A carbamazepine-indomethacin (1:1) cocrystal produced by milling

An X-ray amorphous mixture of carbamazepine and indomethacin transforms upon annealing to produce a novel 1:1 cocrystal, whose structure has been determined from laboratory powder X-ray diffraction (PXRD) data.

Riluzole neuroprotection in a parkinson’s disease model involves suppression of reactive astrocytosis but not GLT-1 regulation

Background Riluzole is a neuroprotective drug used in the treatment of motor neurone disease. Recent evidence suggests that riluzole can up-regulate the expression and activity of the astrocyte glutamate transporter, GLT-1. Given that regulation of glutamate transport is predicted to be neuroprotective in Parkinson's disease, we tested the effect of riluzole in parkinsonian rats which had received a unilateral 6-hydroxydopamine injection into the median forebrain bundle. Results Rats were treated with intraperitoneal riluzole (4 mg/kg or 8 mg/kg), 1 hour before the lesion then once daily for seven days. Riluzole produced a modest but significant attenuation of dopamine neurone degeneration, assessed by suppression of amphetamine-induced rotations, preservation of tyrosine hydroxylase positive neuronal cell bodies in the substantia nigra pars compacta and attenuation of striatal tyrosine hydroxylase protein loss. Seven days after 6-hydroxydopamine lesion, reactive astrocytosis was observed in the striatum, as determined by increases in expression of glial fibrillary acidic protein, however the glutamate transporter, GLT-1, which is also expressed in astrocytes was not regulated by the lesion. Conclusions The results confirm that riluzole is a neuroprotective agent in a rodent model of parkinson’s disease. Riluzole administration did not regulate GLT-1 levels but significantly reduced GFAP levels, in the lesioned striatum. Riluzole suppression of reactive astrocytosis is an intriguing finding which might contribute to the neuroprotective effects of this drug.

Feedback regulation by Atf3 in the endothelin-1-responsive transcriptome of cardiomyocytes: Egr1 is a principal Atf3 target

Endothelin-1 promotes cardiomyocyte hypertrophy by inducing changes in gene expression. Immediate early genes including activating transcription factor 3 (Atf3), Egr1 and Ptgs2 are rapidly and transiently upregulated by endothelin-1 in cardiomyocytes. Atf3 regulates expression of downstream genes and is implicated in negative feedback regulation of other immediate early genes. To identify Atf3-regulated genes, we knocked down Atf3 expression in cardiomyocytes exposed to endothelin-1 and used microarrays to interrogate the transcriptomic effects. Of upregulated mRNAs, expression of 23 (including Egr1, Ptgs2) was enhanced and expression of 25 was inhibited by Atf3 knockdown. Using quantitative PCR, we determined that knockdown of Atf3 had little effect on upregulation of Egr1 mRNA over 30 min, but abolished the subsequent decline, causing sustained Egr1 mRNA expression and enhanced protein expression. This resulted from direct binding of Atf3 to the Egr1 promoter. Mathematical modelling established that Atf3 can suffice to suppress Egr1 expression. Given the widespread co-regulation of Atf3 with Egr1, we suggest that the Atf3-Egr1 negative feedback loop is of general significance. Loss of Atf3 caused abnormal cardiomyocyte growth, presumably resulting from dysregulation of target genes. Our data therefore identify Atf3 as a nexus in cardiomyocyte hypertrophy required to facilitate the full and proper growth response.

Mid-term evaluation of African Technology Policy Studies Network Phase VI Strategic Plan: for the period January 1, 2009 to December 31, 2010

