Sponge-Like Behaviour in Isoreticular Cu(Gly-His-X) Peptide-Based Porous Materials

We report two isoreticular 3D peptide-based porous frameworks formed by coordination of the tripeptides Gly-l-His-Gly and Gly-l-His-l-Lys to Cu(II) which display sponge-like behaviour. These porous materials undergo structural collapse upon evacuation that can be reversed by exposure to water vapour, which permits recovery of the original open channel structure. This is further confirmed by sorption studies that reveal that both solids exhibit selective sorption of H(2)O while CO(2) adsorption does not result in recovery of the original structures. We also show how the pendant aliphatic amine chains, present in the framework from the introduction of the lysine amino acid in the peptidic backbone, can be post-synthetically modified to produce urea-functionalised networks by following methodologies typically used for metal–organic frameworks built from more rigid “classical” linkers

Hospital admission with non-alcoholic fatty liver disease is associated with increased all-cause mortality independent of cardiovascular risk factors

Non-alcoholic fatty liver disease (NAFLD) is common and strongly associated with the metabolic syndrome. Though NAFLD may progress to end-stage liver disease, the top cause of mortality in NAFLD is cardiovascular disease (CVD). Most of the data on liver-related mortality in NAFLD derives from specialist liver centres. It is not clear if the higher reported mortality rates in individuals with non-cirrhotic NAFLD are entirely accounted for by complications of atherosclerosis and diabetes. Therefore, we aimed to describe the CVD burden and mortality in NAFLD when adjusting for metabolic risk factors using a ‘real world’ cohort. We performed a retrospective study of patients followed-up after an admission to non-specialist hospitals with a NAFLD-spectrum diagnosis. Non-cirrhotic NAFLD and NAFLD-cirrhosis patients were defined by ICD-10 codes. Cases were age-/sex-matched with non-NAFLD hospitalised patients. All-cause mortality over 14-years follow-up after discharge was compared between groups using Cox proportional hazard models adjusted for demographics, CVD, and metabolic syndrome components. We identified 1,802 patients with NAFLD-diagnoses: 1,091 with non-cirrhotic NAFLD and 711 with NAFLD-cirrhosis, matched to 24,737 controls. There was an increasing burden of CVD with progression of NAFLD: for congestive heart failure 3.5% control, 4.2% non-cirrhotic NAFLD, 6.6% NAFLD-cirrhosis; and for atrial fibrillation 4.7% control, 5.9% non-cirrhotic NAFLD, 12.1% NAFLD-cirrhosis. Over 14-years follow-up, crude mortality rates were 14.7% control, 13.7% non-cirrhotic NAFLD, and 40.5% NAFLD-cirrhosis. However, after adjusting for demographics, non-cirrhotic NAFLD (HR 1.3 (95% CI 1.1–1.5)) as well as NAFLD-cirrhosis (HR 3.7 (95% CI 3.0–4.5)) patients had higher mortality compared to controls. These differences remained after adjusting for CVD and metabolic syndrome components: non-cirrhotic NAFLD (HR 1.2 (95% CI 1.0–1.4)) and NAFLD-cirrhosis (HR 3.4 (95% CI 2.8–4.2)). In conclusion, from a large non-specialist registry of hospitalised patients, those with non-cirrhotic NAFLD had increased overall mortality compared to controls even after adjusting for CVD

VISTA Deficiency Attenuates Antibody-induced Arthritis and Alters Macrophage Gene Expression in Response to Simulated Immune Complexes

In addition to activated T cells, the immune checkpoint inhibitor “V domain-containing Ig suppressor of T-cell activation” (VISTA) is expressed by myeloid cell types, including macrophages and neutrophils. The importance of VISTA expression by myeloid cells to antibody-induced arthritis and its potential for relevance in human disease was evaluated. Methods: VISTA was immunolocalized in normal and arthritic human synovial tissue sections and synovial tissue lysates were subjected to western blot analysis. The collagen antibody-induced arthritis model (CAIA) was performed with DBA/1 J mice treated with antibodies against VISTA and with VISTA-deficient mice (V-KO). Total mRNA from arthritic joints, spleens, and cultured macrophages was analyzed with NanoString arrays. Cytokines secreted by splenic inflammatory macrophages were determined. In-vitro chemotaxis and signal transduction assays were performed with cultured macrophages. Results: VISTA protein was localized to synovial membrane cells, neutrophils, and scattered cells in lymphocyte-rich foci and was detected by western blot analysis in normal synovium and synovium from rheumatoid arthritis patients. Deficiency of VISTA or treatment of mice with anti-VISTA monoclonal antibodies attenuated CAIA. Joint damage and MMP-3 expression were significantly reduced in V-KO mice. Surface expression of C5a receptor was reduced on monocytes, neutrophils, and cultured macrophages from V-KO. Upon Fc receptor engagement in vitro, gene expression by V-KO macrophages was altered profoundly compared to WT, including a significant induction of IL-1 receptor antagonist (IL1rn). Conclusions: VISTA expression supports immune-complex inflammation in CAIA and VISTA is expressed in human synovium. VISTA supports optimal responses to C5a and modulates macrophage responses to immune complexes

