Interacting Turing-Hopf Instabilities Drive Symmetry-Breaking Transitions in a Mean-Field Model of the Cortex: A Mechanism for the Slow Oscillation

Electrical recordings of brain activity during the transition from wake to anesthetic coma show temporal and spectral alterations that are correlated with gross changes in the underlying brain state. Entry into anesthetic unconsciousness is signposted by the emergence of large, slow oscillations of electrical activity (≲1  Hz) similar to the slow waves observed in natural sleep. Here we present a two-dimensional mean-field model of the cortex in which slow spatiotemporal oscillations arise spontaneously through a Turing (spatial) symmetry-breaking bifurcation that is modulated by a Hopf (temporal) instability. In our model, populations of neurons are densely interlinked by chemical synapses, and by interneuronal gap junctions represented as an inhibitory diffusive coupling. To demonstrate cortical behavior over a wide range of distinct brain states, we explore model dynamics in the vicinity of a general-anesthetic-induced transition from “wake” to “coma.” In this region, the system is poised at a codimension-2 point where competing Turing and Hopf instabilities coexist. We model anesthesia as a moderate reduction in inhibitory diffusion, paired with an increase in inhibitory postsynaptic response, producing a coma state that is characterized by emergent low-frequency oscillations whose dynamics is chaotic in time and space. The effect of long-range axonal white-matter connectivity is probed with the inclusion of a single idealized point-to-point connection. We find that the additional excitation from the long-range connection can provoke seizurelike bursts of cortical activity when inhibitory diffusion is weak, but has little impact on an active cortex. Our proposed dynamic mechanism for the origin of anesthetic slow waves complements—and contrasts with—conventional explanations that require cyclic modulation of ion-channel conductances. We postulate that a similar bifurcation mechanism might underpin the slow waves of natural sleep and comment on the possible consequences of chaotic dynamics for memory processing and learning

Novel urinary biomarkers for the detection of bladder cancer: A systematic review

BACKGROUND: Urinary biomarkers for the diagnosis of bladder cancer represents an area of considerable research which has been tested in both patients presenting with haematuria and non-muscle invasive bladder cancer patients requiring surveillance cystoscopy. In this systematic review, we identify and appraise the diagnostic sensitive and specificity of reported novel biomarkers of different 'omic' class and highlight promising biomarkers investigated to date. METHODS: A MEDLINE/Pubmed systematic search was performed between January 2013 and July 2017 using the following keywords: (bladder cancer OR transitional cell carcinoma OR urothelial cell carcinoma) AND (detection OR diagnosis) AND urine AND (biomarker OR assay). All studies had a minimum of 20 patients in both bladder cancer and control arms and reported sensitivity and/or specificity and/or receiver operating characteristics (ROC) curve. QUADAS-2 tool was used to assess risk of bias and applicability of studies. The search protocol was registered in the PROSPERO database (CRD42016049918). RESULTS: Systematic search yielded 115 reports were included for analysis. In single target biomarkers had a sensitivity of 2-94%, specificity of 46-100%, positive predictive value (PPV) of 47-100% and negative predictive value (NPV) of 21-94%. Multi-target biomarkers achieved a sensitivity of 24-100%, specificity of 48-100%, PPV of 42-95% and NPV of 32-100%. 50 studies achieved a sensitivity and specificity of ≥80%. Protein (n = 59) and transcriptomic (n = 21) biomarkers represents the most studied biomarkers. Multi-target biomarker panels had a better diagnostic accuracy compared to single biomarker targets. Urinary cytology with urinary biomarkers improved the diagnostic ability of the biomarker. The sensitivity and specificity of biomarkers were higher for primary diagnosis compared to patients in the surveillance setting. Most studies were case control studies and did not have a predefined threshold to determine a positive test result indicating a possible risk of bias. CONCLUSION: This comprehensive systematic review provides an update on urinary biomarkers of different 'omic' class and highlights promising biomarkers. Few biomarkers achieve a high sensitivity and negative predictive value. Such biomarkers will require external validation in a prospective observational setting before adoption in clinical practice

Geographic Coincidence of Increased Malaria Transmission Hazard and Vulnerability Occurring at the Periphery of two Tanzanian Villages.

