Reverse Engineering the Gap Gene Network of Drosophila melanogaster

A fundamental problem in functional genomics is to determine the structure and dynamics of genetic networks based on expression data. We describe a new strategy for solving this problem and apply it to recently published data on early Drosophila melanogaster development. Our method is orders of magnitude faster than current fitting methods and allows us to fit different types of rules for expressing regulatory relationships. Specifically, we use our approach to fit models using a smooth nonlinear formalism for modeling gene regulation (gene circuits) as well as models using logical rules based on activation and repression thresholds for transcription factors. Our technique also allows us to infer regulatory relationships de novo or to test network structures suggested by the literature. We fit a series of models to test several outstanding questions about gap gene regulation, including regulation of and by hunchback and the role of autoactivation. Based on our modeling results and validation against the experimental literature, we propose a revised network structure for the gap gene system. Interestingly, some relationships in standard textbook models of gap gene regulation appear to be unnecessary for or even inconsistent with the details of gap gene expression during wild-type development

Hypertension: Development of a prediction model to adjust self-reported hypertension prevalence at the community level

Abstract Background Accurate estimates of hypertension prevalence are critical for assessment of population health and for planning and implementing prevention and health care programs. While self-reported data is often more economically feasible and readily available compared to clinically measured HBP, these reports may underestimate clinical prevalence to varying degrees. Understanding the accuracy of self-reported data and developing prediction models that correct for underreporting of hypertension in self-reported data can be critical tools in the development of more accurate population level estimates, and in planning population-based interventions to reduce the risk of, or more effectively treat, hypertension. This study examines the accuracy of self-reported survey data in describing prevalence of clinically measured hypertension in two racially and ethnically diverse urban samples, and evaluates a mechanism to correct self-reported data in order to more accurately reflect clinical hypertension prevalence. Methods We analyze data from the Detroit Healthy Environments Partnership (HEP) Survey conducted in 2002 and the National Health and Nutrition Examination (NHANES) 2001–2002 restricted to urban areas and participants 25 years and older. We re-calibrate measures of agreement within the HEP sample drawing upon parameter estimates derived from the NHANES urban sample, and assess the quality of the adjustment proposed within the HEP sample. Results Both self-reported and clinically assessed prevalence of hypertension were higher in the HEP sample (29.7 and 40.1, respectively) compared to the NHANES urban sample (25.7 and 33.8, respectively). In both urban samples, self-reported and clinically assessed prevalence is higher than that reported in the full NHANES sample in the same year (22.9 and 30.4, respectively). Sensitivity, specificity and accuracy between clinical and self-reported hypertension prevalence were ‘moderate to good’ within the HEP sample and ‘good to excellent’ within the NHANES sample. Agreement between clinical and self-reported hypertension prevalence was ‘moderate to good’ within the HEP sample (kappa =0.65; 95% CI = 0.63-0.67), and ‘good to excellent’ within the NHANES sample (kappa = 0.75; 95%CI = 0.73-0.80). Application of a ‘correction’ rule based on prediction models for clinical hypertension using the national sample (NHANES) allowed us to re-calibrate sensitivity and specificity estimates for the HEP sample. The adjusted estimates of hypertension in the HEP sample based on two different correction models, 38.1% and 40.5%, were much closer to the observed hypertension prevalence of 40.1%. Conclusions Application of a simple prediction model derived from national NHANES data to self-reported data from the HEP (Detroit based) sample resulted in estimates that more closely approximated clinically measured hypertension prevalence in this urban community. Similar correction models may be useful in obtaining more accurate estimates of hypertension prevalence in other studies that rely on self-reported hypertension.http://deepblue.lib.umich.edu/bitstream/2027.42/112834/1/12913_2011_Article_2187.pd

A solution structure analysis reveals a bent collagen triple helix in the complement activation recognition molecule mannan-binding lectin

Collagen triple helices are critical in the function of mannan-binding lectin (MBL), an oligomeric recognition molecule in complement activation. The MBL collagen regions form complexes with the serine proteases MASP-1 and MASP-2 in order to activate complement, and mutations lead to common immunodeficiencies. To evaluate their structure-function properties, we studied the solution structures of four MBL-like collagen peptides. The thermal stability of the MBL collagen region was much reduced by the presence of a GQG interruption in the typical (X-Y-Gly)n repeat compared to controls. Experimental solution structural data were collected using analytical ultracentrifugation and small angle X-ray and neutron scattering. As controls, we included two standard Pro-Hyp-Gly collagen peptides (POG)10-13, as well as three more peptides with diverse (X-Y-Gly)n sequences that represented other collagen features. These data were quantitatively compared with atomistic linear collagen models derived from crystal structures and 12,000 conformations obtained from molecular dynamics (MD) simulations. All four MBL peptides were bent to varying degrees up to 85o in the best-fit MD models. The best-fit benchmark peptides (POG)n were more linear but exhibited a degree of conformational flexibility. The remaining three peptides showed mostly linear solution structures. In conclusion, the collagen helix is not strictly linear, the degree of flexibility in the triple helix depends on its sequence, and the triple helix with the GQG interruption showed a pronounced bend. The bend in MBL GQG peptides resembles the bend in the collagen of complement C1q and may be key for lectin pathway activation

