Prevalence and risk factors of vertebral compression fractures in female SLE patients

Introduction

The present study objective was to evaluate the incidence of methotrexate (MTX)-specific liver lesions from the analysis of a liver biopsy of inflammatory arthritis patients with elevated liver enzymes.

Methods

A case-control study was performed with 1,571 arthritis patients on long-term low-dose MTX therapy. Results of liver biopsy were analyzed in 41 patients with elevated liver enzymes. The expression of autoimmune markers was also assessed. This population was compared with 41 disease control subjects obtained from the same database, also on MTX but without elevated liver enzymes, matched for age, sex and rheumatic disease.

Results

Compared with the disease controls, patients with liver biopsy showed lower disease duration and lower MTX exposure, weekly and cumulative doses, reflecting shorter treatment duration due to liver abnormalities. Liver biopsies showed 17 autoimmune hepatitis-like (AIH-like) lesions, 13 nonalcoholic steatohepatitis-like lesions, seven limited liver lesions, and two primary biliary cirrhoses. However, MTX-specific lesions with dystrophic nuclei in hepatocytes were seen in only two cases. Liver biopsy lesions were associated with autoimmune markers (P = 0.007); notably, AIH-like lesions were associated with rheumatoid arthritis and with the presence of the HLA-DR shared epitope.

Conclusions

MTX-specific liver lesions are rarely observed in arthritis patients under long-term MTX therapy and elevated liver enzymes.     

Control of Mycosphaerella graminicola on wheat seedlings by medical drugs known to modulate the activity of ATP-binding cassette transporters

Medical drugs known to modulate the activity of human ATP-binding cassette (ABC) transporter proteins (modulators) were tested for the ability to potentiate the activity of the azole fungicide cyproconazole against in vitro growth of Mycosphaerella graminicola and to control disease development due to this pathogen on wheat seedlings. In vitro modulation of cyproconazole activity could be demonstrated in paper disk bioassays. Some of the active modulators (amitriptyline, flavanone, and phenothiazines) increased the accumulation of cyproconazole in M. graminicola, suggesting that they reversed cyproconazole efflux. However, synergism between cyproconazole and modulators against M. graminicola on wheat seedlings could not be shown. Despite their low in vitro toxicity to M. graminicola, some modulators (amitriptyline, loperamide, and promazine) did show significant intrinsic disease control activity in preventive and curative foliar spray tests with wheat seedlings. The results suggest that these compounds have indirect disease control activity based on modulation of fungal ABC transporters essential for virulence and constitute a new class of disease control agents.     

Polymorphisms in base-excision repair and nucleotide-excision repair genes in relation to lung cancer risk

Polymorphisms in DNA repair genes may be associated with differences in DNA repair capacity, thereby influencing the individual susceptibility to smoking-related cancer. We investigated the association of 10 base-excision and nucleotide-excision repair gene polymorphisms (XRCC1 -77 T/C, Arg194Trp, Arg280His and Arg399Gln; APE1 Asp148Glu; OGG1 Ser326Cys; XPA -4 G/A; XPC PAT; XPD Asp312Asn and Lys751Gln) with lung cancer risk in Caucasians. Genotypes were determined by PCR-RFLP and PCR-single base extension assays in 110 lung cancer patients and 110 age- and sex-matched controls, and the results were analyzed using logistic regression adjusted for relevant covariates. A significant association between the APE1 Asp148Glu polymorphism and lung cancer risk was found, with adjusted odds ratios (OR) of 3.38 (p=0.001) for the Asp/Glu genotype and 2.39 (p=0.038) for the Glu/Glu genotype. Gene-smoking interaction analyses revealed a statistically significant interaction between cumulative cigarette smoking and the XRCC1 Arg399Gln and XPD Lys751Gln polymorphisms: these polymorphisms were significantly associated with lung cancer in nonsmokers and light smokers (<25 PY; OR=4.92, p=0.021 for XRCC1 399 Gln/Gln; OR=3.62, p=0.049 for XPD 751 Gln/Gln), but not in heavy smokers (> or =25 PY; OR=0.68, p=0.566 for XRCC1 399 Gln/Gln; OR=0.46, p=0.295 for XPD 751 Gln/Gln). Both the XRCC1 Arg194Trp and Arg280His as well as the OGG1 Ser326Cys heterozygous genotypes were associated with a significantly reduced risk for lung cancer (OR=0.32, p=0.024; OR=0.25, p=0.028; OR=0.51, p=0.033, respectively). No associations with lung cancer risk were found for the XRCC1 -77 T/C, the XPA -4 G/A and the XPC PAT polymorphisms. In conclusion, the APE1 Asp148Glu polymorphism is highly predictive for lung cancer, and cumulative cigarette smoking modifies the associations between the XRCC1 Arg399Gln and the XPD Lys751Gln polymorphisms and lung cancer risk.     

