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Accumulation of filamentous aggregates of tau protein in the brain is a pathological hallmark of Alzheimer's disease (AD) and many other neurodegenerative tauopathies. The filaments adopt disease-specific cross-β amyloid conformations that self-propagate and are implicated in neuronal loss. Development of molecular diagnostics and therapeutics is of critical importance. However, mechanisms of small molecule binding to the amyloid core is poorly understood. We used cryo-electron microscopy to determine a 2.7 Å structure of AD patient-derived tau paired-helical filaments bound to the PET ligand GTP-1. The compound is bound stoichiometrically at a single site along an exposed cleft of each protofilament in a stacked arrangement matching the fibril symmetry. Multiscale modeling reveals pi-pi aromatic interactions that pair favorably with the small molecule-protein contacts, supporting high specificity and affinity for the AD tau conformation. This binding mode offers critical insight into designing compounds to target different amyloid folds found across neurodegenerative diseases.

The Administration for Children and Families (ACF) is conducting a new primary data collection about connected child maltreatment data to expand knowledge related to the capacity of administrative data to examine child maltreatment incidence and related risk and protective factors. We define connected data as state child welfare administrative data that are linked or integrated with administrative data from other state or county systems or agencies. The State Child Welfare Data Linkages Descriptive Study (SCW Descriptive Study) will gather systematic information on the extent to which states connect their child maltreatment data to other state and county data sets; how connected data sets are created, managed, and used; and challenges states face in linking data. This information is not available from existing sources. The SCW Descriptive Study aims to provide important information to the field by documenting the capacity of state child welfare agencies to link data sets with data sets from other agencies. This study aims to present an internally valid description of the connected data capacity of participating state child welfare agencies, not to promote statistical generalization to different sites or service populations.

Chronic high-fat diet (HFD) consumption not only promotes obesity and insulin resistance, but also causes bone loss through mechanisms that are not well understood. Here, we fed wild-type CD-1 mice either chow or a HFD (43% of energy from fat) for 18 weeks; HFD-fed mice exhibited decreased trabecular volume (−28%) and cortical thickness (−14%) compared to chow-fed mice. In HFD-fed mice, bone loss was due to reduced bone formation and mineral apposition, without obvious effects on bone resorption. HFD feeding also increased skeletal expression of sclerostin and caused deterioration of the osteocyte lacunocanalicular network (LCN). In mice fed HFD, skeletal glucocorticoid signaling was activated relative to chow-fed mice, independent of serum corticosterone concentrations. We therefore examined whether skeletal glucocorticoid signaling was necessary for HFD-induced bone loss, using transgenic mice lacking glucocorticoid signaling in osteoblasts and osteocytes (HSD2OB/OCY-tg mice). In HSD2OB/OCY-tg mice, bone formation and mineral apposition rates were not suppressed by HFD, and bone loss was significantly attenuated. Interestingly, in HSD2OB/OCY-tg mice fed HFD, both Wnt signaling (less sclerostin induction, increased β-catenin expression) and glucose uptake were significantly increased, relative to diet- and genotype-matched controls. The osteocyte LCN remained intact in HFD-fed HSD2OB/OCY-tg mice. When fed a HFD, HSD2OB/OCY-tg mice also increased their energy expenditure and were protected against obesity, insulin resistance, and dyslipidemia. Therefore, glucocorticoid signaling in osteoblasts and osteocytes contributes to the suppression of bone formation in HFD-fed mice. Skeletal glucocorticoid signaling is also an important determinant of glucose uptake in bone, which influences the whole-body metabolic response to HFD.

This is a protocol for a scoping review.