The African Technology Policy Studies Network (ATPS) is a multidisciplinary network of researchers, private sector actors, policymakers and civil society. ATPS has the vision to become the leading international centre of excellence and reference in science, technology and innovation (STI) systems research, training and capacity building, communication and sensitization, knowledge brokerage, policy advocacy and outreach in Africa. It has a Regional Secretariat in Nairobi Kenya, and operates through national chapters in 29 countries (including 27 in Africa and two Chapters in the United Kingdom and USA for Africans in the Diaspora) with an expansion plan to cover the entire continent by 2015. The ATPS Phase VI Strategic Plan aims to improve the understanding and functioning of STI processes and systems to strengthen the learning capacity, social responses, and governance of STI for addressing Africa's development challenges, with a specific focus on the Millennium Development Goals (MDGs). A team of external evaluators carried out a midterm review to assess the effectiveness and efficiency of the implementation of the Strategic Plan for the period January 1, 2009 to December 31, 2010. The evaluation methodology involved multiple quantitative and qualitative methods to assess the qualitative and quantitative inputs (human resources, financial resources, time, etc.) into ATPS activities (both thematic and facilitative) and their tangible and intangible outputs, outcomes and impacts. Methods included a questionnaire survey of ATPS members and stakeholders, key informant interviews, and focus group discussions (FGDs) with members in six countries. Effectiveness of Programmes Under all six strategic goals, very good progress has been made towards planned outputs and outcomes. This is evidenced by key performance indicators (KPIs) generated from desk review, ratings from the survey respondents, and the themes that run through the FGDs. Institutional and Programme Cost Effectiveness Institutional Effectiveness: assessment of institutional effectiveness suggests that adequate management frameworks are in place and are being used effectively and transparently. Also technical and financial accounting mechanisms are being followed in accordance with grant agreements and with global good practice. This is evidenced by KPIs generated from desk review. Programme Cost Effectiveness: assessment of cost-effectiveness of execution of programmes shows that organisational structure is efficient, delivering high quality, relevant research at relatively low cost by international standards. The evidence includes KPIs from desk review: administrative costs to programme cost ratio has fallen steadily, to around 10%; average size of research grants is modest, without compromising quality. There is high level of pro bono input by ATPS members. ATPS Programmes Strategic Evaluation ATPS research and STI related activities are indeed unique and well aligned with STI issues and needs facing Africa and globally. The multi-disciplinary and trans-boundary nature of the research activities are creating a unique group of research scientists. The ATPS approach to research and STI issues is paving the way for the so called Third Generation University (3GU). Understanding this unique positioning, an increasing number of international multilateral agencies are seeking partnership with ATPS. ATPS is seeing an increasing level of funding commitments by Donor Partners. Recommendations for ATPS Continued Growth and Effectiveness On-going reform of ATPS administrative structure to continue The on-going reforms that have taken place within the Board, Regional Secretariat, and at the National Chapter coordination levels are welcomed. Such reform should continue until fully functional corporate governance policy and practices are fully established and implemented across the ATPS governance structures. This will further strengthen ATPS to achieve the vision of being the leading STI policy brokerage organization in Africa. Although training in corporate governance has been carried out for all sectors of ATPS leadership structure in recent time, there is some evidence that these systems have not yet been fully implemented effectively within all the governance structures of the organization, especially at the Board and National chapter levels. Future training should emphasize practical application with exercises relevant to ATPS leadership structure from the Board to the National Chapter levels. Training on Transformational Leadership - Leading a Change Though a subject of intense debate amongst economists and social scientists, it is generally agreed that cultural mindsets and attitudes could enhance and/or hinder organizational progress. ATPS’s vision demands transformational leadership skills amongst its leaders from the Board members to the National Chapter Coordinators. To lead such a change, ATPS leaders must understand and avoid personal and cultural mindsets and value systems that hinder change, while embracing those that enhance it. It requires deliberate assessment of cultural, behavioural patterns that could hinder progress and the willingness to be recast into cultural and personal habits that make for progress. Improvement of relationship amongst the Board, Secretariat, and National Chapters A large number of ATPS members and stakeholders feel they do not have effective communications and/or access to Board, National Chapter Coordinators and Regional Secretariat activities. Effort should be made to improve the implementation of ATPS communication strategy to improve on information flows amongst the ATPS management and the members. The results of the survey and the FGDs suggest that progress has been made during the past two years in this direction, but more could be done to ensure effective flow of pertinent information to members following ATPS communications channels. Strategies for Increased Funding for National Chapters There is a big gap between the fundraising skills of the Regional Secretariat and those of the National Coordinators. In some cases, funds successfully raised by the Secretariat and disbursed to national chapters were not followed up with timely progress and financial reports by some national chapters. Adequate training in relevant skills required for effective interactions with STI key policy players should be conducted regularly for National Chapter coordinators and ATPS members. The ongoing training in grant writing should continue and be made continent-wide if funding permits. Funding of National Chapters should be strategic such that capacity in a specific area of research is built which, with time, will not only lead to a strong research capacity in that area, but also strengthen academic programmes. For example, a strong climate change programme is emerging at University of Nigeria Nsukka (UNN), with strong collaborations with Universities from neighbouring States. Strategies to Increase National Government buy-in and support for STI Translating STI research outcomes into policies requires a great deal of emotional intelligence, skills which are often lacking in the first and second generation universities. In the epoch of the science-based or 2GUs, governments were content with universities carrying out scientific research and providing scientific education. Now they desire to see universities as incubators of new science- or technology-based commercial activities, whether by existing firms or start-ups. Hence, governments demand that universities take an active and leading role in the exploitation of their knowledge and they are willing to make funds available to support such activities. Thus, for universities to gain the attention of national leadership they must become centres of excellence and explicit instruments of economic development in the knowledge-based economy. The universities must do this while working collaboratively with government departments, parastatals, and institutions and dedicated research establishments. ATPS should anticipate these shifting changes and devise programmes to assist both government and universities to relate effectively. New administrative structures in member organizations to sustain and manage the emerging STI multidisciplinary teams Second Generation universities (2GUs) tend to focus on pure science and often do not regard the application of their know-how as their task. In contrast, Third Generation Universities (3GUs) objectively stimulate techno-starters – students or academics – to pursue the exploitation or commercialisation of the knowledge they generate. They view this as being equal in importance to the objectives of scientific research and education. Administratively, research in the 2GU era was mainly monodisciplinary and departments were structured along disciplines. The emerging interdisciplinary scientific teams with focus on specific research areas functionally work against the current mono-disciplinary faculty-based, administrative structure of 2GUs. For interdisciplinary teams, the current faculty system is an obstacle. There is a need for new organisational forms for university management that can create responsibilities for the task of know-how exploitation. ATPS must anticipate this and begin to strategize solutions for their member institutions to transition to 3Gus administrative structure, otherwise ATPS growth will plateau, and progress achieved so far may be stunted.

