Parietal cell hyperstimulation and autoimmune gastritis in cholera toxin transgenic mice

The stimulation of gastric acid secretion from parietal cells involves both intracellular calcium and cAMP signaling. To understand the effect of increased cAMP on parietal cell function, we engineered transgenic mice expressing cholera toxin (Ctox), an irreversible stimulator of adenylate cyclase. The parietal cell-specific H(+),K(+)-ATPase beta-subunit promoter was used to drive expression of the cholera toxin A1 subunit (CtoxA1). Transgenic lines were established and tested for Ctox expression, acid content, plasma gastrin, tissue morphology, and cellular composition of the gastric mucosa. Four lines were generated, with Ctox-7 expressing approximately 50-fold higher Ctox than the other lines. Enhanced cAMP signaling in parietal cells was confirmed by observation of hyperphosphorylation of the protein kinase A-regulated proteins LASP-1 and CREB. Basal acid content was elevated and circulating gastrin was reduced in Ctox transgenic lines. Analysis of gastric morphology revealed a progressive cellular transformation in Ctox-7. Expanded patches of mucous neck cells were observed as early as 3 mo of age, and by 15 mo, extensive mucous cell metaplasia was observed in parallel with almost complete loss of parietal and chief cells. Detection of anti-parietal cell antibodies, inflammatory cell infiltrates, and increased expression of the Th1 cytokine IFN-gamma in Ctox-7 mice suggested that autoimmune destruction of the tissue caused atrophic gastritis. Thus constitutively high parietal cell cAMP results in high acid secretion and a compensatory reduction in circulating gastrin. High Ctox in parietal cells can also induce progressive changes in the cellular architecture of the gastric glands, corresponding to the development of anti-parietal cell antibodies and autoimmune gastritis.     

Isolation by landscape in populations of a prized edible mushroom Tricholoma matsutake

Tricholoma matsutake, a wild edible ectomycorrhizal mushroom, is revered for its distinguished flavor and iconic significance. Here, we test for landscape effects on T. matsutake gene flow and population structure in the Eastern Himalayas. Using single-nucleotide polymorphic (SNP) DNA markers, isolation by distance patterns were tested on eight populations within and between watersheds. We find that high, treeless ridgelines are effective barriers to gene flow, even at distances less than 65 km, whereas populations located within watersheds are structured at greater distances. Mantel tests demonstrated a significant positive correlation between F _st and a “landscape distance” measured as the shortest distance between population pairs below treeline r = 0.574, P = 0.002, whereas strict euclidian distances do not correlate. AMOVA analysis revealed significant partitioning with 91% of the genetic variance found within populations and 7% found between watersheds, indicative of sexually recombining populations with limited gene flow between watersheds. We show that landscape is an important determinant of air-dispersed ectomycorrhizal species population structure in heterogeneous landscapes.     

Proline periodicity modulates the self-assembly properties of elastin-like polypeptides

Elastin is a self-assembling protein of the extracellular matrix that provides tissues with elastic extensibility and recoil. The monomeric precursor, tropoelastin, is highly hydrophobic yet remains substantially disordered and flexible in solution, due in large part to a high combined threshold of proline and glycine residues within hydrophobic sequences. In fact, proline-poor elastin-like sequences are known to form amyloid-like fibrils, rich in β-structure, from solution. On this basis, it is clear that hydrophobic elastin sequences are in general optimized to avoid an amyloid fate. However, a small number of hydrophobic domains near the C terminus of tropoelastin are substantially depleted of proline residues. Here we investigated the specific contribution of proline number and spacing to the structure and self-assembly propensities of elastin-like polypeptides. Increasing the spacing between proline residues significantly decreased the ability of polypeptides to reversibly self-associate. Real-time imaging of the assembly process revealed the presence of smaller colloidal droplets that displayed enhanced propensity to cluster into dense networks. Structural characterization showed that these aggregates were enriched in β-structure but unable to bind thioflavin-T. These data strongly support a model where proline-poor regions of the elastin monomer provide a unique contribution to assembly and suggest a role for localized β-sheet in mediating self-assembly interactions.     

Plasma levels of osteopontin identify patients at risk for organ damage in systemic lupus erythematosus

Introduction

Osteopontin (OPN) has been implicated as a mediator of Th17 regulation via type I interferon (IFN) receptor signaling and in macrophage activity at sites of tissue repair. This study assessed whether increased circulating plasma OPN (cOPN) precedes development of organ damage in pediatric systemic lupus erythematosus (pSLE) and compared it to circulating plasma neutrophil gelatinase-associated lipocalin (cNGAL), a predictor of increased SLE disease activity.

Methods

cOPN and cNGAL were measured in prospectively followed pSLE (n = 42) and adult SLE (aSLE; n = 23) patients and age-matched controls. Time-adjusted cumulative disease activity and disease damage were respectively assessed using adjusted-mean SLE disease activity index (SLEDAI) (AMS) and SLICC/ACR damage index (SDI).