Adequate cell production for adoptive cell transfer therapies such as Chimeric Antigen Receptor (CAR)-T cell therapy remains a critical barrier to treatment for indications that fail to achieve clinical success. One such disease is Chronic Lymphocytic Leukemia (CLL), a B-cell lymphoma with their characteristically exhausted T cells, marked by a progressive loss of the ability to secrete cytokines and proliferate, as well as an increase in the expression of checkpoint inhibitor molecules such as PD-1. The goal of this thesis is to characterize the functional differences or specific biomarkers within the CLL patient population that is indicative of the proliferation outcomes. Conventional clinical markers such as Rai stage or PD-1 expression alone were inadequate to describe the complex variability among patients. In order to better characterize exhaustion using microscopy-based cell function assays, we developed a sample sparing microscopy chamber that requires as little as 1000 cells per sample. The microscopy chambers were mass produced via injection molding, and made compatible with the antibody microcontact printing technique developed in the Kam lab. The chambers typically reduced cell usage per experiment by 20-fold. This reduction allowed us to measure IL-2 secretion, T cell arrest response to activating antibody patterns (pattern alignment), and motility of scarce human samples simultaneously from a single experiment. Results from these functional readouts along with other clinical markers were used as inputs for a multifactor exploratory analysis to cluster patients according to their functional similarities from the combination of responses in an unbiased manner. The resulting clusters based on the combination of the top 3 parameters IL-2, pattern alignment, and PD-1 resulted in better separation of patient groups and provided a basis for predicting max doubling outcomes from these inputs. We further used motility measurements as a way to understand initial T cell response to activation before the stop response, which was measured as pattern alignment previously. The time it takes for cells to come to a stop at the signal was most informative for translating T cell activation response to a stop response, and eventually to downstream effector functions of cytokine secretion and proliferation. The results of this work provide a powerful framework to describe different donors, and can be applied to cells from additional donors to guide future cell expansion studies.

Haematogenous dissemination of M. tuberculosis (Mtb) is critical to pathogenesis of progressive tuberculous infection in animal models. Using a novel phage-based blood assay, we report the first concordant evidence in well-characterised immunocompetent human cohorts, demonstrating associations of Mtb bacteraemia with progressive phenotypes of latent infection and active pulmonary TB respectively.

In Species of Spaces Georges Perec suggests various ‘Practical exercises’ as a means to investigate the street. The instructions propose its exhaustive exploration through attention to what would be most obvious, common and therefore usually of no interest; to take up this methodology, investigators are told to go about things ‘more slowly, almost stupidly’. As part of his project to reveal and understand the infra-ordinary, in Approaches to what, Perec makes clear that the purpose of such activity is to wrest ‘common things’ from the dross in which they remain mired and to give them a tongue, to ‘speak of what is, of what we are.’ As an artist-scholar researching ‘everyday’ places through essayistic photographic practice, I am drawn to Perec’s specific injunction ‘Force yourself to see more flatly’, which reflects for me photography’s ultimate translation of dimensional space into flat picture plane, and relates to what David Campany has described as modernist photography’s ‘heightened interest in the surfaces of the world’.\ud \ud This contribution emerges from photographic research, which takes up very literally the Perequian practice of seeing flatly, and attending to what is ‘most colourless’: it investigates therefore, via the constraint of black and white image-making, the material surfaces encountered along the 12 minute walk from my home to the tram stop from which I commute to my university job. That Perec makes clear his interest in ‘A town: stone, concrete, asphalt’, and recognises the ‘invisible underground proliferation of conduits’, or the ‘underneath’ of limestone, marl, chalk, gypsum, sand and lignite, encourages me to consider what lies exactly underfoot, passing unremarked on so many daily journeys. This visual essaying of the surface of a place (given that properly speaking an essay is a trial, test or experiment) will be excerpted for the current context, accompanied by a reflection upon Perecquian photographic practice as a method of artistic research, and what a determinedly superficial attention reveals about the infra-ordinariness of place.

The hallmarks of Alzheimer's disease (AD) are the accumulation of Aβ plaques and neurofibrillary tangles composed of hyperphosphorylated tau. We developed sensitive cellular assays using human embryonic kidney-293T cells to quantify intracellular self-propagating conformers of Aβ in brain samples from patients with AD or other neurodegenerative diseases. Postmortem brain tissue from patients with AD had measurable amounts of pathological Aβ conformers. Individuals over 80 years of age had the lowest amounts of prion-like Aβ and phosphorylated tau. Unexpectedly, the longevity-dependent decrease in self-propagating tau conformers occurred in spite of increasing amounts of total insoluble tau. When corrected for the abundance of insoluble tau, the ability of postmortem AD brain homogenates to induce misfolded tau in the cellular assays showed an exponential decrease with longevity, with a half-life of about one decade over the age range of 37 to 99 years. Thus, our findings demonstrate an inverse correlation between longevity in patients with AD and the abundance of pathological tau conformers. Our cellular assays can be applied to patient selection for clinical studies and the development of new drugs and diagnostics for AD.

