Subsequent Interference Research Articles

Myotonic Dystrophy: From Bench to Bedside

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant disorders classically characterized by muscle weakness, myotonia, and early-onset cataracts. Patients may also experience dysfunction of the heart, brain, gastrointestinal, endocrine, skin, and respiratory systems. The pathogenesis of myotonic dystrophy is related to trinucleotide (DM1) and tetranucleotide (DM2) repeat expansions that produce toxic mutant mRNA with subsequent interference of RNA-splicing mechanisms. Optimal disease management includes symptomatic care, screens for asymptomatic disease, counseling, and a multidisciplinary approach. The authors review the pathogenesis, clinical features, diagnostic tests, and standard management of DM1 and DM2 and outline promising clinical research for patients with these disorders.

The role of the brain’s frontal eye fields in constructing frame of reference

Establishing contextual reference during discourse is a vital part of language function. Personal pronouns (e.g., he/she/it) are used to refer to previously experienced objects, utterances and events. These items, however, are often no longer present in the environment and have to be maintained and manipulated in working memory (WM). One aspect of this is the construction of a spatial frame of reference (e.g., "He was in front of it" where "he" is established as figure and "it" is the ground). The WM processes underlying this function may be different from those involved in establishing a non-spatial relation (e.g., "He was older than her"). The brain's frontal eye fields (FEFs), responsible for eye movement control, are known to be involved in processing spatial WM. This paper reviews both functional magnetic resonance imaging experiments and a subsequent behavioral interference study demonstrating a specific role for the FEFs and the brain's eye movement control system in manipulation of WM content for establishing object-centered spatial reference frames during verbally cued recall of recent visual and linguistic experiences.

Identification of VHY/Dusp15 as a Regulator of Oligodendrocyte Differentiation through a Systematic Genomics Approach

Multiple sclerosis (MS) is a neuroinflammatory disease characterized by a progressive loss of myelin and a failure of oligodendrocyte (OL)-mediated remyelination, particularly in the progressive phases of the disease. An improved understanding of the signaling mechanisms that control differentiation of OL precursors may lead to the identification of new therapeutic targets for remyelination in MS. About 100 mammalian Protein Tyrosine Phosphatases (PTPs) are known, many of which are involved in signaling both in health and disease. We have undertaken a systematic genomic approach to evaluate PTP gene activity in multiple sclerosis autopsies and in related in vivo and in vitro models of the disease. This effort led to the identification of Dusp15/VHY, a PTP previously believed to be expressed only in testis, as being transcriptionally regulated during OL differentiation and in MS lesions. Subsequent RNA interference studies revealed that Dusp15/VHY is a key regulator of OL differentiation. Finally, we identified PDGFR-beta and SNX6 as novel and specific Dusp15 substrates, providing an indication as to how this PTP might exert control over OL differentiation.

Slow wave sleep during a daytime nap is necessary for protection from subsequent interference and long-term retention

While it is now generally accepted that sleep facilitates the processing of newly acquired declarative information, questions still remain as to the type and length of sleep necessary to best benefit declarative memories. A better understanding could lend support in one direction or another as to the much-debated role of sleep, be it passive, permissive, or active, in memory processing. The present study employed a napping paradigm and compared performance on a bimodal paired-associates task of those who obtained a 10-min nap, containing only Stages 1 and 2 sleep, to those whose nap contained slow-wave sleep (SWS) and rapid eye movement (REM) sleep (60-min nap), as well as to subjects who remained awake. Measurements were obtained for baseline performance at training, after a sleep/no sleep interval for short-term retention, after a subsequent stimulus-related interference task, and again after a weeklong retention period. While all groups learned the information similarly, both nap groups performed better than the Wake group when examining short-term retention, approximately 1.5h after training (10-min p=.052, 60-min p=.002). However, performance benefits seen in the 10-min nap group proved to be temporary. Performance after a stimulus-related interference task revealed significantly better memory retention in the 60-min nap group, with interference disrupting the memory trace far less than both the Wake and 10-min nap groups (p<.001, p=.006, respectively). After a weeklong retention period, sleep’s benefit to memory persisted in the 60-min nap group, with performance significantly greater than both the Wake and 10-min nap groups (p<.001, p=.004, respectively). It is our conclusion that SWS, obtained only by those in the 60-min nap group, served to actively facilitate the consolidation of learned bimodal paired-associates, supported by theories such as the Standard Theory of Consolidation as well as the Synaptic Homeostasis Hypothesis.

