Evaluation of racial and ethnic disparities of glycemic control in the Health and Retirement Study. 2003 Diabetes Survey

Objective. To examine and evaluate racial and ethnic disparities in glycemic control among HRS respondents with diabetes aged 55-94 years. ^ Methods. The HRS Diabetes 2003 database provides data on blood-drawn glycemic control and self-reported demographics, socioeconomic status, clinical, health access and self-care characteristics. 1,141 non-Hispanic White, non-Hispanic Black, and Hispanic respondents were included in multiple logistic regression of glycemic control. ^ Results. The rate of poor control was significantly higher among Blacks (61.5%, 105/171) and Hispanics (65.3% 72/110) than among Whites (45.0% 387/860) (p < 0.01). After controlling for influential covariates and interactions, Blacks and Hispanics had a three-fold increased risk for poor control compared to Whites when duration was five years or less. ^ Conclusions. Clinical and self-perception variables, like duration, medication, and self-rated poor diabetes control affected glycemic control independent of race and ethnicity, but there remains unexplained racial and ethnic disparities for newly-diagnosed individuals. This is the first study to find an interaction between duration and race and ethnicity on glycemic control. Future research should incorporate cultural beliefs and attitudes about diabetes control that may explain the racial and ethnic disparity. ^

INTEGRATIVE BIOMARKER IDENTIFICATION AND CLASSIFICATION USING HIGH THROUGHPUT ASSAYS

It is well accepted that tumorigenesis is a multi-step procedure involving aberrant functioning of genes regulating cell proliferation, differentiation, apoptosis, genome stability, angiogenesis and motility. To obtain a full understanding of tumorigenesis, it is necessary to collect information on all aspects of cell activity. Recent advances in high throughput technologies allow biologists to generate massive amounts of data, more than might have been imagined decades ago. These advances have made it possible to launch comprehensive projects such as (TCGA) and (ICGC) which systematically characterize the molecular fingerprints of cancer cells using gene expression, methylation, copy number, microRNA and SNP microarrays as well as next generation sequencing assays interrogating somatic mutation, insertion, deletion, translocation and structural rearrangements. Given the massive amount of data, a major challenge is to integrate information from multiple sources and formulate testable hypotheses. This thesis focuses on developing methodologies for integrative analyses of genomic assays profiled on the same set of samples. We have developed several novel methods for integrative biomarker identification and cancer classification. We introduce a regression-based approach to identify biomarkers predictive to therapy response or survival by integrating multiple assays including gene expression, methylation and copy number data through penalized regression. To identify key cancer-specific genes accounting for multiple mechanisms of regulation, we have developed the integIRTy software that provides robust and reliable inferences about gene alteration by automatically adjusting for sample heterogeneity as well as technical artifacts using Item Response Theory. To cope with the increasing need for accurate cancer diagnosis and individualized therapy, we have developed a robust and powerful algorithm called SIBER to systematically identify bimodally expressed genes using next generation RNAseq data. We have shown that prediction models built from these bimodal genes have the same accuracy as models built from all genes. Further, prediction models with dichotomized gene expression measurements based on their bimodal shapes still perform well. The effectiveness of outcome prediction using discretized signals paves the road for more accurate and interpretable cancer classification by integrating signals from multiple sources.

Multiple roles of charged amino acids in cytoplasmic loop 7 for expression and function of the multidrug and organic anion transporter MRP1 (ABCC1)

Multidrug resistance protein MRP1 mediates the ATP-dependent efflux of many chemotherapeutic agents and organic anions. MRP1 has two nucleotide binding sites (NBSs) and three membrane spanning domains (MSDs) containing 17 transmembrane helices linked by extracellular and cytoplasmic loops (CL). Homology models suggest that CL7 (amino acids 1141-1195) is in a position where it could participate in signaling between the MSDs and NBSs during the transport process. We have individually replaced eight charged residues in CL7 with Ala, and in some cases, an amino acid with the same charge, and then investigated the effects on MRP1 expression, transport activity, and nucleotide and substrate interactions. A triple mutant in which Glu(1169), Glu(1170), and Glu(1172) were all replaced with Ala was also examined. The properties of R1173A and E1184A were comparable with those of wild-type MRP1, whereas the remaining mutants were either poorly expressed (R1166A, D1183A) or exhibited reduced transport of one or more organic anions (E1144A, D1179A, K1181A, (1169)AAQA). Same charge mutant D1183E was also not expressed, whereas expression and activity of R1166K were similar to wild-type MRP1. The moderate substrate-selective changes in transport activity displayed by mutants E1144A, D1179A, K1181A, and (1169)AAQA were accompanied by changes in orthovanadate-induced trapping of [alpha-(32)P]azidoADP by NBS2 indicating changes in ATP hydrolysis or release of ADP. In the case of E1144A, estradiol glucuronide no longer inhibited trapping of azidoADP. Together, our results demonstrate the extreme sensitivity of CL7 to mutation, consistent with its critical and complex dual role in both the proper folding and transport activity of MRP1.

