Investigating the regulation of AMP-activated protein kinase and SNF1

AMP-activated protein kinase (AMPK) has long been known to play a critical role in the maintenance of energy homeostasis through direct interaction with or altering gene and protein expression of key players in diverse metabolic pathways. AMPK has been implicated in a number of diseases with roots in metabolic dysregulation, including obesity, type 2 diabetes and cancer. Elucidating the regulation of AMPK is an important part in understanding the progression of these diseases, and for developing small molecule modulators of AMPK activity which could have therapeutic applications. AMPK activity is determined by the phosphorylation status of T172 in the activation loop of the α subunit kinase domain. Binding of AMP to the γ subunit also increases its activity, primarily by preventing dephosphorylation of T172 but also by direct allosteric activation of the complex. The overall aim of this study was to investigate nucleotide regulation of AMPK. Site-directed mutagenesis studies showed that loss of highly conserved residues in γ1 disrupts regulation of both dephosphorylation and allosteric activation of AMPK by AMP. However, my studies revealed that these mutations do not have site-specific effects. The role of ADP in AMPK regulation was also investigated following the observation that this nucleotide also prevented dephosphorylation and inactivation of AMPK. The action of ADP on AMPK activity was characterised in wild-type complexes and insights from new structures of the active AMPK complex has provided insight into the molecular mechanism underlying AMP/ADP protection and dephosphorylation of T172. The yeast homologue of AMPK, SNF1, plays a central role in responding to glucose limitation and adaption to alternative carbon sources. Recombinant SNF1 complexes were used to show that ADP is the long-sought metabolite responsible for transmitting this low glucose signal and activates SNF1 by a similar mechanism to that seen in AMPK, preventing dephosphorylation and inactivation. Together these studies identify an important activator of both AMPK and SNF1, drawing parallels between these two systems and characterising a highly conserved regulatory mechanism, suggesting that ADP may represent a unifying trigger for activation of AMPK homologues in diverse species. Finally a potential link between AMPK and redox metabolism was identified in the form of NADH, opening new avenues of research in this field

Perpetrators of intimate femicide : a study of forensic records

Includes bibliographical references (leaves 90-96).Intimate femicide is prevalent in South Africa, and represents the lethal end of a continuum of male perpetrated intimate partner violence. For various reasons attention has only begun to be paid to intimate femicide in the last three decades. International research has established existing rates for intimate femicide, mostly in North America and the United Kingdom, and has confirmed that intimate femicide constitutes a unique form of homicide, which does not fit with the established patterns for other forms of homicide. South African studies have predominantly focused on establishing the rate of intimate femicide in the country. This study sought to examine a smaller number of intimate femicides (n=24) within a broader context in order to provide information, not only on the perpetrator and the victim, but also the state and status of their relationship, and to investigate how the perpetrator accounts for the event

Enabling Sustainable Economic Growth in Developing Countries: Targeted Tourism Management in the Caucasus Region

Once declared the “number one economic reformer in the world” by the World Bank, Georgia has yet to live up to the great growth and modernization expectations established during the country’s rampant economic catch-up phase after the Revolution of Roses in 2003. With its rich cultural history, beautiful landscapes, and unparalleled centuries-old customs, Georgia is well set up to benefit from the globally growing tourism industry and has worked with international organizations to craft a comprehensive tourism strategy intended to create foreign interest in the tiny Caucasus nation to help it emerge from the massive shadow cast by its much larger and more prominent neighbor, Turkey. Providing an in-depth analysis of Georgia’s historical and current economic situation, its complicated relations to the Russian Federation, as well as a portrait of its demographic and cultural context as background, this paper takes note of a series of systematic challenges, including but not limited to, the disparity of average labor productivity levels across sectors and the associated imbalance between total employment and economic contribution of different industries, the lack of diversification in the targeted tourism base and the resultingly high sensitivity to regional political tensions, as well as an inequitable education system that fails to efficiently cater to both, individual and national interests. Further, this paper proposes a number of interconnectedly designed solutions to capitalize on the resulting not-yet realized economic potential, most prominently emphasizing the acquisition of new traveler interest through globally targeted marketing strategies relying on the value proposition associated with intangible cultural heritage, the restructuring of the national education system to integrate an international focal point across all school levels and to offer a separate track of vocational training as a foundation for careers in the tourism industry, as well as a modernized approach to data collection and analysis to more effectively extract relevant patterns from tourism flows and the management of heritage sites. It is hoped that the presented insights can assist Georgia to emerge on to a path of sustainable economic growth, in turn generating economic development for the local population and helping the country establish itself as a global player in the post-pandemic world’s tourism industry

