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Given the gut microbiota’s contribution to pathogenesis of autoimmune diseases, microbiota characteristics could potentially be used to predict disease susceptibility or progression. Although various gut commensals have been proposed as risk factors for autoimmune disease development, predictions based on microbiota composition alone remain unreliable. Here, we evaluated a common approach to identify a potential microbial risk factor from complex communities, followed by in-depth evaluation of its risk factor properties using an autoimmune neuroinflammation disease model in mice harboring several distinct, defined microbiota compositions. We found that the relative abundances of commensal taxa across distinct communities are poorly suited to assess the disease-mediating property of a given microbiota. Instead, the presence of certain microbial risk factors allowed us to determine the probability of severe disease, but failed to predict the individual disease course. We investigated multiple other microbiota-associated characteristics by applying 16S rRNA gene sequencing, metatranscriptomic and metabolomic approaches, as well as in-depth analysis of host immune responses and intestinal barrier integrity-associated readouts. By leveraging gnotobiotic mouse models harboring six defined compositions, we identified the IgA coating index ofBacteroides ovatusas a reliable individual disease risk predictor before disease onset, due to its ability to reflect autoimmunity-mediating properties of a given gut microbial network within a specific host. In summary, our data suggest that common taxonomic analysis approaches should be refined by taxonomic network analyses or combined with microbiota function-related readouts to reliably assess disease predisposition of a given host−microbiota combination.

Background and aimsHaving anecdotally noted a high frequency of lobar-restricted cerebral microbleeds (CMBs) mimicking cerebral amyloid angiopathy (CAA) in patients with previous cardiac surgery (especially valve replacement) presenting to our transient ischaemic attack (TIA) clinic, we set out to objectively determine the frequency and distribution of microbleeds in this population.MethodsWe performed a retrospective comparative cohort study in consecutive patients presenting to two TIA clinics with either: (1) previous coronary artery bypass grafting (CABG) (n=41); (2) previous valve replacement (n=41) or (3) probable CAA (n=41), as per the Modified Boston Criteria, without prior cardiac surgery. Microbleed number and distribution was determined and compared.ResultsAt least one lobar-restricted microbleed was found in the majority of cardiac surgery patients (65%) and 32/82 (39%) met diagnostic criteria for CAA. Valve replacement patients had a higher microbleed prevalence (90 vs 51%, pConclusionLobar-restricted microbleeds are common in patients with past cardiac surgery, however a higher proportion of these CMBs involve the SWM than in patients with CAA.

Alterations in the gut microbiome, including diet-driven changes, are linked to the rising prevalence of food allergy, yet little is known about how specific gut bacteria incite breakdown of oral tolerance. Here, we show that depriving specific-pathogen-free mice of dietary fiber leads to an increase of the mucolytic bacterium Akkermansia muciniphila, which is associated with a surge in the colonic type 2 immune cells and IgE-coated commensals, and microbiota-mediated gut mucosal barrier dysfunction. These changes manifest into exacerbated sensitization to food allergens, ovalbumin and peanut. To demonstrate the causal role of A. muciniphila, we employed a tractable synthetic human gut microbiota in gnotobiotic mice. The presence of A. muciniphila within the microbiota, combined with fiber deprivation, resulted in stronger anti-commensal IgE coating and type 2 immune responses, which worsened symptoms of food allergy. Our study supports a mechanistic link between diet and a mucolytic gut microbe in regulating food allergy.

Inflammatory bowel disease (IBD) is a chronic condition characterized by periods of spontaneous intestinal inflammation and is increasing in industrialized populations. Combined with host genetic predisposition, diet and gut bacteria are thought to be prominent features contributing to IBD, but little is known about the precise mechanisms involved. Here, we show that low dietary fiber promotes bacterial erosion of protective colonic mucus, leading to lethal colitis in mice lacking the IBD-associated cytokine, interleukin-10. Diet-induced inflammation is driven by mucin-degrading bacteria-mediated Th1 immune responses and is preceded by expansion of natural killer T cells and reduced immunoglobulin A coating of some bacteria. Surprisingly, an exclusive enteral nutrition diet, also lacking dietary fiber, reduced disease by increasing bacterial production of isobutyrate, which was dependent on the presence of a specific bacterial species, Eubacterium rectale. Our results illuminate a mechanistic framework using gnotobiotic mice to unravel the complex web of diet, host and microbial factors that influence IBD.

