Repeated bouts of eccentrically biased endurance exercise stimulate salivary IgA secretion rate

To determine the salivary secretory immunoglobulin A (sIgA) response to repeated bouts of unaccustomed, downhill running (eccentrically biased) and examine potential protective immunological adaption from a repeated bout effect. Eleven active but untrained males (age: 19.7±0.4 years; VO_2peak: 47.8± 3.6 ml · kg⁻¹ · min ⁻¹) performed two 60 min bouts (Run 1 and Run 2) of downhill running (−13.5% gradient), separated by 14 days, at a speed eliciting 75% of their VO_2peak on a level grade. Saliva samples were collected before (baseline), immediately post exercise (IPE), and every hour for 12 h and every 24 h for 6 days after each run. Salivary sIgA concentration was measured and sIgA secretion rate was calculated. Results were analysed using repeated measures ANOVA (12 h period: 2x14; 24 h intervals: 2x7; p ≤ 0.05) with Tukey post-hoc tests where appropriate. Results are reported as means ± SE. There was a significant (p < 0.0001) interaction effect for sIgA secretion rate, IPE, with higher values after Run 2, as well as a significant (p < 0.01) time effect with elevated levels IPE and between 24 h and 144 h. There was a run effect (p < 0.0001), with the sIgA secretion rate significantly higher after Run 2. Repeated bouts of unaccustomed, eccentrically biased exercise induced alterations in the salivary sIgA secretion rate. This may serve as a protective mucosal adaptation to exercise-induced tissue damage.     

Origins of cultivars of Chrysanthemum—Evidence from the chloroplast genome and nuclear LFY gene

The origins of cultivated chrysanthemums have attracted considerable attention, but they remain poorly known. Here, we reconstructed the phylogeny of representative well‐known cultivars and wild species of the genus Chrysanthemum using chloroplast genomes and the nuclear LEAFY gene. Our results suggest that geographic and ecological factors may determine the opportunities for wild species to be involved in the origin of the cultivars. The wild species C. indicum, C. zawadskii, C. dichrum, C. nankingense, C. argyrophyllum, and C. vestitum were likely directly or indirectly involved as paternal species of most of the chrysanthemum cultivars examined in this study. Yet, the maternal species is supported to be a lineage of an extinct wild Chrysanthemum species and its subsequent cultivars, as all accessions of chrysanthemum cultivars sampled formed a strongly supported clade, distinct from all other species of Chrysanthemum in the plastome tree. Thus, the cultivated chrysanthemums originated from multiple hybridizations involving several paternal species rather than only two or a few wild species, with an extinct species and its subsequent cultivars serving as the maternal parents. This finding is consistent with Chrysanthemum having high rates of hybridization and gene flow, which has been demonstrated within previous studies; nevertheless, it is important to unravel the role of an extinct wild Chrysanthemum species as the ultimate maternal parent species for all the chrysanthemum cultivars. Our results also suggest that C. vestitum from Tianzhu and Funiu Mountains in Anhui and Henan Provinces of China represent two distinct cryptic species.     

Low bone mineral density in men with chronic obstructive pulmonary disease

Background

Osteoporosis is common in patients with COPD but the likely multi-factorial causes contributing to this condition (e.g. sex, age, smoking, therapy) mask the potential contribution from elements related to COPD. In order to study osteoporosis and bone mineral density (BMD) related to COPD, we studied a well-defined group of patients and controls.

Methods

BMD, forced expiratory volume in one second (FEV₁), circulating bone biomarkers and biochemistry were determined in 30 clinically stable male ex-smokers with confirmed COPD and 15 age matched "ex-smoker" male controls. None of the patients were on inhaled corticosteroids or received more than one short course of steroids.

Results

Mean (SD) FEV₁% predicted of patients was 64(6)%, the majority having Global Initiative for Chronic Obstructive Lung Disease (GOLD) II airflow obstruction. There were 5/30 patients and 1/15 controls who were osteoporotic, while a further 17 patients and 5 controls were osteopenic. The BMD at the hip was lower in patients than controls, but not at the lumbar spine. Mean values of procollagen type 1 amino-terminal propeptide and osteocalcin, both markers of bone formation, and Type 1 collagen β C-telopeptide, a marker of bone resorption, were similar between patients and controls. However, all bone biomarkers were inversely related to hip BMD in patients (r = -0.51, r = -0.67, r = -0.57, p < 0.05) but did not relate to lumbar spine BMD. 25-OH Vitamin D was lower in patients.

