The DNA‐passage activity of topoisomerase II accidentally produces DNA knots and interlinks within and between chromatin fibers. Fortunately, these unwanted DNA entanglements are actively removed by some mechanism. Here we present an outline on DNA knot formation and discuss recent studies that have investigated how intracellular DNA knots are removed. First, although topoisomerase II is able to minimize DNA entanglements in vitro to below equilibrium values, it is unclear whether such capacity performs equally in vivo in chromatinized DNA. Second, (...) DNA supercoiling could bias topoisomerase II to untangle the DNA. However, experimental evidence indicates that transcriptional supercoiling of intracellular DNA boosts knot formation. Last, cohesin and condensin could tighten DNA entanglements via DNA loop extrusion (LE) and force their dissolution by topoisomerase II. Recent observations indicate that condensin activity promotes the removal of DNA knots during interphase and mitosis. This activity might facilitate the spatial organization and dynamics of chromatin. (shrink)

Literacy is an essential skill. Learning to read is a requirement for becoming a self-providing human being. However, while spoken language is acquired naturally with exposure to language without explicit instruction, reading and writing need to be taught explicitly. Decades of research have shown that well-structured teaching of phonological awareness, letter knowledge, and letter-to-sound mapping is crucial in building solid foundations for the acquisition of reading. During the COVID-19 pandemic, children worldwide did not have access to consistent and structured teaching (...) and are, as a consequence, predicted to be behind in the development of their reading skills. Subsequent evidence confirms this prediction. With the best evidence-based practice in mind, we developed an online version of a well-structured early literacy training program for 5-year-old children. This 2-week online Reading Camp program is designed for pre-K children. It incorporates critical components of the fundamental skills essential to learning to read and is taught online in an interactive, multi-sensory, and peer-learning environment. We measure the participants’ literacy skills and other related skills before and after participating in the online Reading Camp and compare the results to no-treatment controls. Results show that children who participated in the online Reading Camp improved significantly on all parameters in relation to controls. Our results demonstrate that a well-structured evidence-based reading instruction program, even if online and short-term, benefits 5-year-old children in learning to read. With the potential to scale up this online program, the evidence presented here, alongside previous evidence for the efficacy of the in-person program, indicates that the online Reading Camp program is effective and can be used to tackle a variety of questions regarding structural and functional plasticity in the early stages of reading acquisition. (shrink)

It was, until recently, accepted that the two classes of acetylcholine (ACh) receptors are distinct in an important sense: muscarinic ACh receptors signal via heterotrimeric GTP binding proteins (G proteins), whereas nicotinic ACh receptors (nAChRs) open to allow flux of Na+, Ca2+, and K+ ions into the cell after activation. Here we present evidence of direct coupling between G proteins and nAChRs in neurons. Based on proteomic, biophysical, and functional evidence, we hypothesize that binding to G proteins modulates the activity (...) and signaling of nAChRs in cells. It is important to note that while this hypothesis is new for the nAChR, it is consistent with known interactions between G proteins and structurally related ligand‐gated ion channels. Therefore, it underscores an evolutionarily conserved metabotropic mechanism of G protein signaling via nAChR channels.Also watch the Video Abstract. (shrink)

It was, until recently, accepted that the two classes of acetylcholine (ACh) receptors are distinct in an important sense: muscarinic ACh receptors signal via heterotrimeric GTP binding proteins (G proteins), whereas nicotinic ACh receptors (nAChRs) open to allow flux of Na+, Ca2+, and K+ ions into the cell after activation. Here we present evidence of direct coupling between G proteins and nAChRs in neurons. Based on proteomic, biophysical, and functional evidence, we hypothesize that binding to G proteins modulates the activity (...) and signaling of nAChRs in cells. It is important to note that while this hypothesis is new for the nAChR, it is consistent with known interactions between G proteins and structurally related ligand‐gated ion channels. Therefore, it underscores an evolutionarily conserved metabotropic mechanism of G protein signaling via nAChR channels.Also watch the Video Abstract. (shrink)

