Inositol pyrophosphates inhibit Akt signaling, thereby regulating insulin sensitivity and weight gain

The inositol pyrophosphate IP7 (5-diphosphoinositolpentakisphosphate), formed by a family of three inositol hexakisphosphate kinases (IP6Ks), modulates diverse cellular activities. We now report that IP7 is a physiologic inhibitor of Akt, a serine/threonine kinase that regulates glucose homeostasis and protein translation, respectively, via the GSK3β and mTOR pathways. Thus, Akt and mTOR signaling are dramatically augmented and GSK3β signaling reduced in skeletal muscle, white adipose tissue, and liver of mice with targeted deletion of IP6K1. IP7 affects this pathway by potently inhibiting the PDK1 phosphorylation of Akt, preventing its activation and thereby affecting insulin signaling. IP6K1 knockout mice manifest insulin sensitivity and are resistant to obesity elicited by high-fat diet or aging. Inhibition of IP6K1 may afford a therapeutic approach to obesity and diabetes.     

Earthworm-assisted bioremediation of petroleum hydrocarbon–contaminated soils from motorcar mechanic workshops in Ibadan,Oyo State,southwestern Nigeria

Enhanced microbial bioremediation of petroleum hydrocarbon–contaminated (PHC) soils with the earthworm Alma millisoni and the bacterium Bacillus spp. was conducted. The petroleum-contaminated topsoils (PCTS) (0–15 cm) collected from motorcar mechanic workshops were thoroughly mixed, sieved, and air dried for 7 days. The pH, water holding capacity (WHC), total nitrogen (N), organic carbon (OC), heavy metal (HM), and bacteriological analysis of the soil samples were evaluated. The indigenous bacterial isolates were subjected to 1%, 5%, and 50% of spent engine oil (SEO), incubated for 7 days at 37°C, and the isolate with the highest tolerance pattern was used for the remediation. Out of four indigenous bacteria isolated, Bacillus spp. had the highest tolerance to SEO. Preliminary exposure assessments of A. millisoni to PHC soils (100%, 60%, 50%, and 40% PHC) were carried out using 48-h avoidance response, coiling exhibition, swollen clitelium, 14-day survival tests, and antioxidant enzyme activities such as catalase (CAT), superoxide dismutase (SOD), glutathione S-transferase (GST), and glutathione peroxidase (GPx). Subsequently, four treatments of 1 kg soil mixed with 100%, 75%, 50%, and 0% PCTS were designed and spiked with 20 g of dried cow dung. Each of the treatments consisted of four setups, viz., A. millisoni alone, A. millisoni and Bacillus spp., Bacillus spp. alone, and control. The bacterial counts, total petroleum hydrocarbon (TPH), total and bioavailable HM, and total OC and N of the soils were evaluated every 7 days for 35 days. Significant increases in the activities of CAT, SOD, GPx, and GST compared with control were recorded in A. millisoni exposed to the various treatments. Treatment with combined A. millisoni and Bacillus spp. resulted in significant (p < .05) reduction in TPH, reduction in total and bioavailable heavy metals, and increased total OC and N of the soil compared with other treatments. The percentage reduction in TPH and heavy metals with concomitant increase in total OC and total N recorded in the 50% PHC soils followed the order A. millisoni and Bacillus spp. > A. millisoni alone > Bacillus spp. alone. Hence, enhanced bioremediation using A. millisoni and Bacillus spp. may be a good biocatalyst in the remediation of petroleum hydrocarbon–contaminated soils.     

Intracellular Symbionts and Other Bacteria Associated with Deer Ticks (Ixodes scapularis) from Nantucket and Wellfleet, Cape Cod, Massachusetts

The diversity of bacteria associated with the deer tick (Ixodes scapularis) was assessed using PCR amplification, cloning, and sequencing of 16S rRNA genes originating from seven ticks collected from Nantucket Island and Wellfleet, Cape Cod, Mass. The majority of sequences obtained originated from gram-negative proteobacteria. Four intracellular bacteria were detected including strains of Ehrlichia, Rickettsia, and Wolbachia and an organism related to intracellular insect symbionts from the Cytophaga-Flavobacterium-Bacteroides group. Several strains of members of the Sphingomonadaceae were also detected in all but one tick. The results provide a view of the diversity of bacteria associated with I. scapularis ticks in the field.     

Discovery of novel pyrazolo[1,5-a]pyrimidines as potent pan-Pim inhibitors by structure- and property-based drug design

Pim kinases are promising targets for the development of cancer therapeutics. Among the three Pim isoforms, Pim-2 is particularly important in multiple myeloma, yet is the most difficult to inhibit due to its high affinity for ATP. We identified compound 1 via high throughput screening. Using property-based drug design and co-crystal structures with Pim-1 kinase to guide analog design, we were able to improve potency against all three Pim isoforms including a significant 10,000-fold gain against Pim-2. Compound 17 is a novel lead with low picomolar potency on all three Pim kinase isoforms.     

Sex differences in myocardial infarct size are abolished by sarcolemmal KATP channel blockade in rat

This study was conducted to examine the relationship between myocardial ATP-sensitive potassium (K(ATP)) channels and sex differences in myocardial infarct size after in vitro ischemia-reperfusion (I/R). Hearts from adult male and female Sprague-Dawley rats were excised and exposed to an I/R protocol (1 h of ischemia, followed by 2 h of reperfusion) on a modified Langendorff apparatus. Hearts from female rats showed significantly smaller infarct sizes than hearts from males (23 +/- 4 vs. 40 +/- 5% of the zone at risk, respectively; P < 0.05). Administration of HMR-1098, a sarcolemmal K(ATP) channel blocker, abolished the sex difference in infarct size (42 +/- 4 vs. 45 +/- 5% of the zone at risk in hearts from female and male rats, respectively; P = not significant). Further experiments showed that blocking the K(ATP) channels in ischemia, and not reperfusion, was sufficient to increase infarct size in female rats. These data demonstrate that sarcolemmal K(ATP) channels are centrally involved in mechanisms that underlie sex differences in the susceptibility of the intact heart to I/R injury.     

The use of cluster analysis to help determine the function of plasmids in marine Vibrio species

A phenotypic matrix was established for 512 marine Vibrio species previously surveyed for plasmid incidence and characteristics. The organisms were subjected to a variety of tests to determined phenetic groups and plasmid functions. Both physiologic and plasmid function tests were used to cluster the strains by numerical taxonomy. The resulting phenotypic clusters showed an uneven distribution of plasmids. Some clusters contained isolates with no plasmids and other clusters contained isolates with a high incidence of plasmids. Traits correlating with plasmid occurrence in clusters included bioluminescence and antibiotic and heavy metal resistance. These characteristics were assumed to be either plasmid-mediated or plasmid-associated traits. Cluster analysis was found to be a successful method for relating the presence of plasmids with specific traits.