Solving navigational uncertainty using grid cells on robots

To successfully navigate their habitats, many mammals use a combination of two mechanisms, path integration and calibration using landmarks, which together enable them to estimate their location and orientation, or pose. In large natural environments, both these mechanisms are characterized by uncertainty: the path integration process is subject to the accumulation of error, while landmark calibration is limited by perceptual ambiguity. It remains unclear how animals form coherent spatial representations in the presence of such uncertainty. Navigation research using robots has determined that uncertainty can be effectively addressed by maintaining multiple probabilistic estimates of a robot's pose. Here we show how conjunctive grid cells in dorsocaudal medial entorhinal cortex (dMEC) may maintain multiple estimates of pose using a brain-based robot navigation system known as RatSLAM. Based both on rodent spatially-responsive cells and functional engineering principles, the cells at the core of the RatSLAM computational model have similar characteristics to rodent grid cells, which we demonstrate by replicating the seminal Moser experiments. We apply the RatSLAM model to a new experimental paradigm designed to examine the responses of a robot or animal in the presence of perceptual ambiguity. Our computational approach enables us to observe short-term population coding of multiple location hypotheses, a phenomenon which would not be easily observable in rodent recordings. We present behavioral and neural evidence demonstrating that the conjunctive grid cells maintain and propagate multiple estimates of pose, enabling the correct pose estimate to be resolved over time even without uniquely identifying cues. While recent research has focused on the grid-like firing characteristics, accuracy and representational capacity of grid cells, our results identify a possible critical and unique role for conjunctive grid cells in filtering sensory uncertainty. We anticipate our study to be a starting point for animal experiments that test navigation in perceptually ambiguous environments.

Whitefly Transmission and Efficient ssDNA Accumulation of Bean Golden Mosaic Geminivirus Require Functional Coat Protein

Bean golden mosaic geminivirus (BGMV) has a bipartite genome composed of two circular ssDNA components (DNA-A and DNA-B) and is transmitted by the whitefly, Bemisia tabaci. DNA-A encodes the viral replication proteins and the coat protein. To determine the role of BGMV coat protein systemic infection and whitefly transmission, two deletions and a restriction fragment inversion were introduced into the BGMV coat protein gene. All three coat protein mutants produced systemic infections when coinoculated with DNA-B onto Phaseolus vulgaris using electric discharge particle acceleration "particle gun." However, they were not sap transmissible and coat protein was not detected in mutant-infected plants. In addition, none of the mutants were transmitted by whiteflies. With all three mutants, ssDNA accumulation of DNA-A and DNA-B was reduced 25- to 50-fold and 3- to 10-fold, respectively, as compared to that of wild-type DNA. No effect on dsDNA-A accumulation was detected and there was 2- to 5-fold increase in dsDNA-B accumulation. Recombinants between the mutated DNA-A and DNA-B forms were identified when the inoculated coat protein mutant was linearized in the common region.

Measuring falls events in acute hospitals-A comparison of three reporting methods to identify missing data in the hospital reporting system

OBJECTIVES: To compare three different methods of falls reporting and examine the characteristics of the data missing from the hospital incident reporting system. DESIGN: Fourteen-month prospective observational study nested within a randomized controlled trial. SETTING: Rehabilitation, stroke, medical, surgical, and orthopedic wards in Perth and Brisbane, Australia. PARTICIPANTS: Fallers (n5153) who were part of a larger trial (1,206 participants, mean age 75.1 � 11.0). MEASUREMENTS: Three falls events reporting measures: participants’ self-report of fall events, fall events reported in participants’ case notes, and falls events reported through the hospital reporting systems. RESULTS: The three reporting systems identified 245 falls events in total. Participants’ case notes captured 226 (92.2%) falls events, hospital incident reporting systems captured 185 (75.5%) falls events, and participant selfreport captured 147 (60.2%) falls events. Falls events were significantly less likely to be recorded in hospital reporting systems when a participant sustained a subsequent fall, (P5.01) or when the fall occurred in the morning shift (P5.01) or afternoon shift (P5.01). CONCLUSION: Falls data missing from hospital incident report systems are not missing completely at random and therefore will introduce bias in some analyses if the factor investigated is related to whether the data ismissing.Multimodal approaches to collecting falls data are preferable to relying on a single source alone.

