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Toxic human amylin (hA) oligomers and aggregates are implicated in the pathogenesis of type 2 diabetes mellitus (T2DM). Although recent studies demonstrated a causal connection between hA uptake and toxicity in pancreatic cells, the mechanism of amylin's clearance following its internalization and its relationship to toxicity is yet to be determined, and hence was investigated here. Using pancreatic rat insulinoma β-cells and human islets as model systems, we show that hA, following its internalization, first accumulates in the cytosol followed by its translocation into nucleus, and to a lesser extent lysosomes, keeping the net cytosolic amylin content low. An increase in hA accumulation in the nucleus of pancreatic cells correlated with its cytotoxicity, suggesting that its excessive accumulation in the nucleus is detrimental. hA interacted with 20S core and 19S lid subunits of the β-cell proteasomal complex, as suggested by immunoprecipitation and confocal microscopy studies, which subsequently resulted in a decrease in the proteasome's proteolytic activity in these cells. In vitro binding and activity assays confirmed an intrinsic and potent ability of amylin to interact with the 20S core complex thereby modulating its proteolytic activity. Interestingly, less toxic and aggregation incapable rat amylin (rA) showed a comparable inhibitory effect on proteasome activity and protein ubiquitination, decoupling amylin aggregation/ toxicity and amylin-induced protein stress. In agreement with these studies, inhibition of proteasomal proteolytic activity significantly increased intracellular amylin content and toxicity. Taken together, our results suggest a pivotal role of proteasomes in amylin's turnover and detoxification in pancreatic cells. [ABSTRACT FROM AUTHOR]

The central nervous system is derived from the neural plate, which undergoes a series of complex morphogenetic events resulting in formation of the neural tube in a process known as neurulation. The cellular behaviors driving neurulation in the cranial region involve forces generated by the neural tissue itself as well as the surrounding epithelium and mesenchyme. Of interest, the cranial mesenchyme underlying the neural plate undergoes stereotypical rearrangements hypothesized to drive elevation of the neural folds. As the neural folds rise, the hyaluronate-rich extracellular matrix greatly expands resulting in increased space between individual cranial mesenchyme cells. Based on inhibitor studies, expansion of the extracellular matrix has been implicated in driving neural fold elevation; however, because the surrounding neural and epidermal ectoderm were also affected by inhibitor exposure, these studies are inconclusive. Similarly, treatment of neurulating embryos with teratogenic doses of retinoic acid results in altered organization of the cranial mesenchyme, but alterations in surrounding tissues are also observed. The strongest evidence for a critical role for the cranial mesenchyme in neural fold elevation comes from studies of genes expressed exclusively in the cranial mesenchyme that when mutated result in exencephaly associated with abnormal organization of the cranial mesenchyme. Twist is the best studied of these and is expressed in both the paraxial mesoderm and neural crest derived cranial mesenchyme. In this article, we review the evidence implicating the cranial mesenchyme in providing a driving force for neural fold elevation to evaluate whether there are sufficient data to support this hypothesis. Birth Defects Research (Part A), 2012. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Hectd1 mutant mouse embryos exhibit the neural tube defect exencephaly associated with abnormal cranial mesenchyme. Cellular rearrangements in cranial mesenchyme are essential during neurulation for elevation of the neural folds. Here we investigate the molecular basis of the abnormal behavior of Hectd1 mutant cranial mesenchyme. We demonstrate that Hectd1 is a functional ubiquitin ligase and that one of its substrates is Hsp90, a chaperone protein with both intra- and extracellular clients. Extracellular Hsp90 enhances migration of multiple cell types. In mutant cranial mesenchyme cells, both secretion of Hsp90 and emigration of cells from cranial mesenchyme explants were enhanced. Importantly, we show that this enhanced emigration was highly dependent on the excess Hsp90 secreted from mutant cells. Together, our data set forth a model whereby increased secretion of Hsp90 in the cranial mesenchyme of Hectd1 mutants is responsible, at least in part, for the altered organization and behavior of these cells and provides a potential molecular mechanism underlying the neural tube defect. [ABSTRACT FROM AUTHOR]

We have used restriction site-dependent polymerase chain reaction (PCR)-based methodology for detection of the α-globin polyadenylation (poly A) signal mutation, AATAAA>AATA- - and Hb Sun Prairie [α130(H13)Ala→Pro, GCT>CCT (α2)] mutation. The former mutation produces Hb H disease in the homozygous state and occurs frequently in the Indian population. It was detected in nine of 77 putative α-thalassemia (α-thal) patients and in three of 13 β-thal intermedia patients tested. Four of the nine α-thal patients were homozygotes for the mutation. The Hb Sun Prairie mutation was confirmed in two α-thal patients, one of whom was a homozygote and the other a heterozygote. [ABSTRACT FROM AUTHOR]

Abstract: This review presents an analysis of current research aimed at deciphering the interplay of cell extrinsic and intrinsic signals required for specification and differentiation of noradrenergic sympathetic ganglion neurons. The development of noradrenergic sympathetic ganglion neurons depends upon expression of a core set of DNA regulatory molecules, including the Phox2 homeodomain proteins and the basic helix–loop–helix proteins, HAND2 and MASH1 whose expression is dependent upon cell extrinsic cues. Both bone morphogenetic protein(s) and cAMP have an integral role in the specification/differentiation of noradrenergic sympathetic ganglion neurons but how signaling downstream of these molecules is integrated and identification of their particular functions is just beginning to be elucidated. Data currently available suggests a model with BMP providing both instructive and permissive cues in a pathway integrated by cAMP and MAPK by activation of both canonical and non-canonical intracellular signaling cascades. [Copyright &y& Elsevier]

Objective To control the birth of thalassemic children in India. Methods Mutations present in the population of eastern India and in carrier parents seeking prenatal diagnosis were detected by the PCR-based technique of ARMS (amplification refractory mutation system) or gap-PCR. To screen for maternal tissue contamination in CVS, haplotypes associated with the β-globin gene clusters were constructed using six polymorphic restriction sites. Prenatal diagnosis was accomplished by checking presence of parental mutation in the DNA from chorionic villus sampling (CVS) collected at 8 to 10 weeks' gestation by appropriate technique. Results Six hundred and fifty (650) unrelated β-thalassemia chromosomes were screened for 11 common mutations to characterize the mutation distribution in this population. Starting from early 2000, 63 families from different parts of West Bengal and from surrounding areas have been offered prenatal counseling for β-thalassemia. Conclusion The population of this region is conscious and willing to accept prenatal diagnosis as a means of control of thalassemia. Copyright © 2004 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

1. In this paper information regarding the various spore-forms of Ganoderma lucidum has been presented. 2. It has been found that besides the normal basidiospores, two other spore types also occur in the fructifications of the fungus collected from Nature or produced in artificial culture. These are 'secondary spores' and 'gasterospores'. 3. Characteristic features of all the spore types have been fully described and their modes of origin noted. 4. All the three types of spores are more or less identical to each other in appearance. But the secondary spores have endospores less verrucose than the endospores of the other two types, whereas the gasterospores are characterised by two opposite notches in their exospores. [ABSTRACT FROM AUTHOR]