Primed T Cell Responses to Chemokines Are Regulated by the Immunoglobulin-Like Molecule CD31

CD31, an immunoglobulin-like molecule expressed by leukocytes and endothelial cells, is thought to contribute to the physiological regulation T cell homeostasis due to the presence of two immunotyrosine-based inhibitory motifs in its cytoplasmic tail. Indeed, loss of CD31 expression leads to uncontrolled T cell-mediated inflammation in a variety of experimental models of disease and certain CD31 polymorphisms correlate with increased disease severity in human graft-versus-host disease and atherosclerosis. The molecular mechanisms underlying CD31-mediated regulation of T cell responses have not yet been clarified. We here show that CD31-mediated signals attenuate T cell chemokinesis both in vitro and in vivo. This effect selectively affects activated/memory T lymphocytes, in which CD31 is clustered on the cell membrane where it segregates to the leading edge. We provide evidence that this molecular segregation, which does not occur in naïve T lymphocytes, might lead to cis-CD31 engagement on the same membrane and subsequent interference with the chemokine-induced PI3K/Akt signalling pathway. We propose that CD31-mediated modulation of memory T cell chemokinesis is a key mechanism by which this molecule contributes to the homeostatic regulation of effector T cell immunity.

Myxoid Liposarcoma-Associated EWSR1-DDIT3 Selectively Represses Osteoblastic and Chondrocytic Transcription in Multipotent Mesenchymal Cells

BackgroundLiposarcomas are the most common class of soft tissue sarcomas, and myxoid liposarcoma is the second most common liposarcoma. EWSR1-DDIT3 is a chimeric fusion protein generated by the myxoid liposarcoma-specific chromosomal translocation t(12;22)(q13;q12). Current studies indicate that multipotent mesenchymal cells are the origin of sarcomas. The mechanism whereby EWSR1-DDIT3 contributes to the phenotypic selection of target cells during oncogenic transformation remains to be elucidated.Methodology/Principal FindingsReporter assays showed that the EWSR1-DDIT3 myxoid liposarcoma fusion protein, but not its wild-type counterparts EWSR1 and DDIT3, selectively repressed the transcriptional activity of cell lineage-specific marker genes in multipotent mesenchymal C3H10T1/2 cells. Specifically, the osteoblastic marker Opn promoter and chondrocytic marker Col11a2 promoter were repressed, while the adipocytic marker Ppar-γ2 promoter was not affected. Mutation analyses, transient ChIP assays, and treatment of cells with trichostatin A (a potent inhibitor of histone deacetylases) or 5-Aza-2′-deoxycytidine (a methylation-resistant cytosine homolog) revealed the possible molecular mechanisms underlying the above-mentioned selective transcriptional repression. The first is a genetic action of the EWSR1-DDIT3 fusion protein, which results in binding to the functional C/EBP site within Opn and Col11a2 promoters through interaction of its DNA-binding domain and subsequent interference with endogenous C/EBPβ function. Another possible mechanism is an epigenetic action of EWSR1-DDIT3, which enhances histone deacetylation, DNA methylation, and histone H3K9 trimethylation at the transcriptional repression site. We hypothesize that EWSR1-DDIT3-mediated transcriptional regulation may modulate the target cell lineage through target gene-specific genetic and epigenetic conversions.Conclusions/SignificanceThis study elucidates the molecular mechanisms underlying EWSR1-DDIT3 fusion protein-mediated phenotypic selection of putative target multipotent mesenchymal cells during myxoid liposarcoma development. A better understanding of this process is fundamental to the elucidation of possible direct lineage reprogramming in oncogenic sarcoma transformation mediated by fusion proteins.

