Phosphatidylinositol 4,5‐bisphosphate (PI4,5P2) is a key lipid signaling molecule that regulates a vast array of biological activities. PI4,5P2 can act directly as a messenger or can be utilized as a precursor to generate other messengers: inositol trisphosphate, diacylglycerol, or phosphatidylinositol 3,4,5‐trisphosphate. PI4,5P2 interacts with hundreds of different effector proteins. The enormous diversity of PI4,5P2 effector proteins and the spatio‐temporal control of PI4,5P2 generation allow PI4,5P2 signaling to control a broad spectrum of cellular (...) functions. PI4,5P2 is synthesized by phosphatidylinositol phosphate kinases (PIPKs). The array of PIPKs in cells enables their targeting to specific subcellular compartments through interactions with targeting factors that are often PI4,5P2 effectors. These interactions are a mechanism to define spatial and temporal PI4,5P2 synthesis and the specificity of PI4,5P2 signaling. In turn, the regulation of PI4,5P2 effectors at specific cellular compartments has implications for understanding how PI4,5P2 controls cellular processes and its role in diseases. (shrink)

Initially identified as a key phosphoinositide that controls membrane trafficking at the Golgi complex, phosphatidylinositol‐4‐phosphate (PI4P) has emerged as a key molecule in the regulation of a diverse array of cellular functions. In this review we will discuss selected examples of the findings that in the last few years have significantly increased our awareness of the regulation and roles of PI4P in the Golgi complex and beyond. We will also highlight the role of PI4P in infection and cancer. We believe (...) that, with the increasing number of regulators and effectors of PI4P identified, the time is ripe for a more integrated approach of study. A first step in this direction is the delineation of PI4P‐centered molecular networks that we provide using data from low and high throughput studies in yeast and mammals. (shrink)

There is an urgent need for novel protection strategies to sustainably secure crop production under changing climates. Studying microbial effectors, defined as microbe‐derived proteins that alter signalling inside plant cells, has advanced our understanding of plant immunity and microbial plant colonisation strategies. Our understanding of effectors in the establishment and beneficial outcome of plant symbioses is less well known. Combining functional and comparative interaction assays uncovered specific symbiont effector targets in highly interconnected plant signalling networks and revealed the potential (...) of effectors in beneficially modulating plant traits. The diverse functionality of symbiont effectors differs from the paradigmatic immuno‐suppressive function of pathogen effectors. These effectors provide solutions for improving crop resilience against climate stress by their evolution‐driven specification in host protein targeting and modulation. Symbiont effectors represent stringent tools not only to identify genetic targets for crop breeding, but to serve as applicable agents in crop management strategies under changing environments. (shrink)

Motor inhibitory control, the ability to suppress unwanted actions, has been previously shown to rely on domain-general IC processes that are involved in a wide range of IC tasks. Nevertheless, the existence of effector-specific regions and activation patterns that would differentiate manual vs. oculomotor response inhibition remains unknown. In this study, we investigated the brain dynamics supporting these two response effectors with the same IC task paradigm. We examined the behavioral performance and electrophysiological activity in a group of healthy (...) young people with a Go/NoGo task using the index finger for the manual modality and the eyes for the oculomotor modality. By computing topographic analysis of variance, we found significant differences between topographies of scalp recorded potentials of the two response effectors between 250 and 325 ms post-stimulus onset. The source estimations localized this effect within the left precuneus, a part of the superior parietal lobule, showing stronger activity in the oculomotor modality than in the manual modality. Behaviorally, we found a significant positive correlation in response time between the two modalities. Our collective results revealed that while domain-general IC processes would be engaged across different response effectors in the same IC task, effector-specific activation patterns exist. In this case, the stronger activation of the left precuneus likely accounts for the increased demand for visual attentional processes in the oculomotor Go/NoGo task. (shrink)

Several studies have illuminated how processing manual action verbs (MaVs) affects the programming or execution of concurrent hand movements. Here, to circumvent key confounds in extant designs, we conducted the first assessment of motor–language integration during handwriting—a task in which linguistic and motoric processes are co‐substantiated. Participants copied MaVs, non‐manual action verbs, and non‐action verbs as we collected measures of motor programming and motor execution. Programming latencies were similar across conditions, but execution was faster for MaVs than for the other (...) categories, regardless of whether word meanings were accessed implicitly or explicitly. In line with the Hand‐Action‐Network Dynamic Language Embodiment (HANDLE) model, such findings suggest that effector‐congruent verbs can prime manual movements even during highly automatized tasks in which motoric and verbal processes are naturally intertwined. Our paradigm opens new avenues for fine‐grained explorations of embodied language processes. (shrink)

The immune system has evolved to detect and remove foreign or non‐self molecules from the body. To perform this task, the system has coupled together specific recognition with non‐specific effector mechanisms in at least two distinct fashions, as outlined in this review.