Conclusions

Men with COPD had a greater prevalence of osteoporosis and osteopenia than age matched male controls, with a marked difference in BMD at the hip. Bone biomarkers suggest increased bone turnover.     

Role of amino acid hydrophobicity, aromaticity, and molecular volume on IAPP(20-29) amyloid self-assembly

Aromatic amino acids strongly promote cross-β amyloid formation; whether the amyloidogenicity of aromatic residues is due to high hydrophobicity and β-sheet propensity or formation of stabilizing π-π interactions has been debated. To clarify the role of aromatic residues on amyloid formation, the islet amyloid polypeptide 20-29 fragment [IAPP(20-29)], which contains a single aromatic residue (Phe 23), was adopted as a model. The side chain of residue 23 does not self-associate in cross-β fibrils of IAPP(20-29) (Nielsen et al., Angew Chem Int Ed 2009;48:2118-2121), allowing investigation of the amyloidogenicity of aromatic amino acids in a context where direct π-π interactions do not occur. We prepared variants of IAPP(20-29) in which Tyr, Leu, Phe, pentafluorophenylalanine (F5-Phe), Trp, cyclohexylalanine (Cha), α-naphthylalanine (1-Nap), or β-naphthylalanine (2-Nap) (in order of increasing peptide hydrophobicity) were incorporated at position 23 (SNNXGAILSS-NH2), and the kinetic and thermodynamic effects of these mutations on cross-β self-assembly were assessed. The Tyr, Leu, and Trp 23 variants failed to readily self-assemble at concentrations up to 1.5 mM, while the Cha 23 mutant fibrillized with attenuated kinetics and similar thermodynamic stability relative to the wild-type Phe 23 peptide. Conversely, the F5-Phe, 1-Nap, and 2-Nap 23 variants self-assembled at enhanced rates, forming fibrils with greater thermodynamic stability than the wild-type peptide. These results indicate that the high amyloidogenicity of aromatic amino acids is a function of hydrophobicity, β-sheet propensity, and planar geometry and not the ability to form stabilizing or directing π-π bonds.     

Population genetic structure and evolutionary history of Psammochloa villosa (Trin.) Bor (Poaceae) revealed by AFLP marker

Psammochloa villosa is an ecologically important desert grass that occurs in the Inner Mongolian Plateau where it is frequently the dominant species and is involved in sand stabilization and wind breaking. We sought to generate a preliminary demographic framework for P. villosa to support the future studies of this species, its conservation, and sustainable utilization. To accomplish this, we characterized the genetic diversity and structure of 210 individuals from 43 natural populations of P. villosa using amplified fragment length polymorphism (AFLP) markers. We obtained 1,728 well‐defined amplified bands from eight pairs of primers, of which 1,654 bands (95.7%) were polymorphic. Results obtained from the AFLPs suggested effective alleles among populations of 1.32, a Nei''s standard genetic distance value of 0.206, a Shannon index of 0.332, a coefficient of gene differentiation (G _ST) of 0.469, and a gene flow parameter (Nm) of 0.576. All these values indicate that there is abundant genetic diversity in P. villosa, but limited gene flow. An analysis of molecular variance (AMOVA) showed that genetic variation mainly exists within populations (64.2%), and we found that the most genetically similar populations were often not geographically adjacent. Thus, this suggests that the mechanisms of gene flow are surprisingly complex in this species and may occur over long distances. In addition, we predicted the distribution dynamics of P. villosa based on the spatial distribution modeling and found that its range has contracted continuously since the last interglacial period. We speculate that dry, cold climates have been critical in determining the geographic distribution of P. villosa during the Quaternary period. Our study provides new insights into the population genetics and evolutionary history of P. villosa in the Inner Mongolian Plateau and provides a resource that can be used to design in situ conservation actions and prioritize sustainable utilization.     

