Calnexin Delta 185-520 partially reverses the misprocessing of the Delta F508 cystic fibrosis transmembrane conductance regulator

We analyzed the interrelation between the efficiency of a gene expression and the nucleotide composition of all protein-coding sequences in 38 unicellular organisms whose complete genomic sequences are known. These organisms comprise 37 prokaryotic (29 eubacteria and eight archaebacteria) and one eukaryotic (yeast) species. We demonstrated that frequency analysis of gene codon composition fails to reflect adequately the gene expression efficiency of all these organisms. We constructed a measure, the elongation efficiency index, that considers simultaneously the information on codon frequencies and the degree of mRNA local self-complementarity. This measure recognizes the ribosome-coding genes as highly expressed in all the unicellular organisms studied. According to our analysis, these species fall into five groups differentiated by the process that makes the key contribution to the elongation rate.     

Ketogenic Essential Amino Acids Modulate Lipid Synthetic Pathways and Prevent Hepatic Steatosis in Mice

Background

Although dietary ketogenic essential amino acid (KAA) content modifies accumulation of hepatic lipids, the molecular interactions between KAAs and lipid metabolism are yet to be fully elucidated.

Methodology/Principal Findings

We designed a diet with a high ratio (E/N) of essential amino acids (EAAs) to non-EAAs by partially replacing dietary protein with 5 major free KAAs (Leu, Ile, Val, Lys and Thr) without altering carbohydrate and fat content. This high-KAA diet was assessed for its preventive effects on diet-induced hepatic steatosis and whole-animal insulin resistance. C57B6 mice were fed with a high-fat diet, and hyperinsulinemic ob/ob mice were fed with a high-fat or high-sucrose diet. The high-KAA diet improved hepatic steatosis with decreased de novo lipogensis (DNL) fluxes as well as reduced expressions of lipogenic genes. In C57B6 mice, the high-KAA diet lowered postprandial insulin secretion and improved glucose tolerance, in association with restored expression of muscle insulin signaling proteins repressed by the high-fat diet. Lipotoxic metabolites and their synthetic fluxes were also evaluated with reference to insulin resistance. The high-KAA diet lowered muscle and liver ceramides, both by reducing dietary lipid incorporation into muscular ceramides and preventing incorporation of DNL-derived fatty acids into hepatic ceramides.

Conclusion

Our results indicate that dietary KAA intake improves hepatic steatosis and insulin resistance by modulating lipid synthetic pathways.     

Application of a Combination of a Knowledge-Based Algorithm and 2-Stage Screening to Hypothesis-Free Genomic Data on Irinotecan-Treated Patients for Identification of a Candidate Single Nucleotide Polymorphism Related to an Adverse Effect

Interindividual variation in a drug response among patients is known to cause serious problems in medicine. Genomic information has been proposed as the basis for “personalized” health care. The genome-wide association study (GWAS) is a powerful technique for examining single nucleotide polymorphisms (SNPs) and their relationship with drug response variation; however, when using only GWAS, it often happens that no useful SNPs are identified due to multiple testing problems. Therefore, in a previous study, we proposed a combined method consisting of a knowledge-based algorithm, 2 stages of screening, and a permutation test for identifying SNPs. In the present study, we applied this method to a pharmacogenomics study where 109,365 SNPs were genotyped using Illumina Human-1 BeadChip in 168 cancer patients treated with irinotecan chemotherapy. We identified the SNP rs9351963 in potassium voltage-gated channel subfamily KQT member 5 (KCNQ5) as a candidate factor related to incidence of irinotecan-induced diarrhea. The p value for rs9351963 was 3.31×10⁻⁵ in Fisher''s exact test and 0.0289 in the permutation test (when multiple testing problems were corrected). Additionally, rs9351963 was clearly superior to the clinical parameters and the model involving rs9351963 showed sensitivity of 77.8% and specificity of 57.6% in the evaluation by means of logistic regression. Recent studies showed that KCNQ4 and KCNQ5 genes encode members of the M channel expressed in gastrointestinal smooth muscle and suggested that these genes are associated with irritable bowel syndrome and similar peristalsis diseases. These results suggest that rs9351963 in KCNQ5 is a possible predictive factor of incidence of diarrhea in cancer patients treated with irinotecan chemotherapy and for selecting chemotherapy regimens, such as irinotecan alone or a combination of irinotecan with a KCNQ5 opener. Nonetheless, clinical importance of rs9351963 should be further elucidated.     

