Genetic mechanisms underlying the pathogenesis of tropical calcific pancreatitis

Chronic pancreatitis is known to be a heterogeneous disease with varied etiologies.Tropical calcific pancreatitis(TCP) is a severe form of chronic pancreatitis unique to developing countries.With growing evidence of genetic factors contributing to the pathogenesis of TCP,this review is aimed at compiling the available information in this field.We also propose a two hit model to explain the sequence of events in the pathogenesis of TCP.

Comprehensive screening for reg1α gene rules out association with tropical calcific pancreatitis

AIM: To investigate the allelic and haplotypic association of reg1α gene with tropical calcific pancreatitis (TCP). Since TCP is known to have a variable genetic basis, we investigated the interaction between mutations in the susceptibility genes, SPINK1 and CTSB with reg1α polymorphisms. METHODS: We analyzed the polymorphisms in the reg1α gene by sequencing the gene including its promoter region in 195 TCP patients and 150 ethnically matched controls, compared their allele and haplotype frequencies, and their association with the pathogenesis and pancreaticolithiasis in TCP and fibro-calculous pancreatic diabetes. RESULTS: We found 8 reported and 2 novel polymo-rphisms including an insertion-deletion polymorphism in the promoter region of reg1α. None of the 5' UTR variants altered any known transcription factor binding sites, neither did any show a statistically significant association with TCP. No association with any reg1α variants was observed on dichotomization of patients based on their N34S SPINK1 or L26V CTSB status. CONCLUSION: Polymorphisms in reg1α gene, including the regulatory variants singly or in combination with the known mutations in SPINK1 and/or CTSB genes, are not associated with tropical calcific pancreatitis.

DCK confers sensitivity of DCTD-positive cancer cells to oxidized methylcytidines

Dear Editor,Cytidine analogs,such as decitabine(DAC)and cytarabine(ara-C),have been widely used in the clinical treatment for several cancer types,including myelodysplastic syndrome and acute myeloid leukemia(AML;Appelbaum et al.1999;Saba 2007).However,drug resistance causing treatment failure and disease relapse is an unresolved problem to date.Certain cancer cells rely on the salvage enzymes cytidine deaminase(CDA)and dCMP deaminase(DCTD)to inactivate these cytidine derivative drugs by deamination(Jamieson et al.1987;Ebrahem et al.2012).It is imperative to develop new categories of chemotherapeutic nucleosides to overcome the drug resistance caused by such increased cellular deamination activity.

HT-SuperSAGE of the gut tissue of a Vip3Aa-resistant Heliothis virescens (Lepidoptera: Noctuidae) strain provides insights into the basis of resistance

Multitoxin Bt-crops expressing insecticidal toxins with different modes of action, for example, Cry and Vip, are expected to improve resistance management in target pests. While Cry1A resistance has been relatively well characterized in some insect species, this is not the case for Vip3A, for which no mechanism of resistance has yet been identified. Here we applied HT-SuperSAGE to analyze the transcriptome of the gut tissue of tobacco budworm Heliothis virescens (F.) laboratory-selected for Vip3Aa resistance. From a total of 1 324 252 sequence reads, 5 895 126-bp tags were obtained representing 17 751 nonsingleton unique transcripts (UniTags) from genetically similar Vip3Aa-resistant (Vip- Sel) and susceptible control (Vip-Unsel) strains. Differential expression was significant (≥2.5 fold or ≤0.4;P < 0.05) for 1989 sequences (11.2% of total UniTags), where 420 represented overexpressed (OE) and 1569 underexpressed (UE) genes in Vip-Sel. BLASTN searches mapped 419 UniTags to H. virescens sequence contigs, of which, 416 (106 OE and 310 UE) were unambiguously annotated to proteins in NCBI nonredundant protein databases. Gene Ontology distributed 345 of annotated UniTags in 14 functional categories with metabolism (including serine-type hydrolases) and translation/ribosome biogenesis being the most prevalent. A UniTag homologous to a particular member of the REsponse to PAThogen (REPAT) family was found among most overexpressed, while UniTags related to the putative Vip3Aa-binding ribosomal protein S2 (RpS2) were underexpressed. qRT-PCR of a subset of UniTags validated the HT-SuperSAGE data. This study is the first providing lepidopteran gut transcriptome associated with Vip3Aa resistance and a foundation for future attempts to elucidate the resistance mechanism.

SD3, an Arabidopsis thaliana Homolog of TIM21, Affects Intracellular ATP Levels and Seedling Development

It is poorly understood how plants control their growth by cell division, elongation, and differentiation. We have characterized a seedling-lethal mutant segregation distortion 3 （sd3） that showed a very dwarf phenotype when grown in the light and, in the dark, had short hypocotyls with reduced ploidy levels. The corresponding gene of SD3 encodes a protein with high similarity to yeast translocase on the inner mitochondrial membrane 21 （TIM21）, which is a component of the TIM23 complex. Indeed, SD3 protein fused to GFP localized in the mitochondria. SD3 overexpression increased cotyledon size in the light and hypocotyl thickness in the dark. The expression of genes for several subunits of the respiratory-chain complexes III and IV was up-regulated in SD3-overexpressing plants. Furthermore, these plants showed high levels of ATP whereas those of sd3 were low. These results suggested that SD3 induced an increase in cell size by raising the expression of the respiratory-chain subunit genes and hence increased the intracellular ATP levels, We propose that intracellular ATP levels regulated by mitochondria control plant organ size.