Automated pancreatic islet viability assessment for transplantation using bright-field deep morphological signature

Islets transplanted for type-1 diabetes have their viability reduced by warm ischemia, dimethyloxalylglycine (DMOG; hypoxia model), oxidative stress and cytokine injury. This results in frequent transplant failures and the major burden of patients having to undergo multiple rounds of treatment for insulin independence. Presently there is no reliable measure to assess islet preparation viability prior to clinical transplantation. We investigated deep morphological signatures (DMS) for detecting the exposure of islets to viability compromising insults from brightfield images. Accuracies ranged from 98 % to 68 % for; ROS damage, pro-inflammatory cytokines, warm ischemia and DMOG. When islets were disaggregated to single cells to enable higher throughput data collection, good accuracy was still obtained (83-71 %). Encapsulation of islets reduced accuracy for cytokine exposure, but it was still high (78 %). Unsupervised modelling of the DMS for islet preparations transplanted into a syngeneic mouse model was able to predict whether or not they would restore glucose control with 100 % accuracy. Our strategy for constructing DMS' is effective for the assessment of islet pre-transplant viability. If translated into the clinic, standard equipment could be used to prospectively identify non-functional islet preparations unable to contribute to the restoration of glucose control and reduce the burden of unsuccessful treatments.Abbas Habibalahi, Jared M. Campbell, Stacey N. Walters, Saabah B. Mahbub, Ayad G. Anwer, Shane T. Grey, Ewa M. Goldy

Pancreatic Islet Viability Assessment Using Hyperspectral Imaging of Autofluorescence

Islets prepared for transplantation into type 1 diabetes patients are exposed to compromising intrinsic and extrinsic factors that contribute to early graft failure, necessitating repeated islet infusions for clinical insulin independence. A lack of reliable pre-transplant measures to determine islet viability severely limits the success of islet transplantation and will limit future beta cell replacement strategies. We applied hyperspectral fluorescent microscopy to determine whether we could non-invasively detect islet damage induced by oxidative stress, hypoxia, cytokine injury, and warm ischaemia, and so predict transplant outcomes in a mouse model. In assessing islet spectral signals for NAD(P)H, flavins, collagen-I, and cytochrome-C in intact islets, we distinguished islets compromised by oxidative stress (ROS) (AUC = 1.00), hypoxia (AUC = 0.69), cytokine exposure (AUC = 0.94), and warm ischaemia (AUC = 0.94) compared to islets harvested from pristine anaesthetised heart-beating mouse donors. Significantly, with unsupervised assessment we defined an autofluorescent score for ischaemic islets that accurately predicted the restoration of glucose control in diabetic recipients following transplantation. Similar results were obtained for islet single cell suspensions, suggesting translational utility in the context of emerging beta cell replacement strategies. These data show that the pre-transplant hyperspectral imaging of islet autofluorescence has promise for predicting islet viability and transplant success.Jared M. Campbell, Stacey N. Walters, Abbas Habibalahi, Saabah B. Mahbub, Ayad G. Anwer, Shannon Handley, Shane T. Grey, and Ewa M. Goldy

D6-branes and torsion

The D6-brane spectrum of type IIA vacua based on twisted tori and RR background fluxes is analyzed. In particular, we compute the torsion factors of the (co)homology groups H_n and describe the effect that they have on D6-brane physics. For instance, the fact that H_3 contains Z_N subgroups explains why RR tadpole conditions are affected by geometric fluxes. In addition, the presence of torsional (co)homology shows why some D6-brane moduli are lifted, and it suggests how the D-brane discretum appears in type IIA flux compactifications. Finally, we give a clear, geometrical understanding of the Freed-Witten anomaly in the present type IIA setup, and discuss its consequences for the construction of semi-realistic flux vacua.Comment: 35 pages, 1 figure. One reference adde

Donor-Acceptor Stacking Arrangements in Bulk and Thin-Film High-Mobility Conjugated Polymers Characterized Using Molecular Modelling and MAS and Surface-Enhanced Solid-State NMR Spectroscopy

peer reviewe

Using behavior-analytic implicit tests to assess sexual interests among normal and sex-offender populations

The development of implicit tests for measuring biases and behavioral predispositions is a recent development within psychology. While such tests are usually researched within a social-cognitive paradigm, behavioral researchers have also begun to view these tests as potential tests of conditioning histories, including in the sexual domain. The objective of this paper is to illustrate the utility of a behavioral approach to implicit testing and means by which implicit tests can be built to the standards of behavioral psychologists. Research findings illustrating the short history of implicit testing within the experimental analysis of behavior are reviewed. Relevant parallel and overlapping research findings from the field of social cognition and on the Implicit Association Test are also outlined. New preliminary data obtained with both normal and sex offender populations are described in order to illustrate how behavior-analytically conceived implicit tests may have potential as investigative tools for assessing histories of sexual arousal conditioning and derived stimulus associations. It is concluded that popular implicit tests are likely sensitive to conditioned and derived stimulus associations in the history of the test-taker rather than 'unconscious cognitions', per se

Living at Home with Family: Psychological Adaptation and Well-being Among Family Carers and Adults with an Intellectual Disability