Jacaric acid, a linolenic acid isomer with a conjugated triene system, has a strong antitumor effect in vitro and in vivo

In this study, we compared the cytotoxic effects of natural conjugated linolenic acids (CLnAs) on human adenocarcinoma cells (DLD-1) in vitro, with the goal of finding CLnA isomers with strong cytotoxic effects. The antitumor effect of the CLnA with the strongest cytotoxic effect was then examined in mice. The results showed that all CLnA isomers have strong cytotoxic effects on DLD-1 cells, with jacaric acid (JA) having the strongest effect. Examination of the mechanism of cell death showed that CLnAs induce apoptosis in DLD-1 cells via lipid peroxidation. The intracellular levels of incorporated CLnAs were measured to examine the reason for differences in cytotoxic effects. These results showed that JA was taken into cells efficiently. Collectively, these results suggest that the cytotoxic effect of CLnAs is dependent on intracellular incorporation and induction of apoptosis via lipid peroxidation. JA also had a strong preventive antitumor effect in vivo in nude mice into which DLD-1 cells were transplanted. These results suggest that JA can be used as a dietary constituent for prevention of cancer.     

Apoptotic myocytes generate monocyte chemoattractant protein-1 and mediate macrophage recruitment.

The mechanisms by which apoptotic myocytes are removed by macrophages have not been fully elucidated. This study examined whether apoptotic myocytes actively recruit macrophages by generating monocyte chemoattractant protein-1 (MCP-1) in experiments in vitro and in vivo. Neonatal rat cardiac myocytes were incubated for 4 h in the presence or absence of staurosporine (STS, 0.2-1 mumol/l), an apoptosis inducer. Nuclear staining with DAPI showed that STS induced apoptosis in a dose-dependent fashion. STS (1 mumol/l) caused extensive DNA fragmentation and increased caspase-3 activity compared with a serum-deprived control. MCP-1 mRNA and protein levels in myocytes increased twofold and fourfold, respectively, on STS treatment, and immunochemical staining revealed that apoptotic myocytes expressed MCP-1. To elucidate the role of MCP-1 expressed in apoptotic myocytes to recruit macrophages/monocytes, rat monocytes were incubated in the supernatant of STS-treated myocytes using a trans-well system. The culture medium of STS-treated myocytes recruited monocytes in a MCP-1-dependent fashion. In addition, experiments were performed in vivo using ischemia-reperfused rat hearts. Rats were subjected to 30 min of ligation of the left coronary artery followed by 24 h of reperfusion. After the reperfusion, in the ischemic border myocardium, 17.1 +/- 1.1% of myocytes were terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) positive. Moreover, double staining using the TUNEL technique and immunohistochemistry with MCP-1 antibody showed that 69.8 +/- 3.9% of TUNEL-positive myocytes expressed MCP-1 protein. Concomitantly, activated macrophages infiltrated the areas of apoptosis remarkably. These results suggest that apoptotic myocytes produce MCP-1, which have a critical role in the active recruitment of macrophages.     

