The acidic (leucine‐rich) nuclear phosphoprotein 32 kDa (ANP32) family is composed of small, evolutionarily conserved proteins characterized by an N‐terminal leucine‐rich repeat domain and a C‐terminal low‐complexity acidic region. The mammalian family members (ANP32A, ANP32B, and ANP32E) are ascribed physiologically diverse functions including chromatin modification and remodelling, apoptotic caspase modulation, protein phosphatase inhibition, as well as regulation of intracellular transport. In addition to reviewing the widespread literature on the topic, we present a concept of the ANP32s as having (...) a whip‐like structure. We also present hypotheses that ANP32C and other intronless sequences should not currently be considered bona fide family members, that their disparate necessity in development may be due to compensatory mechanisms, that their contrasting roles in cancer are likely context‐dependent, along with an underlying hypothesis that ANP32s represent an important node of physiological regulation by virtue of their diverse biochemical activities. (shrink)

We introduce a new model of reduction inspired by Kemeny and Oppenheim’s model [Kemeny & Oppenheim 1956] and argue that this model is operative in a “ruthlessly reductive” part of current neuroscience. Kemeny and Oppenheim’s model was quickly rejected in mid-20th-century philosophy of science and replaced by models developed by Ernest Nagel and Kenneth Schaffner [Nagel 1961], [Schaffner 1967]. We think that Kemeny and Oppenheim’s model was correctly rejected, given what a “theory of reduction” was supposed to account for at (...) that time. But their guiding insights about what constitutes scientific reduction—increases in explanatory scope and systematization—reflect actual practices of current reductionistic neuroscience. The key rehabilitative step to make their insights fit current scientific details is to restate them using resources from recent work on causal-mechanistic explanation. We begin with a scientific case study, drawn from the relatively new field of “molecular and cellular cognition”. It provides an explanation of the well-known Ebbinghaus spacing effect on learning and memory in terms of interactions between a transcriptional enhancer protein and its inhibiting phosphatase in neurons recruited into the memory trace. Next we briefly describe some popular models of reduction from mid-20th-century philosophy of science. We point out how these models fail to illuminate key features of our scientific case study. Finally we present our causal-mechanistically updated Kemeny and Oppenheim-inspired model and argue that it nicely accounts for the details of our scientific case study. We close with a remark that will hopefully undercut the surprise many may feel to learn that a long-rejected philosophical account of reduction actually is at work in one of the most prominent reductionistic endeavors in current science. (shrink)

Calcineurin is a Ca2+/calmodulin‐activated protein phosphatase that is conserved in eukaryotes, from yeast to humans, and is the conserved target of the immunosuppressive drugs cyclosporin A (CsA) and FK506. Genetic studies in yeast and fungi established the molecular basis of calcineurin inhibition by the cyclophilin A–CsA and FKBP12–FK506 complexes. Calcineurin also functions in fungi to control a myriad of physiological processes including cell cycle progression, cation homeostasis, and morphogenesis. Recent investigations into the molecular mechanisms of pathogenesis in Candida (...) albicans and Cryptococcus neoformans, two fungi that cause life‐threatening infections in humans, have revealed an essential role for calcineurin in morphogenesis, virulence, and antifungal drug action. Novel non‐immunosuppressive analogs of the calcineurin inhibitors CsA and FK506 that retain antifungal activity have been identified and hold promise as candidate antifungal drugs. In addition, comparisons of calcineurin function in both fungi and humans may identify fungal‐specific components of calcineurin‐signaling pathways that could be targeted for therapy, as well as conserved elements of calcium signaling events. BioEssays 24:894–903, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

