Metabolism of Maillard reaction products by the human gut microbiota - implications for health

The human colonic microbiota imparts metabolic versatility on the colon, interacts at many levels in healthy intestinal and systemic metabolism, and plays protective roles in chronic disease and acute infection. Colonic bacterial metabolism is largely dependant on dietary residues from the upper gut. Carbohydrates, resistant to digestion, drive colonic bacterial fermentation and the resulting end products are considered beneficial. Many colonic species ferment proteins but the end products are not always beneficial and include toxic compounds, such as amines and phenols. Most components of a typical Western diet are heat processed. The Maillard reaction, involving food protein and sugar, is a complex network of reactions occurring during thermal processing. The resultant modified protein resists digestion in the small intestine but is available for colonic bacterial fermentation. Little is known about the fate of the modified protein but some Maillard reaction products (MRP) are biologically active by, e.g. altering bacterial population levels within the colon or, upon absorption, interacting with human disease mechanisms by induction of inflammatory responses. This review presents current understanding of the interactions between MRP and intestinal bacteria. Recent scientific advances offering the possibility of elucidating the consequences of microbe-MRP interactions within the gut are discussed.

Novel approaches to the analysis of the Maillard reaction of proteins

The Maillard reaction comprises a complex network of reactions which has proven to be of great importance in both food science and medicine. The majority of methods developed for studying the Maillard reaction in food have focused on model systems containing amino acids and monosaccharides. In this study, a number of electrophoretic techniques, including two-dimensional gel electrophoresis and capillary electrophoresis, are presented. These have been developed specifically for the analysis of the Maillard reaction of food proteins, and are giving important insights into this complex process.

Analysis of HSC activity and compensatory Hox gene expression profile in Hoxb cluster mutant fetal liver cells

Overexpression of Hoxb4 in bone marrow cells promotes expansion of hematopoietic stem cell (HSC) populations in vivo and in vitro, indicating that this homeoprotein can activate the genetic program that determines self-renewal. However, this function cannot be solely attributed to Hoxb4 because Hoxb4(-/-) mice are viable and have an apparently normal HSC number. Quantitative polymerase chain reaction analysis showed that Hoxb4(-/-) c-Kit(+) fetal liver cells expressed moderately higher levels of several Hoxb cluster genes than control cells, raising the possibility that normal HSC activity in Hoxb4(-/-) mice is due to a compensatory up-regulation of other Hoxb genes. In this study, we investigated the competitive repopulation potential of HSCs lacking Hoxb4 alone, or in conjunction with 8 other Hoxb genes. Our results show that Hoxb4(-/-) and Hoxb1-b9(-/-) fetal liver cells retain full competitive repopulation potential and the ability to regenerate all myeloid and lymphoid lineages. Quantitative Hox gene expression profiling in purified c-KIt(+) Hoxb1-bg(-/-) fetal liver cells revealed an interaction between the Hoxa, b, and c clusters with variation in expression levels of Hoxa4, -a11, and -c4. Together, these studies show a complex network of genetic interactions between several Hox genes in primitive hematopoietic cells and demonstrate that HSCs lacking up to 30% of the active Hox genes remain fully competent.

Spatio-temporal analysis of DNA damage repair using the X-ray microbeam

Cellular response to radiation damage is made by a complex network of pathways and feedback loops whose spatiotemporal organization is still unclear despite its decisive role in determining the fate of the damaged cell. The single-cell approach and the high spatial resolution offered by microbeams provide the perfect tool to study and quantify the dynamic processes associated with the induction and repair of DNA damage. The soft X-ray microbeam has been used to follow the development of radiation induced foci in live cells by monitoring their size and intensity as a function of dose and time using yellow fluorescent protein (YFP) tagging techniques. Preliminary data indicate a delayed and linear rising of the intensity signal indicating a slow kinetic for the accumulation of DNA repair protein 53BP1. A slow and limited foci diffusion has also been observed. Further investigations are required to assess whatever such diffusion is consistent with a random walk pattern or if it is the result of a more structured lesion processing phenomenon. In conclusion, our data indicates that the use of microbeams coupled to live cell microscopy represent a sophisticated approach for visualizing and quantifying the dynamics changes of DNA proteins at the damaged sites.

