In the beginning of the 20th century the groundbreaking work of Ramon y Cajal firmly established the neuron doctrine, according to which neurons are the basic structural and functional units of the nervous system. Von Weldeyer coined the term “neuron” in 1891, but the huge leap forward in neuroscience was due to Cajal’s meticulous microscopic observations of brain sections stained with an improved version of Golgi’s la reazione nera (black reaction). The latter improvement of Golgi’s technique made it possible to (...) visualize the arborizations of single neurons that were “colored brownish black even to their finest branchlets, standing out with unsurpassable clarity upon a transparent yellow background. All was sharp as a sketch with Chinese ink”. The high quality of both the visualization of individual nerve cells and the work performed on studying the anatomy of the central nervous system lead Ramon y Cajal to the conclusion that axons output the nervous impulses to the dendrites or the soma of other target neurons. (shrink)

Twenty five years ago, Sir John Carew Eccles together with Friedrich Beck proposed a quantum mechanical model of neurotransmitter release at synapses in the human cerebral cortex. The model endorsed causal influence of human consciousness upon the functioning of synapses in the brain through quantum tunneling of unidentified quasiparticles that trigger the exocytosis of synaptic vesicles, thereby initiating the transmission of information from the presynaptic towards the postsynaptic neuron. Here, we provide a molecular upgrade of the Beck and Eccles model (...) by identifying the quantum quasiparticles as Davydov solitons that twist the protein α-helices and trigger exocytosis of synaptic vesicles through helical zipping of the SNARE protein complex. We also calculate the observable probabilities for exocytosis based on the mass of this quasiparticle, along with the characteristics of the potential energy barrier through which tunneling is necessary. We further review the current experimental evidence in support of this novel bio-molecular model as presented. (shrink)

SNAREs (soluble N‐ethylmaleimide‐sensitive factor attachment protein receptors) are a large family of proteins that are present on all organelles involved in intracellular vesicle trafficking and secretion. The interaction of complementary SNAREs found on opposing membranes presents an attractive lock‐and‐key mechanism, which may underlie the specificity of vesicle trafficking. Moreover, formation of the tight complex between a vesicle membrane SNARE and corresponding target membrane SNAREs could drive membrane fusion. In synapses, this tight complex, also referred to as the synaptic (...) core complex, is essential for neurotransmitter release. However, recent observations in knockout mice lacking major synaptic SNAREs challenge the prevailing notion on the executive role of these proteins in fusion and open up several questions about their exact role(s) in neurotransmitter release. Persistence of a form of regulated neurotransmitter release in these mutant mice also raises the possibility that other cognate or non‐cognate SNAREs may partially compensate for the loss of a particular SNARE. Future analysis of SNARE function in central synapses will also have implications for the role of these molecules in other vesicle trafficking events such as endocytosis and vesicle replenishment. Such analysis can provide a molecular basis for synaptic processes including certain forms of short‐term synaptic plasticity. BioEssays 24:926–936, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

In vitro reconstitution assays are commonly used to study biological membrane fusion. However, to date, most ensemble and single‐vesicle experiments involving SNARE proteins have been performed only with lipid‐mixing, but not content‐mixing indicators. Through simultaneous detection of lipid and small content‐mixing indicators, we found that lipid mixing often occurs seconds prior to content mixing, or without any content mixing at all, during a 50‐seconds observation period, for Ca2+‐triggered fusion with SNAREs, full‐length synaptotagmin‐1, and complexin. Our results illustrate the (...) caveats of commonly used bulk lipid‐mixing fusion experiments. We recommend that proteoliposome fusion experiments should always employ content‐mixing indicators in addition to, or in place of, lipid‐mixing indicators. (shrink)

What response is to be given to the immoralist's question ‘Why should I be just?’? I say ‘response’ because it is not clear that the immoralist is looking for an answer. His question seems to be rhetorical, even contemptuous. It nevertheless presents a challenge to morality. The immoralist's position is that it is irrational to take justice and fairness seriously and that his own advantage or self-interest is the only rational consideration for him. This is not a moral position although (...) it is a normative position; the immoralist has an alternative to the moral life but not an alternative morality. The immoralist is not a moralist with idiosyncratic views on what is just and fair—what he might call ‘true’ justice or ‘natural’ justice. On the contrary, where some co-operative mutually beneficial project is involved he presumably recognizes what is fair much as we all do. What he does not recognize is the rationality of being fair. Nor is this because he thinks there is some other consideration which overrides justice in this particular case. He does not deal with our complaint ‘But that isn't fair!’ by presenting other, allegedly overriding, considerations. Rather, such a complaint is not granted an initial relevance. ‘Why should I be just?’ he says. (shrink)

