A simple and robust method for connecting small-molecule drugs using gene-expression signatures

Interaction of a drug or chemical with a biological system can result in a gene-expression profile or signature characteristic of the event. Using a suitably robust algorithm these signatures can potentially be used to connect molecules with similar pharmacological or toxicological properties. The Connectivity Map was a novel concept and innovative tool first introduced by Lamb et al to connect small molecules, genes, and diseases using genomic signatures [Lamb et al (2006), Science 313, 1929-1935]. However, the Connectivity Map had some limitations, particularly there was no effective safeguard against false connections if the observed connections were considered on an individual-by-individual basis. Further when several connections to the same small-molecule compound were viewed as a set, the implicit null hypothesis tested was not the most relevant one for the discovery of real connections. Here we propose a simple and robust method for constructing the reference gene-expression profiles and a new connection scoring scheme, which importantly allows the valuation of statistical significance of all the connections observed. We tested the new method with the two example gene-signatures (HDAC inhibitors and Estrogens) used by Lamb et al and also a new gene signature of immunosuppressive drugs. Our testing with this new method shows that it achieves a higher level of specificity and sensitivity than the original method. For example, our method successfully identified raloxifene and tamoxifen as having significant anti-estrogen effects, while Lamb et al's Connectivity Map failed to identify these. With these properties our new method has potential use in drug development for the recognition of pharmacological and toxicological properties in new drug candidates.Comment: 8 pages, 2 figures, and 2 tables; supplementary data supplied as a ZIP fil

Using microscopic video data measures for driver behavior analysis during adverse winter weather: opportunities and challenges

ABSTRACT: This paper presents a driver behavior analysis using microscopic video data measures including vehicle speed, lane-changing ratio, and time to collision. An analytical framework was developed to evaluate the effect of adverse winter weather conditions on highway driving behavior based on automated (computer) and manual methods. The research was conducted through two case studies. The first case study was conducted to evaluate the feasibility of applying an automated approach to extracting driver behavior data based on 15 video recordings obtained in the winter 2013 at three different locations on the Don Valley Parkway in Toronto, Canada. A comparison was made between the automated approach and manual approach, and issues in collecting data using the automated approach under winter conditions were identified. The second case study was based on high quality data collected in the winter 2014, at a location on Highway 25 in Montreal, Canada. The results demonstrate the effectiveness of the automated analytical framework in analyzing driver behavior, as well as evaluating the impact of adverse winter weather conditions on driver behavior. This approach could be applied to evaluate winter maintenance strategies and crash risk on highways during adverse winter weather conditions

Complex patterns of local adaptation in teosinte

Populations of widely distributed species often encounter and adapt to specific environmental conditions. However, comprehensive characterization of the genetic basis of adaptation is demanding, requiring genome-wide genotype data, multiple sampled populations, and a good understanding of population structure. We have used environmental and high-density genotype data to describe the genetic basis of local adaptation in 21 populations of teosinte, the wild ancestor of maize. We found that altitude, dispersal events and admixture among subspecies formed a complex hierarchical genetic structure within teosinte. Patterns of linkage disequilibrium revealed four mega-base scale inversions that segregated among populations and had altitudinal clines. Based on patterns of differentiation and correlation with environmental variation, inversions and nongenic regions play an important role in local adaptation of teosinte. Further, we note that strongly differentiated individual populations can bias the identification of adaptive loci. The role of inversions in local adaptation has been predicted by theory and requires attention as genome-wide data become available for additional plant species. These results also suggest a potentially important role for noncoding variation, especially in large plant genomes in which the gene space represents a fraction of the entire genome

Defending the genome from the enemy within:mechanisms of retrotransposon suppression in the mouse germline

The viability of any species requires that the genome is kept stable as it is transmitted from generation to generation by the germ cells. One of the challenges to transgenerational genome stability is the potential mutagenic activity of transposable genetic elements, particularly retrotransposons. There are many different types of retrotransposon in mammalian genomes, and these target different points in germline development to amplify and integrate into new genomic locations. Germ cells, and their pluripotent developmental precursors, have evolved a variety of genome defence mechanisms that suppress retrotransposon activity and maintain genome stability across the generations. Here, we review recent advances in understanding how retrotransposon activity is suppressed in the mammalian germline, how genes involved in germline genome defence mechanisms are regulated, and the consequences of mutating these genome defence genes for the developing germline

Positive psychology of Malaysian students: impacts of engagement, motivation, self-compassion and wellbeing on mental health

