Genes Influencing Circadian Differences in Blood Pressure in Hypertensive Mice

Essential hypertension is a common multifactorial heritable condition in which increased sympathetic outflow from the central nervous system is involved in the elevation in blood pressure (BP), as well as the exaggerated morning surge in BP that is a risk factor for myocardial infarction and stroke in hypertensive patients. The Schlager BPH/2J mouse is a genetic model of hypertension in which increased sympathetic outflow from the hypothalamus has an important etiological role in the elevation of BP. Schlager hypertensive mice exhibit a large variation in BP between the active and inactive periods of the day, and also show a morning surge in BP. To investigate the genes responsible for the circadian variation in BP in hypertension, hypothalamic tissue was collected from BPH/2J and normotensive BPN/3J mice at the ‘peak’ (n = 12) and ‘trough’ (n = 6) of diurnal BP. Using Affymetrix GeneChip® Mouse Gene 1.0 ST Arrays, validation by quantitative real-time PCR and a statistical method that adjusted for clock genes, we identified 212 hypothalamic genes whose expression differed between ‘peak’ and ‘trough’ BP in the hypertensive strain. These included genes with known roles in BP regulation, such as vasopressin, oxytocin and thyrotropin releasing hormone, as well as genes not recognized previously as regulators of BP, including chemokine (C-C motif) ligand 19, hypocretin and zinc finger and BTB domain containing 16. Gene ontology analysis showed an enrichment of terms for inflammatory response, mitochondrial proton-transporting ATP synthase complex, structural constituent of ribosome, amongst others. In conclusion, we have identified genes whose expression differs between the peak and trough of 24-hour circadian BP in BPH/2J mice, pointing to mechanisms responsible for diurnal variation in BP. The findings may assist in the elucidation of the mechanism for the morning surge in BP in essential hypertension

Modeling the pharmacodynamics of passive membrane permeability

Small molecule permeability through cellular membranes is critical to a better understanding of pharmacodynamics and the drug discovery endeavor. Such permeability may be estimated as a function of the free energy change of barrier crossing by invoking the barrier domain model, which posits that permeation is limited by passage through a single “barrier domain” and assumes diffusivity differences among compounds of similar structure are negligible. Inspired by the work of Rezai and co-workers (JACS 128:14073–14080, 2006), we estimate this free energy change as the difference in implicit solvation free energies in chloroform and water, but extend their model to include solute conformational affects. Using a set of eleven structurally diverse FDA approved compounds and a set of thirteen congeneric molecules, we show that the solvation free energies are dominated by the global minima, which allows solute conformational distributions to be effectively neglected. For the set of tested compounds, the best correlation with experiment is obtained when the implicit chloroform global minimum is used to evaluate the solvation free energy difference

Engineering a novel self-powering electrochemical biosensor

This paper records the efforts of a multi-disciplinary team of undergraduate students from Glasgow University to collectively design and carry out a 10 week project in Synthetic Biology as part of the international Genetic Engineered Machine competition (iGEM). The aim of the project was to design and build a self-powering electrochemical biosensor called ‘ElectrEcoBlu’. The novelty of this engineered machine lies in coupling a biosensor with a microbial fuel cell to transduce a pollution input into an easily measurable electrical output signal. The device consists of two components; the sensor element which is modular, allowing for customisation to detect a range of input signals as required, and the universal reporter element which is responsible for generating an electrical signal as an output. The genetic components produce pyocyanin, a competitive electron mediator for microbial fuel cells, thus enabling the generation of an electrical current in the presence of target chemical pollutants. The pollutants tested in our implementation were toluene and salicylate. ElectrEcoBlu is expected to drive forward the development of a new generation of biosensors. Our approach exploited a range of state-of-the-art modelling techniques in a unified framework of qualitative, stochastic and continuous approaches to support the design and guide the construction of this novel biological machine. This work shows that integrating engineering techniques with scientific methodologies can provide new insights into genetic regulation and can be considered as a reference framework for the development of biochemical systems in synthetic biology

Making a Step Forward Towards Urban Resilience. The Contribution of Digital Innovation

Starting from 'wicked problem' theory as the landmark for framing disaster events in terms of policy issue for city governments, this paper highlights the contribution provided by Big Data analytics and digital innovation in dealing with disaster risks. The research aims at answering the following question: what is the role that 'smart technologies' play in strengthening urban resilience to disaster risks

"Courting the multinational": Subnational institutional capacity and foreign market insidership

peer-reviewedSignificant contemporary challenges face an internationalizing firm, including the non-ergodic nature of investment, and the liability of outsidership. Recent revisions to the Uppsala internationalization process model reflect these challenges, whereby “insidership” is represented as realized, successful foreign market entry. Drawing upon socio-spatial concepts from international business and economic geography, this paper demonstrates the endogeneity of subnational institutions in shaping foreign market insidership within an advanced economy. Employing a multi-method research design with almost 60 subnational actors, the role and interaction of subnational institutions within the internationalization process are explored. Our findings illustrate how customized coalitions of subnational institutions effectively initiate, negotiate and accelerate insidership of inward investment within the foreign market both prior to and during formal entry. Key aspects of this dynamic include communicating tangible and intangible locational resources, initiating functional and relevant business relationships, and facilitating access to codified and tacit knowledge. This paper embellishes the Uppsala internationalization process model by demonstrating the capacity of subnational institutions to participate actively with foreign market insidership, and in so doing advances understanding of how the risk and uncertainty associated with foreign market entry are currently navigated.ACCEPTEDpeer-reviewe

