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71.

Introduction

Methotrexate (MTX) exerts at least part of its anti-inflammatory effects through adenosine receptors (ADOR). The aims of this study were to determine the expression of all four adenosine receptor genes (ADORA1, ADORA2A, ADORA2B, ADORA3 and ADORA3variant) in rheumatoid synovial tissue and any influence of MTX exposure on this expression. Furthermore, we investigated whether polymorphisms within ADORA3 were associated with response and/or adverse effects associated with MTX.

Methods

Adenosine receptor gene expression was undertaken using PCR in 20 rheumatoid arthritis (RA) synovial samples. A separate cohort of 225 RA patients receiving MTX was genotyped for SNPs in the ADORA3 receptor gene. Double immunofluorescence was used to identify cells expressing ADOR protein.

Results

All ADOR genes were expressed in all synovial samples. ADORA3 and A3variant were the dominant subtypes expressed irrespective of MTX therapy. Expression of ADORA2A and ADORA2B was increased in patients receiving MTX compared to those not receiving MTX. There was no association between the ADORA3 rs1544224 SNP and high and low disease activity or MTX-associated adverse effects. ADORA2B protein expression was most obvious in vascular endothelial cells whereas ADORA3 protein was more abundant and expressed by synovial fibroblasts.

Conclusions

We have shown that adenosine receptors are expressed in RA synovium. There is differential expression of receptors such that ADORA3 is expressed at significantly higher levels. This evidence demonstrates the potential for MTX to exert its anti-inflammatory effects at the primary site of pathology within the joints of patients with RA.  相似文献   
72.
It is common among competitive baseball players to swing bats while in the batter's box in an attempt to improve their batting performance. Players use bats of different weights during this time, and only a few studies have evaluated the optimal bat weight to increase performance. Previous studies have not investigated the optimal rest period after a warm-up with bats of varying weights. Therefore, we tested the peak bat velocity of 16 National Collegiate Athletic Association Division II intercollegiate baseball players at 1, 2, 4, and 8 minutes, after warming up with bats of 5 different weights. Measured variables were peak bat velocity at peak acceleration (PVPA), peak bat velocity of the swing (PV), peak bat acceleration (PA), and time to reach peak acceleration (TPA) using a chronograph, which measured the batting velocity in real time every 10 milliseconds throughout the swing. A repeated measure analysis of variance was run to assess group, time, and group by time interactions. If any main effects were found, a Tukey post hoc was employed to locate differences. There were significant (p ≤ 0.05) time effects for PVPA, PV, and PA but not for TPA. The PVPA, PV, and PA all increased over time, peaking from 4 to 8 minutes. There were no significant differences in any of the variables among the 5 bat weights used in the warm-up (p > 0.05). However, there were significant differences in PVPA, PV, and PA after 2, 4, and 8 minutes of rest compared with the preexperimental warm-up and 1-minute post-warm-up. From a practical standpoint, batters should warm up early and quickly in the batter's box to maximize the amount of recovery time before they swing at the plate. In addition, batters may want to take their time getting ready at the plate or take some pitches while at-bat in an attempt to maximize performance. Alternatively, the data imply that pitchers should throw their fastest pitch near the beginning of the at-bat to correspond with the potentially slower bat speeds of the batter.  相似文献   
73.
The primary objective of this investigation was to identify which components of endurance training (e.g., modality, duration, frequency) are detrimental to resistance training outcomes. A meta-analysis of 21 studies was performed with a total of 422 effect sizes (ESs). Criteria for the study included were (a) compare strength training alone to strength plus endurance training (concurrent) or to compare combinations of concurrent training; (b) the outcome measures include at least one measure of strength, power, or hypertrophy; and (c) the data necessary to calculate ESs must be included or available. The mean ES for hypertrophy for strength training was 1.23; for endurance training, it was 0.27; and for concurrent training, it was 0.85, with strength and concurrent training being significantly greater than endurance training only. The mean ES for strength development for strength training was 1.76; for endurance training, it was 0.78; and for concurrent training, it was 1.44. Strength and concurrent training was significantly greater than endurance training. The mean ES for