A new approach to construct pathway connected networks and its application in dose responsive gene expression profiles of rat liver regulated by 2,4DNT

<p>Abstract</p> <p>Background</p> <p>Military and industrial activities have lead to reported release of 2,4-dinitrotoluene (2,4DNT) into soil, groundwater or surface water. It has been reported that 2,4DNT can induce toxic effects on humans and other organisms. However the mechanism of 2,4DNT induced toxicity is still unclear. Although a series of methods for gene network construction have been developed, few instances of applying such technology to generate pathway connected networks have been reported.</p> <p>Results</p> <p>Microarray analyses were conducted using liver tissue of rats collected 24h after exposure to a single oral gavage with one of five concentrations of 2,4DNT. We observed a strong dose response of differentially expressed genes after 2,4DNT treatment. The most affected pathways included: long term depression, breast cancer regulation by stathmin1, WNT Signaling; and PI3K signaling pathways. In addition, we propose a new approach to construct pathway connected networks regulated by 2,4DNT. We also observed clear dose response pathway networks regulated by 2,4DNT.</p> <p>Conclusions</p> <p>We developed a new method for constructing pathway connected networks. This new method was successfully applied to microarray data from liver tissue of 2,4DNT exposed animals and resulted in the identification of unique dose responsive biomarkers in regards to affected pathways.</p

The relationship of neurocognition and negative symptoms to social and role functioning over time in individuals at clinical high risk in the first phase of the North American Prodrome Longitudinal Study

OBJECTIVES: Impaired social, role, and neurocognitive functioning are preillness characteristics of people who later develop psychosis. In people with schizophrenia, neurocognition and negative symptoms are associated with functional impairment. We examined the relative contributions of neurocognition and symptoms to social and role functioning over time in clinically high-risk (CHR) individuals and determined if negative symptoms mediated the influence of cognition on functioning. METHODS: Social, role, and neurocognitive functioning and positive, negative, and disorganized symptoms were assessed in 167 individuals at CHR for psychosis in the North American Prodrome Longitudinal Study Phase 1 (NAPLS-1), of whom 96 were reassessed at 12 months. RESULTS: Regression analyses indicated that negative symptoms accounted for unique variance in social and role functioning at baseline and follow-up. Composite neurocognition accounted for unique, but modest, variance in social and role functioning at baseline and in role functioning at follow-up. Negative symptoms mediated the relationship between composite neurocognition and social and role functioning across time points. In exploratory analyses, individual tests (IQ estimate, Digit Symbol/Coding, verbal memory) selectively accounted for social and role functioning at baseline and follow-up after accounting for symptoms. When negative symptom items with content overlapping with social and role functioning measures were removed, the relationship between neurocognition and social and role functioning was strengthened. CONCLUSION: The modest overlap among neurocognition, negative symptoms, and social and role functioning indicates that these domains make substantially separate contributions to CHR individuals

Negative symptoms and impaired social functioning predict later psychosis in Latino youth at clinical high risk in the North American prodromal longitudinal studies consortium

AIM: Examining ethnically related variables in evaluating those at risk for psychosis is critical. This study investigated sociodemographic and clinical characteristics of Latino versus non-Latino clinical high-risk (CHR) subjects and healthy control (HC) subjects in the first North American Prodrome Longitudinal Study. METHODS: Fifty-six Latino CHR subjects were compared to 25 Latino HC and 423 non-Latino CHR subjects across clinical and demographic variables. Thirty-nine of the 56 CHR subjects completed at least one subsequent clinical evaluation over the 2.5-year period with 39% developing a psychotic illness. Characteristics of Latino CHR subjects who later converted to psychosis (‘converters’) were compared to those who did not (‘non-converters’). RESULTS: Latino CHR subjects were younger than non-Latino CHR subjects and had less education than Latino HC subjects and non-Latino CHR counterparts. Latino CHR converters had higher scores than Latino non-converters on the Structured Interview for Prodromal Syndromes total negative symptoms that were accounted for by decreased expression of emotion and personal hygiene/social attentiveness subsections. Latino CHR converters scored lower on the global functioning:social scale, indicating worse social functioning than Latino non-converters. CONCLUSION: Based on this sample, Latino CHR subjects may seek treatment earlier and have less education than non-Latino CHR subjects. Deficits in social functioning and impaired personal hygiene/social attentiveness among Latino CHR subjects predicted later psychosis and may represent important areas for future study. Larger sample sizes are needed to more thoroughly investigate the observed ethnic differences and risk factors for psychosis in Latino youth