The study of intrinsic phosphorylation dynamics and kinetics in the context of complex protein architecture in vivo has been challenging: Method limitations have prevented significant advances in the understanding of the highly variable turnover of phosphate groups, synergy, and cooperativity between P‐sites. However, over the last decade, powerful analytical technologies have been developed to determine the full catalog of the phosphoproteome for many species. The curated databases of phospho sites found by mass spectrometry analysis and the computationally predicted sites based (...) on the linear sequence of kinase motifs are valuable tools. They allow investigation of the complexity of phosphorylation in vivo, albeit with strong discrepancies between different methods. A series of hypothetical scenarios on combinatorial processive phosphorylation is proposed that are likely unverifiable with current methodologies. These proposed a priori postulates could be considered as possible extensions of the known schemes of the activation/inhibition signaling process in vivo. (shrink)

Both W9 and OP3‐4 were known to bind the receptor activator of NF‐κB ligand (RANKL), inhibiting osteoclastogenesis. Recently, both peptides were shown to stimulate osteoblast differentiation; however, the mechanism underlying the activity of these peptides remains to be clarified. A primary osteoblast culture showed that rapamycin, an mTORC1 inhibitor, which was recently demonstrated to be an important serine/threonine kinase for bone formation, inhibited the peptide‐induced alkaline phosphatase activity. Furthermore, both peptides promoted the phosphorylation of Akt and S6K1, an upstream (...) molecule of mTORC1 and the effector molecule of mTORC1, respectively. In the in vivo calvarial defect model, W9 and OP3‐4 accelerated BMP‐2‐induced bone formation to a similar extent, which was confirmed by histomorphometric analyses using fluorescence images of undecalcified sections. Our data suggest that these RANKL‐binding peptides could stimulate the mTORC1 activity, which might play a role in the acceleration of BMP‐2‐induced bone regeneration by the RANKL‐binding peptides. (shrink)

Inhibition, associated with self-efficacy, enables people to control thought and action and inhibit disturbing stimulus and impulsion and has certain evolutionary significance. This study analyzed the neural correlates of inhibition modulated by self-efficacy. Self-efficacy was assessed by using the survey adapted from the Motivated Strategies for Learning Questionnaire. Fifty college students divided into low and high self-efficacy groups participated in the experiments. Their ability to conduct inhibitory control was studied through Go/No-Go tasks. During the tasks, we recorded students’ (...) brain activity, focusing on N2 and P3 components in the event-related potential. Larger No-Go N2 amplitudes for the high self-efficacy group were found compared with the low self-efficacy group. Conflict detection as represented by N2 was modulated by self-efficacy, whereas conflict inhibition as represented by P3 was not modulated by self-efficacy. The highly self-efficacious students were more capable of detecting conflicts but not necessarily more capable of inhibiting action given that conflict was detected. Taken together, these findings offer neurophysiological evidence of the important regulatory role of self-efficacy in inhibitory control ability development. (shrink)

Entry into mitosis is driven by the activity of kinases, which phosphorylate over 7000 proteins on multiple sites. For cells to exit mitosis and segregate their genome correctly, these phosphorylations must be removed in a specific temporal order. This raises a critical and important question: how are specific phosphorylation sites on an individual protein removed? Traditionally, the temporal order of dephosphorylation was attributed to decreasing kinase activity. However, recent evidence in human cells has identified unique patterns of dephosphorylation during mammalian (...) mitotic exit that cannot be fully explained by the loss of kinase activity. This suggests that specificity is determined in part by phosphatases. In this review, we explore how the physicochemical properties of an individual phosphosite and its surrounding amino acids can affect interactions with a phosphatase. These positive and negative interactions in turn help determine the specific pattern of dephosphorylation required for correct mitotic exit. (shrink)

Recent studies suggest that instrumental hypnosis is a useful experimental tool to investigate emotional and language processing effects. However, the capacity of hypnotic suggestions to intervene during the response inhibition of emotional words remains elusive. This study investigated whether hypnotic suggestion can improve the inhibition of prepotent negative word responses in an emotional Hayling sentence completion task. High-suggestible participants performed a computerised emotional Hayling task. They were first asked to select the appropriate words ending highly predictable sentences among (...) two propositions (initiation part), and then to select the filler words that did not end the sentences correctly (inhibition part). Half of the expected final words had a negative emotional valence, while the other half was neutral. The task was performed in a control condition (without suggestion) and with a hypnotic suggestion to decrease emotional reactivity. The results revealed that hypnotic suggestion (compared to the control condition) hastened response times on negative final words in the inhibition part, showing that hypnotic suggestion can enhance cognitive control over prepotent negative word responses in a sentence completion task. We suggest that this modulation stems from a reduction in the emotional relevance of the final words caused by the hypnotic suggestion. (shrink)

