Architecture as the background to collective life

This project develops an approach towards the arrangement and design of the primary elements - public facilities and spaces - that necessarily complement the provision of subsidised housing in South Africa. The historical response to the housing shortage in South Africa has been the provision of a remarkable number of individual housing units, but with insufficient funds and attention given to the urban infrastructure, public spaces and facilities that go hand in hand with housing in livable urban environments. This project considers a subsidy housing project where the social facilities are considered upfront, and are seen as an opportunity to create interesting, people-centred places in the development - this thesis is the search for an architecture which forms the backdrop, and framework for growth, for collective urban life. This paper is structured around six sections: thinking, siting, urban design, programming, making and designing. These sections explore, respectively, the theoretical proposal with regards to social facilities and public spaces, the strategic siting of an area of subsidised housing and its associated primary elements, an urban design proposal for the whole development, the programming of the whole site and the individual cluster of facilities that I consider in more detail, the spatial and technological realisation of the public fronts of three case study buildings, and finally the exploration and manifestation of these ideas through a design. My project is being done in conjunction with another student, Rob Richardson, who is looking at creative housing within the limit of the government subsidy. Together we make a proposal for an overall living environment which takes the form of an acupunctural insertion of subsidised housing and the associated primary elements into an area of Wynburg, Cape Town

Anisotropic thermodynamic and transport properties of single crystalline CaKFe4_{4}As4_{4}

Single crystalline, single phase CaKFe$_{4}$As$_{4}$ has been grown out of a high temperature, quaternary melt. Temperature dependent measurements of x-ray diffraction, anisotropic electrical resistivity, elastoresistivity, thermoelectric power, Hall effect, magnetization and specific heat, combined with field dependent measurements of electrical resistivity and field and pressure dependent measurements of magnetization indicate that CaKFe$_{4}$As$_{4}$ is an ordered, stoichiometric, Fe-based superconductor with a superconducting critical temperature, $T_c$ = 35.0 $\pm$ 0.2 K. Other than superconductivity, there is no indication of any other phase transition for 1.8 K $\leq T \leq$ 300 K. All of these thermodynamic and transport data reveal striking similarities to that found for optimally- or slightly over-doped (Ba$_{1-x}$K$_x$)Fe$_2$As$_2$, suggesting that stoichiometric CaKFe$_4$As$_4$ is intrinsically close to what is referred to as "optimal-doped" on a generalized, Fe-based superconductor, phase diagram. The anisotropic superconducting upper critical field, $H_{c\text{2}}(T)$, of CaKFe$_{4}$As$_{4}$ was determined up to 630 kOe. The anisotropy parameter $\gamma(T)=H_{c\text{2}}^{\perp}/H_{c\text{2}}^{\|}$, for $H$ applied perpendicular and parallel to the c-axis, decreases from $\simeq 2.5$ at $T_c$ to $\simeq 1.5$ at 25 K which can be explained by interplay of paramagnetic pairbreaking and orbital effects. The slopes of $dH_{c\text{2}}^{\|}/dT\simeq-44$ kOe/K and $dH_{c\text{2}}^{\perp}/dT \simeq-109$ kOe/K at $T_c$ yield an electron mass anisotropy of $m_{\perp}/m_{\|}\simeq 1/6$ and short Ginzburg-Landau coherence lengths $\xi_{\|}(0)\simeq 5.8 \text{\AA}$ and $\xi_{\perp}(0)\simeq 14.3 \text{\AA}$. The value of $H_{c\text{2}}^{\perp}(0)$ can be extrapolated to $\simeq 920$ kOe, well above the BCS paramagnetic limit.Comment: 13 pages, 15 figures, part of arXiv:1606.02241 is include

The Association between Hypertension and Depression and Anxiety Disorders: Results from a Nationally-Representative Sample of South African Adults

OBJECTIVE:Growing evidence suggests high levels of comorbidity between hypertension and mental illness but there are few data from low- and middle-income countries. We examined the association between hypertension and depression and anxiety in South Africa. METHODS:Data come from a nationally-representative survey of adults (n = 4351). The Composite International Diagnostic Interview was used to measure DSM-IV mental disorders during the previous 12-months. The relationships between self-reported hypertension and anxiety disorders, depressive disorders and comorbid anxiety-depression were assessed after adjustment for participant characteristics including experience of trauma and other chronic physical conditions. RESULTS:Overall 16.7% reported a previous medical diagnosis of hypertension, and 8.1% and 4.9% were found to have a 12-month anxiety or depressive disorder, respectively. In adjusted analyses, hypertension diagnosis was associated with 12-month anxiety disorders [Odds ratio (OR) = 1.55, 95% Confidence interval (CI) = 1.10-2.18] but not 12-month depressive disorders or 12-month comorbid anxiety-depression. Hypertension in the absence of other chronic physical conditions was not associated with any of the 12-month mental health outcomes (p-values all <0.05), while being diagnosed with both hypertension and another chronic physical condition were associated with 12-month anxiety disorders (OR = 2.25, 95% CI = 1.46-3.45), but not 12-month depressive disorders or comorbid anxiety-depression. CONCLUSIONS:These are the first population-based estimates to demonstrate an association between hypertension and mental disorders in sub-Saharan Africa. Further investigation is needed into role of traumatic life events in the aetiology of hypertension as well as the temporality of the association between hypertension and mental disorders

Helicobacter pylori Adapts to Chronic Infection and Gastric Disease via pH-Responsive BabA-Mediated Adherence

