The best‐characterized model pathway of protein folding, that of disulphide bond formation in the small protein BPTI, has been questioned recently. A reinvestigation of that pathway, using alternative methods, concluded that the intermediates with non‐native disulphide bonds accumulated to lower levels than previously had been observed(17). On this basis, a revised pathway was proposed that simply omitted those intermediates. Even if totally correct, however, the new observations are not inconsistent with the important characteristics of the original pathway and even (...) confirmed many of them. Certain crucial observations that were the experimental basis for the original pathway were ignored, and these observations invalidate the revised pathway. (shrink)

The centriole is a widely conserved organelle required for the assembly of centrosomes, cilia, and flagella. Its striking feature – the nine‐fold symmetrical structure, was discovered over 70 years ago by transmission electron microscopy, and since elaborated mostly by cryo‐electron microscopy and super‐resolution microscopy. Here, we review the discoveries that led to the current understanding of how the nine‐fold symmetrical structure is built. We focus on the recent findings of the centriole structure in high resolution, its assembly pathways, and (...) its nine‐fold distributed components. We propose a model that the assembly of the nine‐fold symmetrical centriole depends on the concerted efforts of its core proteins. Also see the video abstract here:https://youtu.be/m4h_3II_WJo. (shrink)

The coupling of protein synthesis and folding is a crucial yet poorly understood aspect of cellular protein folding. Over the past few years, it has become possible to experimentally follow and define protein folding on the ribosome, revealing principles that shape co‐translational folding and distinguish it from refolding in solution. Here, we highlight some of these recent findings from biochemical and biophysical studies and their potential significance for cellular protein biogenesis. In particular, we focus on nascent (...) chain interactions with the ribosome, interactions within the nascent protein, modulation of translation elongation rates, and the role of mechanical force that accompanies nascent protein folding. The ability to obtain mechanistic insight in molecular detail has set the stage for exploring the intricate process of nascent protein folding. We believe that the aspects discussed here will be generally important for understanding how protein synthesis and folding are coupled and regulated. (shrink)

The process of protein folding in the cell is now known to depend on the action of other proteins. These proteins include molecular chaperones, Which interact non‐covalently with proteins as they fold and improve the final yields of active protein in the cell. The precise mechanism by which molecular chaperones act is obscure. Experiments reported recently(1) show that for one molecular chaperone (Cpn60, typified by the E. coli protein GroEL), the folding reaction is driven by cycles of binding (...) and release of the co‐chaperone Cpn10 (known as GroES in E. coli). These alternate with binding and release of the unfolded protein substrate. These cycles come about because of the opposite effects of Cpn10 and unfolded protein on the Cpn60 complex: the former stabilises the ADP‐bound state of Cpn60, whereas the latter stimulates ADP‐ATP exchange. This model proposes that the substrate protein goes through multiple cycles of binding and release, and is released into the cavity of the Cpn60 complex where it can undergo folding without interacting with other nearby folding intermediates. This is consistent with the ability of Cpn60 proteins to enhance folding by blocking pathways to aggregation. (shrink)

We suggest a new view of secretory and membrane protein folding that emphasizes the role of pathways of biogenesis in generating functional and conformational heterogeneity. In this view, heterogeneity results from action of accessory factors either directly binding specific sequences of the nascent chain, or indirectly, changing the environment in which a particular domain is synthesized. Entrained by signaling pathways, these variables create a combinatorial set of necessary‐but‐not‐sufficient conditions that enhance synthesis and folding of particular alternate, (...) functional, conformational forms. We therefore propose that protein conformation is productively regulated by the cell during translocation across the endoplasmic reticulum (ER), a concept that may account for currently poorly understood aspects of physiological function, natural selection, and disease pathogenesis. BioEssays 24:741–748, 2002. © 2002 Wiley Periodicals, Inc. (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)

