A hierarchical model of transcriptional dynamics allows robust estimation of transcription rates in populations of single cells with variable gene copy number

Motivation: cis-regulatory DNA sequence elements, such as enhancers and silencers, function to control the spatial and temporal expression of their target genes. Although the overall levels of gene expression in large cell populations seem to be precisely controlled, transcription of individual genes in single cells is extremely variable in real time. It is, therefore, important to understand how these cis-regulatory elements function to dynamically control transcription at single-cell resolution. Recently, statistical methods have been proposed to back calculate the rates involved in mRNA transcription using parameter estimation of a mathematical model of transcription and translation. However, a major complication in these approaches is that some of the parameters, particularly those corresponding to the gene copy number and transcription rate, cannot be distinguished; therefore, these methods cannot be used when the copy number is unknown. Results: Here, we develop a hierarchical Bayesian model to estimate biokinetic parameters from live cell enhancer–promoter reporter measurements performed on a population of single cells. This allows us to investigate transcriptional dynamics when the copy number is variable across the population. We validate our method using synthetic data and then apply it to quantify the function of two known developmental enhancers in real time and in single cells

The New Business Corporation Act: The Basics

Handouts provided at the UK/CLE seminar on the New Business Corporation Act on October 1, 1988

Water Exchange across the Blood-Brain Barrier in Obstructive Sleep Apnea: An MRI Diffusion-Weighted Pseudo-Continuous Arterial Spin Labeling Study

Obstructive sleep apnea (OSA) subjects show brain injury in sites that control autonomic, cognitive, and mood functions that are deficient in the condition. The processes contributing to injury may include altered blood-brain barrier (BBB) actions. Our aim was to examine BBB function, based on diffusion-weighted pseudo-continuous arterial spin labeling (DW-pCASL) procedures, in OSA compared to controls. We performed DW-pCASL imaging in nine OSA and nine controls on a 3.0-Tesla MRI scanner. Global mean gray and white matter arterial transient time (ATT, an index of large artery integrity), water exchange rate across the BBB (Kw, BBB function), DW-pCASL ratio, and cerebral blood flow (CBF) values were compared between OSA and control subjects. RESULTS: Global mean gray and white matter ATT (OSA vs. controls; gray matter, 1.691 ± .120 vs. 1.658 ± .109 second, P = .49; white matter, 1.700 ± .115 vs. 1.650 ± .114 second, P = .44), and CBF values (gray matter, 57.4 ± 15.8 vs. 58.2 ± 10.7 ml/100 g/min, P = .67; white matter, 24.2 ± 7.0 vs. 24.6 ± 6.7 ml/100 g/min, P = .91) did not differ significantly, but global gray and white matter Kw (gray matter, 158.0 ± 28.9 vs. 220.8 ± 40.6 min-1, P = .002; white matter, 177.5 ± 57.2 vs. 261.1 ± 51.0 min-1, P = .006), and DW-pCASL ratio (gray matter, .727 ± .076 vs. .823 ± .069, P = .011; white matter, .722 ± .144 vs. .888 ± .100, P = .004) values were significantly reduced in OSA over controls. OSA subjects show compromised BBB function, but intact large artery integrity. The BBB alterations may introduce neural damage contributing to abnormal functions in OSA, and suggest a need to repair BBB function with strategies commonly used in other fields

Father-daughter Incest: Comparison of Treated Cases to Untreated Control Subjects

Treatment of father daughter incest (FDI) survivors using the victim advocacy/child welfare approach to FDI that predominates today in the US has never been compared to results in untreated control subjects in any published report. In the present study, thirty-two survivors of FDI who received treatment based on the victim advocacy/child welfare approach to FDI were compared to 32 control subjects who did not receive treatment. No significant differences were found using analysis of variance on 21 scales and subscales. Statistical analysis of the data from all 64 of the FDI survivors showed that items reflecting a poor self-image and a history of maternal depression predicted more problematic scores on the depression scale. Those who scored higher on religiosity were less likely to be depressed. Redesigned therapy for FDI aimed, first and foremost, at healing the survivors and validated by prospective randomized trials is needed

