TRIB2 in human AML: a biological and clinical investigation

Acute myeloid leukemia (AML) involves the proliferation, abnormal survival and arrest of cells at a very early stage of myeloid cell differentiation. The biological and clinical heterogeneity of this disease complicates treatment and highlights the significance of understanding the underlying causes of AML, which may constitute potential therapeutic targets, as well as offer prognostic information. Tribbles homolog 2 (Trib2) is a potent murine oncogene capable of inducing transplantable AML with complete penetrance. The pathogenicity of Trib2 is attributed to its ability to induce proteasomal degradation of the full length isoform of the transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα p42). The role of TRIB2 in human AML cells, however, has not been systematically investigated or targeted. Across human cancers, TRIB2 oncogenic activity was found to be associated with its elevated expression. In the context of AML, TRIB2 overexpression was suggested to be associated with the large and heterogeneous subset of cytogenetically normal AML patients. Based upon the observation that overexpression of TRIB2 has a role in cellular transformation, the effect of modulating its expression in human AML was examined in a human AML cell line that expresses high levels of TRIB2, U937 cells. Specific suppression of TRIB2 led to impaired cell growth, as a consequence of both an increase in apoptosis and a decrease in cell proliferation. Consistent with these in vitro results, TRIB2 silencing strongly reduced progression of the U937 in vivo xenografts, accompanied by detection of a lower spleen weight when compared with mice transplanted with TRIB2- expressing control cells. Gene expression analysis suggested that TRIB2 modulates apoptosis and cell-cycle sensitivity by influencing the expression of a subset of genes known to have implications on these phenotypes. Furthermore, TRIB2 was found to be expressed in a significant subset of AML patient samples analysed. To investigate whether increased expression of this gene could be afforded prognostic significance, primary AML cells with dichotomized levels of TRIB2 transcripts were evaluated in terms of their xenoengraftment potential, an assay reported to correlate with disease aggressiveness observed in humans. A small cohort of analysed samples with higher TRIB2 expression did not associate with preferential leukaemic cell engraftment in highly immune-deficient mice, hence, not predicting for an adverse prognosis. However, further experiments including a larger cohort of well characterized AML patients would be needed to clarify TRIB2 significance in the diagnostic setting. Collectively, these data support a functional role for TRIB2 in the maintenance of the oncogenic properties of human AML cells and suggest TRIB2 can be considered a rational therapeutic target. Proteasome inhibition has emerged as an attractive target for the development of novel anti-cancer therapies and results from translational research and clinical trials support the idea that proteasome inhibitors should be considered in the treatment of AML. The present study argued that proteasome inhibition would effectively inhibit the function of TRIB2 by abrogating C/EBPα p42 protein degradation and that it would be an effective pharmacological targeting strategy in TRIB2-positive AMLs. Here, a number of cell models expressing high levels of TRIB2 were successfully targeted by treatment with proteasome inhibitors, as demonstrated by multiple measurements that included increased cytotoxicity, inhibition of clonogenic growth and anti-AML activity in vivo. Mechanistically, it was shown that block of the TRIB2 degradative function led to an increase of C/EBPα p42 and that response was specific to the TRIB2-C/EBPα axis. Specificity was addressed by a panel of experiments showing that U937 cells (express detectable levels of endogenous TRIB2 and C/EBPα) treated with the proteasome inhibitor bortezomib (Brtz) displayed a higher cytotoxic response upon TRIB2 overexpression and that ectopic expression of C/EBPα rescued cell death. Additionally, in C/EBPα-negative leukaemia cells, K562 and Kasumi 1, Brtz-induced toxicity was not increased following TRIB2 overexpression supporting the specificity of the compound on the TRIB2-C/EBPα axis. Together these findings provide pre-clinical evidence that TRIB2- expressing AML cells can be pharmacologically targeted with proteasome inhibition due, in part, to blockage of the TRIB2 proteolytic function on C/EBPα p42. A large body of evidence indicates that AML arises through the stepwise acquisition of genetic and epigenetic changes. Mass spectrometry data has identified an interaction between TRIB2 and the epigenetic regulator Protein Arginine Methyltransferase 5 (PRMT5). Following assessment of TRIB2‟s role in AML cell survival and effective targeting of the TRIB2-C/EBPα degradation pathway, a putative TRIB2/PRMT5 cooperation was investigated in order to gain a deeper understanding of the molecular network in which TRIB2 acts as a potent myeloid oncogene. First, a microarray data set was interrogated for PRMT5 expression levels and the primary enzyme responsible for symmetric dimethylation was found to be transcribed at significantly higher levels in AML patients when compared to healthy controls. Next, depletion of PRMT5 in the U937 cell line was shown to reduce the transformative phenotype in the high expressing TRIB2 AML cells, which suggests that PRMT5 and TRIB2 may cooperate to maintain the leukaemogenic potential. Importantly, PRMT5 was identified as a TRIB2-interacting protein by means of a protein tagging approach to purify TRIB2 complexes from 293T cells. These findings trigger further research aimed at understanding the underlying mechanism and the functional significance of this interplay. In summary, the present study provides experimental evidence that TRIB2 has an important oncogenic role in human AML maintenance and, importantly in such a molecularly heterogeneous disease, provides the rational basis to consider proteasome inhibition as an effective targeting strategy for AML patients with high TRIB2 expression. Finally, the identification of PRMT5 as a TRIB2-interacting protein opens a new level of regulation to consider in AML. This work may contribute to our further understanding and therapeutic strategies in acute leukaemias.