Interactions between landcover pattern and geospatial processing methods:effects on landscape metrics and classification accuracy

Remote sensing data is routinely used in ecology to investigate the relationship between landscape pattern as characterised by land use and land cover maps, and ecological processes. Multiple factors related to the representation of geographic phenomenon have been shown to affect characterisation of landscape pattern resulting in spatial uncertainty. This study investigated the effect of the interaction between landscape spatial pattern and geospatial processing methods statistically; unlike most papers which consider the effect of each factor in isolation only. This is important since data used to calculate landscape metrics typically undergo a series of data abstraction processing tasks and are rarely performed in isolation. The geospatial processing methods tested were the aggregation method and the choice of pixel size used to aggregate data. These were compared to two components of landscape pattern, spatial heterogeneity and the proportion of landcover class area. The interactions and their effect on the final landcover map were described using landscape metrics to measure landscape pattern and classification accuracy (response variables). All landscape metrics and classification accuracy were shown to be affected by both landscape pattern and by processing methods. Large variability in the response of those variables and interactions between the explanatory variables were observed. However, even though interactions occurred, this only affected the magnitude of the difference in landscape metric values. Thus, provided that the same processing methods are used, landscapes should retain their ranking when their landscape metrics are compared. For example, highly fragmented landscapes will always have larger values for the landscape metric "number of patches" than less fragmented landscapes. But the magnitude of difference between the landscapes may change and therefore absolute values of landscape metrics may need to be interpreted with caution. The explanatory variables which had the largest effects were spatial heterogeneity and pixel size. These explanatory variables tended to result in large main effects and large interactions. The high variability in the response variables and the interaction of the explanatory variables indicate it would be difficult to make generalisations about the impact of processing on landscape pattern as only two processing methods were tested and it is likely that untested processing methods will potentially result in even greater spatial uncertainty. © 2013 Elsevier B.V.

There is nothing that 'identifies me to that place' : Aboriginal Women's perceptions of health spaces and places

There is a growing body of literature within social and cultural geography that explores notions of place, space, culture, race and identity. The more recent works suggest that places are experienced and understood in multiple ways and are embedded within an array of politics. Memmott and Long, who have undertaken place-based research with Australian Indigenous people, present the theoretical position that ‘place is made and takes on meaning through an interaction process involving mutual accommodation between people and the environment’. They outline that places and their cultural meanings are generated through one or a combination of three types of people–environment interactions. These include: a place that is created by altering the physical characteristics of a piece of environment and which might encompass a feature or features which are natural or made; a place that is created totally through behaviour that is carried out within a specific area, therefore that specific behaviour becomes connected to that specific place; and a place created by people moving or being moved from one environment to another and establishing a new place where boundaries are created and activities carried out. All these ideas of places are challenged and confirmed by what Indigenous women have said about their particular use of, and relationship with, space within several health services in Rockhampton, Central Queensland. As my title suggests, Indigenous women do not see themselves as ‘neutral’ or ‘non-racialised’ citizens who enter and ‘use’ a supposedly neutral health service. Instead, Aboriginal women demonstrate they are active recognisers of places that would identify them within the particular health place. That is, they as Aboriginal women didn’t just ‘make’ place, the places and spaces ‘make’ them. The health services were identified as sites within which spatial relations could begin to grow with recognition of themselves as Aboriginal women in place, or instead create a sense of marginality in the failure of the spaces to identify them. The women’s voices within this paper are drawn from interviews undertaken with twenty Aboriginal women in Rockhampton, Central Queensland, Australia, who participated in a research project exploring ‘how the relationship between health services and Aboriginal women can be more empowering from the viewpoints of Aboriginal women’. The assumption underpinning this study was that empowering and re-empowering practices for Aboriginal women can lead to improved health outcomes. Throughout the interviews women shared some of their lived realities including some of their thoughts on identity, the body, employment in the health sector, service delivery and their notions of health service spaces and places. Their thoughts on health service spaces and places provide an understanding of the lived reality for Aboriginal women and are explored and incorporated within this paper.