Diffusion modeling of interference in vibrotactile working memory

The nature of interference in working memory has been a subject of discussion for decades. It has previously been argued that irrelevant stimuli can interfere with working memory by being encoded into memory. Previous findings have suggested that irrelevant sensory activity can interfere with the storage of information in tactile working memory. More recently, it has been suggested that this type of interference may operate through the overwriting of stored information by interfering sensory stimuli, even when participants are instructed to ignore such stimuli. Such a mechanism of interference is consistent with previous theoretical proposals. In the present study, we use a computational diffusion model to demonstrate that previous empirical findings are best explained by the encoding of irrelevant sensory information and subsequent interference.

Identification of Lipases Involved in PBAN Stimulated Pheromone Production in Bombyx mori Using the DGE and RNAi Approaches

BackgroundPheromone biosynthesis activating neuropeptide (PBAN) is a neurohormone that regulates sex pheromone synthesis in female moths. Bombyx mori is a model organism that has been used to explore the signal transduction pattern of PBAN, which is mediated by a G-protein coupled receptor (GPCR). Although significant progress has been made in elucidating PBAN-regulated lipolysis that releases the precursor of the sex pheromone, little is known about the molecular components involved in this step. To better elucidate the molecular mechanisms of PBAN-stimulated lipolysis of cytoplasmic lipid droplets (LDs), the associated lipase genes involved in PBAN- regulated sex pheromone biosynthesis were identified using digital gene expression (DGE) and subsequent RNA interference (RNAi).ResultsThree DGE libraries were constructed from pheromone glands (PGs) at different developed stages, namely, 72 hours before eclosion (−72 h), new emergence (0 h) and 72 h after eclosion (72 h), to investigate the gene expression profiles during PG development. The DGE evaluated over 5.6 million clean tags in each PG sample and revealed numerous genes that were differentially expressed at these stages. Most importantly, seven lipases were found to be richly expressed during the key stage of sex pheromone synthesis and release (new emergence). RNAi-mediated knockdown confirmed for the first time that four of these seven lipases play important roles in sex pheromone synthesis.ConclusionThis study has identified four lipases directly involved in PBAN-stimulated sex pheromone biosynthesis, which improve our understanding of the lipases involved in releasing bombykol precursors from triacylglycerols (TAGs) within the cytoplasmic LDs.

Individualistic and Collectivistic Approach in Athlete Support Programmes in the German High-Performance Sport System

This study assessed the relative significance of athlete-related interventions and of repeated athlete selections and de-selections (individualistic and collectivistic approach) in the development of the collective of successful senior performers through athlete support programmes in Germany. The results from a longitudinal analysis of careers in the squad system over seven years (n=4,686) and a questionnaire panel study over three years (n=244) revealed that the annual turnover of squad members was 44%. Results also showed that the younger the first recruitment of an athlete, the younger the exit out of the system (r=0.92), and the higher the squad level reached, the higher was the age of recruitment into a squad. Interventions applied to the selected athletes showed no significant effects on subsequent interferences in the training process or on attainment of success. The collective of successful senior athletes was developed through regular athlete selection and de-selection rather than effects of athlete-related interventions. The observations are discussed with regard to (a) dissimilar individual career trajectories likely to lead to early inclusion in the support system compared to those likely to lead to long-term senior success, and (b) the functionality of de-coupling self-display and action at the collective level of the organisations.

The Late Positive Potential Predicts Subsequent Interference with Target Processing