Case management and Think First completion

“The final, definitive version of this article has been published in the Journal, Probation Journal, Vol 53 Issue 3, 2006, Copyright The Trade Union and Professional Association for Family Court and Probation Staff, by SAGE Publications Ltd at: http://prb.sagepub.com/ " DOI: 10.1177/0264550506066771This article considers the findings of a small-scale study of the practice of case managers supervising offenders required to attend the Think First Group. It explores the interface between one-to-one and group-based work within multi-modal programmes of supervision and seeks to identify those practices that support individuals in completing a group.Peer reviewe

Effects of the sex of the perpetrator on victims’ subsequent sexual behaviors and adulthood sexual orientations

Data from 2,828 female and 1,556 male adult participants from a general population convenience sample were used to measure the effect of the sex of the perpetrator on the adult sexual orientation of the victims of child sexual abuse (CSA) by adult male or female perpetrators and early incest with parents or early incest with siblings. Sexual behaviors with female perpetrators tended to promote an orientation toward sex with females and analogous behaviors with male perpetrators tended to promote an orientation toward sex with males in victims of both sexes. Many forms of incest or CSA increased the likelihood the victims would subsequently engage in behaviors with other partners or begin masturbating using adult male or female images. The subsequent early behaviors with other partners and masturbating using images of both male and female adults significantly enhanced or attenuated the conditioning resulting from interacting with the initial perpetrator. The victims’ adult sexual orientations could be statistically predicted using regression equations that took into account the sexual behaviors with both adult and underage partners and whether or not the participant had masturbated using images of male or female adults. The results were consistent with conditioning and counter-conditioning theories

Effect on life expectancy of temporal sequence in a multimorbidity cluster of psychosis, diabetes, and congestive heart failure among 1·7 million individuals in Wales with 20-year follow-up : a retrospective cohort study using linked data

Funding: This work was supported by Health Data Research UK (HDRUK) Measuring and Understanding Multimorbidity using Routine Data in the UK (MUrMuRUK; award numbers HDR-9006 and CFC0110). HDRUK is funded by the UK Medical Research Council (MRC), Engineering and Physical Sciences Research Council, Economic and Social Research Council, NIHR (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation, and Wellcome Trust. This work also was co-funded by the MRC and NIHR (grant number MR/S027750/1). The work was supported by the Administrative Data Research (ADR) Wales programme of work, part of the Economic and Social Research Council (part of UK Research and Innovation) funded ADR UK (grant ES/S007393/1). RKO is supported by a Springboard award (SBF006\1122) funded by the Academy of Medical Sciences, Wellcome Trust, Government Department of Business, Energy and Industrial Strategy, British Heart Foundation, and Diabetes UK. SS is part funded by the NIHR Applied Research Collaboration West Midlands, the NIHR Health Protection Research Unit (HPRU) in Gastrointestinal Infections, and the NIHR HPRU in Genomics and Enabling Data.Background To inform targeted public health strategies, it is crucial to understand how coexisting diseases develop over time and their associated impacts on patient outcomes and health-care resources. This study aimed to examine how psychosis, diabetes, and congestive heart failure, in a cluster of physical–mental health multimorbidity, develop and coexist over time, and to assess the associated effects of different temporal sequences of these diseases on life expectancy in Wales. Methods In this retrospective cohort study, we used population-scale, individual-level, anonymised, linked, demographic, administrative, and electronic health record data from the Wales Multimorbidity e-Cohort. We included data on all individuals aged 25 years and older who were living in Wales on Jan 1, 2000 (the start of follow-up), with follow-up continuing until Dec 31, 2019, first break in Welsh residency, or death. Multistate models were applied to these data to model trajectories of disease in multimorbidity and their associated effect on all-cause mortality, accounting for competing risks. Life expectancy was calculated as the restricted mean survival time (bound by the maximum follow-up of 20 years) for each of the transitions from the health states to death. Cox regression models were used to estimate baseline hazards for transitions between health states, adjusted for sex, age, and area-level deprivation (Welsh Index of Multiple Deprivation [WIMD] quintile). Findings Our analyses included data for 1 675 585 individuals (811 393 [48·4%] men and 864 192 [51·6%] women) with a median age of 51·0 years (IQR 37·0–65·0) at cohort entry. The order of disease acquisition in cases of multimorbidity had an important and complex association with patient life expectancy. Individuals who developed diabetes, psychosis, and congestive heart failure, in that order (DPC), had reduced life expectancy compared with people who developed the same three conditions in a different order: for a 50-year-old man in the third quintile of the WIMD (on which we based our main analyses to allow comparability), DPC was associated with a loss in life expectancy of 13·23 years (SD 0·80) compared with the general otherwise healthy or otherwise diseased population. Congestive heart failure as a single condition was associated with mean a loss in life expectancy of 12·38 years (0·00), and with a loss of 12·95 years (0·06) when preceded by psychosis and 13·45 years (0·13) when followed by psychosis. Findings were robust in people of older ages, more deprived populations, and women, except that the trajectory of psychosis, congestive heart failure, and diabetes was associated with higher mortality in women than men. Within 5 years of an initial diagnosis of diabetes, the risk of developing psychosis or congestive heart failure, or both, was increased. Interpretation The order in which individuals develop psychosis, diabetes, and congestive heart failure as combinations of conditions can substantially affect life expectancy. Multistate models offer a flexible framework to assess temporal sequences of diseases and allow identification of periods of increased risk of developing subsequent conditions and death.Publisher PDFPeer reviewe