The impact of pain on the quality of life of people with multiple sclerosis: A community survey

The purpose of this study was to examine the impact of pain on functioning across multiple quality of life (QOL) domains among individuals with multiple sclerosis (MS). A total of 219 people were recruited from a regional MS society membership database to serve as the community-based study sample. All participants completed a questionnaire containing items about their demographic and clinical characteristics, validated measures of QOL and MS-related disability, and a question on whether or not they had experienced clinically significant pain in the preceding 2 weeks. Respondents who reported pain then completed an in-person structured pain interview assessing pain characteristics (intensity, quality, location, extent, and duration). Comparisons between participants with and without MS-related pain demonstrated that pain prevalence and intensity were strongly correlated with QOL: physical health, psychological health, level of independence, and global QOL were more likely to be impaired among people with MS when pain was present, and the extent of impairment was associated with the intensity of pain. Moreover, these relationships remained significant even after statistically controlling for multiple demographic and clinical covariates associated with self-reported QOL. These findings suggest that for people with MS, pain is an important source of distress and disability beyond that caused by neurologic impairments.

Fluorescence spectrometric study on the interactions of isoprocarb and sodium 2-isopropylphenate with bovine serum albumin

The binding interaction of the pesticide Isoprocarb and its degradation product, sodium 2-isopropylphenate, with bovine serum albumin (BSA) was studied by spectrofluorimetry under simulated physiological conditions. Both Isoprocarb and sodium 2-isopropylphenate quenched the intrinsic fluorescence of BSA. This quenching proceeded via a static mechanism. The thermodynamic parameters (ΔH°, ΔS° and ΔG°) obtained from the fluorescence data measured at two different temperatures showed that the binding of Isoprocarb to BSA involved hydrogen bonds and that of sodium 2-isopropylphenate to BSA involved hydrophobic and electrostatic interactions. Synchronous fluorescence spectroscopy of the interaction of BSA with either Isoprocarb or sodium 2-isopropylphenate showed that the molecular structure of the BSA was changed significantly, which is consistent with the known toxicity of the pesticide, i.e., the protein is denatured. The sodium 2-isopropylphenate, was estimated to be about 4–5 times more toxic than its parent, Isoprocarb. Synchronous fluorescence spectroscopy and the resolution of the three-way excitation–emission fluorescence spectra by the PARAFAC method extracted the relative concentration profiles of BSA, Isoprocab and sodium 2-isopropylphenate as a function of the added sodium 2-isopropylphenate. These profiles showed that the degradation product, sodium 2-isopropylphenate, displaced the pesticide in a competitive reaction with the BSA protein.

Exercise, appetite, and energy balance: The interactions between energy expenditure and intake, and the implications for weight management

This book disseminates current information pertaining to the modulatory effects of foods and other food substances on behavior and neurological pathways and, importantly, vice versa. This ranges from the neuroendocrine control of eating to the effects of life-threatening disease on eating behavior. The importance of this contribution to the scientific literature lies in the fact that food and eating are an essential component of cultural heritage but the effects of perturbations in the food/cognitive axis can be profound. The complex interrelationship between neuropsychological processing, diet, and behavioral outcome is explored within the context of the most contemporary psychobiological research in the area. This comprehensive psychobiology- and pathology-themed text examines the broad spectrum of diet, behavioral, and neuropsychological interactions from normative function to occurrences of severe and enduring psychopathological processes

Crosstalk between developmental and tumour-specific signalling pathways : kallikrein-related serine peptidases and nodal in prostrate cancer