The current study investigated the association between neural engagement with task-irrelevant images and subsequent interference with target processing using the Emotional Interrupt paradigm [Mitchell, D., Richell, R., Leonard, A., & Blair, R. Emotion at the expense of cognition: Psychopathic individuals outperform controls on an operant response task. Journal of Abnormal Psychology, 115, 559, 2006]. Consistent with previous studies, PCA-derived factors corresponding to the early posterior negativity, P300, and late positive potential (LPP) were enhanced for emotional (i.e., both unpleasant and pleasant) compared with neutral distracters, and the P300 elicited by targets was smaller following emotional compared with neutral pictures. In addition, RTs were increased to targets that followed emotional pictures. Within-subject analyses demonstrated that slow trials were characterized by a smaller P300 and were preceded by pictures with a larger LPP. Additionally, between-subject analyses indicate that individuals with a larger LPP also demonstrated slower RTs to targets and reduced target-elicited P300s. All results were specific to the LPP and were not observed for either the early posterior negativity or the P300 elicited by task-irrelevant pictures. By relating the LPP to subsequent behavioral and ERP interference in both within- and between-subject analyses, the current study provides direct support for the notion that LPP indexes attentional engagement with visual stimuli that is uniquely associated with subsequent interference in terms of both RT slowing and P300 reduction to targets.

Geminiviruses Subvert Ubiquitination by Altering CSN-Mediated Derubylation of SCF E3 Ligase Complexes and Inhibit Jasmonate Signaling inArabidopsis thaliana

Viruses must create a suitable cell environment and elude defense mechanisms, which likely involves interactions with host proteins and subsequent interference with or usurpation of cellular machinery. Here, we describe a novel strategy used by plant DNA viruses (Geminiviruses) to redirect ubiquitination by interfering with the activity of the CSN (COP9 signalosome) complex. We show that geminiviral C2 protein interacts with CSN5, and its expression in transgenic plants compromises CSN activity on CUL1. Several responses regulated by the CUL1-based SCF ubiquitin E3 ligases (including responses to jasmonates, auxins, gibberellins, ethylene, and abscisic acid) are altered in these plants. Impairment of SCF function is confirmed by stabilization of yellow fluorescent protein-GAI, a substrate of the SCF(SLY1). Transcriptomic analysis of these transgenic plants highlights the response to jasmonates as the main SCF-dependent process affected by C2. Exogenous jasmonate treatment of Arabidopsis thaliana plants disrupts geminivirus infection, suggesting that the suppression of the jasmonate response might be crucial for infection. Our findings suggest that C2 affects the activity of SCFs, most likely through interference with the CSN. As SCFs are key regulators of many cellular processes, the capability of viruses to selectively interfere with or hijack the activity of these complexes might define a novel and powerful strategy in viral infections.

Mdm2 Regulates Estrogen Receptor and Estrogen-responsiveness in Breast Cancer Cells

Murine double minute clone 2 (MDM2) is a multifunctional protein, which modulates nuclear receptor-mediated transactivation. In this study, we show that MDM2 significantly enhanced estrogen receptor α (ERα) and ERα/specificity protein-mediated transactivation in MCF-7 and ZR-75 breast cancer cells. This was demonstrated by both MDM2 overexpression and knockdown experiments by RNA interference. ERα interacted with wild-type MDM2 and deletion mutants of MDM2 containing amino acids 1-342 (C-terminal deletion) and 134-490 (N-terminal deletion), but not 134-342. In contrast, only wild-type but not mutant MDM2 enhanced ERα-mediated transactivation. Protein-protein interactions in vitro were 17β-estradiol (E(2)) independent, whereas fluorescent resonance energy transfer experiments in living cells showed that E(2) enhanced ERα-MDM2 interactions. Subsequent RNA interference and mammalian two-hybrid experiments suggested that MDM2 did not directly interact with endogenous coactivators such as the steroid receptor coactivators but played a role in enhancing ERα-mediating gene expression and estrogen responsiveness through interactions with ERα.

Early-Stage Dynamics of Light-Matter Interaction Leading to the Insulator-to-Metal Transition in a Charge Ordered Organic Crystal

Ultrafast dynamics of the light-matter interaction in a charge-ordered molecular insulator α-(BEDT-TTF)2I3 were studied by pump-probe spectroscopy using few-optical-cycle infrared pulses (pulse width 12 fs). Coherent oscillation of the correlated electrons and subsequent Fano destructive interference with intramolecular vibration were observed in time domain; the results indicated a crucial role for electron-electron interplay in the light-matter interaction leading to the photoinduced insulator-to-metal transition. The qualitative features of this correlated electron motion were reproduced by calculations based on exact many-electron-phonon wave functions.