The goal of malaria elimination necessitates an improved understanding of any fine-scale geographic variations in transmission risk so that complementary vector control tools can be integrated into current vector control programmes as supplementary measures that are spatially targeted to maximize impact upon residual transmission. This study examines the distribution of host-seeking malaria vectors at households within two villages in rural Tanzania. Host-seeking mosquitoes were sampled from 72 randomly selected households in two villages on a monthly basis throughout 2008 using CDC light-traps placed beside occupied nets. Spatial autocorrelation in the dataset was examined using the Moran's I statistic and the location of any clusters was identified using the Getis-Ord Gi* statistic. Statistical associations between the household characteristics and clusters of mosquitoes were assessed using a generalized linear model for each species. For both Anopheles gambiae sensu lato and Anopheles funestus, the density of host-seeking females was spatially autocorrelated, or clustered. For both species, houses with low densities were clustered in the semi-urban village centre while houses with high densities were clustered in the periphery of the villages. Clusters of houses with low or high densities of An. gambiae s.l. were influenced by the number of residents in nearby houses. The occurrence of high-density clusters of An. gambiae s.l. was associated with lower elevations while An. funestus was also associated with higher elevations. Distance from the village centre was also positively correlated with the number of household occupants and having houses constructed with open eaves. The results of the current study highlight that complementary vector control tools could be most effectively targeted to the periphery of villages where the households potentially have a higher hazard (mosquito densities) and vulnerability (open eaves and larger households) to malaria infection

Choosing party leaders: Anglophone democracies, British parties and the limits of comparative politics

Since 1965, Britain’s major political parties have radically, and repeatedly, changed the ways in which they choose their leaders. Building on a recent comparative study of party leadership selection in the five principal Anglophone (‘Westminster’) parliamentary democracies (Cross and Blais, 2012a), this article first outlines a theoretical framework that purports to explain why the major parties in three of those countries, including Britain, have adopted such reform. It then examines why five major British parties have done so since 1965. It argues that, while Cross and Blais’ study makes a significant contribution to our knowledge and understanding of processes of party leadership selection reform in Anglophone parliamentary democracies, it has limited explanatory power when applied to changes enacted by the major parties in modern and contemporary Britain. Instead, the adoption of such reform in the British context is ultimately best understood and explained by examining both the internal politics and external circumstances of individual parties

Metal-macrofauna interactions determine microbial community structure and function in copper contaminated sediments

Peer reviewedPublisher PD

Ecology: a prerequisite for malaria elimination and eradication

* Existing front-line vector control measures, such as insecticide-treated nets and residual sprays, cannot break the transmission cycle of Plasmodium falciparum in the most intensely endemic parts of Africa and the Pacific * The goal of malaria eradication will require urgent strategic investment into understanding the ecology and evolution of the mosquito vectors that transmit malaria * Priority areas will include understanding aspects of the mosquito life cycle beyond the blood feeding processes which directly mediate malaria transmission * Global commitment to malaria eradication necessitates a corresponding long-term commitment to vector ecolog

Entomological Surveillance of Behavioural Resilience and Resistance in Residual Malaria Vector Populations.

The most potent malaria vectors rely heavily upon human blood so they are vulnerable to attack with insecticide-treated nets (ITNs) and indoor residual spraying (IRS) within houses. Mosquito taxa that can avoid feeding or resting indoors, or by obtaining blood from animals, mediate a growing proportion of the dwindling transmission that persists as ITNs and IRS are scaled up. Increasing frequency of behavioural evasion traits within persisting residual vector systems usually reflect the successful suppression of the most potent and vulnerable vector taxa by IRS or ITNs, rather than their failure. Many of the commonly observed changes in mosquito behavioural patterns following intervention scale-up may well be explained by modified taxonomic composition and expression of phenotypically plastic behavioural preferences, rather than altered innate preferences of individuals or populations. Detailed review of the contemporary evidence base does not yet provide any clear-cut example of true behavioural resistance and is, therefore, consistent with the hypothesis presented. Caution should be exercised before over-interpreting most existing reports of increased frequency of behavioural traits which enable mosquitoes to evade fatal contact with insecticides: this may simply be the result of suppressing the most behaviourally vulnerable of the vector taxa that constituted the original transmission system. Mosquito taxa which have always exhibited such evasive traits may be more accurately described as behaviourally resilient, rather than resistant. Ongoing national or regional entomological monitoring surveys of physiological susceptibility to insecticides should be supplemented with biologically and epidemiologically meaningfully estimates of malaria vector population dynamics and the behavioural phenotypes that determine intervention impact, in order to design, select, evaluate and optimize the implementation of vector control measures

Environmental factors associated with the malaria vectors Anopheles gambiae and Anopheles funestus in Kenya