Prostate cancer is an important male health issue. The strategies used to diagnose and treat prostate cancer underscore the cell and molecular interactions that promote disease progression. Prostate cancer is histologically defined by increasingly undifferentiated tumour cells and therapeutically targeted by androgen ablation. Even as the normal glandular architecture of the adult prostate is lost, prostate cancer cells remain dependent on the androgen receptor (AR) for growth and survival. This project focused on androgen-regulated gene expression, altered cellular differentiation, and the nexus between these two concepts. The AR controls prostate development, homeostasis and cancer progression by regulating the expression of downstream genes. Kallikrein-related serine peptidases are prominent transcriptional targets of AR in the adult prostate. Kallikrein 3 (KLK3), which is commonly referred to as prostate-specific antigen, is the current serum biomarker for prostate cancer. Other kallikreins are potential adjunct biomarkers. As secreted proteases, kallikreins act through enzyme cascades that may modulate the prostate cancer microenvironment. Both as a panel of biomarkers and cascade of proteases, the roles of kallikreins are interconnected. Yet the expression and regulation of different kallikreins in prostate cancer has not been compared. In this study, a spectrum of prostate cell lines was used to evaluate the expression profile of all 15 members of the kallikrein family. A cluster of genes was co-ordinately expressed in androgenresponsive cell lines. This group of kallikreins included KLK2, 3, 4 and 15, which are located adjacent to one another at the centromeric end of the kallikrein locus. KLK14 was also of interest, because it was ubiquitously expressed among the prostate cell lines. Immunohistochemistry showed that these 5 kallikreins are co-expressed in benign and malignant prostate tissue. The androgen-regulated expression of KLK2 and KLK3 is well-characterised, but has not been compared with other kallikreins. Therefore, KLK2, 3, 4, 14 and 15 expression were all measured in time course and dose response experiments with androgens, AR-antagonist treatments, hormone deprivation experiments and cells transfected with AR siRNA. Collectively, these experiments demonstrated that prostatic kallikreins are specifically and directly regulated by the AR. The data also revealed that kallikrein genes are differentially regulated by androgens; KLK2 and KLK3 were strongly up-regulated, KLK4 and KLK15 were modestly up-regulated, and KLK14 was repressed. Notably, KLK14 is located at the telomeric end of the kallikrein locus, far away from the centromeric cluster of kallikreins that are stimulated by androgens. These results show that the expression of KLK2, 3, 4, 14 and 15 is maintained in prostate cancer, but that these genes exhibit different responses to androgens. This makes the kallikrein locus an ideal model to investigate AR signalling. The increasingly dedifferentiated phenotype of aggressive prostate cancer cells is accompanied by the re-expression of signalling molecules that are usually expressed during embryogenesis and foetal tissue development. The Wnt pathway is one developmental cascade that is reactivated in prostate cancer. The canonical Wnt cascade regulates the intracellular levels of β-catenin, a potent transcriptional co-activator of T-cell factor (TCF) transcription factors. Notably, β-catenin can also bind to the AR and synergistically stimulate androgen-mediated gene expression. This is at the expense of typical Wnt/TCF target genes, because the AR:β-catenin and TCF:β-catenin interactions are mutually exclusive. The effect of β-catenin on kallikrein expression was examined to further investigate the role of β-catenin in prostate cancer. Stable knockdown of β-catenin in LNCaP prostate cancer cells attenuated the androgen-regulated expression of KLK2, 3, 4 and 15, but not KLK14. To test whether KLK14 is instead a TCF:β-catenin target gene, the endogenous levels of β-catenin were increased by inhibiting its degradation. Although KLK14 expression was up-regulated by these treatments, siRNA knockdown of β-catenin demonstrated that this effect was independent of β-catenin. These results show that β-catenin is required for maximal expression of KLK2, 3, 4 and 15, but not KLK14. Developmental cells and tumour cells express a similar repertoire of signalling molecules, which means that these different cell types are responsive to one another. Previous reports have shown that stem cells and foetal tissues can reprogram aggressive cancer cells to less aggressive phenotypes by restoring the balance to developmental signalling pathways that are highly dysregulated in cancer. To investigate this phenomenon in prostate cancer, DU145 and PC-3 prostate cancer cells were cultured on matrices pre-conditioned with human embryonic stem cells (hESCs). Soft agar assays showed that prostate cancer cells exposed to hESC conditioned matrices had reduced clonogenicity compared with cells harvested from control matrices. A recent study demonstrated that this effect was partially due to hESC-derived Lefty, an antagonist of Nodal. A member of the transforming growth factor β (TGFβ) superfamily, Nodal regulates embryogenesis and is re-expressed in cancer. The role of Nodal in prostate cancer has not previously been reported. Therefore, the expression and function of the Nodal signalling pathway in prostate cancer was investigated. Western blots confirmed that Nodal is expressed in DU145 and PC-3 cells. Immunohistochemistry revealed greater expression of Nodal in malignant versus benign glands. Notably, the Nodal inhibitor, Lefty, was not expressed at the mRNA level in any prostate cell lines tested. The Nodal signalling pathway is functionally active in prostate cancer cells. Recombinant Nodal treatments triggered downstream phosphorylation of Smad2 in DU145 and LNCaP cells, and stably-transfected Nodal increased the clonogencity of LNCaP cells. Nodal was also found to modulate AR signalling. Nodal reduced the activity of an androgen-regulated KLK3 promoter construct in luciferase assays and attenuated the endogenous expression of AR target genes including prostatic kallikreins. These results demonstrate that Nodal is a novel example of a developmental signalling molecule that is reexpressed in prostate cancer and may have a functional role in prostate cancer progression. In summary, this project clarifies the role of androgens and changing cellular differentiation in prostate cancer by characterising the expression and function of the downstream genes encoding kallikrein-related serine proteases and Nodal. Furthermore, this study emphasises the similarities between prostate cancer and early development, and the crosstalk between developmental signalling pathways and the AR axis. The outcomes of this project also affirm the utility of the kallikrein locus as a model system to monitor tumour progression and the phenotype of prostate cancer cells.