Most recent texts in moral philosophy have either concentrated on practical moral issues or else, if theoretical, have tended toward one-sided presentations of recent, fashionable views. Discussions of applied ethics cannot go very far without revealing underlying philosophical assumptions about how deeper, more general issues are treated. Similarly, recent approaches to ethics are difficult to understand without a knowledge of the context of the historical views against which these approaches are reacting. The Nature of Moral Thinking will satisfy the intellectually (...) curious student, providing a solid and fair discussion of the classical philosophical questions about our moral thinking, surveying the main types of meta-ethical and normative ethical theories, while not excluding the more recent discussions of moral realism, of anti-realism, and of virtue morality. Francis Snare demonstrates that glib intellectualistic thinking about morality, especially in regard to relativism andsubjectivism, is seriously flawed. He also focuses attention on the question of whether particular theories of the origins of morality (for example, those of Nietzsche and Marx) undermine morality. All students and teachers of ethics and philosophy will find this book one of the most complete and detailed introductory-level surveys of the foundations of ethics with emphasis on the problems of the subjectivity, the relativity, and the origins of morality. (shrink)

This 1991 book is about the continuing influence of Hume's ideas on moral and political philosophy. In part, it is a critical exegesis of Hume's most impressive and challenging doctrines in Book III of the Treatise of Human Nature on such topics as morals, motivation, justice, and social institutions. However, the main thrust of the argument is to throw into relief the importance of that discussion for contemporary philosophy. While the author subjects most contemporary defences of Humean doctrines to intense (...) criticism, he also seeks to discover what versions of Hume's theories might still be defensible and viable. (shrink)

Much of the plausibility of non-cognitivism in meta-ethics rests on the following argument derived from hume: 1) cognitive judgments alone can never have any motivational influence on our actions, 2) moral judgments have a motivational influence on our actions, and 3) therefore, no moral judgment is simply a cognitive judgment. this paper subjects various forms of this argument to criticism.

_The Nature of Moral Thinking_ is an introductory text to the questions of ethics, offering a solid philosophical and historical basis for understanding the central issues. Francis Snare discusses in detail the classical philosophical arguments of Plato and Butler in relation to relativism and subjectivism and treats Marx and Nietzsche in regard to the origins and explanation of morality.

_The Nature of Moral Thinking_ is an introductory text to the questions of ethics, offering a solid philosophical and historical basis for understanding the central issues. Francis Snare discusses in detail the classical philosophical arguments of Plato and Butler in relation to relativism and subjectivism and treats Marx and Nietzsche in regard to the origins and explanation of morality.

Let it be allowed, though virtue or moral rectitude does indeed consist in affection to and pursuit of what is right and good, as such; yet, that when we sit down in a cool hour, we can neither justify to ourselves this or any other pursuit, till we are convinced that it will be for our happiness, or at least not contrary to it.—Butler, Sermon XIThere are a number of different grounds on which philosophers have argued that the question “Should (...) I be moral?” is unintelligible or at least somewhat odd. Some evidently are unable to understand ‘should’ in any other way than ‘morally ought’, with the consequence that the question can admit of no answer but the affirmative. Others, influenced by the later Wittgenstein, hold that, although ‘should ’-questions have a role within the moral language game, the ‘should’ in the question above has no real function, it is like a ‘machine idling,’ and we can attribute no real sense to it. Now I consider neither of these arguments to be successful or even very plausible, but I do wish to consider a further argument which is logically independent of the above and which appears, initially at least, to be quite plausible. (shrink)

