Cardiovascular risk and systemic inflammation in male professional rugby: a cross-sectional study

Objective: To investigate cardiovascular risk factors’ prevalence and association with systemic inflammation in professional male rugby players (RP). Methods: A cross-sectional investigation of 46 professional male RP (26.1±4.1 years) cardiovascular risk factors were compared by position. Inflammatory markers were compared with healthy controls (n=13) and patients with rheumatoid arthritis (RA) (n=10). Results: Twenty-six per cent of RP had no risk factors, 49% had 1–2 cardiovascular risk factors and 25% had 3–4 risk factors. Forwards had greater body fat (p<0.001), visceral fat (p<0.001), glucose (p=0.025), and C reactive protein (CRP) (p=0.023) compared with backs. RP demonstrated more favourable lipid and glucose profiles than reference values for the general population. Most RP (n=28, 61%) had elevated blood pressure (≥140/90 mm Hg). RP had higher vascular adhesion molecule-1 (VCAM-1) (p=0.004) and intracellular adhesion molecule-1 (ICAM-1) (p=0.002) than healthy controls. RP had lower CRP than patients with RA (p=0.009), while one-third (n=15) displayed equivalent ICAM-1 and VCAM-1 levels. Multivariate clustering and principal component analysis biplots revealed higher triglycerides, inflammatory markers, and worse body composition were associated with forwards. Conclusions: Despite athletic status, most of this rugby cohort had at least one cardiovascular risk factor. Concomitantly, these RP demonstrated increased levels of inflammation, with one-third, primarily forwards, displaying equivalent levels to patients with inflammatory disease. Further studies are needed to unravel the prognostic implications of increased inflammation in RP because unchecked, chronic inflammation may lead to increased cardiovascular disease risk

P(VDF-TrFE) Copolymer Dynamics as a Function of Temperature and Pressure in the Vicinity of the Curie Transition

We report on the phase behavior and the respective dynamics in random P(VDF-TrFE) copolymers using standard and temperature-modulated differential scanning calorimetry, X-ray diffraction, and a combination of temperature- and pressure-dependent dielectric spectroscopy measurements. Depending on the copolymer composition, the coexistence of three/four weakly ordered phases was identified in the vicinity of the Curie transition (Tc). With respect to the dynamics, we demonstrate that the segmental dynamics associated with the relaxation of constrained amorphous VDF segments at the crystal/amorphous "phase"can be used as a marker of the Curie transition. The corresponding segmental relaxation freezes at about 50 K above the lower liquid-to-glass temperature associated with the freezing of amorphous segments away from the interface. Pressure-dependent dielectric measurements provided quantitative insight into (i) the molecular origin of the segmental processes (by employing the pressure sensitivity of relaxation times and the pressure coefficient of the respective Tg's), (ii) the nature of the phase transition at Tc, and (iii) information about the stability of phases under the variation of temperature and pressure (through the T-P phase diagram). We show that Tc increases linearly with pressure and is accompanied by small volume changes, implying a weakly first-order thermodynamic transition. Furthermore, pressure stabilizes the ferroelectric phase over a broader temperature range. This could extend the operating temperature range of ferroelectric devices based on P(VDF-TrFE) copolymers. </p

Computational approaches in rheumatic diseases – Deciphering complex spatio-temporal cell interactions

Inflammatory arthritis, including rheumatoid (RA), and psoriatic (PsA) arthritis, are clinically and immunologically heterogeneous diseases with no identified cure. Chronic inflammation of the synovial tissue ushers loss of function of the joint that severely impacts the patient’s quality of life, eventually leading to disability and life-threatening comorbidities. The pathogenesis of synovial inflammation is the consequence of compounded immune and stromal cell interactions influenced by genetic and environmental factors. Deciphering the complexity of the synovial cellular landscape has accelerated primarily due to the utilisation of bulk and single cell RNA sequencing. Particularly the capacity to generate cell-cell interaction networks could reveal evidence of previously unappreciated processes leading to disease. However, there is currently a lack of universal nomenclature as a result of varied experimental and technological approaches that discombobulates the study of synovial inflammation. While spatial transcriptomic analysis that combines anatomical information with transcriptomic data of synovial tissue biopsies promises to provide more insights into disease pathogenesis, in vitro functional assays with single-cell resolution will be required to validate current bioinformatic applications. In order to provide a comprehensive approach and translate experimental data to clinical practice, a combination of clinical and molecular data with machine learning has the potential to enhance patient stratification and identify individuals at risk of arthritis that would benefit from early therapeutic intervention. This review aims to provide a comprehensive understanding of the effect of computational approaches in deciphering synovial inflammation pathogenesis and discuss the impact that further experimental and novel computational tools may have on therapeutic target identification and drug development

Cyclic Topologies in Linear α,ω-Dihydroxy Polyisoprenes by Dielectric Spectroscopy

A series of mono- and di-functionalized polyisoprenes (PIs) bearing hydroxyl (OH−) end-group(s) with different molar masses ranging from 2 to 30 kg mol–1 were synthesized and studied by a combination of temperature- and pressure-dependent dielectric spectroscopy and rheology. In the di-functionalized PIs, the −OH end-group interactions result in a mixture of linear and cyclic configurations (up to 45% cyclic configurations for the lower molar masses). The formation of cyclic topologies due to increased H-bonding interactions restricted the backbone mobility and increased the glass temperature, Tg, especially for the lower molar masses. Moreover, an additional process (termed α*) was evidenced in the dielectric spectroscopy in the range between the segmental process and the global chain relaxation. It followed a Vogel–Fulcher–Tammann temperature dependence, freezing at a temperature in the vicinity of the liquid-to-glass temperature, being independent of molar mass. Its molecular origin was identified by employing the pressure sensitivity of the characteristic relaxation times and the pressure dependence of Tg. It reflects the relaxation of segments in the vicinity of the H-bonded groups. Overall, this study provided information on the impact of weakly associating polar end-groups (hydroxyl) on the molecular dynamics of type-A polymers. Furthermore, it suggested promising routes for designing polymers with a higher concentration (>50%) of cyclic topologies, for example, by employing (i) short chains with (ii) strongly associating end groups (stronger than the hydroxyl end-groups)