Good results for early treatment of clinically isolated syndrome prior to multiple sclerosis with interferon beta-1b and glatiramer

Background: The first sign of developing multiple sclerosis is a clinically isolated syndrome that resembles a multiple sclerosis relapse. Objective/methods: The objective was to review the clinical trials of two medicines in clinically isolated syndromes (interferon β and glatiramer acetate) to determine whether they prevent progression to definite multiple sclerosis. Results: In the BENEFIT trial, after 2 years, 45% of subjects in the placebo group developed clinically definite multiple sclerosis, and the rate was lower in the interferon β-1b group. Then all subjects were offered interferon β-1b, and the original interferon β-1b group became the early treatment group, and the placebo group became the delayed treatment group. After 5 years, the number of subjects with clinical definite multiple sclerosis remained lower in the early treatment than late treatment group. In the PreCISe trial, after 2 years, the time for 25% of the subjects to convert to definite multiple sclerosis was prolonged in the glatiramer group. Conclusions: Interferon β-1b and glatiramer acetate slow the progression of clinically isolated syndromes to definite multiple sclerosis. However, it is not known whether this early treatment slows the progression to the physical disabilities experienced in multiple sclerosis.

UHT milk contains multiple forms of αS1-casein that undergo degradative changes during storage

Milk proteins are susceptible to chemical changes during processing and storage. We used proteomic tools to analyse bovine αS1-casein in UHT milk. 2-D gels of freshly processed milk αS1-casein was presented as five or more spots due to genetic polymorphism and variable phosphorylation. MS analysis after phosphopeptide enrichment allowed discrimination between phosphorylation states and genetic variants. We identified a new alternatively-spliced isoform with a deletion of exon 17, producing a new C-terminal sequence, K164SQVNSEGLHSYGL177, with a novel phosphorylation site at S174. Storage of UHT milk at elevated temperatures produced additional, more acidic αS1-casein spots on the gels and decreased the resolution of minor forms. MS analysis indicated that non-enzymatic deamidation and loss of the N-terminal dipeptide were the major contributors to the changing spot pattern. These results highlight the important role of storage temperature in the stability of milk proteins and the utility of proteomic techniques for analysis of proteins in food.