Abnormalities in the ability of cells to properly degrade proteins have been identified in many neurodegenerative diseases. Recent work has implicated synaptojanin 1 (SynJ1) in Alzheimer's disease and Parkinson's disease, although the role of this polyphosphoinositide phosphatase in protein degradation has not been thoroughly described. Here, we dissected in vivo the role of SynJ1 in endolysosomal trafficking in zebrafish cone photoreceptors using a SynJ1‐deficient zebrafish mutant, nrca14. We found that loss of SynJ1 leads to specific accumulation of late endosomes (...) and autophagosomes early in photoreceptor development. An analysis of autophagic flux revealed that autophagosomes accumulate because of a defect in maturation. In addition we found an increase in vesicles that are highly enriched for PI(3)P, but negative for an early endosome marker in nrca14 cones. A mutational analysis of SynJ1 enzymatic domains found that activity of the 5'phosphatase, but not the Sac1 domain, is required to rescue both aberrant late endosomes and autophagosomes. Finally, modulating activity of the PI(4,5)P2 regulator, Arf6, rescued the disrupted trafficking pathways in nrca14 cones. Our study describes a specific role for SynJ1 in autophagosomal and endosomal trafficking and provides evidence that PI(4,5)P2 participates in autophagy in a neuronal cell type. -/- . (shrink)

In 5 experiments, participants read text that was briefly replaced by a transient image for 33 ms at random intervals. A decrease in saccadic frequency, referred to as saccadic inhibition, occurred as early as 60 –70 ms following the onset of abrupt changes in visual input. It was demonstrated that the saccadic inhibition was influenced by the saliency of the visual event (Experiment 3) and was not produced in response to abrupt but irrelevant auditory stimuli (Experiment 1). Display (...) changes restricted to an area either inside or outside the perceptual span required for normal reading produced strong saccadic inhibition (Experiment 2). Finally, Experiments 4 and 5 demonstrated higher level cognitive or attentional modulation of the saccadic inhibition effect. (shrink)

Anamniote animals, such as fish and amphibians, are able to regenerate damaged CNS nerves following injury, but regeneration in the mammalian CNS tracts, such as the optic nerve, does not occur. However, severed adult mammalian retinal axons can regenerate into peripheral nerve segments grafted into the brain and this finding has emphasized the importance of the environment in explaining regenerative failure in the adult mammalian CNS. Following lesions, regenerating axons encounter the glial cells, oligodendrocytes and astro‐cytes, and their derivatives, respectively (...) myelin and the astrocytic scar. Experiments to investigate the influence of these components on axon growth in culture have revealed cell‐surface and extracellular matrix molecules that inhibit axon extension and growth cone motility. Structural and functional characterization of these ligands and their receptors is underway, and may solve the interesting neurobiological conundrum posed by the failure of mammalian CNS regeneration. Simultaneously, this might allow new possibilities for treatment of the severe clinical disabilities resulting from injury to the brain and spinal cord. (shrink)

The tendency for people to remember less as members of a group than they would be capable of were they to remember alone is a phenomenon known as collaborative inhibition. The article offers a phenomenological account of this highly counterintuitive effect of group remembering. It argues that the mutual failure to live up to one’s potential does not warrant the standard, strongly negative views about the role of others in recall. Rather, the phenomenon may imply that sharedness itself becomes (...) constitutive of the process in the sense that interaction partners co-determine what and how to remember. Drawing on phenomenological approaches to remembering and second-person engagement, the article argues that individuals participating in shared remembering co-construct their memories by reciprocally and dynamically incorporating each other’s perspectives, attitudes, and emotions about their shared past. (shrink)