Low frequency of CHEK2 1100delC allele in Australian multiple-case breast cancer families : functional analysis in heterozygous individuals

A protein-truncating variant of CHEK2, 1100delC, is associated with a moderate increase in breast cancer risk. We have determined the prevalence of this allele in index cases from 300 Australian multiple-case breast cancer families, 95% of which had been found to be negative for mutations in BRCA1 and BRCA2. Only two (0.6%) index cases heterozygous for the CHEK2 mutation were identified. All available relatives in these two families were genotyped, but there was no evidence of co-segregation between the CHEK2 variant and breast cancer. Lymphoblastoid cell lines established from a heterozygous carrier contained approximately 20% of the CHEK2 1100delC mRNA relative to wild-type CHEK2 transcript. However, no truncated CHK2 protein was detectable. Analyses of expression and phosphorylation of wild-type CHK2 suggest that the variant is likely to act by haploinsufficiency. Analysis of CDC25A degradation, a downstream target of CHK2, suggests that some compensation occurs to allow normal degradation of CDC25A. Such compensation of the 1100delC defect in CHEK2 might explain the rather low breast cancer risk associated with the CHEK2 variant, compared to that associated with truncating mutations in BRCA1 or BRCA2.

Multiple human single-stranded DNA binding proteins function in genome maintenance : structural, biochemical and functional analysis

DNA exists predominantly in a duplex form that is preserved via specific base pairing. This base pairing affords a considerable degree of protection against chemical or physical damage and preserves coding potential. However, there are many situations, e.g. during DNA damage and programmed cellular processes such as DNA replication and transcription, in which the DNA duplex is separated into two singlestranded DNA (ssDNA) strands. This ssDNA is vulnerable to attack by nucleases, binding by inappropriate proteins and chemical attack. It is very important to control the generation of ssDNA and protect it when it forms, and for this reason all cellular organisms and many viruses encode a ssDNA binding protein (SSB). All known SSBs use an oligosaccharide/oligonucleotide binding (OB)-fold domain for DNA binding. SSBs have multiple roles in binding and sequestering ssDNA, detecting DNA damage, stimulating strand-exchange proteins and helicases, and mediation of protein–protein interactions. Recently two additional human SSBs have been identified that are more closely related to bacterial and archaeal SSBs. Prior to this it was believed that replication protein A, RPA, was the only human equivalent of bacterial SSB. RPA is thought to be required for most aspects of DNA metabolism including DNA replication, recombination and repair. This review will discuss in further detail the biological pathways in which human SSBs function.

Physical and functional interaction of the archaeal single-stranded DNA-binding protein SSB with RNA polymerase

Archaeal transcription utilizes a complex multisubunit RNA polymerase and the basal transcription factors TBP and TF(II)B, closely resembling its eukaryal counterpart. We have uncovered a tight physical and functional interaction between RNA polymerase and the single-stranded DNA-binding protein SSB in Sulfolobus solfataricus. SSB stimulates transcription from promoters in vitro under TBP-limiting conditions and supports transcription in the absence of TBP. SSB also rescues transcription from repression by reconstituted chromatin. We demonstrate the potential for promoter melting by SSB, suggesting a plausible basis for the stimulation of transcription. This stimulation requires both the single-stranded DNA-binding domain and the acidic C-terminal tail of the SSB. The tail forms a stable interaction with RNA polymerase. These data reveal an unexpected role for single-stranded DNA-binding proteins in transcription in archaea.