Survival, differentiation, and neuroprotective mechanisms of human stem cells complexed with neurotrophin-3-releasing pharmacologically active microcarriers in an ex vivo model of Parkinson's disease

International audience

'Danger Theory: The Link between AIS and IDS?'

Abstract We present ideas about creating a next generation Intrusion Detection System (IDS) based on the latest immunological theories. The central challenge with computer security is determining the difference between normal and potentially harmful activity. For half a century, developers have protected their systems by coding rules that identify and block specific events. However, the nature of current and future threats in conjunction with ever larger IT systems urgently requires the development of automated and adaptive defensive tools. A promising solution is emerging in the form of Artificial Immune Systems (AIS): The Human Immune System (HIS) can detect and defend against harmful and previously unseen invaders, so can we not build a similar Intrusion Detection System (IDS) for our computers? Presumably, those systems would then have the same beneficial properties as HIS like error tolerance, adaptation and self-monitoring. Current AIS have been successful on test systems, but the algorithms rely on self-nonself discrimination, as stipulated in classical immunology. However, immunologist are increasingly finding fault with traditional self-nonself thinking and a new 'Danger Theory' (DT) is emerging. This new theory suggests that the immune system reacts to threats based on the correlation of various (danger) signals and it provides a method of 'grounding' the immune response, i.e. linking it directly to the attacker. Little is currently understood of the precise nature and correlation of these signals and the theory is a topic of hot debate. It is the aim of this research to investigate this correlation and to translate the DT into the realms of computer security, thereby creating AIS that are no longer limited by self-nonself discrimination. It should be noted that we do not intend to defend this controversial theory per se, although as a deliverable this project will add to the body of knowledge in this area. Rather we are interested in its merits for scaling up AIS applications by overcoming self-nonself discrimination problems.