This review portraits FK506 binding protein (FKBP) 51 as “reactivity protein” and collates recent publications to develop the concept of FKBP51 as contributor to different levels of adaptation. Adaptation is a fundamental process that enables unicellular and multicellular organisms to adjust their molecular circuits and structural conditions in reaction to environmental changes threatening their homeostasis. FKBP51 is known as chaperone and co‐chaperone of heat shock protein (HSP) 90, thus involved in processes ensuring correct protein folding in response to proteotoxic stress. (...) In mammals, FKBP51 both shapes the stress response and is calibrated by the stress levels through an ultrashort molecular feedback loop. More recently, it has been linked to several intracellular pathways related to the reactivity to drug exposure and stress. Through its role in autophagy and DNA methylation in particular it influences adaptive pathways, possibly also in a transgenerational fashion.Also see the video abstract here. (shrink)

Autophagy promotes both health and disease, depending on tissue types and genetic contexts, yet the regulatory mechanism remain incompletely understood. Our recent publication has uncovered a coherent FOXO‐SNAI feed‐forward loop in autophagy, which is evolutionarily conserved from Drosophila to human. In addition, it's revealed that DNA binding plays a critical role in intracellular localization of nucleocytoplasmic shuttling proteins. Based on these findings, herein we further integrate mechanistic insights of FOXO‐SNAI regulatory interplay in autophagy and unravel the potential link (...) of FOXO‐induced autophagy with SNAI in diseases. Besides, the generality of DNA‐retention mechanism on transcription factor nuclear localization is illustrated with wide‐ranging discussion, and more functions potentially regulated by FOXO‐SNAI feedforward loop are provided. Elucidation of these unsolved paradigms will expand the understanding of FOXO‐SNAI interplay and facilitate the development of new therapeutics targeting FOXO‐SNAI axis in diseases. (shrink)

Amyloid β peptide (βA4) accumulates as plaques in the brains of individuals with Alzheimer's disease and Down's syndrome, and may contribute to the cognitive decline that is a feature of these diseases. βA4 is a normal product of cell metabolism, derived from the amyloid precursor protein (APP), but the biological functions of these molecules are not fully known. A hypothetical, descriptive model of the biological interrelationships between βA4 and APP is presented. APPS, the soluble form of APP, which is released (...) at the neuronal surface, and βA4 are envisaged as physiological ligands which have reciprocal paracrine effects on neuronal growth and neurite extension. Differential expression of these factors, manifest as changes in the APPS:βA4 ratio, may therefore have growth‐promoting or growth‐inhibiting effects on neurons. These effects may be mediated through separate cell‐surface interactions but common intracellular effector systems, such as calcium and protein kinase C. In turn, the intracellular events may control the relative production of each ligand from APP through negative feedback loops. Disturbances of these control mechanisms may permit pathological overproduction, and hence accumulation, of βA4. Such a model may also have therapeutic implications. (shrink)

Despite the recent progress in the description of the molecular mechanisms of proliferation and differentiation controls in vitro, the regulation of the homeostasis of normal stratified epithelia remains unclear in vivo. Computer simulation represents a powerful tool to investigate the complex field of cell proliferation regulation networks. It provides huge computation capabilities to test, in a dynamic in silico context, hypotheses about the many pathways and feedback loops involved in cell growth and proliferation controls.Our approach combines a model of cell (...) proliferation and a spatial representation of cells in 2D using the Voronoi graph. The cell proliferation model includes intracellular (cyclins, Cyclin Dependent Kinases - CDKs, Retinoblastoma protein - Rb, CDK inhibitors) and extracellular controls (growth and differentiation factors, integrins). The Voronoi graph associates a polygon with every cell and the set of these polygons defines the tissue architecture. Thus, the model provides a quantitative model of extracellular signals and cell motility as a function of the neighborhood during time dependent simulations. (shrink)

Iron uptake and storage in mammalian cells is at least partly regulated at a posttranscriptional level by the iron regulatory proteins (IRP‐1 and IRP‐2). These cytoplasmic regulators share 79% similarity in protein sequence and bind tightly to conserved mRNA stem‐loops, named iron‐responsive elements (IREs). The IRP:IRE interaction underlies the regulation of translation and stability of several mRNAs central to iron metabolism. The question of why the cell requires two such closely related regulatory proteins may be resloved as we learn more (...) about the expression and regulation of these proteins. It is evident so far that, despite similarities, the IRPs differ in several important respects. They are coordinately regulated by cellular iron, but whereas IRP‐1 is inactivated by high iron levels, IRP‐2 is rapidly degraded. Further differences arise in their expression and RNA‐binding specificity. The two proteins each recognise a large repertoire of IRE‐like sequences, including a small group of exclusive RNA targets. These findings hint that IRP‐1 and IRP‐2 may bind preferenitially to certain mRNAs in vivo, possibly extending their known functions beyond the regulation of intracellular iron homeostasis. (shrink)