Functional development in clinical high risk youth: Prediction of schizophrenia versus other psychotic disorders

This study evaluates premorbid social and academic functioning in clinical high-risk individuals as predictors of transition to schizophrenia versus another psychotic disorder. Participants were 54 individuals enrolled in phase one of the North American Prodrome Longitudinal Study who over two and a half years of follow-up met criteria for schizophrenia/schizophreniform disorder (n=28) or another psychotic disorder (n=26). Social and academic functioning in childhood, early adolescence, and late adolescence was assessed at baseline using the Cannon-Spoor Premorbid Adjustment Scale. Social maladjustment in late adolescence predicted significantly higher odds of transition to schizophrenia versus another psychotic disorder independent of childhood and early adolescent adjustment (OR = 4.02) and conveyed unique risk over academic maladjustment (O R= 5.64). Premorbid academic maladjustment was not associated with psychotic disorder diagnosis. Results support diagnostic specificity of premorbid social dysfunction to schizophrenia in clinical high-risk youth and underscore an important role for social maladjustment in the developmental pathology of schizophrenia and its prediction. (C) 2013 Elsevier Ireland Ltd. All rights reserved

Relation between cannabis use and subcortical volumes in people at clinical high risk of psychosis

Among people at genetic risk of schizophrenia, those who use cannabis show smaller thalamic and hippocampal volumes. We evaluated this relationship in people at clinical high risk (CHR) of psychosis. The Alcohol and Drug Use Scale was used to identify 132 CHR cannabis users, the majority of whom were non-dependent cannabis users, 387 CHR non-users, and 204 healthy control non-users, and all participants completed magnetic resonance imaging scans. Volumes of the thalamus, hippocampus and amygdala were extracted with FreeSurfer, and compared across groups. Comparing all CHR participants with healthy control participants revealed no significant differences in volumes of any ROI. However, when comparing CHR users to CHR non-users, a significant ROI × Cannabis group effect emerged: CHR users showed significantly smaller amygdala compared to CHR non-users. However, when limiting analysis to CHR subjects who reported using alcohol at a ‘use without impairment’ severity level, the amygdala effect was non-significant; rather, smaller hippocampal volumes were seen in CHR cannabis users compared to non-users. Controlling statistically for effects of alcohol and tobacco use rendered all results non-significant. These results highlight the importance of controlling for residual confounding effects of other substance use when examining the relationship between cannabis use and neural structure

Traumatic brain injury in individuals at clinical high risk for psychosis

Recent research suggests that a traumatic brain injury (TBI) can significantly increase the risk of later development of psychosis. However, it is unknown whether people at clinical high risk (CHR) of psychosis have experienced TBI at higher rates, compared to otherwise healthy individuals. This study evaluated the prevalence of mild TBI, whether it was related to past trauma and the relationship of mild TBI to later transition to psychosis

Social cognition over time in individuals at clinical high risk for psychosis: Findings from the NAPLS-2 cohort

Deficits in social cognition are well established in schizophrenia and have been observed prior to the illness onset. Compared to healthy controls (HCs), individuals at clinical high risk of psychosis (CHR) are said to show deficits in social cognition similar to those observed in patients experiencing a first episode of psychosis. These deficits have been observed in several domains of social cognition, such as theory of mind (ToM), emotion perception and social perception. In the current study, the stability of three domains of social cognition (ToM, social perception and facial emotion perception) was assessed over time along and their association with both clinical symptoms and the later development of psychosis. Six hundred and seventy-five CHR individuals and 264 HC participants completed four tests of social cognition at baseline. Of those, 160 CHR and 155 HC participants completed assessments at all three time points (baseline, 1 year and 2 years) as part of their participation in the North American Prodrome Longitudinal Study. The CHR group performed poorer on all tests of social cognition across all time points compared to HCs. Social cognition was not associated with attenuated positive symptoms at any time point in the study. CHR individuals who developed a psychotic disorder during the course of the study did not differ in social cognition compared to those who did not develop psychosis. This longitudinal study demonstrated mild to moderate, but persistent ToM and social perception impairments in those at CHR for psychosis compared to HCs