BACKGROUND & AIMSHost-secreted gastrointestinal mucus plays a key role in the expulsion of intestinal nematode parasites. A balance between mucin secretion by the host and the gut microbial mucin foraging is essential to maintain the intestinal homeostasis, yet little is known about how changes in the mucin–microbiome interactions affect worm infection. Here, we aimed to examine how increased mucin foraging activity by the microbiome changes the course of the parasitic infection by modulating the host immune responses.METHODSWe employed a gnotobiotic mouse model containing a 14-member synthetic human gut microbiota that facilitates functional interpretations, including diet-driven manipulation of the microbiota toward mucin foraging. We infected the mice with a robust murine nematode, Trichuris muris, that closely resembles human infection with Trichuris trichiura. We investigated the temporal dynamics of worm infection including worm burden and the host immune responses, and connected these readouts to the microbial changes and metabolic activity toward mucin foraging.RESULTSThe microbial mucin foraging was further increased during worm infection only in mice with pre-enhanced mucin degrading capacity. The elevated mucin foraging coincides with a shift in host immune responses from susceptible (chronic, Th1 type) to resistant (acute, Th2 type), which promotes worm clearance. The relative abundances of mucin-generalist bacteria drammatically increased during worm clearance, but not during worm retention.CONCLUSIONSThese results point to a mechanism whereby skewing the metabolic activity of the microbiome toward mucin glycoproteins promotes resistance to worm infection. Our study documents a clinically-relevant, novel link in the microbiome–parasite–host immune axis, which is important prerequisite knowledge in treating parasitic infections.

Sulfur-containing amino acids, Methionine (Met) and Cysteine (Cys), are very susceptible to Reactive Oxygen Species (ROS). Therefore, sulfur-based reactions regulate many biological processes, playing a key role in maintaining cellular redox homeostasis and modulating intracellular signaling cascades. In oxidative conditions, Met acts as a ROS scavenger, through Met sulfoxide formation, while thiol/disulfide interchange reactions take place between Cys residues as a response to many environmental stimuli. In this work, we apply a QM/MM theoretical–computational approach, which combines quantum–mechanical calculations with classical molecular dynamics simulations to estimate the free energy profile for the above-mentioned reactions in solution. The results obtained, in good agreement with experimental data, show the validity of our approach in modeling sulfur-based reactions, enabling us to study these mechanisms in more complex biological systems.

Four NDM-1 mutants (L218T, L221T, L269H and L221T/Y229W) were generated in order to investigate the role of leucines positioned in L10 loop. A detailed kinetic analysis stated that these amino acid substitutions modified the hydrolytic profile of NDM-1 against some ��-lactams. Significant reduction of kcat values of L218T and L221T for carbapenems, cefazolin, cefoxitin and cefepime was observed. The stability of the NDM-1 and its mutants was explored by thermofluor assay in real-time PCR. The determination of TmB and TmD demonstrated that NDM-1 and L218T were the most stable enzymes. Molecular dynamic studies were performed to justify the differences observed in the kinetic behavior of the mutants. In particular, L218T fluctuated more than NDM-1 in L10, whereas L221T would seem to cause a drift between residues 75 and 125. L221T/Y229W double mutant exhibited a decrease in the flexibility with respect to L221T, explaining enzyme activity improvement towards some ��-lactams. Distances between Zn1-Zn2 and Zn1-OH- or Zn2- OH- remained unaffected in all systems analysed. Significant changes were found between Zn1/Zn2 and first sphere coordination residues.

Surgical repair with implantation of a mitral annuloplasty ring is the gold standard treatment for mitral regurgitation. However, outcomes are variable and recurrent mitral regurgitation is not uncommon. A REshapeable Mitral Annuloplasty DevIce (REMADI) is proposed, which consists of a fully encapsulated low melting temperature alloy. The alloy is solid and rigid at body temperature and provides traction force to shape the annulus. When heated using a noncontact method, the alloy melts and the REMADI becomes malleable. The REMADI is engaged with the mitral valve annulus using anchors which automatically deploy upon contact. A passive beating porcine heart model was used to demonstrate the feasibility of the REMADI device, which was deployed, engaged, and used to reduce the diameter of the mitral valve annulus.