<p>Abstract</p> <p>Background</p> <p>The <it>Anopheles gambiae </it>and <it>Anopheles funestus </it>mosquito species complexes are the primary vectors of <it>Plasmodium falciparum </it>malaria in sub-Saharan Africa. To better understand the environmental factors influencing these species, the abundance, distribution and transmission data from a south-eastern Kenyan study were retrospectively analysed, and the climate, vegetation and elevation data in key locations compared.</p> <p>Methods</p> <p>Thirty villages in Malindi, Kilifi and Kwale Districts with data on <it>An. gambiae sensu strict</it>, <it>Anopheles arabiensis</it> and <it>An. funestus</it> entomological inoculation rates (EIRs), were used as focal points for spatial and environmental analyses. Transmission patterns were examined for spatial autocorrelation using the Moran's <it>I </it>statistic, and for the clustering of high or low EIR values using the Getis-Ord Gi* statistic. Environmental data were derived from remote-sensed satellite sources of precipitation, temperature, specific humidity, Normalized Difference Vegetation Index (NDVI), and elevation. The relationship between transmission and environmental measures was examined using bivariate correlations, and by comparing environmental means between locations of high and low clustering using the Mann-Whitney <it>U </it>test.</p> <p>Results</p> <p>Spatial analyses indicated positive autocorrelation of <it>An. arabiensis </it>and <it>An. funestus </it>transmission, but not of <it>An. gambiae s.s</it>., which was found to be widespread across the study region. The spatial clustering of high EIR values for <it>An. arabiensis </it>was confined to the lowland areas of Malindi, and for <it>An. funestus </it>to the southern districts of Kilifi and Kwale. Overall, <it>An. gambiae s.s</it>. and <it>An. arabiensis </it>had similar spatial and environmental trends, with higher transmission associated with higher precipitation, but lower temperature, humidity and NDVI measures than those locations with lower transmission by these species and/or in locations where transmission by <it>An. funestus </it>was high. Statistical comparisons indicated that precipitation and temperatures were significantly different between the <it>An. arabiensis </it>and <it>An. funestus </it>high and low transmission locations.</p> <p>Conclusion</p> <p>These finding suggest that the abundance, distribution and malaria transmission of different malaria vectors are driven by different environmental factors. A better understanding of the specific ecological parameters of each malaria mosquito species will help define their current distributions, and how they may currently and prospectively be affected by climate change, interventions and other factors.</p

Heterogeneity of O6-alkylguanine DNA-alkyltransferase expression in human breast tumours

An important determinant of cellular resistance to chemotherapeutic O6-alkylating agents, which comprise methylating and chloroethylating agents, is the ability of cells to repair alkylation damage at the O6-position of guanine in DNA. This is achieved by a specific DNA repair enzyme O6-alkylguanine DNA-alkyltransferase. In this study O6-alkylguanine DNA-alkyltransferase expression was measured in human breast tumours using both biochemical and immunohistochemical techniques. O6-alkylguanine DNA-alkyltransferase activity was then compared with known clinical prognostic indices to assess the potential role of O6-alkylguanine DNA-alkyltransferase in predicting the behaviour of this common malignancy. The application of both biochemical and immunohistochemical techniques was feasible and practical. Most breast tumours expressed high levels of O6-alkylguanine DNA-alkyltransferase. Immunohistochemical analysis showed marked variation in expression not only between individuals but also within individual tumours, and in the same patient, between metastases and between primary tumour and metastatic site. O6-alkylguanine DNA-alkyltransferase activity in tissue extracts significantly correlated not only with immunohistochemical staining intensity determined by subjective quantitation, but also with measures of protein levels using a computerised image analysis system including mean grey (P<0.001), percentage of cells positive for O6-alkylguanine DNA-alkyltransferase (P<0.001), and integrated optical density (P<0.001). O6-alkylguanine DNA-alkyltransferase expression did not correlate with any of the established clinical prognostic indicators for current treatment regimens. However, immunohistochemical offers a rapid and convenient method for assessing potential utility of O6-alkylating agents or O6-alkylguanine DNA-alkyltransferase inactivating agents in future studies of breast cancer treatment

A framework for monitoring the safety of water services: from measurements to security

The sustainable developments goals (SDGs) introduced monitoring of drinking water quality to the international development agenda. At present, Escherichia coli are the primary measure by which we evaluate the safety of drinking water from an infectious disease perspective. Here, we propose and apply a framework to reflect on the purposes of and approaches to monitoring drinking water safety. To deliver SDG 6.1, universal access to safe drinking water, a new approach to monitoring is needed. At present, we rely heavily on single measures of E. coli contamination to meet a normative definition of safety. Achieving and sustaining universal access to safe drinking water will require monitoring that can inform decision making on whether services are managed to ensure safety and security of access