This paper explores a special kind of loop of grounding: cosmic loops. A cosmic loop is a loop that intuitively requires us to go "around" the entire universe to come back to the original ground. After describing several kinds of cosmic loop scenarios, I will discuss what we can learn from these scenarios about constraints on grounding; the conceivability of cosmic loops; the possibility of cosmic loops; and the prospects for salvaging local reflexivity, asymmetry and transitivity (...) of grounding in a world containing a cosmic loop of ground. The considerations raised in this paper also bear on what we should think about relations that are meant to support grounding relations: in particular, revisions to theories of the part-whole relation are discussed. (shrink)

Intracellular pH (pHi) regulation is a homeostatic function of all cells. Additionally, the plasma membrane‐based transporters controlling pHi are involved in growth factor activation, cell proliferation and salt transport – all processes active in early embryos. pHi regulation in the early embryos of many species exhibits unique features: in mouse preimplantation embryos, mechanisms for correcting excess acid apparently are inactive, while excess base is removed by the mechanism common in differentiated cells. Additionally, unlike differentiated cells, mouse preimplantation embryos are (...) highly permeable to H+ until the blastocyst stage, where the epithelial cells surrounding the embryo are impermeable. In several non‐mammalian species, of which the best‐studied is sea urchin, cytoplasmic alkalinization at fertilization is necessary for development of the embryo, and elevated pHi must be maintained during early development. Thus, pHi regulatory mechanisms appear to be important for early embryo development in many species. (shrink)

Mitochondria exist in large numbers per cell. Therefore, the strength of natural selection on individual mtDNAs for their contribution to cellular fitness is weak whereas the strength of selection in favor of mtDNAs that increase their own replication without regard for cellular functions is strong. This problem has been solved for most mitochondrial genes by their transfer to the nucleus but a few critical genes remain encoded by mtDNA. Organisms manage the evolution of mtDNA to prevent mutational decay of essential (...) services mitochondria provide to their hosts. Bottlenecks of mitochondrial numbers in female germlines increase the homogeneity of mtDNAs within cells and allow intraorganismal selection to eliminate cells with low quality mitochondria. Mechanisms of intracellular “quality control” allow direct selection on the competence of individual mtDNAs. These processes maintain the integrity of mtDNAs within the germline but are inadequate to indefinitely maintain mitochondrial function in somatic cells. (shrink)

Endocrinologists apply the idea of feedback loops to explain how hormones regulate certain bodily functions such as glucose metabolism. In particular, feedback loops focus on the maintenance of the plasma concentrations of glucose within a narrow range. Here, we put forward a different, organicist perspective on the endocrine regulation of glycaemia, by relying on the pivotal concept of closure of constraints. From this perspective, biological systems are understood as organized ones, which means that they are constituted of a set of (...) mutually dependent functional structures acting as constraints, whose maintenance depends on their reciprocal interactions. Closure refers specifically to the mutual dependence among functional constraints in an organism. We show that, when compared to feedback loops, organizational closure can generate much richer descriptions of the processes and constraints at play in the metabolism and regulation of glycaemia, by making explicit the different hierarchical orders involved. We expect that the proposed theoretical framework will open the way to the construction of original mathematical models, which would provide a better understanding of endocrine regulation from an organicist perspective. (shrink)

