Inhibition of p38 pathway leads to OA-like changes in a rat animal model

Objectives The p38 mitogen-activated protein kinase (MAPK) signal transduction pathway is involved in a variety of inflammatory responses, including cytokine generation, cell differentiation proliferation and apoptosis. Here, we examined the effects of systemic p38 MAPK inhibition on cartilage cells and osteoarthritis (OA) disease progression by both in vitro and in vivo approaches. Methods p38 kinase activity was evaluated in normal and OA cartilage cells by measuring the amount of phosphorylated protein. To examine the function of p38 signaling pathway in vitro, normal chondrocytes were isolated and differentiated in the presence or absence of p38 inhibitor; SB203580 and analysed for chondrogenic phenotype. Effect of systemic p38 MAPK inhibition in normal and OA (induced by menisectomy) rats were analysed by treating animals with vehicle alone (DMS0) or p38 inhibitor (SB203580). Damage to the femur and tibial plateau was evaluated by modified Mankin score, histology and immunohistochemistry. Results Our in vitro studies have revealed that a down-regulation of chondrogenic and increase of hypertrophic gene expression occurs in the normal chondrocytes, when p38 is neutralized by a pharmacological inhibitor. We further observed that the basal levels of p38 phosphorylation were decreased in OA chondrocytes compared with normal chondrocytes. These findings together indicate the importance of this pathway in the regulation of cartilage physiology and its relevance to OA pathogenesis. At in vivo level, systematic administration of a specific p38 MAPK inhibitor, SB203580, continuously for over a month led to a significant loss of proteoglycan; aggrecan and cartilage thickness. On the other hand, SB203580 treated normal rats showed a significant increase in TUNEL positive cells, cartilage hypertrophy markers such as Type 10 collagen, Runt-related transcription factor and Matrix metalloproteinase-13 and substantially induced OA like phenotypic changes in the normal rats. In addition, menisectomy induced OA rat models that were treated with p38 inhibitor showed aggravation of cartilage damage. Conclusions In summary, this study has provided evidence that the component of the p38 MAPK pathway is important to maintain the cartilage health and its inhibition can lead to severe cartilage degenerative changes. The observations in this study highlight the possibility of using activators of the p38 pathway as an alternative approach in the treatment of OA.

Train control to reduce delays upon service disturbances at railway junctions

Train delay is one of the most important indexes to evaluate the service quality of the railway. Because of the interactions of movement among trains, a delayed train may conflict with trains scheduled on other lines at junction area. Train that loses conflict may be forced to stop or slow down because of restrictive signals, which consequently leads to the loss of run-time and probably enlarges more delays. This paper proposes a time-saving train control method to recover delays as soon as possible. In the proposed method, golden section search is adopted to identify the optimal train speed at the expected time of restrictive signal aspect upgrades, which enables the train to depart from the conflicting area as soon as possible. A heuristic method is then developed to attain the advisory train speed profile assisting drivers in train control. Simulation study indicates that the proposed method enables the train to recover delays as soon as possible in case of disturbances at railway junctions, in comparison with the traditional maximum traction strategy and the green wave strategy.

Evidence for time dependency of molecular rate estimates

Long-term changes in the genetic composition of a population occur by the fixation of new mutations, a process known as substitution. The rate at which mutations arise in a population and the rate at which they are fixed are expected to be equal under neutral conditions (Kimura, 1968). Between the appearance of a new mutation and its eventual fate of fixation or loss, there will be a period in which it exists as a transient polymorphism in the population (Kimura and Ohta, 1971). If the majority of mutations are deleterious (and nonlethal), the fixation probabilities of these transient polymorphisms are reduced and the mutation rate will exceed the substitution rate (Kimura, 1983). Consequently, different apparent rates may be observed on different time scales of the molecular evolutionary process (Penny, 2005; Penny and Holmes, 2001). The substitution rate of the mitochondrial protein-coding genes of birds and mammals has been traditionally recognized to be about 0.01 substitutions/site/million years (Myr) (Brown et al., 1979; Ho, 2007; Irwin et al., 1991; Shields and Wilson, 1987), with the noncoding D-loop evolving several times more quickly (e.g., Pesole et al., 1992; Quinn, 1992). Over the past decade, there has been mounting evidence that instantaneous mutation rates substantially exceed substitution rates, in a range of organisms (e.g., Denver et al., 2000; Howell et al., 2003; Lambert et al., 2002; Mao et al., 2006; Mumm et al., 1997; Parsons et al., 1997; Santos et al., 2005). The immediate reaction to the first of these findings was that the polymorphisms generated by the elevated mutation rate are short-lived, perhaps extending back only a few hundred years (Gibbons, 1998; Macaulay et al., 1997). That is, purifying selection was thought to remove these polymorphisms very rapidly.