Effects of gelation temperature on the Mozzarella-type curd made from buffalo and cows’ milk. 1: Rheology & microstructure

The rheology and microstructure of Mozzarella-type curds made from buffalo and cows’ milk were measured at gelation temperatures of 28, 34 and 39 °C after chymosin addition. The maximum curd strength (G′) was obtained at a gelation temperature of 34 °C in both types of bovine milk. The viscoelasticity (tan δ) of both curds was increased with increasing gelation temperature. The rennet coagulation time was reduced with increase of gelation temperature in both types of milk. Frequency sweep data (0.1–10Hz was recorded 90 min after chymosin addition, and both milk samples showed characteristics of weak viscoelastic gel systems. When both milk samples were subjected to shear stress to break the curd system at constant shear rate, 95 min after chymosin addition, the maximum yield stress was obtained at the gelation temperatures of 34 °C and 28 °C in buffalo and cows’ curd respectively. The cryo-SEM and CLSM techniques were used to observe the microstructure of Mozzarella-type curd. The porosity was measured using image J software. The cryo-SEM and CLSM micrographs showed that minimum porosity was observed at the gelation temperature of 34 °C in both types of milk. Buffalo curd showed minimum porosity at similar gelation temperature when compared to cows’ curd. This may be due to higher protein concentration in buffalo milk.

Mozzarella-type curd made from buffalo, cows’ and ultrafiltered cows’ milk. 1. Rheology and microstructure

Rennet-induced curd was made from both natural buffalo and cows’ milk, and ultrafiltered cows’ milk (cows’ milk was concentrated such that it had a chemical composition approximately equivalent to that of the buffalo milk). These milk samples were compared on the basis of their rheology, physicochemical characteristics and curd microstructure. The ionic and soluble calcium contents were found to be similar in all milk samples studied. The total and casein bound calcium were higher in concentrated cows’ milk than in standard cows’ milk. Both cows’ milk types were found to have lower total and casein bound calcium than the buffalo milk. This is probably due to concentration of the colloidal part of milk (casein), during the ultrafiltration (UF) process. The rennet coagulation time was similar in UF cows’ and buffalo milk while both were shorter when compared with that of the cows’ milk. The dynamic moduli (G′, G″) values were higher in both the buffalo and UF cows’ milk than in the cows’ milk after 90 min coagulation. The loss tangent, however, was found to be similar in both the UF cows’ and buffalo milk curds and was lower than that observed for the cows’ milk (0.42, 0.42 and 0.48, respectively). The frequency profile of each type of curd was recorded 90 min after the enzyme addition (0.1–10 Hz); all samples were found to be “weak” viscoelastic, frequency dependent gels. The yield stress was also measured 95 min after the enzyme addition, and a higher value was observed in buffalo milk curd when compared with other curd samples made from both the natural cows’ milk and the UF cows’ milk. The cryo-scanning electron and confocal laser scanning micrographs showed that curd structure appeared to be more “dense” and less porous in buffalo milk than cows’ milk even after concentration to equivalent levels of protein/total solids to those found in the buffalo milk.