Stepwise reduction of functional spinal structures increase range of motion and change lordosis angle

Many investigators have performed studies on specific defect situations or determined the contribution on isolated structures. Investigating the contribution of functional structures requires obtaining the kinematic response directly on spinal segments. The purpose of this study was to quantify the function of anatomical components on lumbar segments for different loading magnitudes. Eight spinal segments (L4-5) with a median age of 52 years (ranging from 38 to 59 years) and a low degree of disc degeneration were utilized for the in vitro testing. Specimens were mounted in a custom-built spine tester and loaded with pure moments (1-10 N m) to move within three anatomical planes at a loading rate of 1.0 degrees /s. Anatomy was successively reduced by: ligaments, facet capsules, joints and nucleus. Data were evaluated for range of motion, neutral zone and lordosis angle. Transection of posterior ligaments predominantly increased specimen flexion for all bending moments applied. Supraspinous ligament also indicated to resist in extension slightly, whereas the facet capsules did not. Facet joints contributed to axial rotation, but not in lateral bending. The anterior longitudinal ligament was found to slightly resist in axial rotation, but strongly in extension. Nucleotomy caused largest increase of all movements. The unloaded posture of the specimens changed after ligament dissection, indicating ligament pretension. The region of lumbar spine is interesting for finite element (FE) simulation due to the high evidence of disc degeneration and injuries. This study may help to understand the function of specific anatomical structures and assists in FE model calibration. We suggest to start a calibration procedure for such models with the smallest functional structure (annulus) and to cumulatively add further structures.     

A syntactic model to design and verify synthetic genetic constructs derived from standard biological parts

MOTIVATION: The sequence of artificial genetic constructs is composed of multiple functional fragments, or genetic parts, involved in different molecular steps of gene expression mechanisms. Biologists have deciphered structural rules that the design of genetic constructs needs to follow in order to ensure a successful completion of the gene expression process, but these rules have not been formalized, making it challenging for non-specialists to benefit from the recent progress in gene synthesis. RESULTS: We show that context-free grammars (CFG) can formalize these design principles. This approach provides a path to organizing libraries of genetic parts according to their biological functions, which correspond to the syntactic categories of the CFG. It also provides a framework for the systematic design of new genetic constructs consistent with the design principles expressed in the CFG. Using parsing algorithms, this syntactic model enables the verification of existing constructs. We illustrate these possibilities by describing a CFG that generates the most common architectures of genetic constructs in Escherichia coli. AVAILABILITY: A web site allows readers to experiment with the algorithms presented in this article: www.genocad.org. SUPPLEMENTARY INFORMATION: Sequences and models are available at Bioinformatics online.     

Eating yourself sick: transmission of disease as a function of foraging ecology

Species interactions may profoundly influence disease outbreaks. However, disease ecology has only begun to integrate interactions between hosts and their food resources (foraging ecology) despite that hosts often encounter their parasites while feeding. A zooplankton–fungal system illustrated this central connection between foraging and transmission. Using experiments that varied food density for Daphnia hosts, density of fungal spores and body size of Daphnia , we produced mechanistic yet general models for disease transmission rate based on broadly applicable components of feeding biology. Best performing models could explain why prevalence of infection declined at high food density and rose sharply as host size increased (a pattern echoed in nature). In comparison, the classic mass-action model for transmission performed quite poorly. These foraging-based models should broadly apply to systems in which hosts encounter parasites while eating, and they will catalyse future integration of the roles of Daphnia as grazer and host.     

Engineering proteinase K using machine learning and synthetic genes

Background  

Altering a protein's function by changing its sequence allows natural proteins to be converted into useful molecular tools. Current protein engineering methods are limited by a lack of high throughput physical or computational tests that can accurately predict protein activity under conditions relevant to its final application. Here we describe a new synthetic biology approach to protein engineering that avoids these limitations by combining high throughput gene synthesis with machine learning-based design algorithms.     

Piliation of Lactobacillus rhamnosus GG Promotes Adhesion,Phagocytosis, and Cytokine Modulation in Macrophages

Recently, spaCBA-encoded pili on the cell surface of Lactobacillus rhamnosus GG were identified to be key molecules for binding to human intestinal mucus and Caco-2 intestinal epithelial cells. Here, we investigated the role of the SpaCBA pilus of L. rhamnosus GG in the interaction with macrophages in vitro by comparing the wild type with surface mutants. Our results show that SpaCBA pili play a significant role in the capacity for adhesion to macrophages and also promote bacterial uptake by these phagocytic cells. Interestingly, our data suggest that SpaCBA pili also mediate anti-inflammatory effects by induction of interleukin-10 (IL-10) mRNA and reduction of interleukin-6 (IL-6) mRNA in a murine RAW 264.7 macrophage cell line. These pili appear to mediate these effects indirectly by promoting close contact with the macrophages, facilitating the exertion of anti-inflammatory effects by other surface molecules via yet unknown mechanisms. Blockage of complement receptor 3 (CR3), previously identified to be a receptor for streptococcal pili, significantly decreased the uptake of pilus-expressing strains in RAW 264.7 cells, while the expression of IL-10 and IL-6 mRNA by these macrophages was not affected by this blocking. On the other hand, blockage of Toll-like receptor 2 (TLR2) significantly reduced the expression of IL-6 mRNA irrespective of the presence of pili.