THE PROJECT OF THIS PAPER IS TO GIVE AN EXPLICIT DEFINITION OF 'PRIMA FACIE' DUTY EMPLOYING THE NOTION OF DUTY (SIMPLICITER) AS THE ONLY MORAL NOTION. THIS DEFINITION AVOIDS THE CIRCULARITY OF SOME DEFINITIONS WHILE ALSO BEING SUFFICIENTLY GENERAL SO AS NOT TO DEPEND ON THE ADOPTION OF ANY PARTICULAR MORAL VIEWPOINT. THIS PAPER ATTACKS THE VIEW THAT A MORAL PHILOSOPHER (OR AN ANTHROPOLOGIST DESCRIBING A MORAL CODE) CAN ALWAYS IN PRINCIPLE AVOID EMPLOYING THE NOTION OF A 'PRIMA FACIE' DUTY (...) SIMPLY BY GIVING A CAREFUL STATEMENT OF EACH RULE MAKING EXPLICIT ITS EXCEPTIONS. (shrink)

We can enjoy and suffer many kinds of human goods and evils. The goods include not only experiences and enjoyments but also the having and exercise of various talents and abilities, the receipt of recognitions and rewards, successes, employments, opportunities. The evils include not only pains and frustrations but also defects such as ugliness, disabilities such as paralysis or retardation, lack of standard opportunities such as unemployment, financial loss, failure, disgrace. It is tempting to say that wherever a person has (...) a good he has an advantage and when he suffers an evil he is, in that respect, disadvantaged. However this usage can make it look as if all human goods and evils are subject matter for distributive justice. In fact that is not the conventional view. (shrink)

Intercellular communication is an essential process in all multicellular organisms. During this process, molecules secreted by one cell will bind to a receptor on the cognate cell leading to the subsequent uptake of the receptor‐ligand complex. Once inside, the cell then determines the fate of the receptor‐ligand complex and any other proteins that were endocytosed together. Approximately 80% of endocytosed material is recycled back to the plasma membrane either directly or indirectly via the Golgi apparatus and the remaining 20% (...) is delivered to the lysosome for degradation. Although most pathways have been identified, we still lack understanding on how specificity in sorting of recycling cargos into different pathways is achieved, and how the cell reaches high accuracy of these processes in the absence of clear sorting signals in the bulk of the client proteins. In this review, we will summarize our current understanding of the mechanism behind recycling cargo sorting and propose a model of differential affinities between cargo and cargo receptors/adaptors with regards to iterative sorting in endosomes. (shrink)

Several general anesthetics produce their sedative effect by activating endogenous sleep pathways. We propose that general anesthesia is a two‐step process targeting sleep circuits at low doses, and synaptic release mechanisms across the entire brain at the higher doses required for surgery. Our hypothesis synthesizes data from a variety of model systems, some which require sleep (e.g. rodents and adult flies) and others that probably do not sleep (e.g. adult nematodes and cultured cell lines). Non‐sleeping systems can be made insensitive (...) (or hypersensitive) to some anesthetics by modifying a single pre‐synaptic protein, syntaxin1A. This suggests that the synaptic release machinery, centered on the highly conserved SNARE complex, is an important target of general anesthetics in all animals. A careful consideration of SNARE architecture uncovers a potential mechanism for general anesthesia, which may be the primary target in animals that do not sleep, but a secondary target in animals that sleep. (shrink)

The direction and specificity of endolysosomal membrane trafficking is tightly regulated by various cytosolic and membrane‐bound factors, including soluble NSF attachment protein receptors (SNAREs), Rab GTPases, and phosphoinositides. Another trafficking regulatory factor is juxta‐organellar Ca2+, which is hypothesized to be released from the lumen of endolysosomes and to be present at higher concentrations near fusion/fission sites. The recent identification and characterization of several Ca2+ channel proteins from endolysosomal membranes has provided a unique opportunity to examine the roles of Ca2+ (...) and Ca2+ channels in the membrane trafficking of endolysosomes. SNAREs, Rab GTPases, and phosphoinositides have been reported to regulate plasma membrane ion channels, thereby suggesting that these trafficking regulators may also modulate endolysosomal dynamics by controlling Ca2+ flux across endolysosomal membranes. In this paper, we discuss the roles of phosphoinositides, Ca2+, and potential interactions between endolysosomal Ca2+ channels and phosphoinositides in endolysosomal dynamics. (shrink)

Synaptophysin (Syp) was the first synaptic vesicle (SV) protein to be cloned. Since its discovery in 1985, it has been used by us and by many laboratories around the world as an invaluable marker to study the distribution of synapses in the brain and to uncover the basic features of the life cycle of SVs. Although single gene ablation of Syp does not lead to an overt phenotype, a large body of experimental data both in vitro and in vivo indicate (...) that Syp (alone or in association with homologous proteins) is involved in multiple, important aspects of SV exo‐endocytosis, including regulation of SNARE assembly into the fusion core complex, formation of the fusion pore initiating neurotransmitter release, activation of SV endocytosis and SV biogenesis. In this article, we summarise the main results of the studies on Syp carried out by our and other laboratories, and explain why we believe that Syp plays a major role in SV trafficking. BioEssays 26:445–453, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