In a critique of contemporary universities, the philosopher and art theorist Gerald Raunig contends that ‘wild and transversal writing is tamed and fed into the creativity-destroying apparatuses of disciplining institutions’ wherein researchers are required ‘to squeeze the last vestiges of their powers of invention into the straitjacket of the essay industry.’ At the heart of this ‘taming’ lies what he describes as researchers’ subjection to the ‘fetish of method’ and a reduction of the modes of expression, forms and styles of writing, which he claims ‘have brought about a crass uniformity in the languages in which academics can publish.’ \ud In this situation, Georges Perec’s generous creative and critical experiments, and his ‘inter-in-disciplinarity’ (a term coined by Johnnie Grattan and Michael Sheringham) seem to counter some of the circumscriptions upon method within the contemporary academy. Via attention to the investigation of actual sites, and a series of spatial metaphors – of not staying put and crossing borders, of meandering and getting sidetracked, of oscillating or shimmering between positions – I want to reflect upon Perec’s passage through conceptual fields, in order to draw out some potential implications for academic research through practice. Perec’s willingness ‘just to see what happens’ offers an invitation to wander beyond our disciplinary boundaries: using the project and essay forms as methodological tools, along with the role of the ‘knowing’ amateur, I will argue for alternative, more mobile considerations of the intellectual and affective rigour applied to creative and critical work.

The production of a new bio-based bovine gelatin (BG) film with incorporation of pea protein isolate (PPI), psyllium gum (PSY) and tragacanth (TRA) gum, and plasticized with glycerol, was completed via a two-stage fluidized bed agglomeration and casting techniques. Fluidization technique was used as a novel method to prepare instant film-forming powder (IFFP) in order to improve the films’ physicochemical, mechanical and handling properties. The incorporation of PSY, TRA, and PPI greatly improved the physicochemical, thermal and mechanical properties of the film as compared to control films. Composite films containing high glycerol concentration displayed significant (p

Contribution to Unlimited Imprint, a new PDF Publication \ud Real Life Manifesto: Original vs. New\ud Issue one - original \ud \ud Unlimited Imprint is a journal of visuality that sits within the shifting dissemination of images and ideas today. \ud The works and letters in this PDF publication are designed to be printed at home and once printed are an original artwork within an unlimited edition. \ud \ud The journal is disseminated freely under copyleft. Meaning all material can be shared, gleamed, edited, hacked, quoted, and remixed, as long as these outcomes are shared in the same spirit of copyleft. \ud \ud Anyone who signs up to receive Unlimited Imprint can access, print and take ownership of the content, including editing and redistributing. \ud \ud The first edition of Unlimited Imprint is based around the theme original/the original.

This chapter discusses the curious facial recognition performed upon everyday things and places - currently so popular on the internet – when faces are read into cheese graters, parking meters, coat hooks and the like. The phenomenon of pareidolia occurs because the human visual system has a tendency to extract patterns from noise, thus perceiving ‘meaning’ in random source material. The chapter uses this current fascination as the occasion to think about our desire to read meaning and significance into things. As an artist/scholar working with the everyday, rather than attempting to pin down definitive interpretations, I am interested in enlarging what can be generated from the ordinary objects and materials that surround us.\ud Keywords: pareidolia; the everyday; artistic research; pattern; constellation

Practising Place is a programme of public conversations, designed to examine the relationship between art practice and place. Each event is hosted at a different venue in the North of England and explores a specific aspect of place by bringing artists together with people from different backgrounds, who share a common area of interest.\ud \ud ‘Forms of Inscription’ examined the relationship between communication, meaning and landscape, through reference to Joanne Lee's and Paul Wilson's individual research. Foregrounding the, often overlooked, ephemera of everyday places, such as ‘chewing gum constellations’, fly tipping sites, and the typography of working men’s clubs, Lee and Wilson presented their own methods of ‘close looking’, and discussed the value of interdisciplinary approaches to engaging with a place.\ud \ud The discussion also coincided with In Return – a group exhibition at Sheffield Institute of Arts Gallery, which explored the legacy of post-industrial landscapes and production, and included new work by Joanne Lee, developed in response to her explorations of Sheffield’s Don Valley.