Przestrzenne formy upamiętniania Zagłady

This book is a synthesizing reflection on the Holocaust commemoration, in which space becomes a starting point for discussion. The author understands space primarily as an amalgam of physical and social components, where various commemorative processes may occur. The first part of the book draws attention to the material aspect of space, which determines its character and function. Material culture has been a long ignored and depreciated dimension of human culture in the humanities and social sciences, because it was perceived as passive and fully controlled by human will, and therefore insignificant in the course of social and historical processes. An example of the Nazi system perfectly illustrates how important were the restrictions and prohibitions on the usage of mundane objects, and in general, the whole material culture in relation to macro and micro space management — the state, cities, neighborhoods and houses, but also parks and swimming pools, factories and offices or shops and theaters. The importance of things and space was also clearly visible in exploitative policies present in overcrowded ghettos and concentration and death camps. For this very reason, when we study spatial forms of Holocaust commemoration, it should be acknowledged that the first traces, proofs and mementoes of the murdered were their things. The first "monuments" showing the enormity of the destruction are thus primarily gigantic piles of objects — shoes, glasses, toys, clothes, suitcases, toothbrushes, etc., which together with the extensive camps’ space try to recall the scale of a crime impossible to understand or imagine. The first chapter shows the importance of introducing the material dimension in thinking about space and commemoration, and it ends with a question about one of the key concepts for the book, a monument, which can be understood as both object (singular or plural) and architecture (sculptures, buildings, highways). However, the term monument tends to be used rather in a later and traditional sense, as an architectural, figurative form commemorating the heroic deeds, carved in stone or cast in bronze. Therefore, the next chapter reconstructs this narrower line of thinking, together with a discussion about what form a monument commemorating a subject as delicate and sensitive as the Holocaust should take on. This leads to an idea of the counter-monument, the concept which was supposed to be the answer to the mentioned representational dilemma on the one hand, and which would disassociate it from the Nazi’s traditional monuments on the other hand. This chapter clarifies the counter-monument definition and explains the misunderstandings and confusions generated on the basis of this concept by following the dynamics of the new commemorative form and by investigating monuments from the ‘80s and ‘90s erected in Germany. In the next chapter, I examine various forms of the Holocaust commemoration in Berlin, a city famous for its bold, monumental, and even controversial projects. We find among them the entire spectrum of memorials – big, monumental, and abstract forms, like Peter Eisenman’s Memorial to the Murdered Jews of Europe or Daniel Liebeskind’s Jewish Museum Berlin; flat, invisible, and employing the idea of emptiness, like Christian Boltanski’s Missing House or Micha Ullman’s Book Burning Memorial; the dispersed and decentralized, like Renata Stih and Frieder Schnock’s Memory Places or Gunter Demnig’s Stumbling Blocks. I enrich descriptions of the monuments by signaling at this point their second, extended life, which manifests itself in the alternative modes of (mis)use, consisting of various social activities or artistic performances. The formal wealth of the outlined projects creates a wide panorama of possible solutions to the Holocaust commemoration problems. However, the discussions accompanying the building of monuments and their "future life" after realization emphasize the importance of the social component that permeates the biography of the monument, and therefore significantly influences its foreseen design. The book also addresses the relationship of space, place and memory in a specific situation, when commemoration is performed secretly or remains as unrealized potential. Although place is the most common space associated with memory, today the nature of this relationship changes, and is what indicates popularity and employment of such terms as Marc Augé’s non-places or Pierre Nora’s site of memory. I include and develop these concepts about space and memory in my reflections to describe qualitatively different phenomena occurring in Central and Eastern European countries. These are unsettling places in rural areas like glades or parking lots, markets and playgrounds in urban settings. I link them to the post-war time and modernization processes and call them sites of non-memory and non-sites of memory. Another part of the book deals with a completely different form of commemoration called Mystery of memory. Grodzka Gate - NN Theatre in Lublin initiated it in 2000 and as a form it situates itself closer to the art of theater than architecture. Real spaces and places of everyday interactions become a stage for these performances, such as the “Jewish town” in Lublin or the Majdanek concentration camp. The minimalist scenography modifies space and reveals its previously unseen dimensions, while the actors — residents and people especially related to places like survivors and Righteous Among the Nations — are involved in the course of the show thanks to various rituals and symbolic gestures. The performance should be distinguished from social actions, because it incorporates tools known from religious rituals and art, which together saturate the mystery of memory with an aura of uniqueness. The last discussed commemoration mode takes the form of exposition space. I examine an exhibition concerning the fate of the incarcerated children presented in one of the barracks of the Majdanek State Museum in Lublin. The Primer – Children in Majdanek Camp is unique for several reasons. First, because even though it is exhibited in the camp barrack, it uses a completely different filter to tell the story of the camp in comparison to the exhibitions in the rest of the barracks. For this reason, one experiences immersing oneself in all subsequent levels of space and narrative accompanying them – at first, in a general narrative about the camp, and later in a specifically arranged space marked by children’s experiences, their language and thinking, and hence formed in a way more accessible for younger visitors. Second, the exhibition resigns from didacticism and distancing descriptions, and takes an advantage of eyewitnesses and survivors’ testimonies instead. Third, the exhibition space evokes an aura of strangeness similar to a fairy tale or a dream. It is accomplished thanks to the arrangement of various, usually highly symbolic material objects, and by favoring the fragrance and phonic sensations, movement, while belittling visual stimulations. The exhibition creates an impression of a place open to thinking and experiencing, and functions as an asylum, a radically different form to its camp surrounding characterized by a more overwhelming and austere space.