Pyrrolo[2,3-d]pyrimidines containing an extended 5-substituent as potent and selective inhibitors of lck I

Pyrrolo[2,3-d]pyrimidines containing a 5-(4-phenoxyphenyl) substituent are potent and selective inhibitors of Ick in vitro; some compounds are selective for lck over src. Data are shown for two compounds demonstrating that they are potent and selective inhibitors of IL2 production in cells.     

Home-based versus hospital-based cardiac rehabilitation after myocardial infarction or revascularisation: design and rationale of the Birmingham Rehabilitation Uptake Maximisation Study (BRUM): a randomised controlled trial [ISRCTN72884263]

Background

Cardiac rehabilitation following myocardial infarction reduces subsequent mortality, but uptake and adherence to rehabilitation programmes remains poor, particularly among women, the elderly and ethnic minority groups. Evidence of the effectiveness of home-based cardiac rehabilitation remains limited. This trial evaluates the effectiveness and cost-effectiveness of home-based compared to hospital-based cardiac rehabilitation.

Methods/design

A pragmatic randomised controlled trial of home-based compared with hospital-based cardiac rehabilitation in four hospitals serving a multi-ethnic inner city population in the United Kingdom was designed. The home programme is nurse-facilitated, manual-based using the Heart Manual. The hospital programmes offer comprehensive cardiac rehabilitation in an out-patient setting.

Patients

We will randomise 650 adult, English or Punjabi-speaking patients of low-medium risk following myocardial infarction, coronary angioplasty or coronary artery bypass graft who have been referred for cardiac rehabilitation.

Main outcome measures

Serum cholesterol, smoking cessation, blood pressure, Hospital Anxiety and Depression Score, distance walked on Shuttle walk-test measured at 6, 12 and 24 months. Adherence to the programmes will be estimated using patient self-reports of activity. In-depth interviews with non-attendees and non-adherers will ascertain patient views and the acceptability of the programmes and provide insights about non-attendance and aims to generate a theory of attendance at cardiac rehabilitation. The economic analysis will measure National Health Service costs using resource inputs. Patient costs will be established from the qualitative research, in particular how they affect adherence.

Discussion

More data are needed on the role of home-based versus hospital-based cardiac rehabilitation for patients following myocardial infarction and revascularisation, which would be provided by the Birmingham Rehabilitation Uptake Maximisation Study (BRUM) study and has implications for the clinical management of these patients. A novel feature of this study is the inclusion of non-English Punjabi speakers.     

Direct phosphorylation of NF-kappaB1 p105 by the IkappaB kinase complex on serine 927 is essential for signal-induced p105 proteolysis

The p105 precursor protein of NF-kappaB1 acts as an NF-kappaB inhibitory protein, retaining associated Rel subunits in the cytoplasm of unstimulated cells. Tumor necrosis factor alpha (TNFalpha) and interleukin-1alpha (IL-1alpha) stimulate p105 degradation, releasing associated Rel subunits to translocate into the nucleus. By using knockout embryonic fibroblasts, it was first established that the IkappaB kinase (IKK) complex is essential for these pro-inflammatory cytokines to trigger efficiently p105 degradation. The p105 PEST domain contains a motif (Asp-Ser(927)-Gly-Val-Glu-Thr), related to the IKK target sequence in IkappaBalpha, which is conserved between human, mouse, rat, and chicken p105. Analysis of a panel of human p105 mutants in which serine/threonine residues within and adjacent to this motif were individually changed to alanine established that only serine 927 is essential for p105 proteolysis triggered by IKK2 overexpression. This residue is also required for TNFalpha and IL-1alpha to stimulate p105 degradation. By using a specific anti-phosphopeptide antibody, it was confirmed that IKK2 overexpression induces serine 927 phosphorylation of co-transfected p105 and that endogenous p105 is also rapidly phosphorylated on this residue after TNFalpha or IL-1alpha stimulation. In vitro kinase assays with purified proteins demonstrated that both IKK1 and IKK2 can directly phosphorylate p105 on serine 927. Together these experiments indicate that the IKK complex regulates the signal-induced proteolysis of NF-kappaB1 p105 by direct phosphorylation of serine 927 in its PEST domain.