Identifying cis-regulatory elements by statistical analysis and phylogenetic footprinting and analyzing their coexistence and related gene ontology

Discovery of cis-regulatory elements in gene promoters is a highly challenging research issue in computational molecular biology. This paper presents a novel approach to searching putative cis-regulatory elements in human promoters by first finding 8-mer sequences of high statistical significance from gene promoters of humans, mice, and Drosophila melanogaster, respectively, and then identifying the most conserved ones across the three species (phylogenetic footprinting). In this study, a conservation analysis on both closely related species (humans and mice) and distantly related species (humans/mice and Drosophila) is conducted not only to examine more candidates but also to improve the prediction accuracy. We have found 124 putative cis-regulatory elements and grouped these into 20 clusters. The investigation on the coexistence of these clusters in human gene promoters reveals that SP1, EGR, and NRF-1 are the dominant clusters appearing in the combinatorial combination of up to five clusters. Gene Ontology (GO) analysis also shows that many GO categories of transcription factors binding to these cis-regulatory elements match the GO categories of genes whose promoters contain these elements. Compared with previous research, the contribution of this study lies not only in the finding of new cis-regulatory elements, but also in its pioneering exploration on the coexistence of discovered elements and the GO relationship between transcription factors and regulated genes. This exploration verifies the putative cis-regulatory elements that have been found from this study and also gives new insight on the regulation mechanisms of gene expression.

Changing philosophies and tools for statistical inferences in behavioral ecology

Recent developments in ecological statistics have reached behavioral ecology, and an increasing number of studies now apply analytical tools that incorporate alternatives to the conventional null hypothesis testing based on significance levels. However, these approaches continue to receive mixed support in our field. Because our statistical choices can influence research design and the interpretation of data, there is a compelling case for reaching consensus on statistical philosophy and practice. Here, we provide a brief overview of the recently proposed approaches and open an online forum for future discussion (https://bestat.ecoinformatics.org/). From the perspective of practicing behavioral ecologists relying on either correlative or experimental data, we review the most relevant features of information theoretic approaches, Bayesian inference, and effect size statistics. We also discuss concerns about data quality, missing data, and repeatability. We emphasize the necessity of moving away from a heavy reliance on statistical significance while focusing attention on biological relevance and effect sizes, with the recognition that uncertainty is an inherent feature of biological data. Furthermore, we point to the importance of integrating previous knowledge in the current analysis, for which novel approaches offer a variety of tools. We note, however, that the drawbacks and benefits of these approaches have yet to be carefully examined in association with behavioral data. Therefore, we encourage a philosophical change in the interpretation of statistical outcomes, whereas we still retain a pluralistic perspective for making objective statistical choices given the uncertainties around different approaches in behavioral ecology. We provide recommendations on how these concepts could be made apparent in the presentation of statistical outputs in scientific papers.

Statistical comparisons of non-deterministic IR systems using two dimensional variance

Retrieval systems with non-deterministic output are widely used in information retrieval. Common examples include sampling, approximation algorithms, or interactive user input. The effectiveness of such systems differs not just for different topics, but also for different instances of the system. The inherent variance presents a dilemma - What is the best way to measure the effectiveness of a non-deterministic IR system? Existing approaches to IR evaluation do not consider this problem, or the potential impact on statistical significance. In this paper, we explore how such variance can affect system comparisons, and propose an evaluation framework and methodologies capable of doing this comparison. Using the context of distributed information retrieval as a case study for our investigation, we show that the approaches provide a consistent and reliable methodology to compare the effectiveness of a non-deterministic system with a deterministic or another non-deterministic system. In addition, we present a statistical best-practice that can be used to safely show how a non-deterministic IR system has equivalent effectiveness to another IR system, and how to avoid the common pitfall of misusing a lack of significance as a proof that two systems have equivalent effectiveness.