© Copyright 2015, Mary Ann Liebert, Inc..Signal transducer and activator of transcription factor 3 is hyperactivated in head and neck squamous cell carcinomas. Cumulative evidence indicates that IL-6 production by HNSCC cells and/or stromal cells in the tumor microenvironment activates STAT3 and contributes to tumor progression and drug resistance. A library of 94,491 compounds from the Molecular Library Screening Center Network was screened for the ability to inhibit interleukin-6 -induced pSTAT3 activation. For contractual reasons, the primary high-content screening campaign was (...) conducted over several months in 3 distinct phases; 1,068 primary HCS actives remained after cytotoxic or fluorescent outliers were eliminated. One thousand one hundred eighty-seven compounds were cherry-picked for confirmation; actives identified in the primary HCS and compounds selected by a structural similarity search of the remaining MLSCN library using hits identified in phases I and II of the screen. Actives were confirmed in pSTAT3 IC50 assays, and an IFNγ-induced pSTAT1 activation assay was used to prioritize selective inhibitors of STAT3 activation that would not inhibit STAT1 tumor suppressor functions. Two hundred three concentration-dependent inhibitors of IL-6-induced pSTAT3 activation were identified and 89 of these also produced IC50s against IFN-γ-induced pSTAT1 activation. Forty-nine compounds met our hit criteria: they reproducibly inhibited IL-6-induced pSTAT3 activation by ≥70% at 20 μM; their pSTAT3 activation IC50s were ≤25 μM; they were ≥2-fold selective for pSTAT3 inhibition over pSTAT1 inhibition; a cross target query of PubChem indicated that they were not biologically promiscuous; and they were ≥90% pure. Twenty-six chemically tractable hits that passed filters for nuisance compounds and had acceptable drug-like and ADME-Tox properties by computational evaluation were purchased for characterization. The hit structures were distributed among 5 clusters and 8 singletons. Twenty-four compounds inhibited IL-6-induced pSTAT3 activation with IC50s ≤20 μM and 13 were ≥3-fold selective versus inhibition of pSTAT1 activation. Eighteen hits inhibited the growth of HNSCC cell lines with average IC50s ≤ 20 μM. Four chemical series were progressed into lead optimization: the guanidinoquinazolines, the triazolothiadiazines, the amino alcohols, and an oxazole-piperazine singleton. (shrink)

During the past two decades, philosophers of biology have increasingly turned their attention to mechanisms of biological phenomena. Through analyses of mechanistic proposals advanced by biologists, the goal of these philosophers is to understand what a mechanism is and how mechanisms explain. These analyses have generally focused on mechanistic proposals for phenomenon that occur at the cellular or sub-cellular level, such as synapse firing, protein synthesis, or metabolic pathway operation. Little is said about the mechanisms of the macromolecular reactions that (...) underpin these phenomena. These reactions comprise a diverse family of reaction types, and include protein folding, macromolecular complex formation, receptor-ligand interactions, and enzyme catalysis. In this paper, I develop an account of mechanism that focuses exclusively on macromolecular reactions. I begin by reviewing how mechanism is understood in enzymology, and how mechanistic concepts of enzymology apply to macromolecular reactions in general. We will see that the mechanism of a macromolecular reaction is most accurately described as a progression of reaction intermediates, where the evolution of intermediates, from one to the next, is characterized by an energetic coupling between chemistry and protein dynamics. I then make the case that this description necessitates a grounding in a process ontology. To describe the mechanism by which a macromolecular reaction occurs is to describe a process. (shrink)

Recently, interest in the unique pathways linking discrete positive emotions to specific health outcomes has gained increasing attention, but the role of awe is yet to be elucidated. Awe is a complex and transformative emotion that can restructure individuals' mental frames so deeply that it could be considered a therapeutic asset for major mental health major issues, including depression. Despite sparse evidence showing a potential connection between depression and awe, this link has not been combined into a proposal resulting (...) in specific intervention guidelines. The aim of this perspective was three-fold: to provide a new unifying model of awe's functioning—the Matryoshka model; to show systematic and explicit connections between this emotion and depression; and to suggest specific guidelines of intervention utilizing the potential therapeutic role of awe for mental health, specifically for depression. This theoretical endeavor in its entirety has been framed within the health domain. (shrink)

Machine learning is used more and more in scientific contexts, from the recent breakthroughs with AlphaFold2 in protein fold prediction to the use of ML in parametrization for large climate/astronomy models. Yet it is unclear whether we can obtain scientific explanations from such models. I argue that when machine learning is used to conduct causal inference we can give a new positive answer to this question. However, these ML models are purpose-built models and there are technical results showing that standard (...) machine learning models cannot be used for the same type of causal inference. Instead, there is a pathway to causal explanations from predictive ML models through new explainability techniques; specifically, new methods to extract structural equation models from such ML models. The extracted models are likely to suffer from issues though: they will often fail to account for confounders and colliders, as well as deliver simply incorrect causal graphs due to ML models tendency to violate physical laws such as the conservation of energy. In this case, extracted graphs are a starting point for new explanations, but predictive accuracy is no guarantee for good explanations. (shrink)

