Molecular mechanisms underpinning IFN-gamma and TNF-alpha synergy in intestinal epithelial cells

Cytokine-driven signalling shapes immune homeostasis and guides inflammatory responses mainly through induction of specific gene expression programmes both within and outside the immune cell compartment. These transcriptional outputs are often amplified via cytokine synergy, which sets a stimulatory threshold that safeguards from exacerbated inflammation and immunopathology. In this study, we investigated the molecular mechanisms underpinning synergy between two pivotal Th1 cytokines, IFN-γ and TNF-α, in human intestinal epithelial cells. These two proinflammatory mediators induce a unique state of signalling and transcriptional synergy implicated in processes such as antiviral and antitumour immunity, intestinal barrier and pancreatic β-cell dysfunction. Since its discovery more than 30 years ago, this biological phenomenon remains, however, only partially defined. Here, using a functional genomics approach including RNAi perturbation screens and small-molecule inhibitors, we identified two new regulators of IFN-γ/TNF-α-induced chemokine and antiviral gene and protein expression, a Bcl-2 protein BCL-G and a histone demethylase UTX. We also discovered that IFN-γ/TNF-α synergise to trigger a coordinated shutdown of major receptor tyrosine kinases expression in colon cancer cells. Together, these findings extend our current understanding of how IFN-γ/TNF-α synergy elicits qualitatively and quantitatively distinct outputs in the intestinal epithelium. Given the well-documented role of this synergistic state in immunopathology of various disorders, our results may help to inform the identification of high quality and biologically relevant druggable targets for diseases characterised by an IFN-γ/TNF-α high immune signature

Traceable Radiometry Underpinning Terrestrial- and Helio-Studies (truths)

The Traceable Radiometry Underpinning Terrestrial- and Helio- Studies (TRUTHS) mission offers a novel approach to the provision of key scientific data with unprecedented radiometric accuracy for Earth Observation (EO) and solar studies, which will also establish well-calibrated reference targets/standards to support other EO missions. This paper presents the TRUTHS mission and its objectives. TRUTHS will be the first satellite mission to calibrate its EO instrumentation directly to SI in orbit, overcoming the usual uncertainties associated with drifts of sensor gain and spectral shape by using an electrical rather than an optical standard as the basis of its calibration. The range of instruments flown as part of the payload will also provide accurate input data to improve atmospheric radiative transfer codes by anchoring boundary conditions, through simultaneous measurements of aerosols, particulates and radiances at various heights. Therefore, TRUTHS will significantly improve the performance and accuracy of EO missions with broad global or operational aims, as well as more dedicated missions. The provision of reference standards will also improve synergy between missions by reducing errors due to different calibration biases and offer cost reductions for future missions by reducing the demands for on-board calibration systems. Such improvements are important for the future success of strategies such as Global Monitoring for Environment and Security (GMES) and the implementation and monitoring of international treaties such as the Kyoto Protocol. TRUTHS will achieve these aims by measuring the geophysical variables of solar and lunar irradiance, together with both polarised and unpolarised spectral radiance of the Moon, Earth and its atmosphere.

Revealing and quantifying the impaired phonological analysis underpinning impaired comprehension in Wernicke’s aphasia

Wernicke’s aphasia is a condition which results in severely disrupted language comprehension following a lesion to the left temporo-parietal region. A phonological analysis deficit has traditionally been held to be at the root of the comprehension impairment in WA, a view consistent with current functional neuroimaging which finds areas in the superior temporal cortex responsive to phonological stimuli. However behavioural evidence to support the link between a phonological analysis deficit and auditory comprehension has not been yet shown. This study extends seminal work by Blumstein et al. (1977) to investigate the relationship between acoustic-phonological perception, measured through phonological discrimination, and auditory comprehension in a case series of Wernicke’s aphasia participants. A novel adaptive phonological discrimination task was used to obtain reliable thresholds of the phonological perceptual distance required between nonwords before they could be discriminated. Wernicke’s aphasia participants showed significantly elevated thresholds compared to age and hearing matched control participants. Acoustic-phonological thresholds correlated strongly with auditory comprehension abilities in Wernicke’s aphasia. In contrast, nonverbal semantic skills showed no relationship with auditory comprehension. The results are evaluated in the context of recent neurobiological models of language and suggest that impaired acoustic-phonological perception underlies the comprehension impairment in Wernicke’s aphasia and favour models of language which propose a leftward asymmetry in phonological analysis.

The integration of proteomics and systems approaches to map regulatory mechanisms underpinning platelet function.