The paper starts with a thesis on the dialectical structure of modern law that goes back the European revolutionary tradition and constitutes a legal structure that is at once emancipatory and repressive. Once it became democratic the modern nation states has solved more or less successfully the crises that emerged in modern Europe since the 16th Century. Yet, this state did not escape the dialectical snares of modern law and modern legal regimes. It’s greatest advance, the exclusion of inequalities presupposed (...) the exclusion of the internal other of blacks, workers, women etc, and the other that stemmed from the non-European world that furthermore was under European colonial rule or other forms of European, Northamerican and Japanese imperial control. Yet, the wars and revolutions of the 20th Century let to a complete reconstruction, new foundation and globalization of all national and international law. The evolutionary advance of the 20th Century was the emergence of world law, and this enabled the construction of international and national welfarism and the global expansion of the exclusion of inequalities. Nevertheless the dialectic of enlightenment came back again and led to new forms of postnational domination, hegemony, oppression and exclusion. The final section tries to detect some ideas and principles how to overcome the crisis. (shrink)

Frank Snare had a puzzle. Noncognitivism implies No-Ought-From-Is but No- Ought-From-Is does not imply non-cognitivism. How then can we derive non-cognitivism from No-Ought-From-Is? Via an abductive argument. If we combine non-cognitivism with the conservativeness of logic (the idea that in a valid argument the conclusion is contained in the premises), this implies No-Ought-From-Is. Hence if No-Ought-From-Is is true, we can arrive at non-cognitivism via an inference to the best explanation. With prescriptivism we can make this argument more precise. I (...) develop an account of imperative consequence that underwrites Hare’s principle that you cannot derive imperatives from indicatives. Thus if moral judgments contain an imperative component, it will be impossible to derive moral conclusions from indicative or non-moral premises. Given this account of imperative consequence, we can explain No-Ought-From-Is without appealing to anything as nebulous as the conservativeness of logic. Hence if No-Ought-From-Is is true, we have an inference to the best explanation for prescriptivism. Both lines of argument face problems from Prior. Given Prior’s counterexamples, No-Ought-From-Is as originally conceived is false. The version that survives is No-Non-Vacuous-Ought-From-Is. But the best explanation of this does not include non-cognitivism. With prescriptivism it is worse. For the version of No-Ought-From-Is that prescriptivism ‘explains’ – that is, the version of No-Ought-From-Is that prescriptivism implies – would exclude Prior’s counter-examples to Autonomy as invalid. But they are not invalid. Thus Prior’s counter-examples to No-Ought-From- Is refute prescriptivism. Thus from 1960 onwards R. M.Hare was a dead philosopher walking. But if non-cognitivism cannot be derived from No-Ought-From-Is, this suggests that it is not what Hume was trying to prove. I argue that what Hume was trying to prove is that moral truths are not demonstrable. To be demonstrable, a proposition must be either self-evident or logically derivable from self-evident propositions. By Treatise 3.1.1.27, Hume had proved to his own satisfaction that no moral propositions are self-evident. That leaves open the possibility that they are logically derivable from self-evident but NON-moral propositions. The point of No-Ought-From-Is was to exclude this possibility. If you cannot logically derive moral conclusions from non-moral premises, you cannot demonstrate the truths of morality by deriving them from self-evident but NON-moral truths. I also discuss why Hume abandoned No-Ought-From-Is in the EPM. He had no need of it since he thought he had a proof that (with some exceptions) no nontrivial truths are demonstrable. Hence no non-trivial MORAL truths are demonstrable. No-Ought-From-Is drops out as unnecessary. (shrink)