Ben-Yehuda, Lavy, Linchevski, and Sfard (2005) propose that there are four distinctive features of mathematical discourse: uses of words, the use of uniquely mathematical visual mediators, special discursive routines, and endorsed narratives. Utilizing modified talk- and think-aloud protocols for research in naturalistic settings this research explored: (1) the potential utility of the proposed four distinctive features of mathematical discourse as an analytic tool in studying mathematical cognition and mathematical cognitive processes, and (2) the interaction (or lack of interaction) between the four distinctive features of mathematical discourse in order to contemplate implications to students’ underlying or emergent mathematical cognition. Our findings suggest that there may be a unique interaction between particular features of mathematical discourse, and an absence of this interaction may be an important indicator for additional support for the learner. Implications to teaching, learning, and future research will be discussed.

This essay notes how the extent of the current recession is made visible in the mouldering creep of whited-out shop windows – high street commerce overtaken by a fuzzy bloom of cloudy paint. It appears in Abigale Neate Wilson’s ‘White window’ artists book. (A4 Four-color riso, spiral-bound, edition of 50) The publication was launched March 28-29 2015 at Open Space's PMF VI – The 6th Annual Publication & Multiples Fair at Baltimore Design School.

An increasing number of studies argues that self-propagating protein conformations (i.e., prions) feature in the pathogenesis of several common neurodegenerative diseases. Mounting evidence contends that aggregates of the amyloid-β (Aβ) peptide become self-propagating in Alzheimer's disease (AD) patients. An important characteristic of prions is their ability to replicate distinct strains, the biological information for which is enciphered within different conformations of protein aggregates. To investigate whether distinct strains of Aβ prions can be discerned in AD patients, we performed transmission studies in susceptible transgenic mice using brain homogenates from sporadic or heritable (Arctic and Swedish) AD cases. Mice inoculated with the Arctic AD sample exhibited a pathology that could be distinguished from mice inoculated with the Swedish or sporadic AD samples, which was judged by differential accumulation of Aβ isoforms and the morphology of cerebrovascular Aβ deposition. Unlike Swedish AD- or sporadic AD-inoculated animals, Arctic AD-inoculated mice, like Arctic AD patients, displayed a prominent Aβ38-containing cerebral amyloid angiopathy. The divergent transmission behavior of the Arctic AD sample compared with the Swedish and sporadic AD samples was maintained during second passage in mice, showing that Aβ strains are serially transmissible. We conclude that at least two distinct strains of Aβ prions can be discerned in the brains of AD patients and that strain fidelity was preserved on serial passage in mice. Our results provide a potential explanation for the clinical and pathological heterogeneity observed in AD patients.

An essay contribution to a publication appearing as part of the 37 pieces of flair project. 37 pieces of flair is a 3 part season of arts and cinema starting in September with 4 film screenings at The Star and Shadow Cinema, Newcastle-upon-Tyne, followed by a publication launch in early October and concluding with an exhibition and events programme at The NewBridge Project, Newcastle-upon-Tyne throughout November. Unlike countless other mental health themed Film Seasons or exhibitions, 37 pieces of flair will focus its attention less upon the individual stories of enduring mental health problems and rather take a step back in an attempt to grasp a broader look at, or investigation of, the society and its culture from which they emerge.\ud Curated by Andrew Wilson and Toby Lloyd for the NewBridge Project the exhibition features John Smith, Graham Dolphin, David Foggo, Dave Sherry and Roy Andersson, and continues until 17 January 2015.\ud The publication will be launched at The NewBridge Project, 12 NewBridge St. West, Newcastle upon Tyne, NE1 8AW from 6 – 9pm, Friday 21 November as part of the exhibition preview. It includes a diverse collection of writing and artworks by Alisdair Cameron, Joanne Lee, David Korowicz, Chris Erskine, Mark Fisher, Harry Palmer, Andrew Wilson, Sneha Solanki, Amy Mackeldon, Tom Walker, Pauline Sallis, Topsy Qu’ret, Nick Malyan, Joe Posset and Francis Mckee.\ud I spoke about the political dimensions of friendship at the closing event for the ‘37 pieces of flair’ exhibition at The NewBridge Project, Newcastle-upon-Tyne. Disconnected Paragraphs: Friends reunited & a daily dose of democratic material or sweetshop toxicity, also involved Harry Palmer and took place in the NewBridge Project Space on Friday 16th January.