The era of AI-based decision-making fast approaches, and anxiety is mounting about when, and why, we should keep “humans in the loop” (“HITL”). Thus far, commentary has focused primarily on two questions: whether, and when, keeping humans involved will improve the results of decision-making (making them safer or more accurate), and whether, and when, non-accuracy-related values—legitimacy, dignity, and so forth—are vindicated by the inclusion of humans in decision-making. Here, we take up a related but distinct question, which has eluded (...) the scholarship thus far: does it matter if humans appear to be in the loop of decision-making, independent from whether they actually are? In other words, what is stake in the disjunction between whether humans in fact have ultimate authority over decision-making versus whether humans merely seem, from the outside, to have such authority? Our argument proceeds in four parts. First, we build our formal model, enriching the HITL question to include not only whether humans are actually in the loop of decision-making, but also whether they appear to be so. Second, we describe situations in which the actuality and appearance of HITL align: those that seem to involve human judgment and actually do, and those that seem automated and actually are. Third, we explore instances of misalignment: situations in which systems that seem to involve human judgment actually do not, and situations in which systems that hold themselves out as automated actually rely on humans operating “behind the curtain.” Fourth, we examine the normative issues that result from HITL misalignment, arguing that it challenges individual decision-making about automated systems and complicates collective governance of automation. (shrink)

Since the realisation that the antigen‐binding regions of antibodies, the variable (V) regions, can be uncoupled from the rest of the molecule to create fragments that recognise and abrogate particular protein functions in cells, the use of antibody fragments inside cells has become an important tool in bioscience. Diverse libraries of antibody fragments plus in vivo screening can be used to isolate single chain variable fragments comprising VH and VL segments or single V‐region domains. Some of these are interfering antibody (...) fragments that compete with protein‐protein interactions, providing lead molecules for drug interactions that until now have been considered difficult or undruggable. It may be possible to deliver or express antibody fragments in target cells as macrodrugs per se. In future incarnations of intracellular antibodies, however, the structural information of the interaction interface of target and antibody fragment should facilitate development of binding site mimics as small drug‐like molecules. This is a new dawn for intracellular antibody fragments both as macrodrugs and as precursors of drugs to treat human diseases and should finally lead to the removal of the epithet of the ‘undruggable’ protein‐protein interactions. (shrink)

Actin performs structural as well as motor‐like functions in eukaryotic cells. Orthologues of actin have also been identified in bacteria, where they perform an essential function during cell growth. Bacterial actins are implicated in the maintenance of rod‐shaped cell morphology, and appear to form a cytoskeletal structure, localising as helical filaments underneath the cell membrane. Recently, a plasmid‐borne actin orthologue has been shown to perform a mitotic‐like function during segregation of a plasmid, and chromosomally encoded actin proteins were found to (...) play an important role in chromosome segregation. Based on the findings that actin filaments are dynamic structures in two bacterial species, we propose that actins perform motor functions rather than a purely structural role in bacteria. We suggest that an intracellular motor exists in bacteria that could be derived from an ancestral actin motor that was present in cells early in evolution. BioEssays 26:1209–1216, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Lysosomes are the site of degradation of obsolete intracellular material during autophagy and of extracellular macromolecules following endocytosis and phagocytosis. The membrane of lysosomes and late endosomes is enriched in highly glycosylated transmembrane proteins of largely unknown function. Significant progress has been made in recent years towards elucidating the pathways by which these lysosomal membrane proteins are delivered to late endosomes and lysosomes. While some lysosomal membrane proteins follow the constitutive secretory pathway and reach lysosomes indirectly via the cell (...) surface and endocytosis, others exit the trans‐Golgi network in clathrin‐coated vesicles for direct delivery to endosomes and lysosomes. Sorting from the Golgi or the plasma membrane into the endosomal system is mediated by signals encoded by the short cytosolic domain of these proteins. This review will discuss the role of lysosomal membrane proteins in the biogenesis of the late endosomal and lysosomal membranes, with particular emphasis on the structural features and molecular mechanisms underlying the intracellular trafficking of these proteins. (shrink)

Protection against bacterial and viral pathogens by antibodies has always been thought to end at the cell surface. Once inside the cell, a pathogen was understood to be safe from humoral immunity. However, it has now been found that antibodies can routinely enter cells attached to viral particles and mediate an intracellular immune response. Antibody‐coated virions are detected inside the cell by means of an intracellular antibody receptor, TRIM21, which directs their degradation by recruitment of the ubiquitin‐proteasome system. (...) In this article we assess how this discovery alters our view of the way in which antibodies neutralise viral infection. We also consider the antiviral function of TRIM21 in the context of its other reported roles in immune signalling and autoimmunity. Finally, we discuss the conceptual implications of intracellular antibody immunity and how it alters our view of the discrete separation of extracellular and intracellular environments. (shrink)

