The ReSIST Resilience Knowledge Base

We describe a prototype knowledge base that uses semantic web technologies to provide a service for querying a large and expanding collection of public data about resilience, dependability and security. We report progress and identify opportunities to support resilience-explicit computing by developing metadata-based descriptions of resilience mechanisms that can be used to support design time and, potentially, run-time decision making

Living with multimorbidity? The lived experience of multiple chronic conditions in later life

Multimorbidity is defined biomedically as the co-existence of two or more long-term conditions in an individual. Globally, the number of people living with multiple conditions is increasing, posing stark challenges both to the clinical management of patients and the organisation of health systems. Qualitative literature has begun to address how concurrency affects the self-management of chronic conditions, and the concept of illness prioritisation predominates. In this article, we adopt a phenomenological lens to show how older people with multiple conditions experience illness. This UK study was qualitative and longitudinal in design. Sampling was purposive and drew upon an existing cohort study. In total, 15 older people living with multiple conditions took part in 27 in-depth interviews. The practical stages of analysis were guided by Constructivist Grounded Theory. We argue that the concept of multimorbidity as biomedically imagined has limited relevance to lived experience, while concurrency may also be erroneous. In response, we outline a lived experience of multiple chronic conditions in later life, which highlights differences between clinical and lay assumptions and makes the latter visible

Site-specific recombinatorics : in situ cellular barcoding with the Cre Lox system

Background: Cellular barcoding is a recently developed biotechnology tool that enables the familial identification of progeny of individual cells in vivo. In immunology, it has been used to track the burst-sizes of multiple distinct responding T cells over several adaptive immune responses. In the study of hematopoiesis, it revealed fate heterogeneity amongst phenotypically identical multipotent cells. Most existing approaches rely on ex vivo viral transduction of cells with barcodes followed by adoptive transfer into an animal, which works well for some systems, but precludes barcoding cells in their native environment such as those inside solid tissues. Results: With a view to overcoming this limitation, we propose a new design for a genetic barcoding construct based on the Cre Lox system that induces randomly created stable barcodes in cells in situ by exploiting inherent sequence distance constraints during site-specific recombination. We identify the cassette whose provably maximal code diversity is several orders of magnitude higher than what is attainable with previously considered Cre Lox barcoding approaches, exceeding the number of lymphocytes or hematopoietic progenitor cells in mice. Conclusions: Its high diversity and in situ applicability, make the proposed Cre Lox based tagging system suitable for whole tissue or even whole animal barcoding. Moreover, it can be built using established technology

Mouse eye gene microarrays for investigating ocular development and disease

AbstractMicroarray technology can facilitate simultaneous expression analysis of thousands of genes and assist in delineating cellular pathways involved in development or disease pathogenesis. Since public databases and commercial cDNA microarrays have an under-representation of eye-expressed genes, we generated over 3000 expressed sequence tags from three unamplified mouse eye/retina cDNA libraries. These eye-expressed genes were used to produce cDNA microarrays. Methodology for printing of slides, hybridization, scanning and data analysis has been optimized. The I-gene microarrays will be useful for establishing expression profiles of the mouse eye/retina and provide a resource for defining molecular pathways involved in development, aging and disease

Maternal Inheritance of a Recessive RBP4 Defect in Canine Congenital Eye Disease

Maternally skewed transmission of traits has been associated with genomic imprinting and oocytederived mRNA. We report canine congenital eye malformations, caused by an amino acid deletion (K12deI) near the N terminus of retinol-binding protein (RBP4). The disease is only expressed when both dam and offspring are deletion homozygotes. RBP carries vitamin A (retinol) from hepatic stores to peripheral tissues, including the placenta and developing eye, where it is required to synthesize retinoic acid. Gestational vitamin A deficiency is a known risk factor for ocular birth defects. The K12del mutation disrupts RBP folding in vivo, decreasing its secretion from hepatocytes to serum. The maternal penetrance effect arises from an impairment in the sequential transfer of retinol across the placenta, via RBP encoded by maternal and fetal genomes. Our results demonstrate a mode of recessive maternal inheritance, with a physiological basis, and they extend previous observations on dominant-negative RBP4 alleles in humans.Peer reviewe

The prevalence of renal impairment in individuals seeking HIV testing in Urban Malawi

Background: Chronic kidney disease (CKD) poses a major health threat to people living in low- and middle-income countries, especially when it is combined with HIV, antiretroviral treatment (ART) or communicable and non-communicable diseases. Data about the prevalence of CKD and its association with other diseases is scarce, particularly in HIV-negative individuals. This study estimated the prevalence of CKD in individuals who were either HIV-positive (and ART-naïve) or HIV-negative in an urban Malawian population. Methods: This cross-sectional study was conducted at a HIV Testing and Counselling Centre in Lilongwe, Malawi. Consecutive clients who were ≥18 years and consented to participate were enrolled over a 3-month period. Clients were screened for potential renal disease and other conditions. Their blood pressure was measured, urine examined via dipstick and albumin/creatinine ratio and blood drawn for creatinine, cystatin C and sero-markers for schistosomiasis. Estimated glomerular filtration (eGFR) rate was calculated using a cystatin C-based formula and classified according to the matching CKD stages by K/DOQI (The National Kidney Foundation Kidney Disease Outcome Quality Initiative). We performed a descriptive analysis and compared differences between HIV-positive (and ART naïve) and -negative participants. Results: Out of 381 consecutive clients who were approached between January and March 2012, 366 consented and 363 (48% female; 32% HIV-positive) were included in the analysis. Reasons for exclusion were missing samples or previous use of ART. HIV-positive and negative clients did not differ significantly with regard to age, sex or medical history, but they did differ for BMI—21.3 (±3.4) vs. 24 (±5.1), respectively (p < 0.001). Participants also differed with regard to serum cystatin C levels, but not creatinine. Reduced kidney function (according to CKD stages 2–5) was significantly more frequent 15.5 vs. 3.6%, respectively (p  < 0.001) among HIV-positive clients compared to the HIV-negative group. Differences in renal function were most pronounced in the eGFR range 60–89 ml/min/1.73 m2 accompanied by proteinuria with results as 11.2% vs. 1.2%, respectively for clients who were HIV-positive vs. HIV-negative (p = 0.001). Conclusions: Reduced glomerular filtration and/or proteinuria occurred in 15.5% of HIV-positive, and 3.6% of HIV-negative patients in this urban Malawian cohort. Since generalized renal monitoring is not feasible in Malawi or other resource-limited countries, strategies to identify patients at risk for higher stages of CKD and appropriate preventive measures are needed for both HIV-positive and HIV-negative patients

Motor-free force generation in biological systems

A central part of soft matter physics is the investigation of effects in an active environment. These systems are driven out of equilibrium by a constant energy consumption. In biological systems, for instance, energy is consumed in the dynamic polymerization process of cytoskeletal filaments or by motor-filament interactions. These active processes convert chemical energy into mechanical work and impede a trapping of cellular structures in thermodynamically frozen states. Thus, active soft matter is crucial for biological systems to fulfill a broad range of tasks. Inherent physical principles relying on entropy maximizing arguments, however, cannot be easily switched off even in active systems. Cells might even employ these principles to accomplish certain tasks without the need to arrange elaborate, energy dissipating structures. Within the presented studies we demonstrate possibilities how biological relevant forces can be generated in the absence of any active accessory proteins. The presented studies are based on the cytoskeletal key components actin and microtubules. We demonstrate different approaches ranging from light induced softening to cross-linker expansion, which realize entropy driven contractions of the according system