Empirical analysis on relationship between traffic conditions and crash occurrences

This paper investigates relationship between traffic conditions and the crash occurrence likelihood (COL) using the I-880 data. To remedy the data limitations and the methodological shortcomings suffered by previous studies, a multiresolution data processing method is proposed and implemented, upon which binary logistic models were developed. The major findings of this paper are: 1) traffic conditions have significant impacts on COL at the study site; Specifically, COL in a congested (transitioning) traffic flow is about 6 (1.6) times of that in a free flow condition; 2)Speed variance alone is not sufficient to capture traffic dynamics’ impact on COL; a traffic chaos indicator that integrates speed, speed variance, and flow is proposed and shows a promising performance; 3) Models based on aggregated data shall be interpreted with caution. Generally, conclusions obtained from such models shall not be generalized to individual vehicles (drivers) without further evidences using high-resolution data and it is dubious to either claim or disclaim speed kills based on aggregated data.

Combination of MEK-ERK inhibitor and hyaluronic acid has a synergistic effect on anti-hypertrophic and pro-chondrogenic activities in osteoarthritis treatment

We hypothesised that a potentially disease-modifying osteoarthritis (OA) drug such as hyaluronic acid (HA) given in combination with anti-inflammatory signalling agents such as mitogen-activated protein kinase kinase–extracellular signal-regulated kinase (MEK-ERK) signalling inhibitor (U0126) could result in additive or synergistic effects on preventing the degeneration of articular cartilage. Chondrocyte differentiation and hypertrophy were evaluated using human OA primary cells treated with either HA or U0126, or the combination of HA + U0126. Cartilage degeneration in menisectomy (MSX) induced rat OA model was investigated by intra-articular delivery of either HA or U0126, or the combination of HA + U0126. Histology, immunostaining, RT-qPCR, Western blotting and zymography were performed to assess the expression of cartilage matrix proteins and hypertrophic markers. Phosphorylated ERK (pERK)1/2-positive chondrocytes were significantly higher in OA samples compared with those in healthy control suggesting the pathological role of that pathway in OA. It was noted that HA + U0126 significantly reduced the levels of pERK, chondrocyte hypertrophic markers (COL10 and RUNX2) and degenerative markers (ADAMTs5 and MMP-13), however, increased the levels of chondrogenic markers (COL2) compared to untreated or the application of HA or U0126 alone. In agreement with the results in vitro, intra-articular delivery of HA + U0126 showed significant therapeutic improvement of cartilage in rat MSX OA model compared with untreated or the application of HA or U0126 alone. Our study suggests that the combination of HA and MEK-ERK inhibition has a synergistic effect on preventing cartilage degeneration.

Photocatalytic reduction of carbon dioxide to formic acid, formaldehyde, and methanol using dye-sensitized TiO2 film

A bifunctionalized TiO2 film containing a dye-sensitized zone and a catalysis zone is designed for visible-light photocatalytic reduction of CO2 to chemicals continuously. Charge separation can be accomplished with electron transferring to catalysis zone and positive charge transforming to anode. Highly efficient conversion of CO2 to formic acid, formaldehyde, and methanol is achieved through the transferring electrons on conduction bands (CB) of TiO2. Reduction of CO2 and O2 evolution take place in separated solutions on different catalysts. The separated solution carried out in this photo-reactor system can avoid CO2 reduction products being oxidized by anode. The yields of reduction products were enhanced remarkably by external electrical power. This study provides not only a new photocatalytic system but also a potential of renewable energy source via carbon dioxide.