The ‘causal-constitution’ fallacy, the ‘cognitive bloat’ worry, and the persisting theoretical confusion about the fundamental difference between the hypotheses of embedded (HEMC) and extended (HEC) cognition are three interrelated worries, whose common point—and the problem they accentuate—is the lack of a principled criterion of constitution. Attempting to address the ‘causal-constitution’ fallacy, mathematically oriented philosophers of mind have previously suggested that the presence of non-linear relations between the inner and the outer contributions is sufficient for cognitive extension. The abstract idea of (...) non-linearity, however, can be easily misunderstood and has, in the past, led to incorrect and counterintuitive conclusions about what may count as part of one’s overall cognitive system. In order to prevent any further mistakes I revisit dynamical systems theory to study the nature of the continuous mutual interactions that give rise to the aforementioned non-linear relations. Moreover, focusing on these interactions will allow us to provide two distinct arguments in support of the ontological postulation of extended cognitive systems, as well as an objective criterion of constitution. Accordingly, I put forward a version of HEC that treats continuous mutual interactions (and the resultant non-linear relations) not just as sufficient but also as necessary for cognitive extension. Such a qualified version of HEC may exclude certain alleged cases of cognitive extension where the agent does not mutually interact with his artifacts (e.g., shopping lists and directory services), but it is immune both to the ‘causal-constitution’ fallacy and the ‘cognitive bloat’ worry, and it can be sharply distinguished from HEMC. (shrink)

Background: Newer “closed-loop” neurostimulation devices in development could, in theory, induce changes to patients’ personalities and self-perceptions. Empirically, however, only limited data of patient and family experiences exist. Responsive neurostimulation (RNS) as a treatment for refractory epilepsy is the first approved and commercially available closed-loop brain stimulation system in clinical practice, presenting an opportunity to observe how conceptual neuroethical concerns manifest in clinical treatment. Methods: We conducted ethnographic research at a single academic medical center with an active RNS (...) treatment program and collected data via direct observation of clinic visits and in-depth interviews with 12 patients and their caregivers. We used deductive and inductive analyses to identify the relationship between these devices and patient changes in personality and self-perception. Results: Participants generally did not attribute changes in patients’ personalities or self-perception to implantation of or stimulation using RNS. They did report that RNS affected patients’ experiences and conceptions of illness. In particular, the capacity to store and display electrophysiological data produced a common frame of reference and a shared vocabulary among patients and clinicians .Discussion: Empirical experiences of a clinical population being treated with closed-loop neuromodulation do not corroborate theoretical concerns about RNS devices described by neuroethicists and technology developers. However, closed-loop devices demonstrated an ability to change illness experiences. Even without altering identify and self-perception, they provided new cultural tools and metaphors for conceiving of epilepsy as an illness and of the process of diagnosis and treatment. These findings call attention to the need to situate neuroethical concerns in the broader contexts of patients’ illness experiences and social circumstances. (shrink)

The current debate on closed-loop brain devices (CBDs) focuses on their use in a medical context; possible criminal justice applications have not received scholarly attention. Unlike in medicine, in criminal justice, CBDs might be offered on behalf of the State and for the purpose of protecting security, rather than realising healthcare aims. It would be possible to deploy CBDs in the rehabilitation of convicted offenders, similarly to the much-debated possibility of employing other brain interventions in this context. Although such (...) use of CBDs could in principle be consensual, there are significant differences between the choice faced by a criminal offender offered a CBD in the context of criminal justice, and that faced by a patient offered a CBD in an ordinary healthcare context. Employment of CBDs in criminal justice thus raises ethical and legal intricacies not raised by healthcare applications. This paper examines some of these issues under three heads: autonomy, human rights, and accountability. (shrink)