As with certain other self-reflexive emotions, such as guilt and shame, our understanding of self-hatred may be aided by views of the mind which posit an internalized other whose perspective on oneself embodies and focuses a set of concerns and values, and whose perspective one is in some sense vulnerable to. To feel guilt for some transgression is not solely to feel the anger that one would feel toward another’s trespasses, now directed back onto oneself as an object of that (...) anger; it is at the same time to react to that anger – perhaps, for example, to accept it as deserved, or to welcome the lashing of one’s bad conscience. To feel shame before oneself is not just to see oneself in some compromising way, it is to feel compromised by one’s own gaze. Likewise, the person who hates herself does not feel the hatred that she might have for another, simply taking herself as object of that attitude. She is not merely the seat of an internalized hostile voice and perspective that she may, for example, react to with indifference. She does not only tell herself that she is “worthless” but, will typically feel herself so in response. And her suffering may not just result from pain she is inclined to inflict, but suffering that, in some sense, she is inclined to suffer. But how is this so? How, in self-hatred, does one become not only subject to, but vulnerable and even receptive to one’s own hostility? (shrink)

The subtitle of the essay that Robert Markley attacks had, in its penultimate version, a parenthetical word that was ultimately dropped. It read, “ Metaphysical Snares of Ideological Criticism.” The editor of Critical Inquiry, W. J. T. Mitchell, politely suggested that my subtitle was redundant: snares, he observed, are by nature avoidable. Indeed they are. In fact, my parentheses were intended to indicate that the word didn’t really need to be there. The self-conscious redundancy was intended to underlines the fact (...) that the essay was not attacking ideological criticism in general, but only certain tendencies that seemed especially prevalent in ideological critiques of abstract ideas. Seeking support for my redundancy, I appealed to a sagacious friend, who promptly urged me to follow Mitchell’s suggestion and drop the “avoidable,” parentheses or no parentheses. I was asking my title to do too much, he observed; the essay itself would make it quite clear that I was undertaking to refine and strengthen the techniques of ideological criticism by urging that its pitfalls be avoided.If I had declined to follow this eminently reasonable advice and had retained the word “avoidable,” would that have kept Markley from so radically misconstruing my project? After all, near the end of his rebuttal, he acknowledges that “Kenshur is right … in one respect,” that there is a “lot of not particularly interesting pseudo-Marxist criticism being written” . If I had underscored my own sympathy toward and links with the new historicism—something that I could have done in all good conscience—would that have disarmed him? Or if I now undertook, after the fact, to offer assurances that I, like Markley, was working from within the capacious and self-critical Marxist tradition and trying to distinguish its strengths from its weaknesses, would that impel him, like Gilda Radner’s Emily Litella , meekly to say, “Never mind”? Perhaps, but somehow I doubt it. Oscar Kenshur is associate professor of comparative literature at Indiana University. He is author of Open Form and the Shape of Ideas and is completing Dilemmas of Enlightenment, a study that traces shifts in the ideological significance of early modern ideas about intellectual method, religious toleration, and female chastity. (shrink)

The Protein Ontology (PRO) provides a formal, logically-based classification of specific protein classes including structured representations of protein isoforms, variants and modified forms. Initially focused on proteins found in human, mouse and Escherichia coli, PRO now includes representations of protein complexes. The PRO Consortium works in concert with the developers of other biomedical ontologies and protein knowledge bases to provide the ability to formally organize and integrate representations of precise protein forms so as to enhance accessibility to results of (...) protein research. PRO (http://pir.georgetown.edu/pro) is part of the Open Biomedical Ontologies (OBO) Foundry. (shrink)

Protein disulfide isomerase (PDI) is one of the most abundant and critical protein folding catalysts in the endoplasmic reticulum of eukaryotic cells. PDI consists of four thioredoxin domains and interacts with a wide range of substrate and partner proteins due to its intrinsic conformational flexibility. PDI plays multifunctional roles in a variety of pathophysiological events, both as an oxidoreductase and a molecular chaperone. Recent studies have revealed that the conformation and activity of PDI can be regulated in multiple ways, (...) including posttranslational modification and substrate/ligand binding. Here, we summarize recent advances in understanding the function and regulation of PDI in different pathological and physiological events. We propose that the multifunctional roles of PDI are regulated by multiple mechanisms. Furthermore, we discuss future directions for the study of PDI, emphasizing how different regulatory modes are linked to the conformational changes and biological functions of PDI in the context of diverse pathophysiologies. (shrink)