Social media metrics : are we measuring business value?

Over the past few years many organizations that directly or indirectly interact with consumers have invested heavily into a social media presence. As a consequence some success indicators are openly available to users of many social media platforms, such as the number of fans (or followers, members, visitors and others) or the amount of content(tweets, images, shares or other content). Many organizations additionally track their social activities internally to understand audience reach, consumer influence, brand image, consumer preference or other key metrics that make sense for a business. However, most of the immediately available social media success metrics are activity-based and many organizations are struggling with establishing a direct relationship to business success. This paper systematically reviews some of the common social media metrics/ratings used by organisations, critically analyse its business value and identify gaps formulating research questions for empirical study and concluding with recommendations and suggestions for future research.

Agility : customer's perspective

In competitive environments agility is emerging as an important determinant of success. Despite the widely accepted importance of agility there has been paucity in research on this construct, especially the customer’s perspective of agility. Rise of digital natives together with growth of ubiquitous information systems has changed the way firms engage with their customers. Firms are finding it difficult to establish sustained loyalty hence the long term sustained advantage over competition. Hence, firms are increasingly investing substantial resources on dynamic Customer Relationship Management systems such as mobile-CRMS to better engage with customers to sense and respond quickly (Agility of the firm) to their demands. This paper investigates firm’s customer agility from customer’s perspective, and we propose a model to understand firm’s customer agility from customer’s point of view. The proposed model is derived based on previous conceptions of agility and the expectation confirmation theory (ECT). This paper reports the initial findings of this study obtained through a pilot test. The findings of the study demonstrate that customer’s view point on firm’s customer agility is an important determinant of achieving success through sustained competitive advantage.

Digital social signal processing - theorectical underpinning and research agenda

Organizations make increasingly use of social media in order to compete for customer awareness and improve the quality of their goods and services. Multiple techniques of social media analysis are already in use. Nevertheless, theoretical underpinnings and a sound research agenda are still unavailable in this field at the present time. In order to contribute to setting up such an agenda, we introduce digital social signal processing (DSSP) as a new research stream in IS that requires multi-facetted investigations. Our DSSP concept is founded upon a set of four sequential activities: sensing digital social signals that are emitted by individuals on social media; decoding online data of social media in order to reconstruct digital social signals; matching the signals with consumers’ life events; and configuring individualized goods and service offerings tailored to the individual needs of customers. We further contribute to tying loose ends of different research areas together, in order to frame DSSP as a field for further investigation. We conclude with developing a research agenda.

Employees' adoption of enterprise web 2.0 : the role of technological attributes

Although the adoption of Enterprise Web 2.0 within organisations is beneficial, it could meet with employees’ resistance and the adoption process can be lengthy. The successful implementation of Enterprise Web 2.0 is based on employee involvement and adoption of such social technology. This paper is part of a larger research project that explored the adoption of Web 2.0 by individuals within enterprises. Using a qualitative study, the findings show that there are number of adoption influences including technological, individual and contextual issues. This paper presents Web 2.0 technological attributes that influence its adoption. The found attributes are: friendliness, reliability, mobility, technical compatibility, discoverability, transparency and Web 2.0 type.

Measuring IS-support : a conceptual model

This paper reports on a conceptual model of a larger research effort proceeding from a central interest in the importance of assessing the IS-Support provided to key-user groups. This study conceptualised a new multidimensional IS-Support construct with four dimensions: training, documentation, assistance and authorisation, which form the overarching construct – IS-Support. We argue that a holistic measure for assessing IS-Support should consist of dimensions, and measures, that together assess the variety of the support provided to IS key-user groups. The proposed IS-Support construct is defined as the support the IS key-user groups receive to increase their capabilities in utilising information systems within the organisation. With two interrelated phases, conceptualisation phase and validation phase, to rigorously hypothesise and validate a measurement model, the IS-Support model, proposed in this study, is intended to include the characteristics of analytic theory.