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)

Fold‐switching proteins, which remodel their secondary and tertiary structures in response to cellular stimuli, suggest a new view of protein fold space. For decades, experimental evidence has indicated that protein fold space is discrete: dissimilar folds are encoded by dissimilar amino acid sequences. Challenging this assumption, fold‐switching proteins interconnect discrete groups of dissimilar protein folds, making protein fold space fluid. Three recent observations support the concept of fluid fold space: (1) some amino acid sequences interconvert between (...) folds with distinct secondary structures, (2) some naturally occurring sequences have switched folds by stepwise mutation, and (3) fold switching is evolutionarily selected and likely confers advantage. These observations indicate that minor amino acid sequence modifications can transform protein structure and function. Consequently, proteomic structural and functional diversity may be expanded by alternative splicing, small nucleotide polymorphisms, post‐translational modifications, and modified translation rates. (shrink)

Complexes of two or more proteins form many, if not most, of the intracellular “machines” that execute physical and chemical work, and transmit information. Complexes can form from stochastic post‐translational interactions of fully formed proteins, but recent attention has shifted to co‐translational interactions in which the most common mechanism involves binding of a mature constituent to an incomplete polypeptide emerging from a translating ribosome. Studies in yeast have revealed co‐translational interactions during formation of multiple major complexes, and (...) together with recent mammalian cell studies, suggest widespread utilization of the mechanism. These translation‐dependent interactions can involve a single or multiple mRNA templates, can be uni‐ or bi‐directional, and can use multi‐protein sub‐complexes as a binding component. Here, we discuss benefits of co‐translational complex assembly including accuracy and efficiency, overcoming hidden interfaces, localized and hierarchical assembly, and reduction of orphan protein degradation, toxicity, and dominant‐negative pathogenesis, all serving to improve cell fitness. (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)

In a recent issue of Nature Communications Ukleja and co‐workers reported a cryo‐EM 3D reconstruction of the Ccr4‐Not complex from Schizosaccharomyces pombe with an immunolocalization of the different subunits. The newly gained architectural knowledge provides cues to apprehend the functional diversity of this major eukaryotic regulator. Indeed, in the cytoplasm alone, Ccr4‐Not regulates translational repression, decapping and deadenylation, and the Not module additionally plays a positive role in translation. The spatial distribution of the subunits within the structure is compatible (...) with a model proposing that the Ccr4‐Not complex interacts with the 5′ and 3′ ends of target mRNAs, allowing different functional modules of the complex to act at different stages of the translation process, possibly within a circular constellation of the mRNA. This work opens new avenues, and reveals important gaps in our understanding regarding structure and mode of function of the Ccr4‐Not complex that need to be addressed in the future. (shrink)

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)

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)

In concert with the selective pressures affecting protein folding and function in the extreme environments in which they can exist, proteins in Archaea have evolved to present permanent molecular adaptations at the amino acid sequence level. Such adaptations may not, however, suffice when Archaea encounter transient changes in their surroundings. Post‐translational modifications offer a rapid and reversible layer of adaptation for proteins to cope with such situations. Here, it is proposed that Archaea further augment their ability to (...) survive changing growth conditions by modifying the extent, position, and, where relevant, the composition of different post‐translational modifications, as a function of the environment. Support for this hypothesis comes from recent reports describing how patterns of protein glycosylation, methylation, and other post‐translational modifications of archaeal proteins are altered in response to environmental change. Indeed, adjusting post‐translational modifications as a means to cope with environmental variability may also hold true beyond the Archaea. (shrink)

The origins and evolution of the Archaea, Bacteria, and Eukarya remain controversial. Phylogenomic‐wide studies of molecular features that are evolutionarily conserved, such as protein structural domains, suggest Archaea is the first domain of life to diversify from a stem line of descent. This line embodies the last universal common ancestor of cellular life. Here, we propose that ancestors of Euryarchaeota co‐evolved with those of Bacteria prior to the diversification of Eukarya. This co‐evolutionary scenario is supported by comparative genomic and (...) phylogenomic analyses of the distributions of fold families of domains in the proteomes of free‐living organisms, which show horizontal gene recruitments and informational process homologies. It also benefits from the molecular study of cell physiologies responsible for membrane phospholipids, methanogenesis, methane oxidation, cell division, gas vesicles, and the cell wall. Our theory however challenges popular cell fusion and two‐domain of life scenarios derived from sequence analysis, demanding phylogenetic reconciliation. (shrink)