Implications of transient changes of optical and surface properties of solids during femtosecond laser pulse irradiation to the formation of laser-induced periodic surface structures

The formation of laser-induced periodic surface structures (LIPSS) upon irradiation of silicon wafer surfaces by linearly polarized Ti:sapphire femtosecond laser pulses (pulse duration 130 fs, central wavelength 800 nm) is studied experimentally and theoretically. In the experiments, so-called low-spatial frequency LIPSS (LSFL) were found with periods smaller than the laser wavelength and an orientation perpendicular to the polarization. The experimental results are analyzed by means of a new theoretical approach, which combines the widely accepted LIPSS theory of Sipe et al. with a Drude model, in order to account for transient (intra-pulse) changes of the optical properties of the irradiated materials. It is found that the LSFL formation is caused by the excitation of surface plasmon polaritons, SPPs, once the initially semiconducting material turns to a metallic state upon formation of a dense free-electron-plasma in the material and the subsequent interference between its electrical field with that of the incident laser beam resulting in a spatially modulated energy deposition at the surface. Moreover, the influence of the laser-excited carrier density and the role of the feedback upon the multi-pulse irradiation and its relation to the excitation of SPP in a grating-like surface structure is discussed.

Diffraction assisted rough ground effect.

Ground effect results from the interference between sound traveling directly from a point source to a receiver and that reflected coherently from the ground. The frequencies associated with first and subsequent order destructive interference in excess attenuation spectra are determined by the source-receiver geometry and the ground impedance. Typically if the ground is hard and smooth, then at grazing incidence the first destructive interference occurs at too high a frequency to be useful in noise control. However, the effective impedance of a rough, hard surface is finite, and destructive interference can occur at much lower frequencies over a hard, rough surface than if the surface is smooth. If the roughness is spaced periodically, then the phenomenon of diffraction assisted ground effect occurs. Instead of the single destructive minimum observed with randomly spaced roughness elements, a cluster of two or three destructive interference peaks are observed. This phenomenon has been explored through laboratory experiments using semi-cylindrical, rectangular, and wedge-shaped strips placed on a glass sheet. Use of multiple scattering theory for semi-cylindrical roughness on a hard surface shows that the diffraction assisted effect depends on the number of roughness elements and their spacing. The extent to which the phenomenon could be exploited for noise control is discussed. [Work supported by European Community FP7 project no. 234306.]

A SERI technique reveals an immunosuppressive activity of a serine-rich protein encoded in Cotesia plutellae bracovirus

Polydnavirus genome is segmented and dispersed on host wasp chromosome. After replication, the segments form double- stranded circular DNAs and embedded in viral coat proteins. These viral particles are delivered into a parasitized host along with parasitoid eggs. A serine-rich protein (SRP) is predicted in a polydnavirus, Cotesia plutellae bracovirus (CpBV), genome in its segment no. 33 (CpBV-S33), creating CpBVSRP1. This study explored its expression and physiological function in the diamondback moth, Plutella xylostella, larvae parasitized by C. plutellae. CpBV-SRP1 encodes 122 amino acids with 26 serines and several predicted phosphorylation sites. It is persistently expressed in all tested tissues of parasitized P. xylostella including hemocyte, fat body, and gut. Its physiological function was analyzed by injecting CpBV-S33 and inducing its expression in nonparasitized P. xylostella by a technique called SERI (segment expression and RNA interference). The expression of CpBV-SRP1 significantly impaired the spreading behavior and total cell count of hemocytes of treated larvae. Subsequent RNA interference of CpBV-SRP1 rescued the immunosuppressive response. This study reports the persistent expression of CpBV-SRP1 in a parasitized host and its parasitic role in suppressing the host immune response by altering hemocyte behavior and survival.