Price exhaustion and number preference : time and price confluence in Australian stock prices

Confluence occurs when different trading filters generate signals that point to the same directional move. Using regression analysis, this paper investigates confluence trading signals associated with number preference and price exhaustion, for a sample of Australian stocks. The results show that certain price levels tend to act as psychological barriers, and that price exhaustion signals are a real phenomenon in the Australian stock market. It is shown also that confluence exists in the Australian stock market. Importantly, confluence is associated with price retracements that are of economic and statistical significance, offering profitable trading opportunities. The results suggest that Australian stocks do not follow a random walk.

Frequency distribution of TATA box and extension sequences on human promoters

TATA box is one of the most important transcription factor binding sites. But the exact sequences of TATA box are still not very clear yet. In this study, we conducted a dedicated analysis on the frequency distribution of TATA Box and its extension sequences on human promoters. Sixteen TATA elements derived from TATA Box motif, TATAWAWN, were classified into three distribution patterns: peak, bottom-peak and bottom. Fourteen TATA extension sequences (up to two base extensions) were predicted to be the new TATA Box elements because of their high motif factors, which indicate their statistical significance. Statistical analysis on the promoters of mouse, zebrafish and drosophila melanogaster verified seven of these elements. It was also observed that the distribution of TATA elements on the promoters of housekeeping genes are very similar with their distribution on the promoters of tissue specific genes in human.

Additive effect of interferential therapyover pelvic floor exercise alone in the treatment of female urinary stress and urge incontinence: A randomized controlled trial

This pilot study attempted to examine the additional efficacy of interferential therapy in reducing the symptoms of urinary stress and urge incontinence. Twenty-four subjects were randomly allocated to the experimental group, which received interferential therapy plus pelvic floor exercises, or the control group, which received pelvic floor exercises only. Treatment was given three times a week for 4 weeks. Subjects were given urinary diaries to record urinary symptoms (including frequency of passing urine and number of times woken by desire to pass urine) for 5 days prior to and after treatment. Perineometer readings, pad weighing test and start/stop test were also performed in a physiotherapy clinic before and at completion of treatment regimes. Significant improvements were observed in all the outcome variables in the experimental group, but in only the perineometer readings in controls. When the changes from pre- to post-treatment were compared between the two groups, four of the dependent variables did not reach statistical significance. Power analysis indicated that the sample size for each group needed to be 70 for all results to be statistically significant. This study shows that interferential therapy plus pelvic floor exercise appears to be a more effective treatment modality than pelvic floor muscle strengthening exercise alone for incontinence, but a larger trial with longer followup is needed before definitive conclusions can be reached.

Monitoring of immune responses to a herbal immuno-modulator in patients with advanced colorectal cancer.

Many herbal medicines are widely used as immuno-modulators in Asian countries. Ganoderma lucidum (Lingzhi) is one of the most commonly used herbs in Asia and preclinical studies have established that the polysaccharide fractions of G. lucidum have potent immuno-modulating effects. However, clinical evidence for this is scanty. The present open-labeled study aimed to evaluate the effects of G. lucidum polysaccharides on selected immune functions in patients with advanced colorectal cancer. Forty-seven patients were enrolled and treated with oral G. lucidum at 5.4 g/day for 12 weeks. Selected immune parameters were monitored using various immunological methods throughout the study. In 41 assessable cancer patients, treatment with G. lucidum tended to increase mitogenic reactivity to phytohemagglutinin, counts of CD3, CD4, CD8 and CD56 lymphocytes, plasma concentrations of interleukin (IL)-2, IL-6 and interferon (IFN)-γ, and NK activity, whereas plasma concentrations of IL-1 and tumor necrosis factor (TNF)-α were decreased. For all of these parameters, no statistical significance was observed when a comparison was conducted between baseline and those values after a 12-week treatment with G. lucidum. The changes of IL-1 were correlated with those for IL-6, IFN-γ, CD3, CD4, CD8 and NK activity (p < 0.05) and IL-2 changes were correlated with those for IL-6, CD8 and NK activity. The results indicate that G. lucidum may have potential immuno-modulating effect in patients with advanced colorectal cancer. Further studies are needed to explore the benefits and safety of G. lucidum in cancer patients.

