ERAP2 functional knockout in humans does not alter surface heavy chains or HLA-B27, inflammatory cytokines or endoplasmic reticulum stress markers

Introduction Single nucleotide polymorphisms in ERAP2 are strongly associated with ankylosing spondylitis (AS). One AS-associated single nucleotide polymorphism, rs2248374, causes a truncated ERAP2 protein that is degraded by nonsense-mediated decay. Approximately 25% of the populations of European ancestry are therefore natural ERAP2 knockouts. We investigated the effect of this associated variant on HLA class I allele presentation, surface heavy chains, endoplasmic reticulum (ER) stress markers and cytokine gene transcription in AS. Methods Patients with AS and healthy controls with either AA or GG homozygous status for rs2248374 were studied. Antibodies to CD14, CD19-ECD, HLA-A-B-C, Valpha7.2, CD161, anti-HC10 and anti-HLA-B27 were used to analyse peripheral blood mononuclear cells. Expression levels of ER stress markers (GRP78 and CHOP) and proinflammatory genes (tumour necrosis factor (TNF), IL6, IL17 and IL22) were assessed by qPCR. Results There was no significant difference in HLAclass I allele presentation or major histocompatibility class I heavy chains or ER stress markers GRP78 and CHOP or proinflammatory gene expression between genotypes for rs2248374 either between cases, between cases and controls, and between controls. Discussion Large differences were not seen in HLAB27 expression or cytokine levels between subjects with and without ERAP2 in AS cases and controls. This suggests that ERAP2 is more likely to influence AS risk through other mechanisms.

Sphingosine-1-phosphate mediates proliferation maintaining the multipotency of human adult bone marrow and adipose tissue-derived stem cells

High renewal and maintenance of multipotency of human adult stem cells (hSCs), are a prerequisite for experimental analysis as well as for potential clinical usages. The most widely used strategy for hSC culture and proliferation is using serum. However, serum is poorly defined and has a considerable degree of inter-batch variation, which makes it difficult for large-scale mesenchymal stem cells (MSCs) expansion in homogeneous culture conditions. Moreover, it is often observed that cells grown in serum-containing media spontaneously differentiate into unknown and/or undesired phenotypes. Another way of maintaining hSC development is using cytokines and/or tissue-specific growth factors; this is a very expensive approach and can lead to early unwanted differentiation. In order to circumvent these issues, we investigated the role of sphingosine-1-phosphate (S1P), in the growth and multipotency maintenance of human bone marrow and adipose tissue-derived MSCs. We show that S1P induces growth, and in combination with reduced serum, or with the growth factors FGF and platelet-derived growth factor-AB, S1P has an enhancing effect on growth. We also show that the MSCs cultured in S1P-supplemented media are able to maintain their differentiation potential for at least as long as that for cells grown in the usual serum-containing media. This is shown by the ability of cells grown in S1P-containing media to be able to undergo osteogenic as well as adipogenic differentiation. This is of interest, since S1P is a relatively inexpensive natural product, which can be obtained in homogeneous high-purity batches: this will minimize costs and potentially reduce the unwanted side effects observed with serum. Taken together, S1P is able to induce proliferation while maintaining the multipotency of different human stem cells, suggesting a potential for S1P in developing serum-free or serum-reduced defined medium for adult stem cell cultures.

Ghrelin and obestatin concentrations during puberty: Relationships with adiposity, nutrition and physical activity

Ghrelin and obestatin are two peptides associated with appetite control and the regulation of energy balance in adults. It is intuitive that they have an important role in growth and development during puberty. Therefore, it is acknowledged that these peptides, in addition to others, form part of the substrate underlying energy homeostasis which in turn will contribute to body weight regulation and could explain changes in energy balance during puberty. Both peptides originate from the stomach; hence, it is intuitive that they are involved in generating signals from tissue stores which influence food intake. This could be manifested via alterations in the drive to eat (i.e. hunger), eating behaviors and appetite regulation. Furthermore, there is some evidence that these peptides might also be associated with physical activity behaviors and metabolism. Anecdotally, children and adolescents experience behavioral and metabolic changes during growth and development which will be associated with physiological changes.

The relationship between substrate metabolism, exercise and appetite control : does glycogen availability influence the motivation to eat, energy intake or food choice?