As targeted proteins that move within the cell, the steroid receptors have become very useful probes for understanding the linked phenomena of protein folding and transport. From the study of steroid receptor‐associated proteins it has become clear over the past two years that these receptors are bound to a multiprotein complex containing at least two heat shock proteins, hsp90 and hsp56. Attachment of receptors to this complex in a cell‐free system appears to require the protein unfolding/folding (...) activity of a third heat shock protein, hsp70. Like the oncogenic tyrosine kinase pp60src, steroid receptors bind to this complex of chaperone proteins at the time of their translation. Binding of the receptor to the hsp90 component of the system occurs through the hormone binding domain and is under strict hormonal control. The hormone binding domain of the receptor acts as a transferable regulatory unit that confers both tight hormonal control and hsp90 binding onto chimaeric proteins. The model of folding and transport being developed for steroid receptors leads to some general suggestions regarding the folding and transport of targeted proteins in the cell. (shrink)

Molecular chaperones facilitate the correct folding of other proteins under physiological and stress conditions. Recently it has become evident that various co‐chaperone proteins regulate the cellular functions of these chaperones, particularly Hsp70 and Hsp90. Hop is one of the most extensively studied co‐chaperones that is able to directly associate with both Hsp70 and Hsp90. The current dogma proposes that Hop functions primarily as an adaptor that directs Hsp90 to Hsp70‐client protein complexes in the cytoplasm. However, recent evidence suggests (...) that Hop can also modulate the chaperone activities of these Hsps, and that it is not dedicated to Hsp70 and Hsp90. While the co‐chaperone function of Hop within the cytoplasm has been extensively studied, its association with nuclear complexes and prion proteins remains to be elucidated. This article will review the structural features of Hop, and the evidence that its biological function is considerably broader than previously envisaged. BioEssays 26:1058–1068, 2004. © 2004 Wiley Periodicals, Inc. (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)

The biogenesis of RNAs and proteins is a threat to the cell. Indeed, the act of transcription and nascent RNAs challenge DNA stability. Both RNAs and nascent proteins can also initiate the formation of toxic aggregates because of their physicochemical properties. In reviewing the literature, I show that co-transcriptional and co-translational biophysical constraints can trigger DNA instability that in turn increases the likelihood that sequences that alleviate the constraints emerge over evolutionary time. These directed genetic variations rely on the (...) biogenesis of small RNAs that are transcribed directly from challenged DNA regions or processed from the transcripts that directly or indirectly generate constraints or aggregates. These small RNAs can then target the genomic regions from which they initially originate and increase the local mutation rate of the targeted loci. This mechanism is based on molecular pathways involved in anti-parasite genome defence systems, and implies that gene expression-related biophysical constraints represent a driving force of genome evolution. Are randomly generated mutations the only source of genetic variation during evolution? This paper describes the molecular mechanisms by which co-transcriptional and co-translational biophysical constraints trigger genetic variations in targeted-genomic sequences in an RNA-depending manner. This directed-mutational process that drives genome evolution is related to antiparasite genome defence systems. (shrink)

In this paper we propose a theoretical model of protein folding and protein evolution in which a polypeptide (sequence/structure) is assumed to behave as a Maxwell Demon or Information Gathering and Using System (IGUS) that performs measurements aiming at the construction of the native structure. Our model proposes that a physical meaning to Shannon information (H) and Chaitin's algorithmic information (K) parameters can be both defined and referred from the IGUS standpoint. Our hypothesis accounts for the interdependence (...) of protein folding and protein evolution through mutual influencing relationships mediated by the IGUS. In brief, IGUS activity in protein folding determines long term tendencies that emerge at the evolutionary time-scale.Thus, protein evolution is a consequence of measurements executed by proteins at the cellular level, where the IGUS imposes a tendency to attain a highly unique stable native form that promotes the updating of the information content. The folding kinetics observed is, thus, the outcome of an evolutionary process where the polypeptide-IGUS drives the evolution of its linear sequence. Finally, we describe protein evolution as an entropic process that tends to increase the content of mutual algorithmic information between the sequence and the structure. This model enables one: 1. To comprehend that full determination of the three-dimensional structure by the linear sequence is a tendency where satisfaction is only possible at thermodynamic equilibrium .2. To account for the observed randomness of the amino acid sequences. 3. To predict an alternation of periods of selection and neutral diffusion during protein evolutionary time. (shrink)