Inspiratory muscle training for improving inspiratory muscle strength and functional capacity in older adults: a systematic review and meta-analysis

Background The ageing process can result in the decrease of respiratory muscle strength and consequently increased work of breathing and associated breathlessness during activities of daily living in older adults. Objective This systematic review and meta-analysis aims to determine the effects of inspiratory muscle training (IMT) in healthy older adults. Methods A systematic literature search was conducted across four databases (Medline/Pubmed, Web of Science, Cochrane Library CINAHL) using a search strategy consisting of both MeSH and text words including older adults, IMT and functional capacity. The eligibility criteria for selecting studies involved controlled trials investigating IMT via resistive or threshold loading in older adults (>60 years) without a long-term condition. Results Seven studies provided mean change scores for inspiratory muscle pressure and three studies for functional capacity. A significant improvement was found for maximal inspiratory pressure (PImax) following training (n = 7, 3.03 [2.44, 3.61], P = <0.00001) but not for functional capacity (n = 3, 2.42 [−1.28, 6.12], P = 0.20). There was no significant correlation between baseline PImax and post-intervention change in PImax values (n = 7, r = 0.342, P = 0.453). Conclusions IMT can be beneficial in terms of improving inspiratory muscle strength in older adults regardless of their initial degree of inspiratory muscle weakness. Further research is required to investigate the effect of IMT on functional capacity and quality of life in older adults

Universals, Laws, and Governance

Proponents of the dispositional theory of properties typically claim that their view is not one that offers a realist, governing conception of laws. My first aim is to show that, contrary to this claim, if one commits to dispositionalism then one does not automatically give up on a robust, realist theory of laws. This is because dispositionalism can readily be developed within a Platonic framework of universals. Second, I argue that there are good reasons for realist dispositionalists to favour a Platonic view. This is because the alternative Aristotelian version of dispositionalism, on which universals are immanent entities, is unstable for various reasons. My final aim is to address a common criticism facing Platonic theories of laws, which is the problem of how external entities can play an explanatory role where the world’s law-like patterns of behaviour are concerned. I argue that the Platonists’ response to the one over many problem can help to shed light on this matter, and a possible solution is sketched, one which makes use of the notions of essence, constitution and ontological dependence

VISTA Deficiency Attenuates Antibody-induced Arthritis and Alters Macrophage Gene Expression in Response to Simulated Immune Complexes

In addition to activated T cells, the immune checkpoint inhibitor “V domain-containing Ig suppressor of T-cell activation” (VISTA) is expressed by myeloid cell types, including macrophages and neutrophils. The importance of VISTA expression by myeloid cells to antibody-induced arthritis and its potential for relevance in human disease was evaluated. Methods: VISTA was immunolocalized in normal and arthritic human synovial tissue sections and synovial tissue lysates were subjected to western blot analysis. The collagen antibody-induced arthritis model (CAIA) was performed with DBA/1 J mice treated with antibodies against VISTA and with VISTA-deficient mice (V-KO). Total mRNA from arthritic joints, spleens, and cultured macrophages was analyzed with NanoString arrays. Cytokines secreted by splenic inflammatory macrophages were determined. In-vitro chemotaxis and signal transduction assays were performed with cultured macrophages. Results: VISTA protein was localized to synovial membrane cells, neutrophils, and scattered cells in lymphocyte-rich foci and was detected by western blot analysis in normal synovium and synovium from rheumatoid arthritis patients. Deficiency of VISTA or treatment of mice with anti-VISTA monoclonal antibodies attenuated CAIA. Joint damage and MMP-3 expression were significantly reduced in V-KO mice. Surface expression of C5a receptor was reduced on monocytes, neutrophils, and cultured macrophages from V-KO. Upon Fc receptor engagement in vitro, gene expression by V-KO macrophages was altered profoundly compared to WT, including a significant induction of IL-1 receptor antagonist (IL1rn). Conclusions: VISTA expression supports immune-complex inflammation in CAIA and VISTA is expressed in human synovium. VISTA supports optimal responses to C5a and modulates macrophage responses to immune complexes

The preparation of large surface area lanthanum based perovskite supports for AuPt nanoparticles: tuning the glycerol oxidation reaction pathway by switching the perovskite B site