Multiple distribution static synchronous compensators for distribution feeder voltage support

The potential of multiple distribution static synchronous compensators (DSTATCOMs) to improve the voltage profile of radial distribution networks has been reported in the literature by few authors. However, the operation of multiple DSTATCOMs across a distribution feeder may introduce control interactions and/or voltage instability. This study proposes a control scheme that alleviates interactions among controllers and enhances proper reactive power sharing among DSTATCOMs. A generalised mathematical model is presented to analyse the interactions among any number of DSTATCOMs in the network. The criterion for controller design is developed by conducting eigenvalue analysis on this mathematical model. The proposed control scheme is tested in time domain on a sample radial distribution feeder installed with multiple DSTATCOMs and test results are presented.

Dynamics of rod and cone photoreceptor interactions under mesopic light levels

Visual adaptation regulates contrast sensitivity during dynamically changing light conditions (Crawford, 1947; Hecht, Haig & Chase, 1937). These adaptation dynamics are unknown under dim (mesopic) light levels when the rod (R) and long (L), medium (M) and short (S) wavelength cone photoreceptor classes contribute to vision via interactions in shared non-opponent Magnocellular (MC), chromatically opponent Parvocellular (PC) and Koniocellular (KC) visual pathways (Dacey, 2000). This study investigated the time-course of adaptation and post-receptoral pathways mediating receptor specific rod and cone interactions under mesopic illumination. A four-primary photostimulator (Pokorny, Smithson & Quinlan, 2004) was used to independently control the activity of the four photoreceptor classes and their post-receptoral visual athways in human observers. In the first experiment, the contrast sensitivity and time-course of visual adaptation under mesopic illumination were measured for receptoral (L, S, R) and post-receptoral (LMS, LMSR, L-M) stimuli. An incremental (Rapid-ON) sawtooth conditioning pulse biased detection to ON-cells within the visual pathways and sensitivity was assayed relative to pulse onset using a briefly presented incremental probe that did not alter adaptation. Cone.Cone interactions with luminance stimuli (L cone, LMS, LMSR) reduced sensitivity by 15% and the time course of recovery was 25± 5ms-1 (μ ± SEM). PC mediated (+L-M) chromatic stimuli sensitivity loss was less (8%) than for luminance and recovery was slower (μ = 2.95 ± 0.05 ms-1), with KC mediated (S cone) chromatic stimuli showing a high sensitivity loss (38%) and the slowest recovery time (1.6 ± 0.2 ms-1). Rod-Rod interactions increased sensitivity by 20% and the time course of recovery was 0.7 ± 0.2 ms-1 (μ ± SD). Compared to these interaction types, Rod-Cone interactions reduced sensitivity to a lesser degree (5%) and showed the fastest recovery (μ = 43 ± 7 ms-1). In the second experiment, rod contribution to the magnocellular, parvocellular and koniocellular post-receptoral pathways under mesopic illumination was determined as a function of incremental stimulus duration and waveform (rectangular; sawtooth) using a rod colour match procedure (Cao, Pokorny & Smith, 2005; Cao, Pokorny, Smith & Zele, 2008a). For a 30% rod increment, a cone match required a decrease in [L/(L+M)] and an increase in [L+M] and [S/(L+M)], giving a greenish-blue and brighter appearance for probe durations of 75 ms or longer. Probe durations less than 75 ms showed an increase in [L+M] and no change in chromaticity [L/(L+M) or S/(L+M)], uggesting mediation by the MC pathway only for short duration rod stimuli. s We advance previous studies by determining the time-course and nature of photoreceptor specific retinal interactions in the three post-receptoral pathways under mesopic illumination. In the first experiment, the time-course of adaptation for ON cell processing was determined, revealing opponent cell facilitation in chromatic PC and KC pathways. The Rod-Rod and Rod-Cone data identify previously unknown interaction types that act to maintain contrast sensitivity during dynamically changing light conditions and improve the speed of light adaptation under mesopic light levels. The second experiment determined the degree of rod contribution to the inferred post-eceptoral pathways as a function of the temporal properties of the rod signal. r The understanding of the mechanisms underlying interactions between photoreceptors under mesopic illumination has implications for the study of retinal disease. Visual function has been shown to be reduced in persons with age-related maculopathy (ARM) risk genotypes prior to clinical signs of the disease (Feigl, Cao, Morris & Zele, 2011) and disturbances in rod-mediated adaptation have been shown in early phases of ARM (Dimitrov, Guymer, Zele, Anderson & Vingrys, 2008; Feigl, Brown, Lovie-Kitchin & Swann, 2005). Also, the understanding of retinal networks controlling vision enables the development of international lighting standards to optimise visual performance nder dim light levels (e.g. work-place environments, transportation).