To explore whether the generation of new protein folds could be linked to metallic cofactor recruitment, we identified the oldest examples of folds for manganese, iron, zinc, and copper proteins by analyzing their fold‐domain mapping patterns. We discovered that the generation of these folds was tightly coupled to corresponding metals. We found that the emerging order for these folds, i.e., manganese and iron protein folds appeared earlier than zinc and copper counterparts, coincides with the putative bioavailability of the (...) corresponding metals in the ancient anoxic ocean. Therefore, we conclude that metallic cofactors, like organic cofactors, play an evolutionary role in the formation of new protein folds. This link could be explained by the emergence of protein structures with novel folds that could fulfill the new protein functions introduced by the metallic cofactors. These findings not only have important implications for understanding the evolutionary mechanisms of protein architectures, but also provide a further interpretation for the evolutionary story of superoxide dismutases. (shrink)

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 protein folding problem is one of the foundational problems of biochemistry and it is still considered unsolved. It basically consists of two main questions: what are the factors determining the stability of the protein’s native structure and how does the protein acquire it starting from an unfolded state. Since its first formulation, two main explanatory approaches have dominated the field of protein folding research: a thermodynamic approach focused on energetic features and a kinetic (...) approach focused on the temporal development of protein chains and structural considerations. Although these two approaches are tightly intertwined in biochemical practice and largely agree on which are the parts and activities in which the phenomenon under study should be decomposed to, there nevertheless exist important contrasts that have had repercussions on the development of the field and still engender vigorous debate. We shall analyse the historical development of the field and crucial aspects of current scientific debates. On this basis, we argue that the main sources of disagreement centre on the causal interpretation of thermodynamic and kinetic explanations, on the explanatory relevance assigned to different features of the phenomena under study and on the status of the ontological assumptions concerning the entities under study. (shrink)

The ribosomal polypeptide tunnel exit is the site where a variety of factors interact with newly synthesized proteins to guide them through the early steps of their biogenesis. In mitochondrial ribosomes, this site has been considerably modified in the course of evolution. In contrast to all other translation systems, mitochondrial ribosomes are responsible for the synthesis of only a few hydrophobic membrane proteins that are essential subunits of the mitochondrial respiratory chain. Membrane insertion of these proteins occurs co‐translationally and is (...) connected to a sophisticated assembly process that not only includes the assembly of the different subunits but also the acquisition of redox co‐factors. Here, we describe how mitochondrial translation is organized in the context of respiratory chain assembly and speculate how alteration of the ribosomal tunnel exit might allow the establishment of a subset of specialized ribosomes that individually organize the early steps in the biogenesis of distinct mitochondrially‐encoded proteins. (shrink)

The discovery of “molecular chaperones” has dramatically changed our concept of cellular protein folding. Rather than folding spontaneously, most newly synthesized polypeptide chains seem to acquire their native conformation in a reaction mediated by these versatile helper proteins. Understanding the structure and function of molecular chaperones is likely to yield useful applications for medicine and biotechnology in the future.

In this paper I attempt to study the notion of “folding of a semiotic continuum” in a direction of a possible application to the biological processes. More specifically, the process of obtaining protein structures is compared in this paper to the folding of a semiotic continuum. Consequently, peptide chain is presented as a continuous line potential to be formed in order to create functional units. The functional units are protein structures having certain function in the cell (...) or organism. Moreover, protein folding is analyzed in terms of tension between syntax and semantics. (shrink)

Prediction is more than testing established theory by examining whether the prediction matches the data. To show this, I examine the practices of a community of scientists, known as threaders, who are attempting to predict the final, folded structure of a protein from its primary structure, i.e., its amino acid sequence. These scientists employ a careful and deliberate methodology of prediction. A key feature of the methodology is calibration. They calibrate in order to construct better models. The construction leads (...) to knowledge of how to construct or build an object. Thus, prediction serves a cognitive goal of model construction and not just model or theory testing. The kind of knowledge that results is relevantly different than theoretical knowledge. (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)