An Investigation into the Management of Natural Heritage Sites

UNESCO currently oversees the preservation of 209 Natural Heritage sites around the globe which have been selected based on their irreplaceability and their testament to nature’s astounding ecological diversity. It is the mission of the Natural Heritage Convention to preserve their beauty for future generations while making it universally accessible to present ones. In a time when the tourism industry is blossoming more than ever before, this double mission naturally poses the challenge of balancing the benefits and potential threats of increased tourism to Natural Heritage sites. This paper examines the regulations governing the operation of Natural Heritage properties and assesses relevant data on the efficiency of the Natural Heritage Programme as a whole. Realizing that more than three quarters of Natural Heritage sites struggle with problems relating to management, it is concluded that there are two major areas for improvement if it is the goal to increase the sites’ capacity in entertaining tourist visits and capturing their value without sacrificing the preservation of the sites in the process: standardization of management processes and controlled tourism development. The solutions suggested in this paper aim to incorporate the respective local communities into the future operation of Natural Heritage sites, promoting economic growth and development in otherwise often underdeveloped areas while allowing for nature’s beauty to be conserved for many generations to come

Technical Supplement for the article A Meta-Analysis of the Correlations Among Broad Intelligences: Understanding their Relations

This technical supplement was developed by the author along with their report, “A eta analysis of the correlations among broad intelligences: Understanding their relations” as part of a single, ongoing research project. The original report provides the general purpose and theoretical overview of the project, as well as the key analyses. This supplement also includes pieces of that material where relevant but focuses on detailing the programming and data analyses of the project to a far greater extent

Análisis de las temperaturas extremas en las Islas Canarias y su relación con los avisos de alertas meteorológicas

Ponencia presentada en: IX Congreso de la Asociación Española de Climatología celebrado en Almería entre el 28 y el 30 de octubre de 2014.[ES]El objetivo del artículo es el análisis de los valores extremos del régimen térmico en el archipiélago canario durante los últimos sesenta años, con el fin de establecer su frecuencia y su relación con los umbrales de avisos de riesgo por calor determinados por la AEMET. Para ello se analizan siete series trabajando (i) el ritmo anual de las temperaturas máximas a través de los calendarios diarios (ii) la duración del calor a partir del análisis de rachas y (iii) la frecuencia y evolución de las noches cálidas tropicales. Los resultados indican que la frecuencia de los días muy calurosos en las islas, por los que hubiese sido necesario emitir avisos por el riesgo que entrañan, es escasa porque no han superado los dos centenares en sesenta años; que su duración no excede de 24 horas, y que son las noches tropicales las que experimentan el mayor incremento, pasando del 12% de las noches del año, en la década de los 50, al 40% en la actualidad. Su frecuencia casi se ha triplicado en ese tiempo.[EN]The aim of this paper is to analyze the extreme values of the thermal regime in the Canary Islands over the last sixty years, in order to establish their frequency and their relationship with the weather warning for high temperatures issued by the Spanish Meteorological Office. The seven available series are analyzed (i) the annual rate of maximum temperatures from the daily calendars (ii) the duration of the heat from the analysis of spells and (iii) the frequency and trends of warm tropical nights. The results indicate that the frequency of very hot days in the Canary Islands, for which it had been necessary to issue warnings about the risk posed, is scarce given that there have been less than two hundred in sixty years, their duration is usually no longer than 24 hours and that it is the tropical nights which have experienced the largest increase, from 12% in the 1950s to 40% of the nights of the year nowadays. One can say that their frequency has nearly tripled in that time

Temporal variations in supraglacial debris distribution on Baltoro Glacier, Karakoram between 2001 and 2012