Segmental Dynamics in Multicyclic Polystyrenes

The segmental dynamics and the corresponding glass temperature, <i>T</i>_g, were investigated in a monocyclic and in the corresponding linear polystyrene as well as in a series of multicyclic polystyrenes, all with the same total molecular weight, with dielectric spectroscopy and DSC. There is a strong reduction of <i>T</i>_g with decreasing molecular weight for linear chains but only a moderate reduction for cyclic chains and this below a certain critical molecular weight (<i>M</i>_n ∼ 18 000 g/mol). These data contradict the Gibbs–Di Marzio lattice model predicting an increasing glass temperature with decreasing molecular weight of cyclic polymers. In multicyclic polystyrenes the results emphasize the role of constrained segments at the coupling sites (linkers) on determining practically all features of segmental dynamics: the exact temperature dependence of relaxation times and associated <i>T</i>_g, the dielectric strength, the distribution of relaxation times, and fragility. A nearly linear increase of <i>T</i>_g was found with increasing number of intramolecular constraints. Furthermore, the total molecular weight is an irrelevant parameter in discussing the dynamics of multicyclic polymers. An alternative approach that is based on the concept of free volume emphasizes intermolecular contributions and predicts the same amount of fractional free volume for multicyclic polystyrenes at their respective glass temperature (3.3%) but differences in the respective thermal expansion coefficient of free volume

Schistosoma mansoni Worm Infection Regulates the Intestinal Microbiota and Susceptibility to Colitis

Infection with parasite helminths induces potent modulation of the immune system of the host. Epidemiological and animal studies have shown that helminth infections can suppress or exacerbate unrelated autoimmune, allergic, and other inflammatory disorders. There is growing evidence that helminth infection-mediated suppression of bystander inflammatory responses is influenced by alterations in the intestinal microbiome modulating metabolic and immune functions of the infected host. We analyzed the fecal microbiota of mice infected with adult male Schistosoma mansoni worms, which are less susceptible to experimental colitis, and male- and female-worm-infected mice, which are highly sensitive to colitis. While both groups of infected mice developed a disrupted microbiota, there were marked alterations in mice with male and female worm infections. Antibiotic-treated recipients that were cohoused with both types of S. mansoni worm-infected mice acquired a colitogenic microbiome, leading to increased susceptibility to experimental colitis. Following anthelmintic treatment to remove worms from worm-only-infected mice, the mice developed exacerbated colitis. This study provides evidence that adult male S. mansoni worm infection modulates the host's immune system and suppresses bystander colitis while limiting dysbiosis of the host's intestinal microbiome during infection

ACPA Status Correlates with Differential Immune Profile in Patients with Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a progressive erosive autoimmune disease that affects 1% of the world population. Anti-citrullinated protein autoantibodies (ACPA) are routinely used for the diagnosis of RA, however 20–30% of patients are ACPA negative. ACPA status is a delineator of RA disease endotypes with similar clinical manifestation but potentially different pathophysiology. Profiling of key peripheral blood and synovial tissue immune populations including B cells, T follicular helper (Tfh) cells and CD4 T cell proinflammatory cytokine responses could elucidate the underlying immunological mechanisms involved and inform a treat to target approach for both ACPA-positive and ACPA-negative RA. Detailed high dimensionality flow cytometric analysis with supervised and unsupervised algorithm analysis revealed unique RA patient peripheral blood B cell and Tfh cell profiles. Synovial tissue single cell analysis of B cell subpopulation distribution was similar between ACPA− and ACPA+ RA patients, highlighting a key role for specific B cell subsets in both disease endotypes. Interestingly, synovial tissue single cell analysis of CD4 T cell proinflammatory cytokine production was markedly different between ACPA− and APCA+ RA patients. RNAseq analysis of RA patient synovial tissue highlighted disease endotype specific gene signatures. ACPA status associates with unique immune profile signatures that reinforce the need for a treat to target approach for both endotypes of RA

Composition of the Schistosoma mansoni worm secretome: Identification of immune modulatory Cyclophilin A

<div><p>The helminth <i>Schistosoma mansoni</i> modulates the infected host’s immune system to facilitate its own survival, by producing excretory/secretory molecules that interact with a variety of the host’s cell types including those of the immune system. Herein, we characterise the <i>S</i>. <i>mansoni</i> adult male worm secretome and identify 111 proteins, including 7 vaccine candidates and several molecules with potential immunomodulatory activity. Amongst the molecules present in the secretome, a 17-19kDa protein analogous to human cyclophilin A was identified. Given the ability of cyclophilin A to modulate the immune system by regulating antigen presenting cell activity, we sought to determine whether recombinant <i>S</i>. <i>mansoni</i> Cyclophilin A (rSmCypA) is capable of modulating bone-marrow derived dendritic cell (BMDC) and T cell responses under <i>in vitro</i> conditions. rSmCypA was enzymatically active and able to alter the pro-inflammatory cytokine profile of LPS-activated dendritic cells. rSmCypA also modulated DC function in the induction of CD4⁺ T cell proliferation with a preferential expansion of Treg cells. This work demonstrates the unique protein composition of the <i>S</i>. <i>mansoni</i> male worm secretome and immunomodulatory activity of <i>S</i>. <i>mansoni</i> Cyclophilin A.</p></div