Platelets in the circulation are triggered by vascular damage to activate, aggregate and form a thrombus that prevents excessive blood loss. Platelet activation is stringently regulated by intracellular signalling cascades, which when activated inappropriately lead to myocardial infarction and stroke. Strategies to address platelet dysfunction have included proteomics approaches which have lead to the discovery of a number of novel regulatory proteins of potential therapeutic value. Global analysis of platelet proteomes may enhance the outcome of these studies by arranging this information in a contextual manner that recapitulates established signalling complexes and predicts novel regulatory processes. Platelet signalling networks have already begun to be exploited with interrogation of protein datasets using in silico methodologies that locate functionally feasible protein clusters for subsequent biochemical validation. Characterization of these biological systems through analysis of spatial and temporal organization of component proteins is developing alongside advances in the proteomics field. This focused review highlights advances in platelet proteomics data mining approaches that complement the emerging systems biology field. We have also highlighted nucleated cell types as key examples that can inform platelet research. Therapeutic translation of these modern approaches to understanding platelet regulatory mechanisms will enable the development of novel anti-thrombotic strategies.

Investigating mechanisms underpinning the detrimental impact of a high-fat diet in the developing and adult hypermuscular myostatin null mouse

Background: Obese adults are prone to develop metabolic and cardiovascular diseases. Furthermore, over-weight expectant mothers give birth to large babies who also have increased likelihood of developing metabolic and cardiovascular diseases. Fundamental advancements to better understand the pathophysiology of obesity are critical in the development of anti-obesity therapies not only for this but also future generations. Skeletal muscle plays a major role in fat metabolism and much work has focused in promoting this activity in order to control the development of obesity. Research has evaluated myostatin inhibition as a strategy to prevent the development of obesity and concluded in some cases that it offers a protective mechanism against a high-fat diet. Results: We hypothesised that myostatin inhibition should protect not only the mother but also its developing foetus from the detrimental effects of a high-fat diet. Unexpectedly, we found muscle development was attenuated in the foetus of myostatin null mice raised on a high-fat diet. We therefore re-examined the effect of the high-fat diet on adults and found myostatin null mice were more susceptible to diet-induced obesity through a mechanism involving impairment of inter-organ fat utilization. Conclusions: Loss of myostatin alters fatty acid uptake and oxidation in skeletal muscle and liver. We show that abnormally high metabolic activity of fat in myostatin null mice is decreased by a high-fat diet resulting in excessive adipose deposition and lipotoxicity. Collectively, our genetic loss-of-function studies offer an explanation of the lean phenotype displayed by a host of animals lacking myostatin signalling. Keywords: Muscle, Obesity, High-fat diet, Metabolism, Myostatin

Coupling between respiratory and sympathetic activities as a novel mechanism underpinning neurogenic hypertension

Enhanced sympathetic outflow to the heart and resistance vessels greatly contributes to the onset and maintenance of neurogenic hypertension. There is a consensus that the development of hypertension (clinical and experimental) is associated with an impairment of sympathetic reflex control by arterial baroreceptors. More recently, chronic peripheral chemoreflex activation, as observed in obstructive sleep apnea, has been proposed as another important risk factor for hypertension. In this review, we present and discuss recent experimental evidence showing that changes in the respiratory pattern, elicited by chronic intermittent hypoxia, play a key role in increasing sympathetic activity and arterial pressure in rats. This concept parallels results observed in other models of neurogenic hypertension, such as spontaneously hypertensive rats and rats with angiotensin II–salt-induced hypertension, pointing out alterations in the central coupling of respiratory and sympathetic activities as a novel mechanism underlying the development of neurogenic hypertension.

Unified underpinning of human mobility in the real world and cyberspace

Acknowledgments This work is supported by National Science Foundation of China (Grant No. 61573064, 61074116 and 11547188), the Youth Scholars Program of Beijing Normal University (grant No. 2014NT38), and the Fundamental Research Funds for the Central Universities Beijing Nova Programme, China. XYY acknowledges the support from the National Natural Science Foundation of China (Grant No. 61304177) and the Fundamental Research Funds of BJTU (Grant No. 2015RC042).

Concerning the house museum and the picturesque landscape in the work of Sir John Soane : with raw hints for post-heritage museum space

The picturesque aesthetic in the work of Sir John Soane, architect and collector, resonates in the major work of his very personal practice – the development of his house museum, now the Soane Museum in Lincoln’s Inn Fields in London. Soane was actively involved with the debates, practices and proponents of picturesque and classical practices in architecture and landscape and his lectures reveal these influences in the making of The Soane, which was built to contain and present diverse collections of classical and contemporary art and architecture alongside scavenged curiosities. The Soane Museum has been described as a picturesque landscape, where a pictorial style, together with a carefully defined itinerary, has resulted in the ‘apotheosis of the Picturesque interior’. Soane also experimented with making mock ruinscapes within gardens, which led him to construct faux architectures alluding to archaeological practices based upon the ruin and the fragment. These ideas framed the making of interior landscapes expressed through spatial juxtapositions of room and corridor furnished with the collected object that characterise The Soane Museum. This paper is a personal journey through the Museum which describes and then reviews aspects of Soane’s work in the context of contemporary theories on ‘new’ museology. It describes the underpinning picturesque practices that Soane employed to exceed the boundaries between interior and exterior landscapes and the collection. It then applies particular picturesque principles drawn from visiting The Soane to a speculative project for a house/landscape museum for the Oratunga historic property in outback South Australia, where the often, normalising effects of conservation practices are reviewed using minimal architectural intervention through a celebration of ruinous states.