Adenosine transport in cultured human umbilical vein endothelial cells (HUVEC) was characterized and shown to be mediated by a single facilitated diffusion mechanism. Initial rates of adenosine influx at 22 degrees C were saturable [apparent Michaelis constant, 69 +/- 10 mu M; maximum velocity (V-max), 600 +/- 70 pmol.10(6) cells(-1).s(-1)] and inhibited by nitrobenzylthioinosine (NBMPR). Formycin B had an unusually high affinity [inhibitory constant K-i), 18 +/- 4.3 mu M], whereas inosine had a low affinity (K-i, 440 +/- 68 mu (...) M) and nucleobases were without effect on adenosine influx. The number of transporters (1.2 x 10(6) sites/cell) was estimated by NBMPR equilibrium binding (apparent dissociation constant, 0.11 +/- 0.01 nM; maximum binding, 2.0 +/- 0.15 pmol/10(6) cells). In addition, we compared these endothelial cells with those obtained from cords from pregnancies complicated by diabetes (HUVEC-D), since embriopathy may occur in these conditions. HUVEC-D exhibited a 2.3-fold reduction in both the V-max for adenosine influx and the maximum number of NBMPR binding sites (260 +/- 40 pmol.10(6) cells(-1).s(-1) and 0.86 +/- 0.08 pmol/10(6) cells, respectively). However, the turnover number for each nucleoside transporter in normal and diabetic HUVEC was similar (approximate to 300 adenosine molecules/s). Adenosine metabolism at 10 mu M in HUVEC-D was modified compared with normal cells. Intracellular phosphorylation (> 90%) was the predominant pathway in normal HUVEC, whereas in HUVEC-D, substantial levels of adenine and adenosine were detected. The present results demonstrate therefore the downregulation of the NBMPR-sensitive nucleoside transporter and changes in adenosine metabolism in HUVEC from diabetic pregnancies. (shrink)

Outer membrane proteins (OMPs) maintain the viability of Gram‐negative bacteria by functioning as receptors, transporters, ion channels, lipases, and porins. Folding and assembly of OMPs involves synchronized action of chaperones and multi‐protein machineries which escort the highly hydrophobic polypeptides to their target outer membrane in a folding competent state. Previous studies have identified proteins and their involvement along the OMP biogenesis pathway. Yet, the mechanisms of action and the intriguing ability of all these molecular machines to work without (...) the typical cellular energy source of ATP, but solely based on thermodynamic principles, are still not well understood. Here, we highlight how different single‐molecule studies can shed additional light on the mechanisms and kinetics of OMP biogenesis. (shrink)

Here we discuss the challenge posed by self-organization to the Darwinian conception of evolution. As we point out, natural selection can only be the major creative agency in evolution if all or most of the adaptive complexity manifest in living organisms is built up over many generations by the cumulative selection of naturally occurring small, random mutations or variants, i.e., additive, incremental steps over an extended period of time. Biological self-organization—witnessed classically in the folding of a protein, or in (...) the formation of the cell membrane—is a fundamentally different means of generating complexity. We agree that self-organizing systems may be fine-tuned by selection and that self-organization may be therefore considered a complementary mechanism to natural selection as a causal agency in the evolution of life. But we argue that if self-organization proves to be a common mechanism for the generation of adaptive order from the molecular to the organismic level, then this will greatly undermine the Darwinian claim that natural selection is the major creative agency in evolution. We also point out that although complex self-organizing systems are easy to create in the electronic realm of cellular automata, to date translating in silico simulations into real material structures that self-organize into complex forms from local interactions between their constituents has not proved easy. This suggests that self-organizing systems analogous to those utilized by biological systems are at least rare and may indeed represent, as pre-Darwinists believed, a unique ascending hierarchy of natural forms. Such a unique adaptive hierarchy would pose another major challenge to the current Darwinian view of evolution, as it would mean the basic forms of life are necessary features of the order of nature and that the major pathways of evolution are determined by physical law, or more specifically by the self-organizing properties of biomatter, rather than natural selection. (shrink)