Directional RNA deep sequencing sheds new light on the transcriptional response of Anabaena sp. strain PCC 7120 to combined-nitrogen deprivation

Background: Cyanobacteria are potential sources of renewable chemicals and biofuels and serve as model organisms for bacterial photosynthesis, nitrogen fixation, and responses to environmental changes. Anabaena (Nostoc) sp. strain PCC 7120 (hereafter Anabaena) is a multicellular filamentous cyanobacterium that can "fix" atmospheric nitrogen into ammonia when grown in the absence of a source of combined nitrogen. Because the nitrogenase enzyme is oxygen sensitive, Anabaena forms specialized cells called heterocysts that create a microoxic environment for nitrogen fixation. We have employed directional RNA-seq to map the Anabaena transcriptome during vegetative cell growth and in response to combined-nitrogen deprivation, which induces filaments to undergo heterocyst development. Our data provide an unprecedented view of transcriptional changes in Anabaena filaments during the induction of heterocyst development and transition to diazotrophic growth. Results: Using the Illumina short read platform and a directional RNA-seq protocol, we obtained deep sequencing data for RNA extracted from filaments at 0, 6, 12, and 21 hours after the removal of combined nitrogen. The RNA-seq data provided information on transcript abundance and boundaries for the entire transcriptome. From these data, we detected novel antisense transcripts within the UTRs (untranslated regions) and coding regions of key genes involved in heterocyst development, suggesting that antisense RNAs may be important regulators of the nitrogen response. In addition, many 5' UTRs were longer than anticipated, sometimes extending into upstream open reading frames (ORFs), and operons often showed complex structure and regulation. Finally, many genes that had not been previously identified as being involved in heterocyst development showed regulation, providing new candidates for future studies in this model organism. Conclusions: Directional RNA-seq data were obtained that provide comprehensive mapping of transcript boundaries and abundance for all transcribed RNAs in Anabaena filaments during the response to nitrogen deprivation. We have identified genes and noncoding RNAs that are transcriptionally regulated during heterocyst development. These data provide detailed information on the Anabaena transcriptome as filaments undergo heterocyst development and begin nitrogen fixation

Focused Examination of the Intestinal lamina Propria Yields Greater Molecular Insight into Mechanisms Underlying SIV Induced Immune Dysfunction

Background: The Gastrointestinal (GI) tract is critical to AIDS pathogenesis as it is the primary site for viral transmission and a major site of viral replication and CD4 + T cell destruction. Consequently GI disease, a major complication of HIV/SIV infection can facilitate translocation of lumenal bacterial products causing localized/systemic immune activation leading to AIDS progression. Methodology/Principal Findings: To better understand the molecular mechanisms underlying GI disease we analyzed global gene expression profiles sequentially in the intestine of the same animals prior to and at 21 and 90d post SIV infection (PI). More importantly we maximized information gathering by examining distinct mucosal components (intraepithelial lymphocytes, lamina propria leukocytes [LPL], epithelium and fibrovascular stroma) separately. The use of sequential intestinal resections combined with focused examination of distinct mucosal compartments represents novel approaches not previously attempted. Here we report data pertaining to the LPL. A significant increase (61.7-fold) in immune defense/inflammation, cell adhesion/migration, cell signaling, transcription and cell division/differentiation genes were observed at 21 and 90d PI. Genes associated with the JAK-STAT pathway (IL21, IL12R, STAT5A, IL10, SOCS1) and T-cell activation (NFATc1, CDK6, Gelsolin, Moesin) were notably upregulated at 21d PI. Markedly downregulated genes at 21d PI included IL17D/IL27 and IL28B/IFNc3 (anti-HIV/viral), activation induced cytidine deaminase (B-cell function) an

Re-examination of the Controversial Coexistence of Traumatic Brain Injury and Posttraumatic Stress Disorder: Misdiagnosis and Self-Report Measures

The coexistence of traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) remains a controversial issue in the literature. To address this controversy, we focused primarily on the civilian-related literature of TBI and PTSD. Some investigators have argued that individuals who had been rendered unconscious or suffered amnesia due to a TBI are unable to develop PTSD because they would be unable to consciously experience the symptoms of fear, helplessness, and horror associated with the development of PTSD. Other investigators have reported that individuals who sustain TBI, regardless of its severity, can develop PTSD even in the context of prolonged unconsciousness. A careful review of the methodologies employed in these studies reveals that investigators who relied on clinical interviews of TBI patients to diagnose PTSD found little or no evidence of PTSD. In contrast, investigators who relied on PTSD questionnaires to diagnose PTSD found considerable evidence of PTSD. Further analysis revealed that many of the TBI patients who were initially diagnosed with PTSD according to self-report questionnaires did not meet the diagnostic criteria for PTSD upon completion of a clinical interview. In particular, patients with severe TBI were often misdiagnosed with PTSD. A number of investigators found that many of the severe TBI patients failed to follow the questionnaire instructions and erroneously endorsed PTSD symptoms because of their cognitive difficulties. Because PTSD questionnaires are not designed to discriminate between PTSD and TBI symptoms or determine whether a patient's responses are accurate or exaggerated, studies that rely on self-report questionnaires to evaluate PTSD in TBI patients are at risk of misdiagnosing PTSD. Further research should evaluate the degree to which misdiagnosis of PTSD occurs in individuals who have sustained mild TBI