The impact of logging roads on dung beetle assemblages in a tropical rainforest reserve

The demand for timber products is facilitating the degradation and opening up of large areas of intact habitats rich in biodiversity. Logging creates an extensive network of access roads within the forest, yet these are commonly ignored or excluded when assessing impacts of logging on forest biodiversity. Here we determine the impact of these roads on the overall condition of selectively logged forests in Borneo, Southeast Asia. Focusing on dung beetles along > 40 km logging roads we determine: (i) the magnitude and extent of edge effects alongside logging roads; (ii) whether vegetation characteristics can explain patterns in dung beetle communities, and; (iii) how the inclusion of road edge forest impacts dung beetle assemblages within the overall logged landscape. We found that while vegetation structure was significantly affected up to 34 m from the road edge, impacts on dung beetle communities penetrated much further and were discernible up to 170 m into the forest interior. We found larger species and particularly tunnelling species responded more than other functional groups which were also influenced by micro-habitat variation. We provide important new insights into the long-term ecological impacts of tropical logging. We also support calls for improved logging road design both during and after timber extraction to conserve more effectively biodiversity in production forests, for instance, by considering the minimum volume of timber, per unit length of logging road needed to justify road construction. In particular, we suggest that governments and certification bodies need to highlight more clearly the biodiversity and environmental impacts of logging roads

Evasion of anti-growth signaling: a key step in tumorigenesis and potential target for treatment and prophylaxis by natural compounds

The evasion of anti-growth signaling is an important characteristic of cancer cells. In order to continue to proliferate, cancer cells must somehow uncouple themselves from the many signals that exist to slow down cell growth. Here, we define the anti-growth signaling process, and review several important pathways involved in growth signaling: p53, phosphatase and tensin homolog (PTEN), retinoblastoma protein (Rb), Hippo, growth differentiation factor 15 (GDF15), AT-rich interactive domain 1A (ARID1A), Notch, insulin-like growth factor (IGF), and Krüppel-like factor 5 (KLF5) pathways. Aberrations in these processes in cancer cells involve mutations and thus the suppression of genes that prevent growth, as well as mutation and activation of genes involved in driving cell growth. Using these pathways as examples, we prioritize molecular targets that might be leveraged to promote anti-growth signaling in cancer cells. Interestingly, naturally-occurring phytochemicals found in human diets (either singly or as mixtures) may promote anti-growth signaling, and do so without the potentially adverse effects associated with synthetic chemicals. We review examples of naturally-occurring phytochemicals that may be applied to prevent cancer by antagonizing growth signaling, and propose one phytochemical for each pathway. These are: epigallocatechin-3-gallate (EGCG) for the Rb pathway, luteolin for p53, curcumin for PTEN, porphyrins for Hippo, genistein for GDF15, resveratrol for ARID1A, withaferin A for Notch and diguelin for the IGF1-receptor pathway. The coordination of anti-growth signaling and natural compound studies will provide insight into the future application of these compounds in the clinical setting