power development for strength training only was 0.91; for endurance training, it was 0.11; and for concurrent training, it was 0.55. Significant differences were found between all the 3 groups. For moderator variables, resistance training concurrently with running, but not cycling, resulted in significant decrements in both hypertrophy and strength. Correlational analysis identified significant negative relationships between frequency (-0.26 to -0.35) and duration (-0.29 to -0.75) of endurance training for hypertrophy, strength, and power. Significant relationships (p < 0.05) between ES for decreased body fat and % maximal heart rate (r = -0.60) were also found. Our results indicate that interference effects of endurance training are a factor of the modality, frequency, and duration of the endurance training selected.  相似文献   
74.
In most adult humans, hepatitis B is a self-limiting disease leading to life-long protective immunity, which is the consequence of a robust adaptive immune response occurring weeks after hepatitis B virus (HBV) infection. Notably, HBV-specific T cells can be detected shortly after infection, but the mechanisms underlying this early immune priming and its consequences for subsequent control of viral replication are poorly understood. Using primary human and mouse hepatocytes and mouse models of transgenic and adenoviral HBV expression, we show that HBV-expressing hepatocytes produce endoplasmic reticulum (ER)-associated endogenous antigenic lipids including lysophospholipids that are generated by HBV-induced secretory phospholipases and that lead to activation of natural killer T (NKT) cells. The absence of NKT cells or CD1d or a defect in ER-associated transfer of lipids onto CD1d results in diminished HBV-specific T and B cell responses and delayed viral control in mice. NKT cells may therefore contribute to control of HBV infection through sensing of HBV-induced modified self-lipids.  相似文献   
75.
Establishing if species contractions were the result of natural phenomena or human induced landscape changes is essential for managing natural populations. Fishers (Martes pennanti) in California occur in two geographically and genetically isolated populations in the northwestern mountains and southern Sierra Nevada. Their isolation is hypothesized to have resulted from a decline in abundance and distribution associated with European settlement in the 1800s. However, there is little evidence to establish that fisher occupied the area between the two extant populations at that time. We analyzed 10 microsatellite loci from 275 contemporary and 21 historical fisher samples (1880–1920) to evaluate the demographic history of fisher in California. We did not find any evidence of a recent (post-European) bottleneck in the northwestern population. In the southern Sierra Nevada, genetic subdivision within the population strongly influenced bottleneck tests. After accounting for genetic subdivision, we found a bottleneck signal only in the northern and central portions of the southern Sierra Nevada, indicating that the southernmost tip of these mountains may have acted as a refugium for fisher during the anthropogenic changes of the late 19th and early 20th centuries. Using a coalescent-based Bayesian analysis, we detected a 90% decline in effective population size and dated the time of decline to over a thousand years ago. We hypothesize that fisher distribution in California contracted to the two current population areas pre-European settlement, and that portions of the southern Sierra Nevada subsequently experienced another more recent bottleneck post-European settlement.  相似文献   
76.
The field of molecular paleontology has recently made significant contributions to anthropology and biology. Hundreds of ancient DNA studies have been published, but none has targeted fossil coralline algae. Using regions of the SSU gene, we analyzed rDNA from fossil coralline algae of varying ages and states of preservation from Spain, Papua New Guinea (PNG), and the Great Barrier Reef (GBR). Specimens from PNG, GBR, and some localities from Spain did not contain endogenous ancient DNA. Reproducible sequence data were obtained from specimens ~550 years old from near Cadiz, Spain, and from rocky‐shore deposits in Carboneras, Almeria Province of Spain (~78,000 years before present [YBP]). Based on BLAST searches and a phylogenetic analysis of sequences, an undescribed coralline alga belonging to the Melobesioideae was discovered in the Carboneras material as well as the following coralline genera: Jania, Lithophyllum, Lithothamnion, Mesophyllum, and Phymatolithon. DNA from fleshy brown and red macroalgae was also discovered in the specimens from Carboneras. The coralline algae identified using molecular techniques were in agreement with those based on morphological methods. The identified taxa are common in the present‐day southeastern Spain littoral zone. Amino acid racemization, concentration ratios, and specific concentrations failed to show a correlation between biomolecular preservation and PCR amplification success. Results suggest that molecular investigations on fossil algae, although limited by technical difficulties, are feasible. Validity of our results was established using authentication criteria and a self‐critical approach to compliance.  相似文献   