International audienceThe BabA adhesin mediates high-affinity binding of Helicobacter pylori to the ABO blood group antigen-glycosylated gastric mucosa. Here we show that BabA is acid responsive-binding is reduced at low pH and restored by acid neutralization. Acid responsiveness differs among strains; often correlates with different intragastric regions and evolves during chronic infection and disease progression; and depends on pH sensor sequences in BabA and on pH reversible formation of high-affinity binding BabA multimers. We propose that BabA's extraordinary reversible acid responsiveness enables tight mucosal bacterial adherence while also allowing an effective escape from epithelial cells and mucus that are shed into the acidic bactericidal lumen and that bio-selection and changes in BabA binding properties through mutation and recombination with babA-related genes are selected by differences among individuals and by changes in gastric acidity over time. These processes generate diverse H. pylori subpopulations, in which BabA's adaptive evolution contributes to H. pylori persistence and overt gastric disease

A large-scale genome-wide association study meta-analysis of cannabis use disorder

Summary Background Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50–70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder. Methods To conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations. Findings We identified two genome-wide significant loci: a novel chromosome 7 locus (FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07–1·15, p=1·84 × 10−9) and the previously identified chromosome 8 locus (near CHRNA2 and EPHX2, lead SNP rs4732724; OR 0·89, 95% CI 0·86–0·93, p=6·46 × 10−9). Cannabis use disorder and cannabis use were genetically correlated (rg 0·50, p=1·50 × 10−21), but they showed significantly different genetic correlations with 12 of the 22 traits we tested, suggesting at least partially different genetic underpinnings of cannabis use and cannabis use disorder. Cannabis use disorder was positively genetically correlated with other psychopathology, including ADHD, major depression, and schizophrenia. Interpretation These findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between genetic liability to cannabis use and cannabis use disorder. Funding National Institute of Mental Health; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing; The European Commission, Horizon 2020; National Institute of Child Health and Human Development; Health Research Council of New Zealand; National Institute on Aging; Wellcome Trust Case Control Consortium; UK Research and Innovation Medical Research Council (UKRI MRC); The Brain & Behavior Research Foundation; National Institute on Deafness and Other Communication Disorders; Substance Abuse and Mental Health Services Administration (SAMHSA); National Institute of Biomedical Imaging and Bioengineering; National Health and Medical Research Council (NHMRC) Australia; Tobacco-Related Disease Research Program of the University of California; Families for Borderline Personality Disorder Research (Beth and Rob Elliott) 2018 NARSAD Young Investigator Grant; The National Child Health Research Foundation (Cure Kids); The Canterbury Medical Research Foundation; The New Zealand Lottery Grants Board; The University of Otago; The Carney Centre for Pharmacogenomics; The James Hume Bequest Fund; National Institutes of Health: Genes, Environment and Health Initiative; National Institutes of Health; National Cancer Institute; The William T Grant Foundation; Australian Research Council; The Virginia Tobacco Settlement Foundation; The VISN 1 and VISN 4 Mental Illness Research, Education, and Clinical Centers of the US Department of Veterans Affairs; The 5th Framework Programme (FP-5) GenomEUtwin Project; The Lundbeck Foundation; NIH-funded Shared Instrumentation Grant S10RR025141; Clinical Translational Sciences Award grants; National Institute of Neurological Disorders and Stroke; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences.Peer reviewe

Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma

SummaryWe report a comprehensive molecular characterization of pheochromocytomas and paragangliomas (PCCs/PGLs), a rare tumor type. Multi-platform integration revealed that PCCs/PGLs are driven by diverse alterations affecting multiple genes and pathways. Pathogenic germline mutations occurred in eight PCC/PGL susceptibility genes. We identified CSDE1 as a somatically mutated driver gene, complementing four known drivers (HRAS, RET, EPAS1, and NF1). We also discovered fusion genes in PCCs/PGLs, involving MAML3, BRAF, NGFR, and NF1. Integrated analysis classified PCCs/PGLs into four molecularly defined groups: a kinase signaling subtype, a pseudohypoxia subtype, a Wnt-altered subtype, driven by MAML3 and CSDE1, and a cortical admixture subtype. Correlates of metastatic PCCs/PGLs included the MAML3 fusion gene. This integrated molecular characterization provides a comprehensive foundation for developing PCC/PGL precision medicine

Genetic effects on gene expression across human tissues

Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of diseas

Shared genetic risk between eating disorder- and substance-use-related phenotypes:Evidence from genome-wide association studies

First published: 16 February 202

Significant benefits of AIP testing and clinical screening in familial isolated and young-onset pituitary tumors

Context Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design 12-year prospective, observational study. Participants & Setting We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course

Polygenic prediction of educational attainment within and between families from genome-wide association analyses in 3 million individuals

We conduct a genome-wide association study (GWAS) of educational attainment (EA) in a sample of ~3 million individuals and identify 3,952 approximately uncorrelated genome-wide-significant single-nucleotide polymorphisms (SNPs). A genome-wide polygenic predictor, or polygenic index (PGI), explains 12-16% of EA variance and contributes to risk prediction for ten diseases. Direct effects (i.e., controlling for parental PGIs) explain roughly half the PGI's magnitude of association with EA and other phenotypes. The correlation between mate-pair PGIs is far too large to be consistent with phenotypic assortment alone, implying additional assortment on PGI-associated factors. In an additional GWAS of dominance deviations from the additive model, we identify no genome-wide-significant SNPs, and a separate X-chromosome additive GWAS identifies 57