Results

Compared to controls, elevated cOPN and cNGAL were observed in pSLE and aSLE. cNGAL preceded worsening SLEDAI by 3-6 months (P = 0.04), but was not associated with increased 6-month AMS. High baseline cOPN, which was associated with high IFNalpha activity and expression of autoantibodies to nucleic acids, positively correlated with 6-month AMS (r = 0.51 and 0.52, P = 0.001 and 0.01 in pSLE and aSLE, respectively) and was associated with SDI increase at 12 months in pSLE (P = 0.001). Risk factors for change in SDI in pSLE were cOPN (OR 7.5, 95% CI [2.9-20], P = 0.03), but not cNGAL, cumulative prednisone, disease duration, immunosuppression use, gender or ancestry using univariate and multivariate logistic regression. The area under the curve (AUC) when generating the receiver-operating characteristic (ROC) of baseline cOPN sensitivity and specificity for the indication of SLE patients with an increase of SDI over a 12 month period is 0.543 (95% CI 0.347-0.738; positive predictive value 95% and negative predictive value 38%).

Conclusion

High circulating OPN levels preceded increased cumulative disease activity and organ damage in SLE patients, especially in pSLE, and its value as a predictor of poor outcome should be further validated in large longitudinal cohorts.     

The phenotype and genotype of rheumatoid arthritis in the Democratic Republic of Congo

Introduction

Little is known about rheumatoid arthritis in the black, particularly in Congolese, populations. Our objective was to describe the phenotype and genotype of rheumatoid arthritis (RA) in Congolese.

Methods

All consecutive rheumatoid arthritis (RA) patients attending Kinshasa University Hospital in a three-year time period were included. Demographics, clinical features and tobacco consumption were noted. Disease Activity Score (DAS)-28 based on the erythrocyte sedimentation rate (ESR), Health Assessment Questionnaire (HAQ), anti-citrullinated peptide antibodies (CCP) antibodies and rheumatoid factor (RF) were determined. Radiographs were scored according to Sharp-van der Heijde. On a subset of patients and controls HLA-DRB1 typing was performed.

Results

A total of 114 females and 14 males aged 51.2 ± 14.9 were included. Mean duration of symptoms was four years. Moderate tobacco consumption was reported in a minority of patients. DAS-28 at first visit was >5.1 and HAQ ≥0.5 in all patients. X-rays showed joint erosions and/or joint space narrowing, mostly of a moderate grade in 55.8% of patients. Anti-CCP and/or RF were present in 48.6% of patients with available data (n = 72) and in 3.0% of controls (n = 67). Radiographic changes and nodules were more frequent in RF or anti-CCP positive patients. One copy of the shared epitope was found in 13 patients (35.1%) and 3 controls (12.5%). Two copies were found in one patient (2.7%) and in one control (4.2%).

Conclusion

Congolese patients with RA consult long after disease onset. Despite this delay, the majority presents without major damage and is RF, anti-CCP and SE negative. We put forward the hypothesis that besides different environmental factors there is probably also a particular genetic risk profile in Congolese patients, different from the HLA-DRB1 shared epitope.     

A novel harmony search-K means hybrid algorithm for clustering gene expression data

Recent progress in bioinformatics research has led to the accumulation of huge quantities of biological data at various data sources. The DNA microarray technology makes it possible to simultaneously analyze large number of genes across different samples. Clustering of microarray data can reveal the hidden gene expression patterns from large quantities of expression data that in turn offers tremendous possibilities in functional genomics, comparative genomics, disease diagnosis and drug development. The k- ¬means clustering algorithm is widely used for many practical applications. But the original k-¬means algorithm has several drawbacks. It is computationally expensive and generates locally optimal solutions based on the random choice of the initial centroids. Several methods have been proposed in the literature for improving the performance of the k-¬means algorithm. A meta-heuristic optimization algorithm named harmony search helps find out near-global optimal solutions by searching the entire solution space. Low clustering accuracy of the existing algorithms limits their use in many crucial applications of life sciences. In this paper we propose a novel Harmony Search-K means Hybrid (HSKH) algorithm for clustering the gene expression data. Experimental results show that the proposed algorithm produces clusters with better accuracy in comparison with the existing algorithms.     

Genes to ecosystems: exploring the frontiers of ecology with one of the smallest biological units

Genes and their expression levels in individual species can structure whole communities and affect ecosystem processes. Although much has been written about community and ecosystem phenotypes with a few model systems, such as poplar and goldenrod, here we explore the potential application of a community genetics approach with systems involving invasive species, climate change and pollution. We argue that community genetics can reveal patterns and processes that otherwise might remain undetected. To further facilitate the community genetics or genes-to-ecosystem concept, we propose four community genetics postulates that allow for the conclusion of a causal relationship between the gene and its effect on the ecosystem. Although most current studies do not satisfy these criteria completely, several come close and, in so doing, begin to provide a genetic-based understanding of communities and ecosystems, as well as a sound basis for conservation and management practices.     

