role of viral infections in the genesis of dysplasias of the uterine cervix

A study of 80 cases of dysplasia of the uterine cervix showed the coexistence of HPV infections in 52 cases. This association (65%) shows the important role played by the human papilloma virus in the genesis of cancer of the cervix.     

Diabetic Retinopathy as a Cause of Blindness in the Province of Turin,North-west Italy,in 1967–1991

Diabetes is known to be a major contributor to blindness in industrialized countries but few data are available on the situation in Italy. As an introductory step to the implementation of permanent screening for diabetic retinopathy, a search was carried out on the causes of visual loss in the provincial territory surrounding Turin, the main city of North-West Italy. The case notes of all 4549 residents in the province who were certified blind between 1967 and 1991 were examined with regard to cause, age at onset, and year of onset of visual acuity 1/20. Diabetic retinopathy was the second commonest cause of bilateral blindness (13.1 % of cases), preceded by cataract (26.7%) and followed by myopia (11.1%), optic atrophy (8.9%), glaucoma (8.9%), retinitis pigmentosa (7.2%), and senile macular degeneration (4.1%). Diabetic retinopathy was the commonest eye disease among those who became blind between the ages of 50 and 70 and remained the leading cause of visual loss when the age groups 20 to 70 were pooled together. The incidence of diabetic retinopathy-related blindness did not show any trend to decrease over the 25 years investigated. It is concluded that, in spite of widespread availability of facilities for its assessment and treatment, diabetic retinopathy remains a leading cause of blindness in North-West Italy. This fully justifies the implementation of screening programmes and efficient referral chains for the early detection and prompt treatment of this complication of diabetes.     

Burden of anemia among indigenous populations

An international perspective of the magnitude of anemia in indigenous peoples is currently lacking. The present systematic review was performed to characterize the global prevalence, severity, and etiology of anemia in indigenous peoples by conducting a systematic search of original research published in English from 1996 to February 2010 using PubMed, Medline, and Embase. A total of 50 studies, representing the following 13 countries, met the inclusion criteria: Australia, Brazil, Canada, Guatemala, India, Kenya, Malaysia, Mexico, New Zealand, Sri Lanka, Tanzania, the United States, and Venezuela. Results indicate major deficiencies in the coverage and quality of anemia monitoring data for indigenous populations worldwide. The burden of anemia is overwhelmingly higher among indigenous groups compared to the general population and represents a moderate (20-39.9%) to severe (≥40%) public health problem. For the most part, the etiology of anemia is preventable and includes inadequate diet, poor living conditions, and high infection rates (i.e., malaria and intestinal parasites). A concerted global effort is needed to reduce the worldwide burden of anemia in these marginalized populations.     

2,7-disubstituted-pyrrolo[2,1-f][1,2,4]triazines: new variant of an old template and application to the discovery of anaplastic lymphoma kinase (ALK) inhibitors with in vivo antitumor activity

A novel 2,7-disubstituted-pyrrolo[2,1-f][1,2,4]triazine scaffold has been designed as a new kinase inhibitor platform mimicking the bioactive conformation of the well-known diaminopyrimidine motif. The design, synthesis, and validation of this new pyrrolo[2,1-f][1,2,4]triazine scaffold will be described for inhibitors of anaplastic lymphoma kinase (ALK). Importantly, incorporation of appropriate potency and selectivity determinants has led to the discovery of several advanced leads that were orally efficacious in animal models of anaplastic large cell lymphoma (ALCL). A lead inhibitor (30) displaying superior efficacy was identified and in depth in vitro/in vivo characterization will be presented.     

Strategies to mitigate the bioactivation of 2-anilino-7-aryl-pyrrolo[2,1-f][1,2,4]triazines: identification of orally bioavailable, efficacious ALK inhibitors

Chemical strategies to mitigate cytochrome P450-mediated bioactivation of novel 2,7-disubstituted pyrrolo[2,1-f][1,2,4]triazine ALK inhibitors are described along with synthesis and biological activity. Piperidine-derived analogues showing minimal microsomal reactive metabolite formation were discovered. Potent, selective, and metabolically stable ALK inhibitors from this class were identified, and an orally bioavailable compound (32) with antitumor efficacy in ALK-driven xenografts in mouse models was extensively characterized.