The Impact of a Simulated Clinical Experience on CEGEP Nursing Students’ Perceptions of Self-Efficacy and Achievement

Abstract : Providing high-quality clinical experiences to prepare students for the complexities of the current health-care system has become a challenge for nurse educators. Additionally, there are concerns that the current model of clinical practice is suboptimal. Consequently, nursing programs have explored the partial replacement of traditional in-hospital clinical experiences with a simulated clinical experience. Despite research demonstrating numerous benefits to students following participation in simulation activities, insufficient research conducted within Québec exists to convince the governing bodies (Ordre des infirmières et des infirmiers du Québec, OIIQ; Ministère de L’Éducation supérieur, de la Recherche, de la Science et de la Technologie) to fully embrace simulation as part of nurse training. The purpose of this study was to examine the use of a simulated clinical experience (SCE) as a viable, partial pedagogical substitute for traditional clinical experience by examining the effects of a SCE on CEGEP nursing students’ perceptions of self-efficacy (confidence), and their ability to achieve course objectives. The findings will contribute new information to the current body of research in simulation. The specific case of obstetrical practice was examined. Based on two sections of the Nursing III-Health and Illness (180-30K-AB) course, the sample was comprised of 65 students (thirty-one students from section 0001 and thirty-four students from section 0002) whose mean age was 24.8 years. With two sections of the course available, the opportunity for comparison was possible. A triangulation mixed method design was used. An adapted version of Ravert’s (2004) Nursing Skills for Evaluation tool was utilized to collect data regarding students’ perceptions of confidence related to the nursing skills required for care of mothers and their newborns. Students’ performance and achievement of course objectives was measured through an Objective Structured Clinical Examination (OSCE) consisting of three marked stations designed to test the theoretical and clinical aspects of course content. The OSCE was administered at the end of the semester following completion of the traditional clinical experience. Students’ qualitative comments on the post -test survey, along with journal entries served to support the quantitative scale evaluation. Two of the twelve days (15 hours) allocated for obstetrical clinical experience were replaced by a SCE (17%) over the course of the semester. Students participated in various simulation activities developed to address a range of cognitive, psychomotor and critical thinking skills. Scenarios incorporating the use of human patient simulators, and designed using the Jeffries Framework (2005), exposed students to the care of families and infants during the perinatal period to both reflect and build upon class and course content in achievement of course objectives and program competencies. Active participation in all simulation activities exposed students to Bandura’s four main sources of experience (mastery experiences, vicarious experiences, social persuasion, and physiologic/emotional responses) to enhance the development of students’ self-efficacy. Results of the pre-test and post-test summative scores revealed a statistically significant increase in student confidence in performing skills related to maternal and newborn care (p < .0001) following participation in the SCE. Confidence pre-test and post-test scores were not affected by the students’ section. Skills related to the care of the post-partum mother following vaginal or Caesarean section delivery showed the greatest change in confidence ratings. OSCE results showed a mean total class score (both sections) of 57.4 (70.0 %) with normal distribution. Mean scores were 56.5 (68.9%) for section 0001 and 58.3 (71.1%) for section 0002. Total scores were similar between sections (p =0.342) based on pairwise comparison. Analysis of OSCE scores as compared to students’ final course grade revealed similar distributions. Finally, qualitative analysis identified how students’ perceived the SCE. Students cited gains in knowledge, development of psychomotor skills and improved clinical judgement following participation in simulation activities. These were attributed to the « hands on » practice obtained from working in small groups, a safe and authentic learning environment and one in which students could make mistakes and correct errors as having the greatest impact on learning through simulation.

