Response of harpacticoid copepods to habitat structure at a deep-sea site

Given the quiescent physical environment and the low rates of bioturbation in the deep sea, biologically produced structures, such as animals tubes, may play an important role in creating habitat heterogeneity. In San Diego Trough, the cirratulid polychaete Tharyx luticastellus builds and inhabits a robust mud concretion (a mudball). Mudballs are abundant and persist after the worm has died or abandoned them. Our analysis of twelve 6.6-cm-diameter cores from 32° 51.02 N, 117° 46.97 W, taken with the submersible SEA CLIFF, indicate that one of 29 species of harpacticoids common in San Diego Trough is associated with Tharyx mudballs. This species (of the genus Heteropsyllus) responded only to mudballs containing worms, suggesting that any effects of the inanimate structure were not the cause of the association. We could detect no difference in bacterial numbers in sediments between control and occupied-mudball samples. This result suggests that the response does not result from gross differences in food levels near a mudball, but the possibility that there are differences in some preferred food cannot be discounted. An univestigated possibility is that Heteropsyllus responds to occupied mudballs because the worm's presence deters some (presumably small) predator.     

Intercellular communication in the rat anterior pituitary gland: an in vivo and in vitro study

The concept of "stimulus-secretion coupling" suggested by Douglas and co-workers to explain the events related to monamine discharge by the adrenal medulla (5, 7) may be applied to other endocrine tissues, such as adrenal cortex (36), pancreatic islets (4), and magnocellular hypothalamic neurons (6), which exhibit a similar ion-dependent process of hormone elaboration. In addition, they share another feature, that of joining neighbor cells via membrane junctions (12, 26, and Fletcher, unpublished observation). Given this, and the reports that hormone secretion by the pars distalis also involves a secretagogue-induced decrease in membrane bioelectric potential accompanied by a rise in cellular [Ca++] (27, 34, 41), it was appropriate to test the possibility that cells of the anterior pituitary gland are united by junctions.     

Repeated oral administration of capsaicin increases anxiety-like behaviours with prolonged stress-response in rats

This study was conducted to examine the psycho-emotional effects of repeated oral exposure to capsaicin, the principal active component of chili peppers. Each rat received 1 mL of 0.02% capsaicin into its oral cavity daily, and was subjected to behavioural tests following 10 daily administrations of capsaicin. Stereotypy counts and rostral grooming were significantly increased, and caudal grooming decreased, in capsaicin-treated rats during the ambulatory activity test. In elevated plus maze test, not only the time spent in open arms but also the percent arm entry into open arms was reduced in capsaicin-treated rats compared with control rats. In forced swim test, although swimming duration was decreased, struggling increased in the capsaicin group, immobility duration did not differ between the groups. Repeated oral capsaicin did not affect the basal levels of plasma corticosterone; however, the stress-induced elevation of plasma corticosterone was prolonged in capsaicin treated rats. Oral capsaicin exposure significantly increased c-Fos expression not only in the nucleus tractus of solitarius but also in the paraventricular nucleus. Results suggest that repeated oral exposure to capsaicin increases anxiety-like behaviours in rats, and dysfunction of the hypothalamic-pituitary-adrenal axis may play a role in its pathophysiology.     

Techniques for optimization of queries on integrated biological resources

Today, scientific data are inevitably digitized, stored in a wide variety of formats, and are accessible over the Internet. Scientific discovery increasingly involves accessing multiple heterogeneous data sources, integrating the results of complex queries, and applying further analysis and visualization applications in order to collect datasets of interest. Building a scientific integration platform to support these critical tasks requires accessing and manipulating data extracted from flat files or databases, documents retrieved from the Web, as well as data that are locally materialized in warehouses or generated by software. The lack of efficiency of existing approaches can significantly affect the process with lengthy delays while accessing critical resources or with the failure of the system to report any results. Some queries take so much time to be answered that their results are returned via email, making their integration with other results a tedious task. This paper presents several issues that need to be addressed to provide seamless and efficient integration of biomolecular data. Identified challenges include: capturing and representing various domain specific computational capabilities supported by a source including sequence or text search engines and traditional query processing; developing a methodology to acquire and represent semantic knowledge and metadata about source contents, overlap in source contents, and access costs; developing cost and semantics based decision support tools to select sources and capabilities, and to generate efficient query evaluation plans.     

Synthesis of 1-D- and 1-L-myo-inosityl 2-N-acetamido-2-deoxy-alpha-D-glucopyranoside establishes substrate specificity of the Mycobacterium tuberculosis enzyme AcGI deacetylase

Mycothiol (MSH, 1-D-myo-inosityl 2-(N-acetyl-L-cysteinyl)amido-2-deoxy-alpha-D-glucopyranoside) is the principal low molecular weight thiol in actinomycetes. The enzyme 1-D-myo-inosityl 2-N-acetamido-2-deoxy-alpha-D-glucopyranoside deacetylase (AcGI deacetylase) is involved in the biosynthesis of MSH and forms the free amine 1-D-myo-inosityl 2-amino-2-deoxy-alpha-D-glucopyranoside, which is used in the third of four steps of MSH biosynthesis. Here, we report the synthesis of two isomers of AcGI, which contain either 1-L-myo-inositol or 1-D-myo-inositol. These synthetic products were used to investigate substrate specificity of the Mycobacterium tuberculosis enzyme AcGI deacetylase.     