We reconstruct genetic determinism as a reductionist thesis to the effect that the molecular properties of cells can be accounted for to a great extent by their genetic outfit. The non-reductionist arguments offered at this molecular level often use the relationship between structure and function as their point of departure. By contrast, we develop a non-reductionist argument that is confined to the structural characteristics of biomolecules; no appeal to functions is made. We raise two kinds of objections against the reducibility (...) claim underlying genetic determinism. First, some conceptual distinctions at the protein level cannot be captured on a genetic basis. A one-to-many relationship between DNA sequences and proteins emerges from them. Second, the relationship between genes and proteins is characterized by explanatory loops or reciprocal explanatory dependence. The presence of proteins is explained by the transcription from corresponding DNA sequences, and the latter is in turn accounted for by the action of proteins. By contrast, a reductive account requires a unidirectional explanatory dependence. (shrink)

According to Hugh Mellor in Real Time II (1998, Ch. 12), assuming the logical independence of causal facts and the 'law of large numbers', causal loops are impossible because if they were possible they would produce inconsistent sets of frequencies. I clarify the argument, and argue that it would be preferable to abandon the relevant independence assumption in the case of causal loops.

According to Hugh Mellor in Real Time II, assuming the logical independence of causal facts and the ‘law of large numbers’, causal loops are impossible because if they were possible they would produce inconsistent sets of frequencies. I clarify the argument, and argue that it would be preferable to abandon the relevant independence assumption in the case of causal loops.

In this paper, I discuss whether the results of loop quantum gravity (LQG) constitute a fatal blow to Humeanism. There is at least a prima facie reason for believing so: while Humeanism regards spatiotemporal relations as fundamental, LQG describes the fundamental layer of our reality in terms of spin networks, which are not in spacetime. However, the question should be tackled more carefully. After explaining the importance of the debate on the tenability of Humeanism in light of LQG, and (...) having presented the Humean doctrine, I review two cases which present serious threats to Humeanism, one concerning the fundamentality of vectorial quantities and the other concerning quantum entanglement. In particular, I recall the strategies that are usually employed in these two cases in order to save Humeanism: in the first case, the strategy consists in amending the characterization of the Humean mosaic; in the second case, it consists in adopting a realist or nomological interpretation of the wave function. These solutions will turn out to be helpful in my discussion of LQG where, after describing LQG, I show that Humeans might save their doctrine either by endorsing a realist interpretation of spin networks, or by giving them a nomological status and, at the same time, by revisiting the characterization of the Humean mosaic. However, I conclude that both solutions are wanting. (shrink)

The ontological issues at stake given the theory of loop quantum gravity include the status of spacetime, the nature and reality of spin-networks, the relationship of classical spacetime to issues of causation and the status of the abstract-concrete distinction. I this paper I argue that, while spacetime seems to disappear, the spirit of substantival spacetime lives on under certain interpretations of the theory. Moreover, in order for there to be physical spin-networks, and not merely mathematical artifacts, I argue that (...) we must interpret the theory as including a substantival background manifold. This latter result is important for any project which interprets spacetime as an emergent structure from physical spin-networks. (shrink)

It is shown that the Riemannian curvature of the 3-dimensional hypersurfaces in space-time, described by the Wilson loop integral, can be represented by a quaternion quantum operator induced by the SU(2) gauge potential, thus providing a justification for quaternion quantum gravity at the Tev energy scale.

In the following article we first present the growing trend of incorporating neuroscience into the law, and the growing acceptance of and trust in neuroscience’s mechanistic and reductionistic explanations of the human mind. We then present and discuss some studies that show how nudging peoples’ beliefs about matters related to human agency (such as free will, decision-making, or self-control) towards a more deterministic, mechanistic and/or reductionistic conception, exerts an influence on their very actions, mentality, and brain processes. We suggest that (...) the neuroscientific view of the human mind exerts an influence on the very cognitive phenomena neuroscience falsely believes to be studying objectively. This holds especially when we consider the systematic integration of neuroscience into the public domain, such as the law. For, such an integration acts as a reinforcement of the public’s and legal decision-makers’ endorsement of and trust in neuroscience’s view of human nature that further changes how people think and act. Such looping effects of neurolaw are probably inevitable. Accordingly, we should be aware of the scope of neuroscientific explanations and be careful not to overstate neuroscientific evidence and findings in legal contexts. (shrink)

Human behavior is not always independent of the ways in which humans are scientifically classified. That there are looping effects of human kinds has been used as an argument for the methodological separation of the natural and the human sciences and to justify social constructionist claims. We suggest that these arguments rely on false presuppositions and present a mechanisms-based account of looping that provides a better way to understand the phenomenon and its theoretical and philosophical implications.