Danger theory: the link between AIS and IDS?

We present ideas about creating a next generation Intrusion Detection System (IDS) based on the latest immunological theories. The central challenge with computer security is determining the difference between normal and potentially harmful activity. For half a century, developers have protected their systems by coding rules that identify and block specific events. However, the nature of current and future threats in conjunction with ever larger IT systems urgently requires the development of automated and adaptive defensive tools. A promising solution is emerging in the form of Artificial Immune Systems (AIS): The Human Immune System (HIS) can detect and defend against harmful and previously unseen invaders, so can we not build a similar Intrusion Detection System (IDS) for our computers? Presumably, those systems would then have the same beneficial properties as HIS like error tolerance, adaptation and self-monitoring. Current AIS have been successful on test systems, but the algorithms rely on self-nonself discrimination, as stipulated in classical immunology. However, immunologist are increasingly finding fault with traditional self-nonself thinking and a new ‘Danger Theory’ (DT) is emerging. This new theory suggests that the immune system reacts to threats based on the correlation of various (danger) signals and it provides a method of ‘grounding’ the immune response, i.e. linking it directly to the attacker. Little is currently understood of the precise nature and correlation of these signals and the theory is a topic of hot debate. It is the aim of this research to investigate this correlation and to translate the DT into the realms of computer security, thereby creating AIS that are no longer limited by self-nonself discrimination. It should be noted that we do not intend to defend this controversial theory per se, although as a deliverable this project will add to the body of knowledge in this area. Rather we are interested in its merits for scaling up AIS applications by overcoming self-nonself discrimination problems.

Forensic Injustice: Human Rights, Archival Science and Racialized Feminicide in Guatemala

The call to access and preserve the state records that document crimes committed by the state during Guatemala’s civil war has become an archival imperative entangled with neoliberal human rights discourses of “truth, justice, and memory.” 200,000 people were killed and disappeared in Guatemala’s civil war including acts of genocide in which 85% of massacres involved sexual violence committed against Mayan women. This dissertation argues that in an attempt to tell the official story of the civil war, American Human Rights organizations and academic institutions have constructed a normative identity whose humanity is attached to a scientific and evidentiary value as well as an archival status representing the materiality and institutionality of the record. Consequently, Human Rights discourses grounded in Western knowledges, in particular archival science and law, which prioritize the appearance of truth erase the material and epistemological experience of indigenous women during wartimes. As a result, the subjectivity that has surfaced on the record as most legible has mostly pertained to non-indigenous, middle class, urban, leftist men who were victims of enforced disappearance not genocide. This dissertation investigates this conflicting narrative that remembers a non-indigenous revolutionary masculine hero and grants him justice in human rights courtrooms simply because of a document attesting to his death. A main research question addressed in this project is why the promise of "truth and justice" under the name of human rights becomes a contentious site for gendered indigenous bodies? I conduct a discursive and rhetorical analysis of documentary film, declassified Guatemalan police and military records such as Operation Sofia, a military log known for “documenting the genocide” during rural counterinsurgencies executed by the military. I interrogate the ways in which racialized feminicides or the hyper-sexualized racial violence that has historically dehumanized indigenous women falls outside of discourses of vision constructed by Western positivist knowledges to reinscribe the ideal human right subject. I argue for alternative epistemological frames that recognize genocide as sexualized and gendered structures that have simultaneously produced racialized feminicides in order to disrupt the colonial structures of capitalism, patriarchy and heterosexuality. Ironically, these structures of power remain untouched by the dominant human rights discourse and its academic, NGO, and state collaborators that seek "truth and justice" in post-conflict Guatemala.