A crucially important part of the biosphere – the virosphere – is too often overlooked. Inclusion of the virosphere into the global picture of protein structure space reveals that 63 protein domain superfamilies in viruses do not have any structural and evolutionary relatives in modern cellular organisms. More than half of these have functions which are not virus‐specific and thus might be a source of new folds and functions for cellular life. The number of viruses on the planet (...) exceeds that of cells by an order of magnitude and viruses evolve up to six orders of magnitude faster. As a result, cellular species are subject to a constitutive ‘flow‐through’ of new viral genetic material. Due to this and the relaxed evolutionary constraints in viruses, the transfer of domains between host‐to‐virus could be a mechanism for accelerated protein evolution. The virosphere could be an engine for the genesis of protein structures, and may even have been so before the last universal common ancestor of cellular life. (shrink)

Mutagenesis makes it possible to examine the effect of amino acid replacements on the folding and stability of proteins. The evaluation of kinetic and equilibrium folding data using reaction coordinate diagrams allows one to determine the roles that single amino acids play in the folding mechanism.

We develop a general method for applying functional models to natural systems and cite recent progress in protein modeling that demonstrates the power of this approach. Functional modeling constrains the range of acceptable structural models of a system, reduces the difficulty of finding them, and improves their fidelity. However, functional models are distinctly different from the structural models that are more commonly applied in science. In particular, structural and functional models ask different questions and provide different kinds of answers. (...) As we clarify these differences and articulate how to use these models jointly, we extend our ability to do science and gain insight into the proper use of the terms organization , order , and emergence when describing systems in nature. (shrink)

The expression of protein‐encoding genes is a complex process culminating in the production of mature mRNA and its translation by the ribosomes. The production of a mature mRNA involves an intricate series of processing steps. The majority of eukaryotic protein‐encoding genes contain intron sequences that disrupt the protein‐encoding frame, and hence have to be removed from immature mRNA prior to translation into protein. The mechanism involved in the selection of correct splice sites is incompletely understood. A (...) considerable body of evidence suggests that the splicing machinery has suboptimal efficiency and fidelity leading to substantial processing inaccuracy. Here we discuss a recently published article1 that extends observations that cells rely on nonsense‐mediated mRNA decay (NMD) to compensate for such suboptimal processing accuracy. Intriguingly these authors provide evidence for a strong selective pressure in favour of premature termination of mRNA translation in the event of intron retention. The analysis presented implies a positive role of NMD in transcript diversification through alternative splicing and suggest that this ancient surveillance mechanism may have co‐evolved with intron acquisition born from the need for quality control of splicing patterns. BioEssays 30:926–928, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Numerous accessory factors modulate RNA polymerase response to regulatory signals and cellular cues and establish communications with co‐transcriptional RNA processing. Transcription regulators are astonishingly diverse, with similar mechanisms arising via convergent evolution. NusG/Spt5 elongation factors comprise the only universally conserved and ancient family of regulators. They bind to the conserved clamp helices domain of RNA polymerase, which also interacts with non‐homologous initiation factors in all domains of life, and reach across the DNA channel to form processivity clamps that enable uninterrupted (...) RNA chain synthesis. In addition to this ubiquitous function, NusG homologs exert diverse, and sometimes opposite, effects on gene expression by competing with each other and other regulators for binding to the clamp helices and by recruiting auxiliary factors that facilitate termination, antitermination, splicing, translation, etc. This surprisingly diverse range of activities and the underlying unprecedented structural changes make studies of these “transformer” proteins both challenging and rewarding. (shrink)

Glycosylation refers to the co‐ and post‐translational modification of protein and lipids by monosaccharides or oligosaccharide chains. The surface of mammalian cells is decorated by a heterogeneous and highly complex array of protein and lipid linked glycan structures that vary significantly between different cell types, raising questions about their roles in development and disease pathogenesis. This review will begin by focusing on recent findings that define roles for cell surface protein and lipid glycosylation in pluripotent stem (...) cells and their functional impact during normal development. Then, we will describe how patient derived induced pluripotent stem cells are being used to model human diseases such as congenital disorders of glycosylation. Collectively, these studies indicate that cell surface glycans perform critical roles in human development and disease. (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)