Recent theory suggests that action prediction relies of a motor emulation mechanism that works by mapping observed actions onto the observer action system so that predictions can be generated using that same predictive mechanisms that underlie action control. This suggests that action prediction may be more accurate when there is a more direct mapping between the stimulus and the observer. We tested this hypothesis by comparing prediction accuracy for two stimulus types. A mannequin stimulus which contained information about the effectors (...) used to produce the action and a point stimulus, which contained identical dynamic information but no effector information. Prediction was more accurate for the mannequin stimulus. However, this effect was dependent on the observer having previous experience performing the observed action. This suggests that experienced and na¨ıve observers might generate predictions in qualitatively difference ways, which may relate to the presence of an internal representation of the action laid down through action performance. (shrink)

RAS GTPases play essential roles in normal development and are direct drivers of human cancers. Three decades of study have failed to wholly characterize pathways stimulated by activated RAS, driven by engagement with ‘effector’ proteins that have RAS binding domains (RBDs). Bone fide effectors must bind directly to RAS GTPases in a nucleotide‐dependent manner, and this interaction must impart a clear change in effector activity. Despite this, for most proteins currently deemed effectors there is little mechanistic understanding of (...) how binding to the GTPase alters protein function. There has also been limited effort to comprehensively resolve the specificity of effector binding to the full array of RAS superfamily GTPase proteins. This review will summarize what is known about RAS‐driven activation for an array of potential effector proteins, focusing on structural and mechanistic effects and highlighting how little is still known regarding this key paradigm of cellular signal transduction. (shrink)

Phosphoinositides modulate a plethora of functions including signal transduction and membrane trafficking. PtdInsPs are thought to consist of seven interconvertible species that localize to a specific organelle, to which they recruit a set of cognate effector proteins. Here, in reviewing the literature, we argue that this model needs revision. First, PtdInsPs can carry a variety of acyl chains, greatly boosting their molecular diversity. Second, PtdInsPs are more promiscuous in their localization than is usually acknowledged. Third, PtdInsP interconversion is likely (...) achieved through kinase-phosphatase enzyme complexes that coordinate their activities and channel substrates without affecting bulk substrate population. Additionally, we contend that despite hundreds of PtdInsP effectors, our attention is biased toward few proteins. Lastly, we recognize that PtdInsPs can act to nucleate coincidence detection at the effector level, as in PDK1 and Akt. Overall, better integrated models of PtdInsP regulation and function are not only possible but needed. Phosphoinositides are lipids that control many cellular functions. However, the field of PtdInsP signaling is dominated by several dogmatic notions. Here, we offer an updated glimpse on the current state of the field regarding molecular diversity, localization, organization of modifying enzymes, effector types, and effector organization. (shrink)

Performance of bimanual motor actions requires coordinated and integrated bilateral communication, but in some bimanual tasks, neural interactions and crosstalk might cause bilateral interference. The level of interference probably depends on the proportions of bilateral interneurons connecting homologous areas of the motor cortex in the two hemispheres. The neuromuscular system for proximal muscles has a higher number of bilateral interneurons connecting homologous areas of the motor cortex compared to distal muscles. Based on the differences in neurophysiological organization for proximal vs. (...) distal effectors in the upper extremities, the purpose of the present experiment was to evaluate how the level of bilateral interference depends on whether the bilateral interference task is performed with homologous or non-homologous effectors as the primary task. Fourteen participants first performed a unilateral primary motor task with the dominant arm with proximal and distal controlled joysticks. Performance in the unilateral condition with the dominant arm was compared to the same effector’s performance when two different bilateral interference tasks were performed simultaneously with the non-dominant arm. The two different bilateral interference tasks were subdivided into homologous and non-homologous effectors. The results showed a significant decrease in performance for both proximal and distal controlled joysticks, and this effect was independent of whether the bilateral interference tasks were introduced with homologous or non-homologous effectors. The overall performance decrease as a result of bilateral interference was larger for proximal compared to distal controlled joysticks. Furthermore, a proximal bilateral interference caused a larger performance decrement independent of whether the primary motor task was controlled by a proximal or distal joystick. A novel finding was that the distal joystick performance equally interfered with either homologous or non-homologous interference tasks performed simultaneously. The results indicate that the proximal–distal distinction is an important organismic constraint on motor control and for understanding bilateral communication and interference in general and, in particular, how bilateral interference caused by homologous vs. non-homologous effectors impacts motor performance for proximal and distal effectors. The results seem to map neuroanatomical and neurophysiological differences for these effectors. (shrink)