In everyday parlance, "inhibition" suggests repression, tight control, the opposite of freedom. In medicine and psychotherapy the term is commonplace, its definition understood. Relating how inhibition—the word and the concept—became a bridge between society at large and the natural sciences of mind and brain, Smith constructs an engagingly original history of our view of ourselves. Not until the late nineteenth century did the term "inhibition" become common in English, connoting the dependency of reason and of civilization itself (...) on the repression of "the beast within." This usage followed a century of Enlightenment thought about human nature and the nature of the human mind. Smith traces theories of inhibitory control from the moralistic psychologies of the early nineteenth century to the famous twentieth-century schools of Sherrington, Pavlov, and Freud. He finds that the meanings of "inhibition" cross disciplinary boundaries and outline the growth of our belief in the self-regulated person. (shrink)

When must a specific cognitive habit be called upon to solve a problem? In the subject’s learning process, “knowing-to” is connected with a conscious particular judgment of truth or “aha” moment enacting a new behavioral schema. This paper comments on recent experiments supporting the view that a shift from automatic to controlled forms of inhibition, involving conscious attention, is crucial for detecting errors and activating a new strategy in complex cognitive situations. The part that consciousness plays in this process (...) agrees with its philosophical description as “judge of truth”, and can thus be regarded as an essential precursor to the development of higher cognitive habits. In this regard, John Henry Newman’s explanation of human assent to truth, for which our consciousness of self is always prior, proves to be decisive. (shrink)

Phosphotyrosine phosphatases (PTPases) are the enzymes which remove phosphate groups from protein tyrosine residues. An enormous number of phosphatases have been cloned and sequenced during the past decade, many of which are expressed in haematopoietic cells. This review focuses on the biochemistry and cell biology of three phosphatases, the transmembrane CD45 and the cytosolic SH2‐domain‐containing PTPases SHP‐1 and SHP‐2, to illustrate the diverse ways in which PTPases regulate receptor signal transduction. The involvement of these and other PTPases has been demonstrated (...) in haematopoietic cell development, apoptosis, activation and non‐responsiveness. A common theme in the actions of many haematopoietic cell PTPases is the way in which they modulate the thresholds for receptor signalling, thereby regulating critical events in the positive and negative selection of lymphocytes. There is growing interest in haematopoietic PTPases and their associated regulatory proteins as targets for pharmaceutical intervention and in the involvement of these enzymes in human disease. (shrink)

We recently described a novel form of stress‐associated bidirectional plasticity at GABA synapses onto hypothalamic parvocellular neuroendocrine cells (PNCs), the apex of the hypothalamus‐pituitary‐adrenal axis. This plasticity may contribute to neuroendocrine adaptation. However, this GABA synapse plasticity likely does not translate into a simple more and less of inhibition because the ionic driving force for Cl−, the primary charge carrier for GABAA receptors, is dynamic. Specifically, stress impairs a Cl− extrusion mechanism in PNCs. This not only renders the steady‐state (...) GABA response less hyperpolarizing but also makes PNCs susceptible to the activity‐dependent accumulation of Cl−. Accordingly, GABA synapse plasticity impacts both the robustness of GABA voltage response and dynamic Cl− loading, imposing nonlinear influences on PNC excitability during circuit activities. This theoretical consideration predicts roles for GABA transmission far more versatile than canonical inhibition. We propose potential impacts of GABA synapse plasticity on the experience‐dependent fine‐tuning of neuroendocrine stress responses. (shrink)

This book is a thought-provoking assessment of assumptions inhibiting progress in comparative biology. The volume is inspired by a list generated years earlier by Donn Rosen, one of the most influential, innovative and productive comparative biologists of the latter 20th century. His list has assumed almost legendary status among comparative evolutionary biologists. Surprisingly many of the obstructing assumptions implicated by Rosen remain relevant today. Any comparative biologist hoping to avoid such assumptions in their own research will benefit from this introspective (...) volume. (shrink)