Firstly we consider the new results about enzymatic capabilities in the RNA. In this framework we analyse the sequence-folding duality as a precursor of the genotype/phenotype duality. We discuss then which are the evolutive potentialities and limitations for a system with the absence and the presence of a nucleic acid to proteins translator code. We study the arise of the code in the living systems as a form of deep interlooking between the logic of the machinery and its hardware, (...) discussing some problems that abstract modelization of this process implies. Finaly we propose to redefine the informational vocabulary usually employed in Molecular Biology. (shrink)

In this article we criticize the way in which the concept of information is used in the biological sciences. First, we start by giving a revised and larger definition of genetic information, by underlining the fact that the linear sequence map of the human genome is an incomplete description of our genetic information. This is because information on genome function and gene regulation is also encoded in the way DNA molecule is folded up with proteins to form chromatin structures. Secondly, (...) we point forward the need of constructing a theory in which the informational language (code, program, computation) so characteristic of molecular biology be completed by (and somehow translated into) the language of dynamical systems (phase space, bifurcations, trajectories) and the language of topology (deformations, plasticity, forms). Our traditional modes of system representation, involving fixed sets of sequential states together with imposed mechanical laws, strictly pertain to an extremely limited class of systems that can be called simple (static) systems or mechanisms. Biological systems are not in this class, and they must be called complex or dynamic. Complex systems can only be in some sense approximated, locally and temporally, by simple ones. Such a fundamental change of viewpoint leads to a number of theoretical and experimental consequences. (shrink)

Firstly we consider the new results about enzymatic capabilities in the RNA. In this framework we analyse the sequence-folding duality as a precursor of the genotype/phenotype duality. We discuss then which are the evolutive potentialities and limitations for a system with the absence and the presence of a nucleic acid to proteins translator code. We study the arise of the code in the living systems as a form of deep interlooking between the logic of the machinery and its hardware, (...) discussing some problems that abstract modelization of this process implies. Finaly we propose to redefine the informational vocabulary usually employed in Molecular Biology. (shrink)