The way in which metabolic fuels are utilised can alter the expression of behaviour in the interests of regulating energy balance and fuel availability. This is consistent with the notion that the regulation of appetite is a psychobiological process, in which physiological mediators act as drivers of behaviour. The glycogenostatic theory suggests that glycogen availability is central in eliciting negative feedback signals to restore energy homeostasis. Due to its limited storage capacity, carbohydrate availability is tightly regulated and its restoration is a high metabolic priority following depletion. It has been proposed that such depletion may act as a biological cue to stimulate compensatory energy intake in an effort to restore availability. Due to the increased energy demand, aerobic exercise may act as a biological cue to trigger compensatory eating as a result of perturbations to muscle and liver glycogen stores. However, studies manipulating glycogen availability over short-term periods (1-3 days) using exercise, diet or both have often produced equivocal findings. There is limited but growing evidence to suggest that carbohydrate balance is involved in the short-term regulation of food intake, with a negative carbohydrate balance having been shown to predict greater ad libitum feeding. Furthermore, a negative carbohydrate balance has been shown to be predictive of weight gain. However, further research is needed to support these findings as the current research in this area is limited. In addition, the specific neural or hormonal signal through which carbohydrate availability could regulate energy intake is at present unknown. Identification of this signal or pathway is imperative if a casual relationship is to be established. Without this, the possibility remains that the associations found between carbohydrate balance and food intake are incidental.

Modulation of depth-dependent properties in tissue-engineered cartilage with a semi-permeable membrane and perfusion : a continuum model of matrix metabolism and transport

The functional properties of cartilaginous tissues are determined predominantly by the content, distribution, and organization of proteoglycan and collagen in the extracellular matrix. Extracellular matrix accumulates in tissue-engineered cartilage constructs by metabolism and transport of matrix molecules, processes that are modulated by physical and chemical factors. Constructs incubated under free-swelling conditions with freely permeable or highly permeable membranes exhibit symmetric surface regions of soft tissue. The variation in tissue properties with depth from the surfaces suggests the hypothesis that the transport processes mediated by the boundary conditions govern the distribution of proteoglycan in such constructs. A continuum model (DiMicco and Sah in Transport Porus Med 50:57-73, 2003) was extended to test the effects of membrane permeability and perfusion on proteoglycan accumulation in tissue-engineered cartilage. The concentrations of soluble, bound, and degraded proteoglycan were analyzed as functions of time, space, and non-dimensional parameters for several experimental configurations. The results of the model suggest that the boundary condition at the membrane surface and the rate of perfusion, described by non-dimensional parameters, are important determinants of the pattern of proteoglycan accumulation. With perfusion, the proteoglycan profile is skewed, and decreases or increases in magnitude depending on the level of flow-based stimulation. Utilization of a semi-permeable membrane with or without unidirectional flow may lead to tissues with depth-increasing proteoglycan content, resembling native articular cartilage.

Comparison between electrically evoked and voluntary isometric contractions for biceps brachii muscle oxidative metabolism using near-infrared spectroscopy

This study compared voluntary (VOL) and electrically evoked isometric contractions by muscle stimulation (EMS) for changes in biceps brachii muscle oxygenation (tissue oxygenation index, ΔTOI) and total haemoglobin concentration (ΔtHb = oxygenated haemoglobin + deoxygenated haemoglobin) determined by near-infrared spectroscopy. Twelve men performed EMS with one arm followed 24 h later by VOL with the contralateral arm, consisting of 30 repeated (1-s contraction, 1-s relaxation) isometric contractions at 30% of maximal voluntary contraction (MVC) for the first 60 s, and maximal intensity contractions thereafter (MVC for VOL and maximal tolerable current at 30 Hz for EMS) until MVC decreased ∼30% of pre-exercise MVC. During the 30 contractions at 30% MVC, ΔTOI decrease was significantly (P < 0.05) greater and ∼tHb was significantly (P < 0.05) lower for EMS than VOL, suggesting that the metabolic demand for oxygen in EMS is greater than VOL at the same torque level. However, during maximal intensity contractions, although EMS torque (∼40% of VOL) was significantly (P < 0.05) lower than VOL, ΔTOI was similar and ΔtHb was significantly (P < 0.05) lower for EMS than VOL towards the end, without significant differences between the two sessions in the recovery period. It is concluded that the oxygen demand of the activated biceps brachii muscle in EMS is comparable to VOL at maximal intensity. © Springer-Verlag 2009.

Water sensitive urban design through the lens of urban metabolism

Stormwater pollution has been recognised as one of the main causes of aquatic ecosystem degradation and poses a significant threat to both the goal of ecological sustainable development as well as human health and wellbeing. In response, water sensitive urban design (WSUD) practices have been put forward as a strategy to mitigate the detrimental impacts of urban stormwater runoff quality and to safeguard ecosystem functions. However, despite studies that support its efficiency in urban stormwater management, the mainstreaming of WSUD remains a significant challenge. This paper proposes that viewing WSUD through the lens of the integrated urban metabolism framework which encourages an interdisciplinary approach and facilitates dialogue through knowledge transfer is a strategy in which the implementation of WSUD can be mainstreamed.