The purpose of this thesis was to examine well-being among family carers and adults with an intellectual disability (ID). In a series of four studies, I examined 1) parents’ experiences and feelings during the process of seeking out-of-home accommodation for their adult child with ID, 2) how adults with an ID who live at home report on their own well-being, 3) the physical and psychological health of family carers and 4) factors related to the process of moving out of the family home in adulthood. Chapter 1 provides a background picture of adulthood with an ID, examining health and support issues and what has been achieved in terms of policy and strategies in the UK. Estimations of future need for adults with ID have also been explored. Adopting a qualitative design, Chapter 2 examines the experiences of families seeking out-of-home accommodation for their relative with ID. Little attention has been given to the first-hand experiences of families as they undertake this process. Thematic analysis identified implicit themes in the data, which included families’ reasons for seeking housing and experiences within a process which families reported as stressful and frustrating. In Chapter 3, secondary data analysis was undertaken on a large national survey of adults with an ID in England (Emerson, Malam, Davies, & Spencer, 2005). An examination of adults’ self-reported health and well-being was undertaken exploring associations with living circumstances. Results of multivariate modelling showed those who lived at home were more likely to report better well-being and health. The latter, however, only when their support needs were lower. Results highlight the important role of families to the emotional development of a relative with ID, whilst also highlighting potential disparities in access to health care for these individuals. Chapter 4, a large scale quantitative project was undertaken to examine both positive and negative aspects of the caregiving experience and explore the self-reported health and well-being of family carers co-residing with an adult relative with ID. Families in the UK report experiencing poorer health outcomes than non-caregivers. Psychological resources (coping and support received) were associated with better psychological adjustment and more positive gains from the caregiving role. Overall factors associated with physical health appear to differ from those associated with psychological health. Further research with more representative non-caregiving peers is needed. Chapter 5 adopted a prospective design to examine the dynamics of placement tendencies of families of adults with ID and factors associated change in placement decisions and behaviours. The majority of families who had placed their relative out-of-home had initially recorded higher scores on the Placement Tendency Index (PTI, Blacher, 1990). The rate of placement of adults appeared to occur more rapidly than previously demonstrated with children. This may result from the more normative context of seeking a placement for an adult relative. Unadjusted ORs indicated only families’ coping strategies were significantly associated with continued home care. Other factors were not significantly related to changes in PTI scores. Changes in placement decision of families of adults with ID may be more affected by factors external to the family, such as availability of appropriate accommodation. Findings from these empirical studies were discussed in relation to their implications to policy and practice and recommendations for future research were made

Effect of acute hypoxia on muscle blood flow, VO(2p), and [HHb] kinetics during leg extension exercise in older men.

The adjustment of pulmonary oxygen uptake (VO2p), heart rate (HR), limb blood flow (LBF), and muscle deoxygenation [HHb] was examined during the transition to moderate-intensity, knee-extension exercise in six older adults (70 \ub1 4 years) under two conditions: normoxia (FIO2 = 20.9 %) and hypoxia (FIO2 = 15 %). The subjects performed repeated step transitions from an active baseline (3 W) to an absolute work rate (21 W) in both conditions. Phase 2 VO2p, HR, LBF, and [HHb] data were fit with an exponential model. Under hypoxic conditions, no change was observed in HR kinetics, on the other hand, LBF kinetics was faster (normoxia 34 \ub1 3 s; hypoxia 28 \ub1 2), whereas the overall [HHb] adjustment ( \u3c4\u2032=TD+\u3c4 ) was slower (normoxia 28 \ub1 2; hypoxia 33 \ub1 4 s). Phase 2 VO2p kinetics were unchanged (p < 0.05). The faster LBF kinetics and slower [HHb] kinetics reflect an improved matching between O2 delivery and O2 utilization at the microvascular level, preventing the phase 2 VO2p kinetics from become slower in hypoxia. Moreover, the absolute blood flow values were higher in hypoxia (1.17 \ub1 0.2 L min 121) compared to normoxia (0.96 \ub1 0.2 L min 121) during the steady-state exercise at 21 W. These findings support the idea that, for older adults exercising at a low work rate, an increase of limb blood flow offsets the drop in arterial oxygen content (CaO2) caused by breathing an hypoxic mixture

A bend, flip and trap mechanism for transposon integration

Cut-and-paste DNA transposons of the mariner/Tc1 family are useful tools for genome engineering and are inserted specifically at TA target sites. A crystal structure of the mariner transposase Mos1 (derived from Drosophila mauritiana), in complex with transposon ends covalently joined to target DNA, portrays the transposition machinery after DNA integration. It reveals severe distortion of target DNA and flipping of the target adenines into extra-helical positions. Fluorescence experiments confirm dynamic base flipping in solution. Transposase residues W159, R186, F187 and K190 stabilise the target DNA distortions and are required for efficient transposon integration and transposition in vitro. Transposase recognises the flipped target adenines via base-specific interactions with backbone atoms, offering a molecular basis for TA target sequence selection. Our results will provide a template for re-designing mariner/Tc1 transposases with modified target specificities

Ethical identity What is it? What of it?

SIGLEAvailable from British Library Document Supply Centre-DSC:9350.8326(no 01/15) / BLDSC - British Library Document Supply CentreGBUnited Kingdo