Investigations on the interplays between Schistosoma mansoni, praziquantel and the gut microbiome

Schistosomiasis is a neglected tropical disease burdening millions of people. One drug, praziquantel, is currently used for treatment and control. Clinically relevant drug resistance has not yet been described, but there is considerable heterogeneity in treatment outcomes, ranging from cure to only moderate egg reduction rates. The objectives of this study are to investigate potential worm-induced dysbacteriosis of the gut microbiota and to assess whether a specific microbiome profile could influence praziquantel response.; Using V3 and V4 regions of 16S rRNA genes, we screened the gut microbiota of 34 Schistosoma mansoni infected and uninfected children from Côte d'Ivoire. From each infected child one pre-treatment, one 24-hour and one 21-day follow-up sample after administering 60 mg/kg praziquantel or placebo, were collected.; Overall taxonomic profiling and diversity indicators were found to be close to a "healthy" gut structure in all children. Slight overall compositional changes were observed between S. mansoni-infected and non-infected children. Praziquantel treatment was not linked to a major shift in the gut taxonomic profiles, thus reinforcing the good safety profile of the drug by ruling out off-targets effects on the gut microbes.16S rRNA gene of the Fusobacteriales order was significantly more abundant in cured individuals, both at baseline and 24 hours post-treatment. A real-time qPCR confirmed the over-abundance of Fusobacterium spp. in cured children. Fusobacterium spp. abundance could also be correlated with treatment induced S. mansoni egg-reduction.; Our study suggests that neither a S. mansoni infection nor praziquantel administration triggers a significant effect on the microbial composition and that a higher abundance of Fusobacterium spp., before treatment, is associated with higher efficacy of praziquantel in the treatment of S. mansoni infections.; International Standard Randomised Controlled Trial, number ISRCTN15280205

Continuous engagement of a self-specific activation receptor induces NK cell tolerance

Natural killer (NK) cell tolerance mechanisms are incompletely understood. One possibility is that they possess self-specific activation receptors that result in hyporesponsiveness unless modulated by self–major histocompatability complex (MHC)–specific inhibitory receptors. As putative self-specific activation receptors have not been well characterized, we studied a transgenic C57BL/6 mouse that ubiquitously expresses m157 (m157-Tg), which is the murine cytomegalovirus (MCMV)–encoded ligand for the Ly49H NK cell activation receptor. The transgenic mice were more susceptible to MCMV infection and were unable to reject m157-Tg bone marrow, suggesting defects in Ly49H+ NK cells. There was a reversible hyporesponsiveness of Ly49H+ NK cells that extended to Ly49H-independent stimuli. Continuous Ly49H–m157 interaction was necessary for the functional defects. Interestingly, functional defects occurred when mature wild-type NK cells were adoptively transferred to m157-Tg mice, suggesting that mature NK cells may acquire hyporesponsiveness. Importantly, NK cell tolerance caused by Ly49H–m157 interaction was similar in NK cells regardless of expression of Ly49C, an inhibitory receptor specific for a self-MHC allele in C57BL/6 mice. Thus, engagement of self-specific activation receptors in vivo induces an NK cell tolerance effect that is not affected by self-MHC–specific inhibitory receptors

Systemic sclerosis without antinuclear antibodies or Raynaud's phenomenon: a multicentre study in the prospective EULAR Scleroderma Trials and Research (EUSTAR) database

Objective. To assess patients with SSc who present without circulating ANAs or RP. Methods. Five thousand three hundred and ninety patients who fulfilled the ACR criteria for SSc and were enrolled in the EULAR Scleroderma Trials and Research (EUSTAR) database were screened for the absence of both RP and circulating ANA. To differentiate SSc from its mimics, additional information was gathered using a standardized questionnaire. Results. Five thousand three hundred and seventy-eight (99.8%) of the 5390 SSc patients in the EUSTAR database had either detectable ANA or a history of RP. Twelve (0.2%) patients lacked both circulating ANA and RP. Details of the medical history could be obtained for seven patients. Three cases were compatible with ANA-negative and RP-negative SSc and were not typical of any known SSc mimic. Four patients had a malignancy: two had breast cancer, one had multiple myeloma with possible scleromyxoedema and one had bladder carcinoma. There was no temporal relationship between the onset of skin fibrosis and that of the tumour. Although no patient with confirmed nephrogenic systemic fibrosis was identified among the cases of ANA-negative and RP-negative SSc, the presentation of one patient could be compatible with that of nephrogenic systemic fibrosis other than for the absence of chronic kidney disease or of known prior gadolinium exposure. Conclusion. We have identified a very small subgroup of SSc patients who lack both circulating ANA and RP, none of whom fulfils the diagnostic criteria for any known SSc mimic. Prospective studies are needed to elucidate the clinical presentation, evolution and outcome of such patient