Transports and budgets in a 1/4 ° global ocean reanalysis 1989–2010

Large-scale ocean transports of heat and freshwater have not been well monitored, and yet the regional budgets of these quantities are important to understanding the role of the oceans in climate and climate change. In contrast, atmospheric heat and freshwater transports are commonly assessed from atmospheric reanalysis products, despite the presence of non-conserving data assimilation based on the wealth of distributed atmospheric observations as constraints. The ability to carry out ocean reanalyses globally at eddy-permitting resolutions of 1/4 ° or better, along with new global ocean observation programs, now makes a similar approach viable for the ocean. In this paper we examine the budgets and transports within a global high resolution ocean model constrained by ocean data assimilation, and compare them with independent oceanic and atmospheric estimates.

MYOD-1 in normal colonic mucosa - role as a putative biomarker?

Background DNA methylation of promoter-associated CpG islands of certain genes may play a role in the development of colorectal cancer. The MYOD-1 gene which is a muscle differentiation gene has been showed to be significantly methylated in colorectal cancer which, is an age related event. However the role of this gene in the colonic mucosa is not understood and whether methylation occurs in subjects without colon cancer. In this study, we have determined the frequency of methylation of the MYOD-1 gene in normal colonic mucosa and investigated to see if this is associated with established colorectal cancer risk factors primarily ageing. Results We analysed colonic mucosal biopsies in 218 normal individuals and demonstrated that in most individuals promoter hypermethylation was not quantified for MYOD-1. However, promoter hypermethylation increased significantly with age (p < 0.001 using regression analysis) and this was gender independent. We also showed that gene promoter methylation increased positively with an increase in waist to hip (WHR) ratio - the latter is also a known risk factor for colon cancer development. Conclusions Our study suggests that promoter gene hypermethylation of the MYOD-1 gene increases significantly with age in normal individuals and thus may offer potential as a putative biomarker for colorectal cancer.

The role of phase separation and feed cycle length in leach beds coupled to methanogenic reactors for digestion of a solid substrate (Part 1): Optimisation of reactors’ performance

A two-phase system composed by a leach bed and a methanogenic reactor was modified for the first time to improve volumetric substrate degradation and methane yields from a complex substrate (maize; Zea mays). The system, which was operated for consecutive feed cycles of different durations for 120 days, was highly flexible and its performance improved by altering operational conditions. Daily substrate degradation was higher the shorter the feed cycle, reaching 8.5 g TSdestroyed d�1 (7-day feed cycle) but the overall substrate degradation was higher by up to 55% when longer feed cycles (14 and 28 days) were applied. The same occurred with volumetric methane yields, reaching 0.839 m3 (m3)�1 d�1. The system performed better than others on specific methane yields, reaching 0.434 m3 kg�1 TSadded, in the 14-day and 28-day systems. The UASB and AF designs performed similarly as second stage reactors on methane yields, SCOD and VFA removal efficiencies.

Observational tracking of the 2D structure of coronal mass ejections between the sun and 1 AU

The Solar TErrestrial RElations Observatory (STEREO) provides high cadence and high resolution images of the structure and morphology of coronal mass ejections (CMEs) in the inner heliosphere. CME directions and propagation speeds have often been estimated through the use of time-elongation maps obtained from the STEREO Heliospheric Imager (HI) data. Many of these CMEs have been identified by citizen scientists working within the SolarStormWatch project ( www.solarstormwatch.com ) as they work towards providing robust real-time identification of Earth-directed CMEs. The wide field of view of HI allows scientists to directly observe the two-dimensional (2D) structures, while the relative simplicity of time-elongation analysis means that it can be easily applied to many such events, thereby enabling a much deeper understanding of how CMEs evolve between the Sun and the Earth. For events with certain orientations, both the rear and front edges of the CME can be monitored at varying heliocentric distances (R) between the Sun and 1 AU. Here we take four example events with measurable position angle widths and identified by the citizen scientists. These events were chosen for the clarity of their structure within the HI cameras and their long track lengths in the time-elongation maps. We show a linear dependency with R for the growth of the radial width (W) and the 2D aspect ratio (χ) of these CMEs, which are measured out to ≈ 0.7 AU. We estimated the radial width from a linear best fit for the average of the four CMEs. We obtained the relationships W=0.14R+0.04 for the width and χ=2.5R+0.86 for the aspect ratio (W and R in units of AU).