Measuring the use of information and communication technologies (ICTs) in the classroom

In 2003, the “ICT Curriculum Integration Performance Measurement Instrument” was developed froman extensive review ofthe contemporary international and Australian research pertaining to the definition and measurement of ICT curriculum integration in classrooms (Proctor, Watson, & Finger, 2003). The 45-item instrument that resulted was based on theories and methodologies identified by the literature review. This paper describes psychometric results from a large-scale evaluation of the instrument subsequently conducted, as recommended by Proctor, Watson, and Finger (2003). The resultant 20-item, two-factor instrument, now called “Learning with ICTs: Measuring ICT Use in the Curriculum,” is both statistically and theoretically robust. This paper should be read in association with the original paper published in Computers in the Schools(Proctor, Watson, & Finger, 2003) that described in detail the theoretical framework underpinning the development of the instrument.

Discussion Paper : Proposed CDIO Standard 13 - Internationalisation and Mobility

The benefits and growing need for international transparency in engineering qualifications, simple cross-credit processes, international dual awards and mechanisms to encourage student mobility, are receiving much attention around the world at present. In response, there are a number of global initiatives now looking at how these issues may be addressed, particularly in Europe, North America and Australia. CDIO has adopted 12 Standards as guiding principles for program reform and evaluation. The 12 CDIO Standards address program philosophy curriculum development, design-build experiences and workspaces, new methods of teaching and learning, faculty/academic development, and assessment and evaluation. However, none of the Standards address international qualifications nor student mobility. This discussion paper presents the underpinning case for introducing the 13th CDIO Standard, Internationalization and Mobility.

There is nothing that 'identifies me to that place' : Aboriginal Women's perceptions of health spaces and places

There is a growing body of literature within social and cultural geography that explores notions of place, space, culture, race and identity. The more recent works suggest that places are experienced and understood in multiple ways and are embedded within an array of politics. Memmott and Long, who have undertaken place-based research with Australian Indigenous people, present the theoretical position that ‘place is made and takes on meaning through an interaction process involving mutual accommodation between people and the environment’. They outline that places and their cultural meanings are generated through one or a combination of three types of people–environment interactions. These include: a place that is created by altering the physical characteristics of a piece of environment and which might encompass a feature or features which are natural or made; a place that is created totally through behaviour that is carried out within a specific area, therefore that specific behaviour becomes connected to that specific place; and a place created by people moving or being moved from one environment to another and establishing a new place where boundaries are created and activities carried out. All these ideas of places are challenged and confirmed by what Indigenous women have said about their particular use of, and relationship with, space within several health services in Rockhampton, Central Queensland. As my title suggests, Indigenous women do not see themselves as ‘neutral’ or ‘non-racialised’ citizens who enter and ‘use’ a supposedly neutral health service. Instead, Aboriginal women demonstrate they are active recognisers of places that would identify them within the particular health place. That is, they as Aboriginal women didn’t just ‘make’ place, the places and spaces ‘make’ them. The health services were identified as sites within which spatial relations could begin to grow with recognition of themselves as Aboriginal women in place, or instead create a sense of marginality in the failure of the spaces to identify them. The women’s voices within this paper are drawn from interviews undertaken with twenty Aboriginal women in Rockhampton, Central Queensland, Australia, who participated in a research project exploring ‘how the relationship between health services and Aboriginal women can be more empowering from the viewpoints of Aboriginal women’. The assumption underpinning this study was that empowering and re-empowering practices for Aboriginal women can lead to improved health outcomes. Throughout the interviews women shared some of their lived realities including some of their thoughts on identity, the body, employment in the health sector, service delivery and their notions of health service spaces and places. Their thoughts on health service spaces and places provide an understanding of the lived reality for Aboriginal women and are explored and incorporated within this paper.

The PG500 series : novel heparan sulfate mimetics as potent angiogenesis and heparanase inhibitors for cancer therapy

Heparan sulfate mimetics, which we have called the PG500 series, have been developed to target the inhibition of both angiogenesis and heparanase activity. This series extends the technology underpinning PI-88, a mixture of highly sulfated oligosaccharides which reached Phase III clinical development for hepatocellular carcinoma. Advances in the chemistry of the PG500 series provide numerous advantages over PI-88. These new compounds are fully sulfated, single entity oligosaccharides attached to a lipophilic moiety, which have been optimized for drug development. The rational design of these compounds has led to vast improvements in potency compared to PI-88, based on in vitro angiogenesis assays and in vivo tumor models. Based on these and other data, PG545 has been selected as the lead clinical candidate for oncology and is currently undergoing formal preclinical development as a novel treatment for advanced cancer.