Kurt Gödel’s Incompleteness theorem is well known in Mathematics/Logic/Philosophy circles. Gödel was able to find a way for any given P (UTM), (read as, “P of UTM” for “Program of Universal Truth Machine”), actually to write down a complicated polynomial that has a solution iff (=if and only if), G is true, where G stands for a Gödel-sentence. So, if G’s truth is a necessary condition for the truth of a given polynomial, then P (UTM) has to answer first that (...) G is true in order to secure the truth of the said polynomial. But, interestingly, P (UTM) could never answer that G was true. This necessarily implies that there is at least one truth a P (UTM), however large it may be, cannot speak out. Daya Krishna and Karl Potter’s controversy regarding the construal of India’s Philosophies dates back to the time of Potter’s publication of “Presuppositions of India’s Philosophies” (1963, Englewood Cliffs Prentice-Hall Inc.) In attacking many of India’s philosophies, Daya Krishna appears to have unwittingly touched a crucial point: how can there be the knowledge of a ‘non-cognitive’ mokṣa? [‘mokṣa’ is the final state of existence of an individual away from Social Contract]—See this author’s Indian Social Contract and its Dissolution (2008) mokṣa does not permit the knowledge of one’s own self in the ordinary way with threefold distinction, i.e., subject–knowledge-object or knower–knowledge–known. But what is important is to demonstrate whether such ‘knowledge’ of non-cognitive mokṣa state can be logically shown, in a language, to be possible to attain, and that there is no contradiction involved in such demonstration, because, no one can possibly express the ‘experience-itself’ in language. Hence, if such ‘knowledge’ can be shown to be logically not impossible in language, then, not only Daya Krishna’s arguments against ‘non-cognitive mokṣa’ get refuted but also it would show the possibility of achieving ‘completeness’ in its truest sense, as opposed to Gödel’s ‘Incompleteness’. In such circumstances, man would himself become a Universal Truth Machine. This is because the final state of mokṣa is construed as the state of complete knowledge in Advaita. This possibility of ‘completeness’ is set in this paper in the backdrop of Śrī Śaṅkarācārya’s Advaitic (Non-dualistic) claim involved in the mahāvākyas (extra-ordinary propositions). (Mahāvākyas that Śaṅkara refers to are basically taken from different Upaniṣads. For example, “Aham Brahmāsmi” is from Bṛhadāraṇyaka Upanisad, and “Tattvamasi” is from Chāndogya Upaniṣad. Śrī Śaṅkarācārya has written extensively. His main works include his Commentary on Brahma-Sūtras, on major Upaniṣads, and on ŚrīmadBhagavadGītā, called Bhāṣyas of them, respectively. Almost all these works are available in English translation published by Advaita Ashrama, 5 Dehi Entally Road, Calcutta, 700014.) On the other hand, the ‘Incompleteness’ of Gödel is due to the intervening G-sentence, which has an adverse self-referential element. Gödel’s incompleteness theorem in its mathematical form with an elaborate introduction by R.W. Braithwaite can be found in Meltzer (Kurt Gödel: on formally undecidable propositions of principia mathematica and related systems. Oliver & Boyd, Edinburgh, 1962). The present author believes first that semantic content cannot be substituted by any amount of arithmoquining, (Arithmoquining or arithmatization means, as Braithwaite says,—“Gödel’s novel metamathematical method is that of attaching numbers to the signs, to the series of signs (formulae) and to the series of series of signs (“proof-schemata”) which occur in his formal system…Gödel invented what might be called co-ordinate metamathematics…”) Meltzer (1962 p. 7). In Antone (2006) it is said “The problem is that he (Gödel) tries to replace an abstract version of the number (which can exist) with the concept of a real number version of that abstract notion. We can state the abstraction of what the number needs to be, [the arithmoquining of a number cannot be a proof-pair and an arithmoquine] but that is a concept that cannot be turned into a specific number, because by definition no such number can exist.”.), especially so where first-hand personal experience is called for. Therefore, what ultimately rules is the semanticity as in a first-hand experience. Similar points are voiced, albeit implicitly, in Antone (Who understands Gödel’s incompleteness theorem, 2006). (“…it is so important to understand that Gödel’s theorem only is true with respect to formal systems—which is the exact opposite of the analogous UTM (Antone (2006) webpage 2. And galatomic says in the same discussion chain that “saying” that it ((is)) only true for formal systems is more significant… We only know the world through “formal” categories of understanding… If the world as it is in itself has no incompleteness problem, which I am sure is true, it does not mean much, because that is not the world of time and space that we experience. So it is more significant that formal systems are incomplete than the inexperiencable ‘World in Itself’ has no such problem.—galatomic”) Antone (2006) webpage 2. Nevertheless galatomic certainly, but unwittingly succeeds in highlighting the possibility of experiencing the ‘completeness’ Second, even if any formal system including the system of Advaita of Śaṅkara is to be subsumed or interpreted under Gödel’s theorem, or Tarski’s semantic unprovability theses, the ultimate appeal would lie to the point of human involvement in realizing completeness since any formal system is ‘Incomplete’ always by its very nature as ‘objectual’, and fails to comprehend the ‘subject’ within its fold. (shrink)

The dialectic discourse of the ‘gene’ as the unit of heredity deduced from the phenotype, whether an intervening variable or a hypothetical construct, appeared to be settled with the presentation of the molecular model of DNA: the gene was reduced to a sequence of DNA that is transcribed into RNA that is translated into a polypeptide; the polypeptides may fold into proteins that are involved in cellular metabolism and structure, and hence function. This path turned out to be more bewildering (...) the more the regulation of products and functions were uncovered in the contexts of integrated cellular systems. Philosophers struggling to define a unified concept of the gene as the basic entity of genetics confronted those who suggested several different ‘genes’ according to the conceptual frameworks of the experimentalists. Researchers increasingly regarded genes de facto as generic terms for describing their empiric data, and with improved DNA-sequencing capacities these entities were as a rule bottom-up nucleotide sequences that determine functions. Only recently did empiricists return to discuss conceptual considerations, including top-down definitions of units of function that through cellular mechanisms select the DNA sequences which comprise ‘genomic-footprints’ of functional entities. (shrink)