Segregation of chromosomes during mitosis requires the interaction of dynamic microtubules with the kinetochore, a large protein structure established on the centromere region of sister chromatids. The core microtubule‐binding activity of the kinetochore resides in the KMN network, an outer kinetochore complex. As part of the KMN network, the Ndc80 complex, which is composed of Ndc80, Nuf2, Spc24, and Spc25, is able to bind directly to microtubules and has the ability to track with depolymerizing microtubules to produce chromosome movement. The (...) Ndc80 complex binds directly to microtubules through a calponin homology domain and an unstructured tail in the N terminus of the Ndc80 protein. A recent flurry of papers has highlighted the importance of an internal loop region in Ndc80 in establishing end‐on attachment to microtubules. Here I discuss these recent findings that suggest that the Ndc80 internal loop functions as a binding site for proteins required for kinetochore‐microtubule interactions. (shrink)

In our previous work we have introduced loop-type sequent calculi for propositional linear discrete tense logic and proved that these calculi are sound and complete. Decision procedures using the calculi have been constructed for the considered logic. In the present paper we restrict ourselves to the logic with the unary temporal operators “next” and “henceforth always”. Proof-theory of the sequent calculus of this logic is considered, focusing on loop specification in backward proof-search. We describe cyclic sequents and prove (...) that any loop consists of only cyclic sequents. A class of sequents for which backward proof-search do not require loop-check is presented. It is shown how sequents can be coded by binary strings that are used in backward proof-search for the sake of more efficient loop-check. (shrink)

Epistemologists spend a great deal of time thinking about how we should respond to our evidence. They spend far less time thinking about the ways that evidence can be acquired in the first place. This is an oversight. Some ways of acquiring evidence are better than others. Many normative epistemologies struggle to accommodate this fact. In this article I develop one that can and does. I identify a phenomenon – epistemic feedback loops – in which evidence acquisition has gone awry, (...) with the result that even beliefs based on the evidence are irrational. Examples include evidence acquired under the influence of confirmation bias and evidence acquired under the influence of cognitively penetrated experiences caused by implicit bias. I then develop a theoretical framework which enables us to understand why beliefs that are the outputs of epistemic feedback loops are irrational. Finally, I argue that many popular approaches to epistemic normativity may need to be abandoned on the grounds that they cannot comfortably explain feedback loops. The scope of this last claim is broad: it includes almost all contemporary theories of justified/rational belief and of the epistemology of cognitive penetration. (shrink)

Recent philosophy of measurement has emphasized the existence of both diachronic and synchronic “loops,” or feedback processes, in the epistemic achievements of measurement. A widespread response has been to conclude that measurement outcomes do not convey interest-independent facts about the world, and that only a coherentist epistemology of measurement is viable. In contrast, I argue that a form of measurement realism is consistent with these results. The insight is that antecedent structure in measuring spaces constrains our empirical procedures such that (...) successful measurement conveys a limited, but veridical knowledge of “fixed points,” or stable, interest- independent features of the world. (shrink)

Background: Treating medication-refractory freezing of gait in Parkinson’s disease remains challenging despite several trials reporting improvements in motor symptoms using subthalamic nucleus or globus pallidus internus deep brain stimulation. Pedunculopontine nucleus region DBS has been used for medication-refractory FoG, with mixed findings. FoG, as a paroxysmal phenomenon, provides an ideal framework for the possibility of closed-loop DBS.Methods: In this clinical trial, five subjects with medication-refractory FoG underwent bilateral GPi DBS implantation to address levodopa-responsive PD symptoms with open-loop stimulation. (...) Additionally, PPN DBS leads were implanted for CL-DBS to treat FoG. The primary outcome of the study was a 40% improvement in medication-refractory FoG in 60% of subjects at 6 months when “on” PPN CL-DBS. Secondary outcomes included device feasibility to gauge the recruitment potential of this four-lead DBS approach for a potentially larger clinical trial. Safety was judged based on adverse events and explantation rate.Findings: The feasibility of this approach was demonstrated as we recruited five subjects with both “on” and “off” medication freezing. The safety for this population of patients receiving four DBS leads was suboptimal and associated with a high explantation rate of 40%. The primary clinical outcome in three of the five subjects was achieved at 6 months. However, the group analysis of the primary clinical outcome did not reveal any benefit.Interpretation: This study of a human PPN CL-DBS trial in medication-refractory FoG showed feasibility in recruitment, suboptimal safety, and a heterogeneous clinical effect in FoG outcomes. (shrink)