Exploring the relationship between grandparents and their grandchild who has a disability

This thesis reports on the findings of a study which sought to explore the relationship between grandparents and their grandchild who has a disability. In contrast to previous studies, it presents the grandparents’ perspective on the roles and relationships they maintain within their families and adopts a qualitative approach to identify the meanings, symbols and beliefs grandparents attribute to their experiences. Grandparents have played and continue to play an important role in the lives of many families, contributing both symbolic and instrumental support to their grandchildren. Changing life expectancy for older people has meant that many more grandparents and grandchildren now have the opportunity to participate in meaningful interactions and to develop strong relationships. In the future, this will be true for great grandparents and in some cases great great grandparents as well. This presents a number of challenges to all concerned as family members negotiate the often complex arena of family life in the 21st Century. Realizing that a grandchild has a disability adds another degree of complexity to the negotiation of roles and responsibilities of grandparents within families. By focussing on grandparents experiences when their grandchild has a disability, this research both explores a knowledge gap in the current literature and more practicably, will inform both grandparents and their families as they negotiate these challenges. This research makes a significant contribution to knowledge in this area by exploring grandparents’ views on the differences in the relationship they have with their typically developing grandchildren and their grandchild with a disability; the impact having a grandchild with a disability had had on their grandparent identity and whether it impacted on quality of life. As well as reporting on the aims of the study, the papers presented in this thesis report on the key topics and themes identified in the analysis of the transcribed interviews conducted with 22 grandparents whose grandchild has a disability. Article 1 presents an overview of the literature which informs current knowledge in relation to grandparents, presenting a historical and theoretical perspective. Additionally, it presents previous literature which discusses the roles and styles grandparents adopt thus providing a framework which is later used to examine the roles and styles adopted by the grandparents in the study. Article 2 addresses the emotional responses grandparents in the study experienced as they grandparented a child with a disability. Comparing these emotions to that of a roller coaster ride, ranging from absolute sadness and grief to pride and delight, these findings highlight their unique experiences and will be reassuring for other grandparents who experience similar emotional responses. Article 3 discusses from the grandparents’ perspective, how having a grandchild with a disability has impacted on their family. Whilst reporting on the day to day challenges of competing family commitments and conflict, a number of grandparents in this study also commented that the experience had made them closer as a family and that there had been significant changes in how some individual family members now viewed people with disability. Article 4 explores the impact having a grandchild with a disability may have on the grandparents’ sense of identity and enactment of the grandparent role, utilising Neugarten and Weinstein’s (1964) classic grandparenting styles and Kornhaber’s (1996) concepts of latent and functional grandparent identity as a basis for comparison. It provides important insight into grandparenting identity when a child has a disability, suggesting that the grandparenting experience and role enactment may be universal with only the context and delivery varying. In summary, this thesis confirms the valuable role grandparents play in the lives of grandchildren who have a disability and their families. It identifies a number of implications and makes recommendations for future research and practice.

Inferior visual field reductions are associated with poorer functional status among older adults with glaucoma

Purpose: To examine the relationship between visual impairment and functional status in a community-dwelling sample of older adults with glaucoma. Methods: This study included 74 community-dwelling older adults with open-angle glaucoma (aged 74 ± 6 years). Assessment of central vision included high-contrast visual acuity and Pelli-Robson contrast sensitivity. Binocular integrated visual fields were derived from merged monocular Humphrey Field Analyser visual field plots. Functional status outcome measures included physical performance tests (6-min walk test, timed up and go test and lower limb strength), a physical activity questionnaire (Physical Activity Scale for the Elderly) and an overall functional status score. Correlation and linear regression analyses, adjusting for age and gender, examined the association between visual impairment and functional status outcomes. Results: Greater levels of visual impairment were significantly associated with lower levels of functional status among community-dwelling older adults with glaucoma, independent of age and gender. Specifically, lower levels of visual function were associated with slower timed up and go performance, weaker lower limb strength, lower self-reported physical activity, and lower overall functional status scores. Of the components of vision examined, the inferior visual field and contrast factors were the strongest predictors of these functional outcomes, whereas the superior visual field factor was not related to functional status. Conclusions: Greater visual impairment, particularly in the inferior visual field and loss of contrast sensitivity, was associated with poorer functional status among older adults with glaucoma. The findings of this study highlight the potential links between visual impairment and the onset of functional decline. Interventions which promote physical activity among older adults with glaucoma may assist in preventing functional decline, frailty and falls, and improve overall health and well-being.

Participation index : a measure to identify rural transport disadvantage?

