Clark Jeffries

microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder

BackgroundmicroRNAs (miRNAs) are small, noncoding RNA molecules that are now thought to regulate the expression of many mRNAs. They have been implicated in the etiology of a variety of complex diseases, including Tourettes syndrome, Fragile × syndrome, and several types of cancer.ResultsWe hypothesized that schizophrenia might be associated with altered miRNA profiles. To investigate this possibility we compared the expression of 264 human miRNAs from postmortem prefrontal cortex tissue of individuals with schizophrenia (n = 13) or schizoaffective disorder (n = 2) to tissue of 21 psychiatrically unaffected individuals using a custom miRNA microarray. Allowing a 5% false discovery rate, we found that 16 miRNAs were differentially expressed in prefrontal cortex of patient subjects, with 15 expressed at lower levels (fold change 0.63 to 0.89) and 1 at a higher level (fold change 1.77) than in the psychiatrically unaffected comparison subjects. The expression levels of 12 selected miRNAs were also determined by quantitative RT-PCR in our lab. For the eight miRNAs distinguished by being expressed at lower microarray levels in schizophrenia samples versus comparison samples, seven were also expressed at lower levels with quantitative RT-PCR.ConclusionThis study is the first to find altered miRNA profiles in postmortem prefrontal cortex from schizophrenia patients.

Progressive Reduction in Cortical Thickness as Psychosis Develops: A Multisite Longitudinal Neuroimaging Study of Youth at Elevated Clinical Risk

BACKGROUND Individuals at clinical high risk (CHR) who progress to fully psychotic symptoms have been observed to show a steeper rate of cortical gray matter reduction compared with individuals without symptomatic progression and with healthy control subjects. Whether such changes reflect processes associated with the pathophysiology of schizophrenia or exposure to antipsychotic drugs is unknown. METHODS In this multisite study, 274 CHR cases, including 35 individuals who converted to psychosis, and 135 healthy comparison subjects were scanned with magnetic resonance imaging at baseline, 12-month follow-up, or the point of conversion for the subjects who developed fully psychotic symptoms. RESULTS In a traveling subjects substudy, excellent reliability was observed for measures of cortical thickness and subcortical volumes. Controlling for multiple comparisons throughout the brain, CHR subjects who converted to psychosis showed a steeper rate of gray matter loss in the right superior frontal, middle frontal, and medial orbitofrontal cortical regions as well as a greater rate of expansion of the third ventricle compared with CHR subjects who did not convert to psychosis and healthy control subjects. Differential tissue loss was present in subjects who had not received antipsychotic medications during the interscan interval and was predicted by baseline levels of an aggregate measure of proinflammatory cytokines in plasma. CONCLUSIONS These findings demonstrate that the brain changes are not explained by exposure to antipsychotic drugs but likely play a role in psychosis pathophysiology. Given that the cortical changes were more pronounced in subjects with briefer durations of prodromal symptoms, contributing factors may predominantly play a role in acute-onset forms of psychosis.

Expanding the 'central dogma': the regulatory role of nonprotein coding genes and implications for the genetic liability to schizophrenia.

It is now evident that nonprotein coding RNA (ncRNA) plays a critical role in regulating the timing and rate of protein translation. The potential importance of ncRNAs is suggested by the observation that the complexity of an organism is poorly correlated with its number of protein coding genes, yet highly correlated with its number of ncRNA genes, and that in the human genome only a small fraction (2–3%) of genetic transcripts are actually translated into proteins. In this review, we discuss several examples of known RNA mechanisms for the regulation of protein synthesis. We then discuss the possibility that ncRNA regulation of schizophrenia risk genes may underlie the diverse findings of genetic linkage studies including that protein-altering gene polymorphisms are not generally found in schizophrenia. Thus, inadequate or mistimed expression of a functional protein may occur either due to mutation or other dysfunction of the DNA coding base pair sequence, leading to a dysfunctional protein, or due to post-transcriptional events such as abnormal ncRNA regulation of a normal gene. One or more ‘schizophrenia disease genes’ may turn out to include abnormal transcriptional units that code for RNA regulators of protein coding gene expression or to be proximal to such units, rather than to be abnormalities in the protein coding gene itself. Understanding the genetics of schizophrenia and other complex neuropsychiatric disorders might very well include consideration of RNA and epigenetic regulation of protein expression in addition to polymorphisms of the protein coding gene.

Towards a Psychosis Risk Blood Diagnostic for Persons Experiencing High-Risk Symptoms: Preliminary Results From the NAPLS Project