77.
Three of the four family X polymerases, DNA polymerase lambda, DNA polymerase mu, and TdT, have been associated with repair of double-strand DNA breaks by nonhomologous end-joining. Their involvement in this DNA repair process requires an N-terminal BRCT domain that mediates interaction with other protein factors required for recognition and binding of broken DNA ends. Here we present the NMR solution structure of the BRCT domain of DNA polymerase lambda, completing the structural portrait for this family of enzymes. Analysis of the overall fold of the polymerase lambda BRCT domain reveals structural similarity to the BRCT domains of polymerase mu and TdT, yet highlights some key sequence and structural differences that may account for important differences in the biological activities of these enzymes and their roles in nonhomologous end-joining. Mutagenesis studies indicate that the conserved Arg57 residue of Pol lambda plays a more critical role for binding to the XRCC4-Ligase IV complex than its structural homolog in Pol mu, Arg43. In contrast, the hydrophobic Leu60 residue of Pol lambda contributes less significantly to binding than the structurally homologous Phe46 residue of Pol mu. A third leucine residue involved in the binding and activity of Pol mu, is nonconservatively replaced by a glutamine in Pol lambda (Gln64) and, based on binding and activity data, is apparently unimportant for Pol lambda interactions with the NHEJ complex. In conclusion, both the structure of the Pol lambda BRCT domain and its mode of interaction with the other components of the NHEJ complex significantly differ from the two previously studied homologs, Pol mu and TdT.  相似文献   
78.
Objective: Ghrelin and peptide YY (PYY) are two gut hormones that have effects on appetite. Our objectives were to characterize the patterns of secretion of these hormones in response to feeding in school‐age children and determine whether there were differences between normal weight (NW) and overweight (OW) subjects. Methods and Procedures: This was a cross‐sectional study at one tertiary care center. Subjects were 7‐ to 11‐year‐old healthy NW and OW volunteers recruited from local advertisements. Following an overnight fast, the subjects were given a standardized breakfast and lunch and had nine hourly blood samples for total ghrelin and total PYY. We assessed whether ghrelin and PYY levels changed from the preprandial to postprandial state and corresponded to reported hunger/satiety. Results: Hunger ratings were similar between the two groups throughout the study period. Ghrelin was not suppressed after eating, did not rise prior to the next meal, and did not correspond to hunger ratings in either group. PYY increased postprandially and decreased preprandially in the NW group, but OW children exhibited this pattern for only part of the day. PYY levels incompletely corresponded to reported satiety in the OW group. Discussion: Mixed meal consumption had little effect on ghrelin secretion and a variable effect on PYY secretion in young children in our study. Differences that were observed between the groups do not suggest that an abnormality in their secretion contributes to the development of obesity.  相似文献   
79.
80.
Given that signal sequences between secreted proteins of different species can be interchanged, it is reasonable to expect that both mammalian and yeast signal sequence trapping (SST) systems would secrete Haemonchus contortus proteins with similar efficiency and quality. To determine if H. contortus cDNAs that contain a signal sequence could re-establish secretion of a reporter protein, mammalian and yeast SST vectors were designed, 10 H. contortus genes selected, and their respective cDNAs cloned into these two SST vectors. The selected molecules included genes known to code for excretory/secretory or membrane-bound proteins as potential test 'positives', and genes known to code for non-secreted proteins as test 'negatives'. While differentiation between secretion and non-secretion was evident in both systems, the results indicated greater efficiency was achieved when the mammalian system was used. Therefore, mammalian SST using COS cells would be a more useful tool to screen H. contortus cDNA libraries for potential secreted and type-1 integral membrane proteins than yeast SST.  相似文献   
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