Leonard B. Meyer has proposed that when musical tendencies or expectations are inhibited by musical ambiguity or the unexpected, those inhibitions and their subsequent resolutions are likely to be provocative or engaging. Music, Tendencies and Inhibitions will explore the relevance of this theory to music and various other disciplines, and to psychological and natural processes. Each chapter consists of two parts: a presentation and consideration of an aspect of Meyer's theory, and a more associative or rhapsodic section of "Reflections" on (...) this aspect. The book will focus on Meyer's aesthetic rather than his music-theoretical proclivities, and is intended for academics and students in various fields as well as educated non-academics. The music scene is fluctuating, Meyer suggests, in that new and original styles or techniques are continuously emerging or developing on a small scale; it is static in that many of these developments seem unrelated, and are not likely to be grasped or progress as a whole. It will be posited that this theory foreshadowed and reflects important ideologies of contemporary culture, including postmodernism. (shrink)

& The present study investigated saccadic inhibition in both voluntary and stimulus-elicited saccades. Two experiments examined saccadic inhibition caused by an irrelevant flash occurring subsequent to target onset. In each trial, participants were required to perform a single saccade following the presentation of a black target on a gray background, 48 to the left or to the right of screen center. In some trials (flash trials), after a variable delay, a 33-msec flash was displayed at the top and (...) bottom third of the monitor (these regions turned white). In all experimental conditions, histograms of flash-to-saccade latencies documented a decrease in saccadic frequency, forming a dip, time-locked to the flash and occurring as early as 60–70 msec following its onset. The fast latency of this effect strongly suggests a low-level, reflex-like, oculomotor effect, which was referred to as saccadic inhibition. A novel procedure was developed to allow comparisons of saccadic inhibition even across conditions, which in the absence of a flash (no-. (shrink)

DNA gyrase, an enzyme unique to prokaryotes, has been implicated in almost all processes that involve DNA. Although efficient inhibitors of this protein have been known for more than 20 years, none of them have enjoyed prolonged pharmaceutical success. It is only recently that the mechanisms of inhibition for some of these classes of drugs have been established unequivocally by X‐ray crystallography. It is hoped that this detailed structural information will assist the design of novel, effective inhibitors of DNA (...) gyrase. (shrink)

Stimuli that resemble humans, but are not perfectly human-like, are disliked compared to distinctly human and nonhuman stimuli. Accounts of this “Uncanny Valley” effect often focus on how changes in human resemblance can evoke different emotional responses. We present an alternate account based on the novel hypothesis that the Uncanny Valley is not directly related to ‘human-likeness’ per se, but instead reflects a more general form of stimulus devaluation that occurs when inhibition is triggered to resolve conflict between competing (...) stimulus-related representations. We consider existing support for this inhibitory-devaluation hypothesis and further assess its feasibility through tests of two corresponding predictions that arise from the link between conflict-resolving inhibition and aversive response: 1) that the pronounced disliking of Uncanny-type stimuli will occur for any image that strongly activates multiple competing stimulus representations, even in the absence of any human-likeness, and 2) that the negative peak of an ‘Uncanny Valley’ should occur at the point of greatest stimulus-related conflict and not (in the presence of human-likeness) always closer to the ‘human’ end of a perceptual continuum. We measured affective responses to a set of line drawings representing nonhuman animal-animal morphs, in which each continuum midpoint was a bistable image (Exp. 1), as well as to sets of human-robot and human-animal computer-generated morphs (Exp. 2). Affective trends depicting classic Uncanny Valley functions occurred for all continua, including the nonhuman stimuli. Images at continua midpoints elicited significantly more negative affect than images at endpoints, even when the continua included a human endpoint. This illustrates the feasibility of the inhibitory-devaluation hypothesis and the need for further research into the possibility that the strong dislike of Uncanny-type stimuli reflects the negative affective consequences of cognitive inhibition. (shrink)