Resumen: El objetivo de este trabajo es defender el uso tanto de métodos cualitativos como de métodos cuantitativos en investigación en filosofía del lenguaje. Concretamente, defenderé que la mejor opción para llevar a cabo este tipo de investigación es usar métodos propios de la lingüística de corpus, pero aplicando también métodos cualitativos. Para ello, argumentaré a favor de la idea de bucles virtuosos, procesos de retroalimentación entre ambos métodos que pueden producir ciertos hallazgos que serían imposibles de descubrir si solo (...) se usara uno de los dos tipos de método. Abstract: This paper aims to defend the use of both qualitative and quantitative methods in research in language philosophy. Specifically, I would argue that the best option for conducting this type of research is to use methods of corpus linguistics, but also applying qualitative methods. For this, I will argue in favor of the idea of virtuous loops, feedback processes between both methods that can produce findings that would be impossible to discover if only one of the two methods were used. (shrink)

Machine learning algorithms reshape how people communicate, exchange, and associate; how institutions sort them and slot them into social positions; and how they experience life, down to the most ordinary and intimate aspects. In this article, we draw on examples from the field of social media to review the commonalities, interactions, and contradictions between the dispositions of people and those of machines as they learn from and make sense of each other.

This article argues that the causal loops that occur in some time-travel scenarios and in certain solutions of the theory of relativity are no more mysterious than the infinitely descending causal chains familiar from Newtonian mechanics.

Judith Jarvis Thomson's Loop Case is particularly significant in normative ethics because it questions the validity of the intuitively plausible Doctrine of Double Effect, according to which there is a significant difference between harm that is intended and harm that is merely foreseen and not intended. Recently, Frances Kamm has argued that what she calls the Doctrine of Triple Effect, which draws a distinction between acting because-of and acting in-order-to, can account for our judgment about the Loop Case. (...) In this paper, I first argue that even if the distinction drawn by DTE can be sustained, it does not seem to apply to the Loop Case. Moreover, I question whether this distinction has any normative significance. The upshot is that I am skeptical that DTE can explain our judgment about the Loop Case. (shrink)

Closed Loop medical devices such as Closed Loop Deep Brain Stimulation and Brain Computer Interface are some of the emerging neurotechnologies. New generations of implantable brain–computer interfaces have recently gained success in human clinical trials. These implants detect specific neuronal patterns and provide the subject with information to respond to these patterns. Further, Closed Loop brain devices give control to the subject so that he can respond and decide on a therapeutic goal. Although the implants have improved (...) subjects’ quality of life, their use has raised varied ethical concerns. The aim of this study is to provide an overview of the ethical implications specific to the therapeutic goals of closed loop brain implants. The authors analyze the related work qualitatively and quantitatively so as to help readers in understanding the various ethical implications of closed loop brain implants. (shrink)

Libertarians often portray the decision to use enhancement technologies purely as a matter of individual choice, affecting the person who uses them but no one else. Yet individual choices often add up to large social changes that profoundly affect the lives of other people, effectively pushing individual choices in a particular direction. It seems plausible that self-reinforcing loops such as those that have driven the adoption of technologies like cars and air-conditioners might also play a role in the adoption of (...) enhancement technologies, effectively exerting pressure on people to use a technology that they might otherwise resist. (shrink)

The aim of this paper is to present a loop-free decision procedure for modal propositional logics K4, S4 and S5. We prove that the procedure terminates and that it is sound and complete. The procedure is based on the method of Socratic proofs for modal logics, which is grounded in the logic of questions IEL.

The aim of this paper is to present a loop-free decision procedure for modal propositional logics K4, S4 and S5. We prove that the procedure terminates and that it is sound and complete. The procedure is based on the method of Socratic proofs for modal logics, which is grounded in the logic of questions IEL.