This paper develops a composite participation index (PI) to identify patterns of transport disadvantage in space and time. It is operationalised using 157 weekly activity-travel diaries data collected from three case study areas in rural Northern Ireland. A review of activity space and travel behaviour research found that six dimensional indicators of activity spaces were typically used including the number of unique locations visited, distance travelled, area of activity spaces, frequency of activity participation, types of activity participated in, and duration of participation in order to identify transport disadvantage. A combined measure using six individual indices were developed based on the six dimensional indicators of activity spaces, by taking into account the relativity of the measures for weekdays, weekends, and for a week. Factor analyses were conducted to derive weights of these indices to form the PI measure. Multivariate analysis using general linear models of the different indicators/indices identified new patterns of transport disadvantage. The research found that: indicator based measures and index based measures are complement each other; interactions between different factors generated new patterns of transport disadvantage; and that these patterns vary in space and time. The analysis also indicates that the transport needs of different disadvantaged groups are varied.

Mobility, accessibility and activity participation : a comparative assessment of methods to identify rural transport disadvantage

Traditionally, transport disadvantage has been identified using accessibility analysis although the effectiveness of the accessibility planning approach to improving access to goods and services is not known. This paper undertakes a comparative assessment of measures of mobility, accessibility, and participation used to identify transport disadvantage using the concept of activity spaces. A 7 day activity-travel diary data for 89 individuals was collected from two case study areas located in rural Northern Ireland. A spatial analysis was conducted to select the case study areas using criteria derived from the literature. The criteria are related to the levels of area accessibility and area mobility which are known to influence the nature of transport disadvantage. Using the activity-travel diary data individuals weekly as well as day to day variations in activity-travel patterns were visualised. A model was developed using the ArcGIS ModelBuilder tool and was run to derive scores related to individual levels of mobility, accessibility, and participation in activities from the geovisualisation. Using these scores a multiple regression analysis was conducted to identify patterns of transport disadvantage. This study found a positive association between mobility and accessibility, between mobility and participation, and between accessibility and participation in activities. However, area accessibility and area mobility were found to have little impact on individual mobility, accessibility, and participation in activities. Income vis-àvis ´ car-ownership was found to have a significant impact on individual levels of mobility, and accessibility; whereas participation in activities were found to be a function of individual levels of income and their occupational status.

Functional role of cell surface CUB domain-containing protein 1 in tumour cell dissemination

The function of CUB domain-containing protein 1 (CDCP1), a recently described transmembrane protein expressed on the surface of hematopoietic stem cells and normal and malignant cells of different tissue origin, is not well defined. The contribution of CDCP1 to tumor metastasis was analyzed by using HeLa carcinoma cells overexpressing CDCP1 (HeLa-CDCP1) and a high-disseminating variant of prostate carcinoma PC-3 naturally expressing high levels of CDCP1 (PC3-hi/diss). CDCP1 expression rendered HeLa cells more aggressive in experimental metastasis in immunodeficient mice. Metastatic colonization by HeLa-CDCP1 was effectively inhibited with subtractive immunization-generated, CDCP1-specific monoclonal antibody (mAb) 41-2, suggesting that CDCP1 facilitates relatively late stages of the metastatic cascade. In the chick embryo model, time- and dose-dependent inhibition of HeLa-CDCP1 colonization by mAb 41-2 was analyzed quantitatively to determine when and where CDCP1 functions during metastasis. Quantitative PCR and immunohistochemical analyses indicated that CDCP1 facilitated tumor cell survival soon after vascular arrest. Live cell imaging showed that the function-blocking mechanism of mAb 41-2 involved enhancement of tumor cell apoptosis, confirmed by attenuation of mAb 41-2–mediated effects with the caspase inhibitor z-VAD-fmk. Under proapoptotic conditions in vitro, CDCP1 expression conferred HeLa-CDCP1 cells with resistance to doxorubicin-induced apoptosis, whereas ligation of CDCP1 with mAb 41-2 caused additional enhancement of the apoptotic response. The functional role of naturally expressed CDCP1 was shown by mAb 41-2–mediated inhibition of both experimental and spontaneous metastasis of PC3-hi/diss. These findings confirm that CDCP1 functions as an antiapoptotic molecule and indicate that during metastasis CDCP1 facilitates tumor cell survival likely during or soon after extravasation.