Distribution of supraglacial debris in a glacier system varies spatially and temporally due to differing rates of debris input, transport and deposition. Supraglacial debris distribution governs the thickness of a supraglacial debris layer, an important control on the amount of ablation that occurs under such a debris layer. Characterising supraglacial debris layer thickness on a glacier is therefore key to calculating ablation across a glacier surface. The spatial pattern of debris thickness on Baltoro Glacier has previously been calculated for one discrete point in time (2004) using satellite thermal data and an empirically based relationship between supraglacial debris layer thickness and debris surface temperature identified in the field. Here, the same empirically based relationship was applied to two further datasets (2001, 2012) to calculate debris layer thickness across Baltoro Glacier for three discrete points over an 11-year period (2001, 2004, 2012). Surface velocity and sediment flux were also calculated, as well as debris thickness change between periods. Using these outputs, alongside geomorphological maps of Baltoro Glacier produced for 2001, 2004 and 2012, spatiotemporal changes in debris distribution for a sub-decadal timescale were investigated. Sediment flux remained constant throughout the 11-year period. The greatest changes in debris thickness occurred along medial moraines, the locations of mass movement deposition and areas of interaction between tributary glaciers and the main glacier tongue. The study confirms the occurrence of spatiotemporal changes in supraglacial debris layer thickness on sub-decadal timescales, independent of variation in surface velocity. Instead, variation in rates of debris distribution are primarily attributed to frequency and magnitude of mass movement events over decadal timescales, with climate, regional uplift and erosion rates expected to control debris inputs over centurial to millennial timescales. Inclusion of such spatiotemporal variations in debris thickness in distributed surface energy balance models would increase the accuracy of calculated ablation, leading to a more accurate simulation of glacier mass balance through time, and greater precision in quantification of the response of debris-covered glaciers to climatic change

A multicenter study of Clostridium difficile infection-related colectomy, 2000-2006

BACKGROUND: The incidence of Clostridium difficile infection (CDI) has been increasing. Previous studies report that the number of colectomies for CDI is also rising. Outside of a few notable outbreaks, there are few published data documenting increasing severity of CDI. The specific aims of this multiyear, multicenter study were to assess CDI-related colectomy rates and compare CDI-related colectomy rates by CDI surveillance definition. METHODS: Cases of CDI and patients who underwent colectomy were identified electronically from 5 US tertiary-care centers from July 2000 through June 2006. Chart review was performed to determine if a colectomy was for CDI. Monthly CDI-related colectomy rates were calculated as the number of CDI-related colectomies per 1,000 CDI cases. Data between observational groups were compared using χ(2) and Mann-Whitney U tests. Logistic regression was performed to evaluate risk factors for CDI-related colectomy. RESULTS: 8569 cases of CDI were identified and 75 patients had CDI-related colectomy. The overall colectomy rate was 8.7/1,000 CDI cases. The CDI-related colectomy rate ranged from 0 to 23 per 1,000 CDI episodes across hospitals. The colectomy rates for healthcare facility (HCF)-onset CDI was 4.3/1000 CDI cases and 16.5 /1000 CDI cases for community-onset CDI (p <.05). There were significantly more CDI-related colectomies at hospitals B and C (p<.05). CONCLUSIONS: The overall CDI-related colectomy rate was low, and there was no significant change in the CDI-related colectomy rate over time. Onset of disease outside of the study hospital was an independent risk factor for colectomy

Detailed Annotations of Chest X-Rays via CT Projection for Report Understanding

In clinical radiology reports, doctors capture important information about the patient's health status. They convey their observations from raw medical imaging data about the inner structures of a patient. As such, formulating reports requires medical experts to possess wide-ranging knowledge about anatomical regions with their normal, healthy appearance as well as the ability to recognize abnormalities. This explicit grasp on both the patient's anatomy and their appearance is missing in current medical image-processing systems as annotations are especially difficult to gather. This renders the models to be narrow experts e.g. for identifying specific diseases. In this work, we recover this missing link by adding human anatomy into the mix and enable the association of content in medical reports to their occurrence in associated imagery (medical phrase grounding). To exploit anatomical structures in this scenario, we present a sophisticated automatic pipeline to gather and integrate human bodily structures from computed tomography datasets, which we incorporate in our PAXRay: A Projected dataset for the segmentation of Anatomical structures in X-Ray data. Our evaluation shows that methods that take advantage of anatomical information benefit heavily in visually grounding radiologists' findings, as our anatomical segmentations allow for up to absolute 50% better grounding results on the OpenI dataset as compared to commonly used region proposals. The PAXRay dataset is available at https://constantinseibold.github.io/paxray/.Comment: 33rd British Machine Vision Conference (BMVC 2022

Deposition of impurity metals during campaigns with the JET ITER-like Wall

Post mortem analysis shows that mid and high atomic number metallic impurities are present in deposits on JET plasma facing components with the highest amount of Ni and W, and therefore the largest sink, being found at the top of the inner divertor. Sources are defined as “continuous” or “specific”, in that “continuous” sources arise from ongoing erosion from plasma facing surfaces and “specific” are linked with specific events which decrease over time until they no longer act as a source. This contribution evaluates the sinks and estimates sources, and the balance gives an indication of the dominating processes. Charge exchange neutral erosion is found to be the main source of nickel, whereas erosion of divertor plasma facing components is the main source of tungsten. Specific sources are shown to have little influence over the global mid- and high-Z impurity concentrations in deposits.Peer reviewe