LOCAS – A Low Coverage Assembly Tool for Resequencing Projects

Motivation: Next Generation Sequencing (NGS) is a frequently applied approach to detect sequence variations between highly related genomes. Recent large-scale re-sequencing studies as the Human 1000 Genomes Project utilize NGS data of low coverage to afford sequencing of hundreds of individuals. Here, SNPs and micro-indels can be detected by applying an alignment-consensus approach. However, computational methods capable of discovering other variations such as novel insertions or highly diverged sequence from low coverage NGS data are still lacking. Results: We present LOCAS, a new NGS assembler particularly designed for low coverage assembly of eukaryotic genomes using a mismatch sensitive overlap-layout-consensus approach. LOCAS assembles homologous regions in a homologyguided manner while it performs de novo assemblies of insertions and highly polymorphic target regions subsequently to an alignment-consensus approach. LOCAS has been evaluated in homology-guided assembly scenarios with low sequence coverage of Arabidopsis thaliana strains sequenced as part of the Arabidopsis 1001 Genomes Project. While assembling the same amount of long insertions as state-of-the-art NGS assemblers, LOCAS showed best results regarding contig size, error rate and runtime. Conclusion: LOCAS produces excellent results for homology-guided assembly of eukaryotic genomes with short reads and low sequencing depth, and therefore appears to be the assembly tool of choice for the detection of novel sequenc

FLOWERING REPRESSOR AAA(+) ATPase 1 is a novel regulator of perennial flowering in Arabis alpina

Arabis alpina is a polycarpic perennial, in which PERPETUAL FLOWERING1 (PEP1) regulates flowering and perennial traits in a vernalization-dependent manner. Mutagenesis screens of the pep1 mutant established the role of other flowering time regulators in PEP1-parallel pathways. Here we characterized three allelic enhancers of pep1 (eop002, 085 and 091) which flower early. We mapped the causal mutations and complemented mutants with the identified gene. Using quantitative reverse transcriptase PCR and reporter lines, we determined the protein spatiotemporal expression patterns and localization within the cell. We also characterized its role in Arabidopsis thaliana using CRISPR and in A. alpina by introgressing mutant alleles into a wild-type background. These mutants carried lesions in an AAA(+) ATPase of unknown function, FLOWERING REPRESSOR AAA(+) ATPase 1 (AaFRAT1). AaFRAT1 was detected in the vasculature of young leaf primordia and the rib zone of flowering shoot apical meristems. At the subcellular level, AaFRAT1 was localized at the interphase between the endoplasmic reticulum and peroxisomes. Introgression lines carrying Aafrat1 alleles required less vernalization to flower and reduced number of vegetative axillary branches. By contrast, A. thaliana CRISPR lines showed weak flowering phenotypes. AaFRAT1 contributes to flowering time regulation and the perennial growth habit of A. alpina

Randomised controlled trial of adjunctive inspiratory muscle training for patients with COPD.

BACKGROUND: This study aimed to investigate whether adjunctive inspiratory muscle training (IMT) can enhance the well-established benefits of pulmonary rehabilitation (PR) in patients with COPD. METHODS: 219 patients with COPD (FEV1: 42%±16% predicted) with inspiratory muscle weakness (PImax: 51±15 cm H2O) were randomised into an intervention group (IMT+PR; n=110) or a control group (Sham-IMT+PR; n=109) in this double-blind, multicentre randomised controlled trial between February 2012 and October 2016 (ClinicalTrials.gov NCT01397396). Improvement in 6 min walking distance (6MWD) was a priori defined as the primary outcome. Prespecified secondary outcomes included respiratory muscle function and endurance cycling time. FINDINGS: No significant differences between the intervention group (n=89) and the control group (n=85) in improvements in 6MWD were observed (0.3 m, 95% CI -13 to 14, p=0.967). Patients who completed assessments in the intervention group achieved larger gains in inspiratory muscle strength (effect size: 1.07, p<0.001) and endurance (effect size: 0.79, p<0.001) than patients in the control group. 75 s additional improvement in endurance cycling time (95% CI 1 to 149, p=0.048) and significant reductions in Borg dyspnoea score at isotime during the cycling test (95% CI -1.5 to -0.01, p=0.049) were observed in the intervention group. INTERPRETATION: Improvements in respiratory muscle function after adjunctive IMT did not translate into additional improvements in 6MWD (primary outcome). Additional gains in endurance time and reductions in symptoms of dyspnoea were observed during an endurance cycling test (secondary outcome) TRIAL REGISTRATION NUMBER: NCT01397396; Results

Corticosteroid injection for tennis elbow or lateral epicondylitis: a review of the literature

Lateral epicondylitis or tennis elbow is a painful and functionally limiting entity affecting the upperextremity and is frequently treated by hand surgeons. Corticosteroid injection is one of the most common interventions for lateral epicondylitis or tennis elbow. Here, a review of the medical literature on this treatment is presented