Microarray analyses of peripheral blood cells identifies unique gene expression signature in psoriatic arthritis

Psoriatic arthritis (PsA) is a chronic and erosive form of arthritis of unknown cause. We aimed to characterize the PsA phenotype using gene expression profiling and comparing it with healthy control subjects and patients rheumatoid arthritis (RA). Peripheral blood cells (PBCs) of 19 patients with active PsA and 19 age- and sex-matched control subjects were used in the analyses of PsA, with blood samples collected in PaxGene tubes. A significant alteration in the pattern of expression of 313 genes was noted in the PBCs of PsA patients on Affymetrix U133A arrays: 257 genes were expressed at reduced levels in PsA, and 56 genes were expressed at increased levels, compared with controls. Downregulated genes tended to cluster to certain chromosomal regions, including those containing the psoriasis susceptibility loci PSORS1 and PSORS2. Among the genes with the most significantly reduced expression were those involved in downregulation or suppression of innate and acquired immune responses, such as SIGIRR, STAT3, SHP1, IKBKB, IL-11RA, and TCF7, suggesting inappropriate control that favors proin-flammatory responses. Several members of the MAPK signaling pathway and tumor suppressor genes showed reduced expression. Three proinflammatory genes--S100A8, S100A12, and thioredoxin--showed increased expression. Logistic regression and recursive partitioning analysis determined that one gene, nucleoporin 62 kDa, could correctly classify all controls and 94.7% of the PsA patients. Using a dataset of 48 RA samples for comparison, the combination of two genes, MAP3K3 followed by CACNA1S, was enough to correctly classify all RA and PsA patients. Thus, PBC gene expression profiling identified a gene expression signature that differentiated PsA from RA, and PsA from controls. Several novel genes were differentially expressed in PsA and may prove to be diagnostic biomarkers or serve as new targets for the development of therapies.     

The effect of decapitation on the levels of IAA and ABA in the lateral buds of Betula pendula roth

The level of IAA and ABA in lateral buds of birch shoots 24 h and 5 days after the decapitation of the apical bud was determined. Twenty four hours after decapitation, when visible signs of outgrowth of lateral buds were not observed yet, an increase in the level of IAA and a decrease of ABA, as compared with the buds of non-decapitated shoots, was found. Five days later, when lateral buds were in the period of intensive outgrowth, a decrease in the levels of IAA and ABA was observed. It has been suggested that removing the source of auxin, by the decapitation of the apical bud makes possible the lateral buds to undertake the synthesis of their own auxin. It could lead to the decrease in the content of ABA. These all events could create suitable conditions for the outgrowth of lateral shoots.     

Experimental Control for the Ovariectomized Rat Model: Use of Sham Versus Nonmanipulated Animal

One of 2 models required by the U.S. Food and Drug Administration for registration of a treatment for osteoporosis, the ovariectomized (OVX) rat model, is widely used in scientific studies investigating sex hormone-deficient bone loss. The use of control nonhuman animals is critical because bone turnover may be affected by animal stress, use of anesthetic, and the mechanisms involved in wound healing. Historically, researchers have used sham-operated animals who undergo the same manipulations as the OVX rats, but ethical concerns require consideration of unmanipulated (unoperated) control animals to minimize animal distress and unnecessary procedures. Herein, we report the results of 3 studies including OVX, sham, and unmanipulated rats and the effects on bone mineral density and content (BMD/BMC) during 2 to 6 months postsurgery. Our data indicate that while OVX animals generally had lower BMD and BMC than animals in either of the control groups, no differences were observed between sham and unmanipulated animals at any of the time points assessed. However, because bone turnover is a long-term process, studies with longer duration and multiple endpoints are warranted to confirm these results.     

Damage to the structure of erythrocyte plasma membranes in patients with type-2 hypercholesterolemia