This dissertation contributes timely evidence to the debate surrounding which policies may be most effective at raising college- and career- readiness in the United States. While over 75% of people in the U.S. graduate from high school, less than 25% of the population possesses a college degree. Over 60% of college students are required to take remedial coursework, which does not count for college credit. Using the National Longitudinal Survey of Youth 1997 Geocode, we provide a portrait of college readiness in the United States and discuss how it has been affected by popular high school accountability policies. We then examine the returns to education for students who have been impacted by these policies. Part I discusses different measures of college readiness, comparing their predictive power for success in college. Unlike previous research, our data allow us to examine curricular measures of high school and college readiness in addition to binary measures of educational attainment. After an exploratory analysis of these measures, we examine trends in college readiness over time in the U.S., detailed further within various socioeconomic groups and geographic regions. These college readiness measures are shown to provide information that is distinct from high school graduation rates when predicting college remediation and college graduation. Part II focuses on two types of high school accountability policies that emphasize basic proficiency: high school exit exams and consequential accountability. We develop a simple framework of high school behavior to predict how high schools will target their resources after these policies are implemented. We test the predictions of this model for college readiness. Our measures of college readiness are: the difficulty of students' hardest high school math course, high school completion, attending college without taking remedial math (college preparation), and college graduation by age 23. Identification is based on variation in the timing of state policies, controlling for state-invariant factors, time-varying national shocks, and regional time trends. We conclude that both policies decrease high school coursework difficulty and college preparation, but consequential accountability also decreases rates of high school completion and college graduation by age 23. These trends are not due to higher rates of GED attainment or lower college attendance, which suggests that these accountability policies lowered college readiness of college-goers. The last part of this dissertation addresses longer-term outcomes for students by examining how educational attainment and earnings have been impacted by these school accountability policies. After documenting an overall decrease in educational attainment, we find evidence of heterogeneous impacts by student ability prior to high school and school resources that imply increasing inequality in educational attainment across schools. Then, a two-stage least squares approach is used to measure the returns to schooling for students whose educational attainment was impacted by these policies. We find an earnings return to education of about 10% per completed grade, which is in line with previous literature using education policies as instruments for schooling.

In 1881, Newcomb conjectured that the first significant digits (FSDs) of numbers in statistical tables would follow a logarithmic distribution with the digit “1” occurring most often. However, because Newcomb’s proposal was not presented with a theoretical basis, it was not given much attention. Fifty-seven years later, Benford argued for the same principle and showed it was relevant to a large range of data sets, and the logarithmic FSD distribution became known as “Benford’s Law.” In the mid-1940s, Stigler claimed Benford’s Law contained a theoretical inconsistency and supplied an alternative derivation for the distribution of FSDs. In this paper, we examine the theoretical basis of the Stigler distribution and extend his reasoning by incorporating FSD first moment information and information-theoretic methods.

In 1881, Newcomb conjectured that the first significant digits (FSDs) of numbers in statistical tables would follow a logarithmic distribution with the digit “1†occurring most often. However, because Newcomb’s proposal was not presented with a theoretical basis, it was not given much attention. Fifty-seven years later, Benford argued for the same principle and showed it was relevant to a large range of data sets, and the logarithmic FSD distribution became known as “Benford’s Law.†In the mid-1940s, Stigler claimed Benford’s Law contained a theoretical inconsistency and supplied an alternative derivation for the distribution of FSDs. In this paper, we examine the theoretical basis of the Stigler distribution and extend his reasoning by incorporating FSD first moment information and information-theoretic methods.

Clinical data serve as a necessary basis for medical decisions. Consequently, the importance of methods that help officials quickly identify human tampering of data cannot be underestimated. In this paper, we suggest Benford’s Law as a basis for objectively identifying the presence of experimenter distortions in the outcome of clinical research data. We test this tool on a clinical data set that contains falsified data and discuss the implications of using this and information-theoretic methods as a basis for identifying data manipulation and fraud.