Rho/Rac proteins constitute a subgroup of the Ras superfamily of GTP hydrolases. Although originally implicated in the control of cytoskeletal events, it is currently known that these GTPases coordinate diverse cellular functions, including cell polarity, vesicular trafficking, the cell cycle and transcriptomal dynamics. In this review, we will provide an overview on the recent advances in this field regarding the mechanism of regulation and signaling, and the roles in vivo of this important GTPase family. BioEssays 29:356–370, 2007. © 2007 Wiley (...) Periodicals, Inc. (shrink)

Acute starvation can have long-term consequences that are mediated through epigenetic change. Some of these changes are affected by the activity of AMP-activated protein kinase, a master regulator of cellular energy homeostasis. In Caenorhabditis elegans, the absence of AMPK during a period of starvation in an early larval stage results in developmental defects following their recovery on food, while many of them become sterile. Moreover, the loss of AMPK during this quiescent period results in transgenerational phenotypes that can become progressively (...) worse with each successive generation. Our recent data describe a chromatin-based mechanism of how AMPK mediates adjustment to acute starvation in the germ cells, however, the heritable aspect of this AMPK mutant phenotype remains unresolved. Here, we explore how AMPK might affect this process and speculate how the initial transcription that occurs in the germ cells may adversely affect subsequent germline gene expression and/or genomic integrity. AMPK protects germ cell integrity during acute starvation by blocking inappropriate transcription. How these aberrant transcripts cause transgenerational defects is unclear. AMPK likely regulates germline integrity at multiple levels through several targets. The authors speculate here how AMPK disruption during starvation could result in the observed defects seen at each generation. (shrink)

The exact process that leads to the eruption of autoimmune reactions against β cells and the evolution of diabetes is not fully understood. Macrophages and T cells may launch an initial immune reaction against the pancreatic islets of Langerhans, provoking inflammation and destructive insulitis. The information on the molecular mechanisms of the emergence of β cell injury is controversial and points to possibly important roles for the perforin–granzyme, Fas–Fas-ligand (FasL) and tumor-necrosis-factor-mediated apoptotic pathways. FasL has several unique features that make (...) it a potentially ideal immunomodulatory tool. Most important, FasL is selectively toxic to cytotoxic T cells and less harmful to regulatory T cells. This review discusses the intrinsic sensitivity of β cells to FasL-mediated apoptosis, the conditions that underlie this β cell sensitivity, and the feasibility of using FasL to arrest autoimmunity and prevent islet allograft rejection. In both the autoimmune and transplant settings, it is imperative to progress from the administration of nonspecific immunosuppressive therapy to the concept of β-cell-specific immunomodulation. FasL evolves as a prime candidate for antigen-specific immunomodulation. BioEssays 28: 211–222, 2006. © 2006 Wiley periodicals, Inc. (shrink)

The exact process that leads to the eruption of autoimmune reactions against β cells and the evolution of diabetes is not fully understood. Macrophages and T cells may launch an initial immune reaction against the pancreatic islets of Langerhans, provoking inflammation and destructive insulitis. The information on the molecular mechanisms of the emergence of β cell injury is controversial and points to possibly important roles for the perforin–granzyme, Fas–Fas-ligand (FasL) and tumor-necrosis-factor-mediated apoptotic pathways. FasL has several unique features that make (...) it a potentially ideal immunomodulatory tool. Most important, FasL is selectively toxic to cytotoxic T cells and less harmful to regulatory T cells. This review discusses the intrinsic sensitivity of β cells to FasL-mediated apoptosis, the conditions that underlie this β cell sensitivity, and the feasibility of using FasL to arrest autoimmunity and prevent islet allograft rejection. In both the autoimmune and transplant settings, it is imperative to progress from the administration of nonspecific immunosuppressive therapy to the concept of β-cell-specific immunomodulation. FasL evolves as a prime candidate for antigen-specific immunomodulation. BioEssays 28: 211–222, 2006. © 2006 Wiley periodicals, Inc. (shrink)

Cell signalling mediators derived from membrane phospholipids are frequent participants in biological processes. The family of phosphoinositide 3-kinases (PI3Ks) phosphorylate the membrane lipid phosphatidylinositol, generating second messengers that direct diverse responses. These PI3K products are fundamental for leukocyte migration or chemotaxis, a pivotal event during the immune response. This system is therefore of significant biomedical interest. This review focuses on the biochemistry and signalling pathways of PI3K, with particular emphasis on chemokine (chemotactic cytokine)-directed responses. The key objectives of chemotaxis are (...) motility and direction. The latter—direction—requires distinct events at the front and back of a cell. In light of this, the coordinated localisation of signalling factors, an event choreographed by a sharp intracellular gradient of PI3K-derived products, is a common theme. BioEssays 27:153–163, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