BACKGROUND: Hypercholesterolemia may decrease the deformability of red blood cells which impairs their hemorheological behavior and promotes atherosclerosis.The study involved 60 hypercholesterolemic patients and 30 healthy individuals as the control group.METHODS: The membrane fluidity of erythrocytes was estimated by a spin-label method (5-doxylstearic acid (5-DSA)). The ratio of weakly to strongly (W/S) immobilized residues of erythrocyte membrane-bond maleimide-tempo spin label was studied in oxidative damage to membrane protein. Damage to erythrocyte proteins was also indicated by means of Na(+) K(+) ATPase activity.RESULTS: The membranes of hyperlipidemia (hlp) patients contain larger concentrations of cholesterol 2.16+/-0.24 than do those of the normolipemic individuals 0.31+/-0.24 (P<0.001). The level of Na(+) K(+) ATPase in the erythrocyte membrane from the control group was higher 103.4+/-1.3 (nmolPi/(mgproteinsh)) than in the patient group 93.6+/-3.2 (nmolPi/(mgproteinsh)) (P<0.001). The order parameter S 5-DSA in the control group was 0.745+/-0.009 and in hlp patients was 0.755+/-0.009 (P<0.001). The W/S ratio in the control group amounted to 2.00+/-0.09 and in the hlp patient group was 2.50+/-0.11 (P<0.001).CONCLUSION: Type-2 hypercholesterolemia causes changes in the structure and fluidity of erythrocyte plasma membranes since the excess of cholesterol affects the normal rheology of blood through its interaction with erythrocytes. It also impairs the function and structure of plasma membrane proteins.     

An evaluation of a C-glucuronide as a liver targeting group: conjugate of a glucocorticoid antagonist

A beta-C-glucuronide conjugate of the glucocorticoid receptor antagonist, Mifepristone 1, was prepared which maintained binding affinity, had modest in vitro activity, and was metabolically more stable than the parent. Pharmacokinetic studies suggest that the conjugate is recognized by the liver like O-glucuronides and may undergo a portion of the enterohepatic recirculation loop.     

<Emphasis Type="Italic">Mesotoga prima</Emphasis> gen. nov., sp. nov., the first described mesophilic species of the Thermotogales

A novel mesophilic member of the Thermotogales, strain MesG1.Ag.4.2, was isolated from sediments from Baltimore Harbor, MD, USA. The strain grew optimally at 37 °C with a doubling time of 16.5 h on xylose. Carbohydrates and proteinaceous compounds supported growth and pentoses were preferred over hexoses. The strain was strictly anaerobic and growth was slightly stimulated by thiosulfate, sulfite, and elemental sulfur. The G + C content of its genomic DNA was 45.3 mol%. Strain MesG1.Ag.4.2 and Kosmotoga olearia lipids were analyzed. Strain MesG1.Ag.4.2 contained no long-chain dicarboxylic acids and its major phospholipid was lyso-phosphatidylserine. Long-chain dicarboxylic acids were found in K. olearia and its major phospholipid was cardiolipin, a lipid not yet reported in Thermotogales species. Phylogenetic analyses of its two 16S rRNA genes placed strain MesG1.Ag.4.2 within the bacterial order Thermotogales. Based on the phylogenetic analyses and its low optimal growth temperature, it is proposed that the strain represents a novel species of a new genus within the family Thermotogaceae, order Thermotogales. The name Mesotoga prima gen. nov., sp. nov. is proposed. The type strain of M. prima is MesG1.Ag.4.2 (= DSM 24739 = ATCC BAA-2239).     

Recombination in Thermotoga: implications for species concepts and biogeography

Here we characterize regions of the genomes of eight members of the hyperthermophilic genus Thermotoga. These bacteria differ from each other physiologically and by 3-20% in gene content and occupy physically distinct environments in widely disparate regions of the globe. Among the four different lineages (represented by nine different strains) that we compare, no two are closer than 96% in the average sequences of their genes. By most accepted recent definitions these are different "ecotypes" and different "species." And yet we find compelling evidence for recombination between them. We suggest that no single prokaryotic species concept can accommodate such uncoupling of ecotypic and genetic aspects of cohesion and diversity, and that without a single concept, the question of whether or not prokaryotic species might in general be cosmopolitan cannot be sensibly addressed. We can, however, recast biogeographical questions in terms of the distribution of genes and their alleles.     

Thyroid receptor ligands. Part 4: 4'-amido bioisosteric ligands selective for the thyroid hormone receptor beta

Based on the examination of the X-ray crystallographic structures of the LBD of TRalpha and TRbeta in complex with KB-141 (2), a number of novel 4'-hydroxy bioisosteric thyromimetics were prepared. Optimal affinity and beta-selectivity (33 times), was found with a medium-sized alkyl-substituted amido group; iso-butyl (12c). It can be concluded that bioisosteric replacements of the 4'-hydroxy position represent a new promising class of TRbeta-selective synthetic thyromimetics.