Compounds, creativity and complexity in climate change communication: the case of ‘carbon indulgences’

This article deals with climate change from a linguistic perspective. Climate change is an extremely complex issue that has exercised the minds of experts and policy makers with renewed urgency in recent years. It has prompted an explosion of writing in the media, on the internet and in the domain of popular science and literature, as well as a proliferation of new compounds around the word ‘carbon’ as a hub, such as ‘carbon indulgence’, a new compound that will be studied in this article. Through a linguistic analysis of lexical and discourse formations around such ‘carbon compounds’ we aim to contribute to a broader understanding of the meaning of climate change. Lexical carbon compounds are used here as indicators for observing how human symbolic cultures change and adapt in response to environmental threats and how symbolic innovation and transmission occurs.

Structural characterization and comparative analysis of human and piscine cartilage acidic protein (CRTAC1/CRTAC2)

Dissertação de mestrado, Biotecnologia, Faculdade de Ciências e Tecnologia, Universidade do Algarve, 2014

Toxicological impact of JWH-018 and its phase I metabolite N-(3-hydroxypentyl) on human cell lines

"The emergence and abuse of synthetic cannabinoids has been increasing as an alternative to cannabis, mainly among youth. As their appearance on the drug market has been recent, the pharmacological and toxicological profiles of these psychoactive substances are poorly understood. Current studies suggest that they have stronger effects compared to their natural alternatives and their metabolites retain affinity towards CB1 receptors in CNS. Since studies on its toxicological properties are scarce, the effects of the drug in human derived cell lines were investigated. The present study was designed to explore the toxicological impact of parent drug versus phase I metabolites of synthetic cannabinoids on human cells with and without CB1 receptor. The human cell line of neuroblastoma SH-SY5Y and human kidney cell line HEK-293T were exposed to JWH-018 and to its N-(3-hydroxypentyl) metabolite. Cell toxicity was evaluated using the MTT and LDH assay. Additionally, a dual staining methodology with fluorescent Annexin V-FITC and propidium iodide was performed to address the question of whether JWH-018 N-(3-hydroxypentyl) metabolite is inducing cell death through apoptosis or necrosis, in HEK293T and SH-SY5Y cell lines. The obtained results show that JWH-018 does not cause a statistically significant decrease in cell viability, in contrast to its N-(3-hydroxypentyl) metabolite, which at ≥25μM causes a significant decrease in cell viability. Both cell lines are affected by JWH-018 metabolite. Our results point to higher toxicity of JWH-018 metabolite when compared to its parent drug, suggesting a non-CB1 receptor mediated toxicological mechanism. Comparing the results from Annexin V/PI with MTT and LDH assays of SH-SY5Y and HEK293T in the presence of the synthetic cannabinoid metabolite, emerges the picture that cellular viability decreases and associated death is occurring through necrosis."

Effect on the disability index of adult patients with benign paroxysmal positional vertigo using vestibular rehabilitation and human movement

Objective: determine the effect on the disability index of adult patients with benign paroxysmal positional vertigo (BPPV) using vestibular rehabilitation therapy (VRT) and human movement. Subjects: six subjects with an average age of 49.5 ± 14.22 years who have been diagnosed with benign paroxysmal positional vertigo by an otolaryngologist. Instruments: the Dizziness Handicap Inventory and a questionnaire to determine impact on the quality of life of patients with this pathology (Ceballos and Vargas, 2004). Procedure: subjects underwent vestibular therapy for four weeks together with habituation and balance exercises in a semi-supervised manner. Two measurements were performed, one before and one after the vestibular therapy and researchers determined if there was any improvement in the physical, functional, and emotional dimensions. Statistical analysis: descriptive statistics and Student’s t-test of repeated measures were applied to analyze results obtained. Results: significant statistical differences were found in the physical dimension between the pre-test (19.33 ± 4.67 points) and post-test (13 ± 7.24 points) (t = 2.65; p < 0.05).  In contrast, no significant statistical differences were found in the functional (t = 2.44; p>0.05), emotional (t = 2.37; p>0.05) or general dimensions (t = 2.55; p>0.05). Conclusion: vestibular therapy with a semi-supervised human movement program improved the index of disability due to vertigo (physical dimension) in BPPV subjects.