Talk and web searching in an early years classroom

Recent Australian early childhood policy and curriculum guidelines promoting the use of technologies invite investigations of young children’s practices in classrooms. This study examined the practices of one preparatory year classroom, to show teacher and child interactions as they engaged in Web searching. The study investigated the in situ practices of the teacher and children to show how they accomplished the Web search. The data corpus consists of eight hours of videorecorded interactions over three days where children and teachers engaged in Web searching. One episode was selected that showed a teacher and two children undertaking a Web search. The episode is shown to consist of four phases: deciding on a new search subject, inputting the search query, considering the result options, and exploring the selected result. The sociological perspectives of ethnomethodology and conversation analysis were employed as the conceptual and methodological frameworks of the study, to analyse the video-recorded teacher and child interactions as they co-constructed a Web search. Ethnomethodology is concerned with how people make ‘sense’ in everyday interactions, and conversation analysis focuses on the sequential features of interaction to show how the interaction unfolds moment by moment. This extended single case analysis showed how the Web search was accomplished over multiple turns, and how the children and teacher collaboratively engaged in talk. There are four main findings. The first was that Web searching featured sustained teacher-child interaction, requiring a particular sort of classroom organisation to enable the teacher to work in this sustained way. The second finding was that the teacher’s actions recognised the children’s interactional competence in situ, orchestrating an interactional climate where everyone was heard. The third finding was that the teacher drew upon a range of interactional resources designed to progress the activity at hand, that of accomplishing the Web search. The teacher drew upon the interactional resources of interrogatives, discourse markers, and multi-unit turns during the Web search, and these assisted the teacher and children to co-construct their discussion, decide upon and co-ordinate their future actions, and accomplish the Web search in a timely way. The fourth finding explicates how particular social and pedagogic orders are accomplished through talk, where children collaborated with each other and with the teacher to complete the Web search. The study makes three key recommendations for the field of early childhood education. The study’s first recommendation is that fine-grained transcription and analysis of interaction aids in understanding interactional practices of Web searching. This study offers material for use in professional development, such as using transcribed and videorecorded interactions to highlight how teachers strategically engage with children, that is, how talk works in classroom settings. Another strategy is to focus on the social interactions of members engaging in Web searches, which is likely to be of interest to teachers as they work to engage with children in an increasingly online environment. The second recommendation involves classroom organisation; how teachers consider and plan for extended periods of time for Web searching, and how teachers accommodate children’s prior knowledge of Web searching in their classrooms. The third recommendation is in relation to future empirical research, with suggested possible topics focusing on the social interactions of children as they engage with peers as they Web search, as well as investigations of techno-literacy skills as children use the Internet in the early years.

Genetic polymorphisms in the human tissue kallikrein (KLK) locus and their implication in various malignant and non-malignant diseases

The Kallikrein (KLK) gene locus encodes a family of serine proteases and is the largest contiguous cluster of protease-encoding genes attributed an evolutionary age of 330 million years. The KLK locus has been implicated as a high susceptibility risk loci in numerous cancer studies through the last decade. The KLK3 gene already has established clinical relevance as a biomarker in prostate cancer prognosis through its encoded protein, prostate-specific antigen. Data mined through genome-wide association studies (GWAS) and next-generation sequencing point to many important candidate single nucleotide polymorphisms (SNPs) in KLK3 and other KLK genes. SNPs in the KLK locus have been found to be associated with several diseases including cancer, hypertension, cardiovascular disease and atopic dermatitis. Moreover, introducing a model incorporating SNPs to improve the efficiency of prostate-specific antigen in detecting malignant states of prostate cancer has been recently suggested. Establishing the functional relevance of these newly-discovered SNPs, and their interactions with each other, through in silico investigations followed by experimental validation, can accelerate the discovery of diagnostic and prognostic biomarkers. In this review, we discuss the various genetic association studies on the KLK loci identified either through candidate gene association studies or at the GWAS and post-GWAS front to aid researchers in streamlining their search for the most significant, relevant and therapeutically promising candidate KLK gene and/or SNP for future investigations.