Determination of thalidomide by high performance liquid chromatography: plasma pharmacokinetic studies in the rat

A sensitive and simple high performance liquid chromatography (HPLC) method was developed and validated for the determination of thalidomide in rat plasma. Chromatography was accomplished with a reversed-phase Hypersil C18 column. Mobile phase consisted of acetonitrile-10 mM ammonium acetate buffer (pH 5.50) (28:72, v/v), at a flow rate of 0.8 ml/min. Thalidomide was monitored by ultraviolet detector at 220 nm and it gave a linear response as a function of concentration over 0.02–50 μM. The limit of quantitation in rat plasma was 0.50 ng (0.02 μM plasma concentration) with an aliquot of 20 μl. Results from a 3-day validation study indicated that this method allows for simple and rapid quantitation of thalidomide with excellent accuracy and reliability. Using this validated assay, the effect of coadministered irinotecan (CPT-11) on the plasma pharmacokinetics of thalidomide in rats was determined. Coadministration of CPT-11 (intravenously, 60 mg/kg) increased the maximum plasma concentration (C_max) and area under the plasma concentration–time curve (AUC_{0–10 h}) of thalidomide by 32.29 and 11.66%, respectively, as compared to the control, but none of the effect of CPT-11 was of statistical significance (P > 0.05). Concomitant CPT-11 also caused a 10.04% decrease in plasma clearance (CL) and 14.51% decrease in volume of distribution (V_d) (P > 0.05). These results suggest that coadministered CPT-11 did not significantly alter the plasma pharmacokinetics of thalidomide in rats. Further studies are warranted to explore the pharmacokinetic and pharmacodynamic interactions between CPT-11 and thalidomide.

Enhancing the health of medical students : outcomes of an integrated mindfulness and lifestyle program

Medical students experience various stresses and many poor health behaviours. Previous studies consistently show that student wellbeing is at its lowest pre-exam. Little core-curriculum is traditionally dedicated to providing self-care skills for medical students. This paper describes the development, implementation and outcomes of the Health Enhancement Program (HEP) at Monash University. It comprises mindfulness and ESSENCE lifestyle programs, is experientially-based, and integrates with biomedical sciences, clinical skills and assessment. This study measured the program’s impact on medical student psychological distress and quality of life. A cohort study performed on the 2006 first-year intake measured effects of the HEP on various markers of wellbeing. Instruments used were the depression, anxiety and hostility subscales of the Symptom Checklist-90-R incorporating the Global Severity Index (GSI) and the WHO Quality of Life (WHOQOL) questionnaire. Pre-course data (T1) was gathered mid-semester and post-course data (T2) corresponded with pre-exam week. To examine differences between T1 and T2 repeated measures ANOVA was used for the GSI and two separate repeated measures MANOVAs were used to examine changes in the subscales of the SCL-90-R and the WHOQOL-BREF. Follow-up t-tests were conducted to examine differences between individual subscales. A total of 148 of an eligible 270 students returned data at T1 and T2 giving a response rate of 55%. 90.5% of students reported personally applying the mindfulness practices. Improved student wellbeing was noted on all measures and reached statistical significance for the depression (mean T1 = 0.91, T2 = 0.78; p = 0.01) and hostility (0.62, 0.49; 0.03) subscales and the GSI (0.73, 0.64; 0.02) of the SCL-90, but not the anxiety subscale (0.62, 0.54; 0.11). Statistically significant results were also found for the psychological domain (62.42, 65.62; p < 0.001) but not the physical domain (69.11, 70.90; p = 0.07) of the WHOQOL. This study is the first to demonstrate an overall improvement in medical student wellbeing during the pre-exam period suggesting that the common decline in wellbeing is avoidable. Although the findings of this study indicate the potential for improving student wellbeing at the same time as meeting important learning objectives, the limitations in study design due to the current duration of follow-up and lack of a control group means that the data should be interpreted with caution. Future research should be directed at determining the contribution of individual program components, long-term outcomes, and impacts on future attitudes and clinical practice.

