Fmrp targets or not: Long, highly brain-expressed genes tend to be implicated in autism and brain disorders

BACKGROUND: Many studies have demonstrated a robust statistical overlap between genes whose transcripts are reported as Fragile X Mental Retardation Protein (Fmrp)-binding targets and genes implicated in various psychiatric disorders, including autism. However, it is not clear how to interpret this overlap as the Fmrp protein itself is not considered to be central to all instances of these conditions. FINDINGS: We tested whether Fmrp binding may be a proxy for some other features of these transcripts. Reviewing recent literature on the cross-linking and immunoprecipitation (CLIP)-derived targets of Fmrp in the brain, and the literature on identifying genes thought to mediate autism and other psychiatric disorders, reveals that both appear to be disproportionately made up of highly brain-expressed genes. This suggests a parsimonious explanation—that the overlap between Fmrp targets and neuropsychiatric candidate genes might be secondary to simple features such as transcript length and robust expression in the brain. Indeed, reanalyzing Fmrp high-throughput sequencing of RNAs isolated by CLIP (HITS-CLIP) data suggests that approximately 60% of CLIP tag depth can be predicted by gene expression, coding sequence length, and transcript length. Furthermore, there is a statistically significant overlap between autism candidate genes and random samples of long, highly brain-expressed genes, whether they are Fmrp targets or not. CONCLUSIONS: Comparison of known Fmrp-binding targets to candidate gene lists should be informed by both of these features. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13229-015-0008-1) contains supplementary material, which is available to authorized users

Analyzing Neoliberalism in Theory and Practice: The Case of Performance-Based Funding for Higher Education

Neoliberal ideas – whether the new public management, principal-agent theory, or performance management – have provided rationale for sweeping reforms in the governance and operation of higher education. Despite this, little attention has been devoted to how well neoliberal theory illuminates the policy process by which neoliberal policy is enacted and implemented. This paper expands our understanding of the origins, implementation, and impacts of neoliberal policies by examining the case of performance-based funding (PBF) for higher education in the United States, Europe, Canada, Australia, and elsewhere. With regard to policy origins, neoliberal theory anticipates the key role that top government officials play in the development of PBF but fails to anticipate the important roles of business and higher education institutions in the formation of neoliberal policies. Neoliberal theory notes the important role of monetary incentives as policy instruments and the obstacles posed by gaming on the part of agents, but the implementation of PBF also involves other policy instruments and faces additional obstacles to implementation. Policy outcomes fitting the neoliberal focus on organizational effectiveness and efficiency are only weakly produced by PBF, but PBF is associated with a host of unintended impacts that neoliberal theory ignores

Does this Feel Empowering? Using Métissage to Explore the Effects of Critical Pedagogy

The extent to which critical pedagogy disrupts the relations of dominance inside postsecondary classrooms, or empowers students to take socially just action beyond the classroom has been debated and challenged for decades. Through the use of métissage, an interpretive inquiry method that affords collaborative interrogation of individual narrative writings, we five participants in the same critical pedagogy course conducted a post-course inquiry project in order to explore what we had learned through the course. Through this inquiry project, we have come to a deeper understanding of critical pedagogy praxis. Ultimately, what we learned through the use of this inquiry method maintains important implications for postsecondary educators

On the Comparison of the Long Penetration Mode (LPM) Supersonic Counterflowing Jet to the Supersonic Screech Jet

The authors provide a brief overview of the classic tonal screech noise problem created by underexpanded supersonic jets, briefly describing the fluid dynamic-acoustics feedback mechanism that has been long established as the basis for this well-known aeroacoustics problem. This is followed by a description of the Long Penetration Mode (LPM) supersonic underexpanded counterflowing jet phenomenon which has been demonstrated in several wind tunnel tests and modeled in several computational fluid dynamics (CFD) simulations. The authors provide evidence from test and CFD analysis of LPM that indicates that acoustics feedback and fluid interaction seen in LPM are analogous to the aeroacoustics interactions seen in screech jets. Finally, the authors propose applying certain methodologies to LPM which have been developed and successfully demonstrated in the study of screech jets and mechanically induced excitation in fluid oscillators for decades. The authors conclude that the large body of work done on jet screech, other aeroacoustic phenomena, and fluid oscillators can have direct application to the study and applications of LPM counterflowing supersonic cold flow jets

Induced earthquake families reveal distinctive evolutionary patterns near disposal wells

The timing of events in seismic sequences can provide insights into the physical processes controlling fault slip. In southern Kansas, the rate of earthquakes rose rapidly starting in 2013 following expansion of energy production into the area, demanding the disposal of large volumes of wastewater into deep wells. Seismicity catalogs that are complete to low magnitudes can provide insights into the physical processes that induce seismicity near wastewater disposal. We develop a catalog of over 130,000 earthquakes recorded in southern Kansas from mid‐March 2014 through December 2017 by applying a matched filter algorithm to an original catalog of 5,831 template earthquakes. Detections have nearly identical waveforms to their associated template event and represent slip on nearly co‐located sections of a fault. We select template events with at least 100 associated detections and examine the characteristics of these prolific families of earthquakes. We find that families located close (<10 km) to areas with significant volumes of injected fluids have near‐Poissonian interevent times and the families remain active over longer durations. Families farther from high‐volume injection wells show strong clustering of interevent times and shorter sequence durations. We conclude that increasing pore fluid pressures from nearby disposal of large volumes of wastewater is the primary driver of these long duration episodes, with earthquake‐earthquake interactions driving sequences at greater distance from the wells

Effortful control and parenting: Associations with HPA axis reactivity in early childhood