Introduction: A barrier to preventative treatments for psychosis is the absence of accurate identification of persons at highest risk. A blood test that could substantially increase diagnostic accuracy would enhance development of psychosis prevention interventions. Methods: The North American Prodrome Longitudinal Study project is a multisite endeavor that aims to better understand predictors and mechanisms for the development of psychosis. In this study, we measured expression of plasma analytes reflecting inflammation, oxidative stress, hormones, and metabolism. A “greedy algorithm” selected analytes that best distinguished persons with clinical high-risk symptoms who developed psychosis (CHR-P; n = 32) from unaffected comparison (UC) subjects (n = 35) and from those who did not develop psychosis during a 2-year follow-up (CHR-NP; n = 40). Results: The classifier included 15 analytes (selected from 117), with an area under the receiver operating curve for CHR-P vs UC of 0.91 and CHR-P vs CHR-NP of 0.88. Randomly scrambled group membership followed by reconstructions of the entire classifier method yielded consistently weak classifiers, indicating that the true classifier is highly unlikely to be a chance occurrence. Such randomization methods robustly imply the assays contain consistent information distinguishing the groups which was not obscured by the data normalization method and was revealed by classifier construction. These results support the hypothesis that inflammation, oxidative stress, and dysregulation of hypothalamic-pituitary axes may be prominent in the earliest stages of psychosis. Conclusion: If confirmed in other groups of persons at elevated risk of psychosis, a multiplex blood assay has the potential for high clinical utility.

Simulating association studies

MOTIVATION Reductions in genotyping costs have heightened interest in performing whole genome association scans and in the fine mapping of candidate regions. Improvements in study design and analytic techniques will require the simulation of datasets with realistic patterns of linkage disequilibrium and allele frequencies for typed SNPs. METHODS We describe a general approach to simulate genotyped datasets for standard case-control or affected child trio data, by resampling from existing phased datasets. The approach allows for considerable flexibility in disease models, potentially involving a large number of interacting loci. The method is most applicable for diseases caused by common variants that have not been under strong selection, a class specifically targeted by the International HapMap project. RESULTS Using the three population Phase I/II HapMap data as a testbed for our approach, we have implemented the approach in HAP-SAMPLE, a web-based simulation tool.

Qualitative stability of linear systems

Abstract This paper provides a finitely computable graph-theoretic answer to the following question concerning linear dynamical systems: When, given only the signs of entries (+, -, or 0) in a real square matrix A , can one be certain that all positive trajectories of the system ẋ = Ax are bounded? Matrices having such sign-patterns are called sign-quasistable . With “bounded” replaced by “convergent to the origin,” the matrices are called sign-stable and were fully described in earlier papers. However, when A s digraph has several strong components, so that the system is actually a hierarchy of subsystems, and when some of those subsystems fail to be sign-stable, the recognition of sign-quasistability is a very delicate matter. By means of certain graph color tests, it is possible to identify the system variables that are capable (for some choice of matrix-entry magnitudes and initial conditions) of emitting nonzero constant

Creating advanced functions on network processors: experience and perspectives

In this article we present five case studies of advanced networking functions that detail how a network processor (NP) can provide high performance and also the necessary flexibility compared with ASIC. We first review the basic NP system architectures, and describe the IBM PowerNP architecture from the data plane as well as the control plane point of view. We introduce models for the programmers views of NP that facilitate a global understanding of NP software programming. Then, for each case study, we present results from prototypes as well as general considerations that apply to a wider range of system architectures. Specifically, we investigate the suitability of NP for QoS (active queue management and traffic engineering), header processing (GPRS tunneling protocol), intelligent forwarding (load balancing without flow disruption), payload processing (code interpretation and just-in-time compilation in active networks), and protocol stack termination (SCTP). Finally, we summarize the key features as revealed by each case study, and conclude with remarks on the future of NP.

Bandwidth allocation for non-responsive flows with active queue management

This paper addresses the problem of configuring active queue management systems (e.g. WRED and RIO) for service level specifications in internetworks. In particular, we focus on assured forwarding (AF) for non-responsive flows in differentiated services networks. The difficulty is to determine the correct queue level thresholds that will result in correct drop rates for various AF precedence levels under any combination of offered loads. A new active queue management scheme based on a control algorithm is proposed that senses not only queue levels but also rates of queue levels changes and per flow bit rates to converge automatically to an optimal set of transmit fractions. The scheme has been implemented and tested on a network processor. Results show that the new active queue management scheme protects assured aggregated flow rates during periods of congestion. For non-responsive traffic the buffer occupancy level remains low during 250% offered load.

Some sign patterns that preclude matrix stability

The principal concern of this paper is with real matrices whose undirected graphs are trees. To better understand potential stability of sign pattern classes, two simple criteria are given that preclude stability throughout a sign pattern class. In addition, those sign patterns that preclude eigenvalues with real part equal to 0 are characterized and the constant inertia within such classes is determined. Such tests may be computationally significant, as calculations with specific matrices may be subject to round off error uncertainties.

Qualitative Stability of Certain Nonlinear Systems

To certain nonlinear dynamical systems naturally correspond simplicial complexes. This correspondence is a generalization of the familiar relationship between the interaction matrix of a linear dynamical system and the signed digraph of that matrix. By defining stability in terms of attractor regions (as opposed to attractor trajectories), we can specify qualitative linear algebraic conditions involving the simplicial complex which insure stability of the nonlinear system. The analysis uses only signs of coefficients in the dynamical system. A model of E. Lorenz [3] is an example of a three-dimensional system which fulfills the stability conditions and which is known to have a strange attractor within the attractor region. In summary, the linear qualitative tests described (Theorems 2 and 3) can be applied to certain nonlinear dynamical systems to yield preliminary information about the global stability of such systems.