Alzheimer's disease beta-amyloid peptide is increased in mice deficient in endothelin-converting enzyme

The abnormal accumulation of beta-amyloid (Abeta) in the brain is an early and invariant feature in Alzheimer's disease (AD) and is believed to play a pivotal role in the etiology and pathogenesis of the disease. As such, a major focus of AD research has been the elucidation of the mechanisms responsible for the generation of Abeta. As with any peptide, however, the degree of Abeta accumulation is dependent not only on its production but also on its removal. In cell-based and in vitro models we have previously characterized endothelin-converting enzyme-1 (ECE-1) as an Abeta-degrading enzyme that appears to act intracellularly, thus limiting the amount of Abeta available for secretion. To determine the physiological significance of this activity, we analyzed Abeta levels in the brains of mice deficient for ECE-1 and a closely related enzyme, ECE-2. Significant increases in the levels of both Abeta40 and Abeta42 were found in the brains of these animals when compared with age-matched littermate controls. The increase in Abeta levels in the ECE-deficient mice provides the first direct evidence for a physiological role for both ECE-1 and ECE-2 in limiting Abeta accumulation in the brain and also provides further insight into the factors involved in Abeta clearance in vivo.     

Regulation of amyloid precursor protein processing by presenilin 1 (PS1) and PS2 in PS1 knockout cells

The presenilin 1 (PS1) and PS2 proteins are thought to play roles in processing of amyloid precursor protein (APP), but the nature of this role is not fully understood. Recent studies have shown that PS1 is necessary for cleavage of APP at the gamma-secretase site. We now show that PS1 and PS2 participate in other aspects of APP processing. Fibroblasts generated from PS1 knockout mice have increased levels of the APP cleavage products, secreted APP (APPs), and APP C-terminal fragments, but lower secretion of APPs and Abeta. We have also observed that loss of PS1 prevents protein kinase C or extracellular regulated kinase from increasing production of the APP cleavage products, APPs, and APP C-terminal fragments. Transfection of PS1 -/- cells with PS1 restores the responsiveness of APP processing to protein kinase C and extracellular regulated kinase. This suggests that the changes in APP processing in PS1 -/- cells result strictly from the absence of PS1. Transfection of PS1 -/- cells with PS2 is also able to correct the deficits in APP secretion, which suggests that the PS2 also has the ability to regulate APP processing. Finally, transfection of the truncated PS2 construct, Alg3, into cells lacking PS1 increases APP C-terminal fragments. This suggests that Alg3 can interfere with the processing of APP by PS2. These data point to roles for both PS1 and PS2 in regulating APP processing and suggest that the role of these proteins also includes coupling APP to signal transduction pathways.     

High-throughput screen identifies disulfiram as a potential therapeutic for triple-negative breast cancer cells: Interaction with IQ motif-containing factors

Triple-negative breast cancer (TNBC) represents an aggressive subtype, for which radiation and chemotherapy are the only options. Here we describe the identification of disulfiram, an FDA-approved drug used to treat alcoholism, as well as the related compound thiram, as the most potent growth inhibitors following high-throughput screens of 3185 compounds against multiple TNBC cell lines. The average IC₅₀ for disulfiram was ~300 nM. Drug affinity responsive target stability (DARTS) analysis identified IQ motif-containing factors IQGAP1 and MYH9 as direct binding targets of disulfiram. Indeed, knockdown of these factors reduced, though did not completely abolish, cell growth. Combination treatment with 4 different drugs commonly used to treat TNBC revealed that disulfiram synergizes most effectively with doxorubicin to inhibit cell growth of TNBC cells. Disulfiram and doxorubicin cooperated to induce cell death as well as cellular senescence, and targeted the ESA⁺/CD24^-/low/CD44⁺ cancer stem cell population. Our results suggest that disulfiram may be repurposed to treat TNBC in combination with doxorubicin.     

Novel IL10 gene family associations with systemic juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is the most common cause of chronic childhood disability and encompasses a number of disease subgroups. In this study we have focused on systemic JIA (sJIA), which accounts for approximately 11% of UK JIA cases. This study reports the investigation of three members of the IL10 gene family as candidate susceptibility loci in children with sJIA. DNA from 473 unaffected controls and 172 patients with sJIA was genotyped for a single nucleotide polymorphism (SNP) in IL19 and IL20 and two SNPs in IL10. We examined evidence for association of the four SNPs by single marker and haplotype analysis. Significant differences in allele frequency were observed between cases and controls, for both IL10-1082 (p = 0.031) and IL20-468 (p = 0.028). Furthermore, examination of the haplotypes of IL10-1082 and IL20-468 revealed greater evidence for association (global p = 0.0006). This study demonstrates a significant increased prevalence of the low expressing IL10-1082 genotype in patients with sJIA. In addition, we show a separate association with an IL20 polymorphism, and the IL10-1082A/IL20-468T haplotype. The two marker 'A-T' haplotype confers an odds ratio of 2.24 for sJIA. This positive association suggests an important role for these cytokines in sJIA pathogenesis.