Cases of maternal cannibalism in wild bonobos (<Emphasis Type="Italic">Pan paniscus</Emphasis>) from two different field sites,Wamba and Kokolopori,Democratic Republic of the Congo

Maternal cannibalism, whereby a mother consumes her own offspring, occurs in various animal taxa and is commonly explained by nutritional stress or environmental pressures. It is rare in nonhuman primates and is considered an aberrant behavior only observed under high-stress conditions. It was therefore surprising when, in the first reported case of cannibalism in wild bonobos, a mother consumed part of the dead infant at LuiKotale. Here we report two more cases of maternal cannibalism by wild bonobos at two different study sites, Wamba and Kokolopori. The dead infants’ mothers participated in the cannibalism in both cases. At Kokolopori, although the mother did consume part of the carcass, it was held and shared by another dominant female. At Wamba, the mother was a dominant female within the community and was the primary consumer of the carcass. In both cases, cannibalism resembled other meat-eating events, with the dominant female controlling meat consumption. Infanticide was not observed in either case, but its occurrence could not be ruled out. Although rare, the occurrence of maternal cannibalism at three different study sites suggests that this may represent part of the behavioral repertoire of bonobos, rather than an aberrant behavior.     

Cell Aggregation Factor Produced by Streptomyces sp. Strain No. A-3315

We searched for a new aggregation factor, and found one we named 3315-AF in the culture filtrate of Streptomyces sp. strain No. A-3315. 3315-AF was purified by active carbon treatment, ethanol precipitation, gel filtration on Sepharose 2B, ether extraction, silica gel chromatography and gel filtration on Sephadex LH-20. 3315-AF was found to be a triglyceride which consists of myristic acid, pentadecanoic acid, and palmitic acid. The aggregation activity of 3315-AF was maximum around pH 8.0 at 30°C and the activity increased by addition of metallic ions such as calcium and cobalt. Hyaluronic acid, ovalbumin, BSA, and casein inhibited the aggregation activity. 3315-AF aggregated Proteus vulgaris and HeLa cells as well as Serratia marcescens and weakly aggregated Saccharomyces cerevisiae, Candida albicans, C. neoformans, and Leukemia P388, but it was inert to human erythrocytes and Sarcoma 180.     

Molecular orientation of porphyrins accompanying the formation of chain-aligned DNA films

Porphyrin-containing DNA solid films with several binding orientations were successfully prepared by drying the aqueous solution of porphyrins and DNA in a magnetic field. By the measurement of linear dichroism absorption spectra from three identical spatial directions, the molecular orientations of porphyrins in chain-aligned DNA films were evaluated. Tetra(N-methylpyridinium-4-yl)-porphyrin was found to be bound at the surface of DNA chains like a patch. This orientation is different from the intercalative or groove binding manners observed in solutions. In contrast, tetra(4-sulfonatophenyl)-porphyrin exhibited an orientation perpendicular to the DNA axis, which may be attributed to H-aggregation of porphyrins along the direction parallel to DNA chains. Heme-protein with coiled coil backbone was also aligned along the DNA chains, orienting ferric protoporphyrin parallel to the magnetic field. The major effect for these molecular orientations would be the molecular packing of the rod-disk or the rod-rod systems.     

Flower-Inducing Activity of Phloem Exudate in Cultured Apices from Pharbitis Seedlings

Phloem exudate from cotyledons of photoperiodically inducedPharbitis plants induced flowering in apices excised from non-inducedseedlings and cultured in vitro. The exudate also stimulatedflowering in apices excised from photo-induced seedlings andcultured under long-day conditions. The application of benzoicacid had similar effects. Both the exudate from non-inducedplants and gallic acid suppressed flowering in apices from photo-inducedseedlings. It appears that the phloem exudate contains flower-inducingor flower-suppressing substance(s), depending on the plant materialsfrom which it was collected. (Received August 15, 1989; Accepted May 14, 1990)     

Prevalence of antibodies against human respiratory viruses potentially involving anthropozoonoses in wild bonobos

Primates - One of the current threats to the bonobo (Pan paniscus), a highly endangered ape species only found in the Democratic Republic of the Congo, are anthropozoonoses caused by human...