The correspondence in 1680 and 1681 between John Flamsteed and Isaac Newton on Flamsteed’s theory of the comet of 1680 tells half the story. Related manuscripts reveal Newton was pursuing his own comprehensive line of inquiry based on principles that were the antithesis of Flamsteed’s procedures. Following generally accepted views in England, Newton’s work was marked by critical evaluation of data but marred by uncritical use of simple calculating techniques based on what might be termed Platonic archetypes of straightness. Flamsteed’s (...) intervention provided useful data and allowed Newton to seek additional information. Although Newton supposedly briefly considered a solution that vaguely resembled his parabolic approximation of the path of the comet determined 5 years later, the evidence Newton provided (based on simple hypotheses) did not support such a highly curved path or one in which the sun apart from the solar vortex exerted influence. Newton’s work, including an alleged harmonic law of tails, was quietly abandoned in favor of other work. With new insight, Newton revived work on comets as fully gravitational objects immediately following Halley’s visit in 1684. This little known side of the episode provides a fresh opportunity to examine Newton’s sources and actual practice in developing a new line of inquiry. An appendix dating sections of Newton’s Waste Book entries on comets is included. (shrink)

The Protein Ontology (PRO) web resource provides an integrative framework for protein-centric exploration and enables specific and precise annotation of proteins and protein complexes based on PRO. Functionalities include: browsing, searching and retrieving, terms, displaying selected terms in OBO or OWL format, and supporting URIs. In addition, the PRO website offers multiple ways for the user to request, submit, or modify terms and/or annotation. We will demonstrate the use of these tools for protein research and annotation.

The Protein Ontology (PRO; http://proconsortium.org) formally defines protein entities and explicitly represents their major forms and interrelations. Protein entities represented in PRO corresponding to single amino acid chains are categorized by level of specificity into family, gene, sequence and modification metaclasses, and there is a separate metaclass for protein complexes. All metaclasses also have organism-specific derivatives. PRO complements established sequence databases such as UniProtKB, and interoperates with other biomedical and biological ontologies such as the Gene Ontology (GO). PRO relates to (...) UniProtKB in that PRO’s organism-specific classes of proteins encoded by a specific gene correspond to entities documented in UniProtKB entries. PRO relates to the GO in that PRO’s representations of organism-specific protein complexes are subclasses of the organism-agnostic protein complex terms in the GO Cellular Component Ontology. The past few years have seen growth and changes to the PRO, as well as new points of access to the data and new applications of PRO in immunology and proteomics. Here we describe some of these developments. (shrink)

The KCTD family includes tetramerization (T1) domain containing proteins with diverse biological effects. We identified a novel member of the KCTD family, BTBD10. A comprehensive analysis of protein‐protein interactions (PPIs) allowed us to put forth a number of testable hypotheses concerning the biological functions for individual KCTD proteins. In particular, we predict that KCTD20 participates in the AKT‐mTOR‐p70 S6k signaling cascade, KCTD5 plays a role in cytokinesis in a NEK6 and ch‐TOG‐dependent manner, KCTD10 regulates the RhoA/RhoB pathway. Developmental (...) regulator KCTD15 represses AP‐2α and contributes to energy homeostasis by suppressing early adipogenesis. TNFAIP1‐like KCTD proteins may participate in post‐replication DNA repair through PCNA ubiquitination. KCTD12 may suppress the proliferation of gastrointestinal cells through interference with GABAb signaling. KCTD9 deserves experimental attention as the only eukaryotic protein with a DNA‐like pentapeptide repeat domain. The value of manual curation of PPIs and analysis of existing high‐throughput data should not be underestimated. (shrink)

The major transcript variants of human protein‐coding genes are annotated to a certain degree of accuracy combining manual curation, transcript data, and proteomics evidence. However, there is considerable disagreement on the annotation of about 2000 genes—they can be protein‐coding, noncoding, or pseudogenes—and on the annotation of most of the predicted alternative transcripts. Pure transcriptome mapping approaches seem to be limited in discriminating functional expression from noise. These limitations have partially been overcome by dedicated algorithms to detect alternative spliced micro‐exons and (...) wobble splice variants. Recently, knowledge about splice mechanism and protein structure are incorporated into an algorithm to predict neighboring homologous exons, often spliced in a mutually exclusive manner. Predicted exons are evaluated by transcript data, structural compatibility, and evolutionary conservation, revealing hundreds of novel coding exons and splice mechanism re‐assignments. The emerging human pan‐genome is necessitating distinctive annotations incorporating differences between individuals and between populations. (shrink)