The pore‐forming BCL‐2 family proteins are effectors of mitochondrial poration in apoptosis initiation. Two atypical effectors—BOK and truncated BID (tBID)—join the canonical effectors BAK and BAX. Gene knockout revealed developmental phenotypes in the absence the effectors, supporting their roles in vivo. During apoptosis effectors are activated and change shape from dormant monomers to dynamic oligomers that associate with and permeabilize mitochondria. BID is activated by proteolysis, BOK accumulates on inhibition of its degradation by the E3 ligase gp78, while BAK and (...) BAX undergo direct activation by BH3‐only initiators, autoactivation, and crossactivation. Except tBID, effector oligomers on the mitochondria appear as arcs and rings in super‐resolution microscopy images. The BH3‐in‐groove dimers of BAK and BAX, the tBID monomers, and uncharacterized BOK species are the putative building blocks of apoptotic pores. Effectors interact with lipids and bilayers but the mechanism of membrane poration remains elusive. I discuss effector‐mediated mitochondrial poration. (shrink)

The genetic code has been regarded as arbitrary in the sense that the codon-amino acid assignments could be different than they actually are. This general idea has been spelled out differently by previous, often rather implicit accounts of arbitrariness. They have drawn on the frozen accident theory, on evolutionary contingency, on alternative causal pathways, and on the absence of direct stereochemical interactions between codons and amino acids. It has also been suggested that the arbitrariness of the genetic code justifies attributing (...) semantic information to macromolecules, notably to DNA. I argue that these accounts of arbitrariness are unsatisfactory. I propose that the code is arbitrary in the sense of Jacques Monod's concept of chemical arbitrariness: the genetic code is arbitrary in that any codon requires certain chemical and structural properties to specify a particular amino acid, but these properties are not required in virtue of a principle of chemistry. This notion of arbitrariness is compatible with several recent hypotheses about code evolution. I maintain that the code's chemical arbitrariness is neither sufficient nor necessary for attributing semantic information to nucleic acids. (shrink)

Living organisms act as integrated wholes to maintain themselves. Individual actions can each be explained by characterizing the mechanisms that perform the activity. But these alone do not explain how various activities are coordinated and performed versatilely. We argue that this depends on a specific type of mechanism, a control mechanism. We develop an account of control by examining several extensively studied control mechanisms operative in the bacterium E. coli. On our analysis, what distinguishes a control mechanism from other mechanisms (...) is that it relies on measuring one or more variables, which results in setting constraints in the control mechanism that determine its action on flexible constraints in other mechanisms. In the most basic arrangement, the measurement process directly determines the action of the control mechanism, but in more complex arrangements signals mediate between measurements and effectors. This opens the possibility of multiple responses to the same measurement and responses based on multiple measurements. It also allows crosstalk, resulting in networks of control mechanisms. Such networks integrate the behaviors of the organism but also present a challenge in tailoring responses to particular measurements. We discuss how integrated activity can still result in differential, versatile, responses. (shrink)

The character of computational modelling of cognition depends on an underlying theory of representation. Classical cognitive science has exploited the syntax/semantics theory of representation that derives from logic. But this has had the consequence that the kind of psychological explanation supported by classical cognitive science is " _conceptualist_: " psychological phenomena are modelled in terms of relations that hold between concepts, and between the sensors/effectors and concepts. This kind of explanation is inappropriate for the Proper Treatment of Connectionism.

This is the second article in a series of review articles addressing biosemiotic terminology. The biosemiotic glossary project is designed to integrate views of members within the biosemiotic community based on a standard survey and related publications. The methodology section describes the format of the survey conducted July–August 2014 in preparation of the current review and targeted on Jakob von Uexküll’s term ‘Umwelt’. Next, we summarize denotation, synonyms and antonyms, with special emphasis on the denotation of this term in current (...) biosemiotic usage. The survey findings include ratings of eight citations defining or making use of the term Umwelt. We provide a summary of respondents’ own definitions and suggested term usage. Further sections address etymology, relevant contexts of use, and related terms in English and other languages. A section on the notion’s Uexküllian meaning and later biosemiotic meaning is followed by attempt at synthesis and conclusion. We conclude that the Umwelt is a centerpiece phenomenon, a phenomenon that other phenomena in the living realm are organized around. To sum up Uexküll’s view, we can characterize an Umwelt as the subjective world of an organism, enveloping a perceptual world and an effector world, which is always part of the organism itself and a key component of nature, which is held together by functional cycles connecting different Umwelten. In order to pay respect to Uexküll’s work, we must move from notion to model, from mention of Uexküll’s Umwelt term to actual application of it. (shrink)