Malaysia plays a key role in education of the Asia Pacific, expanding its scholarly output rapidly. However, mental health of Malaysian students is challenging, and their help-seeking is low because of stigma. This study explored the relationships between mental health and positive psychological constructs (academic engagement, motivation, self-compassion, and wellbeing), and evaluated the relative contribution of each positive psychological construct to mental health in Malaysian students. An opportunity sample of 153 students completed the measures regarding these constructs. Correlation, regression, and mediation analyses were conducted. Engagement, amotivation, self-compassion, and wellbeing were associated with, and predicted large variance in mental health. Self-compassion was the strongest independent predictor of mental health among all the positive psychological constructs. Findings can imply the strong links between mental health and positive psychology, especially selfcompassion. Moreover, intervention studies to examine the effects of self-compassion training on mental health of Malaysian students appear to be warranted.N/

Calibration of diffuse correlation spectroscopy with a time-resolved near-infrared technique to yield absolute cerebral blood flow measurements: errata

Abstract: The authors provide corrections to tabular data and a figure, which do not alter the conclusions of the original paper [Biomed. Opt. Express 2, 2068 (2011)]

Quantitative measurement of cerebral blood flow in a juvenile porcine model by depth-resolved near-infrared spectroscopy

Nearly half a million children and young adults are affected by traumatic brain injury each year in the United States. Although adequate cerebral blood flow (CBF) is essential to recovery, complications that disrupt blood flow to the brain and exacerbate neurological injury often go undetected because no adequate bedside measure of CBF exists. In this study we validate a depth-resolved, near-infrared spectroscopy (NIRS) technique that provides quantitative CBF measurement despite significant signal contamination from skull and scalp tissue. The respiration rates of eight anesthetized pigs (weight: 16.2±0.5 kg, age: 1 to 2 months old) are modulated to achieve a range of CBF levels. Concomitant CBF measurements are performed with NIRS and CT perfusion. A significant correlation between CBF measurements from the two techniques is demonstrated (r 2=0.714, slope=0.92, p\u3c0.001), and the bias between the two techniques is -2.83 mL·min -1·100 g -1 (CI 0.95: -19.63 mL·min -1·100 g -1 -13.9 mL·min -1·100 g -1). This study demonstrates that accurate measurements of CBF can be achieved with depth-resolved NIRS despite significant signal contamination from scalp and skull. The ability to measure CBF at the bedside provides a means of detecting, and thereby preventing, secondary ischemia during neurointensive care. © 2010 Society of Photo-Optical Instrumentation Engineers

Assessing tumor physiology by dynamic contrast-enhanced near-infrared spectroscopy

The purpose of this study was to develop a dynamic contrast-enhanced (DCE) near-infrared spectroscopy (NIRS) technique to characterize tumor physiology. Dynamic data were acquired using two contrast agents of different molecular weights, indocyanine green (ICG) and IRDye 800CW carboxylate (IRDcxb). The DCE curves were analyzed using a kinetic model capable of extracting estimates of tumor blood flow (F), capillary transit time (t(c)) and the amount of dye that leaked into the extravascular space (EVS) - characterized by the extraction fraction (E). Data were acquired from five nude rats with tumor xenografts (\u3e10mm) implanted in the neck. Four DCE-NIR datasets (two from each contrast agent) were acquired for each rat. The dye concentration curve in arterial blood, which is required to quantify the model parameters, was measured non-invasively by dye densitometry. A modification to the kinetic model to characterize t(c) as a distribution of possible values, rather than finite, improved the fit of acquired tumor concentration curves, resulting in more reliable estimates. This modified kinetic model identified a difference between the extracted fraction of IRDcxb, 15 +/- 6 %, and ICG, 1.6 +/- 0.6 %, in the tumor, which can be explained by the difference in molecular weight: 67 kDa for ICG since it binds to albumin and 1.17 kDa for IRD. This study demonstrates the ability of DCE-NIRS to quantify tumor physiology. The next step is to adapt this approach with a dual-receptor approach

Avian W and mammalian Y chromosomes convergently retained dosage-sensitive regulators

After birds diverged from mammals, different ancestral autosomes evolved into sex chromosomes in each lineage. In birds, females are ZW and males are ZZ, but in mammals females are XX and males are XY. We sequenced the chicken W chromosome, compared its gene content with our reconstruction of the ancestral autosomes, and followed the evolutionary trajectory of ancestral W-linked genes across birds. Avian W chromosomes evolved in parallel with mammalian Y chromosomes, preserving ancestral genes through selection to maintain the dosage of broadly expressed regulators of key cellular processes. We propose that, like the human Y chromosome, the chicken W chromosome is essential for embryonic viability of the heterogametic sex. Unlike other sequenced sex chromosomes, the chicken W chromosome did not acquire and amplify genes specifically expressed in reproductive tissues. We speculate that the pressures that drive the acquisition of reproduction-related genes on sex chromosomes may be specific to the male germ line