A NATURALISTIC COMPUTATIONAL MODEL OF HUMAN BEHAVIOR IN NAVIGATION AND SEARCH TASKS

Planning, navigation, and search are fundamental human cognitive abilities central to spatial problem solving in search and rescue, law enforcement, and military operations. Despite a wealth of literature concerning naturalistic spatial problem solving in animals, literature on naturalistic spatial problem solving in humans is comparatively lacking and generally conducted by separate camps among which there is little crosstalk. Addressing this deficiency will allow us to predict spatial decision making in operational environments, and understand the factors leading to those decisions. The present dissertation is comprised of two related efforts, (1) a set of empirical research studies intended to identify characteristics of planning, execution, and memory in naturalistic spatial problem solving tasks, and (2) a computational modeling effort to develop a model of naturalistic spatial problem solving. The results of the behavioral studies indicate that problem space hierarchical representations are linear in shape, and that human solutions are produced according to multiple optimization criteria. The Mixed Criteria Model presented in this dissertation accounts for global and local human performance in a traditional and naturalistic Traveling Salesman Problem. The results of the empirical and modeling efforts hold implications for basic and applied science in domains such as problem solving, operations research, human-computer interaction, and artificial intelligence.

Tracing outsideness: young women's institutional journeys and the geographies of closed space

Understanding confinement and its complex workings between individuals and society has been the stated aim of carceral geography and wider studies on detention. This project contributes ethnographic insights from multiple sites of incarceration, working with an under-researched group within confined populations. Focussing on young female detainees in Scotland, this project seeks to understand their experiences of different types of ‘closed’ space. Secure care, prison and closed psychiatric facilities all impact on the complex geographies of these young women’s lives. The fluid but always situated relations of control and care provide the backdrop for their journeys in/out and beyond institutional spaces. Understanding institutional journeys with reference to age and gender allows an insight into the highly mobile, often precarious, and unfamiliar lives of these young women who live on the margins. This thesis employs a mixed-method qualitative approach and explores what Goffman calls the ‘tissue and fabric’ of detention as a complex multi-institutional practice. In order to be able to understand the young women’s gendered, emotional and often repetitive experiences of confinement, analysis of the constitution of ‘closed space’ represents a first step for inquiry. The underlying nature of inner regimes, rules and discipline in closed spaces, provide the background on which confinement is lived, perceived and processed. The second part of the analysis is the exploration of individual experiences ‘on the inside’, ranging from young women’s views on entering a closed institution, the ways in which they adapt or resist the regime, and how they cope with embodied aspects of detention. The third and final step considers the wider context of incarceration by recovering the young women’s journeys through different types of institutional spaces and beyond. The exploration of these journeys challenges and re-develops understandings of mobility and inertia by engaging the relative power of carceral archipelagos and the figure of femina sacra. This project sits comfortably within the field of carceral geography while also pushing at its boundaries. On a conceptual level, a re-engagement with Goffman’s micro-analysis challenges current carceral-geographic theory development. Perhaps more importantly, this project pushes for an engagement with different institutions under the umbrella of carceral geography, thus creating new dialogues on issues like ‘care’ and ‘control’. Finally, an engagement with young women addresses an under-represented population within carceral geography in ways that raise distinctly problematic concerns for academic research and penal policy. Overall, this project aims to show the value of fine grained micro-level research in institutional geographies for extending thinking and understanding about society’s responses to a group of people who live on the margins of social and legal norms.

AD-HOC principles of minimum energy expenditure as corollaries of the constructal law the cases of river basins and human vascular systems

In a recent paper [1] Reis showed that both the principles of extremum of entropy production rate, which are often used in the study of complex systems, are corollaries of the Constructal Law. In fact, both follow from the maximization of overall system conductivities, under appropriate constraints. In this way, the maximum rate of entropy production (MEP) occurs when all the forces in the system are kept constant. On the other hand, the minimum rate of entropy production (mEP) occurs when all the currents that cross the system are kept constant. In this paper it is shown how the so-called principle of "minimum energy expenditure" which is often used as the basis for explaining many morphologic features in biologic systems, and also in inanimate systems, is also a corollary of Bejan's Constructal Law [2]. Following the general proof some cases namely, the scaling laws of human vascular systems and river basins are discussed as illustrations from the side of life, and inanimate systems, respectively.