Genetic and environmental factors leading to Alzheimer's disease (AD) converge in a pathogenic pathway that leads to the accumulation of mis‐folded amyloid peptide (Aβ) in the brain. Removal of Aβ from the brain has thus been the focus of academic and industrial research in the last decade. The concept of immunization therapy could be proven in animal models mimicking amyloid pathology but a multicenter clinical trial in which AD patients were vaccinated with aggregated Aβ has resulted in somewhat unanticipated and (...) partially conflicting results. The occurrence of meningoencephalitis in 6% of vaccinated individuals forced the discontinuation of the clinical study, preventing the generation of sufficient data for an unequivocal statement about the effectiveness of such a therapy approach. This study, however, clearly showed that vaccination induced the production of antibodies against Aβ in some immunized patients. Moreover, circulating anti‐Aβ antibodies are found in healthy humans suggesting a protective role of such physiological antibodies. Nonetheless, the physiological role of the immune system in preventing AD is not fully understood. This article summarizes crucial animal and clinical data underscoring the potential of the immune system for AD treatment. BioEssays 29:927–932, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Introduction of O2 to Earth's early biosphere stimulated remarkable evolutionary adaptations, and a wide range of electron acceptors allowed diverse, energy-yielding metabolic pathways. Enzymatic reduction of O2 yielded a several-fold increase in energy production, enabling evolution of multi-cellular animal life. However, utilization of O2 also presented major challenges as O2 and many of its derived reactive oxygen species are highly toxic, possibly impeding multicellular evolution after the Great Oxidation Event. Remarkably, ROS, and especially hydrogen peroxide, seem to play a (...) major part in early diversification and further development of cellular respiration and other oxygenic pathways, thus becoming an intricate part of evolution of complex life. Hence, although harnessing of chemical and thermo-dynamic properties of O2 for aerobic metabolism is generally considered to be an evolutionary milestone, the ability to use ROS for cell signaling and regulation may have been the first true breakthrough in development of complex life. The importance of Earth's oxygen cycle and reactive oxygen species produced on the evolution of complex life. The ability to detoxify oxygen species is not a trait that emerged as a response to increased O2 levels but rather crucial adaptation to the early Earth's weakly oxic microenvironments. (shrink)

The endoplasmic reticulum (ER) uses various mechanisms to ensure that only properly folded proteins enter the secretory pathway. For proteins that oligomerize in the ER, the proper tertiary and quaternary structures must be achieved before their release. Although some proteins fold before oligomerization, others initiate oligomerization cotranslationally. Here, we discuss these different strategies and some of the unique problems they present for the ER quality control system. One mechanism used by the ER is thiol retention. Thiol retention operates by monitoring (...) the redox state of specific cysteine residue(s) and was discovered in studies on the assembly of IgM, a complex oligomeric glycoprotein. This system is also involved in retaining other unassembled proteins in the ER. Mutations that result in uneven numbers of cysteine residues can subject yet other proteins to thiol retention, altering their oligomerization status and function. The implications of these results on the effects of thiol retention on protein function and cell fate are discussed. BioEssays 20:546–554, 1998. © 1998 John Wiley & Sons Inc. (shrink)

Recent decades have witnessed widespread agrarian transitions in mainland Southeast Asia. This paper examines how agrarian transitions are shaped by multiple drivers of change, and how these interwoven processes have triggered shifts in agricultural extension practices in three countries in the Lower Mekong Basin: Laos, Cambodia, and Vietnam. Drawing on interviews with experts working on the fields of agrarian studies and rural development, this paper argues that agrarian transitions not only put a strain on agricultural extension systems in responding to (...) evolving needs, but they also stimulate the co-production of innovative agricultural extension models to address gaps left by the limited presence of extensionists. The study gains insight into challenges faced by extensionists, including a lack of resources, skills, and capacities to meet growing needs, which simultaneously urged them to excel in their work performance. The paper highlights the proactive role of ‘champions’ in orchestrating collective efforts towards the co-production of innovative agricultural extension models (e.g. Metkasekor), and the formulation of pluralistic extension platforms in enabling such ‘co-learning-to-act’ practices. By translating these insights into the broader contexts of agricultural and rural development in the Mekong region and beyond, this paper aims to make a two-fold contribution. First, it will assert how the ‘business-as-usual’ extension model has failed to adequately address emerging needs as a result of agrarian transitions. Second, it will provide pathways for the recognition and legitimisation of the pluralistic extension approach that fosters stakeholders’ co-learning and productive engagement in extension practices. (shrink)