Gold and gold alloys, in the form of supported nanoparticles, have been shown over the last three decades to be highly effective oxidation catalysts. Mixed metal oxide perovskites, with their high structural tolerance, are ideal for investigating how changes in the chemical composition of supports affect the catalysts' properties, while retaining similar surface areas, morphologies and metal co-ordinations. However, a significant disadvantage of using perovskites as supports is their high crystallinity and small surface area. We report the use of a supercritical carbon dioxide anti-solvent precipitation methodology to prepare large surface area lanthanum based perovskites, making the deposition of 1 wt% AuPt nanoparticles feasible. These catalysts were used for the selective oxidation of glycerol. By changing the elemental composition of the perovskite B site, we dramatically altered the reaction pathway between a sequential oxidation route to glyceric or tartronic acid and a dehydration reaction pathway to lactic acid. Selectivity profiles were correlated to reported oxygen adsorption capacities of the perovskite supports and also to changes in the AuPt nanoparticle morphologies. Extended time on line analysis using the best oxidation catalyst (AuPt/LaMnO3) produced an exceptionally high tartronic acid yield. LaMnO3 produced from alternative preparation methods was found to have lower activities, but gave comparable selectivity profiles to that produced using the supercritical carbon dioxide anti-solvent precipitation methodology

Cognitive behavioural therapy combined with physical activity behavioural modification strategies during pulmonary rehabilitation in patients with COPD

Introduction: Patients with COPD who exhibit elevated levels of anxiety and/or depression are typically less able to improve symptoms and physical activity (PA) levels following a programme of pulmonary rehabilitation (PR). Objective: To provide proof of concept that offering an intervention comprising cognitive behavioural therapy (CBT) alongside PA behavioural modification strategies (BPA) during PR is more effective in improving PA outcomes compared to PR and CBT alone. Methods: Thirty-two patients with COPD (mean±SD: FEV1: 42±14% predicted) were assigned 1:1 to receive PR+CBT+BPA or PR+CBT. BPA comprised motivational interviews, step count monitoring, feedback using a pedometer and goal setting. Assessments included accelerometer-derived steps/day, movement intensity, 6MWD and HADS scores. Results: The magnitude of improvement across PA outcomes was greater for the PR+CBT+BPA compared to the PR+CBT intervention (by 828 steps/day (p=0.029) and by 8039 vector magnitude units (p=0.042), respectively). Compared to PR and CBT alone, the PR+CBT+BPA intervention induced greater clinically meaningful improvements in HADS anxiety scores (by -2 units [95% CI -4 to 1 units]) and 6MWD (by 3320 m). Conclusions: Providing anxious and/or depressed patients with COPD with a combined intervention of CBT and BPA during PR, presents more favourable improvements in PA outcome measures compared to CBT alone during PR

Three members of a peptide family are differentially distributed and elicit differential state-dependent responses in a pattern generator-effector system

C-type allatostatins (AST-Cs) are pleiotropic neuropeptides that are broadly conserved within arthropods; the presence of three AST-C isoforms, encoded by paralog genes, is common. However, these peptides are hypothesized to act through a single receptor, thereby exerting similar bioactivities within each species. We investigated this hypothesis in the American lobster, Homarus americanus, mapping the distributions of AST-C isoforms within relevant regions of the nervous system and digestive tract, and comparing their modulatory influences on the cardiac neuromuscular system. Immunohistochemistry showed that in the pericardial organ, a neuroendocrine release site, AST-C I and/or III and AST-C II are contained within distinct populations of release terminals. Moreover, AST-C I/III-like immunoreactivity was seen in midgut epithelial endocrine cells and the cardiac ganglion (CG), whereas AST-C II-like immunoreactivity was not seen in these tissues. These data suggest that AST-C I and/or III can modulate the CG both locally and hormonally; AST-C II likely acts on the CG solely as a hormonal modulator. Physiological studies demonstrated that all three AST-C isoforms can exert differential effects, including both increases and decreases, on contraction amplitude and frequency when perfused through the heart. However, in contrast to many state-dependent modulatory changes, the changes in contraction amplitude and frequency elicited by the AST-Cs were not functions of the baseline parameters. The responses to AST-C I and III, neither of which is COOH-terminally amidated, are more similar to one another than they are to the responses elicited by AST-C II, which is COOH-terminally amidated. These results suggest that the three AST-C isoforms are differentially distributed in the lobster nervous system/midgut and can elicit distinct behaviors from the cardiac neuromuscular system, with particular structural features, e.g., COOH-terminal amidation, likely important in determining the effects of the peptides. NEW & NOTEWORTHY Multiple isoforms of many peptides exert similar effects on neural circuits. In this study we show that each of the three isoforms of C-type allatostatin (AST-C) can exert differential effects, including both increases and decreases in contraction amplitude and frequency, on the lobster cardiac neuromuscular system. The distribution of effects elicited by the nonamidated isoforms AST-C I and III are more similar to one another than to the effects of the amidated AST-C II