Platelet endothelial cell adhesion molecule-1 signaling inhibits the activation of human platelets

Platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) is a 130-kd transmembrane glycoprotein and a member of the growing family of receptors with immunoreceptor tyrosine-based inhibitory motifs (ITIMs). PECAM-1 is expressed on platelets, certain T cells, monocytes, neutrophils, and vascular endothelial cells and is involved in a range of cellular processes, though the role of PECAM-1 in platelets is unclear. Cross-linking of PECAM-1 results in phosphorylation of the ITIM allowing the recruitment of signaling proteins that bind by way of Src-homology domain 2 interactions. Proteins that have been implicated in the negative regulation of cellular activation by ITIM-bearing receptors include the tyrosine phosphatases SHP-1 and SHP-2. Tyrosine phosphorylation of immunoreceptor tyrosine-based activatory motif (ITAM)-bearing receptors such as the collagen receptor GPVI-Fc receptor gamma-chain complex on platelets leads to activation. Increasing evidence suggests that ITIM- and ITAM-containing receptors may act antagonistically when expressed on the same cell. In this study it is demonstrated that cross-linking PECAM-1 inhibits the aggregation and secretion of platelets in response to collagen and the GPVI-selective agonist convulxin. In these experiments thrombin-mediated platelet aggregation and secretion were also reduced, albeit to a lesser degree than for collagen, suggesting that PECAM-1 function may not be restricted to the inhibition of ITAM-containing receptor pathways. PECAM-1 activation also inhibited platelet protein tyrosine phosphorylation stimulated by convulxin and thrombin; this was accompanied by inhibition of the mobilization of calcium from intracellular stores. These data suggest that PECAM-1 may play a role in the regulation of platelet function in vivo.

Hankel and Toeplitz transforms on H 1: continuity, compactness and Fredholm properties

We revisit the boundedness of Hankel and Toeplitz operators acting on the Hardy space H 1 and give a new proof of the old result stating that the Hankel operator H a is bounded if and only if a has bounded logarithmic mean oscillation. We also establish a sufficient and necessary condition for H a to be compact on H 1. The Fredholm properties of Toeplitz operators on H 1 are studied for symbols in a Banach algebra similar to C + H ∞ under mild additional conditions caused by the differences in the boundedness of Toeplitz operators acting on H 1 and H 2.

The role of protein hydrophobicity in thionin–phospholipid interactions: a comparison of α1 and α2-purothionin adsorbed anionic phospholipid monolayers

The plant defence proteins α1- and α2-purothionin (Pth) are type 1 thionins from common wheat (Triticum aestivum). These highly homologous proteins possess characteristics common amongst antimicrobial peptides and proteins, that is, cationic charge, amphiphilicity and hydrophobicity. Both α1- and α2-Pth possess the same net charge, but differ in relative hydrophobicity as determined by C18 reversed phase HPLC. Brewster angle microscopy, X-ray and neutron reflectometry, external reflection FTIR and associated surface pressure measurements demonstrated that α1 and α2-Pth interact strongly with condensed phase 1,2-dipalmitoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (DPPG) monolayers at the air/liquid interface. Both thionins disrupted the in-plane structure of the anionic phospholipid monolayer, removing lipid during this process and both penetrated the lipid monolayer in addition to adsorbing as a single protein layer to the lipid head-group. However, analysis of the interfacial structures revealed that the α2-Pth showed faster disruption of the lipid film and removed more phospholipid (12%) from the interface than α1-Pth. Correlating the protein properties and lipid binding activity suggests that hydrophobicity plays a key role in the membrane lipid removal activity of thionins.

GTP binding and intramolecular regulation by the ROC domain of Death Associated Protein Kinase 1

The ROCO proteins are a family of large, multidomain proteins characterised by the presence of a Ras of complex proteins (ROC) domain followed by a COR, or C-terminal of ROC, domain. It has previously been shown that the ROC domain of the human ROCO protein Leucine Rich Repeat Kinase 2 (LRRK2) controls its kinase activity. Here, the ability of the ROC domain of another human ROCO protein, Death Associated Protein Kinase 1 (DAPK1), to bind GTP and control its kinase activity has been evaluated. In contrast to LRRK2, loss of GTP binding by DAPK1 does not result in loss of kinase activity, instead acting to modulate this activity. These data highlight the ROC domain of DAPK1 as a target for modifiers of this proteins function, and casts light on the role of ROC domains as intramolecular regulators in complex proteins with implications for a broad range of human diseases.