The unfertilized sea urchin egg is a metabolically quiescent cell. Fertilization results in the activation of a variety of metabolic and biosynthetic pathways, including a 20‐ to 40‐fold increase in the rate of protein synthesis by 2 h after fertilization. This increase is regulated at a purely translational level without the need for new transcription. The greatest part of this increase is due to the translation of stored maternal mRNAs which were not translated in the egg. There is also (...) a 2‐to 3‐fold increase in the peptide elongation rate. The molecular and physiological mechanisms responsible for this activation process are beginning to be understood, and turn out to be much more complex than was anticipated. (shrink)

Receptor oligomerization plays a key role in maintaining genome stability and restricting protein mutagenesis. When properly folded, protein monomers assemble as oligomeric receptors and interact with environmental ligands. In a gene-centered view, the ligand specificity expressed by these receptors is assumed to be causally predetermined by the cell genome. However, this mechanism does not fully explain how differentiated cells have come to express specific receptor repertoires and which combinatorial codes have been explored to activate their associated signaling pathways. It (...) is our contention that the plasma membrane acts as the locus where several contextual cues may be integrated. As such it allows the semiotic selection of those receptor configurations that provide cells with the minimum essential requirements for agency. The occurrence of protein misfolding makes it impossible for receptor monomers to assemble along the membrane and to sustain meaningful relationships with environmental ligands. How could a cell lineage deal with these loss-of-function mutations during evolution and restrain gene redundancy accordingly? In this paper, we will be arguing that the easiest way for bacteria clones to accomplish this goal is by getting rid of cells expressing mutated receptor proteins. The mechanism sustaining this cell selection is also occurring in many somatic tissues and its function is currently believed to counteract in vivo protein mutagenesis. Our discussion will be mainly focused on the significance and semiotic nature of the interplay between membrane receptors and the epigenetic control of gene expression, as mediated by the control of mismatched repairing and protein folding mechanisms. (shrink)

In this paper I examine the relationship between interpreting a fiction and specifying its content. The former plays a major role in literary studies; the latter is of central concern in the philosophical debate on truth in fiction. After elucidating these activities, I argue that they do not coincide but have interesting interdependencies. In particular, I argue that correct interpretations are metaphysically grounded in fictional content. I discuss this claim in detail and show why it is not in tension with (...) the evidential claim that correct interpretations give us epistemic access to fictional content, which I also endorse. (shrink)

We offer an original argument for the existence of universal fictions—that is, fictions within which every possible proposition is true. Specifically, we detail a trio of such fictions, along with an easy-to-follow recipe for generating more. After exploring several consequences and dismissing some objections, we conclude that fiction, unlike reality, is unlimited when it comes to truth.

This paper is about non-fictional objects in fictions and their role as narrators. Two central claims are advanced. In part 1 it is argued that non-fictional objects such as you and me can be part of fictions. This commonsensical idea is elaborated and defended against objections. Building on it, it is argued in part 2 that non-fictional objects can be characters and narrators in fictional narratives. As a consequence, three fundamental and popular claims concerning narrators are rejected. In particular, it (...) is shown that some fictional narratives have non-fictional internal narrators, some have no internal fictional narrator, and, most controversially, that the author of a fictional narrative can be identical to its internal narrator. (shrink)

Researchers working on children's moral understanding maintain that the child's capacity to distinguish morality from convention shows that children regard moral violations as objectively wrong. Education in the moral domain. Cambridge: Cambridge University Press). However, one traditional way to cast the issue of objectivism is to focus not on conventionality, but on whether moral properties depend on our responses, as with properties like icky and fun. This paper argues that the moral/conventional task is inadequate for assessing whether children regard moral (...) properties as response-dependent. Unfortunately, children's understanding of response-dependent properties has been neglected in recent research. Two experiments are reported showing that children are more likely to treat properties like fun and icky as response-dependent than moral properties like good and bad. Hence, this helps support the claim that children are moral objectivists. (shrink)

Recently, Xhignesse has argued that the principle of poetic licence, which roughly states that any class of propositions is true in some possible fiction, ought to be rejected. Here, we defend PPL from Xhignesse’s objection by demonstrating that, properly understood, his purported counter-example case is either irrelevant or unproblematic. The upshot is that Xhignesse has given us no reason to reject PPL.

