The Krüppel-like factor 9 cistrome in mouse hippocampal neurons reveals predominant transcriptional repression via proximal promoter binding

Abstract Background Krüppel-like factor 9 (Klf9) is a zinc finger transcription factor that functions in neural cell differentiation, but little is known about its genomic targets or mechanism of action in neurons. Results We used the mouse hippocampus-derived neuronal cell line HT22 to identify genes regulated by Klf9, and we validated our findings in mouse hippocampus. We engineered HT22 cells to express a Klf9 transgene under control of the tetracycline repressor, and used RNA sequencing to identify genes modulated by Klf9. We found 217 genes repressed and 21 induced by Klf9. We also engineered HT22 cells to co-express biotin ligase and a Klf9 fusion protein containing an N-terminal biotin ligase recognition peptide. Using chromatin-streptavidin precipitation (ChSP) sequencing we identified 3,514 genomic regions where Klf9 associated. Seventy-five percent of these were within 1 kb of transcription start sites, and Klf9 associated in chromatin with 60% of the repressed genes. We analyzed the promoters of several repressed genes containing Klf9 ChSP peaks using transient transfection reporter assays and found that Klf9 repressed promoter activity, which was abolished after mutation of Sp/Klf-like motifs. Knockdown or knockout of Klf9 in HT22 cells caused dysregulation of Klf9 target genes. Chromatin immunoprecipitation assays showed that Klf9 associated in chromatin from mouse hippocampus with genes identified by ChSP sequencing on HT22 cells, and expression of Klf9 target genes was dysregulated in the hippocampus of neonatal Klf9-null mice. Gene ontology analysis revealed that Klf9 genomic targets include genes involved in cystokeletal remodeling, Wnt signaling and inflammation. Conclusions We have identified genomic targets of Klf9 in hippocampal neurons and created a foundation for future studies on how it functions in chromatin, and regulates neuronal morphology and survival across the lifespan.https://deepblue.lib.umich.edu/bitstream/2027.42/136551/1/12864_2017_Article_3640.pd

Histomorphometry of the Sural Nerve for Use as a CFNG in Facial Reanimation Procedures

Facial palsy (FP) is a debilitating nerve pathology. Cross Face Nerve Grafting (CFNG) describes a surgical technique that uses nerve grafts to reanimate the paralyzed face. The sural nerve has been shown to be a reliable nerve graft with little donor side morbidity. Therefore, we aimed to investigate the microanatomy of the sural nerve. Biopsies were obtained from 15 FP patients who underwent CFNG using sural nerve grafts. Histological cross-sections were fixated, stained with PPD, and digitized. Histomorphometry and a validated software-based axon quantification were conducted. The median age of the operated patients was 37 years (5–62 years). There was a significant difference in axonal capacity decrease towards the periphery when comparing proximal vs. distal biopsies (p = 0.047), while the side of nerve harvest showed no significant differences in nerve caliber (proximal p = 0.253, distal p = 0.506) and axonal capacity for proximal and distal biopsies (proximal p = 0.414, distal p = 0.922). Age did not correlate with axonal capacity (proximal: R = −0.201, p = 0.603; distal: R = 0.317, p = 0.292). These novel insights into the microanatomy of the sural nerve may help refine CFNG techniques and individualize FP patient treatment plans, ultimately improving overall patient outcomes

Vortex Motion Noise in Micrometre-Sized Thin Films of the Amorphous Nb0.7Ge0.3 Weak-Pinning Superconductor

We report high-resolution measurements of voltage (V) noise in the mixed state of micrometre-sized thin films of amorphous Nb0.7Ge0.3, which is a good representative of weak-pinning superconductors. There is a remarkable difference between the noise below and above the irreversibility field Birr. Below Birr, in the presence of measurable pinning, the noise at small applied currents resembles shot noise, and in the regime of flux flow at larger currents decreases with increasing voltage due to a progressive ordering of the vortex motion. At magnetic fields B between Birr and the upper critical field Bc2 flux flow is present already at vanishingly small currents. In this regime the noise scales with (1-B/Bc2)^2 V^2 and has a frequency (f) spectrum of 1/f type. We interpret this noise in terms of the properties of strongly driven depinned vortex systems at high vortex density.Comment: 8 pages, 5 figures, version accepted for publication in PR

Sensory Communication

Contains table of contents for Section 2, an introduction and reports on twelve research projects.National Institutes of Health Grant 5 R01 DC00117National Institutes of Health Contract 2 P01 DC00361National Institutes of Health Grant 5 R01 DC00126National Institutes of Health Grant R01-DC00270U.S. Air Force - Office of Scientific Research Contract AFOSR-90-0200National Institutes of Health Grant R29-DC00625U.S. Navy - Office of Naval Research Grant N00014-88-K-0604U.S. Navy - Office of Naval Research Grant N00014-91-J-1454U.S. Navy - Office of Naval Research Grant N00014-92-J-1814U.S. Navy - Naval Training Systems Center Contract N61339-93-M-1213U.S. Navy - Naval Training Systems Center Contract N61339-93-C-0055U.S. Navy - Naval Training Systems Center Contract N61339-93-C-0083U.S. Navy - Office of Naval Research Grant N00014-92-J-4005U.S. Navy - Office of Naval Research Grant N00014-93-1-119

Randomised controlled trial of the short-term effects of OROS-methylphenidate on ADHD symptoms and behavioural outcomes in young male prisoners with attention-deficit/hyperactivity disorder (CIAO-II)