Compost city: underground music, collapsoscapes and urban regeneration

This paper looks at the recent history of Hulme, Manchester, which during the 1980s was home to many of the most successful bands of the post-punk era. This flourishing of underground music was not planned, however. It emerged, through a complex network of urban forces, some physical, some social. The paper develops the concept of the ‘compost city’ a laissez-faire approach to the management of urban culture, which is oppositional to the current vogue for more hands-on cultural industries management.

Global down-regulation of HOX gene expression in PML-RARalpha + acute promyelocytic leukemia identified by small-array real-time PCR

Acute promyelocytic leukemia (APL) is associated with a reciprocal and balanced translocation involving the retinoic acid receptor-alpha (RARalpha). All-trans retinoic acid (ATRA) is used to treat APL and is a potent morphogen that regulates HOX gene expression in embryogenesis and organogenesis. HOX genes are also involved in hematopoiesis and leukemogenesis. Thirty-nine mammalian HOX genes have been identified and classified into 13 paralogous groups clustered on 4 chromosomes. They encode a complex network of transcription regulatory proteins whose precise targets remain poorly understood. The overall function of the network appears to be dictated by gene dosage. To investigate the mechanisms involved in HOX gene regulation in hematopoiesis and leukemogenesis by precise measurement of individual HOX genes, a small-array real-time HOX (SMART-HOX) quantitative polymerase chain reaction (PCR) platform was designed and validated. Application of SMART-HOX to 16 APL bone marrow samples revealed a global down-regulation of 26 HOX genes compared with normal controls. HOX gene expression was also altered during differentiation induced by ATRA in the PML-RARalpha(+) NB4 cell line. PML-RARalpha fusion proteins have been reported to act as part of a repressor complex during myeloid cell differentiation, and a model linking HOX gene expression to this PML-RARalpha repressor complex is now proposed.

Relationships between EEA1 binding partners and their role in endosome fusion

Homotypic fusion between early endosomes requires the phosphatidylinositol 3-phosphate (PI3P)-binding protein, Early Endosomal Autoantigen 1 (EEA1). We have investigated the role of other proteins that interact with EEA1 in the fusion of early endosomes derived from Baby Hamster Kidney (BHK) cells. We confirm a requirement for syntaxin 13, but additionally show that the assay is equally sensitive to reagents specifically targeted against syntaxin 6. Binding of EEA1 to immobilised GST-syntaxin 6 and 13 was directly compared; only syntaxin 6 formed a stable complex with EEA1. Early endosome fusion requires the release of intravesicular calcium, and calmodulin plays a vital role in the fusion pathway, as judged by sensitivity to antagonists. We demonstrate that both EEA1 and syntaxin 13 interact with calmodulin. In the case of EEA1, binding to calmodulin requires an IQ domain, which is adjacent to a C-terminal FYVE domain that specifically binds to PI3P. We have assessed the influence of protein binding partners on EEA1 interaction with PI3P and find that both calmodulin and rab5-GTP are antagonistic to PI3P binding, whilst syntaxins 6 and 13 have no effect. These studies reveal a complex network of interactions between the proteins required for endosome fusion.

Pharmacist-led feedback workshops increase appropriate prescribing of antimicrobials

Objectives To investigate whether and how structured feedback sessions can increase rates of appropriate antimicrobial prescribing by junior doctors.

Methods This was a mixed-methods study, with a conceptual orientation towards complexity and systems thinking. Fourteen junior doctors, in their first year of training, were randomized to intervention (feedback) and 21 to control (routine practice) groups in a single UK teaching hospital. Feedback on their antimicrobial prescribing was given, in writing and via group sessions. Pharmacists assessed the appropriateness of all new antimicrobial prescriptions 2 days per week for 6 months (46 days). The mean normalized prescribing rates of suboptimal to all prescribing were compared between groups using the t-test. Thematic analysis of qualitative interviews with 10 participants investigated whether and how the intervention had impact.