The aim of this study was to initiate the exploration of debiasing methods applicable in real-life settings for achieving lasting improvement in decision making competence regarding multiple decision biases. Here, we tested the potentials of the analogical encoding method for decision debiasing. The advantage of this method is that it can foster the transfer from learning abstract principles to improving behavioral performance. For the purpose of the study, we devised an analogical debiasing technique for 10 biases (covariation detection, insensitivity to (...) sample size, base rate neglect, regression to the mean, outcome bias, sunk cost fallacy, framing effect, anchoring bias, overconfidence bias, planning fallacy) and assessed the susceptibility of the participants ( N = 154) to these biases before and 4 weeks after the training. We also compared the effect of the analogical training to the effect of ‘awareness training’ and a ‘no-training’ control group. Results suggested improved performance of the analogical training group only on tasks where the violations of statistical principles are measured. The interpretation of these findings require further investigation, yet it is possible that analogical training may be the most effective in the case of learning abstract concepts, such as statistical principles, which are otherwise difficult to master. The study encourages a systematic research of debiasing trainings and the development of intervention assessment methods to measure the endurance of behavior change in decision debiasing. (shrink)

Meaningful work is a key element of positive functioning of employees, but what makes work meaningful? Based on research on self-determination theory, basic psychological needs, and prosocial impact, we suggest that there are four psychological satisfactions that substantially influence work meaningfulness across cultures: autonomy (sense of volition), competence (sense of efficacy), relatedness (sense of caring relationships), and beneficence (sense of making a positive contribution). We test the relationships between these satisfactions and perceived meaningful work in Finland (n = 594, employees (...) of several organizations), India (n = 342, collected through Mturk), and the USA (n = 373, collected through Mturk). Regression analyses show that – except for competence in USA – all four satisfactions are significantly and independently associated with meaningful work. Moreover, structural equation modeling shows that they fully mediated the relationship between occupational position and work meaningfulness in India and in the USA. In sum, the results support the importance of these four satisfactions in explaining the psychological underpinnings of meaningful work. (shrink)

In The Fold Deleuze proposes a new and radical way of understanding philosophy and art.

Contemporary philosophy of technology after the empirical turn has surprisingly little to say on the relation between language and technology. This essay describes this gap, offers a preliminary discussion of how language and technology may be related to show that there is a rich conceptual space to be gained, and begins to explore some ways in which the gap could be bridged by starting from within specific philosophical subfields and traditions. One route starts from philosophy of language (both ‘‘analytic’’ and (...) ‘‘continental’’: Searle and Heidegger) and discusses some potential implications for thinking about technology; another starts from artefact-oriented approaches in philosophy of technology and STS and shows that these approaches might helpfully be extended by theorizing relationships between language and techno- logical artefacts. The essay concludes by suggesting a research agenda, which invites more work on the relation between language and technology. (shrink)

The Fold is a book of practical philosophy that takes a radical new approach to aesthetics. Laura U. Marks calls this philosophy "enfolding-unfolding aesthetics," based in ideas derived from Gilles Deleuze and others (G.F.W. Leibniz, David Bohm, and Édouard Glissant) that the universe is folded in on itself. She proposes a theory of mediation as contact and connection across the folds and a set of embodied methods for detecting such cosmic connections. In drawing out this aesthetics, Marks considers the embodied (...) and sensuous dimensions of engaging with audiovisual works and works of art-dimensions that Marks suggests are composed of the very folds that compose everything and everyone: all living beings, from humans to particles, sandwiches to stars, technologies, thoughts and images, in the present, the past, and the future. Making use of art and film, with a focus on African diaspora and Arab cinema, Marks opens ways to strengthen connections to the cosmos and to better trace processes of becoming that are immanent within the fold. (shrink)

This volume investigates alternative epistemological pathways by which knowledge production in Africa can proceed. The contributors, using different intellectual dynamics, explore the existing epistemological dominance of the West—from architecture to gender discourse, from environmental management to democratic governance—and offer distinct and unique arguments that challenge the denigration of the different and differing modes of knowing that the West considered “barbaric” and “primitive.” This volume therefore constitutes a minimal gesture that further contributes to the ongoing discourse on alternative modes of (...) knowing in Africa. (shrink)