There are many entry points into the problem of categorization. Two particularly important ones are the so-called top-down and bottom-up approaches. Top-down approaches such as artificial intelligence begin with the symbolic names and descriptions for some categories already given; computer programs are written to manipulate the symbols. Cognitive modeling involves the further assumption that such symbol-interactions resemble the way our brains do categorization. An explicit expectation of the top-down approach is that it will eventually join with the bottom-up approach, which (...) tries to model how the hardware of the brain works: sensory systems, motor systems and neural activity in general. The assumption is that the symbolic cognitive functions will be implemented in brain function and linked to the sense organs and the organs of movement in roughly the way a program is implemented in a computer, with its links to peripheral devices such as transducers and effectors. (shrink)

The idea that intentions make the difference between voluntary and non-voluntary behaviors is simple and intuitive. At the same time, we lack an understanding of how voluntary actions actually come about, and the unquestioned appeal to intentions as discrete causes of actions offers little if anything in the way of an answer. We cite evidence suggesting that the origin of actions varies depending on context and effector, and argue that actions emerge from a causal web in the brain, rather (...) than a central origin of intentional action. We argue that this causal web need not be confined to the central nervous system, and that proprioceptive feedback might play a counterintuitive role in the decision process. Finally we argue that the complex and dynamic origins of voluntary action and their interplay with the brain’s propensity to predict the immediate future are better studied using a dynamical systems approach. (shrink)

Spatial attention and eye-movements are tightly coupled, but the precise nature of this coupling is controversial. The influential but controversial Premotor theory of attention makes four specific predictions about the relationship between motor preparation and spatial attention. Firstly, spatial attention and motor preparation use the same neural substrates. Secondly, spatial attention is functionally equivalent to planning goal directed actions such as eye-movements (i.e. planning an action is both necessary and sufficient for a shift of spatial attention). Thirdly, planning a goal (...) directed action with any effector system is sufficient to trigger a shift of spatial attention. Fourthly, the eye-movement system has a privileged role in orienting visual spatial attention. This article reviews empirical studies that have tested these predictions. Contrary to predictions one and two there is evidence of anatomical and functional dissociations between endogenous spatial attention and motor preparation. However, there is compelling evidence that exogenous attention is reliant on activation of the oculomotor system. With respect to the third prediction, there is correlational evidence that spatial attention is directed to the endpoint of goal-directed actions but no direct evidence that this attention shift is dependent on motor preparation. The few studies to have directly tested the fourth prediction have produced conflicting results, so the extent to which the oculomotor system has a privileged role in spatial attention remains unclear. Overall, the evidence is not consistent with the view that spatial attention is functionally equivalent to motor preparation so the Premotor theory should be rejected, although a limited version of the Premotor theory in which only exogenous attention is dependent on motor preparation may still be tenable. A plausible alternative account is that activity in the motor system contributes to biased competition between different sensory representations with the winner of the competition becoming the attended item. (shrink)

Recent work in "embodied, embedded" cognitive science links mental contents to large-scale distributed effects: dynamic patterns implicating elements of (what are traditionally seen as) sensing, reasoning and acting. Central to this approach is an idea of biological cognition as profoundly "action-oriented" - geared not to the creation of rich, passive inner models of the world, but to the cheap and efficient production of real-world action in real-world context. A case in point is Hurley's (1998) account of the profound role of (...) motor output in fixing the contents of conscious visual awareness - an account that also emphasizes distributed vehicles and long-range dynamical loops. Such stories can seem dramatically opposed to accounts, such as Milner and Goodale (1995), that stress relatively local mechanisms and that posit firm divisions between processes of visual awareness and of visuomotor action. But such accounts, I argue, can be deeply complimentary and together illustrate an important lesson. The lesson is that cognition may be embodied and action-oriented in two distinct - but complimentary - ways. There is a way of being embodied and action-oriented that implies being closely geared to the fine-grained control of low level effectors (hands, arms, legs and so on). And there is a way of being embodied and action-oriented that implies being closely geared to gross motor intentions, current goals, and schematic motor plans. Human cognition, I suggest, is embodied and action-oriented in both these ways. But the neural systems involved, and the size and scope of the key dynamic loops, may be quite different in each case. (shrink)