Results Data were collected on 204 prescriptions for 166 patients. For the intervention group, the mean normalized rate of suboptimal to all prescribing was 0.32 ± 0.36; for the control group, it was 0.68 ± 0.36. The normalized rates of suboptimal prescribing were significantly different between the groups (P = 0.0005). The qualitative data showed that individuals' prescribing behaviour was influenced by a complex series of dynamic interactions between individual and social variables, such as interplay between personal knowledge and the expectations of others.

Conclusions The feedback intervention increased appropriate prescribing by acting as a positive stimulus within a complex network of behavioural influences. Prescribing behaviour is adaptive and can be positively influenced by structured feedback. Changing doctors' perceptions of acceptable, typical and best practice could reduce suboptimal antimicrobial prescribing.

A systematic literature review of university technology transfer from a quadruple helix perspective: Towards a research agenda

Within recent years, there has been a rapid expansion of the University's role in economic development. This has resulted in University Technology Transfer (UTT) taking place within an increasingly complex network of regional stakeholders. This complexity has resulted in quadruple helix models where the triple helix model of academia, industry and regional government now includes societal based innovation users as a fourth helix. Despite this development, extant research is fragmented and lacks coherent frameworks and conceptualisations which fully depict the dynamic and evolving nature of UTT. Accordingly, this article reviews Mode 2 UTT from a quadruple helix perspective to identify key themes to develop a research agenda which reflects progression from a triple into a quadruple helix ecosystem.

A new Jacobian matrix for optimal learning of single-layer neural networks

This paper investigates the learning of a wide class of single-hidden-layer feedforward neural networks (SLFNs) with two sets of adjustable parameters, i.e., the nonlinear parameters in the hidden nodes and the linear output weights. The main objective is to both speed up the convergence of second-order learning algorithms such as Levenberg-Marquardt (LM), as well as to improve the network performance. This is achieved here by reducing the dimension of the solution space and by introducing a new Jacobian matrix. Unlike conventional supervised learning methods which optimize these two sets of parameters simultaneously, the linear output weights are first converted into dependent parameters, thereby removing the need for their explicit computation. Consequently, the neural network (NN) learning is performed over a solution space of reduced dimension. A new Jacobian matrix is then proposed for use with the popular second-order learning methods in order to achieve a more accurate approximation of the cost function. The efficacy of the proposed method is shown through an analysis of the computational complexity and by presenting simulation results from four different examples.

Data-driven optimal filtering for phase and frequency of noisy oscillations: Application to vortex flow metering

A method for measuring the phase of oscillations from noisy time series is proposed. To obtain the phase, the signal is filtered in such a way that the filter output has minimal relative variation in the amplitude over all filters with complex-valued impulse response. The argument of the filter output yields the phase. Implementation of the algorithm and interpretation of the result are discussed. We argue that the phase obtained by the proposed method has a low susceptibility to measurement noise and a low rate of artificial phase slips. The method is applied for the detection and classification of mode locking in vortex flow meters. A measure for the strength of mode locking is proposed.

Day-Ahead Optimal Charging/Discharging Scheduling for Electric Vehicles in Micro-Grids

A micro-grid is an autonomous system which can be operated and connected to an external system or isolated with the help of energy storage systems (ESSs). While the daily output of distributed generators (DGs) strongly depends on the temporal distribution of natural resources such as wind and solar, unregulated electric vehicle (EV) charging demand will deteriorate the imbalance between the daily load and generation curves. In this paper, a statistical model is presented to describe daily EV charging/discharging behaviour. An optimisation problem is proposed to obtain economic operation for the micro-grid based on this model. In day-ahead scheduling, with estimated information of power generation and load demand, optimal charging/discharging of EVs during 24 hours is obtained. A series of numerical optimization solutions in different scenarios is achieved by serial quadratic programming. The results show that optimal charging/discharging of EVs, a daily load curve can better track the generation curve and the network loss and required ESS capacity are both decreased. The paper also demonstrates cost benefits for EVs and operators.