While activation of the hypothalamic-pituitary-adrenal (HPA) axis is an adaptive response to stress, excessive HPA axis reactivity may be an important marker of childhood vulnerability to psychopathology. Parenting, including parent affect during parent-child interactions, may play an important role in shaping the developing HPA system; however, the association of parent affect may be moderated by child factors, especially children\u27s emerging self-regulatory skills. We therefore tested the relationship between parent affectivity and 160 preschoolers\u27 cortisol reactivity during a laboratory visit, examining children\u27s effortful control (EC) as a moderator. Greater parent negative affectivity was related to greater initial and increasing cortisol over time, but only when children were low in EC. Higher parent positive affectivity was related to a higher baseline cortisol for children with low EC and lower baseline cortisol for children with high EC. Results indicate that children\u27s EC moderates the extent to which parent affect shapes stress reactive systems in early childhood. © 2013 Blackwell Publishing Ltd

MicroRNA profiling reveals marker of motor neuron disease in ALS models

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder marked by the loss of motor neurons (MNs) in the brain and spinal cord, leading to fatally debilitating weakness. Because this disease predominantly affects MNs, we aimed to characterize the distinct expression profile of that cell type to elucidate underlying disease mechanisms and to identify novel targets that inform on MN health during ALS disease time course. microRNAs (miRNAs) are short, noncoding RNAs that can shape the expression profile of a cell and thus often exhibit cell-type-enriched expression. To determine MN-enriched miRNA expression, we used Cre recombinase-dependent miRNA tagging and affinity purification in mice. By defining thein vivomiRNA expression of MNs, all neurons, astrocytes, and microglia, we then focused on MN-enriched miRNAs via a comparative analysis and found that they may functionally distinguish MNs postnatally from other spinal neurons. Characterizing the levels of the MN-enriched miRNAs in CSF harvested from ALS models of MN disease demonstrated that one miRNA (miR-218) tracked with MN loss and was responsive to an ALS therapy in rodent models. Therefore, we have used cellular expression profiling tools to define the distinct miRNA expression of MNs, which is likely to enrich future studies of MN disease. This approach enabled the development of a novel, drug-responsive marker of MN disease in ALS rodents.SIGNIFICANCE STATEMENTAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which motor neurons (MNs) in the brain and spinal cord are selectively lost. To develop tools to aid in our understanding of the distinct expression profiles of MNs and, ultimately, to monitor MN disease progression, we identified small regulatory microRNAs (miRNAs) that were highly enriched or exclusive in MNs. The signal for one of these MN-enriched miRNAs is detectable in spinal tap biofluid from an ALS rat model, where its levels change as disease progresses, suggesting that it may be a clinically useful marker of disease status. Furthermore, rats treated with ALS therapy have restored expression of this MN RNA marker, making it an MN-specific and drug-responsive marker for ALS rodents.</jats:p

Lipidomics Reveals Early Metabolic Changes in Subjects with Schizophrenia: Effects of Atypical Antipsychotics

There is a critical need for mapping early metabolic changes in schizophrenia to capture failures in regulation of biochemical pathways and networks. This information could provide valuable insights about disease mechanisms, trajectory of disease progression, and diagnostic biomarkers. We used a lipidomics platform to measure individual lipid species in 20 drug-naïve patients with a first episode of schizophrenia (FE group), 20 patients with chronic schizophrenia that had not adhered to prescribed medications (RE group), and 29 race-matched control subjects without schizophrenia. Lipid metabolic profiles were evaluated and compared between study groups and within groups before and after treatment with atypical antipsychotics, risperidone and aripiprazole. Finally, we mapped lipid profiles to n3 and n6 fatty acid synthesis pathways to elucidate which enzymes might be affected by disease and treatment. Compared to controls, the FE group showed significant down-regulation of several n3 polyunsaturated fatty acids (PUFAs), including 20:5n3, 22:5n3, and 22:6n3 within the phosphatidylcholine and phosphatidylethanolamine lipid classes. Differences between FE and controls were only observed in the n3 class PUFAs; no differences where noted in n6 class PUFAs. The RE group was not significantly different from controls, although some compositional differences within PUFAs were noted. Drug treatment was able to correct the aberrant PUFA levels noted in FE patients, but changes in re patients were not corrective. Treatment caused increases in both n3 and n6 class lipids. These results supported the hypothesis that phospholipid n3 fatty acid deficits are present early in the course of schizophrenia and tend not to persist throughout its course. These changes in lipid metabolism could indicate a metabolic vulnerability in patients with schizophrenia that occurs early in development of the disease

The Political Origins of State-Level Performance Funding for Higher Education: The Cases of Florida, Illinois, Missouri, South Carolina, Tennessee, and Washington

Performance funding is a method of funding public institutions based not on inputs, such as enrollments, but on outcomes, such as retention, degree completion, and job placement. The principal rationale for performance funding has been that performance funding will prod institutions to be more effective and efficient, particularly in a time of increasing demands on higher education and increasingly straitened state finances. Critics of performance funding have warned that it could potentially provide state officials with an excuse to cut back on the regular state funding of higher education and at the same time provide college officials with an incentive to raise their retention and graduation rates by becoming more selective in their admissions. This report examines in detail the origins of state performance funding in six states: Florida, Illinois, Missouri, South Carolina, Tennessee, and Washington. These states were chosen for analysis because they have considerably different state performance funding systems and histories as well as higher education governance arrangements, political systems, political cultures, and social characteristics—all of which enables the authors to look at the formation of state performance funding systems from a wide variety of angles. Interestingly, analysis reveals that there are striking similarities among these six states, particularly in terms of who were the main supporters and opponents, what beliefs animated them, and what political openings allowed policy entrepreneurs to put performance funding on the decision making agendas of state governments. This analysis yields some important lessons for policymakers, which are discussed at the conclusion of this paper