Within the burgeoning corporate social responsibility (CSR) communication literature, the question of the relationship between CSR practices and CSR communication (or between “walk” and “talk”) has been a central concern. Recently, we observe a growing interest in formative views on the relation between CSR communication and practices, that is, works which ascribe to communication a constitutive role in creating, maintaining, and transforming CSR practices. This article provides an overview of the heterogeneous landscape of formative views on CSR communication scholarship. More (...) specifically, we distinguish between three variants of such formative views: walking-to-talk, talking-to-walk, and t(w)alking. These three orientations differ primarily regarding the temporal dynamics that they ascribe to the relation between CSR communication and practices and regarding the object that is formed through communication. This new typology helps systematize the emerging field of research on CSR communication, and we use it as a compass to provide directions for future research in this area. (shrink)

In this article I reply to three critics. Responding to Cinzia Arruzza, I argue that capital encounters a large spectrum of differences of gender, religion and ethnicity, as well as differences generated by racism. Capital is able to use these differences to its own profit in order to differentiate wages and intensities of exploitation and thereby divide the working class. Responding to Peter Osborne, I contend that my temporal-layered framework elucidates how capital organises and synchronises different temporalities according to the (...) dominant temporality of socially-necessary labour time. I combine Bloch’s idea of ‘multiversum’ and Benjamin’s idea of history in order to show how conflicting temporalities can disclose new political possibilities of liberation. Responding to Harry Harootunian, I articulate the relationship between my reading of Marx and the Postcolonial critique. (shrink)

In this paper, we apply the notion of \(n\)-fold filters to the \(EQ\)-algebras and introduce the concepts of \(n\)-fold pseudo implicative, \(n\)-fold implicative, \(n\)-fold obstinate, \(n\)-fold fantastic prefilters and filters on an \(EQ\)-algebra \(\mathcal{E}\). Then we investigate some properties and relations among them. We prove that the quotient algebra \(\mathcal{E}/F\) modulo an 1-fold pseudo implicative filter of an \(EQ\)-algebra \(\mathcal{E}\) is a good \(EQ\)-algebra and the quotient algebra \(\mathcal{E}/F\) modulo an 1-fold fantastic filter of a good \(EQ\)-algebra \(\mathcal{E}\) is an (...) \(IEQ\)-algebra. (shrink)

We discuss here a series of testable hypotheses concerning the role of chromosome folding into topologically associating domains (TADs). Several lines of evidence suggest that segmental packaging of chromosomal neighborhoods may underlie features of chromatin that span large domains, such as heterochromatin blocks, association with the nuclear lamina and replication timing. By defining which DNA elements preferentially contact each other, the segmentation of chromosomes into TADs may also underlie many properties of long‐range transcriptional regulation. Several observations suggest that TADs (...) can indeed provide a structural basis to regulatory landscapes, by controlling enhancer sharing and allocation. We also discuss how TADs may shape the evolution of chromosomes, by causing maintenance of synteny over large chromosomal segments. Finally we suggest a series of experiments to challenge these ideas and provide concrete examples illustrating how they could be practically applied. (shrink)

How can we know? How can we attain justified belief? These traditional questions in epistemology have inspired philosophers for centuries. Now, in this exceptional work, Alvin Goldman, distinguished scholar and leader in the fields of epistemology and mind, approaches such inquiries as legitimate methods or "pathways" to knowledge. He examines the notion of private and public knowledge, arguing for the epistemic legitimacy of private and introspective methods of gaining knowledge, yet acknowledging the equal importance of social and public mechanisms (...) in the quest for truth. Throughout, he addresses this opposition but proposes a rigorous framework that continues to resolve such contradictions, making this exciting text one of the most important contributions to the theory of knowledge in recent years. (shrink)

In this paper we introduce n -fold implicative basis logic and the related algebras called n -fold implicative BL-algebras. Also we define n -fold implicative filters and we prove some relations between these filters and construct quotient algebras via these filters.

Construction of the eukaryotic ribosome is a complex process in which a nascent ribosomal RNA (rRNA) emerging from RNA Polymerase I hierarchically folds into a native three‐dimensional structure. Modular assembly of individual RNA domains through interactions with ribosomal proteins and a myriad of assembly factors permit efficient disentanglement of the error‐prone RNA folding process. Following these dynamic events, long‐range tertiary interactions are orchestrated to compact rRNA. A combination of genetic, biochemical, and structural studies is now providing clues into how (...) a nascent rRNA is transformed into a functional ribosome with high precision. With this essay, we aim to draw attention to the poorly understood process of establishing correct RNA tertiary contacts during ribosome formation. (shrink)