Background— In recent years, use of transcatheter aortic valve replacement has expanded to include patients at intermediate- and low-risk cohorts. We sought to determine disease prevalence and treatment distribution including transcatheter aortic valve replacement eligibility in low-risk patients across 37 advanced economies. Methods and Results— Four systematic searches were conducted across MEDLINE, EMBASE, and the Cochrane database for studies evaluating disease prevalence, severity, decision making, and survival in patients with aortic stenosis. Estimates of disease prevalence and treatment eligibility were calculated using stochastic simulation and population data for the 37 countries comprising the International Monetary Fund’s advanced economies index. Fifty-six studies comprising 42 965 patients were included across 5 domains: prevalence, severity, symptom status, treatment modality, and outcome. The pooled prevalence in the general population aged 60 to 74 years and >75 years was 2.8% (95% confidence interval [CI], 1.4%–4.1%) and 13.1% (95% CI, 8.2%–17.9%), respectively—corresponding to an estimated 16.1 million (95% CI, 12.2–20.3) people in 37 advanced economies. Of these, an estimated 3.2 million (95% CI, 2.2–4.4) patients have severe aortic stenosis with 1.9 million (95% CI, 1.3–2.6) eligible for surgical aortic valve replacement. There are ≈485 230 (95% CI, 284 550–66 7350) high-risk/inoperable patients, 152 690 (95% CI, 73 410–263 000) intermediate-risk patients, and 378 890 (95% CI, 205 130–610 210) low-risk patients eligible for transcatheter aortic valve replacement. Conclusions— With a prevalence of 4.5%, an estimated 16.1 million people aged ≥60 years across 37 advanced economies have aortic stenosis. Of these, there are ≈1.9 million patients eligible for surgical aortic valve replacement and 1.0 million patients eligible for transcatheter aortic valve replacement.

Few polymeric valves have advanced beyond preclinical investigation despite different polymers, geometries and manufacturing techniques being adopted. Recently, styrenic block copolymers (BCPs) consisting of alternating blocks of glassy and rubbery polymer have been proposed. In order to optimize a

Energy drink consumption has been anecdotally linked with sudden cardiac death and, more recently, myocardial infarction. As myocardial infarction is strongly associated with both platelet and endothelial dysfunction, we tested the hypothesis that energy drink consumption alters platelet and endothelial function.Fifty healthy volunteers (34 male, aged 22+/-2 years) participated in the study. Platelet aggregation and endothelial function were tested before, and 1 hour after, the consumption of 250 mL (1 can) of a sugar-free energy drink. Platelet function was assessed by adenosine diphosphate-induced (1 micromol/L) optical aggregometry in platelet-rich plasma. Endothelial function was assessed via changes in peripheral arterial tonometry and expressed as the reactive hyperemia index (RHI).Compared with baseline values, there was a significant increase in platelet aggregation following energy drink consumption, while no change was observed with control (13.7+/-3.7% vs 0.3+/-0.8% aggregation, respectively, P.01). Similarly, RHI decreased following energy drink consumption (-0.33+/-0.13 vs 0.07+/-0.12 RHI [control], P.05). Mean arterial pressure significantly increased following energy drink consumption, compared with control (P.05). Heart rate was unaffected by energy drink consumption.Energy drink consumption acutely increases platelet aggregation and decreases endothelial function in healthy young adults.

Objectives The purpose of this study was to determine whether patients with paroxysmal “lone” atrial fibrillation (AF) have an abnormal atrial substrate. Background While “AF begets AF,” prompt termination to prevent electrical remodeling does not prevent disease progression. Methods Twenty-five patients with paroxysmal lone AF, without arrhythmia in the week prior, and 25 reference patients with left-sided accessory pathways were studied. Multipolar catheters placed at the lateral right atrium (RA), crista terminalis, coronary sinus, septal RA, and sequentially within the left atrium (LA) determined the effective refractory period (ERP) at 10 sites, conduction time along linear catheters, and conduction characteristics at the crista terminalis. Bi-atrial electroanatomic maps were created to determine regional differences in conduction velocity and voltage. Results Patients with AF demonstrated the following compared with reference patients: larger atrial volumes (RA: 94 ± 18 ml vs. 69 ± 9 ml, p = 0.003; LA: 99 ± 19 ml vs. 77 ± 17 ml, p = 0.006); longer ERP (at 600 ms: 255 ± 25 ms vs. 222 ± 16 ms, p Conclusions Patients with paroxysmal lone AF, remote from arrhythmia, demonstrate bi-atrial abnormalities characterized by structural change, conduction abnormalities, and sinus node dysfunction. These factors are likely contributors to the “second factor” that predisposes to the development and progression of AF.