Strategic control of visual short-term memory during scene viewing

During scene viewing, the eyes and attention are directed serially to objects of interest, and visual short-term memory (VSTM) is used retain information from recently attended objects (H lli th 2004) I th t t d i d h th l t t i ll Experiment 1: Results 100 100 Experiment 2: Results 100 Experiment 3: Results o ngwor , . n e presen s u y, we exam ne w e er peop e can s ra eg ca y control the content of VSTM during scene viewing, retaining task-relevant objects in VSTM even as attention and the eyes are directed to subsequent objects. Participants viewed a set of real-world objects presented serially within a 3-D rendered scene. One object in the sequence was cued by a tone as “to-be-remembered”. At the end of the sequence, memory for the visual form of one object was tested. Participants exhibited tight control over the content of VSTM, successfully protecting task-relevant objects from subsequent interference. Such strategic maintenance of objects in VSTM could play an important role in real-world visual behavior, especially when object information must be maintained across shifts of attention and the eyes to other objects (such as when comparing two er ce nt ag e C or re ct 70 80 90 Cue Position 2 Cue Position 3 Neutral Pe rc en ta ge C or re ct

Indistinguishability and interference in the coherent control of atomic and molecular processes

The subtle and fundamental issue of indistinguishability and interference between independent pathways to the same target state is examined in the context of coherent control of atomic and molecular processes, with emphasis placed on possible "which-way" information due to quantum entanglement established in the quantum dynamics. Because quantum interference between independent pathways to the same target state occurs only when the independent pathways are indistinguishable, it is first shown that creating useful coherence between nondegenerate states of a molecule for subsequent quantum interference manipulation cannot be achieved by collisions between atoms or molecules that are prepared in momentum and energy eigenstates. Coherence can, however, be transferred from light fields to atoms or molecules. Using a particular coherent control scenario, it is shown that this coherence transfer and the subsequent coherent phase control can be readily realized by the most classical states of light, i.e., coherent states of light. It is further demonstrated that quantum states of light may suppress the extent of phase-sensitive coherent control by leaking out some which-way information while "incoherent interference control" scenarios proposed in the literature have automatically ensured the indistinguishability of multiple excitation pathways. The possibility of quantum coherence in photodissociation product states is also understood in terms of the disentanglement between photodissociation fragments. Results offer deeper insights into quantum coherence generation in atomic and molecular processes.

Vestigial and scalloped in the ladybird beetle: a conserved function in wing development and a novel function in pupal ecdysis

In Drosophila melanogaster, Vestigial (Vg) and Scalloped (Sd) form a transcription factor complex and play a crucial role in wing development. To extend our knowledge of insect wing formation, we isolated vg and sd homologues from two ladybird beetle species, Henosepilachna vigintioctopunctata and Harmonia axyridis. Although the ladybird beetle vg homologues had only low homology with D. melanogaster vg, ectopic expression of H. vigintioctopunctata vg induced wing-like tissues in antennae and legs of D. melanogaster. Subsequent larval RNA interference (RNAi) analysis in H. vigintioctopunctata demonstrated conserved functions of vg and sd in wing development, and an unexpected novel function of sd in pupal ecdysis. Furthermore, our results can be applied to the production of a flightless ladybird beetle for biological control purposes using larval RNAi.

Individual Differences in the Attentional Blink

A well-established phenomenon in the study of attention is the attentional blink (AB): a deficit in reporting the second of two targets when it occurs 200-500 ms after the first. Although the effect has been shown to be robust in a wide variety of task conditions, we recently reported that some individuals show little or no AB, and presented psychophysiological evidence that target processing differs in nonblinkers (who do not show an AB) and blinkers (who do show an AB). Here we present evidence that the level of distractor processing and subsequent interference with target identification processes also differs between the two groups. In one task, two masked targets were centrally presented at varying temporal intervals, with or without additional distractors. In a second task, the masked targets were presented eccentrically, with or without the presence of a central sequential stream of the task-irrelevant distractors. In both cases, the presence of distractors led to an increased AB magnitude in blinkers, whereas performance for nonblinkers remained relatively unaffected. The results thus support the hypothesis that nonblinkers are more efficient in ignoring irrelevant information than blinkers.