Background Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent disorder, seen in 20–30% of young adult prisoners. Pharmacoepidemiological studies, a small randomised controlled trial and open trial data of methylphenidate suggest clinically significant reductions in ADHD symptoms, emotional dysregulation, disruptive behaviour and increased engagement with educational activities. Yet, routine treatment of ADHD in offenders is not yet established clinical practice. There is continued uncertainty about the clinical response to methylphenidate (MPH), a first-line treatment for ADHD, in offenders, who often present with an array of complex mental health problems that may be better explained by states of inattentive, overactive, restless and impulsive behaviours. To address this problem, we will conduct an efficacy trial to establish the short-term effects of osmotic-controlled release oral delivery system (OROS)-methylphenidate (Concerta XL), an extended release formulation of MPH, on ADHD symptoms, emotional dysregulation and behaviour. Methods This study is a parallel-arm, randomised, placebo-controlled trial of OROS-MPH on ADHD symptoms, behaviour and functional outcomes in young male prisoners aged 16–25, meeting Diagnostic and Statistical Manual of Mental Disorders, fifth edition criteria for ADHD. Participants are randomised to 8 weeks of treatment with OROS-MPH or placebo, titrated over 5 weeks to balance ADHD symptom improvement against side effects. Two hundred participants will be recruited with a 1:1 ratio of drug to placebo. The primary outcome is change in level of ADHD symptoms after 8 weeks of trial medication. Discussion Potential benefits include improvement in ADHD symptoms, emotional dysregulation, attitudes towards violence and critical incidents and increased engagement with educational and rehabilitation programmes. Demonstrating the efficacy and safety of MPH on ADHD symptoms and associated impairments may provide the data needed to develop effective healthcare pathways for a significant group of young offenders. Establishing efficacy of MPH in this population will provide the foundation needed to establish long-term effectiveness studies with the potential for demonstrating significant reductions in criminal behaviour and improved health-economic outcomes

Simplistic vs. Complex Organization: Markets, Hierarchies, and Networks in an 'Organizational Triangle'

Transaction cost economics explains organizations in a simplistic ‘market-vs.-hierarchy’ dichotomy. In this view, complex real-world coordination forms are simply considered ‘hybrids’ of those ‘pure’ and ideal forms, thus being located on a one-dimensional ‘line’ between them. This ‘organizational dichotomy’ is mainly based on relative marginal transaction costs, relative lengths of value-added chains, and ‘rational choice’ of coordination form. The present paper, in contrast, argues that pure ‘market’ and ‘hierarchy’, even including their potential hybrids, are a theoretically untenable and empirically void set. Coordination forms, it is argued, have to be conceptualized in a fundamentally different way. A relevant ‘organizational space’ must reflect the dimensions of a complex world such as dilemma-prone direct interdependence, resulting in strong strategic uncertainty, mutual externalities, collectivities, and subsequent emergent process. This, in turn, will lead either to (1) informally institutionalized, problem-solving cooperation (the instrumental dimension of the institution) or (2) mutual blockage, lock-in on an inferior path, or power- and status-based market and hierarchy failure (the ceremonial dimension of the institution). This paper establishes emergent instrumental institutionalized cooperation as a genuine organizational dimension which generates a third ‘attractor’ besides ‘market’ and ‘hierarchy’, i.e., informal network. In this way, an ‘organizational triangle’ can be generated which may serve as a more relevant heuristic device for empirical organizational research. Its ideal corners and some ideal hybrids on its edges (such as ideal clusters and ideal hub&spoke networks) still remain empirically void, but its inner space becomes empirically relevant and accessible. The ‘Organizational Triangle’ is tentatively applied (besides casual reference to corporate behavior that has lead to the current financial meltdown), by way of a set of criteria for instrumental problem-solving and a simple formal algorithm, to the cases of the supplier network of ‘DaimlerChrysler US International’ at Tuscaloosa, AL, the open-source network Linux, and the web-platforms Wikipedia and ‘Open-Source Car’. It is considered to properly reflect what is generally theorized in evolutionary-institutional economics of organizations and the firm and might offer some insight for the coming industrial reconstructions of the car and other industries

Learning multiple rules simultaneously: affixes are more salient than reduplications

Language learners encounter numerous opportunities to learn regularities, but need to decide which of these regularities to learn, because some are not productive in their native language. Here, we present an account of rule learning based on perceptual and memory primitives (Endress, Dehaene-Lambertz, & Mehler, 2007; Endress, Nespor, & Mehler, 2009), suggesting that learners preferentially learn regularities that are more salient to them, and that the pattern of salience reflects the frequency of language features across languages. We contrast this view with previous artificial grammar learning research, which suggests that infants “choose” the regularities they learn based on rational, Bayesian criteria (Frank & Tenenbaum, 2011; Gerken, 2006, 2010). In our experiments, adult participants listened to syllable strings starting with a syllable reduplication and always ending with the same “a!x” syllable, or to syllable strings starting with this “a!x” syllable and ending with the “reduplication.” Both a!xation and reduplication are frequently used for morphological marking across languages. We find three crucial results. First, participants learned both regularities simultaneously. Second, a!xation regularities seemed easier to learn than reduplication regularities. Third, regularities in sequence o↵sets were easier to learn than regularities at sequence onsets. We show that these results are inconsistent with previous Bayesian rule learning models, but mesh well with the perceptual or memory primitives view. Further, we show that the pattern of salience revealed in our experiments reflects the distribution of regularities across languages. Ease of acquisition might thus be one determinant of the frequency of regularities across languages