Oestrus in the Julia Creek dunnart (Sminthopsis douglasi) is associated with wheel running behaviour but not necessarily changes in body weight,food consumption or pouch morphology

The Julia Creek dunnart (Sminthopsis douglasi) is an endangered carnivorous marsupial belonging to the family Dasyuridae. This study investigated the oestrous cycle of this species in terms of its reproductive physiology and behaviour to explore more efficient methods of oestrus detection. Ten sexually mature captive female dunnarts were monitored daily at David Fleay Wildlife Park, Burleigh Heads, Australia, from mid September to late December 2006 for changes in urogenital cytology within the urine (0, 1+, 2+ and 3+), running wheel activity, body weight, uneaten food, faecal steroid metabolites (progesterone and oestradiol) and pouch development. Periods of increased running wheel activity were associated (p = 0.004) with an increase in the proportion of cornified urogenital epithelial cells found in the urine; periods of decreasing weight (p < 0.001) and uneaten food (p < 0.001) were also associated with changes in urogenital cytology but not to the point where they would be useful for oestrus detection. Between 60.3% and 92.0% of peak distances (confidence interval 95%) occurred when the epithelial cell index was 2+ or 3+. Only 15.5–37.5% of peak weights (CI: 95%) and 28.1–49.9% of incidences of uneaten food (CI: 95%) occurred when the epithelial cell index was 2+ or 3+. There was no significant difference in the mean length of the oestrous cycle when measured by urogenital cytology (mean ± SD: 25.0 ± 5.7 days; n = 20) or peak distance travelled (mean ± SD: 25.4 ± 5.7 days; n = 20). Changes in the concentration of oestradiol metabolites in Julia Creek Dunnart faeces were not useful in characterising the oestrous cycle. Wheel running activity declined markedly with increased faecal progestagen concentration. The majority of the pouch variables examined showed maximum development during the inter-oestrus period but as there was considerable variation between animals, the pouch was not considered a useful index of oestrus.     

A newly identified group of adolescents at “invisible” risk for psychopathology and suicidal behavior: findings from the SEYLE study

This study explored the prevalence of risk behaviors (excessive alcohol use, illegal drug use, heavy smoking, reduced sleep, overweight, underweight, sedentary behavior, high use of Internet/TV/videogames for reasons not related to school or work, and truancy), and their association with psychopathology and self‐destructive behaviors, in a sample of 12,395 adolescents recruited in randomly selected schools across 11 European countries. Latent class analysis identified three groups of adolescents: a low‐risk group (57.8%) including pupils with low or very low frequency of risk behaviors; a high‐risk group (13.2%) including pupils who scored high on all risk behaviors, and a third group (“invisible” risk, 29%) including pupils who were positive for high use of Internet/TV/videogames for reasons not related to school or work, sedentary behavior and reduced sleep. Pupils in the “invisible” risk group, compared with the high‐risk group, had a similar prevalence of suicidal thoughts (42.2% vs. 44%), anxiety (8% vs. 9.2%), subthreshold depression (33.2% vs. 34%) and depression (13.4% vs. 14.7%). The prevalence of suicide attempts was 5.9% in the “invisible” group, 10.1% in the high‐risk group and 1.7% in the low‐risk group. The prevalence of all risk behaviors increased with age and most of them were significantly more frequent among boys. Girls were significantly more likely to experience internalizing (emotional) psychiatric symptoms. The “invisible” group may represent an important new intervention target group for potentially reducing psychopathology and other untoward outcomes in adolescence, including suicidal behavior.     

Muscle activation patterns of the upper and lower extremity during the windmill softball pitch

Fast-pitch softball has become an increasingly popular sport for female athletes. There has been little research examining the windmill softball pitch in the literature. The purpose of this study was to describe the muscle activation patterns of 3 upper extremity muscles (biceps, triceps, and rhomboids [scapular stabilizers]) and 2 lower extremity muscles (gluteus maximus and medius) during the 5 phases of the windmill softball pitch. Data describing muscle activation were collected on 7 postpubescent softball pitchers (age 17.7 ± 2.6 years; height 169 ± 5.4 cm; mass 69.1 ± 5.4 kg). Surface electromyographic data were collected using a Myopac Jr 10-channel amplifier (RUN Technologies Scientific Systems, Laguna Hills, CA, USA) synchronized with The MotionMonitor? motion capture system (Innovative Sports Training Inc, Chicago IL, USA) and presented as a percent of maximum voluntary isometric contraction. Gluteus maximus activity reached (196.3% maximum voluntary isometric contraction [MVIC]), whereas gluteus medius activity was consistent during the single leg support of phase 3 (101.2% MVIC). Biceps brachii activity was greatest during phase 4 of the pitching motion. Triceps brachii activation was consistently >150% MVIC throughout the entire pitching motion, whereas the scapular stabilizers were most active during phase 2 (170.1% MVIC). The results of this study indicate the extent to which muscles are activated during the windmill softball pitch, and this knowledge can lead to the development of proper preventative and rehabilitative muscle strengthening programs. In addition, clinicians will be able to incorporate strengthening exercises that mimic the timing of maximal muscle activation most used during the windmill pitching phases.