Clinical data serve as a necessary basis for medical decisions. Consequently, the importance of methods that help officials quickly identify human tampering of data cannot be underestimated. In this paper, we suggest Benford’s Law as a basis for objectively identifying the presence of experimenter distortions in the outcome of clinical research data. We test this tool on a clinical data set that contains falsified data and discuss the implications of using this and information-theoretic methods as a basis for identifying data manipulation and fraud.

Recent events in East Timor and other regions have highlighted the dangers of leaving issues of self-determination unresolved for too long. Despite the tact that self-determination is one of the guiding principles of the UN Charter, many controversies over its precise meaning and application continue to preclude a coherent, comprehensive approach to the principle by Stales. This thesis analyses the main controversies over the right of all peoples to self-determination and suggests some conclusions as to the present status of this right under international law. The author also analyses potential approaches to enforcing a legitimate right to self-determination and concludes that there appears to be no effective enforcement mechanism, unless one has the support of a sovereign State in advocating one's cause. Historically, realisation of this right has more often involved a successful campaign of violence or coercion against the party denying the right, and subsequent recognition by the international community of the legitimacy of the campaign. Clearly, this situation is not conducive to international peace and security. The author argues that international criminal law may provide the only effective means of enforcing legitimate rights to self-determination at this time. This conclusion is drawn with reference to Professor M. Cherif Bassiouni's theory of five stages through which a human right evolves, from a mere aspiration, to a right whose breach attracts penal proscriptions. Bassiouni argues that, in international law, a human right becomes a suitable subject for international criminal law when effective enforcement modalities for that right have failed. The thesis concludes with a suggestion that the right to self-determination may be one of the rights protected under the 1998 Rome Statute of the International Criminal Court, within the definition of the crime against humanity of "persecution" (article 7(1)(h) & (2)(g)).

Prefontaine Daniel C., Lee Joanne. The Rule of Law and the Independence of the Judiciary. In: Revue Québécoise de droit international, volume 11-2, 1998. Congrès mondial sur la Déclaration universelle des droits de l'homme. Actes, sous la direction de William Schabas et Geneviève Dufour. pp. 163-186.

Cancers often overexpress multiple clinically relevant oncogenes, but it is not known if combinations of oncogenes in cellular subpopulations within a cancer influence clinical outcomes. Using quantitative multispectral imaging of the prognostically relevant oncogenes MYC, BCL2, and BCL6 in diffuse large B-cell lymphoma (DLBCL), we show that the percentage of cells with a unique combination MYC+BCL2+BCL6− (M+2+6−) consistently predicts survival across four independent cohorts (n = 449), an effect not observed with other combinations including M+2+6+. We show that the M+2+6− percentage can be mathematically derived from quantitative measurements of the individual oncogenes and correlates with survival in IHC (n = 316) and gene expression (n = 2,521) datasets. Comparative bulk/single-cell transcriptomic analyses of DLBCL samples and MYC/BCL2/BCL6-transformed primary B cells identify molecular features, including cyclin D2 and PI3K/AKT as candidate regulators of M+2+6− unfavorable biology. Similar analyses evaluating oncogenic combinations at single-cell resolution in other cancers may facilitate an understanding of cancer evolution and therapy resistance. Significance: Using single-cell–resolved multiplexed imaging, we show that selected subpopulations of cells expressing specific combinations of oncogenes influence clinical outcomes in lymphoma. We describe a probabilistic metric for the estimation of cellular oncogenic coexpression from IHC or bulk transcriptomes, with possible implications for prognostication and therapeutic target discovery in cancer. This article is highlighted in the In This Issue feature, p. 1027

The text responds to the research project and exhibition 're-turning' by artists Andrew Brown, Joanne Lee, Danica Maier, Christine Stevens, which took place in Stoke-on-Trent in 2018, and was a revisit of the Topographies of the Obsolete project, which these artists took part in.\ud The text aims to understand the expereince of artists in relation to the city of Stoke-on-Trent, and in particular, considers the value and standing of the creative individual in relation to industry.