Physical activity and healthy weight maintenance from childhood to adulthood

The objective of this study was to determine whether change in physical activity was associated with maintaining a healthy weight from childhood to adulthood. This prospective cohort study examined 1,594 young Australian adults (48.9% female) aged 27–36 years who were first examined at age 9–15 years as part of a national health and fitness survey. BMI was calculated from measured height and weight, and physical activity was self-reported at both time points; pedometers were also used at follow-up. Change in physical activity was characterized by calculating the difference between baseline and follow-up z-scores. Change scores were categorized as decreasing (large, moderate), stable, or increasing (large, moderate). Healthy weight was defined in childhood as a BMI less than international overweight cutoff points, and in adulthood as BMI<25 kg/m2. Healthy weight maintainers were healthy weight at both time points. Compared with those who demonstrated large relative decreases in physical activity, females in all other groups were 25–37% more likely to be healthy weight maintainers, although associations differed according to the physical activity measure used at follow-up and few reached statistical significance. Although younger males whose relative physical activity moderately or largely increased were 27–34% more likely to be healthy weight maintainers than those whose relative physical activity largely decreased, differences were not statistically significant. In conclusion, relatively increasing and stable physical activity from childhood to adulthood was only weakly associated with healthy weight maintenance. Examining personal, social, and environmental factors associated with healthy weight maintenance will be an important next step in understanding why some groups avoid becoming overweight.

Femoral sulcus angle and increased patella facet cartilage volume in an osteoarthritic population

Objective
The patellofemoral joint is an example of an incongruent articulation commonly affected by osteoarthritis (OA). The relationship between femoral sulcus angle and the development and progression of patellofemoral OA is unclear. The aim of this study was to examine the relationship between the femoral sulcus angle at baseline and patella cartilage volume at baseline and at 2-year follow-up among community based adults with established knee OA.

Methods
One hundred subjects had magnetic resonance imaging of their symptomatic knee at baseline and at 2-year follow-up. From these images, patella cartilage volume was determined. Radiographic skyline views of the patellofemoral joint were taken at baseline to measure the femoral sulcus angle.

Results
For every 1° increase in the femoral sulcus angle (i.e., as the sulcus angle became more shallow) there was an associated 9.1 mm3 (95% CI 3.1, 15.0) increase in medial patella cartilage volume at baseline (P = 0.003). There was a similar trend that approached statistical significance between the femoral sulcus angle and the lateral patella facet cartilage volume at baseline (P = 0.09). There was no association between the femoral sulcus angle at baseline and the change in patella cartilage volume over 2 years in either patellofemoral compartment.

Conclusion
These results infer that the femoral sulcus angle is a cross-sectional determinant of the amount of patella cartilage, but is not a major determinant of the annual change of patella cartilage volume among people with knee OA. These data suggest that a shallower sulcus in the context of established OA may be an advantageous anatomical variant. Further longitudinal studies are required to determine the role of the femoral sulcus angle in OA.

Non-standard work schedules and health outcomes in Australia : some evidence from the HILDA Panel

What does the around-the-clock economic activity mean for workers' health? Despite the fact that non-standard work accounts for an increasing share of the job opportunities, relatively little is known about the potential consequences for health and the existing evidence is ambiguous. In this paper I examine the associations between non-standard job schedules and workers' physical and mental health outcomes using longitudinal data from the Household, Income and Labour Dynamics in Australia (HILDA). Specifically, the four health indicators considered are self-rated health and the SF-36 health indices for general health, mental health and physical functioning. Overall results generally suggest a negative relationship between non-standard work schedules and better health for both males and females. Regarding the statistical significance and magnitudes of the associations, however, we observe apparent differences between males and females. Among females, most of the coefficients in all models are statistically insignificant, which implies very small magnitudes in terms of the correlation between non-standard working hours and health. These results apply uniformly to all health measures investigated. Among males, on the other hand, the negative relationship is more noticeable for self-rated health, general health and physical functioning than for mental health. The pooled OLS and random effects coefficients are usually larger in magnitude and more significant than the fixed effects parameters. Nonetheless, even the more significant coefficients do not imply large effects in absolute terms.