The reovirus cell attachment protein σ1 is a lollipopshaped structure with the fibrous tail anchored to the virion. Since it interacts with the cell receptor, σ1 is a major determinant of reovirus infectivity and tissue tropism. Studies on its structure‐function relationships have been facilitated by the fact that protein σ1 produced in any expression system is capable of binding to cell receptors. The use of site‐specific and deletion mutants has led to the identification and characterization of its virion (...) anchorage and receptor binding domains. Studies on the oligomeric status of σ1 have revealed that σ1 is a homotrimer and that two independent trimerization events at different loci (the N‐ and C‐terminal halves, respectively) of the protein, are involved in its generation. This also accounts for a clearly demonstrable dominant negative effect by a mutant subunit in a wild‐type/mutant σ1 heterotrimer. Current efforts are focused on the involvement of chaperones in the generation of σ1 and on events that take place upon σ1 binding to the cell receptor. Protein σ1 has therefore become an excellent model system for the study of both virus attachment and protein oligomerization and folding mechanisms. (shrink)

Ontologies are being developed throughout the biomedical sciences to address standardization, integration, classification and reasoning needs against the background of an increasingly data-driven research paradigm. In particular, ontologies facilitate the translation of basic research into benefits for the patient by making research results more discoverable and by facilitating knowledge transfer across disciplinary boundaries. Addressing and adequately treating mental illness is one of our most pressing public health challenges. Primary research across multiple disciplines such as psychology, psychiatry, biology, neuroscience and pharmacology (...) needs to be integrated in order to promote a more comprehensive understanding of underlying processes and mechanisms, and this need for integration only becomes more pressing with our increase in understanding of differences among individuals and populations at the molecular level concerning susceptibility to specific illnesses. Substance addiction is a particularly relevant public health challenge in the developed world, affecting a substantial percentage of the population, often co-morbid with other illnesses such as mood disorders. Currently, however, there is no straightforward automated method to combine data of relevance to the study of substance addiction across multiple disciplines and populations. In this contribution, we describe a framework of interlinked, interoperable bio-ontologies for the annotation of primary research data relating to substance addiction, and discuss how this framework enables easy integration of results across disciplinary boundaries. We describe entities and relationships relevant for the description of addiction within the Mental Functioning Ontology, Chemical Entities of Biological Interest Ontology, Protein Ontology, Gene Ontology and the Neuroscience Information Framework ontologies. (shrink)

Histone acetylation has been recognized as an important post‐translational modification of core nucleosomal histones that changes access to the chromatin to allow gene transcription, DNA replication, and repair. Histone acetyltransferases were initially identified as co‐activators that link DNA‐binding transcription factors to the general transcriptional machinery. Over the years, more chromatin‐binding modes have been discovered suggesting direct interaction of histone acetyltransferases and their protein complex partners with histone proteins. While much progress has been made in characterizing histone acetyltransferase complexes (...) biochemically, cell‐free activity assay results are often at odds with in‐cell histone acetyltransferase activities. In‐cell studies suggest specific histone lysine targets, but broad recruitment modes, apparently not relying on specific DNA sequences, but on chromatin of a specific functional state. Here we review the evidence for general versus specific roles of individual nuclear lysine acetyltransferases in light of in vivo and in vitro data in the mammalian system. (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)

Molecular chaperones in cells constantly monitor and bind to exposed hydrophobicity in newly synthesized proteins and assist them in folding or targeting to cellular membranes for insertion. However, proteins can be misfolded or mistargeted, which often causes hydrophobic amino acids to be exposed to the aqueous cytosol. Again, chaperones recognize exposed hydrophobicity in these proteins to prevent nonspecific interactions and aggregation, which are harmful to cells. The chaperone‐bound misfolded proteins are then decorated with ubiquitin chains denoting them for proteasomal (...) degradation. It remains enigmatic how molecular chaperones can mediate both maturation of nascent proteins and ubiquitination of misfolded proteins solely based on their exposed hydrophobic signals. In this review, we propose a dynamic ubiquitination and deubiquitination model in which ubiquitination of newly synthesized proteins serves as a “fix me” signal for either refolding of soluble proteins or retargeting of membrane proteins with the help of chaperones and deubiquitinases. Such a model would provide additional time for aberrant nascent proteins to fold or route for membrane insertion, thus avoiding excessive protein degradation and saving cellular energy spent on protein synthesis. Also see the video abstract here: https://youtu.be/gkElfmqaKG4. (shrink)