An empirical analysis of sugarcane production in Fiji, 1970-2000

Fiji is a small island country in the South Pacific. Sugar is its oldest industry, being in the vanguard of economic growth and development for over a century. Today the oldest industry, not only in Fiji but also in the South Pacific Island countries, is shrivelling and is poised on the precipice of collapse. The literature to date has singled out expiring land leases and the inability of the government to resolve this issue as the key to the current calamity. This paper aims to estimate a sugarcane production model for Fiji, delineating the short-run and long-run determinants. It expands the Cobb-Douglas production function in specifying the sugarcane production model and uses time series data (1970-2000) in estimating it. The major findings are that area harvested and fertiliser (capital), labour force and prices paid to sugarcane farmers have made positive contributions to sugarcane production in both the short- and long-run. The finding on the statistical significance of area harvested has direct relevance to the current land problems in Fiji. It is envisaged that the results will appeal to Fijian policy makers and that a speedy solution to the problem of expiring and non-productive use of sugarcane land will be achieved.

Individual and area-level socioeconomic associations with fast food purchasing

Background It has been suggested that those with lower socioeconomic characteristics would be more likely to seek energy-dense food options such as fast food because of cheaper prices; however, to date the evidence has been inconsistent. This study examines both individual- and area-level socioeconomic characteristics and their independent associations with chain-brand fast food purchasing.

Methods Data from the 2003 Victorian Lifestyle and Neighbourhood Environments Study (VicLANES); a multilevel study of 2547 adults from 49 small-areas in Melbourne, Australia, were used. Multilevel multinomial models adjusted for confounders were used to assess associations between individual socioeconomic position (education, occupation and income) and area socioeconomic characteristics in relation to fast food purchasing from five major fast food chains with outcome categories: never, at least monthly and at least weekly. The study finally assessed whether any potential area-level associations were mediated by fast food access.

Results Increased fast food purchasing was independently associated with lower education, being a blue-collar employee and decreased household income. Results for area-level disadvantage were marginally insignificant after adjustment for individual-level characteristics, although they were suggestive that living in an area with greater levels of disadvantage increased an individual's odds of more frequent fast food purchasing. This effect was further attenuated when measures of fast food restaurant access were included in the models.

Conclusion Independent effects of lower individual-level socioeconomic characteristics and more frequent fast food purchasing for home consumption are demonstrated. Although evidence was suggestive of an independent association with area-level disadvantage this did not reach statistical significance.

Developmental outcomes of children exposed to antidepressants in pregnancy

Objective: To examine the developmental outcomes in children exposed to antidepressants in utero and compare those to children not exposed to these medications
Method: A prospective case-controlled study of children exposed to antidepressants in pregnancy assessed 22 exposed and 19 not exposed children using the Bayley Scales of Infant Development, third edition. The control group was measured at a mean age of 23.09 (SD 3.82) months and the medicated group at 28.53 months (SD 6.22). Maternal variables were assessed using a purpose-designed questionnaire and the Beck Depression Inventory (II) in pregnancy and at three assessments in the postpartum.
Results: Children exposed to antidepressant medication in pregnancy scored lower on motor subscales in particular on fine motor scores than non-exposed children with a moderate effect size of Cohen ’ s d = 0.47 fi ne motor and Cohen ’ s d = 0.43 for gross motor. Due to lack of power these findings did not reach conventional criteria for statistical significance. There was no association found between maternal depression and neurodevelopment.
Conclusions: This finding of a possible effect from antidepressant exposure in pregnancy on children ’ s motor development is similar to the findings from a previous study. Future research is needed which assesses children at an older age using specific assessments of motor development.